OA18626A

OA18626A - Sulfonamides as modulators of sodium channels.

Info

Publication number: OA18626A
Application number: OA1201600008
Authority: OA
Inventors: Corey Anderson; Vijayalaksmi Arumugam; Paul Krenitsky; Brian Richard Bear; Sara Sabina Hadida-Ruah; Andreas P. Termin; James Philip Johnson
Original assignee: Vertex Pharmaceuticals Incorporated
Priority date: 2013-07-19
Filing date: 2014-07-18
Publication date: 2019-01-31

Abstract

The invention relates to compounds of formula I or pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels:

Description

SULFONAMIDES AS MODULATORS OF SODIUM CHANNELS

TECHNICAL FIELD OF THE INVENTION

The invention relates to compounds useful as inhibitors of sodium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of varions disorders including pain.

BACKGROUND OF THE INVENTION

Pain is a protective mechanism that allows healthy animais to avoid tissue damage and to prevent further damage to injured tissue. Nonetheless there are many conditions where pain persists beyond its usefulness, or where patients would benefit from inhibition of pain. Neuropathie pain is a form of chronic pain caused by an injury to the sensory nerves (Dieleman, J.P., et al., Incidence rates and treatment of neuropathie pain conditions in the general population. Pain, 2008.137(3): p. 681-8). Neuropathie pain can be divided into two categories, pain caused by generalized metabolic damage to the nerve and pain caused by a discrète nerve injury. The metabolic neuropathies include post herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Discrète nerve injuries indications include post amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like neuropathie back pain.

Voltage-gated sodium channels (Nav’s) play a critical rôle in pain signaling. Nav’s are key biological mediators of electrical signaling as they are the primary mediators of the rapid upstroke of the action potential of many excitable cell types (e.g. neurons, skeletal myocytes, cardiac myocytes). The evidence for the rôle of these channels in normal physiology, the pathological States arising from mutations in sodium channel genes, preclinical work in animal models, and the clinical pharmacology of known sodium channel modulating agents ail point to the central rôle of Nav’s in pain sensation (Rush, A.M. and T.R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Na vl.8 Sodium Channels. Mol Interv, 2007. 7(4): p. 192-5); England, S., Voltage-gated sodium channels: the search for subtype-selective analgésies. Expert Opin Investig Drugs 17 (12), p. 1849-64 (2008); Krafte, D. S. and Bannon, A. W., Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr Opin Pharmacol 8 (1), p. 50-56 (2008)).

Nav’s are the primary mediators of the rapid upstroke of the action potential of many excitable cell types (e.g. neurons, skeletal myocytes, cardiac myocytes), and thus are critical for the initiation of signaling in those cells (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Because of the rôle Nav’s play in the initiation and propagation of neuronal signais, antagonists that reduce Nav currents can prevent or reduce neural signaling and Nav channels hâve long been considered likely targets to reduce pain in conditions where hyper-excitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, J. J., Voltage-gated sodium channels in neurological disorders. CNS Neurol Disord Drug Targets 7 (2), p. 144-58 (2008)). Several clinically useful analgésies hâve been identified as inhibitors of Nav channels. The local anesthetic drugs such as lidocaine block pain by inhibiting Nav channels, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants that hâve proven effective at reducing pain hâve also been suggested to act by sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. EurJ Pain 6 Suppl A, p. 3-9 (2002); Wang, G. K., Mitchell, J., and Wang, S. Y., Block of persistent late Na⁺ currents by antidepressant sertraline and paroxetine. JMembr Biol 222 (2), p. 79-90 (2008)).

The Nav’s form a subfamily of the voltage-gated ion channel super-family and comprises 9 isoforms, designated Nav 1.1 -Navl .9. The tissue localizations of the nine isoforms vary greatly. Navl .4 is the primary sodium channel of skeletal muscle, and Navl .5 is primary sodium channel of cardiac myocytes. Nav’s 1.7, 1.8 and 1.9 are primarily localized to the peripheral nervous System, while Nav’s 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous Systems. The functional behaviors of the nine isoforms are similar but distinct in the spécifies of their voltage-dependent and kinetic behavior (Catterall, W. A., Goldin, A. L., and Waxman, S. G., International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 57 (4), p. 397 (2005)).

Immediately upon their discovery, Navl .8 channels were identified as likely targets for analgesia (Akopian, A.N., L. Sivilotti, and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62). Since then, Navl .8 has been shown to be the most significant carrier of the sodium current that maintains action potential firing in small DRG neurons (Blair, N.T. and B.P. Bean, Rôles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na⁺ current, and Ca²⁺ current in the action potentials of nociceptive sensory neurons. J Neurosci., 2002. 22(23): p. 10277-90). Nayl.8 is essential for spontaneous firing in damaged neurons, like those that drive neuropathie pain (Roza, C., et al., The tetrodotoxin-resistant Na⁺ channel Nayl.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6; Jarvis, M.F., et al., A-803467, a potent and sélective Nayl.8 sodium channel blocker, atténuâtes neuropathie and inflammatory pain in the rat. Proc Natl Acad Sci. USA, 2007.104(20): p. 8520-5; Joshi, S.K., et al., Involvement of the TTXresistant sodium channel Navl.8 in inflammatory and neuropathie,but not post-operative, pain States. Pain, 2006.123(1-2): pp. 75-82; Lai, J., et al., Inhibition of neuropathie pain by decreased expression of the tetrodotoxin-resistant sodium channel, Nayl.8. Pain, 2002. 95(12): p. 143-52; Dong, X.W., et al., Small interfering RNA-mediated sélective knockdown of Na(y)1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathie rats. Neuroscience, 2007.146(2): p. 812-21; Huang, H.L., et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyperexcitable nerves. Mol Pain, 2008. 4: p. 33; Black, J.A., et al., Multiple sodium channel isoforms and mitogen-activated protein kinases are présent in painful human neuromas. Ann Neurol, 2008. 64(6): p. 644-53; Coward, K., et al., Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain States. Pain, 2000. 85(1-2): p. 41-50; Yiangou, Y., et al., SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett, 2000. 467(2-3): p. 249-52; Ruangsri, S., et al., Relationship of axonal voltage-gated sodium channel 1.8 (Nayl.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J Biol Chem. 286(46): p. 3983647). The small DRG neurons where Nayl.8 is expressed include the nociceptors critical for pain signaling. Nayl.8 is the primary channel that médiates large amplitude action potentials in small neurons of the dorsal root ganglia (Blair, N.T. and B.P. Bean, Rôles of tetrodotoxin (TTX)-sensitive Na⁺ current, TTX-resistant Na⁺ current, and Ca²⁺ current in the action potentials of nociceptive sensory neurons. JNeurosci., 2002. 22(23): p. 10277-90). Nayl.8 is necessary for rapid répétitive action potentials in nociceptors, and for spontaneous activity of damaged neurons. (Choi, J.S. and S.G. Waxman, Physiological interactions between

