Benzenesulfonamide compounds and their use as therapeutic agents

Abstract

To provide benzenesulfonamide compounds and their use as therapeutic agents.SOLUTION: This invention is directed to benzenesulfonamide compounds (which are compounds as stereoisomers, enantiomers or tautomers thereof or mixtures thereof), or pharmaceutically acceptable salts, solvates or prodrugs thereof, for treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy. Of this embodiment, a preferred compound is 4-((1-benzylazetidin-3-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzene-sulfonamide.SELECTED DRAWING: None

Description

Technical Field

[0001] Field of the Invention The present invention relates to benzenesulfonamide compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and pharmaceutical compositions in the treatment of sodium channel-mediated diseases or conditions (such as epilepsy and / or epilepsy seizure disorders) and other diseases and conditions associated with sodium channel mediation.

Background Art

[0002] Background of the Invention Voltage-gated sodium channels (Na V ) are important determinants of cell 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 account for most of the sodium current in neurons of the central nervous system. Na V 1.3 is mainly expressed in embryos. After the neonatal period, Na V 1.1, Na V 1.2, and Na V 1.6 are important isoforms that regulate neuronal signaling in the brain (Catterall, W.A., Annual Review of Pharmacology and Toxicology (2014), Vol. 54, pp. 317-338).

[0003] Na V 1.5 is mainly expressed in cardiomyocytes (including atria, ventricles, sinoatrial node, atrioventricular node, and Purkinje fibers of the heart) (Raymond, C.K. et al., J. Biol. Chem. (2004), Vol. 279, No. 44, pp. 46234-41). Human Na VThe 1.5 mutation results in a number of arrhythmia syndromes (e.g., QT3 prolongation (LQT3), Brugada syndrome (BS), hereditary cardiac conduction defect, sudden unexplained nocturnal death syndrome (SUNDS), and sudden infant death syndrome (SIDS)) (Liu, H. et al., Am. J. Pharmacogenomics (2003), Vol. 3, No. 3, pp. 173-19). Sodium channel blocker therapy is widely used in treating cardiac arrhythmias.

[0004] 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 disrupted. This can occur due to either excessive excitation or a lack of inhibition. Mutations in genes encoding Na V channels are associated with both types of imbalance.

[0005] Na V 1.1 has been identified as a major Na V isoform in inhibitory interneurons (Yu, F. H. et al., Nat. Neurosci. (2006), Vol. 9, pp. 1142-1149). These interneurons form synapses 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 suppressing excitation. This provides negative feedback that allows for controlled signaling and prevents the spread of excitatory waves from local signals to large areas of the brain. Due to this important role of inhibitory interneurons, mutations that impair Na V 1.1 channel function can result in these neurons failing to activate and release GABA (Ogiwara, I. et al., J. Neurosci. (2007), Vol. 27, pp. 5903-5914; Martin, M. S. et al., J. Biol. Chem. (2010), Vol. 285, pp. 9823-9834; Cheah, C. S. et al., Channels (Austin) (2013), Vol. 7, pp. 468-472; and Dut Ton, S. B., et al. (2013), Volume 49, pp. 211 - 220). The results are a loss of the brain's inhibitory tone and a failure to contain the excitability of glutamatergic neurons. This failure of inhibitory interneurons can lead to abnormally widespread synchronous excitation (seizures) of neurons across brain regions.

[0006] Na V Mutations in the gene (SCN1A) encoding Na1.1 fall into two broad classes, namely, those that cause generalized epilepsy with febrile seizures plus (GEFS+) and those that cause severe myoclonic epilepsy in infancy (SMEI) (also known as Dravet syndrome or early infantile epileptic encephalopathy 6 (EIEE6)) (McKusik, V. K., et al., A Epileptic Encephalopathy, Early Infantile 6, EIEE6 (2012), Online Mendelian Inheritance in Man: John Hopkins University). SMEI mutations are heterozygous autosomal dominant mutations 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, F. N., et al., Epilepsy Research (2015), Volume 113, pp. 5 - 10). Patients are born with a normal phenotype and reach developmental milestones until the onset of seizures (typically between 6 months and 1 year of age). This point of onset is thought to be the result of the normal decline in the expression of embryonic isoform Na V 1.3 and the concomitant increase in Na V 1.1. Na V1.1 When the channels do not reach normal levels, this phenotype becomes apparent (Cheah, C.S. et al., Channels (Austin) (2013), Vol. 7, pp. 468 - 472). The first seizures are often induced by febrile episodes and can present as status epilepticus. The seizures persist over the first few years of life, increasing in frequency and severity, and can reach a frequency of over 100 episodes per day. The seizures can be induced by heat or occur spontaneously without an obvious 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). 80 - 85% of patients diagnosed with the Dravet syndrome phenotype are thought to have causative mutations within SCN1A, while the other 15 - 20% of patients have other mutations or the etiology is unknown. In SMEI patients, sudden unexpected death in epilepsy (SUDEP) is highly prevalent, with an estimated 37% of patients dying from SUDEP, but the mechanisms underlying this devastating outcome remain uncertain (Massey, C.A. et al., Nature Reviews Neurology (2014), Vol. 10, pp. 271 - 282). Clinically useful anti - epileptic drugs that non - selectively target voltage - dependent sodium channels, such as carbamazepine and phenytoin, are contraindicated in SMEI patients because these drugs can exacerbate seizures in these patients (Wilmshurst, J.M. et al., Epilepsia (2015), Vol. 56, pp. 1185 - 1197). This is presumably because patients cannot tolerate a further decrease in Na V 1.1 function.

[0007] GEFS+ is often caused by missense SCN1A mutations that induce relatively mild channel dysfunction consistent with a relatively mild seizure phenotype. A number of increasing mutations have been identified, and both the severity and penetrance of the phenotype vary considerably. Many GEFS+ patients escape the seizure phenotype, but not all, and GEFS+ patients with childhood epilepsy are significantly more prone to epilepsy as adults than the general population. Mutations that cause deficiencies in other genes involved in GABAergic signaling (such as SCN1B, which encodes an auxiliary subunit of the sodium channel, and GABRG2, which encodes a subunit of the GABA A receptor) can also cause GEFS+ (Helbig, I., Seminars in N eurology (2015) Volume 35, pages 288 - 292).

[0008] Transgenic mice carrying the same mutations identified in SMEI patients and GEFS+ patients have been developed. In both cases, these mice replicate the human phenotype well, but the penetrance of this phenotype can be significantly affected by the genetic background. Several mouse strains are relatively resistant to this mutation, while in other backgrounds, the same mutation can cause a severe seizure phenotype. These differences are presumed to be due to different levels of expression of other genes that regulate the excitatory phenotype (Miller, A.R. et al., Genes, Brain, and Behavior (2014), Volume 13, pages 163 - 172; Mistry, A.M. et al., Neurobiology of Disease (2014), Volume 65, pages 1 - 11; and Hawkins, N.A. et al., Epilepsy Research (2016), Volume 119, pages 20 - 23).

[0009] In the brain, Na V 1.2 and Na V1.6 is mainly expressed in excitatory glutamatergic neurons. Both channels are particularly enriched in the initial segment of the axon (AIS), a region of the neuron adjacent to the cell body that functions to integrate inputs and initiate the propagation of action potentials to this cell body and distal dendrites (Royeck, M. et al., J. Neurophysiol. (2008), Vol. 100, pp. 2361-2380; Vega, A.V. et al., Neurosci. Lett. (2008), Vol. 442, pp. 69-73; and Hu, W. et al., Nat. Neurosci. (2009), Vol. 12, pp. 996-1002). Na V 1.6 tends to be particularly enriched in the initial AIS (distal from the cell body), where it is thought to function to trigger the initiation of action potentials. Na V 1.2 is more highly localized in the segment of the AIS closest to the cell body. SCN2A (Na V 1.2) and SCN8A (Na V 1.6), mutations in both have been linked to epilepsy and cognitive delay. The effects of these mutations vary both in terms of the level of impact on channel function and the patient phenotype. Na V 1.2 and Na V 1.6 are also expressed in peripheral neurons. Na V 1.6 is particularly enriched at the nodes of Ranvier of myelinated neurons, where it is important for maintaining healthy and high-speed neuronal signaling.

[0010] Only a few Na V1.2 Only mutations are described, and these are mainly associated with pathologies of the central nervous system, particularly 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, L.S. 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 presumably originally an increase in functional mutations. That is, these mutations result in an increase in the amount of sodium current, thereby increasing excitability. There is no reasonable doubt that it is difficult to establish the in vivo effect on channel function, and several of these mutations can still result in a loss of the functional phenotype.

[0011] Mutations in SCN8A similarly show some increase and loss of functional impact on the Na V 1.6 channel, although most of the mutations tested have been associated with an increase in the functional phenotype. For Na V 1.6, most of the mutations tested have been associated with an increase in the functional phenotype. VThe mutations at 1.6 have been associated with epilepsy and autism spectrum disorder (Trudeau, M.M. et al., Journal of Medical Genetics (2006), Vol. 43, pp. 527-530; Veeramah, K.R. et al., Am. J. Hum. Genet. (2012), Vol. 90, pp. 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), Vol. 69, pp. 117-123; Ohba, C. et al., Epilepsia (2014), Vol. 55, pp. 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 most well-characterized 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 often have developmental and cognitive delays, as well as movement disorders that are frequently associated with chronic hypotonia. The most severely affected patients never achieve sufficient motor control for walking. Many do not speak. Less severe phenotypes learn to walk and talk, but have movement disorders and impairment of cognitive and social milestones. Most of the identified mutations are missense mutations, and the specific functional effects of these mutations are presumed to contribute to the phenotypic variability, although the genetic background is also likely involved (Larsen, J. et al., Neurology (2015), Vol. 84, pp. 480-489).In contrast to SMEI patients, anecdotal evidence suggests that antiepileptic drugs that non-selectively target voltage-gated sodium channels may improve the symptoms of EIEE13 patients, but controlled clinical trials have not been completed (Boerma, R.S. et al., Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics (2016), Vol. 13, pp. 192-197). Phenytoin appears to be effective for EIEE13 patients, but at a great cost. Efficacy is achieved only at very high doses, while significant adverse effects are tolerated only when patients are in such immediate need. Adverse effects commonly associated with phenytoin treatment include hepatic necrosis, hirsutism, nervousness, hand tremors, tingling, dizziness, drowsiness, tremors, depression, confusion, fatigue, constipation, dizziness, ataxia, mental state changes, muscle weakness, mood changes, restlessness, irritability, and excitation. Na. V Drugs that selectively target 1.6 appear to retain efficacy while reducing the burden of their adverse events.

[0012] Loss of function mutations in mouse SCN8A result in a phenotype known as motor endplate disease (med), and multiple mutations and phenotypes were associated with the med gene region prior to the identification of the SCN8A gene (Burgess, D.L. et al., Nat. Genet. (1995), Vol. 10, pp. 461-465). SCN8A med Mice with SCN8A V mutations have varying degrees of reduced muscle tone, which med / jo correlates with the degree of dysfunction of the Na V 1.6 function. Mice with SCN8A med have a phenotype with a non-zero loss of function and have Na med / joMice are resistant to seizures induced by chemical insults (fluorothyl, kainic acid, and picrotoxin) (Martin, M. S. et al., Human Molecular Genetics (2007), Vol. 16, pp. 2892-2899; Hawkins, N. A. et al., Neurobiology of Disease (2011), Vol. 41, pp. 655-660; and Makinson, C . D. et al., Neurobiology of Disease (2014), Vol. 68, pp. 16-25). Curiously, SCN8A med / jo mice when crossed with SCN1A null mutant mice to produce mice that are heterozygous for both the SCN1A null allele and the SCN8A med / jo allele, these double mutant mice have a significantly improved seizure and cognitive phenotype compared to mice having only the SCN1A null mutation (Martin, M. S. et al., Human Molecular Genetics (2007), Vol. 16, pp. 2892-2899). Such mice have a similar incidence of spontaneous seizures and mortality to wild-type mice and also have an increased threshold for seizures after chemical insult. Similar results occur when mice having a missense mutation in SCN1A (a model of GEFS+) are crossed with mice having a loss-of-function mutation in SCN8A. Having a single allele of SCN8A med / jo protected GEFS+ model mice from seizures and premature death (Hawkins, N. A. et al., Neurobiology of Disease (2011), Vol. 41, pp. 655-660). The ability of SCN8A knockdown to improve seizure resistance is not limited to knockout where the gene is completely absent throughout the development of the animal. 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, C. D. et al., Neurobiology of Disease (2014), Volume 68, pages 16 - 25). These data show a decreased Na V 1.1 current - induced suppression of inhibitory signaling is, at least in part, counteracted by suppressing excitatory signaling by decreasing the Na V 1.6 current, suggesting that it can be counteracted.

[0013] Voltage - gated sodium channel antagonism is the most common mechanism of widely prescribed antiepileptic drugs (AEDs) (Ochoa, J.R. et al., Sodium Channel Blockers.: Antiepileptic Drugs (2016), Vol. (edited by Benbadis, S.) Medscape News & Perspectives). Carbamazepine, eslicarbazepine, oxcarbazepine, lacosamide, lamotrigine, phenytoin, rufinamide, and zonisamide all act primarily by blocking this function of the Na V channel. Despite this presumed mechanism of action, these drugs are relatively non - discriminatory. They block all Na V channel isoforms indiscriminately, and thus, blocking of Na V 1.1 is predicted to promote seizures. Blocking of Na V 1.6, and perhaps Na V 1.2, is antispasmodic. In addition to sodium channels, these compounds also block other targets, including voltage - gated calcium channels. Selective Na V 1.1 and other off - target receptor - free antagonists are predicted to have both improved potency and a better therapeutic index compared to currently available Na V blockers. V Therefore, epilepsy and other Na 1.6 - related pathological conditions can be effectively treated, and other sodium channels (e.g., Na V 1.1 and / or Na V 1.1 and / or Na VThere is an unmet medical need to treat without the deleterious side effects resulting from the blockade of 1.5). The present invention provides a method of meeting these critical needs.

PRIOR ART DOCUMENTS

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Summary of the Invention

Means for Solving the Problems

[0015] Gist of the Invention The present invention relates to benzenesulfonamide compounds, pharmaceutical compositions containing these compounds, and methods of using the compounds and pharmaceutical compositions of the present invention for treating diseases or conditions mediated by voltage-gated sodium channel activity (in particular, Na V 1.6 activity), such as epilepsy and / or epilepsy seizure disorders.

[0016] Accordingly, in one aspect, the present invention provides a compound of formula (I):

Chemical formula

[0017] The compounds of the invention (which are compounds of formula (I) as defined above) may be used as their individual stereoisomers, enantiomers or tautomers, or mixtures thereof; or as their pharmaceutically acceptable salts, solvates or prodrugs, in the treatment of diseases or conditions associated with voltage-gated sodium channels (preferably Na V 1.6). Preferably, the compounds of the invention are Na V 1.6 inhibitors. More preferably, the compounds of the invention exhibit selectivity for inhibiting Na V 1.5 and / or Na V 1.1 compared to inhibiting Na V 1.6. Without wishing to be bound by theory, such selectivity is thought to advantageously reduce any cardiovascular side effects associated with the inhibition of Na 1.5 and / or Na V 1.1. V is considered to advantageously reduce any cardiovascular side effects associated with the inhibition of Na

[0018] In another aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I) as defined above, as its stereoisomers, enantiomers or tautomers, or mixtures thereof; or as its pharmaceutically acceptable salts, solvates or prodrugs.

[0019] In another aspect, the present invention provides a method for treating epilepsy and / or epileptic seizure disorders in mammals, preferably humans, which comprises administering to a mammal in need thereof a therapeutically effective amount of a stereoisomer, enantiomer or tautomer of a compound of the invention described above, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or administering a pharmaceutical composition comprising a therapeutically effective amount of a compound as a stereoisomer, enantiomer or tautomer of a compound of the invention described above, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable additive.

[0020] In another aspect, the present invention provides a method for treating or reducing the severity of a disease, condition or disorder in a mammal, wherein activation or upregulation of Na V 1.6 is associated with the disease, condition or disorder, which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound as a stereoisomer, enantiomer or tautomer of a compound of the invention described above, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or administering a pharmaceutical composition comprising a therapeutically effective amount of a compound as a stereoisomer, enantiomer or tautomer of a compound of the invention described above, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable additive.

[0021] In another aspect, the present invention provides a method for treating and / or reducing, but not preventing, epilepsy and / or epileptic seizure disorders in mammals, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound as a stereoisomer, enantiomer or tautomer, or a mixture thereof, of a compound of the present invention as described above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or administering a pharmaceutical composition comprising a therapeutically effective amount of a compound as a stereoisomer, enantiomer or tautomer, or a mixture thereof, of a compound of the present invention as described above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable additive.

[0022] In another aspect, the present invention provides a pharmaceutical treatment 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 a pharmaceutical composition comprising a compound of the present invention in combination with an established or future treatment for an indication listed herein.

[0023] In another aspect, the present invention relates to a method for selectively inhibiting a first voltage-gated sodium channel in a mammal preferentially over a second voltage-gated sodium channel, the method comprising administering to the mammal an inhibitory amount of a compound as a stereoisomer, enantiomer or tautomer, or a mixture thereof, of a compound of the present invention as described above; or a pharmaceutically acceptable salt, solvate or prodrug thereof, or an inhibitory amount of a compound as a stereoisomer, enantiomer or tautomer, or a mixture thereof, of a compound of the present invention as described above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient. The method includes the step of administering a pharmaceutical composition containing a compound as a stereoisomer, enantiomer or tautomer, or a mixture thereof, of a compound of the present invention as described above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.

[0024] In another aspect, the present invention relates to the use 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, as a compound in the preparation of a drug for the treatment of a disease or condition related to the activity of voltage-gated sodium channels (preferably Na V 1.6) in mammals (preferably, the disease or condition is epilepsy and / or epileptic seizure disorder), or the use 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, and a pharmaceutically acceptable additive, in a pharmaceutical composition. In certain embodiments, for example, the following items are provided. (Item 1) Formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

DETAILED DESCRIPTION OF THE INVENTION

[0025] Detailed Description of the Invention Definitions In this specification, for certain chemical groups named, an abbreviated representation indicating the total number of carbon atoms that will be found in the indicated chemical group may precede. For example, C7~C 12 Alkyl, as defined below, describes an alkyl group having a total of 7 to 12 carbon atoms, and C4~C 12 Cycloalkylalkyl, as defined below, describes a cycloalkylalkyl group having a total of 4 to 12 carbon atoms. The total number of carbons in the abbreviated representation does not include carbons that may be present in substituents of the described group. In addition to the foregoing, the following terms, unless otherwise specified, have the indicated meanings when used in this specification and the appended claims.

[0026] "Alkyl" consists of only carbon and hydrogen atoms, contains no unsaturation, has 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and is a straight-chain or branched-chain hydrocarbon chain group bonded by a single bond to the rest of the molecule, for example, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. When specifically described in this specification, the alkyl group may optionally be substituted with one of the following groups: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, -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 from 1 to 2), -S(O) t R 22 (where t is from 0 to 2), and -S(O) p N(R 20 )2(where p is from 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).

