Benzenesulfonamide compounds and their use as therapeutic agents

Abstract

To provide benzenesulfonamide compounds, and use thereof as therapeutic agents.SOLUTION: The present invention is directed to benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels (NaV1.6), such as epilepsy and / or epileptic seizure disorders. In another aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound of formula (I), as described above, as a stereoisomer, enantiomer or tautomer thereof or mixtures thereof or a pharmaceutically acceptable salt, solvate or prodrug thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 684,436, filed June 13, 2018, which is incorporated by reference in its entirety.

[0002] FIELD OF THE INVENTION The present invention relates to benzenesulfonamide compounds, pharmaceutical compositions containing the compounds, and methods of using the compounds and pharmaceutical compositions in the treatment of sodium channel-mediated diseases or conditions, such as epilepsy and / or epileptic seizure disorders, and other diseases and conditions associated with sodium channel mediation. [Background technology]

[0003] Background of the Invention Voltage-gated sodium channels (Na V ) are important determinants of cellular excitability in muscle and nerve (Hille, B, Ion Channels of Excitable Membranes (2001), Sunderland, MA, Sinauer Associates, Inc.). In particular, the four isoforms Na V 1.1, Na V 1.2, Na V 1.3, and Na V 1.6 is responsible for the majority of sodium currents in neurons of the central nervous system. V 1.3 is primarily expressed in the embryo. After the neonatal period, Na V 1.1, Na V 1.2, and Na V 1.6 is a key isoform that regulates neuronal signaling in the brain (Catterall, WA, Annual Review of Pharmacology and Toxicology (2014), Vol. 54, pp. 317-338).

[0004] Na V 1.5 is primarily expressed in cardiomyocytes, including the atria, ventricles, sinoatrial node, atrioventricular node, and Purkinje fibers of the heart (Raymond, CK et al., J. Biol. Chem. (2004), Vol. 279, No. 44, pp. 46234-41). Human Na V Mutations in 1.5 result in a number of arrhythmia syndromes, including long QT3 (LQT3), Brugada syndrome (BS), hereditary cardiac conduction defects, sudden nocturnal death syndrome (SUNDS), and sudden infant death syndrome (SIDS) (Liu, H. et al., Am. J. Pharmacogenomics (2003), Vol. 3, No. 3, pp. 173-9). Sodium channel blocker therapy is widely used to treat cardiac arrhythmias.

[0005] Epilepsy is a condition characterized by excessive synchronous excitability in the brain, which occurs when the delicate balance between excitatory and inhibitory signals in the brain is thrown out of equilibrium. This can occur due to either excessive excitation or a lack of inhibition. V Mutations in the genes encoding the channels have been linked to both types of imbalance.

[0006] Na V 1.1 is the major Na+ receptor for inhibitory interneurons V These interneurons synapse with many other neurons, including excitatory glutamatergic neurons. Action potentials in interneurons induce the release of the neurotransmitter GABA onto other neurons, hyperpolarizing them and thus reducing their excitation. This provides a negative feedback loop that allows for controlled signal transduction and prevents local signals from expanding into waves of excitation that spread across large brain regions. Due to this important role in inhibitory interneurons, Na V 1.1 channel machine Mutations that impair this function can result in the failure of these neurons to activate and release GABA (Ogiwara, I. et al., J. Neurosci. (2007), vol. 27, pp. 5903-5914; Martin, MS et al., J. Biol. Chem. (2010), vol. 285, pp. 9823-9834; Cheah, CS et al., Channels (Austin) (2013), vol. 7, pp. 468-472; and Dutton, SB, et al., (2013), vol. 49, pp. 211-220). The result is a loss of inhibitory tone in the brain and a failure to contain the excitability of glutamatergic neurons. This failure of inhibitory interneurons can lead to abnormal, widespread, synchronous excitation of neurons across brain regions (epilepsy).

[0007] Na V Mutations in the gene encoding 1.1 (SCN1A) fall into two broad classes: those causing generalized epilepsy with febrile seizures plus (GEFS+) and those causing severe myoclonic epilepsy of infancy (SMEI), also known as Dravet syndrome or early infantile epileptic encephalopathy 6 (EIEE6) (McKusik, VK, et al., A Epileptic Encephalopathy, Early Infantile 6, EIEE6 (2012), Online Mendelian Inheritance in Man: John Hopkins University). SMEI mutations are heterozygous autosomal dominant and are often caused by gene deletions or truncations that result in channels with little or no function. These mutations have been shown to occur de novo or, in some cases, in asymptomatic mosaic parents (Tuncer, FN et al., Epilepsy Research (2015), Vol. 113, pp. 5-10). Patients are phenotypically normal at birth and progress through developmental milestones until the onset of seizures (typically between age 6 months and age 1 year). This onset occurs when the embryonic isoform Na V Normal decrease in expression of 1.3 and concomitant Na VThis is thought to be the result of an increase in Na V This phenotype becomes evident when 1.1 channels do not reach normal levels (Cheah, C.S., et al., Channels (Austin) (2013), Vol. 7, pp. 468-472). The first seizure is often precipitated by a febrile episode and may manifest as status epilepticus. Seizures persist and increase in frequency and severity over the first few years of life, and can reach a frequency of more than 100 episodes per day. Seizures can be precipitated by fever or occur spontaneously without apparent cause. After the onset of seizures, patients begin to miss developmental milestones, and significant cognitive and behavioral deficits occur (Dravet, C., and Oguni, H., Handbook of Clinical Neurology (2013), Vol. 111, pp. 627-633). Eighty to eighty-five percent of phenotypically diagnosed Dravet syndrome patients are thought to have causative mutations in SCN1A, while the other 15 to 20% of patients have other mutations or are of unknown etiology. Patients with SMEI have a high incidence of sudden unexpected death in epilepsy (SUDEP), with an estimated 37% of patients dying from SUDEP, although the mechanisms underlying this devastating outcome remain uncertain (Massey, CA, et al., Nature Reviews Neurology (2014), Vol. 10, pp. 271-282). Clinically useful antiepileptic drugs that nonselectively target voltage-gated sodium channels, such as carbamazepine and phenytoin, are contraindicated in patients with SMEI. This is because these drugs can worsen seizures in these patients (Wilmshurst, JM et al., Epilepsia (2015), Vol. 56, pp. 1185-1197). V 1.1 It is presumed that this is due to the inability to tolerate further decline in function.

[0008] GEFS+ is often caused by missense SCN1A mutations that induce relatively mild channel dysfunction consistent with a relatively mild seizure phenotype. A large and growing number of mutations have been identified, and both the severity and penetrance of the phenotype vary considerably. Many GEFS+ patients outgrow the seizure phenotype, but not all do. GEFS+ individuals with childhood epilepsy are significantly more susceptible to epilepsy as adults than the general population. Other genes involved in GABAergic signaling (SCN1B, which encodes an auxiliary subunit of the sodium channel, and GABA A Mutations that cause defects in receptor subunits (such as GABRG2) can also cause GEFS+ (Helbig, I., Seminars in Neurology (2015) Vol. 35, pp. 288-292).

[0009] Transgenic mice harboring the same mutations identified in SMEI and GEFS+ patients have been developed. In both cases, these mice closely replicate the human phenotype, although the penetrance of this phenotype can be significantly affected by genetic background. Some mouse strains tolerate this mutation relatively well, while in others, the same mutation can cause a severe seizure phenotype. These differences are presumably due to different levels of expression of other genes that regulate the excitability phenotype (Miller, AR et al., Genes, Brain, and Behavior (2014), Vol. 13, pp. 163-172; Mistry, AM et al., Neurobiology of Disease (2014), Vol. 65, pp. 1-11; and Hawkins, NA et al., Epilepsy Research (2016), Vol. 119, pp. 20-23).

[0010] In the brain, Na V 1.2 and Na V1.6 is primarily expressed in excitatory glutamatergic neurons. Both channels are particularly concentrated in the active initial segment (AIS), a region of the neuron adjacent to the neuronal soma that serves to integrate inputs and initiate action potential propagation to the soma and distal dendrites (Royeck, M. et al., J. Neurophysiol. (2008), vol. 100, pp. 2361-2380; Vega, AV et al., Neurosci. Lett. (2008), vol. 442, pp. 69-73; and Hu, W. et al., Nat. Neurosci. (2009), vol. 12, pp. 996-1002). V Na 1.6 tends to be particularly concentrated in the early AIS (distal to the cell body), where it is thought to act to trigger the initiation of action potentials. V 1.2 is more highly localized in the segment of the AIS closest to the cell body. V 1.2) and SCN8A(Na V Mutations in both Na and Na+ have been linked to epilepsy and cognitive delay. The effects of these mutations vary, both in the level of effect on channel function and in patient phenotype. V 1.2 and Na V Both 1.1 and 6 are also expressed in peripheral neurons. V 1.6 is particularly concentrated at the nodes of Ranvier of myelinated neurons, where it is important for maintaining healthy and fast neuronal signaling.

[0011] Only a small amount of Na VOnly 1.2 mutations have been described, which have been primarily linked to pathologies of the central nervous system, in particular epilepsy (Kearney, J.A. et al., Neuroscience (2001), Vol. 102, pp. 307-317; Zerem, A. et al., European Journal of Paediatric Neurology: EJPN: Official Journal of the European Paediatric Neurology Society (2014), Vol. 18, pp. 567-571; Fukasawa, T. et al., Brain & Development (2015), Vol. 37, pp. 631-634; Howell, K.B. et al., Neurology (2015), Vol. 85, pp. 958-966; Saitoh, M. et al., Epilepsy Research (2015), Vol. 117, pp. 1-6; Samanta, D. et al., Acta Neurologica Belgica (2015), Vol. 115, pp. 773-776; Carroll, LS et al., Psychiatric Genetics (2016), Vol. 26, pp. 60-65; and Schwarz, N. et al., Journal of Neurology (2016), Vol. 263, pp. 334-343). Epilepsy mutations are presumed to be essentially gain of function mutations. These mutations result in an increase in the magnitude of sodium current, thereby increasing excitability. It is difficult to establish beyond a reasonable doubt the effect on channel function in vivo, and some of these mutations may still result in a loss of function phenotype.

[0012] Mutations in SCN8A also cause Na V Although it has been reported that some gain and loss of function effects on Na+ channels. V Regarding 1.6, most mutations tested are associated with an increased functional phenotype. VMutations in 1.6 have been linked to epilepsy and autism spectrum disorders (Trudeau, M. M. et al., Journal of Medical Genetics (2006), 43, 527-530; Veeramah, K. R. et al., Am. J. Hum. Genet. (2012), 90, 502-510; Vaher, U. et al., Journal of Child Neurology (2013); de Kovel, C. G. et al., Epilepsy Research (2014); Estacion, M. et al., Neurobiology of Disease (2014), 69, 117-123; Ohba, C. et al., Epilepsy (2014), 55, 994-1000; Wagnon, J. L. et al., Human Molecular Genetics (2014); Kong, W. et al., Epilepsia (2015), Vol. 56, pp. 431-438; and Larsen, J. et al., Neurology (2015), Vol. 84, pp. 480-489). The best-described SCN8A mutation patients have a syndrome known as early infantile epileptic encephalopathy, 13 (EIEE13). Over 100 EIEE13 patients have been identified. Patients typically develop intractable seizures between birth and 18 months of age. Patients have developmental and cognitive delays, as well as movement disorders often associated with chronic hypotonia. The most severely affected patients never gain sufficient motor control for walking; many do not speak. Less severe phenotypes learn to walk and talk but have motor disabilities and impaired cognitive and social milestones. The majority of identified mutations are missense mutations, and the specific functional effects of these mutations are presumed to contribute to the phenotypic variability, although genetic background is likely also involved (Larsen, J. et al., Neurology (2015), Vol. 84, pp. 480-489).In contrast to patients with SMEI, anecdotal evidence suggests that antiepileptic drugs that nonselectively target voltage-gated sodium channels may improve symptoms in patients with EIEE13, although controlled clinical trials have not been completed (Boerma, RS et al., Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics (2016), Vol. 13, pp. 192-197). Phenytoin appears to offer efficacy in patients with EIEE13, but at a significant cost. Efficacy is achieved only at very high doses, while significant adverse effects are tolerated only if the patient has a pressing need for such treatment. Adverse effects commonly associated with phenytoin treatment include hepatic necrosis, hirsutism, nervousness, hand tremor, numbness, dizziness, lethargy, tremor, depression, confusion, fatigue, constipation, dizziness, ataxia, mental status changes, myasthenia, mood changes, restlessness, irritability, and agitation. Na. V Drugs that selectively target 1.6 are likely to retain efficacy while reducing their adverse event burden.

[0013] Loss of function mutations in SCN8A in mice result in a phenotype known as motor endplate disease (med), and multiple mutations and phenotypes have been linked to the med gene region prior to the identification of the SCN8A gene (Burgess, DL et al., Nat. Genet. (1995), vol. 10, pp. 461-465). med Mice carrying the mutation have varying degrees of hypotonia, which is due to the Na V 1.6 Corresponds to the degree of dysfunction of the SCN8A med / jo Mice with Na have a loss of function but not zero phenotype. V It has 1.6 channels. SCN8A med Mouse and SCN8A med / joMice are resistant to seizures induced by chemical insults (flurothyl, kainic acid, and picrotoxin) (Martin, MS et al., Human Molecular Genetics (2007), vol. 16, pp. 2892-2899; Hawkins, NA et al., Neurobiology of Disease (2011), vol. 41, pp. 655-660; and Makinson, CD et al., Neurobiology of Disease (2014), vol. 68, pp. 16-25). Curiously, SCN8A med / jo Mice with SCN1A null They were crossed with mutant mice and null Alleles and SCN8A med / jo If mice heterozygous for both SCN1A alleles are generated, the double mutant mice will be null They have significantly improved seizure and cognitive phenotypes than mice with the mutation alone (Martin, MS et al., Human Molecular Genetics (2007), Vol. 16, pp. 2892-2899). Such mice have spontaneous seizures and mortality rates similar to wild-type mice, and also have an increased seizure threshold after chemical injury. Similar results occur when mice with missense mutations in SCN1A (a model of GEFS+) are crossed with mice with loss of function mutations in SCN8A. SCN8A med / joCarrying a single allele of SCN8A protected GEFS+ model mice from seizures and premature death (Hawkins, NA et al., Neurobiology of Disease (2011), Vol. 41, pp. 655-660). The ability of SCN8A knockdown to improve seizure resistance is not limited to knockouts where the gene is completely absent throughout animal development. Knockdown of SCN8A in adult mice, either globally or specifically in the hippocampus by a CRE-LOX inducible knockout approach, also increased resistance to electrically and chemically induced seizures (Makinson, CD et al., Neurobiology of Disease (2014), Vol. 68, pp. 16-25). These data support the idea that reduced Na V 1.1 current-induced suppression of inhibitory signaling is due, at least in part, to Na V This suggests that the reduction in the 1.6 current can be counteracted by suppressing excitatory signaling.

[0014] Voltage-gated sodium channel antagonism is the most common mechanism of action for widely prescribed antiepileptic drugs (AEDs) (Ochoa, JR, et al., Sodium Channel Blockers: Antiepileptic Drugs (2016), Vol. (Benbadis, S., ed.) Medscape News & Perspectives). Carbamazepine, eslicarbazepine, oxcarbazepine, lacosamide, lamotrigine, phenytoin, rufinamide, and zonisamide all block sodium channels. V They are thought to work primarily by blocking this function of the channel. Despite this presumed mechanism of action, these drugs are relatively indiscriminate. They block all Na V Blocks channel isoforms indiscriminately, thus blocking Na V Blockade of 1.1 would be predicted to promote convulsions. V 1.6, and possibly Na VBlockade of 1.2 is anticonvulsant. In addition to sodium channels, these compounds also block other targets, including voltage-gated calcium channels. V Selective Na+ receptor 1.1 and other off-target receptors V Antagonists are currently available V It is predicted to have both improved potency and therapeutic index compared to blockers. Therefore, epilepsy and other Na V 1.6 Effectively treat related pathological conditions and other sodium channel (e.g., Na V 1.1 and / or Na V There is an unmet medical need for treatment without the harmful side effects resulting from blockade of 1.5). The present invention provides a method that meets these critical needs. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Hille, B, Ion Channels of Excitable Membranes (2001), Sunderland, MA, Sinauer Associates, Inc. [Non-patent document 2] Catterall, W.A., Annual Review of Pharmacology and Toxicology (2014), Vol. 54, pp. 317-338 [Non-patent document 3] Raymond, CK et al., J. Biol. Chem. (2004), Vol. 279, No. 44, pp. 46234-41 [Non-patent document 4] Liu, H. et al., Am.J.Pharmacogenomics (2003), Volume 3, No. 3, pp. 173-9 [Non-patent document 5] Yu, FH et al., Nat. Neurosci. (2006), Vol. 9, pp. 1142-1149 [Non-patent document 6] Ogiwara, I. et al., J. Neurosci. (2007), Vol. 27, pp. 5903-5914 [Non-Patent Document 7] Martin, MS et al., J. Biol. Chem. (2010), Vol. 285, pp. 9823-9834 [Non-patent document 8] Cheah, C.S. et al., Channels (Austin) (2013), Vol. 7, pp. 468-472 [Non-Patent Document 9] Dutton, SB, et al. (2013), Vol. 49, pp. 211-220 [Non-Patent Document 10] McKusik, VK et al., A Epileptic Encephalopathy, Early Infantile 6, EIEE6 (2012), Online Mendelian Inheritance in Man: John Hopkins University [Non-Patent Document 11] Tuncer, FN et al., Epilepsy Research (2015), Vol. 113, pp. 5-10 [Non-Patent Document 12] Dravet, C. and Oguni, H., Handbook of Clinical Neurology (2013), Vol. 111, pp. 627-633 [Non-Patent Document 13] Massey, CA, et al., Nature Reviews Neurology (2014), Vol. 10, pp. 271-282 [Non-Patent Document 14] Wilmshurst, JM et al., Epilepsia (2015), Vol. 56, pp. 1185-1197 [Non-Patent Document 15] Helbig, I., Seminars in Neurology (2015) Vol. 35, pp. 288-292 [Non-Patent Document 16] Miller, A.R. et al., Genes, Brain, and Behavior (2014), Vol. 13, pp. 163-172 [Non-Patent Document 17] Mistry, AM et al., Neurobiology of Disease (2014), Vol. 65, pp. 1-11 [Non-Patent Document 18] Hawkins, N.A. et al., Epilepsy Research (2016), Vol. 119, pp. 20-23 [Non-Patent Document 19] Royeck, M. et al., J. Neurophysiol. (2008), Vol. 100, pp. 2361-2380 [Non-Patent Document 20] Vega, AV et al., Neurosci. Lett. (2008), Vol. 442, pp. 69-73 [Non-Patent Document 21] Hu, W. et al., Nat. Neurosci. (2009), Vol. 12, pp. 996-1002 [Non-Patent Document 22] Kearney, JA et al., Neuroscience (2001), Vol. 102, pp. 307-317 [Non-Patent Document 23] Zerem, A. et al., European Journal of Paediatric Neurology: EJPN: Official Journal of the European Paediatric Neurology Society (2014), Vol. 18, pp. 567-571 [Non-Patent Document 24] Fukasawa, T. et al., Brain & Development (2015), Vol. 37, pp. 631-634 [Non-Patent Document 25] Howell, KB et al., Neurology (2015), Vol. 85, pp. 958-966 [Non-Patent Document 26] Saitoh, M. et al., Epilepsy Research (2015), Vol. 117, pp. 1-6 [Non-Patent Document 27] Samanta, D. et al., Acta Neurologica Belgica (2015), Vol. 115, pp. 773-776 [Non-patent document 28] Carroll, LS et al., Psychiatric Genetics (2016), Vol. 26, pp. 60-65 [Non-Patent Document 29] Schwarz, N. et al., Journal of Neurology (2016), Vol. 263, pp. 334-343 [Non-Patent Document 30] Trudeau, MM et al., Journal of Medical Genetics (2006), Vol. 43, pp. 527-530 [Non-Patent Document 31] Veeramah, KR et al., Am. J. Hum. Genet. (2012), Vol. 90, pp. 502-510 [Non-Patent Document 32] Estacion, M. et al., Neurobiology of Disease (2014), Vol. 69, pp. 117-123 [Non-Patent Document 33] Ohba, C. et al., Epilepsia (2014), Vol. 55, pp. 994-1000 [Non-Patent Document 34] Kong, W. et al., Epilepsia (2015), Vol. 56, pp. 431-438 [Non-Patent Document 35] Larsen, J. et al., Neurology (2015), Vol. 84, pp. 480-489 [Non-Patent Document 36] Boerma, RS et al., Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics (2016), Vol. 13, pp. 192-197 [Non-Patent Document 37] Burgess, DL et al., Nat. Genet. (1995), Vol. 10, pp. 461-465 [Non-Patent Document 38] Hawkins, N.A. et al., Neurobiology of Disease (2011), Vol. 41, pp. 655-660 [Non-Patent Document 39] Makinson, CD et al., Neurobiology of Disease (2014), Vol. 68, pp. 16-25 Summary of the Invention [Means for solving the problem]

[0016] Summary of the Invention The present invention relates to benzenesulfonamide compounds, pharmaceutical compositions containing these compounds, and compounds that inhibit voltage-gated sodium channel activity (particularly Na V The present invention also relates to methods of using the compounds and pharmaceutical compositions of the present invention to treat diseases or conditions mediated by steroid hormones (e.g., steroid hormone receptor agonists, steroid hormone receptor antagonists ...

[0017] Thus, in one aspect, the present invention provides a compound of formula (I): [ka] as its individual stereoisomer, enantiomer or tautomer, or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, In formula (I): q is 1 or 2; r is 1 or 2; R 1 is hydrogen or alkyl; R 2 is thiazolyl, isothiazolyl, or isoxazolyl; R 3a and R 3b are each independently hydrogen or alkyl; Each R 4 is independently halo or alkyl; R 5 is a halo; Each R 6 is independently halo or alkoxy; R 7 is azabicyclo[2.2.1]heptanylalkyl, or r is 2 and at least one R 6 When R is alkoxy, 7 is ((methyl)(prop-2-yl)amino)alkyl.

[0018] The compounds of the present invention (which are compounds of formula (I) as described above) as their individual stereoisomers, enantiomers or tautomers, or mixtures thereof; or as pharmaceutically acceptable salts, solvates or prodrugs thereof, inhibit voltage-gated sodium channels (preferably Na V 1.6). Preferably, the compounds of the present invention are useful for treating diseases or conditions associated with Na V 1.6 inhibitors. More preferably, the compounds of the present invention are Na V 1.5 and / or Na V Compared to inhibiting 1.1, Na V 1.6. Without wishing to be bound by theory, such selectivity may be due to the V 1.5 and / or Na V This is believed to advantageously reduce any cardiovascular side effects that may be associated with inhibition of 1.1.

[0019] In another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I) as described above, as a stereoisomer, enantiomer or tautomer thereof, or a mixture thereof; or as a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0020] In another aspect, the present invention provides a method for the treatment of epilepsy and / or epileptic seizure disorders in a mammal, preferably a human, comprising administering to a mammal in need thereof a therapeutically effective amount of a stereoisomer, enantiomer or tautomer of a compound of the present invention as described above, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound, as a stereoisomer, enantiomer or tautomer of a compound of the present invention as described above, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.

[0021] In another aspect, the present invention provides Na V Activation or hyperfunction of 1.6 can lead to diseases, conditions, or

[0013] The present invention provides a method for treating or lessening the severity of a disease, condition, or disorder in a mammal associated with a disease, condition, or disorder, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention as a stereoisomer, enantiomer, or tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention as a stereoisomer, enantiomer, or tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0022] In another aspect, the present invention provides a method of treating or alleviating, but not preventing, epilepsy and / or an epileptic seizure disorder in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention as a stereoisomer, enantiomer or tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as described above, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention as a stereoisomer, enantiomer or tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as described above, and a pharmaceutically acceptable excipient.