Nayl.7 and Nayl.8 sodium channels: a computer simulation study. J Neurophysiol. 106(6): p. 3173-84; Renganathan, M., T.R. Cummins, and S.G. Waxman, Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons. JNeurophysiol., 2001. 86(2): p. 629-40; Roza, C., et al., The tetrodotoxin-resistant Na⁺ channel Nayl.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J Physiol., 2003. 550(Pt 3): p. 921-6). In depolarized or damaged DRG neurons, Nayl.8 appears to be the primary driver of hyper-excitablility (Rush, A.M., et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci USA, 2006. 103(21): p. 8245-50). In some animal pain models, Na_v1.8 mRNA expression levels hâve been shown to increase in the DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibres contributes to painful diabetic neuropathy in rats. Brain. 135(Pt 2): p. 359-75; Strickland, I.T., et al., Changes in the expression of NaV1.7, Nayl.8 and Nayl.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur J Pain,

2008.12(5): p. 564-72; Qiu, F., et al., Increased expression of tetrodotoxin-resistant sodium channels Nayl.8 and Nayl.9 within dorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett. 512(2): p. 61-6).

The primary drawback to the known Nay inhibitors is their poor therapeutic window, and this is likely a conséquence of their lack of isoform selectivity. Since Nayl .8 is primarily restricted to the neurons that sense pain, sélective Nayl.8 blockers are unlikely to induce the adverse events common to non-selective Nay blockers. Accordingly, there remains a need to develop additional Nay channel antagonists preferably those that are more Navl.8 sélective and more potent with increased metabolic stability and with fewer side effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, and pharmaceutically acceptable salts and compositions thereof, are useful as inhibitors of voltage-gated sodium channels.

These compounds hâve the general formula I:

I;

or a pharmaceutically acceptable sait thereof.

These compounds and pharmaceutically acceptable salts and compositions are usefiil for treating or lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, chronic pain, gut pain, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia.

Detailed Description of the Invention

In one aspect, the invention provides compounds of formula I:

R¹ O f^il r²Jv AA ?

VjL H O^S'^NH2

R³’tt^O

R⁴ I rVA⁵T T R⁶ R⁶' R⁷

I;

or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence:

R¹ is H, Cl, CH₃, CF₃ or cyclopropyl;

R² is H, F, Cl, CN, CH₃, CF₃ or CHF₂;

R³ is H, F, Cl, CN, CF₃, OCF₃ or CF₂CF₃;

R⁴ is H;

R⁵ is H, F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂;

R⁵' is H, F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂;

R⁶ is H, F or Cl;

R⁶’ is H, F or Cl; and

R⁷ is H, F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂, provided that R , R , and R are not simultaneously hydrogen; and that R⁵, R⁵, R⁶, R⁶, and R⁷ are not simultaneously hydrogen.

For purposes of this invention, the Chemical éléments are identified in accordance with the Periodic Table of the Eléments, CAS version, Handbook of Chemistry and Physics, 75^λ Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry,” 5^ώ Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplifïed by particular classes, subclasses, and species of the invention. As described herein, the variables in formula I encompass spécifie groups, such as, for example, alkyl and cycloalkyl. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that resuit in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, détection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a température of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

The phrase “optionally substituted” may be used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted,” whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Spécifie substituents are described above in the définitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can hâve a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring System, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that resuit in the formation of stable or chemically feasible compounds.

The phrase “up to,” as used herein, refers to zéro or any integer number that is equal or less than the number following the phrase. For example, “up to 4” means any one of 0, 1, 2, 3, and 4.

The term “aliphatic,” “aliphatic group” or “alkyl” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1 - 8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodi ments aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups.

The ternis “cycloaliphatic” or “cycloalkyl” mean a monocyclic hydrocarbon ring, or a polycyclic hydrocarbon ring System that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic and has a single point of attachment to the rest of the molécule.

The term “polycyclic ring System,” as used herein, includes bicyclic and tricyclic 4- to 12- membered structures that form at least two rings, wherein the two rings hâve at least one atom in common (e.g., 2 atoms in common) including fused, bridged, or spirocyclic ring Systems.

The term “halogen” or “halo” as used herein, means F, Cl, Br or I.

Unless otherwise specified, the term “heterocycle,” “heterocyclyl,” “heterocycloaliphatic,” “heterocycloalkyl,” or “heterocyclic” as used herein means nonaromatic, monocyclic, bicyclic, or tricyclic ring Systems in which one or more ring atoms in one or more ring members is an independently selected heteroatom. Heterocyclic ring can be saturated or can contain one or more unsaturated bonds. In some embodiments, the “heterocycle,” “heterocyclyl,” “heterocycloaliphatic,” “heterocycloalkyl,” or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the ring System contains 3 to 7 ring members.

The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, or Silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or Silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4dihydro-2/7-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation but is not aromatic.

The term “alkoxy,” or “thioalkyl,” as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic, bicyclic, and tricyclic ring Systems having a total of five to fourteen ring carbon atoms, wherein at least one ring in the System is aromatic and wherein each ring in the System contains 3 to 7 ring carbon atoms. The term “aryl” may be used interchangeably with the term “aryl ring.”

The term “heteroaryl,” used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy,” refers to monocyclic, bicyclic, and tricyclic ring Systems having a total of five to fourteen ring members, wherein at least one ring in the System is aromatic, at least one ring in the System contains one or more heteroatoms, and wherein each ring in the System contains 3 to 7 ring members. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic.”

Unless otherwise stated, structures depicted herein are also meant to include ail isomeric (e.g., enantiomeric, diastereomeric, and géométrie (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and géométrie (or conformational) mixtures of the présent compounds are within the scope of the invention. Unless otherwise stated, ail tautomeric forms of the compounds of the invention are within the scope of the invention. Thus, included within the scope of the invention are tautomers of compounds of formula I. The structures also include zwitterionic forms of the compounds or salts of formula I where appropriate.

Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched or isotopically-labeled atoms. The isotopically-labeled compounds may hâve one or more atoms replaced by an atom having an atomic mass or mass number usually found in nature. Examples of isotopes présent in compounds of formula I include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ²H, ³H, ¹³C, ^l4C, ^l5N, ^l8O, ^l70,³⁵S and ¹⁸F. Certain isotopically-labeled compounds of formula I, in addition to being usefiil as as therapuetic agents, are also usefiil in drug and/or substrate tissue distribution assays, as analytical tools or as probes in other biological assays. In one aspect of the présent invention, tritiated (e.g., ³H) and carbon-14 (e.g., ¹⁴C) isotopes are usefiil given their ease of detectability. In another aspect of the présent invention, replacement of one or more hydrogen atoms with heavier isotopes such as deuterium, (e.g., ²H) can afford certain therapeutic advantages.

In one embodiment, the invention features a compound of formula I and the attendant définitions, wherein R¹ is H. In another embodiment, R¹ is Cl. In another embodiment,

R¹ is CHj. In another embodiment, R¹ is CF₃. In another embodiment, R¹ is cyclopropyl. In another embodiment, R¹ is H, CF3 or Cl. In another embodiment, R¹ is H or CF3.

In another embodiment, the invention features a compound of formula I and the attendant définitions, wherein R² is H. In another embodiment, R² is F. In another embodiment, R is Cl. In another embodiment, R is CN. In another embodiment, R is CH3. In another embodiment, R is CF3. In another embodiment, R is CHF2. In another embodiment, R² is H, CF₃ or Cl. In another embodiment, R² is H or CF3.

In another embodiment, the invention features a compound of formula I and the attendant définitions, wherein R³ is H. In another embodiment, R³ is F. In another embodiment, R³ is Cl. In another embodiment, R³ is CN. In another embodiment, R³ is CF3. In another embodiment, R³ is OCF3. In another embodiment, R³ is CF2CF3. In another embodiment, R³ is H, CF3, Cl or OCF3. In another embodiment, R³ is H, CF3 or Cl.

In another embodiment, the invention features a compound of formula I and the attendant définitions, wherein R⁵ is H. In another embodiment, R⁵ is F. In another embodiment, R⁵ is Cl. In another embodiment, R⁵ is CH3. In another embodiment, R⁵ is OCH3. In another embodiment, R⁵ is OCH2CH3. In another embodiment, R⁵ is OCH2CH2CH3. In another embodiment, R⁵ is OCHF2.

In another embodiment, the invention features a compound of formula I and the attendant définitions, wherein R⁶ is H. In another embodiment, R⁶ is F. In another embodiment, R⁶ is Cl. In another embodiment, R⁶ is H or F.

In another embodiment, the invention features a compound of formula I and the attendant définitions, wherein R⁷ is H. In another embodiment, R⁷ is F. In another embodiment, R⁷ is Cl. In another embodiment, R⁷ is OCH3. In another embodiment, R⁷ is OCF3. In another embodiment, R⁷ is OCH2CH3. In another embodiment, R⁷ is OCH(CHj)2. In another embodiment, R⁷ is OCHF2. In another embodiment, R⁷ is F, CI, OCH3 or OCF3. In another embodiment, R⁷ is F or OCH3.

In another aspect, the invention provides a compound of formula I-A:

R⁷

I-A or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence:

R² is F, Cl, CN, CH₃, CF₃ or CHF₂; and

R⁷ is F, Cl, OCH₃, OCF3, OCH2CH3, OCH(CH₃)2 or OCHF₂.

In one embodiment, the invention features a compound of formula I-A and the attendant définitions, wherein R is F. In another embodiment, R is Cl. In another embodiment, R² is CN. In another embodiment, R² is CH3. In another embodiment, R² is CF3. In another embodiment, R is CHF2.

In another embodiment, the invention features a compound of formula I-A and the attendant définitions, wherein R⁷ is F. In another embodiment, R⁷ is Cl. In another embodiment, R⁷ is OCH3. In another embodiment, R⁷ is OCF3, In another embodiment, R⁷ is OCH2CH3. In another embodiment, R⁷ is OCH(CH3)2. In another embodiment, R⁷is OCHF₂.

In another aspect, the invention provides a compound of formula I-B:

H

R⁷

I-B or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence:

R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃; and

R⁷ is F, Cl, OCH3, OCF3, OCH2CH3, OCH(CH₃)2 or OCHF₂.

In one embodiment, the invention features a compound of formula I-B and the attendant définitions, wherein R³ is F. In another embodiment, R³ is CI. In another embodiment, o 9

R is CN. In another embodiment, R is CF3. In another embodiment, R is OCF3. In 10 another embodiment, R³ is CF2CF3.

In another embodiment, the invention features a compound of formula I-B and the attendant définitions, wherein R⁷ is F. In another embodiment, R⁷ is Cl. In another embodiment, R⁷ is OCH3. In another embodiment, R⁷ is OCF3. In another embodiment, R⁷ is OCH2CH3. In another embodiment, R⁷ is OCH(CH3)₂. In another embodiment, R⁷ is OCHF₂.

In another aspect, the invention provides a compound of formula I-C:

R¹ O

1A AJCp rvL ΊΟ

R⁷

I-C or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence:

R¹ is Cl, CH₃, CF3 or cyclopropyl;

R⁵ is F, Cl, CH₃, OCH3, OCH2CH3, OCH2CH2CH3 or OCHF₂; and

R⁷ is F, Cl, OCH3, OCH2CH3, OCH(CH₃)2 or OCHF₂.

In one embodiment, the invention features a compound of formula I-C and the attendant définitions, wherein R¹ is Cl. In another embodiment, R¹ is CH3. In another embodiment, R¹ is CF3. In another embodiment, R¹ is cyclopropyl.

In another embodiment, the invention features a compound of formula I-C and the 10 attendant définitions, wherein R⁵ is F. In another embodiment, R⁵ is Cl. In another embodiment, R⁵ is CH3. In another embodiment, R⁵ is OCH3. In another embodiment, R⁵ is OCH2CH3. In another embodiment, R⁵ is OCH2CH2CH3. In another embodiment, R⁵ is OCHF2.

In another embodiment, the invention features a compound of formula I-C and the 15 attendant définitions, wherein R⁷ is F. In another embodiment, R⁷ is Cl. In another embodiment, R⁷ is OCH3. In another embodiment, R⁷ is OCH2CH3. In another embodiment, R⁷ is OCH(CH3)2. In another embodiment, R⁷ is OCHF2.