[0027] "Alkenyl" consists of only carbon and hydrogen atoms, contains at least one double bond, has 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms, and is a straight-chain or branched hydrocarbon chain radical group (e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, and pent-1,4-dienyl, etc.) bonded to the remainder of the molecule by a single bond. When specifically described herein, the alkenyl group may be optionally substituted with one of the following groups: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, -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 from 1 to 2), -S(O) p OR 22 (where p is from 1 to 2), -S(O) t R 22(where t is from 0 to 2), and -S(O) p N(R 20 )2(where p is from 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).

[0028] "Alkylene" or "alkylene chain" refers to a straight-chain or branched-chain divalent hydrocarbon chain consisting of only carbon and hydrogen, containing no unsaturation, and having from 1 to 12 carbon atoms (e.g., methylene, ethylene, propylene, and n-butylene, etc.). The alkylene chain may optionally contain one or more heteroatoms, in which case the carbon in this alkylene chain is replaced by a heteroatom selected from oxygen, nitrogen or sulfur. The alkylene chain is bonded to the remainder of the molecule via a single bond and is bonded to its radical group via a single bond, or is bonded to two parts of the molecule via a single bond at each bonding point. When specifically described herein, the alkylene chain may optionally be substituted by one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, -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 from 1 to 2), -S(O) p OR 22 (where p is from 1 to 2), -S(O) t R 22 (where t is from 0 to 2), and -S(O) p N(R 20 )2(where p is from 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).

[0029] "Aryl" refers to a group of a hydrocarbon ring system containing hydrogen, from 6 to 18 carbon atoms, and at least one aromatic ring. For the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Examples of 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, preiadene, pyrene and triphenylene. When specifically described herein, an aryl group may be alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 21 -OR 20 , -R 21 -OC(O)-R 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 - 2), -R 21 -N=C(OR 20 )R 20 、 -R 21 -S(O) p OR 22 (where p is 1 - 2), -R 21 -S(O) t R 22 (where t is 0 - 2), and -R 21 -S(O) p N(R 20 )2(where p is 1 - 2)(In the formula, each R 20 is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R 21 is, 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 may be optionally substituted by one or more substituents independently selected from the group consisting of. Preferably, for R 1 in this specification, the optional substituents on the optionally substituted aryl group are alkyl, optionally substituted cycloalkyl, halo, haloalkyl, optionally substituted aryl, -R 21 -OR 20 、 -R 21 -C(O)OR 20and -R 21 -N(R 20 )2 (where R 20 and R 21 are as defined above). Preferably, the substituents, if any, on the optionally substituted aryl group for R 5 in this specification are halo.

[0030] "Aralkyl" refers to a group of the formula -R b -R c (wherein R b is an alkylene chain as defined above and R c is one or more aryl groups as defined above), for example, benzyl, diphenylmethyl, etc. The alkylene chain portion of the aralkyl group can be optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl group can be optionally substituted as described above for the aryl group.

[0031] "Cycloalkyl" consists of only carbon and hydrogen atoms, may include a fused or bridged ring system, has 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, is saturated or unsaturated, and is a stable non-aromatic monocyclic or polycyclic hydrocarbon group bonded by a single bond to the rest of the molecule. Examples of monocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic groups include adamantyl, norbornyl, decalinyl, etc. When specifically described in this specification, the cycloalkyl group is 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 )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 - 2), -R 21 -N=C(OR 20 )R 20 、 -R 21 -S(O) p OR 22 (where p is 1 - 2), -R 21 -S(O) t R 22 (where t is 0 - 2), and -R 21 -S(O) p N(R 20 )2(where p is 1 - 2)(In the formula, each R 20 is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R 21 is, independently, a direct bond, or a straight-chain or branched alkylene chain, and each R 22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl) and may be optionally substituted by one or more substituents independently selected from the group consisting of. Preferably, in the present specification, when R 4 and R 1 together with the carbon to which they are attached form an optionally substituted cycloalkyl, the optional substituent on the optionally substituted cycloalkyl group is aryl.

[0032] "Cycloalkylalkyl" refers to a group of the formula -R b R g wherein R b is an alkylene chain as defined above, and R g is a cycloalkyl group as defined above). When specifically described herein, the alkylene chain and / or cycloalkyl radical may be optionally substituted as defined above for optionally substituted alkylene chains and optionally substituted cycloalkyls.

[0033] "Halo" refers to bromo, chloro, fluoro or iodo.

[0034] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-f luoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl and the like. The alkyl portion of the haloalkyl group may be optionally substituted as defined above for alkyl groups.

[0035] "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 specifically stated otherwise herein, the heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system that may include fused, bridged, and spiro ring systems. The nitrogen, carbon, or sulfur atoms within the heterocyclyl group may be optionally oxidized, and the nitrogen atoms may be optionally quaternized. The heterocyclyl group may be partially or fully saturated. Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, dioxinyl, thienyl[1,3]dithianyl, 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. When specifically described herein, the heterocyclyl group may be 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 )2, -R 21 -C(O)R 20 , -R 21 -C(O)OR 20 , -R 21 -C(O)N(R 20 )2, -R21 -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 from 1 to 2), -R 21 -N=C(OR 20 )R 20 、 -R 21 -S(O) p OR 22 (where p is from 1 to 2), -R 21 -S(O) t R 22 (where t is from 0 to 2), and -R 21 -S(O) p N(R 20 )2(where p is from 1 to 2)(In the formula, each R 20 is, independently, hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R 21 is, independently, a direct bond, or a straight-chain or branched alkylene chain, and each R 22 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl) and may be optionally substituted by one or more substituents selected from the group consisting of.

[0036] "N - heterocyclyl" refers to a heterocyclyl radical as defined above that contains at least one nitrogen. The point of attachment of the N - heterocyclyl to the rest of the molecule may be via this nitrogen atom of the N - heterocyclyl or via a carbon atom. When specifically described herein, the N - heterocyclyl radical may be optionally substituted as described above for the optionally substituted heterocyclyl radical.

[0037] "Heterocyclylalkyl" refers to the radical of formula -R b R h wherein R b is an alkylene chain as defined above, and R h is a heterocyclyl radical as defined above. When this heterocyclyl is a nitrogen-containing heterocyclyl, this heterocyclyl may be bonded to this alkyl radical at this nitrogen atom. When specifically described herein, the alkylene chain of the heterocyclylalkyl radical may be optionally substituted as defined above for optionally substituted alkylene chains. When specifically described herein, the heterocyclyl moiety of the heterocyclylalkyl radical may be optionally substituted as defined above for optionally substituted heterocyclyl groups. depending on the need.

[0038] "Heteroaryl" refers to a group 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 the purposes of the present invention, the heteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system (which may include fused or bridged ring systems), and the nitrogen, carbon or sulfur atoms within the heteroaryl group may be oxidized as necessary, and the nitrogen atoms may be quaternized as necessary.Examples include, but are not limited to, 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, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinonyl, benzimidazolylthionyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, 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 (pryrimidinonyl), 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). When specifically described herein, a heteroaryl group is 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 )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 from 1 to 2), -R 21 -N=C(OR 20 )R 20 、 -R 21 -S(O) p OR 22 (where p is from 1 to 2), -R 21 -S(O) t R 22 (where t is from 0 to 2), and -R 21 -S(O) p N(R 20 )2(where p is from 1 to 2)(In the formula, each R 20 is, independently, hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R 21 is, independently, a direct bond, or a straight-chain or branched alkylene chain, and each R 22 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl) and may be optionally substituted by one or more substituents selected from the group consisting of.

[0039] "N - heteroaryl" refers to a heteroaryl radical as defined above that contains at least one nitrogen. The point of attachment of the N - heteroaryl to the remainder of the molecule may be via a nitrogen atom or a carbon atom of this N - heteroaryl. When specifically described herein, the N - heteroaryl radical may be optionally substituted as described above for optionally substituted heteroaryl radicals. Preferably, for R 1 in this specification, the optional substituents on the optionally substituted N - heteroaryl group are alkyl, optionally substituted cycloalkyl, halo, haloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, and - R 21 - OR 20 (where R 20 and R 21 are as defined above for the heteroaryl group). Preferably, for R 2 in this specification, the optional substituents on the optionally substituted N - heteroaryl group are halo.

[0040] "O - heteroaryl" refers to a heteroaryl radical as defined above in which the heteroatom present is only oxygen. The point of attachment of the O - heteroaryl to the remainder of the molecule is via a carbon atom of this O - heteroaryl radical. When specifically described herein, the O - heteroaryl radical may be optionally substituted as described above for optionally substituted heteroaryl radicals. Preferably, for R 1 in this specification, the optional substituents on the optionally substituted O - heteroaryl group are alkyl and haloalkyl.

[0041] "S - heteroaryl" refers to a heteroaryl radical as defined above in which the heteroatom present is only sulfur. The point of attachment of the S - heteroaryl to the remainder of the molecule is via a carbon atom of this S - heteroaryl radical. When specifically described herein, the S - heteroaryl radical can be optionally substituted as described above for optionally substituted heteroaryl radicals. Preferably, the R 1 For, the optional substituent on the optionally substituted S - heteroaryl group for R in this specification is alkyl.

[0042] "Heteroarylalkyl" refers to a radical of the formula - R b R i wherein R b is an alkylene chain as defined above, and R i is a heteroaryl radical as defined above. When specifically described herein, the heteroaryl portion of the heteroarylalkyl radical can be optionally substituted as defined above for optionally substituted heteroaryl groups. When specifically described herein, the alkylene chain portion of the heteroarylalkyl radical can be optionally substituted as defined above for optionally substituted alkylene chains.

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

[0044] The term "prodrug" also means to include any carrier attached by a covalent bond, and when such a prodrug is administered to a mammalian subject, it releases the active compound of the present invention in vivo. The prodrugs of the compounds of the present invention can be prepared by modifying the functional groups present in the compounds of the present invention such that the modifying group is cleaved to the parent compound of the present invention either by a predetermined operation or in vivo. A prodrug contains a compound of the present invention, wherein a hydroxy, amino or mercapto group in the compound of the present invention is bonded to an arbitrary group, and when the prodrug of the compound of the present invention is administered to a mammalian subject, it is cleaved to form a free hydroxy group, a free amino group or a free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols or amide derivatives of amine functional groups in compounds such as those of the present invention.

[0045] The present invention disclosed herein is also intended to encompass all pharmaceutically acceptable compounds of formula (I) that are isotopically labeled, wherein one or more atoms are replaced by atoms having different atomic masses or mass numbers. Examples of isotopes that can be included in the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine (e.g., 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 125I). These radiolabeled compounds can be useful for determining or measuring the efficacy of these compounds, for example, by characterizing the site or mode of action on the sodium channel or the binding affinity for pharmacologically important sites of the sodium channel. Certain isotopically labeled compounds of formula (I) (e.g., compounds containing a radioisotope) are useful in tissue distribution studies of drugs and / or substrates. Tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose because they are easily incorporated and from the perspective of rapid detection means.

[0046] Substitution with heavier isotopes (e.g., deuterium, i.e., 2 H) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or decreased dosing requirements) and can thus be preferred in certain situations. In one embodiment of the invention, the compounds of formula (I) are enriched in deuterium. Such deuterated compounds can be achieved by methods known to those skilled in the art (e.g., exchanging protons with deuterium or synthesizing the molecule using enriched starting materials).

[0047] Substitution with positron-emitting radioisotopes (e.g., 11 C, 18 F, 15 O and 13 N) can be useful in positron emission tomography (PET) studies for testing substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by procedures similar to those described in the examples and preparations as described below, using appropriately isotopically labeled reagents in place of the previously used unlabeled reagents.

[0048] The invention disclosed herein is also intended to encompass the in vivo metabolites of the disclosed compounds. Such products can result from, for example, oxidation, reduction, hydrolysis, amidation, and esterification of the administered compound, primarily due to enzymatic processes. Accordingly, the invention encompasses compounds produced by a process that includes contacting a compound of the invention with a mammal for a time sufficient to obtain its metabolite. This includes. Such products are typically identified by administering a radiolabeled compound of the invention to a mammal (e.g., rat, mouse, guinea pig, monkey, or human) at a detectable dose, allowing sufficient time for metabolism to occur, and isolating the conversion products from urine, blood, or other biological samples.

[0049] By "stable compound" and "stable structure" is meant a compound that is sufficiently strong to withstand isolation to a useful degree of purity from the reaction mixture and formulation into an effective therapeutic agent.

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

[0051] By "optionally" or "optionally," it is meant that the event or situation described subsequently may or may not occur, and this description includes both the case where the event or situation occurs and the case where it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and this description includes both substituted aryl groups and unsubstituted ("non-substituted") aryl groups. When a functional group is described as "optionally substituted" and similarly the substituents on that functional group are also described as "optionally substituted," for the purposes of the present invention, such repetition is limited to up to 5 times, and preferably such repetition is limited to 2 times.

[0052] "Pharmaceutically acceptable carriers, excipients or additives" include, but are not limited to, any adjuvant, carrier, additive, glidant, sweetening agent, excipient, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the US Food and Drug Administration as acceptable for use in humans or livestock.

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

[0054] "Pharmaceutically acceptable acid addition salts" refer to salts formed using inorganic and organic acids that retain the biological effectiveness and properties of the free base and are not inappropriate biologically or otherwise. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Examples of organic acids include, but are 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, 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, undecylenic acid, etc.

[0055] The term "pharmaceutically acceptable basic addition salts" refers to salts that retain the biological effectiveness and characteristics of the free acid and are not inappropriate biologically or otherwise. These salts are prepared by adding an inorganic base or an organic base to the free acid. Examples of salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Preferred inorganic salts are salts of ammonium, sodium, potassium, calcium, and magnesium. Examples of salts derived from organic bases include salts of primary amines, secondary amines, and tertiary amines, substituted amines, such as natural 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, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc., but are not limited to these. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0056] Upon crystallization, solvates of the compounds of the present invention are often formed. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of a compound of the present invention with one or more molecules of a 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 monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., as well as in 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 retain adventitious water or be a mixture of adventitious water and an adventitious solvent.

[0057] "Pharmaceutical composition" refers to a formulation of a compound of the present invention with a medium generally accepted in the art for the delivery of bioactive compounds to mammals such as humans. Such media include all carriers, excipients or additives therefor that are pharmaceutically acceptable.

[0058] "Therapeutically effective amount" refers to an amount of a compound of the present invention sufficient to achieve treatment (as defined below) of a disease or condition mediated by a sodium channel in a mammal, preferably a human, when administered to the mammal, preferably a human. The amount of the 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 routinely by one of ordinary skill in the art in view of the knowledge of one of ordinary skill in the art and this disclosure.

[0059] "Treat" or "treatment", as used herein, is directed to the treatment of a disease or condition 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 when such a mammal is predisposed to the condition but has not yet been diagnosed as having it, (b) inhibiting a disease or condition, i.e., preventing its occurrence, (c) alleviating (or reducing) a disease or condition, i.e., causing regression of the disease or condition, or (d) alleviating (or reducing) symptoms resulting from a disease or condition, e.g., alleviating epilepsy without necessarily preventing the underlying disease or condition.

[0060] As used herein, the terms "disease" and "condition" may be used interchangeably, or a particular disease or condition may have an unknown causative agent (thus, the etiology remains unexplained), and therefore, it may not yet be recognized as a disease and may only be recognized as an undesirable state or syndrome (a particular set of symptoms has been more or less recognized by a clinician).

[0061] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and, thus, can give rise to enantiomers and diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- or, for amino acids, as (D)- or (L)- in terms of absolute stereochemistry. The present invention is intended to embrace all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using a chiral synthon or chiral reagent or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from an appropriate, optically pure precursor or resolution of a racemate (or racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). Where the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers and, unless otherwise specified in particular, the compounds are intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are intended to be embraced.

[0062] "Stereoisomers" refer to compounds that are composed of the same atoms bonded by the same bonds but have different three-dimensional structures that are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, including "enantiomers", which refer to two stereoisomers whose molecules are mirror images that cannot be superimposed on one another. For a detailed description of the structures and properties of enantiomers and stereoisomers, see, for example, Smith, M.B. and J. March, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Edition (Wiley, 2007).

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

[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 bonded to the atom preceding the parentheses. The use of brackets in a substituent indicates that the group within the brackets is also directly bonded to the atom preceding the brackets.

[0065] The chemical nomenclature protocol and structural diagrams used herein are a modified form of the I.U.P.A.C. naming system using the ChemBioDraw Ultra Version 14.0 software program, in which the 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, the substituent is named before the group to which it is attached. For example, cyclopropylethyl contains an ethyl backbone having a cyclopropyl substituent. In chemical structure diagrams, all bonds are specified except for some carbon atoms that are considered to be bonded to sufficient hydrogen atoms to satisfy their valences.

[0066] "Enantiomer" refers to an asymmetric molecule that can exist in two different isomeric forms having different arrangements in space. Other terms used to represent or refer to enantiomers include "stereoisomers" (resulting from different arrangements or stereochemistry around a chiral center; all enantiomers are stereoisomers, but not all stereoisomers are enantiomers) or "optical isomers" (resulting from the optical activity of pure enantiomers, which is the ability of different pure enantiomers to rotate plane-polarized light in different directions).

[0067] The designations "R" and "S" for the absolute configuration of the enantiomers of the present invention may appear as a prefix or a suffix to 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.

[0068] In accordance with the conventions of the standard chemical literature description, as used herein, a filled complete bond as shown in the exemplary structure (A) below, and a dashed complete bond as shown in the following structure (A) mean that these substituents are in a trans configuration with respect to the plane of the ring:

Chemical formula

[0069] Similarly, the bonds in the following exemplary structures (Aa) and (Ab) are in a cis configuration with respect to the plane of this ring:

Chemical formula

[0070] In accordance with the conventions of the standard chemical literature description, as used herein, a complete wedge bond as shown in the following structure (B) means that the substituent (in this case, the R 30 substituent) attached to the ring by this bond is above the plane of this ring when illustrated on the paper in a two-dimensional representation, and a dashed wedge bond as shown in the following structure (B) means that the substituent (in this case, the R 31 substituent) attached to the ring by this bond is below the plane of this ring when shown on the paper in a two-dimensional representation:

Chemical formula

[0071] In accordance with the convention of the description of standard chemical literature, as used herein, the wavy bond as shown in the following structure (C) indicates that its substituent (in this case, R 30 substituent) is either below or above the plane of this ring:

Chem.

[0072] In the formulas illustrated herein, the bonds to substituents and / or the bonds connecting molecular fragments to the remainder of the compound may be shown as crossing one or more of the bonds in the ring structure. This indicates that this bond may be attached to any of the atoms constituting this ring structure (otherwise, as long as a hydrogen atom may be present on that atom). When a specific substituent(s) is not identified with respect to a specific position in the structure, hydrogen(s) is present at this position. For example, in the following structure (D), the bond attaching the R 30 substituent may be on any carbon, including the carbon to which R 31 is attached, provided that the valence is available for such attachment.

Chem.

[0073] "Resolution" or "resolving", when used in reference to a racemic compound or racemic mixture of a compound of the present invention, refers to the separation of the racemic compound or racemic mixture into its two enantiomeric forms (i.e., (+) and (-); (R) form and (S) form).

[0074] "Enantiomeric excess" or "ee", as used herein, refers to a product in which one enantiomer is present in excess over the other and is defined as the absolute difference in the mole fraction of each enantiomer. Enantiomeric excess is typically expressed as a percentage of one enantiomer present in a mixture relative to the other enantiomer. For the purposes of the present invention, the (S)-enantiomer of a compound prepared by the methods disclosed herein is considered to be "substantially free" of the corresponding (R)-enantiomer when the (S)-enantiomer is present with an enantiomeric excess greater than 80%, preferably greater than 90%, more preferably greater than 95%, and most preferably greater than 99%.