[0023] In another aspect, the present invention provides pharmaceutical treatments in combination with one or more other compounds of the present invention, or one or more other accepted treatments, or any combination thereof, to increase the efficacy of current or future drug treatments or to reduce adverse events associated with accepted treatments. In one embodiment, the present invention relates to pharmaceutical compositions that combine a compound of the present invention with an established or future treatment for an indication listed herein.

[0024] In another aspect, the present invention relates to a method of selectively inhibiting a first voltage-gated sodium channel over a second voltage-gated sodium channel in a mammal, comprising administering to the mammal an inhibitory amount of a compound of the present invention as defined above, as a stereoisomer, enantiomer, or tautomer, or mixture thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition containing an inhibitory amount of a compound of the present invention as defined above, as a stereoisomer, enantiomer, or tautomer, or mixture thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0025] In another aspect, the present invention provides a method for detecting a voltage-gated sodium channel (preferably Na 2 O ) in a mammal. V 1.6) (preferably, the disease or condition is epilepsy and / or an epileptic seizure disorder) in the preparation of a medicament for the treatment of a disease or condition associated with the activity of In an embodiment of the present invention, for example, the following items are provided: (Item 1) Formula (I): [ka] the compound as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; In formula (I): q is 1 or 2; r is 1 or 2; R 1 is hydrogen or alkyl; R 2 is thiazolyl, isothiazolyl, or isoxazolyl; R 3a and R 3b are each independently hydrogen or alkyl; Each R 4 is independently halo or alkyl; R 5 is a halo; Each R 6 is independently halo or alkoxy; R 7is azabicyclo[2.2.1]heptanylalkyl, or r is 2 and at least one R 6 When R is alkoxy, 7 is ((methyl)(prop-2-yl)amino)alkyl; the compound as its individual stereoisomer, enantiomer or tautomer, or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof. (Item 2) R 7 The compound according to item 1, wherein is azabicyclo[2.2.1]heptanylalkyl. (Item 3) R 2 The compound according to item 2, wherein is isothiazolyl. (Item 4) 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)benzenesulfonamide; and 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(isothiazol-3-yl)benzenesulfonamide 2,2,2-trifluoroacetate Item 3. The compound according to item 3, selected from: (Item 5) R 2 The compound according to item 2, wherein is thiazolyl. (Item 6) 6. The compound according to item 5, wherein r is 1. (Item 7) 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide; 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate; 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate; and 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate Item 7. The compound according to item 6, selected from: (Item 8) 6. The compound according to item 5, wherein r is 2. (Item 9) 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide; 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate; 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate; 54-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate; (S)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide; and (R)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide Item 9. The compound according to item 8, selected from: (Item 10) R 2 The compound according to item 2, wherein is isoxazolyl. (Item 11) 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide; and 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide 2,2,2-trifluoroacetate 11. The compound according to item 10, selected from: (Item 12) R 7 is ((methyl)(prop-2-yl)amino)alkyl, provided that r is 2 and at least one R 6 is alkoxy. (Item 13) R 2 Item 13. The compound according to item 12, wherein is isothiazolyl. (Item 14) R 2 13. The compound according to item 12, wherein is thiazolyl. (Item 15) 2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; 2,6-difluoro-4-((6-fluoro-3-isopropoxy-2-((isopropyl(methyl)amino)methyl)benzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; 2,3-Difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; 5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate; and 2-Fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate Item 15. The compound according to item 14, selected from: (Item 16) R 2 Item 13. The compound according to item 12, wherein is isoxazolyl. (Item 17) 17. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as its stereoisomer, enantiomer or tautomer, or a mixture thereof. (Item 18) In mammals, Na V 1.6 A method of treating a disease or condition associated with activity, wherein the disease or condition is epilepsy and / or an epileptic seizure disorder, and the method comprises administering to a mammal in need of said treatment a therapeutically effective amount of a compound according to any one of paragraphs 1 to 16, as its stereoisomer, enantiomer or tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof. (Item 19) In mammalian cells, Na V1. A method of reducing ion flux through a cell, comprising contacting the cell with a compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as a stereoisomer, enantiomer or tautomer thereof, or a mixture thereof. (Item 20) 17. A method of selectively inhibiting a first voltage-gated sodium channel in preference to a second voltage-gated sodium channel in a mammal, the method comprising administering to the mammal a modulating amount of a compound according to any one of items 1 to 16, as a stereoisomer, enantiomer or tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof. (Item 21) The first voltage-gated sodium channel is Na V 19. The method according to item 18, wherein the method is 1.6. (Item 22) The second voltage-gated sodium channel is Na V 19. The method according to item 18, wherein the ratio is 1.5. (Item 23) The second voltage-gated sodium channel is Na V 17. The method according to item 16, wherein the method is 1.1. DETAILED DESCRIPTION OF THE INVENTION

[0026] Detailed Description of the Invention definition Certain chemical groups named herein may be preceded by an abbreviation indicating the total number of carbon atoms to be found in the indicated chemical group. For example, C7-C 12 Alkyl refers to an alkyl group having a total of 7 to 12 carbon atoms, as defined below, and includes C4-C 12 Cycloalkylalkyl refers to a cycloalkylalkyl group, as defined below, having a total of 4 to 12 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the described group.

[0027] In addition to the foregoing, the following terms have the indicated meanings when used in this specification and the appended claims, unless otherwise specified.

[0028] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, and more preferably from 1 to 6 carbon atoms, attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. Where specifically noted herein, alkyl groups can be optionally substituted with one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR 20 , -OC(O)-R 20 , -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)OR 22 , -N(R 20 )C(O)R 22 , -N(R 20 )S(O) p R 22 (where p is 1 to 2), -S(O) p OR 22 (where p is 1 to 2), -S(O) t R 22 (where t is 0 to 2), and -S(O) p N(R 20 ) 2 (wherein p is 1 to 2) (wherein each R 20is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl).

[0029] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group (e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc.) consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from 2 to 12 carbon atoms, preferably from 2 to 8 carbon atoms, and attached to the remainder of the molecule by a single bond. As specifically described herein, alkenyl groups can be optionally substituted with one of the following groups: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR 20 , -OC(O)-R 20 , -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)OR 22 , -N(R 20 )C(O)R 22 , -N(R 20 )S(O) p R 22 (where p is 1 to 2), -S(O) p OR 22 (where p is 1 to 2), -S(O) t R 22 (where t is 0 to 2), and -S(O) p N(R 20 ) 2 (wherein p is 1 to 2) (wherein each R 20is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl).

[0030] "Alkoxy" means a group of the formula -OR a a radical of formula (wherein R a is an alkyl group as defined above (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, etc.). Where specifically stated herein, alkyl groups can be optionally substituted as defined above for alkyl radicals. Preferably, "alkoxy" refers to methoxy or isopropoxy.

[0031] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain (e.g., methylene, ethylene, propylene, n-butylene, etc.) consisting solely of carbon and hydrogen, containing no unsaturation, and having 1 to 12 carbon atoms. The alkylene chain can optionally contain one or more heteroatoms, in which case a carbon in the alkylene chain is replaced with a heteroatom selected from oxygen, nitrogen, or sulfur. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond, or to two portions of the molecule through single bonds at each attachment point. As specifically described herein, the alkylene chain can be optionally substituted with one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR 20 , -OC(O)-R 20 , -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -C(O)N(R20 )2, -N(R 20 )C(O)OR 22 , -N(R 20 )C(O)R 22 , -N(R 20 )S(O) p R 22 (where p is 1 to 2), -S(O) p OR 22 (where p is 1 to 2), -S(O) t R 22 (where t is 0 to 2), and -S(O) p N(R 20 )2 (where p is 1 to 2) (where each R 20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R 22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl).

[0032] "Aryl" refers to a hydrocarbon ring system containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For purposes of the present invention, aryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. As specifically described herein, aryl groups include alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 21 -OR20 , -R 21 -OC(O)-R 20 , -R 21 -N(R 20 )2, -R 21 -N(R 20 )-R 23 -OR 20 , -R 21 -C(O)R 20 , -R 21 -C(O)OR 20 , -R 21 -C(O)N(R 20 )2, -R 21 -N(R 20 )C(O)OR 22 , -R 21 -N(R 20 )C(O)R 22 , -R 21 -N(R 20 )S(O) p R 22 (where p is 1 to 2), -R 21 -N=C(OR 20 )R 20 , -R 21 -S(O) p OR 22 (where p is 1 to 2), -R 21 -S(O) t R 22 (where t is between 0 and 2), and -R 21 -S(O) p N(R 20 ) 2 (wherein p is 1 to 2) (wherein each R 20 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 21 are independently a direct bond or a straight or branched alkylene chain, and each R 22 is alkyl, haloalkyl, cycloalkyl, alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 23is a direct bond, or a straight or branched alkylene chain). 1 The optional substituents on the optionally substituted aryl group for -R are alkyl, optionally substituted cycloalkyl, halo, haloalkyl, cyano, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, -R 21 -OR 20 and -R 21 -N(R 20 )2(where R 20 and R 21 is as defined above).

[0033] "Cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic hydrocarbon group, consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, saturated or unsaturated, and attached to the remainder of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, adamantyl, norbornyl, decalinyl, and the like. As specifically described herein, cycloalkyl groups include alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 21 -OR 20 , -R 21 -OC(O)-R 20 , -R 21 -N(R 20 )-R 23 -OR 20 , -R 21 -N(R 20 )2, -R 21 -C(O)R 20 , -R21 -C(O)OR 20 , -R 21 -C(O)N(R 20 )2, -R 21 -N(R 20 )C(O)OR 22 , -R 21 -N(R 20 )C(O)R 22 , -R 21 -N(R 20 )S(O) p R 22 (where p is 1 to 2), -R 21 -N=C(OR 20 )R 20 , -R 21 -S(O) p OR 22 (where p is 1 to 2), -R 21 -S(O) t R 22 (where t is between 0 and 2), and -R 21 -S(O) p N(R 20 ) 2 (wherein p is 1 to 2) (wherein each R 20 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 21 are independently a direct bond or a straight or branched alkylene chain, and each R 22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 23 is a direct bond, or a straight or branched alkylene chain).

[0034] "Cycloalkylalkyl" refers to a group of the formula -R b R g a radical of formula (wherein R b is an alkylene chain as defined above, and R gis a cycloalkyl group as defined above. Where specifically stated herein, the alkylene chain and / or cycloalkyl radical can be optionally substituted as defined above for an optionally substituted alkylene chain and an optionally substituted cycloalkyl.

[0035] "Halo" refers to bromo, chloro, fluoro or iodo.

[0036] "Haloalkyl" refers to an alkyl group, as defined above, that is substituted with one or more halo groups, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, etc. The alkyl portion of a haloalkyl group can be optionally substituted as defined above for an alkyl group.

[0037] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring group, consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms (selected from the group consisting of nitrogen, oxygen, and sulfur). Unless stated otherwise specifically in the specification, a heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused, bridged, and spiro ring systems; the nitrogen, carbon, or sulfur atoms within the heterocyclyl group can be optionally oxidized; the nitrogen atoms can be optionally quaternized; and the heterocyclyl group can be partially or fully saturated. Examples of such heterocyclyl groups include azetidinyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1-azaspiro[3.3]heptan-1-yl, 5-azaspiro[2.3]hexan-5-yl, azabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 1-oxa-6-azaspiro[3.4]octanyl, and 1-oxa-6-azaspiro[3.5]octanyl. 1-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 6-azaspiro[3.4]octan-6-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 2,6-diazaspiro[3.3]heptan-2-yl, dioxolanyl, dioxinyl, thienyl[1,3]di Examples include, but are not limited to, thianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, 1,2,4-thiadiazol-5(4H)-ylidene, tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.As specifically described herein, heterocyclyl groups include alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R. 21 -OR 20 , -R 21 -OC(O)-R 20 , -R 21 -N(R 20 )-R 23 -OR 20 , -R 21 -N(R 20 )2, -R 21 -C(O)R 20 , -R 21 -C(O)OR 20 , -R 21 -C(O)N(R 20 )2, -R 21 -N(R 20 )C(O)OR 22 , -R 21 -N(R 20 )C(O)R 22 , -R 21 -N(R 20 )S(O) p R 22 (where p is 1 to 2), -R 21 -N=C(OR 20 )R 20 , -R 21 -S(O) p OR 22 (where p is 1 to 2), -R 21 -S(O) t R 22 (where t is between 0 and 2), and -R 21 -S(O) p N(R 20 ) 2 (wherein p is 1 to 2) (wherein each R 20 are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 21are independently a direct bond or a straight or branched alkylene chain, and each R 22 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 23 is a direct bond, or a straight or branched alkylene chain).

[0038] "Heterocyclylalkyl" means a group of the formula -R b R h where R b is an alkylene chain as defined above, and R h is a heterocyclyl radical as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, it may be attached to the alkyl radical at the nitrogen atom. Where specifically stated herein, the alkylene chain of a heterocyclylalkyl radical may be optionally substituted as defined above for an optionally substituted alkylene chain. Where specifically described herein, the heterocyclyl portion of the heterocyclylalkyl radical may be optionally substituted as defined above for an optionally substituted heterocyclyl group. 5 An optional substituent on the optionally substituted heterocyclylalkyl group for is halo.

[0039] "Azabicyclo[2.2.1]heptanylalkyl" refers to a group of the formula -R b R j a radical of formula (wherein R b is an alkylene chain as defined above, and R j is azabicyclo[2.2.1]heptanyl). Preferably, R bis a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation, and having from 1 to 8 carbon atoms, preferably a straight divalent hydrocarbon chain consisting of one carbon or a branched divalent carbon chain consisting of two carbons.

[0040] "((methyl)(prop-2-yl)amino)alkyl" refers to a group of the formula -R b N(R a )2 radical (wherein R b is an alkylene chain as defined above, while R a is methyl, and the other R a is prop-2-yl). Preferably, R b is a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation, and having from 1 to 8 carbon atoms, preferably 1 carbon atom.

[0041] "Heteroaryl" refers to a radical of a 5- to 14-membered ring system containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms (selected from the group consisting of nitrogen, oxygen, and sulfur), and at least one aromatic ring. For purposes of this invention, a heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system (which can include fused or bridged ring systems), and the nitrogen, carbon, or sulfur atoms within the heteroaryl group can be optionally oxidized, and the nitrogen atoms can be optionally quaternized.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, and benzothienyl. (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinonyl, benzimidazolethionyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl yl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pyrimidinonyl onyl), pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinonyl, quinazolinyl, quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). As specifically described herein, heteroaryl groups include alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, thioxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R. 21-OR 20 , -R 21 -OC(O)-R 20 , -R 21 -N(R 20 )-R 23 -OR 20 , -R 21 -N(R 20 )2, -R 21 -C(O)R 20 , -R 21 -C(O)OR 20 , -R 21 -C(O)N(R 20 )2, -R 21 -N(R 20 )C(O)OR 22 , -R 21 -N(R 20 )C(O)R 22 , -R 21 -N(R 20 )S(O) p R 22 (where p is 1 to 2), -R 21 -N=C(OR 20 )R 20 , -R 21 -S(O) p OR 22 (where p is 1 to 2), -R 21 -S(O) t R 22 (where t is between 0 and 2), and -R 21 -S(O) p N(R 20 ) 2 (wherein p is 1 to 2) (wherein each R 20 are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 21 are independently a direct bond or a straight or branched alkylene chain, and each R 22 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 23is a direct bond, or a straight or branched alkylene chain). Preferably, R 1 An optional substituent on the optionally substituted bicyclic heteroaryl group for is halo. Preferably, R 1 For the optionally substituted monocyclic heteroaryl group, the optional substituent on the group is alkyl.

[0042] "Heteroarylalkyl" means a group of the formula -R b R i where R b is an alkylene chain as defined above, and R i is a heteroaryl radical as defined above. Where specifically described herein, the heteroaryl portion of the heteroarylalkyl radical can be optionally substituted as defined above for an optionally substituted heteroaryl group. Where specifically described herein, the alkylene chain portion of the heteroarylalkyl radical can be optionally substituted as defined above for an optionally substituted alkylene chain.

[0043] The term "prodrug" is intended to refer to a compound that can be converted into a biologically active compound of the present invention under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the present invention. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the present invention. Prodrugs are usually rapidly transformed in vivo to produce the parent compound of the present invention, for example, by hydrolysis in blood. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T. et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties.

[0044] The term "prodrug" is also meant to include any covalently bonded carrier that releases an active compound of the invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of the invention can be prepared by modifying functional groups present in the compounds of the invention such that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. Prodrugs include compounds of the invention in which a hydroxy, amino, or mercapto group is bonded to any group that is cleaved, respectively, to leave a free hydroxy group, a free amino group, or a free radical when the prodrug of the compound of the invention is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of the invention and the like.

[0045] The invention disclosed herein is also intended to encompass all pharmaceutically acceptable isotopically labeled compounds of formula (I) in which one or more atoms are replaced by an atom having a different atomic mass or mass number. Examples of isotopes that may be contained in the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine (e.g., isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively). 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I). These radiolabeled compounds may be useful, for example, to help determine or measure the effectiveness of these compounds by characterizing the site or mode of action on sodium channels or the binding affinity to pharmacologically important sites of action on sodium channels. Certain isotopically labeled compounds of formula (I) (e.g., compounds containing a radioisotope) are useful in drug and / or substrate tissue distribution studies. The radioisotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and rapid means of detection.

[0046] Heavier isotopes (e.g., deuterium, i.e. 2Substitution with .H) may confer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) resulting from greater metabolic stability and, therefore, may be preferred in some circumstances. In one embodiment of the invention, the compound of formula (I) is enriched with deuterium. Such deuterated compounds can be achieved by methods known to those skilled in the art, such as exchanging a proton with deuterium or synthesizing the molecule using enriched starting materials.

[0047] Positron-emitting isotopes (e.g., 11 C. 18 F, 15 O and 13 Substitution at N) may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) may generally be prepared by conventional techniques known to those skilled in the art, or by procedures analogous to those described in the Examples and Preparations as described below, substituting an appropriately isotopically labeled reagent for the previously used unlabeled reagent.

[0048] The invention disclosed herein is also intended to encompass in vivo metabolic products of the disclosed compounds. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, and the like, of the administered compound, primarily due to enzymatic processes. Accordingly, the invention encompasses compounds produced by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a detectable dose of a radiolabeled compound of the invention to a mammal (e.g., a rat, a mouse, a guinea pig, a monkey, or a human), allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0049] The terms "stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0050] "Mammals" includes both humans and domestic animals, such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), as well as non-domestic animals, such as wildlife. include.

[0051] "Optionally" or "optionally" means that the subsequently described circumstance event may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted aryl" means that the aryl group may be substituted or unsubstituted, and the description includes both substituted aryl groups and aryl groups that have no substitution ("unsubstituted"). If a functional group is described as "optionally substituted," and similarly, a substituent on that functional group is also described as "optionally substituted," then for purposes of this invention, such recurrence is limited to five times, and preferably, such recurrence is limited to two times.

[0052] A "pharmaceutically acceptable carrier, excipient, or additive" includes, but is not limited to, any adjuvant, carrier, additive, glidant, sweetener, filler, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for human or veterinary use.

[0053] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0054] "Pharmaceutically acceptable acid addition salts" refers to salts formed with inorganic and organic acids that retain the biological effectiveness and properties of the free base and are not biologically or otherwise unsuitable, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, and formic acid. , fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0055] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise unsuitable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include salts of primary, secondary, and tertiary amines, substituted amines, such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, and choline. Particularly preferred organic bases include, but are not limited to, isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0056] Crystallization often produces solvates of the compounds of the present invention. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the compounds of the present invention with one or more molecules of solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as corresponding solvated forms. The compounds of the present invention may be true solvates, while in other cases, the compounds of the present invention may simply contain incidental water or may be a mixture of water and incidental solvents.

[0057] A "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of biologically active compounds to a mammal, such as a human. Such a vehicle includes any pharmaceutically acceptable carrier, excipient, or additive therefor.

[0058] A "therapeutically effective amount" refers to the amount of a compound of the present invention that, when administered to a mammal, preferably a human, is sufficient to effect treatment (as defined below) of a sodium channel-mediated disease or condition in the mammal, preferably a human. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the method of administration, and the age of the mammal being treated, but can be determined by routine by one of ordinary skill in the art having regard to their own knowledge and this disclosure.

[0059] "Treat" or "treatment", as used herein, refers to the treatment of a disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes: (a) preventing the occurrence of a disease or condition in a mammal, particularly where such mammal is predisposed to the condition but has not yet been diagnosed as suffering from it; (b) inhibiting the disease or condition, i.e., preventing its occurrence; (c) alleviating (or mitigating) the disease or condition, i.e., causing regression of the disease or condition; or (d) Relieving (or alleviating) symptoms resulting from a disease or condition, for example, alleviating epilepsy without interfering with the underlying disease or condition.

[0060] As used herein, the terms "disease" and "condition" may be used interchangeably or may differ in that a particular disease or condition may not have a known causative agent (and thus the etiology is not yet understood) and therefore is not yet recognized as a disease, but merely as an undesirable state or syndrome (a particular set of symptoms more or less recognized by clinicians).

[0061] The compounds of the present invention, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and may therefore occur as enantiomers and diastereomers, and in terms of absolute stereochemistry, as (R)- or (S)-, or relative to amino acids. Other stereoisomeric forms, which can be defined as (D)- or (L)-, may occur. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from appropriate, optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). Where the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E- and Z-geometric isomers. Likewise, all tautomeric forms are intended to be included.

[0062] "Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but with different, non-interchangeable three-dimensional structures. The present invention contemplates various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another. For a detailed description of the structure and properties of enantiomers and stereoisomers, see, for example, Smith, MB and J. March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Edition (Wiley, 2007).

[0063] "Tautomer" refers to a shift of a proton from one atom of a molecule to another atom of the same molecule. The present invention includes any tautomers of the compounds.

[0064] The use of parentheses and brackets in substituents is used herein to conserve space. Thus, the use of parentheses in a substituent indicates that the group within the parentheses is directly attached to the atom preceding the parentheses. The use of brackets in a substituent indicates that the group within the brackets is also directly attached to the atom preceding the brackets.

[0065] "Enantiomer" refers to an asymmetric molecule that can exist in two different isomeric forms that have different arrangements in space. Other terms used to denote or refer to enantiomers include "stereoisomers" (due to different arrangements or stereochemistry around a chiral center; all enantiomers are stereoisomers, but not all stereoisomers are enantiomers) or "optical isomers" (due to the optical activity of pure enantiomers, which is the ability of different pure enantiomers to rotate plane-polarized light in different directions).

[0066] The designations "R" and "S" for the absolute configuration of the enantiomers of the present invention may appear as prefixes or suffixes in the name of the compound. They may or may not be separated from the name of the enantiomer by a hyphen. They may or may not be connected by a hyphen. They may or may not be enclosed in parentheses.

[0067] In the formulas depicted herein, bonds to substituents and / or bonds connecting molecular fragments to the remainder of the compound may be shown as crossing one or more bonds in a ring structure. This indicates that the bond may be attached to any one of the atoms that make up the ring structure (as long as a hydrogen atom could otherwise reside at that atom). If a specific substituent(s) is not identified for a particular position in a structure, then a hydrogen(s) will reside at that position. For example, in the following structure (D), R 30 The bond attaching a substituent is such that a valence is provided for such attachment. Subject to the condition that 31can be on any carbon, including the carbon to which is attached. [ka]

[0068] "Resolution" or "resolving," when used in reference to a racemate or racemic mixture of a compound of the invention, refers to the separation of the racemate or racemic mixture into its two enantiomeric forms (i.e., (+) and (-); (R) and (S) forms).