In another aspect, the invention provides a compound of formula I-D:

R⁷

I-D or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence:

R² is F, Cl, CN, CH₃, CF₃ or CHF₂;

R⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; and

R⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In one embodiment, the invention features a compound of formula I-D and the attendant définitions, wherein R² is F. In another embodiment, R² is Cl. In another embodiment, R² is CN. In another embodiment, R² is CH3. In another embodiment, R² is CF3. In another embodiment, R is CHF₂. In another embodiment, R is Cl or CF₃.

In another embodiment, the invention features a compound of formula I-D and the attendant définitions, wherein R⁵ is F. In another embodiment, R⁵ is Cl. In another embodiment, R⁵ is CH3. In another embodiment, R⁵ is OCH3. In another embodiment, R⁵ is OCH2CH3. In another embodiment, R⁵ is OCH2CH₂CH₃. In another embodiment, R⁵ is OCHF2. In another embodiment, R⁵ is F, Cl, CH3 or OCH₃.

In another embodiment, the invention features a compound of formula I-D and the attendant définitions, wherein R is F. In another embodiment, R is Cl. In another embodiment, R⁷ is OCH3. In another embodiment, R⁷ is OCF3. In another embodiment, R⁷ is OCH2CH3. In another embodiment, R⁷ is OCH(CH3)₂. In another embodiment, R⁷is OCHF2. In another embodiment, R⁷ is F, Cl, OCH3 or OCF₃.

In another aspect, the invention provides a compound of formula I-E:

I-E or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence: R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃;

R⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; and

R⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In one embodiment, the invention features a compound of formula I-E and the attendant définitions, wherein R is F. In another embodiment, R is Cl. In another embodiment, R³ is CN. In another embodiment, R³ is CF3. In another embodiment, R³ is OCF3. In another embodiment, R is CF₂CF₃. In another embodiment, R is Cl, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-E and the attendant définitions, wherein R⁵ is F. In another embodiment, R⁵ is Cl. In another embodiment, R⁵ is CH3. In another embodiment, R⁵ is OCH3. In another embodiment, R⁵ is OCH2CH3. In another embodiment, R⁵ is OCH2CH₂CH₃. In another embodiment, R⁵ is OCHF2. In another embodiment, R⁵ is F, Cl, CH3 or OCH₃.

In another embodiment, the invention features a compound of formula I-E and the attendant définitions, wherein R⁷ is F. In another embodiment, R⁷ is Cl. In another embodiment, R⁷ is OCH3. In another embodiment, R⁷ is OCF3. In another embodiment, R⁷ is OCH2CH3. In another embodiment, R⁷ is OCH(CH3)₂. In another embodiment, R⁷is OCHF2. In another embodiment, R⁷ is F, Cl, OCH3 or OCF₃.

In another aspect, the invention provides a compound of formula I-F:

R⁷

I-F or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence: R¹ is Cl, CH₃, CF₃ or cyclopropyl;

R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃; and

R⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In one embodiment, the invention features a compound of formula I-F and the attendant définitions, wherein R¹ is Cl. In another embodiment, R¹ is CH3. In another embodiment, R¹ is CF3. In another embodiment, R¹ is cyclopropyl.

In another embodiment, the invention features a compound of formula I-F and the attendant définitions, wherein R³ is F. In another embodiment, R³ is Cl. In another embodiment, R is CN. In another embodiment, R is CF3. In another embodiment, R is OCF3. In another embodiment, R³ is CF2CF₃.

In another embodiment, the invention features a compound of formula I-F and the attendant définitions, wherein R⁷ is F. In another embodiment, R⁷ is Cl. In another embodiment, R⁷ is OCH3. In another embodiment, R⁷ is OCF3. In another embodiment, R⁷ is OCH2CH3. In another embodiment, R⁷ is OCH(CH3)₂. In another embodiment, R⁷is OCHF₂.

In another aspect, the invention provides a compound of formula I-G:

I-G or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence: R² is F, Cl, CN, CH₃, CF₃ or CHF₂;

R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃; and

R⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In one embodiment, the invention features a compound of formula I-G and the attendant définitions, wherein R² is F. In another embodiment, R² is Cl. In another embodiment,

R² is CN. In another embodiment, R² is CH3. In another embodiment, R² is CF3. In another embodiment, R² is CHF2.

In another embodiment, the invention features a compound of formula I-G and the attendant définitions, wherein R³ is F. In another embodiment, R³ is Cl. In another embodiment, R³ is CN. In another embodiment, R³ is CF3. In another embodiment, R³ is OCF3. In another embodiment, R³ is CF2CF3.

In another embodiment, the invention features a compound of formula I-G and the attendant définitions, wherein R⁷ is F. In another embodiment, R⁷ is Cl. In another embodiment, R⁷ is OCH3. In another embodiment, R⁷ is OCF3. In another embodiment, R⁷ is OCH2CH3. In another embodiment, R⁷ is OCH(CH3)2. In another embodiment, R⁷is OCHF₂.

In another aspect, the invention provides a compound of formula I-H:

I-H or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence: R* is Cl, CH3, CF3 or cyclopropyl;

R³ is F, Cl, CN, CF₃, OCF3 or CF₂CF₃;

R⁵ is F, Cl, CH₃, OCH3, OCH2CH3, OCH2CH2CH3 or OCHF₂; and

R⁷ is F, Cl, OCH3, OCF3, OCH2CH3, OCH(CH3)₂ or OCHF₂.

In one embodiment, the invention features a compound of formula I-H and the attendant définitions, wherein R* is Cl. In another embodiment, R¹ is CH3. In another embodiment, R¹ is CF3. In another embodiment, R¹ is cyclopropyl.

In another embodiment, the invention features a compound of formula I-H and the attendant définitions, wherein R³ is F. In another embodiment, R³ is Cl. In another embodiment, R is CN. In another embodiment, R is CF3. In another embodiment, R is OCF3. In another embodiment, R³ is CF2CF3.

In another embodiment, the invention features a compound of formula I-H and the attendant définitions, wherein R⁵ is F. In another embodiment, R⁵ is Cl. In another embodiment, R⁵ is CH3. In another embodiment, R⁵ is OCH3. In another embodiment, R⁵ is OCH2CH3. In another embodiment, R⁵ is OCH2CH2CH3. In another embodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-H and the attendant définitions, wherein R⁷ is F. In another embodiment, R⁷ is F. In another embodiment, R⁷ is Cl. In another embodiment, R⁷ is OCH3. In another embodiment, R⁷is OCF3. In another embodiment, R⁷ is OCH2CH3. In another embodiment, R⁷ is OCH(CH3)2. In another embodiment, R⁷ is OCHF2.