[0075] The chemical nomenclature protocol and structural diagrams used herein are a modified form of the I.U.P.A.C. naming system using the ChemBioDraw Ultra Version 14.0 software program, in which the 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 having a cyclopropyl substituent. In chemical structure diagrams, all bonds are specified except for some carbon atoms that are considered to be bonded to sufficient hydrogen atoms to satisfy their valency.

[0076] Thus, n is 1, m is 1, X is a direct bond, Y is -C(R 11 )R 12 -, R 1 is phenyl, R 2 is thiazol-2-yl, R 3 is -N(R 13 )-, R 4 and R 5 are each hydrogen, R 6 is hydrogen, R 7 is chloro, R 11 is hydrogen, R 12is hydrogen and R 13 The (R)-enantiomer of the compound of formula (I) as described above in the gist of the invention, wherein R 13 is hydrogen, i.e., the following formula:

Chemical formula

[0077] Embodiments of the present invention One aspect of the present invention is the compound of formula (I) as described in the gist of the invention, as an individual stereoisomer, enantiomer or tautomer, or a mixture thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0078] In one embodiment, the compound of formula (I) is such that R 3 is -O-, the compound of formula (I) as an individual stereoisomer, enantiomer or tautomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the compound has the following formula (Ia):

Chemical formula

[0079] In another embodiment, the compound of formula (I) is such that n is 1 or 2; m is 1 or 2; X is a direct bond or -C(R 9 )R 10 -; Y is a direct bond or -C(R 11 )R 12 -; R 1 is hydrogen, alkyl, -R 17 -OR 14 , optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted N - heterocyclyl, optionally substituted N - heteroaryl, optionally substituted O - heteroaryl or optionally substituted S - heteroaryl; R 2 is optionally substituted 5 - membered N - heteroaryl or optionally substituted 6 - membered N - heteroaryl; R 4 and R 5 are each independently hydrogen, alkyl or haloalkyl; or alternatively R 4 and R 1 together with the carbon to which they are attached form an optionally substituted cycloalkyl or optionally substituted aryl, and R 5 , when present, is hydrogen, alkyl, haloalkyl or optionally substituted aryl; each R 6 is independently hydrogen, alkyl, alkenyl, halo, haloalkyl, cyano, -O R 14 or optionally substituted cycloalkyl; R 7 is alkyl, halo, haloalkyl, cyano or -OR 14 ; each R 8 is independently hydrogen, alkyl, halo, haloalkyl or -OR 14 ; or alternatively two R 8 may together with the carbon to which both are attached form an optionally substituted cycloalkyl; R 9 , R 10 , R 11 and R12 each independently is hydrogen, alkyl, haloalkyl, alkyl or -OR 14 or; alternatively R 9 and R 11 together form an optionally substituted alkylene chain, and R 10 and R 12 are as defined above; and R 13 is hydrogen, alkyl or haloalkyl; each R 14 is each independently hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl; and R 17 is a direct bond or an optionally substituted alkylene chain; a compound of formula (Ia) as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as individual stereoisomers, enantiomers or tautomers or mixtures thereof.

[0080] In another embodiment, the compound of formula (I) is a compound of formula (Ia) in which both X and Y are direct bonds, i.e., formula (Ia1):

Chemical formula

[0081] One embodiment of the compound of formula (Ia1) is where R 2 is an optionally substituted 5-membered N-heteroaryl, and is a compound of formula (1a1).

[0082] Among this embodiment, a preferred embodiment is where R 2 is an optionally substituted isoxazolyl, an optionally substituted thiazolyl or an optionally substituted thiadiazolyl, and is a compound of formula (Ia1).

[0083] Among this embodiment, a preferred compound is 4-((1-benzylazetidin-3-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzene-sulfonamide.

[0084] Another preferred embodiment of the compound of formula (Ia1) is where R 2 is an optionally substituted 6-membered N-heteroaryl, and is a compound of formula (Ia1).

[0085] Among this embodiment, a preferred embodiment is where R 2 is an optionally substituted pyridinyl, and is a compound of formula (Ia1). In another embodiment, the compound of formula (I) is a compound of formula (Ia) where X is -C(R 9 )R 10 -, and Y is a direct bond, that is, formula (Ia2):

Chemical formula

[0086] One embodiment of the compound of formula (Ia2) is where R 2 is an optionally substituted 5-membered N-heteroaryl, and is a compound of formula (1a2).

[0087] Among this embodiment, the preferred embodiment is where R 2 is an optionally substituted isoxazolyl, an optionally substituted thiazolyl or an optionally substituted thiadiazolyl, and is a compound of formula (Ia2).

[0088] Among the compounds of formula (Ia2), the preferred compounds are: (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)oxy)-3-ethyl-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)oxy)-3-bromo-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-2-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)oxy)-2,6-difluoro-N-(thiazol-4-yl)-3-vinylbenzenesulfonamide; rac-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (R)-4-((1-Benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)oxy)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-Benzyl-3-methylpyrrolidin-3-yl)oxy)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; and (S)-4-((1-Benzylpyrrolidin-3-yl)oxy)-3-chloro-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide selected from.

[0089] Another preferred embodiment of the compound of formula (Ia2) is where R 2 is an optionally substituted 6-membered N-heteroaryl, the compound of formula (Ia2).

[0090] Among this embodiment, a preferred embodiment is where R 2 is an optionally substituted pyridinyl, the compound of formula (Ia2).

[0091] In another embodiment, the compound of formula (I) is where X is -C(R 9 )R 10 - and Y is -C(R 11 )R 12 -, the compound of formula (Ia), i.e., formula (Ia3):

Chemical formula

[0092] Among this embodiment, a preferred embodiment is a compound of formula (Ia3) wherein R 2 is an optionally substituted 5-membered N-heteroaryl.

[0093] Among this embodiment, a more preferred embodiment is a compound of formula (Ia3) wherein R 2 is an optionally substituted isoxazolyl, an optionally substituted thiazolyl or an optionally substituted thiadiazolyl.

[0094] Among this preferred embodiment, a preferred embodiment is a compound of formula (Ia3) wherein R 1 is an optionally substituted aryl or an optionally substituted aralkyl; and R 9 、R 10 、R 1 1 and R 12 are each independently hydrogen or alkyl.

[0095] Among the compounds of formula (Ia3), preferred compounds are: 5-Chloro-2-fluoro-4-(1-(1-phenylethyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(1-phenylethyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(3-fluorobenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(3-(difluoromethyl)benzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(3-(difluoromethoxy)benzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-((6-methylpyridin-2-yl)methyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(3-methoxybenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(3-chlorobenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(2-fluorobenzyl)-3-methylpiperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(3-methyl-1-(3-methylbenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 4-(1-Benzyl-3-methylpiperidin-4-yloxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(2-fluorobenzyl)-3-methylpiperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(3-methyl-1-(3-methylbenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 4-(1-Benzyl-3-methylpiperidin-4-yloxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(naphthalen-2-ylmethyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(2-fluorobenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(2-methylbenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(3-methylbenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(pyridin-2-ylmethyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(pyridin-3-ylmethyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(pyridin-4-ylmethyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(4-methoxybenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(3,4-dimethylbenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(3,5-dimethylbenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(1-(4-methylbenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 4-(1-Benzylpiperidin-4-yloxy)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-N-(thiazol-2-yl)-4-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yloxy)benzenesulfonamide; 3-Chloro-4-(1-(4-fluorobenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide; 4-(1-Benzylpiperidin-4-yloxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-((1-(cyclohexylmethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-((1-cyclohexylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-N-(thiazol-2-yl)-4-((1-(2-(trifluoromethyl)benzyl)piperidin-4-yl)oxy)benzenesulfonamide; 3-Chloro-4-((1-(2-chlorobenzyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-((1-((4-methylpyridin-2-yl)methyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide; 4-((1-Benzyl-4-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-((1-(3-chlorobenzyl)-4-methylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-((1-(3-(difluoromethyl)benzyl)-4-methylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-chloro-4-((1-(2,3-dihydro-1H-inden-1-yl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide; (R)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide; (R)-5-chloro-2-fluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide; (R)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; (S)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide; 3-chloro-4-((1-(2-phenylpropan-2-yl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide; 5-chloro-2-fluoro-4-((1-(2-phenylpropan-2-yl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide; (R)-2,3-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; (R)-3-chloro-2-fluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; 4-((1-benzylpiperidin-4-yl)oxy)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; 4-((1-benzylpiperidin-4-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; 3-chloro-4-((1-(1-phenylcyclopropyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; 5-Chloro-4-(((3R,4S)-1-(3-(difluoromethyl)benzyl)-3-fluoropiperidin-4-yl)oxy)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (R)-5-Chloro-2-fluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; (R)-3-Chloro-4-((1-(1-(5-chloro-2-fluorophenyl)ethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; (R)-2,6-Difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; (R)-3-Chloro-N-(isoxazol-3-yl)-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)benzenesulfonamide; 3-Chloro-4-((1-phenethylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide; (R)-3-Chloro-4-((1-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; 4-((1-benzylpiperidin-4-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-2-yl)benzenesulfonamide; 4-((1-benzylpiperidin-4-yl)oxy)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide; 4-((cis-1-benzyl-2-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; and 4-((trans-1-benzyl-2-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide. (R)-3-Chloro-4-((1-(1-(5-cyclopropyl-2-fluorophenyl)ethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; (R)-3-Chloro-4-((1-(1-(5-(difluoromethyl)-2-fluorophenyl)ethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; (R)-3-Chloro-2,6-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; 3-Chloro-4-((1-(3-(difluoromethyl)benzyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; (R)-5-Chloro-2-fluoro-4-((1-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; 4-((1-Benzylpiperidin-4-yl)oxy)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (R)-2,6-Difluoro-3-methyl-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; 4-((1-Benzylpiperidin-4-yl)oxy)-3-chloro-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide; and 4-((1-Benzylpiperidin-4-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide selected from.

[0096] Another preferred embodiment of the compound of formula (Ia3) is R 1 is optionally substituted aryl or optionally substituted aralkyl; R 9 and R11 forms an alkylene chain optionally substituted; and R 11 and R 12 are each independently hydrogen or alkyl, is a compound of formula (Ia3).

[0097] Among these embodiments, preferred compounds of formula (Ia3) are: 4-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yloxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; 4-((1R,3r,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yloxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; 4-(((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide; 5-Chloro-4-(((1R,3s,5S)-8-(3-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(((1R,3s,5S)-8-(5-chloro-2-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; 4-(((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide; 3-Chloro-4-(((1R,3s,5S)-8-(3-chloro-4-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide; and 3-chloro-4-(((1R,3S,5S)-8-(3-(difluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide selected from.

[0098] Another preferred embodiment of the compound of formula (Ia3) is R 2 is a compound of formula (Ia3) which is an optionally substituted 6-membered N-heteroaryl.

[0099] Among this embodiment, the preferred embodiment is that R 2 is a compound of formula (Ia3) which is an optionally substituted pyridinyl or an optionally substituted pyrimidinyl.

[0100] Among this embodiment, the preferred compounds of formula (Ia3) are: (R)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(pyrimidin-4-yl)benzenesulfonamide; (R)-3-chloro-N-(5-fluoropyrimidin-2-yl)-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)benzenesulfonamide; (S)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(pyrimidin-4-yl)benzenesulfonamide; 4-((1-benzylpiperidin-4-yl)oxy)-3-chloro-N-(6-fluoropyridin-2-yl)benzenesulfonamide; and 4-((1-benzylpiperidin-4-yl)oxy)-5-chloro-2-fluoro- N-(6-fluoropyridin-2-yl)benzenesulfonamide selected from.

[0101] In another embodiment, the compound of formula (I) is R 3 is -N(R 13)-The compound of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, as its individual stereoisomers, enantiomers or tautomers, or mixtures thereof, wherein the compound has the following formula (Ib): [Chemical formula] and in formula (Ib), m, n, X, Y, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 13 are as defined above in the gist of the invention with respect to the compound of formula (I).

[0102] In another embodiment, the compound of formula (I) is n is 1 or 2; m is 1 or 2; X is a direct bond or -C(R 9 )R 10 -; Y is a direct bond or -C(R 11 )R 12 -; R 1 is hydrogen, alkyl, -R 17 -OR 14 , optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted N - heterocyclyl, optionally substituted N - heteroaryl, optionally substituted O - heteroaryl or optionally substituted S - heteroaryl; R 2 is optionally substituted 5 - membered N - heteroaryl or optionally substituted 6 - membered N - heteroaryl; R 4 and R 5 are each independently hydrogen, alkyl or haloalkyl; or alternatively, R 4 and R 1which, together with the carbon to which they are attached, forms an optionally substituted cycloalkyl or an optionally substituted aryl, and R 5 when present, is hydrogen, alkyl, haloalkyl or an optionally substituted aryl; each R 6 is independently hydrogen, alkyl, alkenyl, halo, haloalkyl, cyano, -OR 14 or an optionally substituted cycloalkyl; R 7 is alkyl, halo, haloalkyl, cyano or -OR 14 ; each R 8 is independently hydrogen, alkyl, halo, haloalkyl or -OR 14 ; or alternatively, two Rs 8 can together with the carbon to which they are both attached form an optionally substituted cycloalkyl; R 9 , R 10 , R 11 and R 12 are each independently hydrogen, alkyl, haloalkyl, alkyl or -OR 14 ; or alternatively, R 9 and R 11 form an optionally substituted alkylene chain, and R 10 and R 12 are as defined above; and R 13 is hydrogen, alkyl or haloalkyl; each R 14 is independently hydrogen, alkyl, haloalkyl, an optionally substituted aryl or an optionally substituted aralkyl; and R 17 is a direct bond or an optionally substituted alkylene chain, The compound of formula (Ib) as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as an individual stereoisomer, enantiomer or tautomer or a mixture thereof.

[0103] In another embodiment, the compound of formula (I) is a compound of formula (Ib) in which both X and Y are direct bonds, i.e., formula (Ib1):

Chemical formula

[0104] One embodiment of the compound of formula (Ib1) is a compound of formula (1b1) wherein R 2 is a 5-membered N-heteroaryl optionally substituted as required.

[0105] Among this embodiment, a preferred embodiment is a compound of formula (Ib1) wherein R 2 is an isoxazolyl optionally substituted as required, a thiazolyl optionally substituted as required or a thiadiazolyl optionally substituted as required.

[0106] Among this embodiment, preferred compounds of formula (Ib1) are: 4-((1-Benzyl-3-methylazetidin-3-yl)amino)-2,6-diflu oro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate; 4-((1-Benzyl-3-methylazetidin-3-yl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; 4-((1-benzyl-3-methylazetidin-3-yl)amino)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide; 4-((1-benzyl-3-methylazetidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; and 4-((1-benzylazetidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide selected from.

[0107] Another preferred embodiment of the compound of formula (Ib1) is R 2 is a 6-membered N-heteroaryl optionally substituted, a compound of formula (Ib1).

[0108] Among this embodiment, a preferred embodiment is R 2 is a pyridinyl optionally substituted, a compound of formula (Ib1).

[0109] In another embodiment, the compound of formula (I) is a compound of formula (Ib) wherein X is -C(R 9 )R 10 -, and Y is a direct bond, that is, formula (Ib2):

Chemical formula

[0110] One embodiment of the compound of formula (Ia2) is a compound of formula (1b2) wherein R 2 is an optionally substituted 5-membered N-heteroaryl.

[0111] Among this embodiment, a preferred embodiment is a compound of formula (Ia2) wherein R 2 is an optionally substituted isoxazolyl, an optionally substituted thiazolyl or an optionally substituted thiadiazolyl.

[0112] Among this embodiment, a preferred embodiment is a compound of formula (Ia2) wherein R 2 is an optionally substituted thiadiazolyl.

[0113] Among this embodiment, preferred compounds of formula (Ib2) are: (S)-3-chloro-4-((1-(3,5-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-3-chloro-4-((1-(2,5-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-3-chloro-4-((1-(2,6-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-3-Chloro-4-((1-(2-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-2,6-Difluoro-3-methyl-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-3-Chloro-2,6-difluoro-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-3-Chloro-4-(ethyl(1-(3-methylbenzyl)pyrrolidin-3-yl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)(ethyl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-3-Chloro-4-(methyl(1-(3-methylbenzyl)pyrrolidin-3-yl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide ; (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (R)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-4-(1-benzylpyrrolidin-3-ylamino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (R)-4-(1-Benzylpyrrolidin-3-ylamino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; 4-(1-Benzylpyrrolidin-3-ylamino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-3-Chloro-4-((1-(3-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-3-Chloro-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-3-Chloro-4-((1-(3-chloro-2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-3-Chloro-4-((1-(5-chloro-2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-3-Chloro-4-((1-(2-fluoro-3-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; and (S)-3-Chloro-4-((1-(2-fluoro-5-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide selected from.

[0114] R 2 Among the preferred embodiments of the compound of formula (Ib2), where R is optionally substituted isoxazolyl, optionally substituted thiazolyl or optionally substituted thiadiazolyl, the preferred embodiment is that R 1 is optionally substituted aryl or optionally substituted aralkyl; and R2 is a thiazolyl or isoxazolyl optionally substituted as required, is a compound of formula (Ib2).