[0069] The chemical naming protocols and structure diagrams used herein are based on ChemDraw A modified version of the IUPAC naming system, using the Professional Version 18.0.0.231 software program, in which compounds of the present invention are named herein as derivatives of a central core structure (e.g., a benzenesulfonamide structure). For complex chemical names used herein, substituents are named before the group to which they are attached. For example, cyclopropylethyl contains an ethyl backbone with cyclopropyl substituents. In chemical structure diagrams, all bonds are identified except for some carbon atoms, which are assumed to be attached to sufficient hydrogen atoms to satisfy valence.

[0070] Therefore, both q and r are 1, and R 1 is hydrogen and R 2 is isothiazol-3-yl, and R 3a and R 3b are hydrogen, and R 4 is fluoro and R 6 is fluoro and R 7 is (7-azabicyclo[2.2.1]heptan-7-yl)methyl, i.e., a compound of formula (I) as described above in the Summary of the Invention, wherein [ka] is designated herein as 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)benzenesulfonamide.

[0071] Embodiments of the present invention One aspect of the present invention is a compound of Formula (I) as described in the Summary of the Invention, as an individual stereoisomer, enantiomer or tautomer, or mixtures thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0072] One embodiment of the present invention is R 7 is azabicyclo[2.2.1]heptanylalkyl.

[0073] Within this embodiment, a further embodiment is R 2 is isothiazolyl.

[0074] Of this further embodiment, preferred embodiments are: 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)benzenesulfonamide; and 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(isothiazol-3-yl)benzenesulfonamide 2,2,2-trifluoroacetate is selected from.

[0075] R 7 Among the embodiments where R is azabicyclo[2.2.1]heptanylalkyl, another embodiment is 2 is thiazolyl.

[0076] Within this embodiment, a further embodiment is a compound of formula (I) wherein r is 1.

[0077] Of this further embodiment, preferred embodiments are: 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide; 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate; 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate; and 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate is selected from.

[0078] R 2 Among further embodiments where is thiazolyl, another further embodiment is a compound of formula (I) where r is 2.

[0079] Of this further embodiment, preferred embodiments are: 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide; 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate; 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate; 4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate; (S)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide; and (R)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazolinone) (4-yl)benzenesulfonamide is selected from.

[0080] R 7 Among the embodiments where R is azabicyclo[2.2.1]heptanylalkyl, another embodiment is 2 is an isoxazolyl.

[0081] Of these embodiments, preferred embodiments include: 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide; and 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide 2,2,2-trifluoroacetate is a compound of formula (I) selected from:

[0082] Another embodiment of the present invention is R 7 is azabicyclo[2.2.1]heptanylalkyl.

[0083] Within this embodiment, a further embodiment is R 7 is ((methyl)(prop-2-yl)amino)alkyl, provided that r is 2 and at least one R 6 is an alkoxy group of formula (I).

[0084] Within this further embodiment, a further embodiment is R 2 is isothiazolyl.

[0085] R 7 is ((methyl)(prop-2-yl)amino)alkyl, r is 2, and at least one R 6 Among further embodiments in which R is alkoxy, another further embodiment is 2 is thiazolyl.

[0086] Within this further embodiment, preferred compounds of formula (I) are: 2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; 2,6-difluoro-4-((6-fluoro-3-isopropoxy-2-((isopropyl(methyl)amino)methyl)benzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; 2,3-Difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; 5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate; and 2-Fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate is selected from.

[0087] R 7 is ((methyl)(prop-2-yl)amino)alkyl, r is 2, and at least one R 6 Among further embodiments in which R is alkoxy, another further embodiment is 2 is isoxazoyl.

[0088] Another embodiment of the present invention is a compound having one R 4 -S(O)2-N(H)-R 2 ortho to the substituent, a compound of formula (I).

[0089] Another embodiment of the present invention is a compound having one R 4 -C(R 3a )(R 3b )- is in the ortho position relative to the compound of formula (I).

[0090] Another embodiment of the present invention is a compound having one R 6 -C(R 3a )(R 3b )- is in the ortho position relative to the compound of formula (I).

[0091] Another embodiment of the present invention is R 5 is fluoro.

[0092] Another embodiment of the present invention is a compound having one R 4 is fluoro.

[0093] Another embodiment of the present invention is a compound having one R 4 is chloro.

[0094] Another embodiment of the present invention is a compound having one R 4 is methyl.

[0095] Another embodiment of the present invention is a compound having one R 4 is fluoro and another R 4 is methyl.

[0096] Another embodiment of the present invention is a compound having one R 6 is fluoro.

[0097] Another embodiment of the present invention is a compound having one R 6 is fluoro and another R 6 is methoxy.

[0098] Another embodiment of the present invention is a compound having one R 6 is fluoro and another R 6 is isopropoxy.

[0099] Another embodiment of the present invention is a compound having one R 6 is fluoro and another R 6 is fluoro.

[0100] Another embodiment of the invention is a method of using a compound of formula (I) as a standard or control in an in vitro or in vivo assay in determining the efficacy of a test compound in modulating voltage-gated sodium channels.

[0101] Another embodiment of the present invention is a compound of formula (Ia), a compound of formula (Ib), a compound of formula (Ic), a compound of formula (Id), a compound of formula (Id), a compound of formula (Ie), a compound of formula (If), a compound of formula (Ig), a compound of formula (Ih), a compound of formula (Ii), a compound of formula (Ij), or a compound of formula (Ik); or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as an individual stereoisomer, enantiomer, or tautomer, or mixtures thereof, as described below in the Preparation of the Compounds of the Invention.

[0102] Another embodiment of the present invention is a process for preparing a compound of Formula (Ia), as depicted in Reaction Scheme 1, as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0103] Another embodiment of the present invention is a process for preparing a compound of Formula (Ib), as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof, as depicted in Reaction Scheme 2; or a pharmaceutically acceptable salt thereof.

[0104] Another embodiment of the present invention is a process for preparing a compound of Formula (Ic), as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof, as depicted in Reaction Scheme 3; or a pharmaceutically acceptable salt thereof.

[0105] Another embodiment of the present invention is a process for preparing a compound of formula (If), as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof, as depicted in Reaction Scheme 3; or a pharmaceutically acceptable salt thereof.

[0106] Another embodiment of the present invention is a process for preparing a compound of Formula (Ig), as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof, as depicted in Reaction Scheme 3; or a pharmaceutically acceptable salt thereof.

[0107] Another embodiment of the present invention is a process for preparing a compound of Formula (Id) as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof, as depicted in Reaction Scheme 4; or a pharmaceutically acceptable salt thereof.

[0108] Another embodiment of the present invention is a process for preparing a compound of Formula (Ie), as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof, as depicted in Reaction Scheme 5; or a pharmaceutically acceptable salt thereof.

[0109] Another embodiment of the present invention is a process for preparing a compound of Formula (Ia), as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof, as depicted in Reaction Scheme 6; or a pharmaceutically acceptable salt thereof.

[0110] Another embodiment of the present invention is a process for preparing a compound of Formula (Ih), as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof, as depicted in Reaction Scheme 7; or a pharmaceutically acceptable salt thereof.

[0111] Another embodiment of the present invention is a process for preparing a compound of Formula (Ii) as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof, as depicted in Reaction Scheme 8; or a pharmaceutically acceptable salt thereof.

[0112] Another embodiment of the present invention is a process for preparing a compound of Formula (Ij), as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof, as depicted in Reaction Scheme 9; or a pharmaceutically acceptable salt thereof.

[0113] Another embodiment of the present invention is a process for preparing a compound of Formula (Ik), as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof, as depicted in Reaction Scheme 9; or a pharmaceutically acceptable salt thereof.

[0114] Any embodiment of the compounds of the invention as described above, as well as any particular R in the compounds of the invention as described above. 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 and R 7 It is understood that any particular substituent described herein with respect to substituents may be independently combined with other embodiments and / or substituents of the invention to form embodiments of the invention not specifically described above. Furthermore, in certain embodiments and / or claims, the recitation of substituents may be combined with any particular R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 When disclosed in terms of substituents, it is understood that one or more substituents may be deleted from this list and the recitation of the remaining substituents is considered to be an embodiment of the invention.

[0115] Another aspect of the present invention is a pharmaceutical composition containing a pharmaceutically acceptable excipient and a compound of the present invention as described above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as a stereoisomer, enantiomer or tautomer, or mixture thereof.

[0116] Another aspect of the present invention is a method for the treatment of Na V 1.6 A method of treating a disease or condition associated with activity, wherein the disease or condition is epilepsy and / or an epileptic seizure disorder, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention as described above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as a stereoisomer, enantiomer or tautomer, or mixture thereof.

[0117] In one embodiment of this aspect, the epilepsy or epileptic seizure disorder is selected from the group consisting of photosensitive epilepsy, self-induced syncope, intractable epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorders, childhood and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, Glut1 deficiency syndrome, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, Landau-Klöffner syndrome, Lennox-Gastaut syndrome (LGS), epilepsy with myoclonic absence, Ohtahara syndrome, Panayiotopoulos syndrome, syndrome), PCDH19 epilepsy, progressive myoclonic epilepsy, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora-type progressive myoclonic epilepsy, neurocutaneous syndrome, tuberous sclerosis complex, early infantile epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epilepsy with febrile convulsions+, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotension, and paroxysmal dyskinesia.

[0118] In one embodiment of this embodiment, the epilepsy or epileptic seizure disorder is selected from Dravet syndrome, infantile spasms / West syndrome, temporal lobe epilepsy, Lennox-Gastaut syndrome (LGS), generalized epilepsy with febrile seizures+, and early infantile epileptic encephalopathy.

[0119] Another aspect of the present invention is to provide a method for the production of Na V 1.6, comprising contacting the cells with a compound of the invention as described above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as a stereoisomer, enantiomer, or tautomer, or a mixture thereof.

[0120] Another aspect of the invention is a method of selectively inhibiting a first voltage-gated sodium channel in preference to a second voltage-gated sodium channel in a mammal, comprising administering to the mammal a modulating amount of a compound of the invention as described above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as a stereoisomer, enantiomer, or tautomer, or mixture thereof.

[0121] In one embodiment of this aspect, the first voltage-gated sodium channel is Na V It is 1.6.

[0122] In another embodiment of this aspect, the first voltage-gated sodium channel is Na V 1.6, and the second voltage-gated sodium channel is Na V It is 1.5.

[0123] In another embodiment of this aspect, the first voltage-gated sodium channel is Na V 1. 6, and the second voltage-gated sodium channel is Na V It's 1.1.

[0124] Specific embodiments of the compounds of the present invention are described in more detail below in the Preparation of Compounds of the Invention and Examples.

[0125] Utility and Testing of the Compounds of the Invention The compounds of the present invention inhibit voltage-gated sodium channels (preferably Na V1.6). Any such modulation, whether it is partial or complete inhibition or prevention of ion flow, is referred to herein as "blocking," and corresponding compounds may be referred to as "blockers" or "inhibitors." Generally, the compounds of the present invention reduce or prevent the flow of sodium ions across cell membranes by inhibiting the voltage-dependent activity of sodium channels, thereby downwardly modulating voltage-gated sodium channel activity and / or preventing sodium channel activity, such as ion flow.

[0126] The compounds of the present invention inhibit the activity of voltage-gated sodium channels (preferably Na V The compounds of the present invention inhibit ion flux through the sodium channel (1.6). The compounds of the present invention are state- or frequency-dependent modulators of sodium channels, with low affinity for the resting / closed state and high affinity for the inactivated state. These compounds likely interact with overlapping sites located in the inner cavity of the sodium conduction pore of the channel, similar to those described for other state-dependent sodium channel blockers (Ceste'le, S. et al., op. cit.). These compounds may also likely interact with sites outside the inner cavity and have an allosteric effect on sodium ion conductance through the channel pore.

[0127] Any of these consequences may ultimately contribute to the overall therapeutic benefit afforded by these compounds.

[0128] Thus, the compounds of the present invention are voltage-gated sodium channel inhibitors (preferably Na V 1.6 inhibitors) and are therefore useful for treating diseases and conditions (preferably epilepsy and / or epileptic seizure disorders) in mammals, preferably humans, and other organisms, including diseases and conditions caused by abnormal voltage-gated sodium channel biological activity (preferably abnormal Na VThe present invention also includes all human diseases and conditions that result from abnormal voltage-gated sodium channel biological activity (e.g., 1.6 activity) or that can be ameliorated by modulation of voltage-gated sodium channel biological activity. Specifically, the compounds of the present invention (i.e., compounds of Formula (I) as described above in the Summary of the Invention, as individual stereoisomers, enantiomers, or tautomers thereof, or mixtures thereof; or as pharmaceutically acceptable salts, solvates, or prodrugs thereof) are useful in treating abnormal voltage-gated sodium channel biological activity in mammals (preferably humans). V 1.6 resulting from the biological activity of Na V The compounds of the present invention are useful for treating diseases and conditions that can be alleviated by modulation (preferably inhibition) of the biological activity of Na. V 1.5 and / or Na V Na in preference to 1.1 V 1.6 is selectively inhibited.

[0129] As defined herein, Na V 1.6 Diseases, disorders, or conditions associated with activity include, but are not limited to, epilepsy and / or epileptic seizure disorders, including photosensitive epilepsy, self-induced syncope, intractable epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorders, childhood and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, Glut1 deficiency syndrome, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, Landau-Klöffner syndrome, Lennox-Gastaut syndrome (LGS), epilepsy with myoclonic absence, Ohtahara syndrome, Panaetopoulos syndrome, and PCDH19. These conditions include, but are not limited to, epilepsy, progressive myoclonic epilepsy, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora-type progressive myoclonic epilepsy, neurocutaneous syndromes, tuberous sclerosis complex, early infantile epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epilepsy with febrile seizures+, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia and paroxysmal dyskinesia.

[0130] Therefore, the present invention relates to compounds, pharmaceutical compositions, and methods of using these compounds and pharmaceutical compositions for the treatment of diseases or conditions associated with the activity of Na V 1.6 in mammals, preferably humans, which method comprises administering to a mammal, preferably a human, in need of such treatment, an effective amount of a compound of the present invention, or a pharmaceutical composition containing a compound of the present invention.

[0131] Na V The general numerical values of the compounds of the present invention in the inhibition of Na

[0132] For example, numerous rodent models have been developed to assess the propensity for seizures or epileptiform activity (Klein, BR et al., (2016), "Models Currently in Active Use. In: Epilepsy Therapy Screening Program", Vol. 2016, National Institute of Neurological Disorders and Stroke). These include acute chemical or electrical injury to induce seizures, and persistent chemical or genetic injury to create seizure-prone animals. These models can be used to determine the relative ability of compounds to promote or prevent seizure activity. The maximal electroshock seizure (MES) assay and the 6-Hz psychomotor seizure test (6Hz) are two examples of acute injury seizure assays used to evaluate anticonvulsant interventions (Suzuki, F. et al., Neuroscience (1995), Vol. 64, pp. 665-674; Barton, ME et al., Epilepsy Research (2001), Vol. 47, pp. 217-227). Both assays involve electrical injury applied by electrodes placed on the cornea or ear to induce acute seizures, which can also be chemically induced, for example, by administration of the proconvulsant ether compound fluorothyl (Makinson, CD et al., Exp. Neurol. (2016), Vol. 275, Part 1, pp. 46-58).

[0133] Genetic epilepsy has been linked to many different genes, including several voltage-gated sodium channel genes. Genetically modified mice can be created that harbor mutations identified in human patients. In some instances, these genetic modifications result in animals that behave quite similarly to the human patient in whom the genetic variation was originally identified. Mutant mice can be used to test anticonvulsant interventions. Such experiments can involve the prevention of spontaneous seizures or can utilize seizure-inducing stimuli similar to those employed in wild-type mice. An animal model of early infantile epileptic encephalopathy 6 (EIEE6) (also known as severe myoclonic epilepsy in infancy or Dravet syndrome) harbors Na V 1.1 It was created by mutating the SCN1A gene, which encodes a voltage-gated sodium channel (Yu, FH et al., Nat. Neurosci. (2006), Vol. 9, pp. 1142-1149). The model of EIEE13 also V 1.6 It is created by mutating the SCN6A gene, which encodes a voltage-gated sodium channel (W Agnon, JL et al., Human Molecular Genetics (2014)). Both of these mouse strains provide an opportunity to evaluate potential therapeutic investigations that may prove useful in clinical patient populations (Martin, MS et al., J. Biol. Chem. (2010), vol. 285, pp. 9823-9834; and Martin, MS et al., Human Molecular Genetics (2007), vol. 16, pp. 2892-2899).

[0134] The present invention provides a method for the treatment of Na V 1.6 readily provides many different avenues for the identification of inhibitory agents. V1.6 The identification of inhibitors can be assessed using a variety of in vitro and in vivo assays, such as measurements of currents, membrane potential, ion flux (e.g., sodium or guanidinium), sodium concentration, second messenger and transcript levels, and using, for example, voltage-sensitive dyes, radioactive tracers, and patch clamp electrophysiology.

[0135] One such protocol involves screening chemical agents for their ability to modulate the activity of sodium channels, thereby identifying them as agents that modulate sodium channel activity.

[0136] Exemplary assays described in Bean et al., J. General Physiology (1983), 83:613-642, and Leuwer, M. et al., Br. J. Pharmacol (2004), 141(1):47-54, use patch clamp techniques to study channel function. Such techniques are known to those skilled in the art, and current technology can be used to develop low- or medium-throughput assays to evaluate compounds for their ability to modulate sodium channel function.

[0137] Throughput of test compounds is an important consideration in the selection of screening assays to use. In some projects where hundreds of thousands of compounds are being tested, it is undesirable to use low throughput procedures. However, in other cases, low throughput is sufficient to identify important differences between a limited number of compounds. In many cases, a combination of assay types will be necessary to identify specific sodium channel modulating compounds.

[0138] Electrophysiological assays using patch clamp techniques are accepted as the gold standard for detailed characterization of sodium channel-compound interactions, as described by Bean et al., op. cit., and Leuwer, M. et al., op. cit. There are manual low-throughput screening (LTS) methods capable of comparing 2-10 compounds per day, recently developed systems for automated medium-throughput screening (MTS) at 20-50 patches (i.e., compounds) per day, and technology from Molecular Devices Corporation (Sunnyvale, CA) that allows automated high-throughput screening (HTS) at 1000-3000 patches (i.e., compounds) per day.

[0139] One automated patch clamp system utilizes planar electrode technology to accelerate drug discovery. Planar electrodes can achieve high-resistance, cell-bound seals followed by stable, low-noise whole-cell recordings comparable to conventional recordings. A suitable device is the PatchXpress 7000A (Axon Instruments Inc., Union City, CA). Various cell lines and culture methods, including adherent cells and cells that grow naturally in suspension, have been ranked for seal success and stability. Immortalized cells (e.g., HEK and CHO) that stably express high concentrations of the relevant sodium ion channel can be adapted to high-density suspension culture.

[0140] Other assays can be selected that allow researchers to identify compounds that block a particular state of the channel, such as its open, closed, or resting state, or the transition from open to closed, closed to resting, or resting to open. Those of skill in the art will generally be familiar with such assays.

[0141] Binding assays are also available, with designs including a traditional radioactive filter-based binding assay or a confocal-based fluorescence system commercially available from Evotec OAI Group of Companies (Hamburg, Germany), both of which are HTS.

[0142] A radioactive flux assay can also be used, in which the channel is stimulated, opened with veratridine or aconitine, and maintained in a stable open state with a toxin, and channel blockers are identified by their ability to prevent ion influx. 22 [Na] and 14 [C] guanidinium ions can be used as a tracer. Live cell FlashPlate & Cytostar-T plates avoid the separation step and are suitable for HTS. Scintillation plate technology makes this method more suitable for HTS. From the functional aspects of this assay, the information content is quite good.

[0143] In yet another format, membrane potential redistribution is measured using the FLIPR System Membrane Potential Kit (HTS), commercially available from Molecular Dynamics (Amersham Biosciences, Piscataway Division, NJ). This method is limited to slow membrane potential changes. Some problems may arise from the natural radioactivity of the compound's fluorescence. Test compounds may also directly affect the fluidity of the cell membrane, resulting in an increase in intracellular dye concentration. However, the functional aspects of this assay provide considerable information content.

[0144] By using sodium dyes, the rate or amount of sodium ion influx through the channel can be measured. This type of assay provides very high information content regarding potential channel blockers. The assay is functional and directly measures Na+ influx. Na+ influx can be measured by using CoroNa Red, SBFI, and / or sodium green (Molecular Probes, Inc. Eugene, OR), all of which are Na-reactive dyes. They can be used in conjunction with the FLIPR instrument. The use of these dyes in screening has not been previously described in the literature. Calcium dyes may also have potential in this format.

[0145] Another assay measures the ability of test compounds to directly block Na influx by using a FRET-based voltage sensor. Commercially available HTS systems include the VIPR™ II FRET system (Aurora Biosciences Corporation, San Diego, CA, a division of Vertex Pharmaceuticals, Inc.), which can also be used with commercially available FRET dyes from Aurora Bioscience. This assay measures responses to voltage changes within 1 second. There is no requirement for modulators of channel function. The assay measures depolarization and hyperpolarization and provides a fractional total output for quantification. A somewhat less expensive MTS version of this assay uses a FLEXstation™ (Molecular Devices Corporation) with FRET dyes from Aurora Biosciences. Other methods for testing the compounds disclosed herein are also well known and readily available to those of skill in the art.

[0146] These results provide a basis for the analysis of the structure-activity relationship (SAR) between the test compounds and the sodium channels. Certain substituents on the core structure of the test compounds tend to provide potent inhibitory compounds. SAR analysis is one of the means currently available to those skilled in the art to identify preferred embodiments of the compounds of the present invention for use as therapeutic agents.

[0147] The modulators thus identified are then tested in various in vivo models to determine whether they are useful for treating diseases or conditions associated with the activity of the sodium channel of interest (preferably Na V 1.6) with minimal adverse events. The assays described in the following section on biological assays are useful for evaluating the biological activity of the compounds of the present invention.

[0148] Typically, the potency of the compounds of the present invention is represented by its IC 50 value ("inhibitory concentration - 50%"), which is a measure of the amount of compound required to achieve 50% inhibition of the activity of the target sodium channel over a specific time period.

[0149] In an alternative use of the present invention, the compounds of the present invention can be used in in vitro or in vivo studies as representative agents for comparative purposes to discover other compounds that are also useful for the treatment of or protection from the various diseases disclosed herein.

[0150] Another aspect of the present invention relates to inhibiting Na V 1.6 activity in a biological sample or in a mammal, preferably a human, the method comprising administering to the mammal, preferably a human, or contacting the biological sample with a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I). The term "biological sample" as used herein includes, without limitation, cell cultures or extracts thereof, biopsy materials obtained from mammals or extracts thereof, and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts.

[0151] Na in biological samples V Inhibition of 1.6 activity is useful for a variety of purposes known to those skilled in the art, including, but not limited to, the study of sodium ion channels in biological and pathological phenomena and the comparative evaluation of new sodium ion channel inhibitors.

[0152] The compounds of the invention as described above in the Summary of the Invention, as stereoisomers, enantiomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, and / or pharmaceutical compositions described herein comprising one or more compounds of the invention as stereoisomers, enantiomers or tautomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, as described above in the Summary of the Invention, and a pharmaceutically acceptable excipient, are useful for inhibiting voltage-gated sodium channel activity (preferably Na V 1.6 Activity).