In another aspect, the invention provides a compound of formula I-J:

I-J or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence: R² is F, Cl, CN, CH₃, CF₃ or CHF₂;

R³ is F, Cl, CN, CF₃, OCF3 or CF₂CF₃;

R⁵ is F, Cl, CH3, OCH3, OCH2CH3, OCH2CH2CH3 or OCHF2; and R⁷ is F, Cl, OCH3, OCF3, OCH2CH3, OCH(CH3)2 or OCHF₂.

In one embodiment, the invention features a compound of formula I-J and the attendant définitions, wherein R² is F. In another embodiment, R² is Cl. In another embodiment, R² is CN. In another embodiment, R² is CH3. In another embodiment, R² is CF3. In another embodiment, R² is CHF2.

In another embodiment, the invention features a compound of formula I-J and the attendant définitions, wherein R is F. In another embodiment, R is Cl. In another embodiment, R³ is CN. In another embodiment, R³ is CF3. In another embodiment, R³ is OCF3. In another embodiment, R³ is CF2CF3.

In another embodiment, the invention features a compound of formula I-J and the attendant définitions, wherein R⁵ is F. In another embodiment, R⁵ is CI. In another embodiment, R⁵ is CH3. In another embodiment, R⁵ is OCH3. In another embodiment, R⁵ is OCH2CH3. In another embodiment, R⁵ is OCH2CH2CH3. In another embodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-J and the attendant définitions, wherein R⁷ is F. In another embodiment, R⁷ is Cl. In another embodiment, R⁷ is OCH3. In another embodiment, R⁷ is OCF3. In another embodiment, R⁷ is OCH2CH3. In another embodiment, R⁷ is OCH(CH3)2. In another embodiment, R⁷is OCHF₂.

In another aspect, the invention provides a compound of formula I-K

I-K or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence:

R¹ is Cl, CH3, CF3 or cyclopropyl; and

R⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂;

In another embodiment, the invention features a compound of formula I-K and the attendant définitions, wherein R¹ is Cl. In another embodiment, R¹ is CH3. In another embodiment, R¹ is CF3. In another embodiment, R¹ is cyclopropyl.

In another embodiment, the invention features a compound of formula I-K and the attendant définitions, wherein R⁵ is F. In another embodiment, R⁵ is Cl. In another embodiment, R⁵ is CH3. In another embodiment, R⁵ is OCH3. In another embodiment, R⁵ is OCH2CH3. In another embodiment, R⁵ is OCH2CH₂CH₃. In another embodiment, R⁵ is OCHF₂.

In another aspect, the invention provides a compound of formula I-L

R⁷

I-L or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence:

R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃;

R⁶ is F or Cl; and

R⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In another embodiment, the invention features a compound of formula I-L and the attendant définitions, wherein R³ is F. In another embodiment, R³ is Cl. In another embodiment, R³ is CN. In another embodiment, R³ is CF3. In another embodiment, R³ is OCF3. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-L and the attendant définitions, wherein R⁶ is F. In another embodiment, R⁶ is Cl. ;

i

In another embodiment, the invention features a compound of formula I-L and the 7 7 attendant définitions, wherein R is F. In another embodiment, R is Cl. In another embodiment, R is OCH3. In another embodiment, R is OCF3. In another embodiment, R⁷ is OCH2CH3. In another embodiment, R⁷ is OCH(CH3)2. In another embodiment, R⁷is OCHF2.

In another aspect, the invention provides a compound of formula I-M

I-M or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence:

R³ is F, Cl, CN, CF₃, OCF3 or CF₂CF₃; and

R⁵ is F, Cl, CH₃, OCH3, OCH2CH3, OCH2CH2CH3 or OCHF₂.

In another embodiment, the invention features a compound of formula I-M and the attendant définitions, wherein R³ is F. In another embodiment, R³ is Cl. In another embodiment, R³ is CN. In another embodiment, R³ is CF3. In another embodiment, R³ is OCF3. In another embodiment, R³ is CF2CF3.

In another embodiment, the invention features a compound of formula I-M and the attendant définitions, wherein R⁵ is F. In another embodiment, R⁵ is Cl. In another embodiment, R⁵ is CH3. In another embodiment, R⁵ is OCH3. In another embodiment, R⁵ is OCH2CH3. In another embodiment, R⁵ is OCH2CH2CH3. In another embodiment, R⁵ is OCHF2.

In another aspect, the invention provides a compound of formula I-N

I-N or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence:

R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃;

R⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; and

R⁶ is F or Cl.

In another embodiment, the invention features a compound of formula I-N and the attendant définitions, wherein R³ is F. In another embodiment, R³ is Cl. In another ο η embodiment, R isCN. In another embodiment, R isCF₃. In another embodiment, R is

OCF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-N and the attendant définitions, wherein R⁵ is F. In another embodiment, R⁵ is Cl. In another embodiment, R⁵ is CH3. In another embodiment, R⁵ is OCH3. In another embodiment, 15 R⁵ is OCH2CH3. In another embodiment, R⁵ is OCH2CH₂CH₃. In another embodiment,

R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-N and the attendant définitions, wherein R⁶ is F. In another embodiment, R⁶ is Cl.

In another aspect, the invention provides a compound of formula 1-0

1-0 or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence:

R¹ is Cl, CH3, CF3 or cyclopropyl;

R³ is F, Cl, CN, CF₃, OCF₃ or CF2CF3;

R⁶ is F, or Cl; and

R⁷ is F, Cl, OCH₃, OCF3, OCH2CH3, OCH(CH₃)₂ or OCHF₂.

In another embodiment, the invention features a compound of formula 1-0 and the attendant définitions, wherein R¹ is Cl. In another embodiment, R¹ is CH3. In another embodiment, R¹ is CF3. In another embodiment, R¹ is cyclopropyl.

In another embodiment, the invention features a compound of formula 1-0 and the attendant définitions, wherein R³ is F. In another embodiment, R³ is Cl. In another embodiment, R is CN. In another embodiment, R is CF3. In another embodiment, R is OCF3. In another embodiment, R³ is CF2CF3.

In another embodiment, the invention features a compound of formula 1-0 and the attendant définitions, wherein R⁶ is F. In another embodiment, R⁶ is Cl.