[0115] Among these preferred embodiments, preferred compounds of formula (Ib2) are: (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-bromo-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-chloro-2-fluoro-4-((1-(3-(2-hydroxypropan-2-yl)benzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-chloro-4-((1-(5-chloro-2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-chloro-2-fluoro-4-((1-(2-fluoro-4-methylbenz yl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-chloro-2-fluoro-4-(methyl(1-(3-phenylpropyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-(2-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-fluoro-4-((1-(2-hydroxybenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-4-((1-(3-hydroxybenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (R)-4-((1-benzylpyrrolidin-3-yl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-(3-(difluoromethoxy)benzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-cyclopropyl-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-(2,5-dichlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; 5-Chloro-2-fluoro-4-(methyl((S)-1-((R)-1-phenylpropyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-(4-propylbenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(2-fluoro-5-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (R)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-(3-(Difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-(2-phenylpropan-2-yl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; 3-Chloro-4-(methyl((S)-1-((R)-1-phenylethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-phenethylpyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isothiazol-3-yl)-5-methylbenzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-2,6- Difluoro-N-(isothiazol-3-yl)-3-methylbenzenesulfonamide; (S)-2-Fluoro-4-((1-(2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(ethyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-3-((3-((2-Chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenyl)(methyl)amino)pyrrolidin-1-yl)methyl)methyl benzoate; (S)-5-Chloro-4-((1-(2-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-(4-(dimethylamino)benzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)(ethyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide; (S)-3-Chloro-4-((1-(5-chloro-2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-bromo-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-4-((1-(3-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-(2,5-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-ethyl-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(3-isopropoxybenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-(4-methylbenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-(2,6-dimethylbenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(3-fluoro-2-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-phenethylpyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-(3-chloro-2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(2-methoxybenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(4-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; 4-(((2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; 3-Chloro-4-(methyl((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-(2,3-Difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-(2,3-Difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-2,6-Difluoro-4-((1-(2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-(3-(Difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-(2,5-Difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-(2,5-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-(3-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-3-Chloro-4-((1-(2-fluoro-5-methylbenzyl)-3-methylpyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-2,5-difluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-4-((1-(2-methoxybenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; 4-(((3S,5S)-1-Benzyl-5-methylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; 5-Chloro-4-(((S)-1-((S)-1-(2-chlorophenyl)propyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-(2-(difluoromethoxy)benzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(4-fluoro-3-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; 5-Chloro-2-fluoro-4-(methyl((S)-1-((S)-1-phenylpropyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; 4-((1-Benzyl-3-methylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-(4-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (R)-4-((1-Benzylpyrrolidin-3-yl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isothiazol-4-yl)-5-methylbenzenesulfonamide; (S)-2,6-Difluoro-4-((1-(3-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; (R)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-(difluoromethyl)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-(2-methylbenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(2-hydroxybenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(3-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-(2,3-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-(3-(trifluoromethyl)benzyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(2-fluoro-3-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(2-fluoro-5-methoxybenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (R)-4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro -N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-(2-methylbenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-4-((1-(4-hydroxybenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)-3-(trifluoromethyl)benzenesulfonamide; (S)-2-Fluoro-4-((1-(2-fluoro-3-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-(2,5-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-(4-bromobenzyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(3-methoxybenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-(2-chloro-6-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-3-Chloro-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((5-Benzyl-5-azaspiro[2.4]heptan-7-yl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((5-Benzyl-5-azaspiro[2.4]heptan-7-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (R)-4-(1-Benzylpyrrolidin-3-ylamino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(1-(3-methylbenzyl)pyrrolidin-3-ylamino)-N-(thiazol-2-yl)benzenesulfonamide; (S)-4-(1-Benzylpyrrolidin-3-ylamino)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide; (R)-5-Chloro-2-fluoro-4-(1-(3-methylbenzyl)pyrrolidin-3-ylamino)-N-(thiazol-2-yl)benzenesulfonamide; (R)-4-(1-Benzylpyrrolidin-3-ylamino)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide; (S)-3-Chloro-4-((1-(3-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide; (S)-3-Chloro-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide bis(trifluoroacetate) salt; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide; 3-Chloro-4-(methyl((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl)benzenesulfonamide; 3-Chloro-4-(methyl((S)-1-((R)-1-phenylethyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl)benzenesulfonamide; 4-((1-Benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; (S)-3-Chloro-4-(methyl(1-(2-phenylpropan-2-yl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (R)-3-Chloro-4-((1-(3-chlorobenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl)benzenesulfonamide; (R)-3-Chloro-4-((1-(3-methylbenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl)benzenesulfonamide; (R)-3-Chloro-4-((1-(2-fluorobenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl)benzenesulfonamide; 4-((trans-1-benzyl-4-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; 4-((cis-1-benzyl-4-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; and (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isoxazol-3-yl)-5-methylbenzenesulfonamide selected from.

[0116] R 2 is, in a preferred embodiment of the compound of formula (Ib2), optionally substituted isoxazolyl, optionally substituted thiazolyl or optionally substituted thiadiazolyl, another preferred embodiment is R 1 is optionally substituted N-heterocyclyl, optionally substituted N-heteroaryl, optionally substituted O-heteroaryl or optionally substituted S-heteroaryl; and R 2 is optionally substituted thiazolyl, is a compound of formula (Ib2).

[0117] Among this preferred embodiment, preferred compounds of formula (Ib2) are: (S)-4-((1-((1,4-Dimethyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((4-methylthiazol-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((2-methylthiazol-4-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((1-methyl-1H-pyrazol-3-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-4-((1-((3-fluoro-6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-((1-benzyl-1H-pyrazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-((5-(trifluoromethyl)furan-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((2-methyloxazol-4-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((5-methylfuran-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-4-((1-((2-isopropyloxazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-((6-methoxypyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-((3-fluoro-6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-(quinolin-8-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-((4-cyclopropylthiazol-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-((6-(azetidin-1-yl)pyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((2-phenylthiazol-4-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl) benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-(thiazol-2-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((2-(trifluoromethyl)thiazol-4-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-((2-cyclopropylthiazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((4-methyloxazol-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-4-((1-((3-isopropoxypyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-4-((1-((3-fluoro-6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-((3-methoxypyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-((6-bromopyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-((1H-Pyrrol-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-((5-methylfuran-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-(thiazol-4-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-((1,5-Dimethyl-1H-pyrazol-3-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-3-Chloro-2,6-difluoro-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-((1-methyl-1H-pyrrol-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-((1H-Indol-3-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((5-(trifluoromethyl)furan-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-(oxazol-4-ylm (S)-2-Fluoro-5-methyl-4-(methyl(1-(oxazol-4-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-4-((1-((3-methoxypyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-((1-methyl-1H-pyrazol-3-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(imidazo[1,5-a]pyridin-3-ylmethyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-((2-(trifluoromethyl)pyridin-4-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-((6-(difluoromethyl)pyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(isoquinolin-8-ylmethyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-((6-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-4-((1-((2-isopropylthiazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-(Benzothiazol-2-ylmethyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((5-methylisothiazol-3-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-(pyrazolo[1,5-a]pyridin-2-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-((1H-Indol-5-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-(thiophen-2-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-((4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-4-((1-((4-isopropylthiazol-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-((5-chlorothiazol-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-((1-(Difluoromethyl)-1H-pyrazol-3-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-2,6-Difluoro-3-methyl-4-(methyl(1-((6-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-((6-(difluoromethyl)-3-fluoropyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-((5-methylthiophen-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-((1-(2,2-Difluoroethyl)-1H-pyrazol-3-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((2-methyl-5-(trifluoromethyl)oxazol-4-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-((2,5-Dimethyloxazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-((4-(trifluoromethyl)thiazol-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; and (S)-2,6-Difluoro-3-methyl-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide selected from.

[0118] R 2 is, when optionally substituted isoxazolyl, optionally substituted thiazolyl or optionally substituted thiadiazolyl, among the preferred embodiments of the compound of formula (Ib2), another preferred embodiment is R 1 is hydrogen, alkyl, -R 17 -OR 14 or optionally substituted cycloalkyl; and R 4 and R 5 are each independently hydrogen, alkyl or haloalkyl; or alternatively R 4 and R 1 together with the carbon to which they are attached form an optionally substituted cycloalkyl or an optionally substituted aryl, and R 5 when present, when present, is hydrogen, alkyl, haloalkyl or optionally substituted aryl, is a compound of formula (Ib2).

[0119] Among this preferred embodiment, preferred compounds of formula (Ib2) are: 2-Fluoro-5-methyl-4-(methyl((S)-1-((1s,3R)-3-phenylcyclobutyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-(2,3-dihydro-1H-inden-2-yl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-(methyl(1-(1-phenylcyclopropyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-(2,3-dihydro-1H-inden-2-yl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-4-((1-(3,3-dimethylbutyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; 4-(((S)-1-((S)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; (S)-5-Chloro-2-fluoro-4-((1-(1-(2-fluorophenyl)cyclobutyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-(2-(benzyloxy)ethyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; 5-Chloro-4-(((S)-1-((R)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; 2-Fluoro-5-methyl-4-(methyl((S)-1-((1r,3S)-3-phenylcyclobutyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (S)-4-((1-(Cyclohexylmethyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; 3-Chloro-4-(((S)-1-((S)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; 5-Chloro-4-(((S)-1-((S)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide; (S)-2-Fluoro-5-methyl-4-(methyl(1-neopentylpyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; and (S)-4-((1-(3,3-Dimethylbutyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide selected from.

[0120] Another preferred embodiment of the compound of formula (Ib2) is R 2 is a 6-membered N-heteroaryl optionally substituted, a compound of formula (Ib2).

[0121] Among this embodiment, the preferred embodiment is R 2 is a pyridinyl optionally substituted, a compound of formula (Ib2).

[0122] Among this preferred embodiment, the preferred compound of formula (Ib2) is: (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(5-fluoropyridin-2-yl)-3-methylbenzenesulfonamide; (S)-5-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(methyl(1-(2-phenylpropan-2-yl)pyrrolidin-3-yl)amino)benzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-3-methylbenzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(5-fluoropyridin-2-yl)-5-methylbenzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(6-fluoropyridin-2-yl)-5-methylbenzenesulfonamide; (S)-4-((1-Benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide bis(trifluoroacetic acid) salt; 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl)amino)benzenesulfonamide; and 5-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(methyl((S)-1-((R)-1-phenylethyl)pyrrolidin-3-yl)amino)benzenesulfonamide selected from.

[0123] In another embodiment, the compound of formula (I) is such that X is -C(R 9 )R 10 -, and Y is -C(R 11 )R 12 -, a compound of formula (Ib), i.e., formula (Ib3):

Chemical formula

[0124] Among these embodiments, a preferred embodiment is a compound of formula (Ib3) wherein R 2 is an optionally substituted 5-membered N-heteroaryl.

[0125] Among these embodiments, a more preferred embodiment is a compound of formula (Ib3) wherein R 2 is an optionally substituted isoxazolyl, an optionally substituted thiazolyl or an optionally substituted thiadiazolyl.

[0126] Among these preferred embodiments, preferred compounds of formula (Ib3) are: (R)-5-Chloro-2-fluoro-4-(methyl(1-(1-phenylethyl)piperidin-4-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; (R)-2-Fluoro-5-methyl-4-(methyl(1-(1-phenylethyl)piperidin-4-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; 4-((1-Benzylpiperidin-4-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide; and 4-(1-Benzylpiperidin-4-ylamino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide selected from.

[0127] Another preferred embodiment of the compound of formula (Ia3) is that R 2 is a 6-membered N-heteroaryl optionally substituted, a compound of formula (Ib3).

[0128] Among this embodiment, the preferred embodiment is that R 2 is a pyridinyl optionally substituted, a compound of formula (Ib3).

[0129] Another embodiment of the present invention is that R 7 is ortho to R 3 a compound of formula (I).

[0130] Another embodiment of the present invention is that R 7 is ortho to R 3 and is halo, formula (I) a compound of.

[0131] Another embodiment of the present invention is that R 7 is chloro or fluoro.

[0132] Another embodiment of the present invention is that R 2is a monocyclic N - heteroaryl optionally substituted, a compound of formula (I). Another embodiment of the present invention is R 2 is a 5 - membered N - heteroaryl optionally substituted, a compound of formula (I). Another embodiment of the present invention is R 2 is a 5 - membered N - heteroaryl optionally substituted selected from isoxazolyl, thiazolyl or thiadiazolyl, a compound of formula (I). Another embodiment of the present invention is R 2 is a 6 - membered N - heteroaryl optionally substituted, a compound of formula (I). Another embodiment of the present invention is R 2 is a 6 - membered N - heteroaryl optionally substituted selected from pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, a compound of formula (I). Another embodiment of the present invention is R 2 is a pyridinyl optionally substituted, a compound of formula (I).

[0133] Another embodiment of the present invention is a method of using a compound of formula (I) as a standard substance or control in an in vitro assay or in vivo assay when determining the potency of a test compound in modulating voltage - dependent sodium channels.

[0134] Any embodiment of the compounds of the present invention as described above, and specific n, m, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 17Any specific substituent described herein with respect to a group may be combined independently of other embodiments and / or substituents of the invention to form embodiments of the invention not specifically described above. Further, in certain embodiments and / or claims, where an enumeration of substituents is disclosed with respect to any particular n, m, X, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 and R 17 groups, it is understood that one or more substituents may be deleted from this enumeration and that the remaining enumeration of substituents is considered to be an embodiment of the invention.

[0135] It is also understood that the conditions described above in the summary of the invention with respect to the compounds of formula (I) apply to all relevant embodiments of the compounds of formula (I) as described above.

[0136] Another aspect of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 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.

[0137] Another aspect of the invention is a method of treating a disease or condition associated with NaV1.6 activity in a mammal, wherein the disease or condition is epilepsy and / or epilepsy seizure disorder, and the method comprises 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 a mixture thereof.

[0138] In one embodiment of this aspect, the epilepsy or epileptic seizure disorder is selected from the group consisting of photosensitive epilepsy, self-induced syncope, refractory epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorder, childhood and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, Glut1 deficiency syndrome, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, Landau-Kleff syndrome, and the like. The condition is selected from: Narr syndrome, Lennox-Gastaut syndrome (LGS), epilepsy with myoclonus absence, Ohtahara syndrome, Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonus epilepsy, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora-type progressive myoclonus 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, hypotonia and paroxysmal dyskinesia.

[0139] 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.

[0140] Another aspect of the invention is a method of decreasing ion flux through NaV1.6 in a mammalian cell, comprising contacting the cell with a compound of the invention, as described above, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, as a stereoisomer, enantiomer or tautomer, or mixture thereof.

[0141] Another aspect of the present invention is a method of selectively inhibiting a first voltage-gated sodium channel over a second voltage-gated sodium channel in a mammal, wherein the method comprises administering to the mammal a modulating amount of 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 a mixture thereof.

[0142] In one embodiment of this aspect, the first voltage-gated sodium channel is Na V 1.6.

[0143] 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 1.5.

[0144] 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 1.1.

[0145] Specific embodiments of the compounds of the present invention are described in more detail in the preparation of the compounds of the present invention below.

[0146] Usefulness and testing of the compounds of the present invention The compounds of the present invention are useful for voltage-dependent sodium channels (preferably Na VRegulate, preferably inhibit, the ion flow through [1.6]. Any such regulation, regardless of whether it is a partial or complete inhibition or prevention of ion flow, is referred to herein as "blocking", and the corresponding compound may be referred to as a "blocker" or "inhibitor". Generally, the compounds of the present invention regulate the activity of voltage-gated sodium channels in a downward direction by inhibiting the voltage-dependent activity of sodium channels, and / or reduce or prevent the flow of sodium ions across the cell membrane by preventing sodium channel activities such as ion flow.

[0147] The compounds of the present invention inhibit the ion flow through voltage-dependent sodium channels (preferably Na V 1.6). The compounds of the present invention are state- or frequency-dependent modifiers of sodium channels, having low affinity for the resting / closed state and high affinity for the inactivated state. These compounds are likely to interact with overlapping sites located within 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., supra). These compounds may also interact with sites outside the inner cavity and may have an allosteric effect on sodium ion conductivity through the channel pore.

[0148] Any of these results may ultimately be involved in the overall therapeutic benefit obtained by these compounds.

[0149] Therefore, the compounds of the present invention are voltage-gated sodium channel inhibitors (preferably, Na V 1.6 inhibitors), and are thus useful for treating diseases and conditions (preferably epilepsy and / or epileptic seizure disorders) in mammals, preferably humans, and other organisms, which involve abnormal voltage-dependent sodium channel biological activities (preferably, abnormal Na VThe therapeutic effects of the present invention include 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 pharma- ceutically acceptable salts, solvates or prodrugs thereof) are capable of inhibiting or reducing 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 1.1 in preference to Na V Selectively inhibits 1.6.

[0150] 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, such as photosensitive epilepsy, self-induced syncope, refractory epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorder, childhood and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, Glut1 deficiency syndrome, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), epilepsy with myoclonic absence, and Ohtahara syndrome. , Panaetopoulos syndrome, PCDH19 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 convulsions+, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia and paroxysmal dyskinesia.

[0151] Accordingly, 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.

[0152] Na V Typical values of the compounds of the present invention in the inhibition of Na 1.6 ion flux can be determined using the assays described in the Biological Assays section below. Alternatively, typical values of the compounds in the treatment of human conditions and diseases can also be established in industry standard animal models to demonstrate the efficacy of the compounds in the treatment of epilepsy and / or epileptic seizure disorders. An animal model of human neuropathic pain conditions has been developed and the results

[0153] For example, numerous rodent models have been developed to evaluate the tendency towards seizure or epileptiform activity (Klein, B.R. et al., (2016), "Models Currently in Active Use. In: Epilepsy Therapy Screening Program", Volume 2016, National Institute of Neurological Disorders and Stroke). These include acute chemical or electrical injuries that induce seizures, as well as persistent chemical or genetic injuries that create animals with a seizure tendency. 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-hertz psychomotor seizure test (6Hz) are two examples of acute injury seizure assays used to evaluate antispasmodic interventions (Suzuki, F. et al., Neuroscience (1995), Vol. 64, pp. 665-674; Barton, M.E. et al., Epilepsy Research (2001), Volume 47, pp. 217-227). Both assays involve electrical injury applied by electrodes placed on the cornea or ear to cause an acute seizure. Acute seizures can also be chemically induced, for example, by administration of the convulsant ether compound fluorothyl (Makinson, C.D. et al., Exp. Neurol. (2016), Volume 275, Part 1, pp. 46-58).

[0154] Genetic epilepsy is associated with many different genes (including multiple voltage-gated sodium channel genes). Genetically modified mice harboring mutations identified in human patients can be generated. In some cases, these genetic modifications result in animals that behave quite similarly to the human patients in whom the genetic variations were first identified. Mutant mice can be used to test the intervention of antiepileptic drugs. Such experiments can include the prevention of spontaneous seizures or 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 of infancy or Dravet syndrome, has been generated by mutating the SCN1A gene encoding the Na V 1.1 voltage-gated sodium channel (Yu, F.H. et al., Nat. Neurosci. (2006), Vol. 9, pp. 1142-1149). A model of EIEE13 has likewise been generated by mutating the SCN6A gene encoding the Na V 1.6 voltage-gated sodium channel (Wagnon, J.L. et al., Human Molecular Genetics (2014)). Both of these mouse strains provide an opportunity to evaluate potential therapeutic investigations that may be useful in clinical patient populations (Martin, M.S. et al., J. Biol. Chem. (2010), Vol. 285, pp. 9823-9834; and Martin, M.S. et al., Human Molecular Genetics (2007), Vol. 16, pp. 2892-2899).

[0155] The present invention readily provides many different means for the identification of Na V 1.6 inhibitory agents that are useful as therapeutic agents. Na V1.6 The identification of inhibitors can be evaluated using a variety of in vitro and in vivo assays, such as measurement of current, measurement of membrane potential, measurement of ion flux (e.g., sodium or guanidinium), measurement of sodium concentration, measurement of second messenger and transcription concentrations, and using, for example, voltage-sensitive dyes, radioactive tracers, and patch-clamp electrophysiological methods.

[0156] One such protocol involves screening for the ability of a chemical to modulate the activity of a sodium channel, thereby identifying it as an agent that modulates the activity of the sodium channel.

[0157] The typical assays described by Bean et al., J. General Physiology (1983), Vol. 83: 613 - 642, and Leuwer, M. et al., Br. J. Pharmacol (2004), Vol. 141(1): 47 - 54, use patch-clamp techniques to study channel action. Such techniques are known to those skilled in the art, and with current technology, low or medium throughput assays can also be developed to evaluate these compounds for their ability to modulate sodium channel action.

[0158] The 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 tested, it is not desirable to use low throughput means. However, in other cases, low throughput may be sufficient to identify important differences between a limited number of compounds. In many cases, it may be necessary to combine assay types to identify specific sodium channel modulating compounds.

[0159] Electrophysiological assays using the patch-clamp method are accepted as criteria for the detailed characterization of sodium channel compound interactions, as described by Bean et al. (supra) and Leuwer, M. et al. (supra). There are manual low-throughput screening (LTS) methods that can compare 2-10 compounds per day, systems recently developed for automated medium-throughput screening (MTS) with 20-50 patches (i.e., compounds) per day, and technologies from Molecular Devices Corporation (Sunnyvale, CA) that enable automated high-throughput screening (HTS) with 1000-3000 patches (i.e., compounds) per day.