[0153] Pharmaceutical Compositions and Administration of the Present Invention The present invention also relates to pharmaceutical compositions containing the compounds of the present invention disclosed herein. In one embodiment, the present invention relates to a composition comprising a compound of the present invention in a pharmaceutically acceptable carrier, excipient, or vehicle in an amount effective to modulate, preferably inhibit, ion flux through voltage-gated sodium channels, e.g., when administered to an animal, preferably a mammal, and most preferably a human patient, to treat a disease mediated by sodium channels (e.g., epilepsy and / or epileptic seizure disorders).

[0154] The compounds of the present invention, or pharmaceutically acceptable salts thereof, can be administered in pure form or in a suitable pharmaceutical composition via any of the accepted modes of drug administration to achieve the same function. The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable carriers, excipients, or additives, and can be formulated into solid, semi-solid, liquid, or gaseous preparations, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administration of such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, and intrasternal injection or infusion techniques. The pharmaceutical compositions of the present invention are formulated so that the active ingredients contained therein are bioavailable when the compositions are administered to a patient. The composition to be administered to a subject or patient may take the form of one or more dosage units, where, for example, a tablet may be a single dosage unit, or a container of the compound of the invention in aerosol form may hold multiple dosage units. Actual methods for preparing such dosage forms are known or apparent to those skilled in the art; see, for example, *The Science and Practice of Pharmacy*, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treating the disease or condition of interest in accordance with the teachings of the present invention.

[0155] The pharmaceutical compositions useful herein also contain a pharmaceutically acceptable carrier, including any suitable excipient or additive, including any pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition and can be administered without undue toxicity. Pharmaceutically acceptable carriers include, but are not limited to, liquids such as water, saline, glycerol, and ethanol. A thorough discussion of pharmaceutically acceptable carriers, excipients, and other additives is provided in Remington's Pharmaceutical Sciences (Mack Pub. Co., NJ latest edition).

[0156] The pharmaceutical composition of the present invention can be in solid or liquid form.In one aspect, carrier(s) are particulate, so that the composition is, for example, in the form of tablet or powder.Carrier(s) can be the liquid that contains the composition, for example, oral syrup, injection liquid or aerosol, and aerosol is useful for, for example, administration by inhalation.

[0157] When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, with semi-solid, semi-liquid, suspension and gel forms being included within the scope of forms considered herein to be either solid or liquid.

[0158] As a solid composition for oral administration, the pharmaceutical composition can be formulated into a powder, granules, compressed tablet, pill, capsule, chewing gum, wafer, or other form. Such solid compositions will usually contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders (such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, gum tragacanth, or gelatin), additives (such as starch, lactose, or dextrin), disintegrants (such as alginic acid, sodium alginate, Primogel, corn starch, etc.), lubricants (such as magnesium stearate or Sterotex), glidants (such as colloidal silicon dioxide), sweeteners (such as sucrose or or saccharin), flavoring agents (e.g., mint, methyl salicylate, or orange flavor), and coloring agents.

[0159] When the pharmaceutical composition is in the form of a capsule, such as a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

[0160] Pharmaceutical compositions may be in the form of liquids, such as elixirs, syrups, solutions, emulsions, or suspensions. Liquids may be for oral administration or for delivery by injection, as two examples. For oral administration, preferred compositions contain one or more sweeteners, preservatives, dyes / colorants, and flavor enhancers in addition to the compounds of the present invention. For injection, compositions may contain one or more surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffers, stabilizers, and isotonic agents.

[0161] Liquid pharmaceutical compositions of the present invention, whether in solution, suspension, or other similar form, may contain one or more of the following adjuvants: sterile excipients, such as water for injection, saline solution, preferably saline, Ringer's solution, isotonic saline, fixed oils (e.g., synthetic monoglycerides or diglycerides, polyethylene glycol, glycerin, propylene glycol, or other solvents that can serve as solvents or suspending media), antibacterial agents (e.g., benzyl alcohol or methylparabens), antioxidants (e.g., ascorbic acid or sodium bisulfate), chelating agents (e.g., ethylenediaminetetraacetic acid), buffers (e.g., acetate, citrate, or phosphate), and agents for adjusting tonicity (e.g., sodium chloride or glucose). Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic. Saline is a preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

[0162] Liquid pharmaceutical compositions of the present invention intended for either parenteral or oral administration should contain an amount of a compound of the present invention such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of a compound of the present invention in the composition. For oral administration, this amount may vary from 0.1% to about 70% by weight of the composition. Preferred oral pharmaceutical compositions contain from about 4% to about 50% of a compound of the present invention. Preferred pharmaceutical compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains 0.01% to 10% by weight of the compound of the present invention, prior to dilution.

[0163] The pharmaceutical composition of the present invention may be intended for topical administration, in which case the carrier may suitably comprise a solution base, emulsion base, ointment base, or gel base. The base may, for example, comprise one or more of the following: petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, diluents (such as water and alcohol), and emulsifiers and stabilizers. A thickener may be present in a pharmaceutical composition for topical administration. For transdermal administration, the composition may comprise a transdermal patch or iontophoresis device. Topical formulations may contain a concentration of the compound of the present invention of about 0.1 w / v% to about 10 w / v% (weight per unit volume).

[0164] The pharmaceutical composition of the present invention can be, for example, in the form of suppository for rectal administration, and this suppository will melt in the rectum and release its drug.The composition for rectal administration can contain an oily base as a suitable non-irritating additive.Such base includes, but is not limited to, lanolin, cocoa butter and polyethylene glycol.

[0165] The pharmaceutical compositions of the present invention may contain various materials that modify the physical form of a solid or liquid dosage unit. For example, the compositions may contain materials that form a coating shell around the active ingredient. The materials that form the coating shell are usually inert and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredient may be placed in a gelatin capsule.

[0166] Pharmaceutical compositions of the invention, in solid or liquid form, may also include an agent that binds to a compound of the invention and thereby aids in delivery of the compound. Suitable agents that act in such a capacity include monoclonal or polyclonal antibodies, proteins, or liposomes.

[0167] The pharmaceutical compositions of the present invention may be comprised of dosage units that can be administered as an aerosol. The term aerosol is used to refer to a variety of systems, ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery can be by liquefied or compressed gas or by a suitable pump system that dispenses the active ingredient. Aerosols of the compounds of the present invention can be delivered in single-phase, two-phase, or three-phase systems to deliver the active ingredient(s). Aerosol delivery includes the necessary containers, activators, valves, subcontainers, etc., which can also be combined to form a kit. Those skilled in the art will be able to determine a preferred aerosol formulation without undue experimentation.

[0168] The pharmaceutical composition of the present invention can be prepared by a method well known in the pharmaceutical field.For example, pharmaceutical compositions intended for administration by injection can be prepared by combining the compound of the present invention with sterile distilled water to form a solution.The addition of a surfactant can promote the formation of a homogeneous solution or suspension.Surfactants are compounds that interact with the compound of the present invention non-covalently to promote the dissolution or homogeneous suspension of the compound in an aqueous delivery system.

[0169] The compounds of the present invention, or pharmaceutically acceptable salts thereof, are administered in a therapeutically effective amount, which will vary depending on various factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, the patient's age, weight, general health, sex, and diet, the mode and time of administration, the rate of excretion, the drug combination, the severity of the particular disorder or condition, and the subject being treated. Generally, a therapeutically effective daily amount is from about 0.001 mg / kg (i.e., 0.07 mg) to about 100 mg / kg (i.e., 7.0 g) (for a 70 kg mammal). Preferably, the therapeutically effective amount is from about 0.01 mg / kg (i.e., 0.7 mg) to about 50 mg / kg (i.e., 3.5 g) (for a 70 kg mammal). More preferably, the therapeutically effective amount is from about 1 mg / kg (i.e., 70 mg) to about 25 mg / kg (i.e., 1.75 g) (for a 70 kg mammal).

[0170] The effective amount ranges provided herein are not intended to be limiting and represent preferred dosage ranges. However, the most preferred dosage will be adjusted to the individual subject, as understood and can be determined by those skilled in the relevant field. (See, e.g., Berkow et al., eds., The Merck Manual, 19th ed., Merck and Co., Rahway, NJ, 2011; Brunton et al., eds., Goodman and Cilman's The Pharmacological Basis of Therapeutics, 12th ed., McGraw-Hill 2011; Avery's Drug Treatment: Principles and Practice of Clinical Pharmacology, 19th ed., Merck and Co., Rahway, NJ, ...). and Therapeutics, 3rd ed., ADIS Press, LTD., Williams and Wilkins, Baltimore, MD. (1987); Ebadi, Pharmacology, Little, Brown and Co., Boston, (1985); Osolci et al. (eds.), Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton, PA; Katzung, Basic and Clinical Pharmacology, Appleton and Lange, Norwalk, CT (1992).

[0171] The total dosage required for each treatment can be administered in multiple doses or in a single dose throughout the day, as needed. Generally, treatment begins with a low dosage that is less than the optimal dose of the compound. Thereafter, the dosage is increased by small increments until the optimal effect under the circumstances is reached. Diagnostic pharmaceutical compounds or compositions can be administered alone or in conjunction with other diagnostic methods and / or pharmaceuticals directed at the pathology or other symptoms of the pathology. The recipient of administration of the compounds and / or compositions of the present invention can be any vertebrate, for example, a mammal. Among mammals, preferred recipients are mammals from the orders Primates (including humans, apes, and monkeys), Arteriodactyla (including horses, goats, cows, sheep, and pigs), Rodentia (including mice, rats, and hamsters), Lagamorpha (including rabbits), and Carnivora (including cats and dogs). Among birds, preferred recipients are turkeys, chickens and other members of the same order. The most preferred recipients are humans.

[0172] For topical application, an effective amount of the pharmaceutical composition of the present invention is preferably administered to a target site adjacent to the peripheral nerve neurons to be treated, such as the skin surface, mucous membrane, etc. Depending on the area to be treated, whether the use is for diagnosis, prevention, or treatment, the severity of the condition, and the nature of the topical vehicle used, this amount generally ranges from about 0.0001 mg to about 1 g of the compound of the present invention per application. A preferred topical preparation is an ointment, in which case about 0.001 mg to about 50 mg of active ingredient is used per cc of ointment base. The pharmaceutical composition can be formulated as a transdermal composition or transdermal delivery device ("patch"). Such compositions include, for example, a lined active compound reservoir, a control membrane, a liner, and a contact adhesive. Such transdermal patches can be used to provide continuous, pulsatile, or on-demand delivery of the compound of the present invention, as needed.

[0173] The compositions of the invention can be formulated using procedures known in the art so as to provide quick, sustained, or delayed release of the active ingredient after administration to a patient. Controlled-release drug delivery systems are well known in the art and include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations.

[0174] The compositions of the present invention can also be delivered via intranasal drug delivery systems for local, systemic, and nose-to-brain drug therapy. Controlled Particle Dispersion (CPD)™ technology, traditional nasal spray bottles, inhalers, or nebulizers are known to those skilled in the art to provide effective local and systemic delivery of drugs by targeting the olfactory region and paranasal sinuses.

[0175] The present invention also relates to an intravaginal shell or core drug delivery device suitable for administration to a female human or animal. The device comprises a sheath-enclosed They may be comprised of an active pharmaceutical ingredient within a polymer matrix and are capable of releasing the compound daily in a substantially zero order pattern, similar to the devices used to deposit testosterone as described in PCT Published Patent Application No. WO 98 / 50016.

[0176] Current methods for ocular delivery include topical administration (eye drops), subconjunctival injection, periorbital injection, intravitreal injection, surgical implantation, and iontophoresis (using a weak electric current to transport ionized drugs to and through body tissues).Those skilled in the art will combine the most suitable additives with the compound for safe and effective intraocular administration.

[0177] The most appropriate route will depend on the nature and severity of the condition being treated. Those skilled in the art are also familiar with determining the mode of administration (e.g., oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, suitable pharmaceutical excipients, and other considerations related to delivery of the compound to a subject in need thereof.

[0178] Combination therapy The compounds of the present invention can be usefully combined with one or more other compounds of the present invention or one or more other therapeutic agents, or any combination thereof, in the treatment of diseases and conditions associated with voltage-gated sodium channel activity. For example, the compounds of the present invention can be administered simultaneously, sequentially, or separately in combination with other therapeutic agents, including, but not limited to, the following: Opiate analgesics, such as morphine, heroin, cocaine, oxymorphine, levorphanol, levallorphan, oxycodone, codeine, dihydrocodeine, propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone, melipidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, and pentazocine; Non-opiate analgesics, such as acetaminophen and salicylates (e.g., aspirin), Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, fenoprofen, ketoprofen, celecoxib, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, and zomepirac; Anticonvulsants, such as carbamazepine, oxcarbazepine, lamotrigine, valproate, topiramate, gabapentin, and pregabalin Antidepressants, such as tricyclic antidepressants, such as amitriptyline, clomipramine, despramine, imipramine, and nortriptyline, COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, and lumiracoxib; α-adrenergic agents, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, and 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline; Barbiturate sedatives, such as amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, theamylal, and thiopental; Tachykinin (NK) antagonists, in particular NK-3 antagonists, NK-2 antagonists or NK-1 antagonists, such as (αR,9R)-7-[3,5-bis(2-methyl-2-propanol)-3-one] (trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637), 5-[[2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl)ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S), etc. Coal tar painkillers, especially paracetamol, Serotonin reuptake inhibitors, such as paroxetine, sertraline, norfluoxetine (fluoxetine desmethylmetabolite), desmethylsertraline, fluvoxamine, paroxetine, citalopram, citalopram desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, ritoxetine, dapoxetine, nefazodone, cericlamine, trazodone, and fluoxetine; noradrenaline (norepinephrine) reuptake inhibitors, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®), in particular selective noradrenaline reuptake inhibitors, such as reboxetine, in particular (S,S)-reboxetine, and venlafaxine duloxetine neuroleptics, sedative / anxiolytics, Dual serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolized O-desmethylvenlafaxine, clomipramine, clomipramine metabolized desmethylclomipramine, duloxetine, milnacipran, and imipramine; Acetylcholinesterase inhibitors, such as donepezil 5-HT3 antagonists, such as ondansetron, Metabotropic glutamate receptor (mGluR) antagonists, Local anesthetics, such as mexiletine and lidocaine Corticosteroids, such as dexamethasone Antiarrhythmic drugs, such as mexiletine and phenytoin Muscarinic antagonists, such as tolterodine, propiverine, tropium chloride, darifenacin, solifenacin, temiverine and ipratropium, cannabinoids, Vanilloid receptor agonists (e.g., resinferratoxin) or antagonists (e.g., capsazepine), Sedatives, such as glutethimide, meprobamate, methaqualone, and dichloralphenazone Anti-anxiety medications, such as benzodiazepines Antidepressants, such as mirtazapine topical medications (e.g., lidocaine, capsacin, and resiniferotoxin), Muscle relaxants, such as benzodiazepines, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, and orphrenazine, antihistamines or H1 antagonists, NMDA acid receptor antagonists, 5-HT receptor agonists / antagonists, PDEV inhibitors, Tramadol®, Cholinergic (nicotinic) analgesics, alpha-2-delta ligands, Prostaglandin E2 subtype antagonists, Leukotriene B4 antagonists, 5-lipoxygenase inhibitors, and 5-HT3 antagonist.

[0179] As used herein, "combination" refers to any mixture or permutation of one or more compounds of the present invention and one or more other compounds of the present invention or one or more additional therapeutic agents. Unless the context clearly indicates otherwise, "combination" can include simultaneous or sustained delivery of a compound of the present invention with one or more therapeutic agents. Unless the context clearly indicates otherwise, "combination" can include dosage forms of a compound of the present invention with another therapeutic agent. Unless the context clearly indicates otherwise, "combination" can include routes of administration of a compound of the present invention with another therapeutic agent. Unless the context clearly indicates otherwise, "combination" can include formulations of a compound of the present invention with another therapeutic agent. Dosage forms, routes of administration, and pharmaceutical compositions include, but are not limited to, those described herein.

[0180] Kit of parts The present invention also provides kits containing pharmaceutical compositions comprising one or more compounds of the present invention. The kits may also contain a voltage-gated ion channel (preferably Na V Also included are instructions for use of the pharmaceutical composition to inhibit the activity of 1.6), for treating epilepsy, and for other uses disclosed herein. Preferably, the commercial package contains one or more unit doses of the pharmaceutical composition. For example, such a unit dose may be sufficient for the preparation of an intravenous injection. Those skilled in the art will appreciate that light and / or air-sensitive compounds may require special packaging and / or formulation. For example, packaging may be used that is light-tight and / or sealed from contact with ambient air and / or formulated with appropriate coatings or additives.

[0181] Preparation of Compounds of the Invention The following reaction schemes illustrate methods of making compounds of formula (I) as their individual stereoisomers, enantiomers or tautomers, or mixtures thereof, or as pharmaceutically acceptable salts, solvates or prodrugs thereof, as described above in the Summary of the Invention.

[0182] It will be understood that those skilled in the art can prepare other compounds of the present invention not explicitly described below in a manner similar to that described below by using appropriate starting components and modifying the synthetic parameters as necessary. It will also be understood that simple functional group transformations (see, for example, Larock, RC Comprehensive Organic Transformations, 2nd Edition (Wiley, 1999)) can be carried out by methods known to those skilled in the art. In general, starting components can be obtained from sources such as Sigma Aldrich, Combi-Blocks, Oakwood Chemicals, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or can be synthesized according to sources known to those skilled in the art (see, for example, Smith, MB and J. March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Edition (Wiley, 2007)), or can be prepared as described herein.

[0183] In the following description, any combination of substituents and / or variables in the described formulae is It is also understood that such combinations are permissible only if they result in stable compounds.

[0184] It will also be understood by those skilled in the art that in the processes described below, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto, and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, and benzyl. Suitable protecting groups for amino include t-butoxycarbonyl and benzyloxycarbonyl, trimethylsilylethoxymethyl, and the like. Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl, or aralkyl), p-methoxybenzyl, and trityl. Suitable protecting groups for carboxylic acid include alkyl esters, aryl esters, or arylalkyl esters.

[0185] Protecting groups can be added or removed in accordance with standard techniques, known to those skilled in the art, and as described herein.

[0186] The use of protecting groups is described in detail in Greene, TW and PG Mughuts, Greene's Protective Groups in Organic Synthesis, (current edition), Wiley. The protecting group may also be a polymer resin, such as a Wang resin or a 2-chlorotrityl-chloride resin.

[0187] Those skilled in the art will appreciate that such protected derivatives of the compounds of the present invention may not themselves possess pharmacological activity, but will form the pharmacologically active compounds of the present invention upon administration to a mammal and subsequent metabolism in the body. Such derivatives may therefore be described as "prodrugs." All prodrugs of the compounds of the present invention are included within the scope of the present invention.

[0188] The compound of formula (I) may contain at least one asymmetric carbon atom and therefore may exist as a racemate, enantiomer, and / or diastereoisomer. Specific enantiomers or diastereoisomers can be prepared by utilizing specific chiral starting materials. Alternatively, a diastereomeric or racemic mixture of a compound of formula (I) can be resolved into its respective enantiomers or diastereoisomers. Methods for resolving diastereomeric or racemic mixtures of a compound of formula (I) as described herein, or an intermediate prepared herein, are well known in the art (e.g., E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds; John Wiley & Sons: New York, 1994; Chapter 7, and references cited therein). Suitable processes such as crystallization (e.g., preferential crystallization, preferential crystallization in the presence of additives), asymmetric transformation of racemates, chemical separation (e.g., formation and separation of diastereomers such as diastereomeric salt mixtures, or use of resolving agents; separation by complexes and clathrates), kinetic separation (e.g., using titanium tartrate catalysts), enzymatic separation (e.g., mediated by lipases), and chromatographic separation (e.g., HPLC using chiral stationary phases and / or simulated moving bed methodology, or supercritical fluid chromatography and related techniques) are some of the examples that may be applied (see, for example, T.J. Ward, Analytical Chemistry, 2002, 2863-2872).

[0189] Preparation of Compounds of Formula (I) Compounds of formula (Ia) are those in which q is 1 and R 3a and R 3b are hydrogen, and R 7 is azabicyclo[2.2.1]heptanylmethyl, and r, R 1 , R 2 , R 5 , and R 6are compounds of Formula (I), as described above in the Summary of the Invention, which may be prepared by the methods disclosed in Reaction Scheme 1 below, where n is 1 to 6, each X is independently fluoro, chloro, or bromo, and R 4a is bromo and R 4b is fluoro and R 8 is alkyl and DPPA is diphenylphosphoryl azide: Reaction Scheme 1 [ka]

[0190] Compounds of formula (A), (B), (D), (E), (G), and (H) are commercially available or can be prepared according to methods known to those skilled in the art or by the methods disclosed herein. Generally, compounds of formula (Ia), as described above in Reaction Scheme 1, are prepared as follows:

[0191] Compounds of formula (A) are first treated with azabicyclo[2.2.1]heptane under standard reaction conditions (such as, but not limited to, using a polar aprotic solvent (such as, but not limited to, dimethyl sulfoxide) in the presence of a base (such as, but not limited to, potassium carbonate) at a temperature between about 0° C. and 80° C. for about 1 to 48 hours) to provide compounds of formula (B).

[0192] Compounds of formula (B) are then treated under standard catalytic hydrogenation conditions (such as using Raney-Ni in the presence of ammonium hydroxide) to give compounds of formula (C).

[0193] Compounds of formula (D) are treated with an appropriate azide (such as diphenylphosphoryl azide) and compounds of formula (E) under standard Schmidt rearrangement conditions to provide compounds of formula (F).

[0194] Compounds of formula (G) are treated with an excess of compounds of formula (H) under arenesulfonylation conditions to provide compounds of formula (J). Compounds of formula (F) are then treated with compounds of formula (J) under standard carbamate sulfonylation conditions to provide compounds of formula (K). Compounds of formula (K) are then treated with compounds of formula (C) under standard aromatic nucleophilic substitution conditions (such as, but not limited to, the use of a polar aprotic solvent (such as, but not limited to, dimethyl sulfoxide) in the presence of a base (such as, N,N-diisopropylethylamine) at a temperature between about 0° C. and 80° C. for about 1 to 48 hours) to provide compounds of formula (L).

[0195] Compounds of formula (L) are then treated under standard arene protodehalogenation conditions to give compounds of formula (M), which are then treated under standard nitrogen deprotection conditions to give compounds of formula (Ia).

[0196] Compounds of formula (Ib) are those in which q is 1, r is 2, and R 1 is hydrogen and R 3a and R 3b are hydrogen, and R 4 is the halo and one R 6 is the halo and one R 6 is alkoxy (-OR 8 ) and R 7 is ((methyl)(prop-2-yl)amino)methyl, and R 2 and R 5 are compounds of Formula (I) as described above in the Summary of the Invention, each as defined in the Summary of the Invention, and may be prepared by the method disclosed in Reaction Scheme 2 below, wherein each X is independently fluoro, chloro, or bromo; and R 6a is the halo and R 8 is an alkyl: Reaction Scheme 2 [ka]

[0197] Compounds of formula (F) are prepared in a manner similar to that described in Reaction Scheme 1 above. Compounds of formula (Ja) are prepared in a manner similar to that described in Reaction Scheme 1 above for compounds of formula (J). Compounds of formula (N) are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. Generally, compounds of formula (Ib), as described in Reaction Scheme 2 above, are prepared as follows:

[0198] A compound of formula (Ja) is treated with a compound of formula (F) in a manner similar to that described above in Reaction Scheme 1 for preparing a compound of formula (K) from a compound of formula (J) and a compound of formula (F) to provide a compound of formula (Ka).

[0199] Compounds of formula (N) are treated under standard arene formylation conditions to form aldehyde compounds of formula (O), which are then treated under standard nucleophilic aromatic substitution conditions to give compounds of formula (P).