In another embodiment, the invention features a compound of formula 1-0 and the attendant définitions, wherein R⁷ is F. In another embodiment, R⁷ is Cl. In another embodiment, R⁷ is OCH3. In another embodiment, R⁷ is OCF3. In another embodiment, R⁷ is OCH2CH3. In another embodiment, R⁷ is OCH(CH3)2. In another embodiment, R⁷is OCHF₂.

In another embodiment, the invention features a compound of formula I, wherein the compound or a pharmaceutically acceptable sait thereof, is selected from Table 1.

Compounds names in Table 1 were generated using ChemBioDrawUltra version 12.0 from Cambridge Soft/Chem Office 2010.

Table 1 Compound Numbers, Structures and Chemical Names

1	0. ,0 f\|Y ^NH2 HN^O Ji T T J cf₃ 2-(4-fluorophenoxy)-N-(3 sulfamoylphenyl)-4(trifluoromethyl)benzamide
2	0. ,0 NH₂ HN. /0 i Y 1 τ 1 j cf₃ 2-(2,4-difluorophenoxy)-N-(3sulfamoylphenyl)-4(trifluoromethyl)benzamide
3	°\z° (ÇT^<NH2HN^.0 /ΐ^,χ-θ^/Ι 1J 1/1 F^^ ^^/^CF₃ 2-(4-fluorophenoxy)-N-(3-

sulfamoylphenyl)-5(trifluoromethyl)benzamide

Cl

4-chloro-2-(4-fluorophenoxy)-5methyl-N-(3sulfamoylphenyl)benzamide

4-cyano-2-(4-fluoro-2methoxyphenoxy)-N-(3 sulfamoylphenyl)benzamide

Cl

2-(2-chloro-4-fluorophenoxy)-5cyano-N-(3sulfamoylphenyl)benzamide

4-chloro-2-(2-chloro-4fluorophenoxy)-N-(3sulfamoylphenyl)benzamide

N

2-(4-fluoro-2-methylphenoxy)-N(3-sulfamoylphenyl)-6(trifluoromethyl)benzamide

4-cyano-2-(4-fluoro-2methylphenoxy)-N-(3sulfamoylphenyl)benzamide

2-(4-fluoro-2-methoxyphenoxy)N-(3-sulfamoylphenyl)-6(trifluoiOmethyl)benzamide

5-chloro-2-(4-fluoro-2methoxyphenoxy)-N-(3sulfamoylphenyl)benzamide

CF₃

2-(4-fluoro-2-methoxyphenoxy)N-(3-sulfamoylphenyl)-4(trifluoromethyl)benzamide

Cl

4-chloro-2-(4-fluoro-2methoxyphenoxy)-N-(3 sulfamoylphenyl)benzamide

5-chloro-2-(2-chloro-4fluorophenoxy)-N-(3 sulfamoylphenyl)benzamide

CF₃

2-(4-fluoro-2-methylphenoxy)-N(3 -sulfamoylphenyl)-4(trifluoromethyl)benzamide

2-(4-methoxyphenoxy)-N-(3sulfamoylphenyl)-5(trifluoromethyQbenzamide

Cl

4-chloro-2-(4-fluoro-2methylphenoxy)-N-(3 sulfamoylphenyQbenzamide

2-(4-ethoxyphenoxy)-N-(3sulfamoylphenyl)-5(tri fluoromethyQbenzamide

5-chloro-2-(4-fluoro-2methylphenoxy)-N-(3 sulfamoylphenyQbenzamide

5-fluoro-2-(4-fluoro-2methylphenoxy)-N-(3 sulfamoylphenyQbenzamide

2-(4-chlorophenoxy)-N-(3sulfamoylphenyl)-5(trifluoromethyQbenzamide

2-(4-fluoro-2-methylphenoxy)-N (3-sulfamoylphenyl)-5(tri fluoromethyQbenzamide

2-(3-fluoro-2-methoxyphenoxy)N-(3 -sul famoylphenyl)-5 (trifluoromethyl)benzamide

2-(2-chloro-4-fluorophenoxy)-N(3-sulfamoylphenyl)-5(trifluoromethyl)benzamide

2-(4-fluoro-2-methoxyphenoxy)N-(3-sulfamoylphenyl)-5(trifluoromethyl)benzamide

2-(3 -fluoro-4-methoxyphenoxy)N-(3-sulfamoylphenyl)-5(trifluoromethyl)benzamide

2-(4-chloro-2-methylphenoxy)-N (3-sulfamoylphenyl)-5(trifluoromethyl)benzamide

2-(2-chloro-4-methoxyphenoxy)N-(3-sulfamoylphenyl)-5(trifluoromethyl)benzamide

N-(3-sulfamoylphenyl)-2-(otolyloxy)-5(trifluoromethyl)benzamide

2-(2-chIoro-4-fluorophenoxy)-N(3-sulfamoylphenyl)-6(trifluoromethyl)benzamide

2-(2-methoxyphenoxy)-N-(3sulfamoylphenyl)-5(trifluoromethyl)benzamide

2-(4-chIoro-2-methoxyphenoxy)N-(3-sulfamoylphenyl)-5(trifluoromethyl)benzamide

2-(2,4-dimethoxyphenoxy)-N-(337 sulfamoylphenyl)-5(trifluoromethyl)benzamide

2-(4-isopropoxyphenoxy)-N-(3sul famoylphenyl)-5(trifluoromethyl)benzamide

2-(2-chloro-4-fluorophenoxy)-6methyl-N-(3sulfamoylphenyQbenzamide

N-(3-sulfamoylphenyl)-2-(4(trifluoromethoxy)phenoxy)-5(trifluoromethyl)benzamide

2-(2-chloro-4-fluorophenoxy)-5(difluoromethyl)-N-(3sulfamoylphenyl)benzamide

2-(4-(difluoromethoxy)phenoxy)N-(3 -sul famoylphenyl)-5(trifluoiOmethyl)benzamide