[0160] One automated patch-clamp system utilizes planar electrode technology to accelerate the drug discovery rate. Planar electrodes can achieve high resistance, cell-attached seals, and subsequently 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 levels of relevant sodium ion channels can be adapted to high-density suspension culture.

[0161] Other assays can be selected that allow researchers to identify compounds that block specific states of the channel, such as its open, closed, or resting state, or transitions from open to closed, closed to resting, or resting to open. Those skilled in the art are generally familiar with such assays.

[0162] Binding assays are also available. Designs include traditional radio-filter-based binding assays or confocal-based fluorescence systems commercially available from the Evotec OAI group of companies (Hamburg, Germany), both of which are HTS.

[0163] Radiometric flow assays can also be used. In this assay, the channel is stimulated, opened with veratridine or aconitine, stabilized in the open state by the toxin, and channel blockers are identified by their ability to prevent ion influx. This assay is radiometric 22 [Na] and 14 [C] guanidinium ions can be used as tracers. FlashPlate & Cytostar-T plates in live cells avoid the separation step and are suitable for HTS. Scintillation plate technology has made this method more advantageous in terms of HTS compatibility. From the functional aspect of this assay, the information content is quite good.

[0164] In yet another format, the redistribution of membrane potential 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. Several problems can arise from the natural radioactivity of the fluorescence of the compound. Test compounds can also directly affect the fluidity of the cell membrane, resulting in an increase in the intracellular dye concentration. However, from the functional aspect of this assay, the information content is quite good.

[0165] By using sodium dyes, the rate or amount of sodium ion influx through channels can be measured. This type of assay provides a very high information content regarding promising 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). These are all Na-reactive dyes. They can be used in combination with a FLIPR device. The use of these dyes in screening has not been described in the literature to date. Calcium dyes may also have potential in this manner.

[0166] In another assay, the ability of a test compound to directly block Na influx is measured by using a FRET-based potential sensor. Commercially available HTS systems include the VIPR (trademark) II FRET system (Aurora Biosciences Corporation, San Diego, CA, a division of Vertex Pharmaceuticals, Inc.) and can be used with FRET dyes also commercially available from Aurora Bioscience. This assay measures responses within 1 second to voltage changes. There is no requirement for modifiers of channel function. This assay measures depolarization and hyperpolarization and provides a ratio metric output for quantification. A somewhat less expensive MTS version of this assay uses the FLEXstation (trademark) (Molecular Devices Corporation) with FRET dyes made by Aurora Biosciences. Other methods of testing the compounds disclosed herein are also well known and readily available to those of skill in the art.

[0167] 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.

[0168] 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 channels 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.

[0169] Typically, the potency of the compounds of the present invention is represented by their 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. For example, representative compounds of the present invention have an IC V in the range of less than 100 nanomolar to less than 10 micromolar in the patch voltage clamp Na 50 1.6 electrophysiology assay described herein.

[0170] 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 the various diseases disclosed herein or for protection from these diseases.

[0171] Another aspect of the present invention relates to Na in biological samples or in mammals, preferably humans VRegarding inhibiting 1.6 activity, this method includes the step of administering to a mammal, preferably a human, or the step of contacting the biological sample with a compound of formula (I) or a pharmaceutical composition containing a compound of formula (I). As used herein, the term "biological sample" 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.

[0172] Na of biological sample V Inhibition of 1.6 activity is useful for various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, the study of sodium ion channels in biological and pathological phenomena, and the comparative evaluation of new sodium ion channel inhibitors.

[0173] The stereoisomers, enantiomers, tautomers of the compounds of the present invention, or the compounds as mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, as described above in the summary of the invention, and / or one or more compounds as stereoisomers, enantiomers or tautomers of the compounds of the present invention or mixtures thereof, as described above in the summary of the invention, or pharmaceutically acceptable salts, solvates or prodrugs thereof, and pharmaceutically acceptable additives, the pharmaceutical compositions described herein can be used for the preparation of drugs for the treatment of diseases or conditions related to voltage-gated sodium channel activity (preferably, Na V 1.6 activity) in mammals.

[0174] The pharmaceutical compositions and administrations of the present invention The present invention also relates to a pharmaceutical composition containing a compound of the present invention disclosed herein. In one embodiment, the present invention provides a composition comprising a pharmaceutically acceptable carrier, additive or excipient in an amount effective to modulate, preferably inhibit, ion flux through voltage-dependent sodium channels for treating a sodium channel-mediated disorder (e.g., epilepsy and / or epileptic seizure disorder), for example, when administered to an animal, preferably a mammal, most preferably a human patient.

[0175] Administration of the compounds of the present invention, either in pure form or in a suitable pharmaceutical composition, or pharmaceutically acceptable salts thereof, can be effected by any of the accepted modes of drug administration for similar utilities. The pharmaceutical compositions of the present invention can be prepared by combining a compound of the present invention with a suitable pharmaceutically acceptable carrier, excipient or additive and formulated into preparations in solid, semi-solid, liquid or gaseous form, 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 administration, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical compositions of the present invention are formulated such that the active ingredient contained therein is bioavailable when the composition is administered to a patient. The composition to be administered to a subject or patient is in the form of one or more dosage units, where, for example, a tablet may be a single dosage unit or a container of a compound of the present invention in aerosol form may maintain multiple dosage units. The actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art. However, for example, refer to The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). In any case, the administered composition contains a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for treating the disease or condition of interest in accordance with the teachings of the present invention.

[0176] Useful pharmaceutical compositions herein also contain a pharmaceutically acceptable carrier, including any suitable excipient or additive, where the carrier includes any pharmaceutical that does not itself induce the production of antibodies harmful to the individual to whom the composition is administered and can be administered without undue toxicity. Examples of 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 presented in Remington’S Pharmaceutical Sciences (Mack Pub.Co., N.J., latest edition).

[0177] The pharmaceutical compositions of the present invention may be in solid or liquid form. In one aspect, the carrier(s) is / are fine particles, and thus the composition is, for example, in the form of a tablet or powder. The carrier(s) may be a liquid having the composition, such as an oral syrup, an injectable liquid, or an aerosol, and the aerosol is useful, for example, for administration by inhalation.

[0178] For the purpose of oral administration, the pharmaceutical composition is preferably in either solid or liquid form, and semi-solid, semi-liquid, suspension, and gel forms are included within the scope of forms considered herein as either solid or liquid.

[0179] As a solid composition for oral administration, the pharmaceutical composition can be formulated into forms such as powders, granules, compressed tablets, pills, capsules, chewing gums, wafers, etc. Such solid compositions usually contain one or more inert excipients or edible carriers. In addition, one or more of the following may be present: binders (such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin, etc.), additives (such as starch, lactose or dextrin, etc.), disintegrants (such as alginic acid, sodium alginate, Primogel, corn starch, etc.), lubricants (such as magnesium stearate or Sterotex, etc.), flow promoters (such as colloidal silicon dioxide, etc.), sweeteners (such as sucrose or saccharin, etc.), flavoring agents (such as peppermint, methyl salicylate or orange flavor, etc.), and coloring agents.

[0180] When the pharmaceutical composition is in the form of capsules, such as gelatin capsules, etc., the pharmaceutical composition may contain, in addition to the substances of the above types, a liquid carrier, such as polyethylene glycol or oil, etc.

[0181] The pharmaceutical composition may be in liquid form, such as elixirs, syrups, solutions, emulsions or suspensions, etc. The liquid may, as two examples, be for oral administration or for delivery by injection. When intended for oral administration, the preferred composition contains, in addition to the compound of the present invention, one or more sweeteners, preservatives, dyes / coloring agents and flavor enhancers. In the composition intended for administration by injection, one or more surfactants, preservatives, wetting agents, dispersants, suspending agents, buffers, stabilizers and isotonic agents may be included.

[0182] The liquid pharmaceutical compositions of the present invention are in the form of solutions, suspensions or other similar forms Regardless of whether or not, it may contain one or more of the following adjuvants: sterile excipients, such as water for injection, physiological saline aqueous solution, preferably physiological saline, Ringer's solution, isotonic saline solution, non-volatile oil (for example, synthetic monoglycerides or diglycerides that can function as solvents or suspension media, polyethylene glycol, glycerin, propylene glycol or other solvents, etc.), antibacterial agents (such as benzyl alcohol or methyl paraben, etc.), antioxidants (such as ascorbic acid or sodium bisulfite, etc.), chelating agents (such as ethylenediaminetetraacetic acid, etc.), buffers (such as acetate, citrate or phosphate, etc.), and agents for adjusting tonicity (such as sodium chloride or glucose, etc.). The parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. The injectable pharmaceutical composition is preferably sterile.

[0183] The liquid pharmaceutical composition of the present invention intended for either parenteral or oral administration should contain an amount of the compound of the present invention such that an appropriate dosage can be obtained. Usually this amount is at least 0.01% of the compound of the present invention in the composition. When intended for oral administration, this amount can vary from 0.1% to about 70% of the weight of the composition. Preferred oral pharmaceutical compositions contain from about 4% to about 50% of the compound of the present invention. Preferred pharmaceutical compositions and preparations according to the present invention are prepared so that, prior to dilution of the present invention, the parenteral dosage unit contains from 0.01% to 10% by weight of the compound.

[0184] The pharmaceutical composition of the present invention may be intended for topical administration, in which case the carrier may suitably contain a solution base, an emulsion base, an ointment base or a gel base. The base may contain, for example, one or more of the following: petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, diluents (such as water and alcohol, etc.), as well as emulsifiers and stabilizers. A thickening agent may be present in the pharmaceutical composition for topical administration. When intended for transdermal administration, the composition may include a transdermal patch or an iontophoresis device. The topical preparation may contain a concentration of the compound of the present invention from about 0.1 w / v% to about 10 w / v% (weight per unit volume).

[0185] The pharmaceutical composition of the present invention can be intended for rectal administration, for example, in the form of a suppository, which will melt in the rectum and release its drug. The composition for rectal administration may contain an oily base as a suitable non-irritating additive. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.

[0186] The pharmaceutical composition of the present invention may contain various substances that modify the physical form of the solid or liquid dosage unit. For example, the composition may include a substance that forms a coating shell around the active ingredient. The substance forming the coating shell is usually inert and may be selected, for example, from sugars, shellac, and other enteric coating agents. Alternatively, the active ingredient may be contained within a gelatin capsule.

[0187] The pharmaceutical composition of the present invention in solid or liquid form may contain an agent that binds to the compound of the present invention and thereby aids in the delivery of the compound. Suitable agents that act in such a capacity include monoclonal or polyclonal antibodies, proteins or liposomes.

[0188] The pharmaceutical composition of the present invention may consist of dosage units that can be administered as an aerosol. The term "aerosol" is used to mean various systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery can be effected by a liquefied or compressed gas or by a suitable pump system for dispensing the active ingredient. This can be done. The aerosol of the compound of the present invention can be delivered in a single-phase, two-phase, or three-phase system for delivering the active ingredient(s). Delivery of the aerosol includes the necessary container, activator, valve, sub-container, etc., and these can be combined together to form a kit. A person skilled in the art can determine the preferred aerosol without undue experimentation.

[0189] The pharmaceutical composition of the present invention can be prepared by methods well known in the pharmaceutical art. For example, a pharmaceutical composition intended for administration by injection can be prepared by combining the compound of the present invention with sterile distilled water so as to form a solution. The addition of a surfactant can facilitate the formation of a homogeneous solution or suspension. A surfactant is a compound that interacts non-covalently with the compound of the present invention so as to facilitate the dissolution or homogeneous suspension of the compound in an aqueous delivery system.

[0190] The compound of the present invention, or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount, which will vary depending on a variety of factors including the activity of the particular compound employed, the metabolic stability and length of action of the compound, the age, weight, general health, sex, and diet of the patient, the mode and time of administration, the rate of excretion, drug combinations, the severity of the particular disorder or condition, and the subject being treated. Generally, a therapeutically effective daily amount will be from about 0.001 mg / kg (i.e., 0.07 mg) to about 100 mg / kg (i.e., 7.0 g), preferably from about 0.01 mg / kg (i.e., 0.7 mg) to about 50 mg / kg (i.e., 3.5 g), more preferably from about 1 mg / kg (i.e., 70 mg) to about 25 mg / kg (i.e., 1.75 g) for a mammalian subject of about 70 kg.

[0191] The ranges of effective amounts provided herein are not intended to be limiting and represent preferred dosage ranges. However, the most preferred dosage will be adjusted according to the individual subject, as will be understood and can be determined by one of ordinary skill in the relevant art. (See, e.g., Berkow et al., eds., The Merck Manual, 19th ed., Merck and Co., Rahway, N.J., 2011; Brunton et al., eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th ed., McGraw-Hill 2011; Avery's Drug Treatment: Principles and Practice of Clinical Pharmacology 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 ed., Mack Publishing Co., Easton, PA; Katzung, Basic and Clinical Pharmacology, Appleton and Lange, Norwalk, CT (1992)).

[0192] The total dosage required for each treatment can be administered in multiple doses or a single dose per day, as needed. Generally, treatment is initiated at a low dosage, less than the optimal dosage of the compound. Thereafter, the dosage is increased in small increments until the optimal effect under the circumstances is reached. The pharmaceutical compounds or compositions for diagnosis can be administered alone or in combination with other diagnostic methods, and / or pharmaceuticals directed to the condition, or other symptoms of the condition. The recipient of administration of the compounds and / or compositions of the present invention can be any vertebrate, such as a mammal. Among mammals, preferred recipients are , the mammalian orders Primate (including humans, apes and monkeys), Arteriodactyla (including horses, goats, cows, sheep, pigs), Rodenta (including mice, rats, and hamsters), Lagomorpha (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 recipient is the human.

[0193] For topical application, it is preferred to administer an effective amount of the pharmaceutical composition according to the invention to a target site adjacent to the peripheral nerve neurons to be treated, such as the skin surface, mucosa, etc. Depending on the site to be treated, whether its use is for diagnosis, prevention or treatment, the severity of the symptoms, and the nature of the topical vehicle used, this amount will generally range from about 0.0001 mg to about 1 g of the compound of the invention per single application. A preferred topical preparation is an ointment, in which case from about 0.001 mg to about 50 mg of the active ingredient is used per 1 cc of the ointment base. The pharmaceutical composition can be formulated as a transdermal composition or as a transdermal delivery device ("patch"). Such compositions include, for example, a backing reservoir of the active compound, a control membrane, a liner and a contact adhesive. By using such a transdermal patch, the compound of the invention can be provided, if desired, with continuous pulsed delivery or on-demand delivery.

[0194] The compositions of the present invention can be formulated to provide immediate, sustained or delayed release of the active ingredient after administration to a patient using procedures known in the art. Osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations can be mentioned as sustained release drug delivery systems. Examples of sustained release systems are provided in U.S. Pat. Nos. 3,845,770 and 4,326,525 and in P.J. Kuzma et al., Regional Anesthesia, Vol. 22(6):543-551 (1997), all of which are incorporated herein by reference.

[0195] The compositions of the present invention can also be delivered via an intranasal drug delivery system for local, systemic, and nose-to-brain drug therapy. It is known to those skilled in the art that Controlled Particle Dispersion (CPD) (trademark) technology, conventional nasal spray bottles, inhalers or nebulizers provide effective delivery of drugs locally and systemically by targeting the olfactory region and paranasal sinuses.

[0196] The present invention also relates to a vaginal sheath or core drug delivery device suitable for administration to human females or female animals. This device may be composed of an active pharmaceutical ingredient in a polymer matrix surrounded by a sheath and, as described in PCT Published Patent Application No. WO98 / 50016, is capable of releasing the compound daily in a substantially zero-order pattern, similar to the device used to attach testosterone.

[0197] Current methods for ocular delivery include topical administration (eye drops), subconjunctival injection, peribulbar injection, intravitreal injection, surgical implantation, and iontophoresis (using a weak electric current to transport ionized drugs into and through body tissues). Those skilled in the art will combine the most suitable additives with the compound for safe and effective intraocular administration.

[0198] The most appropriate route will depend on the nature and severity of the condition being treated. One of ordinary skill in the art is also proficient in determining the method of administration (e.g., oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, appropriate pharmaceutical additives, and other matters related to the delivery of the compound to the subject in need thereof.

[0199] Combination therapy The compounds of the present invention can usefully be 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 related to voltage-gated sodium channel activity. For example, the compounds of the present invention can be administered simultaneously, continuously, or separately in combination with other therapeutic agents including, but not limited to, the following: · Opioid analgesics such as morphine, heroin, cocaine, oxymorphone, levorphanol, levallorphan, oxycodone, codeine, dihydrocodeine, propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, and pentazocine, etc. · Non-opioid analgesics such as acetaminophen, salicylates (e.g., aspirin), etc. · Non-steroidal 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, etc. · Anticonvulsants such as carbamazepine, oxcarbazepine, lamotrigine, valproate, topiramate, gabapentin, and pregabalin, etc. · Antidepressants, such as tricyclic antidepressants, such as amitriptyline, clomipramine, desipramine, imipramine, and nortriptyline, etc., · COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, and lumiracoxib, etc., · α-adrenergic agonists, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, and 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline, etc., · Barbiturate sedatives, such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiopental, and thiamylal, etc., · Tachykinin (NK) antagonists, particularly, NK-3 antagonists, NK-2 antagonists or NK-1 antagonists, such as (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridin-6,13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, raneptitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S), etc., · Coal tar analgesics, particularly paracetamol, · Serotonin reuptake inhibitors, such as paroxetine, sertraline, norfluoxetine (fluoxetine desmethyl metabolite), metabolite demethylsertraline, fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, if oxetin, cyanodothiepin, litoxetine, dapoxetine, nefazodone, sericlamine, trazodone, and fluoxetine, etc., · Norepinephrine (noradrenaline) reuptake inhibitors, such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine, and viloxazine (Vivalan®), especially selective norepinephrine reuptake inhibitors, such as reboxetine, especially (S,S)-reboxetine, and venlafaxine duloxetine, nerve relaxants, sedatives / antianxiety agents, · Dual serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran, and imipramine, etc., · Acetylcholinesterase inhibitors, such as donepezil, etc., · 5-HT3 antagonists, such as ondansetron, etc., · Metabotropic glutamate receptor (mGluR) antagonists, · Local anesthetics, such as mexiletine and lidocaine, etc., · Adrenocortical steroid agents, such as dexamethasone, etc., · Antiarrhythmic agents, such as mexiletine and phenytoin, etc., · Muscarinic antagonists, such as tolterodine, propiverine, tropicium chloride, darifenacin, solifenacin, temiverine, and ipratropium, etc., · Cannabinoids, · Vanilloid receptor agonists (such as resiniferatoxin, etc.) or antagonists (such as capsazepine, etc.), · Sedatives, such as glutethimide, meprobamate, methaqualone, and dichloralphenazone, etc., · Anxiolytics, such as benzodiazepines, etc., · Antidepressants, such as mirtazapine, etc., · Topical agents (such as lidocaine, capsacin, and resiniferotoxin), · Muscle relaxants, such as benzodiazepines, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, and orphenadrine, etc., · Antihistamines or H1 antagonists, · NMDA receptor antagonists, · 5-HT receptor agonists / antagonists, · PDEV inhibitors, · Tramadol (registered trademark), · Cholinergic (nicotinic) analgesics, · α-2-delta ligands, · Prostaglandin E2 subtype antagonists, · Leukotriene B4 antagonists, · 5-lipoxygenase inhibitors, and · 5-HT3 antagonists.