[0200] Compounds of formula (P) are then treated under standard reductive amination conditions to give compounds of formula (Q).

[0201] Compounds of formula (Q) are then treated under standard metal-halogen exchange / formylation / oxime formation conditions to give compounds of formula (R).

[0202] Compounds of formula (R) are then treated under standard oxime reduction conditions to give compounds of formula (S), which are then treated with compounds of formula (Ka) under standard aromatic nucleophilic substitution reaction conditions (such as, but not limited to, using a polar aprotic solvent (such as, but not limited to, dimethyl sulfoxide) in the presence of a base (such as, N,N-diisopropylethylamine) at a temperature between about 0°C and 80°C for about 1 to 48 hours) to give compounds of formula (T).

[0203] Compounds of formula (T) are then treated under standard nitrogen deprotection conditions to give compounds of formula (Ib).

[0204] Alternatively, R 8 Compounds of formula (P), where is methyl, are treated under standard demethylation conditions (such as, but not limited to, treatment with boron tribromide) to give the corresponding hydroxy compounds, which are then treated with an alkyl halide under standard Williamson ether synthesis conditions to give the corresponding alkoxy compounds, which are then treated under the same conditions as described above for the preparation of compounds of formula (Q) to give compounds of formula (Ib).

[0205] Compounds of formula (Ic), formula (If), and formula (Ig) are those in which q is 1 and R 3a and R 3b are hydrogen, and R 7 is azabicyclo[2.2.1]heptanylmethyl, and r, R 1 , R 2 , R 5 , and R 6 are compounds of Formula (I), as described above in the Summary of the Invention, which may be prepared by the methods disclosed in Reaction Scheme 3 below, where n is 1 to 6, each X is independently fluoro, chloro, or bromo, and R 4d is alkyl, and R 4c is chloro or fluoro, and R 8 is an alkyl: Reaction Scheme 3 [ka] Compounds of formula (F), (Jb), and (C) can be prepared by the methods disclosed herein. Generally, compounds of formula (Ia), as described above in Reaction Scheme 3, are prepared as follows:

[0206] Compounds of formula (F) are treated with compounds of formula (Ja) under standard carbamate sulfonylation conditions to provide compounds of formula (Kb). Compounds of formula (Kb) are then treated with compounds of formula (C) under standard aromatic nucleophilic substitution conditions (such as, but not limited to, using a polar aprotic solvent (such as, but not limited to, dimethyl sulfoxide) in the presence of a base (such as, N,N-diisopropylethylamine) at a temperature between about 0° C. and 80° C. for about 1 to 48 hours) to provide compounds of formula (La), which are then treated under standard nitrogen deprotection conditions to provide compounds of formula (Ic).

[0207] Alternatively, the compound of formula (La) can be reacted with a boronic acid derivative (R 4d -B(OH)2) under standard Suzuki-Miyaura cross-coupling conditions (such as, but not limited to, in the presence of a base (such as, but not limited to, tripotassium phosphate) and a solvent (such as, but not limited to, 1,4-dioxane) in the presence of a palladium catalyst, for example, but not limited to, tetrakis(triphenylphosphine)palladium(0) or palladium(II) acetate and tricyclohexylphosphine tetrafluoroborate) at a temperature between about ambient temperature and 150°C for about 30 minutes to 16 hours to form a product, which is then deprotected under standard nitrogen deprotection conditions to provide a compound of formula (If).

[0208] If necessary, compounds of formula (La) are treated under standard nitrogen deprotection conditions to give compounds of formula (Ig).

[0209] Compounds of formula (Id) are those in which q is 2 and R 3a and R 3b are hydrogen, and R 7 is azabicyclo[2.2.1]heptanylmethyl, and r, R 1 , R 2 , R 5 , and R 6are compounds of Formula (I), as described above in the Summary of the Invention, and may be prepared by the methods disclosed in Reaction Scheme 3 below, where n is 1 to 6, each X is fluoro, chloro, or bromo, and R 4d is alkyl, and R 4b is fluoro and Pg 1 is a nitrogen protecting group (such as 4-methoxybenzyl or 2-(trimethylsilyl)ethoxy): Reaction Scheme 4 [ka]

[0210] Compounds of formula (Jc) are prepared in a manner similar to that described above for compounds of formula (J) in Reaction Scheme 1. Compounds of formula (C) are prepared in the manner described above for compounds of formula (C) in Reaction Scheme 1. Generally, compounds of formula (Id), as described above in Reaction Scheme 4, are prepared as follows:

[0211] Compounds of formula R are commercially available or can be prepared by methods known to those skilled in the art. 2 Compounds of -NH2 are treated with compounds of formula (Jc) under standard sulfonamide forming conditions to give compounds of formula (U).

[0212] Compounds of formula (U) are protected under standard nitrogen protection conditions to give compounds of formula (V).

[0213] The compound of formula (V) is then reacted with a compound of formula (C) under standard aromatic nucleophilic substitution conditions (at a temperature between about 0° C. and 80° C. for about 1 to 48 hours, using a base (N,N-diisopropylethyl ether) Treatment with a polar aprotic solvent (such as, but not limited to, dimethylsulfoxide) in the presence of a diamine (such as, but not limited to, an amine) provides a compound of formula (W).

[0214] The compound of formula (W) is then reacted with a boronic acid derivative (R 4d -B(OH)2) under standard Suzuki-Miyaura cross-coupling conditions (such as, but not limited to, the use of a solvent such as, but not limited to, 1,4-dioxane in the presence of a base such as, but not limited to, tripotassium phosphate and a palladium catalyst such as, but not limited to, tetrakis(triphenylphosphine)palladium(0) or palladium(II) acetate and tricyclohexylphosphine tetrafluoroborate) at a temperature between about ambient temperature and 150°C for about 30 minutes to 16 hours to produce a compound of formula (X), which can be deprotected under standard nitrogen deprotection conditions to give a compound of formula (Id).

[0215] Compounds of formula (Ie) are those in which q is 1 and R 3a and R 3b are hydrogen, and one R 4 is alkyl and other R 4 is the halo, and R 7 is azabicyclo[2.2.1]heptanylmethyl, and r, R 1 , R 2 , R 5 , and R 6 are compounds of Formula (I) as described above in the Summary of the Invention, each as defined in the Summary of the Invention, and may be prepared by the methods disclosed in Reaction Scheme 5 below, where n is 1-6, X is fluoro, chloro, or bromo, and R 4a is bromo and R 4d is alkyl, and R 8 is an alkyl: Reaction Scheme 5 [ka]

[0216] Compounds of formula (F) are prepared as described above in Reaction Scheme 1. Compounds of formula (Jb) are prepared in a manner similar to that described herein for compounds of formula (J). Compounds of formula (C) are prepared as described above in Reaction Scheme 1. Generally, compounds of formula (Ie) are prepared as follows, as described above in Reaction Scheme 5:

[0217] A compound of formula (F) is first treated under standard carbamate sulfonylation conditions to give a compound of formula (Kc), which is then treated with a compound of formula (C) under standard aromatic nucleophilic substitution conditions (such as, but not limited to, in the presence of a base (such as, but not limited to, dimethyl sulfoxide) in the presence of a base (such as, N,N-diisopropylethylamine) at ambient temperature for about 1-20 hours) to give a compound of formula (Lb). The compound of formula (Lb) is then reacted with a boronic acid derivative (R 4d -B(OH)2) under standard Suzuki-Miyaura cross-coupling conditions (such as, but not limited to, the use of a solvent such as, but not limited to, 1,4-dioxane in the presence of a base such as, but not limited to, tripotassium phosphate and a palladium catalyst such as, but not limited to, tetrakis(triphenylphosphine)palladium(0) or palladium(II) acetate and tricyclohexylphosphine tetrafluoroborate) at a temperature between about ambient temperature and 150°C for about 30 minutes to 16 hours to produce a compound of formula (Lc), which can be deprotected under standard nitrogen deprotection conditions to give a compound of formula (Ie).

[0218] Compounds of formula (Ia) described in Reaction Scheme 1 above may also be prepared by the method disclosed in Reaction Scheme 6 below, wherein q is 1 and R 3a and R 3b are hydrogen, and R 7 is azabicyclo[2.2.1]heptanylmethyl, and r, R 1 , R 2 , R 5 , and R 6each as defined in the Summary of the Invention, where n is 1-6, X is fluoro, chloro, or bromo, and R 4b is fluoro and Pg 1 is a nitrogen protecting group (such as 4-methoxybenzyl or 2-(trimethylsilyl)ethoxy): Reaction Scheme 6 [ka]

[0219] Compounds of formula (Va) can be prepared by the methods disclosed herein for compounds of formula (V) or by the methods disclosed in PCT Publication No. WO 2018 / 106284. Compounds of formula (C) are prepared by the methods disclosed herein. Generally, compounds of formula (Ia) are prepared as follows, as described above in Reaction Scheme 6:

[0220] A compound of formula (Va) is first treated with a compound of formula (C) under standard aromatic nucleophilic substitution conditions (such as, but not limited to, using a polar aprotic solvent (such as, but not limited to, dimethyl sulfoxide) in the presence of a base (such as potassium carbonate)) to give a compound of formula (Wa), which is then deprotected under standard nitrogen deprotection conditions to give a compound of formula (Ia).

[0221] Compounds of formula (Ih) are those in which q is 1 and R 3a and R 3b are hydrogen, and R 7 is azabicyclo[2.2.1]heptanylmethyl, and r, R 1 , R 2 , R 5 , and R 6 are compounds of Formula (I), as described above in the Summary of the Invention, each as defined in the Summary of the Invention, prepared as described below in Reaction Scheme 7, wherein m is 0-5, each X is independently fluoro, chloro, or bromo, and R 4b is fluoro and R 9is hydrogen or methyl, and Pg 1 is a nitrogen protecting group (such as 4-methoxybenzyl or 2-(trimethylsilyl)ethoxy): Reaction Scheme 7 [ka]

[0222] Compounds of formula (Y) are commercially available or can be prepared by methods known to those skilled in the art. Compounds of formula (C) and (Va) are prepared by methods described herein or known to those skilled in the art. In general, compounds of formula (Ih), as described above in Reaction Scheme 7, are prepared as follows:

[0223] Compounds of formula (Y) are first treated with a brominating agent under standard Appel reaction conditions to give compounds of formula (Z), which are then treated with azabicyclo[2.2.1]heptane under standard reaction conditions (such as, but not limited to, the use of a polar aprotic solvent (such as, but not limited to, dimethyl sulfoxide) in the presence of a base (such as, but not limited to, potassium carbonate) at a temperature between about 0° C. and 80° C. for about 1 to 48 hours) to give compounds of formula (AA). Compounds of formula (AA) are then treated under standard metal-halogen exchange / formylation / oxime formation conditions to give compounds of formula (BB), which are then treated under standard oxime reduction conditions to give compounds of formula (Ca). Compounds of formula (Ca) are then treated with compounds of formula (Va) under standard aromatic nucleophilic substitution conditions (such as, but not limited to, using a polar aprotic solvent (such as, but not limited to, dimethyl sulfoxide) in the presence of a base (such as, N,N-diisopropylethylamine) at a temperature between about 0°C and 80°C for about 1 to 48 hours) to give compounds of formula (Wa), which are then treated under standard nitrogen deprotection conditions to give compounds of formula (Ih).

[0224] R 8Compounds of formula (Ih) where is methyl are further treated under standard chiral resolution conditions, preferably by preparative supercritical fluid chromatography, to provide each enantiomer.

[0225] Compounds of formula (Ii) are those in which q is 1, r is 2, and R 3a and R 3b are hydrogen, and R 7 is ((methyl)(prop-2-yl)amino)methyl, and R 1 , R 2 , and R 5 are compounds of Formula (I), as described above in the Summary of the Invention, prepared as described below in Reaction Scheme 8, wherein X is independently fluoro, chloro, or bromo; and R 4c is chloro or bromo, and R 6a is the halo and R 8 is an alkyl: Reaction Scheme 8 [ka] Compounds of formula (S) and (Kb) are prepared as disclosed herein. Generally, compounds of formula (Ii), as described above in Reaction Scheme 8, are prepared as follows:

[0226] A compound of formula (S) is first reacted with a compound of formula (Kb) under standard aromatic nucleophilic substitution reaction conditions (a polar aprotic solvent such as dimethyl sulfoxide in the presence of a base such as N,N-diisopropylethylamine at a temperature between about 0° C. and 80° C. for about 1 to 48 hours). (including but not limited to the use of a methyl group such as methyltrimethylsilyl) to give compounds of formula (CC), which are then treated under standard nitrogen deprotection conditions to give compounds of formula (Ii).

[0227] Compounds of formula (Ij) and formula (Ik) are compounds in which q is 1, r is 2, and R 3a and R 3b are hydrogen, and R7 is ((methyl)(prop-2-yl)amino)methyl, and R 1 , R 2 , and R 5 are compounds of Formula (I), as described above in the Summary of the Invention, prepared as described below in Reaction Scheme 8, wherein X is independently fluoro, chloro, or bromo; and R 4c is chloro or bromo, and R 4d is alkyl, and R 6a is the halo and R 8 is an alkyl: Reaction Scheme 9 [ka] Compounds of formula (S) and (Kd) are prepared by methods similar to those described herein. Generally, compounds of formula (Ij), as described above in Reaction Scheme 9, are prepared as follows:

[0228] A compound of formula (S) is first treated with a compound of formula (Kd) under standard aromatic nucleophilic substitution reaction conditions (such as, but not limited to, using a polar aprotic solvent (such as, but not limited to, dimethyl sulfoxide) in the presence of a base (such as, N,N-diisopropylethylamine) at a temperature between about 0°C and 80°C for about 1 to 48 hours) to give a compound of formula (DD), which is then treated under standard nitrogen deprotection conditions to give a compound of formula (Ij).

[0229] Alternatively, the compound of formula (DD) can be reacted with a boronic acid derivative (R 4d-B(OH)2) under standard Suzuki-Miyaura cross-coupling conditions (such as, but not limited to, the use of a solvent such as, but not limited to, 1,4-dioxane in the presence of a base such as, but not limited to, tripotassium phosphate and a palladium catalyst such as, but not limited to, tetrakis(triphenylphosphine)palladium(0) or palladium(II) acetate and tricyclohexylphosphine tetrafluoroborate) at a temperature between about ambient temperature and 150°C for about 30 minutes to 16 hours to provide a compound of formula (EE), which is then deprotected under standard nitrogen deprotection conditions to provide a compound of formula (Ik).

[0230] All compounds prepared below that may exist in free base or free acid form can be converted into their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid. The salts of the compounds prepared below can be converted into their free base or acid form by standard techniques. Furthermore, all compounds of the present invention that contain an acid or ester group can be converted into the corresponding ester or acid, respectively, by methods known to those skilled in the art or by methods described herein.

[0231] The following examples of the synthesis of compounds of this invention, and the biological examples that follow, are provided as a guide to aid in the practice of the invention and are not intended as limitations on the scope of the invention.

[0232] In the following examples, all temperatures are listed in degrees Celsius unless otherwise indicated. Commercially available reagents were purchased from suppliers such as Aldrich Chemical Company, Combi-Blocks, TCI, or Oakwood Chemicals and used without further purification unless otherwise indicated. The reactions described below were generally carried out in anhydrous solvents under a positive pressure of nitrogen or argon, or using dry tubing (unless otherwise indicated), and reaction flasks were typically fitted with rubber septa for introduction of substrates and reagents via syringe. Glassware was oven-dried and / or heat-dried. Yields have not been optimized. Melting points were recorded using a Büchi hot-stage apparatus and are uncorrected. 1 H NMR, 19 F and 13 C NMR data were obtained in deuterated CDCI, DMSO-d, CD, CDCN, or acetone-d solvent solutions, and chemical shifts (δ) were reported in parts per million (ppm) relative to trimethylsilane (TMS) or the residual non-deuterated solvent peak as the reference standard. Data are reported as follows, where applicable: chemical shift, multiplicity, coupling constant in Hz, and number of protons, fluorines, or carbon atoms. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hz (Hertz). [Example]

[0233] Example 1 Synthesis of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)benzenesulfonamide [ka] Step 1. Preparation of 2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzonitrile [ka] To a solution of 2-(bromomethyl)-6-fluorobenzonitrile (6.95 g, 32.5 mmol) and 7-azabicyclo[2.2.1]heptane hydrochloride (4.35 g, 32.5 mmol) in anhydrous dimethyl sulfoxide (60 mL) was added potassium carbonate (9.0 g, 65.2 mmol). The resulting suspension was stirred at ambient temperature for 12 hours. The mixture was then diluted with ethyl acetate (400 mL) and water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 0 to 5% methanol in dichloromethane to give the title compound as a yellow oil (6.40 g, 86% yield): MS (ES+) m / z 231.2 (M+1).

[0234] Step 2. Preparation of (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine [ka] To a suspension of 2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzonitrile (6.40 g, 189 mmol) and Raney-Ni (3 mL of approximately 50% w / w aqueous slurry) in methanol (210 mL) was added 30% aqueous ammonium hydroxide (7.5 mL). The suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was then stirred under a hydrogen atmosphere (1 atm) at ambient temperature for 12 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane (250 mL), and the solution was dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave a residue that was further dried by azeotropic distillation with toluene (2 x 50 mL) to give the title compound as a brown syrup (6.70 g, quantitative yield), which was used without further purification: 1 H NMR (300 MHz, CDCl3) δ 7.09 (q, J = 7.2 Hz, 1H), 6.95 (t, J = 8.6 Hz, 2H), 3.87 (s, 2H), 3.53 (s, 2H), 3.17 (t, J = 2.0 Hz, 2H), 2.09 (s, 2H), 1.72 (dd, J = 0.7, 0.4 Hz, 4H), 1.28-1.25 (m, 4H); MS (ES+) m / z 235.2 (M + 1).

[0235] Step 3. Preparation of tert-butyl isothiazol-4-ylcarbamate [ka] To a stirred suspension of isothiazole-3-carboxylic acid (10.02 g, 77.6 mmol) in anhydrous tert-butanol (80 mL) and anhydrous toluene (120 mL) was slowly added triethylamine (13.0 mL, 93.12 mmol). The mixture was stirred at ambient temperature for 5 minutes, and then diphenylphosphoryl azide (18.42 mL, 85.36 mmol) was added dropwise to it. The reaction mixture was stirred at ambient temperature for 1 hour, gradually warmed to 85° C. over 1 hour, and then heated at 85° C. with stirring for 7 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (150 mL) and saturated aqueous sodium bicarbonate solution (150 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to give a residue that was purified by column chromatography eluting with a gradient of 0 to 10% ethyl acetate in heptane. Further purification by column chromatography eluting with a gradient of 0 to 10% ethyl acetate in dichloromethane gave the title compound as a colorless solid (10.33 g, 66% yield): 1 H NMR (400 MHz, CDCl3) δ 8.56 (dd, J = 4.9, 0.6 Hz, 1H), 8.11 (s, 1H), 7.66 (d, J = 4.9 Hz, 1H), 1.53 (s, 9H); MS (ES+) m / z 201.1 (M + 1).

[0236] Step 4. Preparation of 3-bromo-2,4,6-trifluorobenzenesulfonyl chloride [ka] To 2-bromo-1,3,5-trifluorobenzene (50.0 g, 236.0 mmol) was added chlorosulfonic acid (250 mL), and the reaction mixture was heated to 80° C. for 12 hours. After cooling to ambient temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate (2×500 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with petroleum ether to give the title compound as a yellow oil that solidified upon standing (51.0 g, 70% yield): 1 H NMR (400 MHz, CDCl3) δ 7.03 (ddd, J = 9.8, 7.8, 2.2 Hz, 1H).

[0237] Step 5. Preparation of tert-butyl ((3-bromo-2,4,6-trifluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate [ka] To a solution of tert-butyl isothiazol-3-ylcarbamate (6.03 g, 30.11 mmol) in anhydrous tetrahydrofuran (150 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (33 mL, 33.0 mmol). was added at −78° C. The reaction mixture was stirred at −78° C. for 10 minutes, then warmed to ambient temperature and stirred for 1 hour. After the reaction mixture was cooled to −78° C., a cooled (−78° C.) solution of 3-bromo-2,4,6-trifluorobenzenesulfonyl chloride (9.32 g, 30.11 mmol) in anhydrous tetrahydrofuran (150 mL) was added to it via cannula. The reaction mixture was warmed to ambient temperature and stirred for 16 hours. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (80 mL), and the aqueous layer was extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography eluting with a gradient of 0 to 10% ethyl acetate in heptane to give the title compound as a colorless solid (8.35 g, 59% yield):1 MS (ES +) m / z 472.8 (M + 1), 474.8 (M + 1).

[0238] Step 6. Preparation of tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-bromo-2,6-difluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate [ka] To a mixture of tert-butyl ((3-bromo-2,4,6-trifluorophenyl)sulfonyl)-(isothiazol-3-yl)carbamate (10.9 g, 23.03 mmol) and (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine (5.40 g, 23.03 mmol) in anhydrous dimethyl sulfoxide (95 mL) was added N,N-diisopropylethylamine (12.00 mL, 69.09 mmol) dropwise, and the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (80 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (250 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to give a residue that was dissolved in a minimum amount of dichloromethane. To this was then added heptane dropwise until the solution became cloudy, and the resulting mixture was triturated using an ultrasonic bath. The precipitate was collected by filtration, washed with heptane (25 mL), and dried to give the title compound (10.4 g, 66% yield) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J = 4.6 Hz, 1H), 7.31-7.29 (m, 1H), 7.28-7.21 (m, 1H), 7.08-6.98 (m, 2H), 6.54 (dd, J = 13.4, 1.7 Hz, 1H), 6.35-6.28 (m, 1H), 4.68-4.59 (m, 2H), 3.59 (s, 2H), 3.28-3.18 (m, 2H), 1.82 (br s, 4H), 1.44-1.17 (m, 13H); MS (ES +) m / z 687.2 (M + 1), 689.2 (M + 1).

[0239] Step 7. Preparation of tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate [ka] To a mixture of tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-bromo-2,6-difluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate (19.22 g, 27.95 mmol) and triethylamine (39.0 mL, 279.5 mmol) in anhydrous 1,4-dioxane (280 mL) was added formic acid (5.27 mL, 139.8 mmol), and the mixture was sparged with argon for 20 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (3.23 g, 2.80 mmol), and the reaction mixture was heated to 105° C. for 18 hours. After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (250 mL) and saturated aqueous sodium bicarbonate solution (150 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were filtered through a pad of Celite. The filtrate was washed with brine (150 mL) and dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo to give a residue which was triturated in ethanol (150 mL). The resulting solid was collected by filtration and purified by column chromatography eluting with a gradient of 0 to 20% methanol in dichloromethane to give the title compound as a colorless solid (8.81 g, 52% yield): MS (ES+) m / z 609.2 (M+1).

[0240] Step 8. Preparation of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)benzenesulfonamide [ka] To tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate (8.81 g, 14.47 mmol) was added ethanol (360 mL) and water (180 mL), and the reaction mixture was heated to reflux for 5 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in hot ethanol, and the resulting solution was concentrated in vacuo. The residue was triturated with ethanol to give the title compound as a colorless solid (7.098 g, 96% yield): 1 H NMR (300 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.90 (d, J = 4.7 Hz, 1H), 7.41-7.29 (m, 2H), 7.24-7.21 (m, 1H), 7.18-7.10 (m, 1H), 6.91 (d, J = 4.8 Hz, 1H), 6.40-6.31 (m, 2H), 4.47-4.31 (m, 2H), 3.53 (s, 2H), 3.11 (s, 2H), 1.75-1.52 (m, 4H), 1.32-1.12 (m, 4H); 13 C NMR (151 MHz, DMSO) δ 160.9, 160.6, 157.2, 153.5, 150.6, 141.7, 129.3, 125.7, 123.3, 114.2, 114.1, 102.7, 94.8, 58.8, 48.6, 36.9, 27.9; 19 F NMR (565 MHz, DMSO) δ -108.5, -117.7; MS (ES+) m / z 509.0 (M + 1).