CF₃

2-(4-chloro-2-methoxyphenoxy)N-(3-sulfamoylphenyl)-4(trifluoromethyl)benzamide

h₃co

NH₂

CF₃

2-(3 -fluoro-4-methoxyphenoxy)N-(3-sulfamoylphenyl)-4(trifluoromethyl)benzamide

OCH₃

O\/° st NH₂

CF₃2-(2-methoxyphenoxy)-N-(3 sulfamoylphenyl)-4(trifluoromethyl)benzamide

CF₃2-(4-ethoxyphenoxy)-N-(3 sulfamoylphenyl)-4(trifluoromethyl)benzamide

EtO

(\ Ό nh₂

cf₃

2-(2-propoxyphenoxy)-N-(3 sulfamoylphenyl)-4(trifluoromethyl)benzamide

CF₃

2-(4-methoxy-2-methylphenoxy)N-(3 -sulfamoylphenyl)-4(trifluoromethyl)benzamide

CF₃

N-(3-sulfamoylphenyl)-2-(otolyloxy)-4(trifluoromethyl)benzamide

2-(2,4-dimethoxyphenoxy)-N-(3sulfamoylphenyl)-4(trifluoromethyl)benzamide

CF₃

2-(2-chloro-4-methoxyphenoxy)N-(3-sulfamoylphenyl)-4(trifluoromethyl)benzamide

N-(3-sulfamoylphenyl)-2-(4(trifluoromethoxy)phenoxy)-4(trifluoromethyl)benzamide

CF₃

OCF₃

2-(3 -fluoro-2-methoxyphenoxy)N-(3-sulfamoylphenyl)-4(trifluoromethyl)benzamide

2-(4-fluorophenoxy)-N-(3sulfamoylphenyl)-4(trifluoromethoxy)benzamide

CF₃

OCF₃

2-(4-isopropoxyphenoxy)-N-(3 sulfamoylphenyl)-4(trifluoromethyl)benzamide

2-(2-chloro-4-fluorophenoxy)-N(3-sulfamoylphenyl)-4(trifluoromethoxy)benzamide

OCF₃

2-(4-fluoro-2-methoxyphenoxy)N-(3 -sulfamoylphenyl)-4(trifluoromethoxy)benzamide

2-(2-methoxyphenoxy)-N-(3sulfamoylphenyl)-6(trifluoromethyl)benzamide

2-(4-chloro-2-methylphenoxy)-N (3-sulfamoylphenyl)-6(trifluoromethyQbenzamide

2-(3 -fluoro-2-methylphenoxy)-N (3-sulfamoylphenyl)-6(trifluoromethyl)benzamide

N-(3-sulfamoylphenyl)-2-(4(trifluoromethoxy)phenoxy)-6(trifluoromethyl)benzamide

2-(3-fluoro-4-methoxyphenoxy)-

N-(3 -sulfamoylphenyl)-6(trifluoromethyl)benzamide QxzP ^s^nh₂

H₃CO

ocf₃2-(2-chloro-4-methoxyphenoxy)N-(3 -sulfamoylphenyl)-4(trifluoromethoxy)benzamide O. ,0 st nh₂

OCF₃2-(2-chlorophenoxy)-N-(3sulfamoylphenyl)-4(trifluoromethoxy)benzamide

QxzP ^Snh₂ ocf₃

2-(2-(di fluoromethoxy)phenoxy)N-(3-sulfamoylphenyl)-4(trifluoromethoxy)benzamide

OCF₃

CF₃

2-(4-chloro-2-methoxyphenoxy)N-(3 -sul famoylphenyl)-4(trifluoromethoxy)benzamide

OCF₃

2-(3 -chloro-2-methoxyphenoxy)N-(3-sulfamoylphenyl)-4(trifluoromethoxy)benzamide °\/°

CF₃

2-(3 -chloro-4-methoxyphenoxy)N-(3-sulfamoylphenyl)-4(trifluoromethyl)benzamide

2-(3 -chloro-2-methoxyphenoxy)N-(3 -sul famoylphenyl)-4(trifluoromethyl)benzamide

2-(4-fluorophenoxy)-4(perfluoroethyl)-N-(3 sulfamoylphenyl)benzamide

2-(4-fluoro-2-methoxyphenoxy)4-(perfluoroethyl)-N-(3 sulfamoylphenyl)benzamide

2-(4-chloro-2-methoxyphenoxy)4-(perfluoroethyl)-N-(3sulfamoylphenyl)benzamide

2-(2-chloro-4-methoxyphenoxy)4-(perfluoroethyl)-N-(3sulfamoylphenyl)benzamide

CF₃

2-(2-chlorophenoxy)-N-(3sulfamoylphenyl)-4(trifluoromethyl)benzamide

2-(2-chlorophenoxy)-N-(3sulfamoylphenyl)-6(trifluoromethyl)benzamide

2-(2-chloro-4-methoxyphenoxy)N-(3-sulfamoylphenyl)-6(trifluoromethyl)benzamide

Cl

4,5-dichloro-2-(2,4dimethoxyphenoxy)-N-(3sulfamoylphenyl)benzamide

Cl

4,5-dichloro-2-(4-fluoro-2methoxyphenoxy)-N-(3 sulfamoylphenyQbenzamide

Cl 4,5-dichloro-2-(4-chloro-2methoxyphenoxy)-N-(3 sulfamoylphenyQbenzamide

Cl

4,5-dichloro-2-(4fluorophenoxy)-N-(3 sulfamoylphenyQbenzamide

Cl

4,5-dichloro-2-(2-fluoro-4methoxyphenoxy)-N-(3 sulfamoylphenyQbenzamide

Cl

4,5-dichloro-2-(3-fluoro-4methoxyphenoxy)-N-(3 sulfamoylphenyQbenzamide

Cl

4,5-dichloro-2-(2-chloro-4methoxyphenoxy)-N-(3 sulfamoylphenyQbenzamide

Cl 4,5-dichloro-2-(4-fluoro-2methylphenoxy)-N-(3 sulfamoylphenyl)benzamide

Cl

4-chloro-2-(2,4dimethoxyphenoxy)-N-(3sul famoylphenyl)benzamide

Cl

4-chloro-2-(4-chloro-2methoxyphenoxy)-N-(3sulfamoylphenyl)benzamide

H₃CO

NH₂

Cl 4-chloro-2-(2-chloro-4methoxyphenoxy)-N-(3 sulfamoylphenyl)benzamide θ'./θ s' nh₂

O. /0 sf nh₂

Cl 4-chloro-2-(4isopropoxyphenoxy)-N-(3sulfamoylphenyl)benzamide

CF₃

CF₃2-(4-fluorophenoxy)-N-(3sul famoylphenyl)-4,6bis(trifluoromethyl)benzamide

CF₃

F CF₃

2-(4-fluoro-2-methoxyphenoxy)N-(3-sulfamoylphenyl)-4,6bis(trifluoromethyl)benzamide

2-(5-fluoro-2-methoxyphenoxy)N-(3-sulfamoylphenyl)-4,6bis(tri fluoromethyl)benzamide

F CF₃

CF₃

2-(3-fluoro-4-methoxyphenoxy)N-(3-sulfamoylphenyl)-4,6bis(trifluoromethyl)benzamide