[0200] As used herein, "combination" refers to any admixture 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 otherwise clearly stated in the context, "combination" may include simultaneous or sustained delivery of one or more therapeutic agents together with the compounds of the present invention. Unless otherwise clearly stated in the context, "combination" may include dosage forms of another therapeutic agent together with the compounds of the present invention. Unless otherwise clearly stated in the context, "combination" may include routes of administration of another therapeutic agent together with the compounds of the present invention. Unless otherwise clearly stated in the context Unless otherwise indicated, a "combination" may include a formulation of the compound of the invention with another therapeutic agent. Examples of dosage forms, routes of administration, and pharmaceutical compositions include, but are not limited to, those described herein.

[0201] Kit consisting of parts The present invention also provides a kit containing a pharmaceutical composition comprising one or more compounds of the present invention. The kit also includes instructions for use for the use of a pharmaceutical composition for inhibiting the activity of a voltage-gated ion channel (preferably Na V 1.6) for the treatment of epilepsy, and for other uses disclosed herein. Preferably, a commercially available package contains one or more unit doses of the pharmaceutical composition. For example, such a unit dose may be an amount sufficient for the preparation of an intravenous injection. It will be apparent to those skilled in the art that light-sensitive and / or air-sensitive compounds may require special packaging and / or formulation. For example, packaging that is light-impermeable, hermetically sealed from contact with ambient air, and / or formulated with suitable coatings or additives may be used.

[0202] Preparation of the compounds of the present invention The following reaction scheme illustrates a method for preparing the compounds of the present invention, i.e., the compounds of formula (I), as their individual stereoisomers, enantiomers or tautomers, or mixtures thereof, or as their pharmaceutically acceptable salts, solvates or prodrugs.

[0203] It is also understood that one of ordinary skill in the art can make the compounds of the present invention by similar methods or by methods known to one of ordinary skill in the art. It is also understood that one of ordinary skill in the art can make other compounds of the present invention not explicitly described herein in a manner similar to the manner described below, by using appropriate starting components and varying the synthetic parameters as necessary. It is also understood that simple functional group conversions (e.g., see Larock, R.C. Comprehensive Organic Transformations, 2nd Edition (Wiley, 1999)) can be carried out by methods known to one of ordinary skill in the art. Generally, the starting components can be obtained from sources such as, for example, Sigma Aldrich, Combi-Blocks, Oakwood Chemicals, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or can be synthesized according to sources known to one of ordinary skill in the art (e.g., see Smith, M.B. and J. March, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Edition (Wiley, 2007)), or can be prepared as described herein.

[0204] It is also understood that in the following description, combinations of substituents and / or variables of the described formulas are permitted only if such combinations result in stable compounds.

[0205] In the processes described below, it will also be understood by those skilled in the art that the functional groups of intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Appropriate protecting groups (i.e., "oxygen protecting groups") for hydroxyl include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, and benzyl, etc. Appropriate protecting groups (i.e., "nitrogen protecting groups") for amino, amidino and guanidino include t-butoxycarbonyl and benzyloxycarbonyl, etc. Examples include. Appropriate protecting groups (i.e., "sulfur protecting groups") for mercapto include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, and trityl, etc. Appropriate protecting groups for carboxylic acid include alkyl ester, aryl ester or arylalkyl ester.

[0206] Protecting groups are known to those skilled in the art and can be added or removed according to standard techniques as described herein.

[0207] The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Greene’s Protective Groups in Organic Synthesis, (2006), 4th Edition, Wiley. The protecting group may also be a polymer resin, such as Wang resin or 2-chlorotrityl-chloride resin.

[0208] Although such protected derivatives of the compounds of the present invention may themselves not possess pharmacological activity, it should be understood by those skilled in the art that when these are administered to a mammal and then metabolized in the body, they form the pharmacologically active compounds of the present invention. Accordingly, such derivatives may be described as "prodrugs". All prodrugs of the compounds of the present invention are included within the scope of the present invention.

[0209] The compounds of formula (I) may contain at least one asymmetric carbon atom and thus may exist as racemates, enantiomers and / or diastereoisomers. Specific enantiomers or diastereoisomers can be prepared by using specific chiral starting materials. Alternatively, a mixture of diastereoisomers or a racemic mixture of the compounds of formula (I) can be resolved into its respective enantiomers or diastereoisomers. Methods for the resolution of mixtures of diastereoisomers or racemates of compounds of formula (I) or intermediates 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 inclusion compounds), kinetic resolution (e.g., using a titanium tartrate catalyst), enzymatic resolution (e.g., mediated by lipase), and chromatographic separation (e.g., HPLC using a chiral stationary phase and / or simulated moving bed methodology, or supercritical fluid chromatography and related techniques) are but a few examples of processes that can be applied (see, e.g., T.J. Ward, Analytical Chemistry, 2002, 2863 - 2872).

[0210] Preparation of the compounds of formula (I) Generally, the compounds of formula (I) as described above in the summary of the invention can be synthesized according to the general procedure described in Reaction Scheme 1 below. Here, X, Y, n, m, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as described above for the compounds of formula (I) in the summary of the invention: Reaction Scheme 1

Chemical formula

[0211] The compounds of formula (101), (102) and (103) can be commercially available, or prepared according to methods known to those skilled in the art, or by the methods disclosed herein. Generally, the compounds of formula (I) are prepared as follows, as described above in Reaction Scheme 1:

[0212] The compound of formula (101) is a sulfonamide (102) where Z 1Optionally, a hydrogen or nitrogen protecting group (such as, but not limited to, tert-butoxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl) and under standard reaction conditions (such as, but not limited to, in the presence of a base (such as, but not limited to, potassium carbonate or sodium hydride) and using a polar aprotic solvent (such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide)) at a temperature between about 0 °C and 80 °C for about 1 to 48 hours to give a compound of formula (103). The compound of formula (103) is then treated with an acid (such as, but not limited to, trifluoroacetic acid) in a polar aprotic solvent (such as, but not limited to, dichloromethane) at a temperature between about 0 °C and ambient temperature to produce the compound of formula (I), which can be isolated from this reaction mixture by standard techniques. One skilled in the art will also readily recognize that under certain conditions, isolation of the compound of formula (103) can result in the compound of formula (I), which can be isolated from this reaction mixture by standard techniques.

[0213] Alternatively, a compound of formula (I) wherein R 4 is hydrogen can be prepared according to the general procedure described in Reaction Scheme 2 below, where X, Y, n, m, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are as described above for the compound of formula (I) in the summary of the invention: Reaction Scheme 2

Chemical formula

[0214] The compounds of formulas (201), (202), (203), and (204) can be prepared commercially available, or according to methods known to those skilled in the art, or by the methods disclosed herein. Generally, the compounds of formula (I) are prepared as follows, as described in Reaction Scheme 2 above:

[0215] The compound of formula (201) where Z 2 is a nitrogen protecting group (e.g., but not limited to tert-butoxycarbonyl or benzyl) is reacted with a sulfonamide (202) where Z 1 is optionally hydrogen or a nitrogen protecting group (e.g., but not limited to tert-butoxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl) under standard reaction conditions (e.g., the use of a polar aprotic solvent (e.g., but not limited to dimethyl sulfoxide or N,N-dimethylformamide) in the presence of a base (e.g., but not limited to potassium carbonate or sodium hydride)) at a temperature between about 0 °C and 80 °C for about 1 to 48 hours to give a compound of formula (203). The compound of formula (203) is then treated with an acid (e.g., but not limited to trifluoroacetic acid) in a polar aprotic solvent (e.g., but not limited to dichloromethane) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (204). The compound of formula (204) is then reacted with, for example, but not limited to, an aldehyde or ketone of formula (205) in the presence of a reducing agent (e.g., but not limited to sodium triacetoxyborohydride) in a polar aprotic solvent mixture (e.g., but not limited to N,N-dimethylformamide and 1,2-dichloroethane) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (I), which can be isolated from this reaction mixture by standard techniques.

[0216] R 3 is -N(R13 )- and R 4 is hydrogen, a compound of formula (I), i.e., as described above in the embodiments of the present invention, R 4 is hydrogen, a compound of formula (Ib) can be prepared according to the general procedure described in Reaction Scheme 3 below, where X, Y, n, m, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and R 13 are as described above for the compound of formula (Ib) in the embodiments of the present invention: Reaction Scheme 3

Chemical formula

[0217] Compounds of formula (301), (302), (303), (304), (305), (306) and (307) can be commercially available or prepared according to methods known to those skilled in the art or by the methods disclosed herein. Generally, a compound of formula (Ib) is prepared as follows, as described in Reaction Scheme 3 above:

[0218] A compound of formula (301) (where Z 2 is a nitrogen protecting group (e.g., but not limited to, tert-butoxycarbonyl or benzyl)) is reacted with a sulfonamide (302) (where Z 1is optionally equipped with a hydrogen or nitrogen protecting group (e.g., but not limited to, tert-butoxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl) and reacted under standard reaction conditions (e.g., but not limited to, the use of a polar aprotic solvent (e.g., but not limited to, dimethylsulfoxide or N,N-dimethylformamide) in the presence of a base (e.g., but not limited to, potassium carbonate or sodium hydride) at a temperature between about 0° C. and 80° C. for about 1 to 48 hours) to provide a compound of formula (303). The compound of formula (303) is then reacted with an alkylating agent R 13 -Z 3 (304) (Here Z 3 is a leaving group (e.g., but not limited to, bromide, iodide, sulfate), such as, but not limited to, methyl iodide, in the presence of a base (e.g., but not limited to, lithium bis(trimethylsilyl)amide), in a polar aprotic solvent (e.g., but not limited to, tetrahydrofuran) at a temperature between about -78°C and ambient temperature. The compound of formula (305) may then be killed to give a compound of formula (305). The compound of formula (305) may then be treated with an acid, such as, but not limited to, trifluoroacetic acid, in a polar aprotic solvent, such as, but not limited to, dichloromethane, at a temperature between about 0° C. and ambient temperature to produce a compound of formula (306). The compound of formula (306) may then be reacted with, for example, but not limited to, an aldehyde or ketone of formula (307), in the presence of a reducing agent, such as, but not limited to, sodium triacetoxyborohydride, in a polar aprotic solvent mixture, such as, but not limited to, N,N-dimethylformamide and 1,2-dichloroethane, at a temperature between about 0° C. and ambient temperature to produce a compound of formula (I), which may be isolated from the reaction mixture by standard techniques.

[0219] Or, R 3 -N(R13 )- and R 4 is hydrogen, a compound of formula (I), i.e., as described above in the embodiments of the present invention, R 4 is hydrogen, a compound of formula (Ib) can be prepared according to the general procedure described in Reaction Scheme 4 below, where X, Y, n, m, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and R 13 are as described above with respect to the compound of formula (Ib) in the embodiments of the present invention: Reaction Scheme 4

Chemical formula

[0220] Compounds of formula (401), (402), (403), and (404) can be commercially available or prepared according to methods known to those skilled in the art or by the methods disclosed herein. Generally, compounds of formula (Ib) are prepared as follows, as described in Reaction Scheme 4 above:

[0221] A compound of formula (401) (where Z 2 is a protecting group (e.g., but not limited to tert-butoxycarbonyl or benzyl)), a sulfonamide (402) (where Lg 1 is a leaving group (e.g., bromo, iodo, or trifluoromethanesulfonate), and Z 1 is hydrogen or a protecting group (e.g., but not limited to tert-butoxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl)), under standard Buchwald-Hartwig cross-coupling conditions (e.g., in the presence of a base (e.g., but not limited to cesium carbonate) and a palladium catalyst (e.g., 4,5-bis The use of a solvent (such as, but not limited to, toluene) in the presence of a compound consisting of, but not limited to, (diphenylphosphino)-9,9-dimethylxanthene and bis(dibenzylideneacetone)palladium(0), and the reaction is carried out at a temperature between approximately ambient temperature and 120 °C for about 1 to 20 hours to give a compound of formula (403). Subsequently, the compound of formula (403) is treated with an acid (such as, but not limited to, trifluoroacetic acid) in a polar aprotic solvent (such as, but not limited to, dichloromethane) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (404). Then, the compound of formula (404) is reacted, in the presence of a reducing agent (such as, but not limited to, sodium triacetoxyborohydride) with, for example, an aldehyde or ketone of formula (405), but not limited thereto, in a polar aprotic solvent mixture (such as, but not limited to, N,N-dimethylformamide and 1,2-dichloroethane) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (I), which can be isolated from this reaction mixture by standard techniques.

[0222] Alternatively, R 3 is -N(R 13 )-, and R 4 is hydrogen, a compound of formula (I), that is, as described above in an embodiment of the present invention, a compound of formula (Ib) in which R 4 is hydrogen can be prepared according to the general procedure described in Reaction Scheme 5 below, where X, Y, n, m, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 13 are as described above for the compound of formula (Ib) in an embodiment of the present invention: Reaction Scheme 5

Chemical formula

[0223] The compounds of formulas (501), (502), (503), (504), (505), (506) and (507) can be commercially available or prepared according to methods known to those skilled in the art or by the methods disclosed herein. Generally, the compounds of formula (Ib) are prepared as follows, as described in Reaction Scheme 5 above:

[0224] The compound of formula (501) wherein Z 2 is a nitrogen protecting group (e.g., but not limited to tert-butoxycarbonyl or benzyl), is reacted with a sulfonamide (502) wherein Lg 1 is a leaving group (e.g., bromo, iodo or trifluoromethanesulfonate), and Z 1 is hydrogen or a protecting group (e.g., but not limited to tert-butoxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl or 2-(trimethylsilyl)ethoxymethyl), under standard Buchwald-Hartwig cross-coupling conditions (e.g., in the presence of a base (e.g., but not limited to cesium carbonate) and a palladium catalyst (e.g., consisting of but not limited to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and bis(dibenzylideneacetone)palladium(0)), using a solvent (e.g., but not limited to toluene)) at a temperature between approximately ambient temperature and 120 °C for about 1 to 20 hours to give the compound of formula (503). The compound of formula (503) is then reacted with an alkylating agent R 13 -Z 3 (504) wherein Z 3is a leaving group (e.g., but not limited to bromide, iodide, sulfate), such as but not limited to methyl iodide, in the presence of a base (e.g., but not limited to lithium bis(trimethylsilyl)amide), in a polar aprotic solvent (e.g., but not limited to tetrahydrofuran), alkylated at a temperature between about -78 °C and ambient temperature to give a compound of formula (505). Then, the compound of formula (505) is treated with an acid (e.g., but not limited to trifluoroacetic acid) in a polar aprotic solvent (e.g., but not limited to dichloromethane) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (506). Then, the compound of formula (506) is reacted, for example, with an aldehyde or ketone of formula (507) but not limited thereto, in the presence of a reducing agent (e.g., but not limited to sodium triacetoxyborohydride), in a polar aprotic solvent mixture (e.g., but not limited to N,N-dimethylformamide and 1,2-dichloroethane) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (I), which can be isolated from this reaction mixture by standard techniques.

[0225] Alternatively, R 3 is -N(R 13 )-, a compound of formula (I), that is, a compound of formula (Ib) as described above in an embodiment of the present invention, can be prepared according to the general procedure described in Reaction Scheme 6 below, where X, Y, n, m, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 13 are as described above with respect to the compound of formula (Ib) in an embodiment of the present invention: Reaction Scheme 6

Chemical formula

[0226] The compounds of formulas (601), (602) and (603) can be prepared commercially available, or according to methods known to those skilled in the art, or by the methods disclosed herein. Generally, the compounds of formula (Ib) are prepared as follows, as described in Reaction Scheme 5 above:

[0227] The compound of formula (601) is reacted with a sulfonamide (602) where Lg 1 is a leaving group (e.g., but not limited to bromo, iodo or trifluoromethanesulfonate), and Z 1 is hydrogen or a protecting group (e.g., but not limited to tert-butoxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl) under standard Buchwald reaction conditions (e.g., in the presence of a base (e.g., but not limited to cesium carbonate) and a palladium catalyst (e.g., consisting of but not limited to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and bis(dibenzylideneacetone)palladium(0)) in a solvent (e.g., but not limited to toluene)) at a temperature between approximately ambient temperature and 120 °C for about 1 - 20 hours to produce a compound of formula (Ib), which can be isolated from this reaction mixture by standard techniques.

[0228] Under certain conditions, the above conversion gives a compound of formula (603) instead of the compound of formula (Ib). In these instances, Z 1 is removed from the compound of formula (603) by methods known in the art (e.g., using an acid (e.g., but not limited to trifluoroacetic acid) at a temperature between about 0 °C and ambient temperature in a polar aprotic solvent (e.g., but not limited to dichloromethane)) to produce a compound of formula (Ib).

[0229] R 13 The compound of formula (Ib) wherein R is hydrogen can be converted by reaction with an aldehyde (e.g., paraformaldehyde, but not limited thereto) in an acidic solvent (e.g., formic acid or trifluoroacetic acid, but not limited thereto) in the presence of a reducing agent (e.g., sodium triacetoxyborohydride or formic acid, but not limited thereto). Subsequently, the compound of formula (Ib) can be isolated from this reaction mixture by standard techniques. 13 Alternatively, the compound of formula (I), i.e., as described above in the embodiments of the present invention, wherein R is -N(R)-, R is hydrogen, and R is alkyl or cycloalkyl, i.e., the compound of formula (Ib) wherein R is hydrogen and R is alkyl or cycloalkyl, can be prepared according to the general procedure described in Reaction Scheme 7 below, where X, Y, n, m, R, R, R, R, R, R, R, and R are as described above for the compound of formula (Ib) in the embodiments of the present invention, and R is alkyl or cycloalkyl:

[0230] Alternatively, R 3 is -N(R 13 )-, R 4 is hydrogen, and R 7 is alkyl or cycloalkyl, the compound of formula (I), i.e., as described above in the embodiments of the present invention, R 4 is hydrogen, and R 7 is alkyl or cycloalkyl, the compound of formula (Ib) can be prepared according to the general procedure described in Reaction Scheme 7 below, where X, Y, n, m, R 1 , R 2 , R 3 , R 5 , R 6 , R 8 and R 13 are as described above for the compound of formula (Ib) in the embodiments of the present invention, and R 7 is alkyl or cycloalkyl: Reaction Scheme 7

Chemical Formula

[0231] The compounds of formulas (701), (702), (703), (704), (705), (706), (707) and (708) can be prepared commercially available, or according to methods known to those skilled in the art, or by the methods disclosed herein. Generally, the compound of formula ( Ib) is prepared as follows, as described in Reaction Scheme 7 above:

[0232] The compound of formula (701) where Z 2 is a nitrogen protecting group (such as, but not limited to, tert-butoxycarbonyl or benzyl), is reacted with a sulfonamide (702) where Z 1 is optionally hydrogen or a nitrogen protecting group (such as, but not limited to, tert-butoxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl), and Lg 1 is a leaving group (such as, but not limited to, chloro, bromo or iodo) 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 or N,N-dimethylformamide) in the presence of a base (such as, but not limited to, potassium carbonate or sodium hydride)) at a temperature between about 0 °C and 80 °C for about 1 to 48 hours to give the compound of formula (703). Then, the compound of formula (703) is reacted with a boronic acid derivative of formula (704) where Z 4 is for example, B(OH)2 or 4,4,5,5-tetramethyl-1,3,2λ2-dioxaborolane, among others, and R 15is, for example, methyl, ethyl or cyclopropyl, but is not limited thereto) and under standard Suzuki-Miyaura reaction conditions (for example, in the presence of a base (for example, tripotassium phosphate, but not limited thereto) and a palladium catalyst (for example, composed of palladium acetate and tricyclohexylphosphine tetrafluoroborate, but not limited thereto), the use of a solvent (for example, 1,4-dioxane, but not limited thereto), but not limited thereto), at a temperature between approximately ambient temperature and 120 °C, and reacted for about 1 to 20 hours to produce a compound of formula (705). Then, the compound of formula (705) is alkylated with an alkylating agent R 13 -Z 3 (where Z 3 is a leaving group (for example, bromide, iodide, sulfate, but not limited thereto)), for example, methyl iodide, but not limited thereto, in the presence of a base (for example, lithium bis(trimethylsilyl)amide or sodium hydride, but not limited thereto), in a polar aprotic solvent (for example, tetrahydrofuran or N,N-dimethylformamide, but not limited thereto), at a temperature between about -78 °C and ambient temperature to give a compound of formula (706). Then, the compound of formula (706) is treated with an acid (for example, trifluoroacetic acid, but not limited thereto) in a polar aprotic solvent (for example, dichloromethane, but not limited thereto) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (707). Then, the compound of formula (707) is reacted, for example, with an aldehyde or ketone of formula (708), but not limited thereto, in the presence of a reducing agent (for example, sodium triacetoxyborohydride, but not limited thereto), in a polar aprotic solvent mixture (for example, N,N-dimethylformamide and 1,2-dichloroethane, but not limited thereto), at a temperature between about 0 °C and ambient temperature to produce a compound of formula (Ib), which can be isolated from this reaction mixture by standard techniques.