[0241] Example 2 Synthesis of 2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide [ka] Step 1. Preparation of tert-butyl thiazol-4-ylcarbamate [ka] To a solution of thiazole-4-carboxylic acid (150.0 g, 1.16 mol) in anhydrous tert-butanol (1000 mL) was slowly added triethylamine (156.7 g, 1.55 mol) and diphenylphosphoryl azide (383.6 g, 1.39 mol). The reaction mixture was stirred at ambient temperature for 0.5 hours and then heated to 90° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with petroleum ether (1000 mL) and water (1000 mL), and the mixture was stirred at ambient temperature for 12 hours. The mixture was filtered, and the filter cake was extracted with ethyl acetate (3×1000 mL). The combined organic phase was washed with brine (3×1000 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give a residue which was triturated with methanol (200 mL) to give the title compound as a yellowish solid (100.0 g, 43% yield): 1 H NMR (400 MHz, CDCl3) δ 9.92 (br s, 1H), 8.65 (d, J = 2.4 Hz, 1H), 7.35 (br s, 1H), 1.57 (s, 9H); MS (ES+) m / z 223.0 (M + 23).

[0242] Step 2. Preparation of tert-butyl thiazol-4-yl((2,4,6-trifluorophenyl)sulfonyl)carbamate [ka] To a solution of tert-butyl thiazol-4-ylcarbamate (140.0 g, 699.1 mmol) in anhydrous tetrahydrofuran (700 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (758.9 mL, 758.9 mmol) at −78° C. The reaction mixture was warmed to 0° C. and stirred for 20 minutes. After the reaction mixture was cooled to −78° C., a solution of 2,4,6-trifluorobenzenesulfonyl chloride (175.0 g, 758.9 mmol) in anhydrous tetrahydrofuran (200 mL) was slowly added to it. The reaction mixture was warmed to ambient temperature, stirred for 12 hours, and then quenched by the addition of saturated aqueous ammonium chloride (200 mL). The mixture was extracted with ethyl acetate (3×1000 mL). The organic phase was washed with brine (3×1000 mL). The resulting mixture was concentrated in vacuo, dried over anhydrous sodium sulfate, filtered, and the residue was triturated in methanol (100 mL) to give the title compound as a colorless solid (140.0 g, 58% yield): 1 H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 2.1 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 6.85 (br t, J = 8.4 Hz, 2H), 1.39 (s, 9H); MS (ES+) m / z 417.0 (M + twenty three).

[0243] Step 3. Preparation of 2-bromo-3,6-difluorobenzaldehyde [ka] To a solution of 2-bromo-1,4-difluorobenzene (100 g, 518 mmol) in anhydrous tetrahydrofuran (500 mL) was added a solution of lithium diisopropylamide (61.1 g, 570 mmol) in anhydrous tetrahydrofuran (100 mL) over 30 minutes at −78° C. The reaction mixture was then stirred at −78° C. for 1 hour, and N,N-dimethylformamide (45.5 g, 622 mmol) was added thereto. The reaction mixture was stirred at −78° C. for 30 minutes and then quenched by the addition of saturated aqueous ammonium chloride solution (200 mL). The mixture was warmed to ambient temperature and extracted with ethyl acetate (500 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with 5% ethyl acetate in petroleum ether to give the title compound as a colorless oil (69.0 g, 60% yield): 1 H NMR (400MHz, CDCl3) δ 10.35-10.20 (m, 1H), 7.27 (ddd, J = 9.2, 7.4, 4.4 Hz, 1H), 7.08 (dt, J = 9.2, 4.0, Hz, 1H).

[0244] Step 4. Preparation of 2-bromo-3-fluoro-6-methoxybenzaldehyde [ka] To anhydrous methanol (750 mL) was added sodium metal (8.62 g, 375 mmol) slowly in portions over 1 hour. After the final addition, the mixture was stirred for an additional 10 minutes until all the sodium had dissolved. 2-Bromo-3,6-difluorobenzaldehyde (75.0 g, 341 mmol) was then added to the mixture, and the reaction mixture was heated to reflux for 20 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (800 mL) and washed with saturated aqueous ammonium chloride solution (2 x 400 mL). The aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to give a waxy yellow solid, which was used without further purification (82.6 g, quantitative yield): 1 H NMR (300 MHz, CDCl3) δ 10.39 (d, J = 0.8 Hz, 1H), 7.32-7.28 (m, 1H), 6.95 (dd, J = 9.2, 3.8 Hz, 1H), 3.94 (s, 3H).

[0245] Step 5. Preparation of N-(2-bromo-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine [ka] To a flask charged with 2-bromo-3-fluoro-6-methoxybenzaldehyde (82.6 g, 354.4 mmol), anhydrous dichloromethane (1500 mL), glacial acetic acid (1 mL), and N-methylpropan-2-amine (40 g, 459 mmol) were added. The reaction flask was placed in a 21°C water bath, and sodium cyanoborohydride (13.35 g, 212.6 mmol) was added to the reaction mixture in five portions (2.67 g), with 30-minute intervals between each addition. The reaction mixture was stirred at ambient temperature for 8 hours, after which additional N-methylpropan-2-amine (7.0 g, 96.0 mmol) was added thereto. The reaction mixture was stirred at ambient temperature for an additional 16 hours and then quenched by the addition of 1 M sodium hydroxide solution (200 mL). The layers were separated, and the volume of the organic phase was reduced to half in vacuo. The remaining organic phase was washed with 1 M sodium hydroxide solution (200 mL), brine (200 mL), and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate in vacuo gave a residue that was dissolved in ethyl acetate (400 mL) and extracted with 3 M hydrochloric acid (100 mL, 50 mL, and 30 mL). The combined aqueous layers were cooled to 0° C., the pH was adjusted to pH 12 with solid sodium hydroxide, and the aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with 1 M sodium hydroxide solution (100 mL), brine (200 mL), and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate in vacuo gave the title compound as a red oil (81.4 g, 79% yield), which was used without further purification: 1 H NMR (300 MHz, CDCl3) δ 7.02 (dd, J = 9.0, 8.0 Hz, 1H), 6.79 (dd, J = 9.0, 4.2 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 2H), 3.02 (dt, J = 13.2, 6.6 Hz, 1H), 2.20 (s, 3H), 1.13 (d, J = 6.6 Hz, 6H).

[0246] Step 6. Preparation of (E)-6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzaldehyde oxime [ka] Anhydrous tetrahydrofuran (140 mL) was added to a flask charged with N-(2-bromo-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine (10.0 g, 34.5 mmol). The solution was cooled to an internal temperature of 0 °C using an ice-water bath. The bath was removed, and a 1.3 M solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (53 mL, 69 mmol) was added dropwise via an addition funnel over 45 minutes. The reaction mixture was then stirred at ambient temperature for 10 minutes, and an additional solution of 1.3 M isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (53 mL, 69 mmol) was added dropwise over 45 minutes. The reaction mixture was stirred at ambient temperature for 30 minutes, and N,N-dimethylformamide (13 mL, 172.3 mmol) was added to it. After stirring at ambient temperature for 3 hours, a solution of hydroxylamine hydrochloride (14.4 g, 206.8 mmol) in water (40 mL) was added and the reaction mixture was stirred vigorously at ambient temperature for 16 hours. A brine / water mixture (1:1, 200 mL) was then added to the reaction mixture and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was The extract was washed with brine (2 x 50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to give a residue that was purified by column chromatography eluting with a gradient of 20 to 80% ethyl acetate (containing 10% 2-propanol and 10% triethylamine) in heptane to give the title compound as a yellow wax (6.20 g, 71% yield): 1 H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 7.00 (t, J = 9.6 Hz, 1H), 6.83 (dd, J = 9.1, 4.2 Hz, 1H), 3.82 (d, J = 3.2 Hz, 3H), 3.69 (s, 2H), 2.89 (t, J = 6.6 Hz, 1H), 2.10 (s, 3H), 1.10-1.06 (m, 6H), no OH observed.

[0247] Step 7. Preparation of N-(2-(aminomethyl)-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine [ka] To a flask charged with (E)-6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzaldehyde oxime (36.8 g, 145 mmol) was added glacial acetic acid (690 mL). To this was then added zinc powder (56 g, 868 mmol), and the reaction mixture was heated to 65° C. for 1 hour. To this was added a second portion of zinc powder (56 g, 868 mmol), and the reaction mixture was heated to 65° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was filtered through a bed of Celite, and the filter cake was washed with ethyl acetate (2×100 mL). The combined filtrate was concentrated in vacuo, and the residue was dissolved in ethyl acetate (500 mL). To the organic phase was added 5 M sodium hydroxide until the aqueous layer of the mixture reached pH 12. The aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to give the title compound as a red oil (36.4 g, quantitative yield) which was used without further purification: 1 H NMR (300 MHz, CDCl3) δ 6.95 (t, J = 9.1 Hz, 1H), 6.73 (dd, J = 9.0, 4.4 Hz, 1H), 3.84 (d, J = 2.2 Hz, 2H), 3.79 (s, 3H), 3.67 (s, 2H), 2.99-2.83 (m, 1H), 2.47-2.42 (m, 2H), 2.08 (s, 3H), 1.08 (d, J = 6.6 Hz, 6H).

[0248] Step 8. Preparation of tert-butyl ((2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)-amino)methyl)-3-methoxybenzyl)amino)phenyl)sulfonyl)(thiazol-4-yl)carbamate [ka] To a mixture of tert-butyl thiazol-4-yl((2,4,6-trifluorophenyl)sulfonyl)carbamate (26.26 g, 66.58 mmol) and N,N-diisopropylethylamine (23.2 mL, 133.2 mmol) in anhydrous dimethyl sulfoxide (190 mL) was added N-(2-(aminomethyl)-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine (21.00 g, 87.38 mmol). A solution of 2,4-dimethyl-3,4-dichloro-2 ... 1 H NMR (300 MHz, CDCl3) δ 8.79 (d, J = 2.3 Hz, 1H), 8.37 (s, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.02 (t, J = 9.0 Hz, 1H), 6.83 (dd, J = 9.2, 4.4 Hz, 1H), 6.20 (d, J = 12.1 Hz, 2H), 4.35 (s, 2H), 3.82 (s, 3H), 3.70 (s, 2H), 2.99-2.85 (m, 1H), 2.13 (s, 3H), 1.40 (s, 9H), 1.13 (d, J = 6.6 Hz, 6H); MS (ES+) m / z 615.2 (M + 1).

[0249] Step 9. Preparation of 2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide [ka] To a flask containing tert-butyl ((2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)-methyl)-3-methoxybenzyl)amino)phenyl)sulfonyl)(thiazol-4-yl)carbamate (19.67 g, 32.01 mmol) was added 2-butanol (100 mL) and water (40 mL). The slurry was degassed by sparging with nitrogen for 15 minutes and then heated to reflux for 24 hours. The suspension was then cooled to approximately 50° C. and diluted with ethanol (100 mL). The mixture was heated to reflux for an additional hour and then cooled to 35° C. The precipitate was collected by filtration and washed with ethanol (60 mL) to give the title compound as an off-white solid (15.09 g, 92% yield): 1 H NMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 7.42 (s, 1H), 7.14 (t, J = 9.2 Hz, 1H), 7.02 (dd, J = 9.2, 4.6 Hz, 1H), 6.88 (d, J = 2.2 Hz, 1H), 6.37 (d, J = 12.7 Hz, 2H), 4.36 (s, 2H), 3.77 (s, 3H), 3.58 (s, 2H), 2.83-2.70 (m, 1H), 1.98 (s, 3H), 0.95 (d, J = 6.6 Hz, 6H); MS (ES+) m / z 515.0 (M + 1).

[0250] Example 3 Synthesis of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide [ka] Step 1. tert-Butylthiazol-4-yl ((2,3,4-trifluorophenyl) Preparation of (( ... [ka] To a solution of tert-butyl thiazol-4-ylcarbamate (2.87 g, 14.3 mmol) in anhydrous tetrahydrofuran (50 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (14.3 mL, 14.3 mmol) at -50°C. The reaction mixture was warmed to 0°C and stirred for 1 hour. After cooling the reaction mixture to 0°C, a solution of 2,3,4-trifluorobenzenesulfonyl chloride (3.0 g, 13.0 mmol) in anhydrous tetrahydrofuran (60 mL) was slowly added to the reaction mixture. The reaction mixture was warmed to ambient temperature and stirred for 12 hours, then quenched by the addition of saturated aqueous ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 0-30% ethyl acetate in heptane to give the title compound as a colorless solid (4.34 g, 85% yield): 1 H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 2.2 Hz, 1H), 7.93 - 7.82 (m, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.11 (ddt, J = 2.2, 6.8, 9.0 Hz, 1H), 1.29 (s, 9H); MS (ES+) m / z 295.0 (M - 99).

[0251] Step 2. Preparation of tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate [ka] To a solution of (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine (1.19 g, 5.08 mmol) and tert-butyl thiazol-4-yl((2,3,4-trifluorophenyl)sulfonyl)carbamate (1.82 g, 4.62 mmol) in anhydrous dimethyl sulfoxide (35 mL) was added N,N-diisopropylethylamine (2.4 mL, 13.9 mmol). The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was then added dropwise to rapidly stirring aqueous ammonium chloride solution (500 mL), and the resulting precipitate was collected by filtration. The precipitate was dissolved in ethyl acetate (250 mL), washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography eluting with a gradient of 0 to 35% ethyl acetate (containing 10% 2-propanol and 10% trimethylamine) in heptane to give the title compound as a colorless solid (1.09 g, 39% yield): MS (ES+) m / z 609.1 (M+1).

[0252] Step 3. Preparation of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide [ka] To a suspension of tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (1.09 g, 1.79 mmol) in water (20 mL) was added ethanol (40 mL) and the reaction mixture was heated to 80° C. for 8 hours. The reaction mixture was filtered hot through a pad of Celite and then concentrated in vacuo to give a wet slurry. To this was added ethanol (750 mL) and the mixture was heated until a clear solution was obtained. Concentration in vacuo gave a residue which was redissolved in ethanol (750 mL). The residue obtained from concentration in vacuo was triturated with a minimum amount of ethanol to give the title compound as a colorless solid (0.85 g, 93% yield): 1 H NMR (300 MHz, DMSO-d6) δ 11.13-11.12 (m, 1H), 8.87 (d, J = 2.2 Hz, 1H), 7.46-7.40 (m, 1H), 7.32 (td, J = 7.8, 5.9 Hz, 1H), 7.18-7.12 (m, 3H), 6.96 (d, J = 2.2 Hz, 1H), 6.92-6.86 (m, 1H), 4.52-4.51 (m, 2H), 3.59 (s, 2H), 3.15 (s, 2H), 1.72-1.69 (m, 4H), 1.26 (d, J = 6.7 Hz, 4H); 19 F NMR (565 MHz, DMSO-d6) δ -116.6, -137.9, -160.7; MS (ES+) m / z 509.0 (M + 1), 510.0 (M + 1).

[0253] Example 4 Synthesis of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide [ka] Step 1. Preparation of 3-bromo-2,4,6-trifluoro-N-(isoxazol-3-yl)benzenesulfonamide [ka] To a mixture of isoxazol-3-amine (3.96 g, 47.2 mmol), 4-(dimethylamino)-pyridine (1.10 g, 9.00 mmol), and pyridine (9.09 mL, 112.5 mmol) in anhydrous dichloromethane (40 mL) was added a solution of 3-bromo-2,4,6-trifluorobenzene-1-sulfonyl chloride (14.0 g, 45.0 mmol) in anhydrous dichloromethane (50 mL) at 0° C. The reaction mixture was stirred for 1 hour at 50° C. ... Stirred at 0° C. for 0.5 h and at ambient temperature for 12 h. After concentration in vacuo, the residue was purified by column chromatography eluting with a gradient of 30 to 80% ethyl acetate in heptane to give the title compound as a colorless solid (6.65 g, 40% yield): 1 H NMR (400MHz, CDCl3) δ 8.31 (d, J = 1.8 Hz, 1H), 6.94 (ddd, J = 10.0, 7.8, 2.2 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H), NH was observed. figure; 19 F NMR (376 MHz, CDCl3) δ -90.8 (m, 1F), -96.0 (d, J = 9.2 Hz, 1F), -104.3 (d, J = 12.6 Hz, 1F).

[0254] Step 2. Preparation of 3-bromo-2,4,6-trifluoro-N-(isoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide [ka] To a mixture of 3-bromo-2,4,6-trifluoro-N-(isoxazol-3-yl)benzenesulfonamide (6.71 g, 18.8 mmol) and potassium carbonate (5.18 g, 37.6 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (3.76 g, 22.5 mmol) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 2 hours. The reaction mixture was then quenched by the addition of water (300 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography eluting with a gradient of 0 to 20% ethyl acetate in heptane to give the title compound as a yellow solid (8.24 g, 90% yield): 1 H NMR (400MHz, CDCl3) δ 8.31 (d, J = 1.8 Hz, 1H), 6.89 (ddd, J = 10.1, 7.8, 2.2 Hz, 1H), 6.65 (d, J = 1.8 Hz, 1H), 5.42 (s, 2H), 3.77-3.66 (m, 2H), 0.96-0.84 (m, 2H), 0.00 (s, 9H).

[0255] Step 3. Preparation of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-bromo-2,6-difluoro-N-(isoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide [ka] To a mixture of 3-bromo-2,4,6-trifluoro-N-(isoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (8.24 g, 16.9 mmol) and (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine (4.15 g, 17.8 mmol) in anhydrous dimethyl sulfoxide (150 mL) was added N,N-diisopropylethylamine (6.56 g / 8.8 mL, 50.7 mmol), and the reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was then slowly added to a rapidly stirring aqueous ammonium chloride solution (1500 mL), and the resulting precipitate was collected by filtration. The precipitate was then dissolved in ethyl acetate (500 mL). The organic phase was washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluting with a gradient of 0 to 20% ethyl acetate (containing 10% 2-propanol and 10% trimethylamine) in heptane to give the title compound as a colorless solid (6.23 g, 53% yield): MS (ES+) m / z 701.0 (M+1), 703.0 (M+1).

[0256] Step 4. Preparation of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide [ka] To a suspension of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-bromo-2,6-difluoro-N-(isoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)-methyl)benzenesulfonamide (5.33 g, 7.60 mmol) and tripotassium phosphate (9.7 g, 45.6 mmol) in anhydrous 1,4-dioxane (190 mL) was added methylboronic acid (3.64 g, 60.8 mmol), and the mixture was degassed by sparging with argon for 15 minutes. To this was then added tetrakis(triphenylphosphine)palladium(0) (0.88 g, 0.76 mmol), and the reaction mixture was heated to 90° C. for 4 hours. After cooling to ambient temperature, the reaction mixture was filtered through a plug of Celite. The filter cake was washed with 1,4-dioxane (2 x 50 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 0 to 15% ethyl acetate (containing 10% 2-propanol and 10% trimethylamine) in heptane to give the title compound as a colorless solid (4.01 g, 83% yield): 1 H NMR (300 MHz, DMSO-d6) δ 8.82 (d, J = 1.8 Hz, 1H), 7.35-7.28 (m, 1H), 7.23-7.20 (m, 1H), 7.14-7.07 (m, 1H), 6.64-6.54 (m, 3H), 5.28 (s, 2H), 4.54 (dd, J = 4.6, 0.3 Hz, 2H), 3.57 (dd, J = 17.7, 9.7 Hz, 4H), 3.11 (dd, J = 0.9, 0.5 Hz, 2H), 1.88 (d, J = 2.0 Hz, 3H), 1.68-1.64 (m, 4H), 1.24-1.22 (m, 4H), 0.81 (t, J = 8.0 Hz, 2H), -0.06 (s, 9H); MS (ES+) m / z 637.2 (M + 1).

[0257] Step 5. 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl Preparation of (N-(6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide [ka] To a mixture of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (6.33 g, 9.94 mmol) in 1,2-dichloroethane (300 mL) was added trifluoroacetic acid (35 mL, 400 mmol), and the reaction mixture was stirred at ambient temperature for 4 hours. After concentration in vacuo, the residue was purified by column chromatography eluting with a gradient of 0-50% ethyl acetate in heptane, followed by a gradient of 0-15% methanol in dichloromethane, to afford the title compound as its trifluoroacetate salt as a colorless solid. This material was dissolved in dichloromethane (500 mL) and washed with saturated aqueous sodium bicarbonate (2×200 mL). The combined aqueous layers were extracted with dichloromethane (3 x 200 mL). The combined organic layers were partially concentrated, then diluted with an equal volume of acetone and further concentrated. After repeating this partial concentration and dilution with acetone procedure four times, the organic phase was concentrated to dryness. The residual solid was triturated with acetone to give the title compound as a colorless solid (3.10 g, 62% yield): 1 H NMR (300 MHz, DMSO-d6) δ 11.43-11.31 (m, 1H), 8.62 (d, J = 1.5 Hz, 1H), 7.34 (dt, J = 7.8, 5.8 Hz, 1H), 7.26-7.23 (m, 1H), 7.18-7.11 (m, 1H), 6.51 (d, J = 14.0 Hz, 1H), 6.41-6.37 (m, 1H), 6.28 (d, J = 1.8 Hz, 1H), 4.50-4.49 (m, 2H), 3.64 (s, 2H), 3.29-3.26 (m, 2H), 1.89 (d, J = 1.9 Hz, 3H), 1.74-1.68 (m, 4H), 1.31-1.26 (m, 4H); 19 F NMR (565 MHz, DMSO) δ -111.0, -112.2, -116.9; MS (ES+) m / z 507.1 (M + 1).

[0258] Example 5 Synthesis of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide 2,2,2-trifluoroacetate [ka] Step 1. Preparation of tert-butyl ((3-bromo-2,4-difluorophenyl)sulfonyl)(isoxazol-3-yl)carbamate [ka] To a solution of tert-butyl isoxazol-3-ylcarbamate (3.81 g, 20.7 mmol) in anhydrous tetrahydrofuran (160 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (26 mL, 26.0 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 10 minutes, then warmed to ambient temperature and stirred for 1 hour. After the reaction mixture was cooled to −78° C., a cooled (−78° C.) solution of 3-bromo-2,4-difluorobenzenesulfonyl chloride (6.00 g, 20.7 mmol) in anhydrous tetrahydrofuran (100 mL) was added to it via cannula. The reaction mixture was warmed to ambient temperature and stirred for 16 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and quenched by the addition of saturated aqueous ammonium chloride (100 mL). The aqueous layer was separated and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by trituration in diethyl ether (20 mL) to give the title compound as a pale yellow solid (3.50 g, 39% yield): 1 H NMR (300 MHz, DMSO-d6) δ 9.14 (d, J = 1.8 Hz, 1H), 8.16 (ddd, J = 9.1, 8.1, 5.8 Hz, 1H), 7.63 (ddd, J = 9.2, 7.8, 1.5 Hz, 1H), 6.97 (t, J = 1.6 Hz, 1H), 1.30 (s, 9H); 19 F NMR (282 MHz, DMSO-d6) δ -93.4, -98.0; MS (ES+) m / z 438.9 (M + 1), 441.0 (M + 1).