[0233] Alternatively, R3 is -N(R 13 ), where R 4 is hydrogen, and R 7 is alkyl or cycloalkyl, a compound of formula (I), i.e., as described above in embodiments of the present invention, where R 4 is hydrogen, and R 7 is alkyl or cycloalkyl, a compound of formula (Ib) can be prepared according to the general procedure described in Reaction Scheme 8 below, where X, Y, n, m, R 1 , R 2 , R 3 , R 5 , R 6 , R 8 and R 13 are as described above for a compound of formula (Ib) in embodiments of the present invention, and R 7 is alkyl or cycloalkyl: Reaction Scheme 8

Chemical Formula

[0234] Compounds of formula (801), (802), (803), (804), (805), (806), (807), (808) and (809) can be commercially available, or prepared according to methods known to those skilled in the art, or by methods disclosed herein. Generally, compounds of formula (Ib) are prepared as follows, as described in Reaction Scheme 8 above:

[0235] A compound of formula (801) (where Z 2 is a nitrogen - protecting group (e.g., but not limited to tert - butoxycarbonyl)) reacts with a sulfonamide (802) (where Z 1 is optionally hydrogen or a nitrogen - protecting group (e.g., but not limited to tert - butoxycarbonyl, 2,4 - dimethoxybenzyl, 4 - methoxybenzyl, or 2 - (trimethylsilyl)ethoxymethyl), and Lg 1is a leaving group (such as, but not limited to, chloro, bromo or iodo), and a standard reaction condition (such as, but not limited to, the use of a polar aprotic solvent (such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide) in the presence of a base (such as, but not limited to, potassium carbonate or sodium hydride)) at a temperature between about 0 °C and 80 °C for about 1 to 48 hours to give a compound of formula (803). Then, the compound of formula (803) is reacted with a boronic acid derivative of formula (804) (where Z 4 is, for example, B(OH)2 or 4,4,5,5-tetramethyl-1,3,2λ2-dioxaborolane, but not limited thereto, and R 15is, for example, methyl, ethyl or cyclopropyl, but is not limited thereto), and under standard Suzuki-Miyaura reaction conditions (for example, in the presence of a base (for example, potassium phosphate, but not limited thereto), and in the presence of a palladium catalyst (for example, consisting of palladium acetate and tricyclohexylphosphine tetrafluoroborate, but not limited thereto)), using a solvent (for example, 1,4-dioxane, but not limited thereto), but not limited thereto), at a temperature between approximately ambient temperature and 120 °C, the reaction can be carried out for about 1 to 20 hours to produce a compound of formula (805). Subsequently, the compound of formula (805) is treated with an acid (for example, trifluoroacetic acid, but not limited thereto) in a polar aprotic solvent (for example, dichloromethane, but not limited thereto) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (806). Subsequently, the compound of formula (806) is, for example, an aldehyde or ketone of formula (807), but not limited thereto, and in the presence of a reducing agent (for example, sodium triacetoxyborohydride, but not limited thereto), in a polar aprotic solvent mixture (for example, N,N-dimethylformamide and 1,2-dichloroethane, but not limited thereto), at a temperature between about 0 °C and ambient temperature, to give a compound of formula (808). Subsequently, the compound of formula (808) is reacted with an aldehyde of formula (809) (where R 16 is, for example, hydrogen or methyl, but is not limited thereto) and a reducing agent (for example, sodium triacetoxyborohydride, but not limited thereto) in a polar solvent or solvent mixture (for example, trifluoroacetic acid, but not limited thereto) at a temperature between about 0 °C and ambient temperature, alkylated at the aniline nitrogen to produce a compound of formula (Ib), which can be isolated from this reaction mixture by standard techniques.

[0236] Alternatively, as described above in the gist of the invention, R 7The compound of formula (I) wherein is alkyl or cycloalkyl can be prepared according to the general procedure described in Reaction Scheme 9 below, where X, Y, n, m, R 1 R 2 R 3 R 4 R 5 R 6 and R 8 are as described above for the compound of formula (I) in the gist of the invention, and R 7 is alkyl or cycloalkyl: Reaction Scheme 9

Chemical formula

[0237] The compounds of formula (901), (902), (903), (904) and (905) can be commercially available or prepared according to methods known to those skilled in the art or by the methods disclosed herein. Generally, the compound of formula (I) is prepared as follows, as described in Reaction Scheme 9 above:

[0238] The compound of formula (901) is reacted with a sulfonamide (902) (where Z 1 is, optionally, hydrogen or a nitrogen protecting group (such as, but not limited to, tert-butoxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl), and Lg 1 is a leaving group (such as, but not limited to, chloro, bromo or iodo) 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 or N,N-dimethylformamide) in the presence of a base (such as, but not limited to, potassium carbonate or sodium hydride)) at a temperature between about 0 °C and 80 °C for about 1 to 48 hours to give the compound of formula (903). Then, the compound of formula (903) is reacted with a boronic acid derivative of formula (904) (where Z 4is, for example, B(OH)2 or 4,4,5,5-tetramethyl-1,3,2λ2-dioxaborolane, but is not limited thereto, and R 15 is, for example, methyl, ethyl or cyclopropyl, but is not limited thereto), and under standard Suzuki-Miyaura reaction conditions (for example, in the presence of a base (for example, potassium phosphate, but not limited thereto), and in the presence of a palladium catalyst (for example, consisting of palladium acetate and tricyclohexylphosphine tetrafluoroborate, but not limited thereto)), the use of a solvent (for example, 1,4-dioxane, but not limited thereto), at a temperature between approximately ambient temperature and 120 °C, for about 1 to 20 hours to react to produce a compound of formula (I), which can be isolated from this reaction mixture by standard techniques.

[0239] Alternatively, the compound of formula (903) is an organotin reagent of formula (904) (where Z 4 is, for example, trimethylstannyl, but is not limited thereto, and R 15 is, for example, methyl, but is not limited thereto) and under standard Stille coupling conditions (for example, in the presence of an additive (for example, lithium chloride, but not limited thereto), and in the presence of a palladium catalyst (for example, bis(triphenylphosphine)palladium dichloride, but not limited thereto)), the use of a solvent (for example, N,N-dimethylformamide, but not limited thereto), at a temperature between ambient temperature and 120 °C, for about 1 to 20 hours to react to produce a compound of formula (I), which can be isolated from this reaction mixture by standard techniques.

[0240] Under certain conditions, the above conversion gives a compound of formula (905) instead of the compound of formula (I). In these examples, Z 1 ​can be removed from the compound of formula (905) by a method known in the art (for example, but not limited to, the use of an acid (such as, but not limited to, trifluoroacetic acid) at a temperature between about 0 °C and ambient temperature in a polar aprotic solvent (such as, but not limited to, dichloromethane)) to produce the compound of formula (I).

[0241] Alternatively, the compound of formula (I) wherein R is hydrogen as described above in the gist of the invention can be prepared according to the general procedure described in Reaction Scheme 10 below, where X, Y, n, m, R 4 ..., R 1 ..., R 2 ..., R 3 ..., R 5 ..., R 6 ..., R 7 and R 8 are as described above for the compound of formula (I) in the gist of the invention: Reaction Scheme 10

Chemical Formula

[0242] The compounds of formula (1001), (1002), (1003), (1004), (1005), (1006), and (1007) can be commercially available or prepared according to methods known to those skilled in the art or by the methods disclosed herein. Generally, the compound of formula (I) is prepared as follows, as described in Reaction Scheme 10 above:

[0243] The compound of formula (1001) wherein Z 2 is a nitrogen protecting group (such as, but not limited to, tert-butoxycarbonyl) reacts with a sulfonamide (1002) wherein Z 1 is optionally hydrogen or a nitrogen protecting group (such as, but not limited to, tert-butoxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl), and Lg 1is a leaving group (such as, but not limited to, chloro, bromo or iodo), and under standard reaction conditions (such as, but not limited to, in the presence of a base (such as, but not limited to, potassium carbonate or sodium hydride) and using a polar aprotic solvent (such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide), and reacting at a temperature between about 0 °C and 80 °C for about 1 to 48 hours to give a compound of formula (1003). Then, the compound of formula (1003) is a boronic acid derivative of formula (1004) where Z 4 is, for example, B(OH)2 or 4,4,5,5-tetramethyl-1,3,2λ2-dioxaborolane, but is not limited thereto, and R 15is, for example, methyl, ethyl or cyclopropyl, but is not limited thereto), and under standard Suzuki-Miyaura reaction conditions (for example, in the presence of a base (for example, potassium phosphate, but not limited thereto) and a palladium catalyst (for example, consisting of palladium acetate and tricyclohexylphosphine tetrafluoroborate, but not limited thereto)), the use of a solvent (for example, 1,4-dioxane, but not limited thereto), and is reacted at a temperature between approximately ambient temperature and 120 °C for about 1 to 20 hours to obtain a compound of formula (1005). Subsequently, the compound of formula (1005) is treated with an acid (for example, trifluoroacetic acid, but not limited thereto) in a polar aprotic solvent (for example, dichloromethane, but not limited thereto) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (1006). Subsequently, the compound of formula (1006) is reacted, for example, with an aldehyde or ketone of formula (1007), but not limited thereto, in the presence of a reducing agent (for example, sodium triacetoxyborohydride, but not limited thereto) in a polar aprotic solvent mixture (for example, N,N-dimethylformamide and 1,2-dichloroethane, but not limited thereto) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (Ib), which can be isolated from this reaction mixture by standard techniques.

[0244] Alternatively, in an embodiment of the present invention, as described above, R 4 is hydrogen, and the compound of formula (Ib) can be prepared according to the general procedure described in Reaction Scheme 11 below, where X, Y, n, m, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are as described above with respect to the compound of formula (Ib) in an embodiment of the present invention: Reaction Scheme 11

Chemical formula

[0245] The compounds of formulas (1101), (1102), (1103), (1104), (1105), (1106), (1107), (1108), and (1109) can be commercially available or can be prepared according to methods known to those skilled in the art or by the methods disclosed herein. Generally, the compounds of formula (Ib) are prepared as follows, as described in Reaction Scheme 11 above:

[0246] The compound of formula (1101) wherein Z 2 is a nitrogen protecting group (e.g., but not limited to tert-butoxycarbonyl), is reacted with a sulfonamide (1102) wherein Z 1 is optionally hydrogen or a nitrogen protecting group (e.g., but not limited to tert-butoxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl), and Lg 1 is a leaving group (e.g., but not limited to chloro, bromo, or iodo). , under standard reaction conditions (for example, but not limited to, in the presence of a base (such as, but not limited to, potassium carbonate or sodium hydride), the use of a polar aprotic solvent (such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide), but not limited thereto), at a temperature between about 0 °C and 80 °C, and reacted for about 1 to 48 hours to give a compound of formula (1103). Then, the compound of formula (1103) is treated with an acid (such as, but not limited to, trifluoroacetic acid) in a polar aprotic solvent (such as, but not limited to, dichloromethane) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (1104). Then, the compound of formula (1104) is reacted with, for example, but not limited to, an aldehyde or ketone of formula (1105) and a reducing agent (such as, but not limited to, sodium triacetoxyborohydride) in a polar aprotic solvent mixture (such as, but not limited to, N,N-dimethylformamide and 1,2-dichloroethane) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (1106). Then, the compound of formula (1106) is reacted with a boronic acid derivative of formula (1107) (where Z 4 is, for example, B(OH)2 or 4,4,5,5-tetramethyl-1,3,2λ2-dioxaborolane, but not limited thereto, and R 15 is, for example, methyl, ethyl or cyclopropyl, but not limited thereto) under standard Suzuki-Miyaura reaction conditions (for example, in the presence of a base (such as, but not limited to, tripotassium phosphate) and a palladium catalyst (such as, but not limited to, a composition comprising palladium acetate and tricyclohexylphosphine tetrafluoroborate), the use of a solvent (such as, but not limited to, 1,4-dioxane), but not limited thereto), at a temperature between approximately ambient temperature and 120 °C, and reacted for about 1 to 20 hours to produce a compound of formula (1108). Then, the compound of formula (1108) is, for example, an aldehyde or ketone of formula (1109) (where R 16is, for example, hydrogen or methyl, but is not limited thereto), but is not limited thereto, in the presence of a reducing agent (for example, sodium triacetoxyborohydride, but is not limited thereto), in a polar aprotic solvent mixture (for example, N,N-dimethylformamide and 1,2-dichloroethane, but is not limited thereto), at a temperature between about 0 °C and ambient temperature, to produce a compound of formula (Ib), which can be isolated from this reaction mixture by standard techniques.

[0247] Alternatively, in an embodiment of the present invention as described above, R 4 is hydrogen, and R 13 is hydrogen or alkyl, a compound of formula (Ib) can be prepared according to the general procedure described in Reaction Scheme 12 below, where X, Y, n, m, R 1 R 2 R 3 R 5 R 6 R 7 and R 8 are as described above for a compound of formula (Ib) in an embodiment of the present invention, and R 13 is hydrogen or alkyl: Reaction Scheme 12

Chemical formula

[0248] Compounds of formula (1201), (1202), (1203), (1204), (1205), and (1206) can be commercially available or prepared according to methods known to those skilled in the art or by the methods disclosed herein. Generally, a compound of formula (Ib) is prepared as follows, as described in Reaction Scheme 12 above:

[0249] A compound of formula (1201) (where Z 1is, if necessary, a hydrogen or nitrogen protecting group (such as, but not limited to, tert-butoxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl), and Lg 1 which is a leaving group (such as, but not limited to, chloro, bromo or iodo), reacts with a nitrogen nucleophile (such as, but not limited to, sodium azide) 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 or N,N-dimethylformamide)) at a temperature between about 0 °C and 80 °C for about 1 to 48 hours. The compound that can be isolated from this reaction mixture by standard techniques is then treated with a reducing agent (such as, but not limited to, zinc powder) in a polar aprotic solvent (such as, but not limited to, tetrahydrofuran) in the presence of a weak acid (such as, but not limited to, aqueous ammonium chloride) to give the compound of formula (1202).

[0250] Alternatively, Lg in the compound of formula (1202) 1 is converted to R by a standard Suzuki 4 is, for example, B(OH)2 or 4,4,5,5-tetramethyl-1,3,2λ2-dioxaborolane, etc., not limited thereto, and R 15 is, for example, methyl, ethyl or cyclopropyl, etc., not limited thereto) -Miyaura reaction conditions (such as, but not limited to, in the presence of a base (such as, but not limited to, tripotassium phosphate) and a palladium catalyst (such as, but not limited to, a composition comprising palladium acetate and tricyclohexylphosphine tetrafluoroborate)) in a solvent (such as, but not limited to, 1,4-dioxane) at a temperature between approximately ambient temperature and 120 °C for about 1 to 20 hours of reaction to produce the compound of formula (1204). is converted to R 7 to produce the compound of formula (1204).

[0251] Next, the compound of formula (1202) or the compound of formula (1204) is reacted, for example, with a ketone of formula (1205) in the presence of a reducing agent (such as, but not limited to, sodium triacetoxyborohydride) in an acidic solvent (such as, but not limited to, trifluoroacetic acid) at a temperature between about 0 °C and ambient temperature, and then with an aldehyde of formula (1206) (where R 16 is, for example, hydrogen or methyl, but not limited thereto) in the presence of a reducing agent (such as, but not limited to, sodium triacetoxyborohydride) in an acidic solvent (such as, but not limited to, trifluoroacetic acid) at a temperature between about 0 °C and ambient temperature to form the compound of formula (Ib), which can be isolated from this reaction mixture by standard techniques.

[0252] Alternatively, the compound of formula (Ib) as described above in the embodiments of the present invention can be prepared according to the general procedure described in Reaction Scheme 13 below, where X, Y, n, m, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as described above for the compound of formula (Ib) in the embodiments of the present invention, and R 13 is hydrogen or alkyl: Reaction Scheme 13

Chemical formula

[0253] The compounds of formula (1301), (1302), (1303), (1304), (1305), and (1306) can be commercially available or prepared according to methods known to those skilled in the art or by the methods disclosed herein. Generally, the compound of formula (I) is prepared as follows, as described in Reaction Scheme 13 above:

[0254] The compound of formula (1301) is a sulfonamide (1302) where Z 1 is optionally hydrogen or a nitrogen protecting group (e.g., tert-butoxycarbonyl, 2,4-dimethoxy benzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl, but not limited thereto), and Lg 1 is a leaving group (e.g., chloro, bromo or iodo, but not limited thereto), and under standard reaction conditions (e.g., in the presence of a base (e.g., potassium carbonate or sodium hydride, but not limited thereto) in a polar aprotic solvent (e.g., dimethyl sulfoxide or N,N-dimethylformamide, but not limited thereto), but not limited thereto), at a temperature between about 0 °C and 80 °C for about 1 to 48 hours to give a compound of formula (1303). Then, the compound of formula (1303) is reacted with a boronic acid derivative of formula (1304) where Z 4 is for example B(OH)2 or 4,4,5,5-tetramethyl-1,3,2λ2-dioxaborolane, but not limited thereto, and R 15 is for example methyl, ethyl or cyclopropyl, but not limited thereto), and under standard Suzuki-Miyaura reaction conditions (e.g., in the presence of a base (e.g., tripotassium phosphate, but not limited thereto) and in the presence of a palladium catalyst (e.g., consisting of palladium acetate and tricyclohexylphosphine tetrafluoroborate, but not limited thereto) in a solvent (e.g., 1,4-dioxane, but not limited thereto), but not limited thereto), at a temperature between approximately ambient temperature and 120 °C for about 1 to 20 hours to produce a compound of formula (1305). Then, the compound of formula (1305) is reacted with an aldehyde of formula (1306) where R 16For example, in the presence of a reducing agent (such as, but not limited to, sodium triacetoxyborohydride) and a polar solvent or solvent mixture (such as, but not limited to, trifluoroacetic acid), at a temperature between about 0 °C and ambient temperature, with an alkylating agent (such as, but not limited to, hydrogen or methyl), the aniline nitrogen can be alkylated to produce a compound of formula (Ib), which can be isolated from this reaction mixture by standard techniques.