[0259] Step 2. Preparation of tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-bromo-2-fluorophenyl)sulfonyl)(isoxazol-3-yl)carbamate [ka] To a mixture of tert-butyl ((3-bromo-2,4-difluorophenyl)sulfonyl)(isoxazol-3-yl)carbamate (0.439 g, 1.00 mmol) and (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine (0.258 g, 1.10 mmol) in anhydrous dimethyl sulfoxide (10 mL) was added N,N-diisopropylethylamine (0.522 mL, 3.00 mmol) dropwise, and the reaction mixture was stirred at ambient temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (150 mL) and aqueous ammonium chloride solution (50 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (3×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound as a yellow solid (0.269 g, 41% yield), which was used without further purification: MS (ES+) m / z 653.2 (M+1), 655.2 (M+1)).

[0260] Step 3. Preparation of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide 2,2,2-trifluoroacetate [ka] To a suspension of tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-bromo-2-fluorophenyl)sulfonyl)(isoxazol-3-yl)carbamate (0.269 g, 0.412 mmol) and tripotassium phosphate (0.350 g, 1.65 mmol) in anhydrous 1,4-dioxane (10 mL) was added methylboronic acid (0.148 g, 2.47 mmol), and the mixture was degassed by sparging with argon for 15 minutes. To this was then added tetrakis(triphenylphosphine)palladium(0) (0.047 g, 0.041 mmol), and the reaction mixture was heated to 90° C. for 4 hours. After cooling to ambient temperature, the reaction mixture was filtered through a plug of Celite. The filter cake was washed with 1,4-dioxane (2 x 50 mL), and the combined filtrates were concentrated in vacuo. The resulting residue was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) under a nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative reverse-phase HPLC using aqueous acetonitrile containing 0.1% trifluoroacetic acid as an eluent to give the title compound as a colorless solid (0.057 g, 22% yield): 1 H NMR (300 MHz, DMSO-d6) δ 11.52 (s, 1H), 9.55-9.52 (m, 1H), 8.67 (d, J = 1.8 Hz, 1H), 7.60-7.32 (m, 4H), 6.60 (d, J = 9.0 Hz, 1H), 6.36-6.32 (m, 2H), 4.48 (td, J = 1.2, 0.5 Hz, 2H), 4.35-4.33 (m, 2H), 4.14 (s, 2H), 2.20-2.16 (m, 2H), 1.97-1.90 (m, 5H), 1.76-1.67 (m, 4H); MS (ES+) m / z 489.1 (M + 1).

[0261] Example 6 Synthesis of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] Step 1. Preparation of tert-butyl ((3-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate [ka] To a solution of tert-butyl N-thiazol-4-ylcarbamate (110 g, 549 mmol) in tetrahydrofuran (1000 mL) was added lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 659 mL, 659 mmol) at −78° C. After warming the mixture to 5° C., a cooled (−78° C.) solution of 3-chloro-2,4-difluorobenzenesulfonyl chloride (163 g, 659 mmol) in tetrahydrofuran (300 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride (200 mL) and extracted with ethyl acetate (3×1000 mL). The combined organic layers were washed with brine (3×1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with methanol (300 mL) to give the title compound as a colorless solid (75 g, 33% yield): 1 H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.26-8.09 (m, 1H), 8.03 (s, 1H), 7.66 (t, J = 8.6 Hz, 1H), 1.27 (s, 9H); MS (ES+) m / z 432.8 (M + 23), 434.8 (M + 23).

[0262] Step 2. Preparation of tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate [ka] To a suspension of tert-butyl ((3-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (0.410 g, 1.00 mmol) and (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine (0.258 g, 1.10 mmol) in anhydrous dimethyl sulfoxide (10 mL) was added N,N-diisopropylethylamine (0.522 mL, 3.00 mmol), and the reaction mixture was stirred at ambient temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (150 mL) and aqueous ammonium chloride solution (50 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (3×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a yellow solid (0.338 g, 54% yield), which was used without further purification: MS (ES+) m / z 625.2 (M+1), 627.2 (M+1).

[0263] Step 3. Preparation of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] To a solution of tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (0.200 g, 0.320 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (10 mL) and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by preparative reverse-phase HPLC using aqueous acetonitrile containing 0.1% trifluoroacetic acid as eluent to afford the title compound as a colorless solid (0.102 g, 50% yield): 1 H NMR (300 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.61-9.57 (m, 1H), 8.88 (d, J = 2.2 Hz, 1H), 7.60 (t, J = 8.5 Hz, 1H), 7.53-7.31 (m, 3H), 6.98 (d, J = 2.2 Hz, 1H), 6.90-6.87 (m, 1H), 6.72 (d, J = 9.1 Hz, 1H), 4.56-4.55 (m, 2H), 4.37-4.36 (m, 2H), 4.16 (d, J = 0.3 Hz, 2H), 2.21-2.18 (m, 2H), 1.94-1.91 (m, 2H), 1.77-1.66 (m, 4H); MS (ES+) m / z 525.1 (M + 1), 527.1 (M + 1).

[0264] Example 7 Synthesis of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] To a microwave vial was added tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (0.138 g, 0.221 mmol), potassium phosphate tripotassium (0.141 g, 0.663 mmol), methylboronic acid (0.106 g, 1.77 mmol), tricyclohexylphosphine tetrafluoroborate (0.275 g, 0.75 mmol), and anhydrous 1,4-dioxane (4 mL). The resulting suspension was degassed by sparging with argon for 15 minutes, after which palladium(II) acetate (0.007 g, 0.033 mmol) was added to it. The vial was sealed and then heated to 120°C in a microwave reactor for 3 hours. After cooling to ambient temperature, the reaction mixture was filtered through a plug of Celite. The filter cake was washed with 1,4-dioxane (2 x 50 mL), and the combined filtrates were concentrated in vacuo. The resulting residue was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added thereto. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative reverse-phase HPLC using aqueous acetonitrile containing 0.1% trifluoroacetic acid as an eluent to give the title compound as a colorless solid (0.043 g, 31% yield): 1 H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.50 (ddd, J = 2.6, 1.4, 0.7 Hz, 1H), 8.86 (d, J = 2.2 Hz, 1H), 7.55-7.32 (m, 4H), 6.88 (d, J = 2.2 Hz, 1H), 6.56 (d, J = 8.9 Hz, 1H), 6.27-6.24 (m, 1H), 4.46 (dd, J = 2.5, 0.7 Hz, 2H), 4.33 (d, J = 4.9 Hz, 2H), 4.13 (d, J = 0.4 Hz, 2H), 2.19-2.15 (m, 2H), 1.96 (d, J = 1.8 Hz, 3H), 1.96-1.89 (m, 2H), 1.75-1.66 (m, 4H); MS (ES+) m / z 505.1 (M + 1).

[0265] Example 8 Synthesis of 2,6-difluoro-4-((6-fluoro-3-isopropoxy-2-((isopropyl(methyl)amino)methyl)benzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide [ka] Step 1. Preparation of 2-bromo-3-fluoro-6-hydroxybenzaldehyde [ka] To a solution of 2-bromo-3-fluoro-6-methoxybenzaldehyde (5.0 g, 21.5 mmol) in anhydrous dichloromethane (100 mL) was added boron tribromide (2.5 mL, 25.8 mmol) slowly at −78° C. The reaction was then warmed to ambient temperature and stirred for 18 hours. The solution was cooled to 0° C. and quenched by the addition of saturated aqueous ammonium chloride (100 mL). The aqueous layer was extracted with dichloromethane (2×100 mL), and the combined organic layers were washed with brine (2×50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography eluting with 0 to 100% ethyl acetate in heptane to afford the title compound as a colorless oil (2.35 g, 50% yield): 1 H NMR (300 MHz, DMSO-d6) δ 11.37-11.31 (m, 1H), 10.23 (d, J = 16.2 Hz, 1H), 7.58 (dd, J = 9.1, 8.5 Hz, 1H), 7.05 (dd, J = 9.2, 4.3 Hz, 1H).

[0266] Step 2. Preparation of 2-bromo-3-fluoro-6-isopropoxybenzaldehyde [ka] To a mixture of 2-bromo-3-fluoro-6-hydroxybenzaldehyde (1.41 g, 6.44 mmol) and potassium carbonate (2.67 g, 19.3 mmol) in anhydrous N,N-dimethylformamide (35 mL) was added 2-iodopropane (0.77 mL, 7.73 mmol), and the reaction was heated to 60° C. for 18 hours. The reaction was then cooled to ambient temperature and diluted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL), and the combined organic layers were washed with brine (2×50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography eluting with a gradient of 5 to 60% ethyl acetate in heptane to afford the title compound as a yellow oil (1.68 g, quantitative yield): 1 H NMR (300 MHz, CDCl3) δ 10.39 (d, J = 1.2 Hz, 1H), 7.29-7.24 (m, 1H), 6.96 (dd, J = 9.2, 3.9 Hz, 1H), 4.61 (sept, J = 6.1 Hz, 1H), 1.39 (d, J = 6.0 Hz, 6H).

[0267] Step 3. Preparation of N-(2-bromo-3-fluoro-6-isopropoxybenzyl)-N-methylpropan-2-amine [ka] To a mixture of 2-bromo-3-fluoro-6-isopropoxybenzaldehyde (1.67 g, 6.44 mmol) and N-methylpropan-2-amine (1.3 mL, 12.88 mmol) in anhydrous dichloromethane (32 mL) was added sodium triacetoxyborohydride (6.25 g, 29.6 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and then quenched by the addition of saturated aqueous ammonium chloride solution (50 mL). The aqueous layer was extracted with dichloromethane (3 × 50 mL), and the combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluting with a gradient of 0 to 20% methanol in dichloromethane to give the title compound as a colorless oil (2.05 g, quantitative yield): MS (ES+) m / z 318.0 (M+1), 320.0 (M+1).

[0268] Step 4. Preparation of (E)-6-fluoro-3-isopropoxy-2-((isopropyl(methyl)amino)methyl)benzaldehyde oxime [ka] Anhydrous tetrahydrofuran (13 mL) was added to a flask containing N-(2-bromo-3-fluoro-6-isopropoxybenzyl)-N-methylpropan-2-amine (2.05 g, 6.44 mmol), and the mixture was cooled to an internal temperature of 0 °C using an ice-water bath. To this was then added a 1.3 M solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (9.7 mL, 19.32 mmol). The reaction mixture was stirred at 0 °C for 30 minutes, and a second aliquot of a 1.3 M solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (9.7 mL, 19.32 mmol) was added to this. The reaction mixture was stirred at 0 °C for 30 minutes, after which anhydrous N,N-dimethylformamide (5 mL, 64.4 mmol) was added to this. The reaction mixture was warmed to ambient temperature and stirred for 45 minutes. To this was then added 50% aqueous hydroxylamine hydrochloride (4.3 mL, 64.4 mmol), and the reaction mixture was vigorously stirred at ambient temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL), and the combined organic layers were washed with brine (100 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography eluting with a gradient of 10 to 70% ethyl acetate in heptane (containing 10% 2-propanol and 10% triethylamine) to give the title compound as a colorless solid (0.778 g, 43% yield): MS (ES+) m / z 283.2 (M+1).

[0269] Step 5. Preparation of N-(2-(aminomethyl)-3-fluoro-6-isopropoxybenzyl)-N-methylpropan-2-amine [ka] To (E)-6-fluoro-3-isopropoxy-2-((isopropyl(methyl)amino)methyl)benzaldehyde oxime (0.778 g, 2.75 mmol) was added glacial acetic acid (14 mL), and the mixture was stirred for 15 minutes and then cooled in an ice-water bath. To this was then added zinc powder (1.07 g, 16.5 mmol), and the reaction mixture was heated to 60° C. for 1.5 hours. After cooling to ambient temperature, the reaction mixture was filtered, and the filter cake was washed with dichloromethane (3×50 mL). The combined organic filtrate was washed with saturated aqueous sodium bicarbonate solution (3×100 mL), brine (100 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to give the title compound as an orange wax (0.498 g, 67% yield), which was used without further purification: 1 H NMR (300 MHz, CDCl3) δ 7.05-6.97 (m, 1H), 6.84-6.79 (m, 1H), 4.56-4.49 (m, 1H), 4.14-4.09 (m, 2H), 3.91-3.84 (m, 2H), 3.53-3.48 (m, 2H), 3.14-3.05 (m, 1H), 2.28-2.24 (m, 3H), 1.38-1.30 (m, 6H), 1.17-1.08 (m, 6H).

[0270] Step 6. Preparation of 2,6-difluoro-4-((6-fluoro-3-isopropoxy-2-((isopropyl(methyl)amino)methyl)benzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide [ka] To a mixture of tert-butyl thiazol-4-yl((2,4,6-trifluorophenyl)sulfonyl)carbamate (0.729 g, 1.85 mmol) and N-(2-(aminomethyl)-3-fluoro-6-isopropoxybenzyl)-N-methylpropan-2-amine (0.498 g, 1.85 mmol) in anhydrous dimethyl sulfoxide (9 mL) was added N,N-diisopropylethylamine (1.0 mL, 5.55 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The mixture was then diluted with ethyl acetate (50 mL) and saturated aqueous ammonium chloride solution (50 mL). The aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo and purified by column chromatography eluting with a gradient of 5 to 60% ethyl acetate in heptane (containing 10% 2-propanol and 10% triethylamine) to give a colorless oil. The oil was then dissolved in dichloromethane (10 mL) and trifluoroacetic acid (2 mL) was added thereto. The reaction mixture was stirred at ambient temperature for 18 hours and then concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 10 to 80% ethyl acetate in heptane (containing 20% ​​ethanol and 2% saturated ammonium hydroxide) to give the title compound as a colorless solid (0.304 g, 31% yield): 1 H NMR (300 MHz, DMSO-d6) δ 11.22-11.08 (m, 1H), 8.89 (d, J = 2.2 Hz, 1H), 7.45-7.42 ( m, 1H), 7.17-7.09 (m, 1H), 7.07-7.00 (m, 1H), 6.89 (d, J = 2.2 Hz, 1H), 6.38-6.33 (m, 2H), 4.64-4.55 (m, 1H), 4.35-4.33 (m, 2H), 3.66-3.58 (m, 2H), 2.88-2.62 (m, 1H), 2.09-2.01 (m, 3H), 1.26 (d, J = 6.0 Hz, 6H), 1.01-0.97 (m, 6H); MS (ES+) m / z 543.1 (M + 1).

[0271] Example 9 Synthesis of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] Step 1. Preparation of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide [ka] To a mixture of 2,4,6-trifluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide (0.44 g, 1.07 mmol, prepared according to PCT Publication WO 2018 / 106284) and (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine (0.25 g, 1.07 mmol) in anhydrous dimethyl sulfoxide (10 mL) was added potassium carbonate (0.30 g, 2.14 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with water (40 mL), brine (40 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 0 to 40% ethyl acetate (containing 10% isopropanol and 10% triethylamine) in hexane to give the title compound as a colorless solid (0.38 g, 56% yield): MS (ES+) m / z 629.3 (M+1).

[0272] Step 2. Preparation of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] To a solution of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide (0.38 g, 0.75 mmol) in anhydrous dichloromethane (3 mL) was added trifluoroacetic acid (3 mL) and the reaction mixture was heated to reflux for 16 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 0 to 10% methanol in dichloromethane to give the title compound as a colorless solid (0.29 g, 62% yield): 1 H NMR (300 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.56 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 7.59-7.30 (m, 4H), 6.92 (d, J = 2.1 Hz, 1H), 6.41-6.32 (m, 2H), 4.39-4.06 (m, 6H), 2.22-2.06 (m, 2H), 2.01-1.86 (m, 2H), 1.78-1.57 (m, 4H); MS (ES+) m / z 509.1 (M + 1).

[0273] Example 10 Synthesis of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide [ka] Step 1. Preparation of 2-bromo-3-(bromomethyl)-1,4-difluorobenzene [ka] To a solution of (2-bromo-3,6-difluorophenyl)methanol (10.75 g, 48.20 mmol, prepared according to PCT Publication No. WO 2018 / 106284) in anhydrous dichloromethane (150 mL) at 0° C. was added carbon tetrabromide (25.58 g, 77.12 mmol) and triphenylphosphine (15.17 g, 57.84 mmol). The reaction mixture was stirred at 0° C. for 2 hours and then concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 0 to 10% ethyl acetate in heptane to afford the title compound as a colorless oil (8.51 g, 62% yield): 1 H NMR (300 MHz, CDCl3): δ 7.14-7.01 (m, 2H), 4.66-4.61 (m, 2H); MS (ES+) m / z 286.0 (M + 1), 288.0 (M + 1).

[0274] Step 2. Preparation of 7-(2-bromo-3,6-difluorobenzyl)-7-azabicyclo[2.2.1]heptane [ka] 2-(bromomethyl)-6-fluorobenzonitrile was prepared according to the procedure described in Example 1, Step 1. A minor modification was required to replace tolyl with 2-bromo-3-(bromomethyl)-1,4-difluorobenzene to give the title compound as a colorless solid (5.15 g, 98% yield): MS (ES+) m / z 302.0 (M+1), 304.0 (M+1).

[0275] Step 3. Preparation of (E)-2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzaldehyde oxime [ka] Following the procedure described in Example 2, Step 6, with minor modifications required to replace N-(2-bromo-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine with 7-(2-bromo-3,6-difluorobenzyl)-7-azabicyclo[2.2.1]heptane, the title compound was obtained as a colorless solid (1.02 g, 97% yield): MS (ES+) m / z 267.2 (M+1).

[0276] Step 4. Preparation of (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorophenyl)methanamine [ka] To a solution of (E)-2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzaldehyde oxime (0.53 g, 1.98 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C. was added a 1 M solution of lithium aluminum hydride in tetrahydrofuran (4.0 mL, 4.0 mmol). The reaction mixture was stirred at 0° C. for 15 minutes and at ambient temperature for 16 hours, then heated to reflux for 30 minutes. The reaction mixture was cooled to 0° C., and sodium sulfate decahydrate (4.0 g) was added thereto in portions. The reaction mixture was stirred at 0° C. for 30 minutes and then at ambient temperature for 1.5 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (2×10 mL). The combined filtrates were dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate in vacuo afforded the title compound as a brown oil (0.45 g, 90% yield): MS (ES+) m / z 253.2 (M+1).

[0277] Step 5. Preparation of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide [ka] Following the procedure described in Example 9, Step 1, with minor modifications necessary to replace (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine with (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorophenyl)methanamine, the title compound was obtained as a colorless solid (0.19 g, 16% yield): MS (ES+) m / z 647.2 (M+1).

[0278] Step 6. Preparation of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide [ka] Following the procedure described in Example 9, Step 2, with minor modifications necessary to replace 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide with 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide, gave the title compound as a colorless solid (0.096 g, 52% yield): 1 H NMR (300 MHz, DMSO-d6) δ 11.18 (br s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 7.46-7.21 (m, 3H), 6.90 (d, J = 2.2 Hz, 1H), 6.42-6.30 (m, 2H), 4.51-4.39 (m, 2H), 3.61 (br s, 2H), 3.13 (br s, 2H), 1.68 (br s, 4H), 1.29 (br s, 4H); MS (ES+) m / z 527.1 (M + 1).

[0279] Example 11 Synthesis of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] Step 1. Preparation of (2-bromo-3-fluoro-6-methoxyphenyl)methanol [ka] To a solution of 2-bromo-3-fluoro-6-methoxybenzaldehyde (4.19 g, 17.98 mmol) in anhydrous methanol (37 mL) was added sodium borohydride (1.36 g, 35.96 mmol) in portions at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then concentrated in vacuo. The residue was dissolved in saturated aqueous ammonium chloride (100 The resulting mixture was diluted with 1 mL of ethyl acetate (3×60 mL) and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with water (50 mL), brine (60 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (4.23 g, quantitative yield): MS (ES+) m / z 258.0 (M+1), 259.8 (M+1).

[0280] Step 2. Preparation of 2-bromo-3-(bromomethyl)-1-fluoro-4-methoxybenzene [ka] Following the procedure described in Example 10, Step 1, with minor modifications necessary to replace (2-bromo-3,6-difluorophenyl)methanol with (2-bromo-3-fluoro-6-methoxyphenyl)methanol, the title compound was obtained as a colorless solid (2.85 g, 53% yield): 1H NMR (300 MHz, CDCl3) δ 7.12-7.03 (m, 1H), 6.84-6.78 (m, 1H), 4.75-4.70 (m, 2H), 3.90 (s, 3H).

[0281] Step 3. Preparation of 7-(2-bromo-3-fluoro-6-methoxybenzyl)-7-azabicyclo[2.2.1]-heptane [ka] Following the procedure described in Example 1, Step 1, with minor modifications required to replace 2-(bromomethyl)-6-fluorobenzonitrile with 2-bromo-3-(bromomethyl)-1-fluoro-4-methoxybenzene, the title compound was obtained as a colorless solid (2.09 g, 70% yield): MS (ES+) m / z 314.0 (M+1), 316.0 (M+1).

[0282] Step 4. Preparation of (E)-2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzaldehyde oxime [ka] Following the procedure described in Example 2, Step 6, with minor modifications required to replace N-(2-bromo-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine with 7-(2-bromo-3-fluoro-6-methoxybenzyl)-7-azabicyclo[2.2.1]heptane, the title compound was obtained as a colorless solid (1.9 g, 51% yield): MS (ES+) m / z 279.2 (M+1).

[0283] Step 5. (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)- Preparation of 6-fluoro-3-methoxyphenyl)methanamine [ka] Following the procedure described in Example 2, Step 7, with minor modifications necessary to replace (E)-6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzaldehyde oxime with (E)-2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzaldehyde oxime, the title compound was obtained as a colorless solid (0.84 g, 46% yield): MS (ES+) m / z 265.2 (M+1).

[0284] Step 6. Preparation of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide [ka] Following the procedure described in Example 9, Step 1, with minor modifications necessary to replace (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine with (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxyphenyl)methanamine, the title compound was obtained as a colorless solid (0.13 g, 21% yield): MS (ES+) m / z 659.2 (M+1).

[0285] Step 7. Preparation of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] Following the procedure described in Example 9, Step 2, with minor modifications necessary to replace 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide with 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide, the title compound was obtained as a colorless solid (0.096 g). , yield 75%): 1 H NMR (300 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.18 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 7.40-7.31 (m, 1H), 7.20-7.12 (m, 1H), 6.91 (d, J = 2.1 Hz, 1H), 6.58 (s, 1H), 6.40-6.31 (m, 2H), 4.39-4.29 (m, 2H), 4.24-4.01 (m, 4H), 3.86 (s, 3H), 2.26-2.09 (m, 2H), 1.97-1.81 (m, 2H), 1.77-1.51 (m, 4H); MS (ES+) m / z 539.1 (M + 1).

[0286] Example 12 Synthesis of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] Step 1. Preparation of tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate [ka] To a mixture of tert-butyl thiazol-4-yl((2,3,4-trifluorophenyl)sulfonyl)carbamate (0.39 g, 0.99 mmol) and (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxyphenyl)methanamine (0.26 g, 0.99 mmol) in anhydrous dimethyl sulfoxide (10 mL) was added potassium carbonate (0.27 g, 1.98 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluting with a gradient of 0 to 40% ethyl acetate (containing 10% isopropanol and 10% triethylamine) in hexane to give the title compound as a colorless solid (0.12 g, 19% yield): MS (ES+) m / z 639.2 (M+1).

[0287] Step 2. Preparation of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] To a solution of tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (0.12 g, 0.19 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.72 mL, 9.39 mmol). The reaction mixture was stirred at ambient temperature for 3 hours and then concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 0 to 10% methanol in dichloromethane to give the title compound as a colorless solid (0.101 g, 81% yield): 1 H NMR (300 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.07-8.84 (m, 2H), 7.49-7.41 (m, 1H), 7.37-7.29 (m, 1H), 7.19-7.10 (m, 1H), 7.09-7.01 (m, 1H), 6.99 (d, J = 2.2 Hz, 1H), 6.81-6.72 (m, 1H), 4.51-4.41 (m, 2H), 4.30-3.95 (m, 4H), 3.85 (s, 3H), 2.28-2.06 (m, 2H), 1.93-1.55 (m, 6H); MS (ES+) m / z 539.0 (M + 1).