[0255] Alternatively, the compound of formula (1305) can be alkylated at the aniline nitrogen by reaction with an alkylating agent (such as, but not limited to, methyl iodide) in the presence of a base (such as, but not limited to, sodium hydride) in a polar aprotic solvent (such as, but not limited to, N,N-dimethylformamide) at a temperature between about -5 °C and ambient temperature. Subsequently, the alkylated compound is treated with an acid (such as, but not limited to, trifluoroacetic acid) in a polar aprotic solvent (such as, but not limited to, dichloromethane) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (Ib), which can be isolated from this reaction mixture by standard techniques.

[0256] Alternatively, the compound of formula (Ib) as described above in embodiments of the present invention can be prepared according to the general procedure described in Reaction Scheme 14 below, where X, Y, n, m, R 1 、R 2 、R 4 、R 3 、R 5 、R 6 、R 7 、R 8 and R 13 are as described above for the compound of formula (Ib) in embodiments of the present invention: Reaction Scheme 14

Chemical formula

[0257] The compounds of formulas (1401), (1402), (1403), (1404) and (1405) can be commercially available or prepared according to methods known to those skilled in the art or by the methods disclosed herein. Generally, the compounds of formula (Ib) are prepared as follows, as described in Reaction Scheme 14 above:

[0258] The compound of formula (1401) is reacted with a sulfonamide (1402) where Lg 1 is a leaving group (e.g., but not limited to bromo, iodo or trifluoromethanesulfonate), and Z 1 is hydrogen or a protecting group (e.g., but not limited to tert-butoxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl) under standard Buchwald reaction conditions (e.g., in the presence of a base (e.g., but not limited to cesium carbonate) and a palladium catalyst (e.g., consisting of but not limited to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and bis(dibenzylideneacetone)palladium(0) or chloro(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II)) in a solvent (e.g., but not limited to toluene or 2-methyl-2-butanol) at a temperature between approximately ambient temperature and 120 °C for about 1 to 20 hours to produce the compound of formula (1403). Then, the compound of formula (1403) is reacted with an alkylating agent R 13 -Z 3 (1404) where Z 3is a leaving group (e.g., but not limited to bromide, iodide, sulfate), such as but not limited to methyl iodide, and in the presence of a base (e.g., but not limited to sodium hydride), in a polar aprotic solvent (e.g., but not limited to N,N-dimethylformamide), alkylated at a temperature between about 0 °C and ambient temperature to give a compound of formula (1405). The compound of formula (1405) is then treated with an acid (e.g., but not limited to trifluoroacetic acid) in a polar aprotic solvent (e.g., but not limited to dichloromethane) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (Ib), which can be isolated from this reaction mixture by standard techniques.

[0259] In an embodiment of the invention, as described above, R 4 is hydrogen, and at least one R 6 is haloalkyl, a compound of formula (Ib1), which is a compound of formula (Ib), can be prepared according to the general procedure described in reaction scheme 15 below, where X, Y, m, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are as described above with respect to the compound of formula (Ib) in the gist of the invention, n is 1 or 2, and R 6a is haloalkyl: Reaction Scheme 15

Chemical Formula

[0260] The compounds of formulas (1501), (1502), (1503), (1504), and (1505) can be prepared commercially available, or according to methods known to those skilled in the art, or by the methods disclosed herein. Generally, the compounds of formula (I) are prepared as follows, as described in Reaction Scheme 15 above:

[0261] The compound of formula (1501) wherein Z 2 is a nitrogen protecting group (e.g., but not limited to tert-butoxycarbonyl or benzyl), is reacted with a sulfonamide (1502) wherein Z 1 is optionally hydrogen or a nitrogen protecting group (e.g., but not limited to tert-butoxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl), under standard reaction conditions (e.g., but not limited to the use of a polar aprotic solvent (e.g., but not limited to dimethyl sulfoxide or N,N-dimethylformamide) in the presence of a base (e.g., but not limited to potassium carbonate or sodium hydride)) at a temperature between about 0 °C and 80 °C for about 1 to 48 hours to give a compound of formula (1503). The compound of formula (1503) is then treated with a halogenating reagent (e.g., but not limited to diethylaminosulfur trifluoride) in a polar aprotic solvent (e.g., but not limited to dichloromethane) at a temperature between about 0 °C and ambient temperature to produce a compound of formula (1504) wherein R 6a is haloalkyl. The compound of formula (1504) is then treated with an acid (e.g., but not limited to trifluoroacetic acid) in a polar aprotic solvent (e.g., but not limited to dichloromethane) at a temperature between ambient temperature and 120 °C, and then, for example, but not limited to an aldehyde or ketone of formula (1505), in the presence of a reducing agent (e.g., but not limited to sodium triacetoxyborohydride), in a polar aprotic solvent mixture (e.g., N, in (but not limited to) N-dimethylformamide and dichloromethane, reacted at a temperature between about 0 °C and ambient temperature to produce a compound of formula (I), which can be isolated from this reaction mixture by standard techniques.

[0262] Alternatively, a compound of formula (I) as described above in the gist of the invention can be synthesized by those skilled in the art by simple functional group conversion. Thus, R 6 being alkenyl, a compound of formula (I) (but not limited to these) is, in the presence of (but not limited to) carbon-supported palladium with hydrogen, in a solvent such as (but not limited to) methanol and ethyl acetate, by treatment, can be converted to a compound of formula (I) where R 6 is alkyl. Alternatively, R 1 being (methoxycarbonyl)phenyl, a compound of formula (I) (but not limited to these) is, a compound of formula (I) where R 1 is (2-hydroxypropan-2-yl)phenyl, can be converted by reaction with an organometallic reagent (such as, but not limited to, methylmagnesium bromide) in a polar aprotic solvent (such as, but not limited to, tetrahydrofuran).

[0263] All of the compounds described below, which may exist in the form of the free base or free acid, can be converted to their pharmaceutically acceptable salts by treatment with a suitable inorganic or organic base or acid. The salts of the compounds prepared below can be converted to their free base or acid forms by standard techniques. Furthermore, all compounds of the present invention containing an acid or ester group can be converted to the corresponding ester or acid, respectively, by methods known to those skilled in the art or as described herein.

[0264] The following examples regarding the synthesis of the compounds of the present invention, and the subsequent biological examples, are provided as a guide to assist in the implementation of the present invention and are not intended to be a limitation on the scope of the present invention.

[0265] In the following examples, unless otherwise indicated, all temperatures are given in degrees Celsius. 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 following reactions were generally carried out in anhydrous solvents under a positive pressure of nitrogen or argon or using a drying tube (unless otherwise indicated), and reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringes. Glassware was oven dried and / or heat dried. Yields were not optimized. Melting points were recorded using a Buechi hot stage apparatus. Uncorrected. 1 H NMR, 19 F and 13 C NMR data were obtained in deuterated CDCI3, DMSO-d6, CD3OD, CD3CN, or acetone-d6 solvent solutions, and chemical shifts (δ) were reported in parts per million (ppm) relative to trimethylsilane (TMS) as a reference standard or the residual non-deuterated solvent peak. Data were reported as follows, where applicable: chemical shift, multiplicity, coupling constant in Hz, and the number of protons, fluorine or carbon atoms. When the multiplicity of a peak is 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 are reported in Hz (hertz) when given.

Example

[0266] Example 1 Synthesis of 3-chloro-4-((3,3-dimethylpiperidin-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide 2,2,2-trifluoroacetate

Chem.

[0267] Step 1. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Chem.

[0268] To a mixture of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (prepared according to PCT Patent Application Publication No. WO 2010 / 079443, 15.1 g, 60.2 mmol) in anhydrous tetrahydrofuran (200 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (72.1 mL, 72.1 mmol) at 0 °C, and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was cooled to -78 °C, and a solution of 3-chloro-4-fluorobenzenesulfonyl chloride (13.8 g, 60.2 mmol) in anhydrous tetrahydrofuran (40 mL) was added thereto. The reaction mixture was warmed to ambient temperature, stirred for 2 h, and diluted with ethyl acetate (280 mL). The mixture was washed with saturated ammonium chloride solution (2 × 150 mL), brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was triturated in methanol (110 mL) to afford the title compound as a colorless solid (14.8 g, yield 55%): 1 H NMR (300 MHz, CDCl3) δ 8.22 (s, 1H), 7.71-7.65 (m, 2H), 7.20-7.13 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.36 (dd, J = 8.4, 2.4 Hz, 1H), 6.30 (d, J = 2.4 Hz, 1H), 5.31 (s, 2H), 3.79 (s, 3H), 3.68 (s, 3H); MS (ES+) m / z 444.0 (M + 1)., 446.0 (M + 1).

[0269] Step 2: Preparation of tert-butyl 4-hydroxy-3,3-dimethylpiperidine-1-carboxylate

Chem.

[0270] To a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (4.61 g, 20.3 mmol) in anhydrous methanol (75 mL) was added sodium borohydride (0.77 g, 20.3 mmol) at 0 °C. The reaction mixture was warmed to ambient temperature and stirred for 48 h. The mixture was diluted with ethyl acetate (300 mL), washed with 0.5 M hydrochloric acid (4 × 80 mL), brine (3 × 60 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate under reduced pressure gave the title compound as a colorless solid (4.59 g, 99% yield): 1 H NMR (300 MHz, CDCl3) δ 3.90-3.78 (m, 1H), 3.57-3.48 (m, 1H), 3.41 (dd, J = 9.2, 4.2 Hz, 1H), 3.08-2.99 (m, 1H), 2.73 (d, J = 13.4 Hz, 1H), 1.85-1.71 (m, 2H), 1.62-1.55 (m, 1H), 1.42 (s, 9H), 0.95 (s, 3H), 0.88 (s, 3H); MS (ES+) m / z 230.2 (M + 1).

[0271] Step 3. Preparation of tert-butyl 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)phenoxy)-3,3-dimethylpiperidine-1-carboxylate

Chem.

[0272] A solution of tert-butyl 4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (1.37 g, 5.97 mmol) in anhydrous tetrahydrofuran (180 mL) was added dropwise with a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (6.0 mL, 6.0 mmol) at -78 °C. The reaction mixture was warmed to ambient temperature, stirred for 1 h, and then cooled to -78 °C. Then, a mixture of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (2.65 g, 5.97 mmol) in anhydrous tetrahydrofuran (10 mL) was added thereto. The reaction mixture was warmed to ambient temperature, stirred for 4 h, and diluted with ethyl acetate (200 mL). The mixture was washed with saturated ammonium chloride (2 × 200 mL), dried over anhydrous sodium sulfate, and filtered. The residue was obtained by concentration of the filtrate under reduced pressure and purified by column chromatography eluting with 30% ethyl acetate in hexane. The title compound was obtained as a clear oil (2.36 g, yield 61%): 1 H NMR (300 MHz, CDCl3) δ 8.18 (s, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 8.8, 2.3 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.37-6.28 (m, 2H), 5.25 (s, 2H), 4.12 (dd, J = 7.1, 4.4 Hz, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 3.63-3.36 (m, 4H), 3.15 (d, J = 13.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.48 (s, 9H), 1.06 (s, 3H), 1.03 (s, 3H).

[0273] Step 4. Preparation of 3-chloro-4-((3,3-dimethylpiperidin-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide 2,2,2-trifluoroacetate [Chem.]

[0274] To a solution of tert-butyl 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)phenoxy)-3,3-dimethylpiperidine-1-carboxylate (2.36 g, 3.61 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (5 mL), and the resulting mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure, triturated in methanol (60 mL), and filtered. Concentration of the filtrate under reduced pressure gave the title compound as a colorless foam (1.87 g, quantitative yield): H NMR (300 MHz, DMSO-d6) δ 8.79 (br s, 1H), 8.64 (br s, 1H), 8.43 (s, 1H), 7.76 (d, J = 2.3 Hz, 1H), 1 7.70 (dd, J = 8.7, 2.3 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 4.53 7.70 (dd, J = 8.7, 2.3 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 4.53 (dd, J = 7.7, 3.0 Hz, 1H), 3.12 - 2.98 (m, 3H), 2.96 - 2.85 (m, 1H), 2.09 - 1.97 (m, 1H), 1.85 - 1.70 (m, 1H), 1.07 (s, 3H), 1.02 (s, 3H), NH not observed; MS (ES+) m / z 403.0 (M + 1), 405.0 (M + 1).

[0275] Example 2 Synthesis of 4-((1-benzyl-3,3-dimethylpiperidin-4-yl)oxy)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide 2,2,2-trifluoroacetate [Chem.]

[0276] A mixture of 3-chloro-4-((3,3-dimethylpiperidin-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide 2,2,2-trifluoroacetate (0.20 g, 0.39 mmol) and benzaldehyde (0.08 g, 0.78 mmol) in anhydrous 1,2-dichloroethane (8 mL) was added sodium triacetoxyborohydride (0.17 g, 0.78 mmol), and the resulting mixture was stirred for 18 h. The mixture was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride (2×30 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC eluting with a gradient of 10 - 60% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound as a colorless solid (0.075 g, 32% yield): 1 H NMR (300 MHz, DMSO-d6) δ 9.71 (br s, 1H), 8.43 (s, 1H), 7.75 - 7.70 (m, 1H), 7.68 (dd, J = 8.7, 2.3 Hz, 1H), 7.56 - 7.32 (m, 6H), 4.55 - 4.41 (m, 1H), 4.39 - 4.23 (m, 2H), 3.52 - 2.73 (m, 4H), 2.22 - 2.07 (m, 1H), 2.00 - 1.76 (m, 1H), 1.15 (s, 3H), 0.92 (s, 3H), NH was not observed; MS (ES+) m / z 493.0 (M + 1), 495.0 (M + 1).

[0277] Example 3 Synthesis of 3-chloro-4-((1-(3,5-dimethylbenzyl)-3,3-dimethylpiperidin-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide 2,2,2-trifluoroacetate

Chemical formula

[0278] Following the procedure described for Example 2, minor changes were made as necessary to replace benzaldehyde with 3,5-dimethylbenzaldehyde to obtain the title compound as a colorless solid (0.17 g, 67% yield): 1 H NMR (300 MHz, DMSO-d6) δ 9.51 (br s, 1H), 8.43 (s, 1H), 7.74 (d, J = 2.1 Hz, 1H), 7.68 (dd, J = 8.7, 2.1 Hz, 1H), 7.42-7.33 (m, 1H), 7.16-7.03 (m, 3H), 4.5 8-4.40 (m, 1H), 4.29-4.13 (m, 2H), 3.45-3.02 (m, 3H), 2.99-2.78 (m, 1H), 2.26 (s, 6H), 2.19-2.05 (m, 1H), 2.01-1.75 (m, 1H), 1.16 (d, J = 13.1 Hz, 3H), 0.93 (s, 3H) (Note: NH was not observed); MS (ES+) m / z 521.0 (M + 1), 523.0 (M + 1).

[0279] Example 4 Synthesis of 3-chloro-4-((1-(3,5-dichlorobenzyl)-3,3-dimethylpiperidin-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide 2,2,2-trifluoroacetate

Chemical Structure

[0280] Following the procedure described for Example 2, minor changes were made as necessary to replace benzaldehyde with 3,5-chlorobenzaldehyde to obtain the title compound as a colorless solid (0.135 g, 51% yield): 1 H NMR (300 MHz, DMSO-d6) δ 9.92 (broad singlet, 1H), 8.44 (singlet, 1H), 7.76 - 7.62 (multiplet, 5H), 7.37 (doublet, J = 8.9 Hz, 1H), 5.56 (broad singlet, 1H), 4.54 - 4.43 (multiplet, 1H), 4.30 (singlet, 2H), 3.46 - 2.74 (multiplet, 4H), 2.21 - 2.06 (multiplet, 1H), 1.99 - 1.81 (multiplet, 1H), 1.04 (broad singlet, 6H); MS (ES+) m / z 561.0 (M + 1), 563.0, 564.9 (M + 1).

[0281] Example 5 Synthesis of 3 - chloro - 4 - ((1 - (3 - (difluoromethoxy)benzyl)piperidin - 4 - yl)oxy)-N-(thiazol - 2 - yl)benzenesulfonamide

Chemical Structure

[0282] Step 1. Preparation of 3 - chloro - N-(2,4 - dimethoxybenzyl)-4 - fluoro - N-(thiazol - 2 - yl)benzenesulfonamide

Chemical Structure

[0283] To a mixture of N-(2,4 - dimethoxybenzyl)thiazol - 2 - amine (prepared according to WO 2013063459, 35.0 g, 140 mmol) in anhydrous tetrahydrofuran (350 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (182 mL, 182 mmol) at - 78 °C. The reaction mixture was warmed to 0 °C and stirred for 30 minutes. The reaction mixture was cooled to - 78 °C and a solution of 3 - chloro - 4 - fluorobenzenesulfonyl chloride (41.6 g, 182 mmol) in anhydrous tetrahydrofuran (100 mL) was added thereto. The reaction mixture was Warmed to ambient temperature, stirred for 2 hours, quenched by the addition of water (200 mL), and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography eluting with a gradient of 2 - 20% ethyl acetate in petroleum ether, followed by trituration in methanol (2 × 150 mL) gave the title compound as a colorless solid (32.0 g, 50% yield): 1 H NMR (300 MHz, CDCl3) δ 7.86 (dd, J = 8.0, 2.4 Hz, 1H), 7.78 - 7.71 (m, 1H), 7.47 (d, J = 4.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 12.0 Hz, 1H), 7.08 (d, J = 4.0 Hz, 1H), 6.41 - 6.35 (m, 2H), 5.07 (s, 2H), 3.79 (s, 3H), 3.71 (s, 3H); MS (ES+) m / z 464.9 (M + 23)., 467.0 (M + 23).

[0284] Step 2. Preparation of tert-butyl 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenoxy)piperidine-1-carboxylate

Chemical formula

[0285] A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.43 g, 22.0 mmol) in anhydrous tetrahydrofuran (75 mL) was added dropwise with a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (25.0 mL, 25.0 mmol) at -78 °C. The resulting mixture was warmed to ambient temperature and stirred for 1 h. The reaction mixture was cooled to -78 °C and 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide (8.86 g, 20.0 mmol) was added. The resulting mixture was warmed to ambient temperature and stirred for 18 h. The reaction mixture was cooled to 0 °C and a 60% dispersion of sodium hydride in mineral oil (0.80 g, 20.0 mmol) was added thereto. The resulting mixture was heated at 45 °C for 2 h and then cooled to ambient temperature. The reaction mixture was quenched by slowly adding water (100 mL) and diluted with ethyl acetate (250 mL). The mixture was washed with saturated ammonium chloride (2×150 mL), brine (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 10-60% ethyl acetate in hexane to afford...

Claims

【Claim 1】 Epilepsy.

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