[0288] Example 13 Synthesis of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(isothiazol-3-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] Step 1. Preparation of tert-butyl isothiazol-3-yl((2,3,4-trifluorophenyl)sulfonyl)-carbamate [ka] Following the procedure described in Example 1, Step 5, with minor modifications necessary to replace 3-bromo-2,4,6-trifluorobenzenesulfonyl chloride with 2,3,4-trifluorobenzenesulfonyl chloride, the title compound was obtained as a colorless solid (2.74 g, 46% yield): MS (ES+) m / z 395.0 (M+1).

[0289] Step 2. Preparation of tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate [ka] To a mixture of tert-butyl isothiazol-3-yl((2,3,4-trifluorophenyl)sulfonyl)carbamate (0.51 g, 1.30 mmol) and (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine (0.31 g, 1.30 mmol) in anhydrous dimethyl sulfoxide (13 mL) was added potassium carbonate (0.36 g, 2.60 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluting with a gradient of 0 to 40% ethyl acetate in hexanes (containing 10% isopropanol and 10% triethylamine) to give the title compound as a colorless solid (0.144 g, 18% yield): MS (ES+) m / z 609.4 (M+1).

[0290] Step 3. Preparation of 4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(isothiazol-3-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] Following the procedure described in Example 12, Step 2, with minor modifications necessary to replace tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate with tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate, gave the title compound as a colorless solid (0.146 g, 96% yield): 1 H NMR (300 MHz, DMSO-d6) δ 11.69 (s, 1H), 9.30 (s, 1H), 8.91 (d, J = 4.7 Hz, 1H), 7.59-7.51 (m, 1H), 7.49-7.43 (m, 1H), 7.40-7.27 (m, 2H), 7.15-7.07 (m, 1H), 6.94-6.92 (m, 1H), 6.86-6.76 (m, 1H), 4.49 (dd, J = 3.8, 0.4 Hz, 2H), 4.30-4.12 (m, 2H), 4.08-3.87 (m, 2H), 2.22-1.82 (m, 4H), 1.75-1.49 (m, 4H); MS (ES+) m / z 509.0 (M + 1).

[0291] Example 14 4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazole-4 Synthesis of (-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] Step 1. Preparation of 1-(2-bromo-3,6-difluorophenyl)ethan-1-ol [ka] To a solution of 2-bromo-3,6-difluorobenzaldehyde (1 g, 4.53 mmol) in anhydrous diethyl ether was slowly added a solution of 3 M methylmagnesium bromide in diethyl ether (2 mL, 589 mmol) at −10° C. The reaction mixture was stirred at −10° C. for 3 hours, after which an additional solution of 3 M methylmagnesium bromide in diethyl ether (4.53 mL, 13.59 mmol) was added dropwise to it. The reaction mixture was stirred at −10° C. for 1 hour and then poured portionwise into stirred saturated aqueous ammonium chloride solution at 0° C. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography eluting with a gradient of 0 to 20% ethyl acetate in hexane to give the title compound as a colorless oil (0.97 g, 91% yield): 1 H NMR (300 MHz, CDCl3) δ 7.07-6.99 (m, 2H), 5.41-5.30 (m, 1H), 2.56-2.44 (m, 1H), 1.65-1.59 (m, 3H); MS (ES+) m / z 260.2 (M + 23), 262.1 (M+23).

[0292] Step 2. Preparation of 2-bromo-3-(1-bromoethyl)-1,4-difluorobenzene [ka] Following the procedure described in Example 10, Step 1, with minor modifications necessary to replace (2-bromo-3,6-difluorophenyl)methanol with 1-(2-bromo-3,6-difluorophenyl)ethan-1-ol, the title compound was obtained as a colorless solid (8.24 g, 65% yield): 1 H NMR (300 MHz, CDCl3) δ 7.12-6.99 (m, 2H), 5.72-5.57 (m, 1H), 2.18-2.04 (m, 3H).

[0293] Step 3. Preparation of 7-(1-(2-bromo-3,6-difluorophenyl)ethyl)-7-azabicyclo[2.2.1]heptane [ka] To a mixture of 2-bromo-3-(1-bromoethyl)-1,4-difluorobenzene (4.2 g, 14.0 mmol) and 7-azabicyclo[2.2.1]heptane hydrochloride (1.87 g, 14.0 mmol) in anhydrous dimethyl sulfoxide (25 mL) was added potassium carbonate (3.87 g, 28.0 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and then at 80° C. for 4 hours. The reaction mixture was cooled to ambient temperature, diluted with water (100 mL), and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluting with a gradient of 0 to 10% methanol in dichloromethane to give the title compound as a pale yellow oil (2.83 g, 64% yield): MS (ES+) m / z 316.1 (M+1), 318.1 (M+1).

[0294] Step 4. Preparation of (E)-2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzaldehyde oxime [ka] Following the procedure described in Example 2, Step 6, with minor modifications necessary to replace N-(2-bromo-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine with 7-(1-(2-bromo-3,6-difluorophenyl)ethyl)-7-azabicyclo[2.2.1]heptane, the title compound was obtained as a colorless solid (0.635 g, 27% yield): MS (ES+) m / z 281.2 (M+1).

[0295] Step 5. Preparation of (2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorophenyl)methanamine [ka] Following the procedure described in Example 2, Step 7, with minor modifications necessary to replace (E)-6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzaldehyde oxime with (E)-2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzaldehyde oxime, the title compound was obtained as a pale yellow oil (0.53 g, 88% yield): MS (ES+) m / z 267.2 (M+1).

[0296] Step 6. tert-Butyl ((4-((2-(1-(7-azabicyclo[2.2.1] Preparation of heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate [ka] To a mixture of tert-butyl thiazol-4-yl((2,4,6-trifluorophenyl)sulfonyl)carbamate (0.77 g, 1.95 mmol) and (2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorophenyl)methanamine (0.52 g, 1.95 mmol) in anhydrous dimethyl sulfoxide (20 mL) was added N,N-diisopropylethylamine (1.02 mL, 5.85 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluting with a gradient of 0 to 40% ethyl acetate (containing 10% isopropanol and 10% triethylamine) in hexane to give the title compound as a colorless solid (0.58 g, 46% yield): MS (ES+) m / z 641.3 (M+1).

[0297] Step 7. Preparation of 4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] Following the procedure described in Example 12, Step 2, with minor modifications necessary to replace tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate with tert-butyl ((4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate, gave the title compound as a colorless solid (0.47 g, 83% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.24 (s, 1H), 9.49-9.34 (m, 1H), 8.90 (d, J = 2.2 Hz, 1H), 7.57-7.44 (m, 2H), 7.45-7.36 (m, 1H), 6.92 (d, J = 2.2 Hz, 1H), 6.45-6.31 (m, 2H), 4.47-4.11 (m, 4H), 3.60 (s, 1H), 2.28-2.08 (m, 2H), 1.98-1.47 (m, 9H); MS (ES+) m / z 541.3 (M + 1).

[0298] Examples 15A and 15B (S)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazolinone) Synthesis of (R)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide [ka]

[0299] To a mixture of 4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate (0.100 g, 0.153 mmol) in ethyl acetate (50 mL) and water (10 mL) was added aqueous ammonium hydroxide (0.2 mL of a 25-28% solution). The reaction mixture was stirred at 25 °C for 30 min. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by supercritical carbon dioxide and Chiralpak with 30% ethanol (containing 0.1% ammonium hydroxide) as eluent. Purification and resolution by preparative supercritical fluid chromatography using an AS column (250 × 30 mm, 5 μm) gave (S)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide (colorless solid, 0.014 g, 17% yield, 99% ee) as the first-eluting enantiomer and (R)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide (colorless solid, 0.015 g, 18% yield, 96% ee) as the second-eluting enantiomer. The absolute configuration was arbitrarily assigned. Data for (S)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide: 1 H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.97-7.00 (m, 2H), 6.10-6.13 (m, 2H), 4.72 (d, J = 13.6 Hz, 1H), 4.43 (dd, J = 13.6, 2.8 Hz, 1H), 4.13-4.19 (m, 1H), 3.62 (brs, 1H), 2.93 (m, 1H), 1.90-1.96 (m, 2H), 1.72-1.78 (m, 2H), 1.41-1.43 (m, 4H), 1.28-1.37 (m, 3H), 2 No NH observed; 19 F NMR (376 MHz, CDCl3) δ -107.8 (s, 2F), -119.0 (d, J = 17.6, 1F), -119.6 (d, J = 17.5, 1F); MS (ES+) m / z 541.4 (M + 1). (R)-4-((2-(1-(7-azabicyclo[2.2.1]heptane) Data for (3,6-difluorobenzyl)ethyl)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide: 1 H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.90-7.00 (m, 2H), 6.10-6.13 (m, 2H), 4.72 (d, J = 13.6 Hz, 1H), 4.42 (dd, J = 13.6, 2.8 Hz, 1H), 4.13-4.18 (m, 1H), 3.62 (brs, 1H), 2.93 (m, 1H), 1.90-1.96 (m, 2H), 1.72-1.78 (m, 2H), 1.41-1.43 (m, 4H), 1.28-1.37 (m, 3H), 2 No NH observed; 19 F NMR (376 MHz, CDCl3) δ -107.7 (s, 2F), -119.0 (d, J = 17.5, 1F), -119.6 (d, J = 17.4, 1F); MS (ES+) m / z 541.4 (M + 1).

[0300] Example 16 Synthesis of 2,3-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide [ka] Step 1. Preparation of tert-butyl ((2,3-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)phenyl)sulfonyl)(thiazol-4-yl)carbamate [ka] Following the procedure described in Example 12, Step 1, with minor modifications necessary to replace (2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxyphenyl)methanamine with N-(2-(aminomethyl)-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine, the title compound was obtained as a colorless solid (0.06 g, 12% yield): MS (ES+) m / z 615.2 (M+1).

[0301] Step 2. Preparation of 2,3-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide [ka] Following the procedure described in Example 12, Step 2, with minor modifications necessary to replace tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate with tert-butyl ((2,3-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)phenyl)sulfonyl)(thiazol-4-yl)carbamate, gave the title compound as a colorless solid (0.059, 97%): 1 H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.88 (d, J = 2.2 Hz, 1H), 7.69 (s, 1H), 7.47-7.38 (m, 1H), 7.26-7.13 (m, 1H), 7.09-7.01 (m, 1H), 6.99-6.95 (m, 1H), 6.89-6.76 (m, 1H), 4.52-4.37 (m, 2H), 3.95-3.61 (m, 5H), 2.91 (br s, 1H), 2.09 (br s, 3H), 1.08 (br s, 6H); M S (ES+) m / z 515.1 (M + 1).

[0302] Example 17 Synthesis of 5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] Step 1. Preparation of tert-butyl ((5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)phenyl)sulfonyl)(thiazol-4-yl)carbamate [ka] To a mixture of tert-butyl ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (0.85 g, 2.08 mmol, prepared according to U.S. Patent Application Publication No. 2017 / 0334902) and N-(2-(aminomethyl)-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine (0.50 g, 2.08 mmol) in anhydrous dimethyl sulfoxide (17 mL) was added N,N-diisopropylethylamine (1.09 mL, 6.24 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, and filtered. After concentration in vacuo, the residue was purified by column chromatography eluting with a gradient of 0 to 40% ethyl acetate (containing 10% isopropanol and 10% triethylamine) in hexane to give the title compound as a colorless solid (0.60 g, 46% yield): MS (ES+) m / z 631.1 (M+1), 633.1 (M+1).

[0303] Step 2. Preparation of 5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] Following the procedure described in Example 12, Step 2, tert-butyl ((4-((2-((7- Minor modifications were required to replace azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate with tert-butyl ((5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)phenyl)sulfonyl)(thiazol-4-yl)carbamate to afford the title compound as a colorless solid (0.139, 90%): 1 H NMR (300 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.88 (d, J = 2.2 Hz, 1H), 8.42 (s, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.42-7.36 (m, 1H), 7.21-7.09 (m, 1H), 7.00 (t, J = 1.9 Hz, 1H), 6.86-6.78 (m, 1H), 6.75-6.71 (m, 1H), 4.59-4.36 (m, 3H), 4.21-4.06 (m, 1H), 3.83 (s, 3H), 3.68-3.54 (m, 1H), 2.59 (d, J = 4.3 Hz, 3H), 1.33 (dd, J = 15.4, 6.4 Hz, 6H); MS (ES+) m / z 531.0 (M + 1), 533.0 (M + 1).

[0304] Example 18 Synthesis of 2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] Step 1. Preparation of tert-butyl ((2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-5-methylphenyl)sulfonyl)(thiazol-4-yl)carbamate [ka] To a mixture of tert-butyl ((5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)phenyl)sulfonyl)(thiazol-4-yl)carbamate (0.26 g, 0.41 mmol) and methylboronic acid (0.196 g, 3.28 mmol) in anhydrous 1,4-dioxane (10 mL) was added potassium phosphate tribasic (0.21 g, 1.24 mmol), and the mixture was purged with argon for 20 minutes. To this was then added tricyclohexylphosphonium tetrafluoroborate (0.45 g, 0.12 mmol) and palladium(II) acetate (0.014 g, 0.062 mmol), and the resulting mixture was heated at 105 °C. After cooling to ambient temperature, the reaction mixture was filtered through a pad of Celite. The filter pad was washed with ethyl acetate (20 mL), and the combined filtrates were concentrated in vacuo. The resulting residue was diluted with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography eluting with a gradient of 0 to 10% methanol in dichloromethane to afford the title compound as a light brown oil (0.25 g, quantitative yield): MS (ES+) m / z 611. 1(M+1).

[0305] Step 2. Preparation of 2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate [ka] Following the procedure described in Example 12, Step 2, with minor modifications necessary to replace tert-butyl ((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate with tert-butyl ((2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-5-methylphenyl)sulfonyl)(thiazol-4-yl)carbamate, gave the title compound as a colorless solid (0.131, 51%): 1 H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.86 (d, J = 2.2 Hz, 1H), 8.42 (s, 1H), 7.44-7.35 (m, 2H), 7.19-7.12 (m, 1H), 6.88 (d, J = 2.2 Hz, 1H), 6.49 (d, J = 13.7 Hz, 1H), 6.28-6.21 (m, 1H), 4.50-4.30 (m, 3H), 4.18-4.05 (m, 1H), 3.84 (s, 3H), 3.66-3.52 (m, MS (ES+) m / z 511.1 (M + 1).

[0306] Biological assays Various techniques are known in the art for testing the activity of the compounds of the present invention or for determining their solubility in known pharmaceutically acceptable excipients. In order to more fully understand the invention described herein, the following biological assays are described. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the present invention in any way.

[0307] Biological Example 1 Electrophysiological assays (in vitro assays) Patch voltage clamp electrophysiology is used to measure voltage-gated sodium channels (Na V ) block and allows for the determination of the time- and voltage-dependence of block, which has been interpreted as differential binding to the resting, open, and inactivated states of the sodium channel (Hille, B., Journal of General Physiology (1977), 69:497-515).

[0308] The following patch voltage clamp electrophysiology studies can be performed on representative compounds of the present invention using human embryonic kidney (HEK) cells permanently transfected with an expression vector containing a full-length cDNA encoding the desired human sodium channel α-subunit and grown at 37°C in 5% CO2 in culture medium containing 10% FBS, 1% PSG, and 0.5 mg / mL G418. HEK cells used for electrophysiology (EP) recordings have a passage number of less than 40 for all studies and are used within 3 days from the time of plating. Na V 1.1, Na V 1.5 and Na V 1.6 cDNAs (NM_001165964 (SCN1A), NM_000335 (SCN5A), and NM_014191 (SCN8A) respectively) were stably expressed in HEK-293 cells. do.

[0309] Sodium currents are measured using the patch clamp technique, either in the whole-cell configuration, using a PatchXpress automated voltage clamp, or manually using an Axopatch 200B (Axon Instruments) or Model 2400 (AM Systems) amplifier. The manual voltage clamp protocol is as follows: Borosilicate glass micropipettes are fire-polished to a tip diameter that provides a resistance of 2-4 Mohm in the working solution. The pipettes are filled with a solution consisting of 5 mM NaCl, 10 mM CsCl, 120 mM CsF, 0.1 mM CaCl, 2 mM MgCl, 10 mM HEPES, and 10 mM EGTA, adjusted to pH 7.2 with CsOH. The external solution has the following composition: 140 mM NaCl, 5 mM KCl, 2 mM CaCl, 1 mM MgCl, and 10 mM HEPES; the pH is adjusted to 7.4 with NaOH. In some studies, the external solution is reduced by replacing it with an equimolar amount of choline. The osmolarity of the CsF internal solution and the NaCl external solution can be adjusted to 300 mOsm / kg and 310 mOsm / kg, respectively, with glucose. All recordings are performed at ambient temperature in a batch chamber with a volume of 150 μL. Control sodium currents are measured in 0.5% DMSO. Control compounds and representative compounds of the present invention are introduced into the recording chamber through a 4-pinch or 8-pinch valved batch perfusion system manufactured by ALA Scientific Instruments.

[0310] Currents were recorded at a sampling frequency of 40 kHz, filtered at 5 Hz, and stored using a Digidata-1322A analog / digital interface with pClamp software (Axon Instruments). DC resistance compensation was applied (60-80%). Cells were excluded if the current showed poor voltage control (as judged by the IV relationship during stepwise activation). All statistics in this study are given as mean ± SD.

[0311] The membrane potential is maintained at the voltage at which channel inactivation is complete. This voltage is then stepped back to a very negative voltage (Vhold=-150 mV) for 20 ms, and then a test pulse is applied to quantify compound blockade. The brief repolarization of 20 ms is long enough for compound-free channels to fully recover from the rapid inactivation, but compound-bound channels recover more slowly, so negligible recovery may occur during this interval. The percentage decrease in sodium current after compound washout is considered to be the percentage blockade of the sodium channel.

[0312] Biological Example 2 Sodium influx assay (in vitro assay) This sodium influx assay employs the use of the cell-permeable sodium-sensitive dye ANG2 to quantify the influx of sodium ions through sodium channels that are maintained open by the use of sodium channel modulators. This high-throughput sodium influx assay allows for the rapid profiling and characterization of sodium channel blockers.

[0313] Briefly, Trex HEK293 cells were stably transfected with an inducible expression vector containing a full-length cDNA encoding the desired human sodium channel α-subunit and an expression vector containing a full-length cDNA encoding the β1-subunit. The sodium channel-expressing cell lines were induced with tetracycline (1 μg / mL) and plated onto 384-well PDL-coated plates at a density of 25K-30K cells / well in culture medium (DMEM containing 10% FBS and 1% L-glutamine). After overnight incubation (37°C, 5% CO), the culture medium was removed, and cells were loaded with 5 μM ANG2 dye for 1–1.5 h in Buffer 1 (155 mM NMDG, 5 mM KCl, 2 mM CaCl, 1 mM MgCl, 10 mM HEPES, 10 mM glucose, pH 7.4 with Tris). The Access dye was removed, and cells were incubated with test compounds in Buffer 1 containing sodium channel modulators for 1 h at room temperature. A 1:1 addition of Na / K challenge buffer (140 mM NaCl, 20 mM HEPES, 1 mM CaCl, 15 mM KCl, 1 mM MgCl, 10 mM glucose, pH 7.4 with Tris) was performed, and the plate was read using a Hamamatsu FDSS μCell with an excitation wavelength of 530 nm and an emission wavelength set at 558 nm. The percent inhibition of sodium ion influx was calculated for each test compound at each test concentration and expressed as IC 50 value was determined.

[0314] Representative compounds of the present invention, when tested in this model, exhibited Na V 1.6, Na V 1.5 and Na V It showed an affinity for the inactivated state of 1.1.

[0315] The example numbers provided in Table 1 correspond to the example numbers herein, and "flux" refers to the sodium influx assay. [Table 1]

[0316] Biological Example 3 Electrical stimulation seizure assay Many electrostimulation seizure tests have been used to identify compounds with anticonvulsant activity, i.e., that trigger the seizure threshold. Two examples of electrostimulation seizure assays frequently used in the field are the 6 Hz psychomotor seizure assay (6 Hz) and the maximal electroshock seizure (MES) assay. The 6 Hz assay is considered a model of partial seizures observed in humans (Loescher, W. and Schmidt, D., Epilepsy Res. (1988), Vol. 2, pp. 145-81; Barton, ME et al., Epilepsy Res. (2001), Vol. 47, pp. 217-27). The MES assay is a model of generalized tonic-clonic seizures in humans and provides an indication of a compound's ability to prevent seizure spread when all neural circuits in the brain are most active. These seizures are highly reproducible and electrophysiologically consistent with human seizures (Toman et al., 1946; Piredda et al., 1984; White et al., 1995). Experiments can be performed using healthy animals or seizure-prone animals that have been genetically modified to model inherited epilepsy syndromes (Piredda, SG et al., J. Pharmacol. Exp. Ther. (1985), 232, 741-5; Toman, JE et al., J. Neurophysiol. l. (1946), Vol. 9, pp. 231-9; and White, HS et al., Ital. J. Neurol. Sci. (1995), Vol. 16(1-2), pp. 73-7).

[0317] To facilitate testing, mice can be pretreated with the test compound or an appropriate vehicle before administering the electric shock. Each treatment group (n = 4-8 mice / group) is examined for anticonvulsant activity at various time points after compound and vehicle administration. First, 30 minutes before stimulation, the eyes of the mice are anesthetized by topically applying one drop of 0.5% Alcaine (proparacaine hydrochloride) to each eye. Seizures are then induced by placing electrodes in the eyes that deliver a transcorneal current.

[0318] 6Hz Psychomotor Seizure Test: After pretreatment, each mouse is challenged with a 3-second low-frequency (6 Hz, 0.3 ms pulse width) stimulus delivered through corneal electrodes at several intensities (12-44 mA). Animals are manually restrained, immediately released after stimulation, and observed for the presence or absence of seizure activity. Typically, 6 Hz stimulation produces a seizure characterized by a minimal clonic phase followed by typical motility (including vibrissa twitching and tail lift) or by generalized tonic-clonic seizures. The presence, type, and latency (in seconds) of seizures after current application are monitored. Animals that do not exhibit clonic or generalized tonic-clonic seizures are considered "protected." All animals are euthanized at the end of the assay. Plasma and brain samples are collected.

[0319] Maximum Electric Shock Test (MES): After pretreatment, each mouse is challenged for 0.2-0.5 seconds with an alternating current (60 Hz, 0.4-0.6 ms pulse width) delivered through corneal electrodes at a high intensity (44-55 mA).

[0320] Typically, MES stimulation produces generalized tonic seizures, possibly followed by clonic seizures, locomotor behavior, and tail lift. The presence, type, and latency (in seconds) of seizures after current application are monitored. Animals are considered "protected" from MES-induced seizures upon abolition of the hindlimb tonic extensor component of the seizures. After the seizures, mice are expected to regain normal exploratory behavior within 1 to 4 minutes. Seizure latency is recorded with a 1-minute cutoff, after which all animals are euthanized.

[0321] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referenced herein are hereby incorporated by reference in their entirety.

[0322] Although the foregoing invention has been described in some detail for ease of understanding, it will be apparent that certain changes and modifications can be practiced within the scope of the appended claims. Therefore, the described embodiments are illustrative and not restrictive, and the invention is not to be limited to the details shown herein, but may be modified within the scope of the appended claims and their equivalents.

Claims

[Claim 1] Epilepsy.

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