2-(4-fluoro-2-methylphenoxy)-N(3-sulfamoylphenyl)-4,6bis(trifluoromethyl)benzamide

CF₃

2-(2-fluoro-4-methoxyphenoxy)N-(3-sulfamoylphenyl)-4,6bis(trifluoromethyl)benzamide

Cl

2,4-dichloro-6-(4fluorophenoxy)-N-(3sulfamoylphenyl)benzamide

Cl

2,4-dichloro-6-(4-fluoro-2methoxyphenoxy)-N-(3sulfamoylphenyl)benzamide

2,4-dichloro-6-(4-chloro-2methoxyphenoxy)-N-(3 sulfamoylphenyl)benzamide

Cl

2,4-dichloro-6-(4-fluoro-2methylphenoxy)-N-(3sulfamoylphenyl)benzamide

2,4-dichloro-6-(2-fluoro-4methoxyphenoxy)-N-(3 sulfamoylphenyl)benzamide

Cl

2,4-dichloro-N-(3sulfamoylphenyl)-6-(4(trifluoromethoxy)phenoxy)benza mide

F CF₃

2-cyclopropyl-6-(3-fluoro-4methoxyphenoxy)-N-(3sulfamoylphenyl)-4(trifluoromethyl)benzamide

In one embodiment, the compound is 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5(trifluoromethyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4(trifluoromethyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2-(2-chloro-4-fluorophenoxy)-N-(3sulfamoylphenyl)-5-(trifluoromethyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2-(2-chloro-4-fluorophenoxy)-N-(3sulfamoylphenyl)-6-(trifluoromethyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2-(2-chloro-4-fluorophenoxy)-5(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3sulfamoylphenyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2-(4-chloro-2-methoxyphenoxy)-4(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2-(4-fluoro-2-methoxyphenoxy)-N-(3sulfamoylphenyl)-5-(trifluoromethyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3sulfamoylphenyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2,4-dichIoro-6-(4-fluoro-2-methylphenoxy)-N(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2-(4-fluoro-2-methoxyphenoxy)-N-(3sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2-(4-fluoro-2-methylphenoxy)-N-(3sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3sulfamoylphenyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2-(4-fluoro-2-methoxyphenoxy)-N-(3suIfamoylphenyl)-4-(trifluoromethoxy)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2-(4-fluoro-2-methoxyphenoxy)-N-(3sulfamoylphenyl)-4-(trifluoromethyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 4,5-dichloro-2-(4-fluorophenoxy)-N-(3sulfamoylphenyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2-(4-fluoro-2-methoxyphenoxy)-4(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3sulfamoylphenyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3sulfamoylphenyl)benzamide or a pharmaceutically acceptable sait thereof.

In another embodiment, the compound is N-(3-sulfamoylphenyl)-2-(4(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide.

Salts, Compositions, Uses, Formulation,Administration and Additional Agents

Pharmaceutically acceptable salts and compositions

As discussed herein, the invention provides compounds that are inhibitors of voltage-gated sodium channels, and thus the présent compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to chronic pain, gut pain, neuropathie 41 pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia. Accordingly, in another aspect of the invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. In another embodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable sait thereof of and one or more pharmaceutically acceptable carriers or vehicles.

It will also be appreciated that certain of the compounds of invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable dérivative thereof. According to the invention, a pharmaceutically acceptable dérivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or dérivative which upon administration to a subject in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a métabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable sait” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animais without undue toxicity, irritation, allergie response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable sait” means any non-toxic sait or sait of an ester of a compound of this invention that, upon administration to a récipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active métabolite or residue thereof. As used herein, the term “inhibitorily active métabolite or residue thereof’ means that a métabolite or residue thereof is also an inhibitor of a voltage-gated sodium channel.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycérophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stéarate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali métal, alkaline earth métal, ammonium and N⁺(Cm alkyl)4 salts. This invention also envisions the quatemization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quatemization. Représentative alkali or alkaline earth métal salts include sodium, lithium, potassium, calcium, magnésium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quatemary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

As described herein, the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and ail solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonie agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the préparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stéarate, lecithin, sérum proteins, such as human sérum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloïdal silica, magnésium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its dérivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; com oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnésium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonie saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnésium stéarate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be présent in the composition, according to the judgment of the formulator.

In another aspect, the invention features a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier.

In another aspect, the invention features a pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable sait thereof of the compounds of formula I and one or more pharmaceutically acceptable carriers or vehicles.

Uses of Compounds and Pharmaceutically Acceptable Salis and Compositions

In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject a compound of formula I or a pharmaceutically acceptable sait thereof or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is Navl.8.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia comprising administering an effective amount of a compound, a pharmaceutically acceptable sait thereof or a pharmaceutical composition of the compounds of formula I.

In another aspect, the invention features a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia comprising administering an effective amount of a compound or a pharmaceutically acceptable sait thereof or a pharmaceutical composition of the compounds of formula I.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of gut pain wherein gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain or interstitial cystitis pain.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of neuropathie pain wherein neuropathie pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, buming mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex régional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomie cephalalgia.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of musculoskeletal pain wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, bum pain or dental pain.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of idiopathic pain wherein idiopathic pain comprises fibromyalgia pain.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of inflammatory pain wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia comprising administering an effective amount of a compound or a pharmaceutically acceptable sait thereof or a pharmaceutical composition of the compounds of formula I with one or more additional therapeutic agents administered concurrently with, prior to, or subséquent to treatment with the compound or pharmaceutical composition.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain or interstitial cystitis pain wherein said method comprises administering an effective amount of a compound, a pharmaceutically acceptable sait thereof or a pharmaceutical composition of the compounds of formula I.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of neuropathie pain, wherein neuropathie pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, buming mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex régional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomie cephalalgia wherein said method comprises administering an effective amount of a compound, a pharmaceutically acceptable sait thereof or a pharmaceutical composition of the compounds of formula I.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, bum pain or dental pain wherein said method comprises administering an effective amount of a compound, a pharmaceutically acceptable sait thereof or a pharmaceutical composition of the compounds of formula I.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia wherein said method comprises administering an effective amount of a compound, a pharmaceutically acceptable sait thereof or a pharmaceutical composition of the compounds of formula I.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain wherein said method comprises administering an effective amount of a compound, a pharmaceutically acceptable sait thereof or a pharmaceutical composition of the compounds of formula I.

In yet another aspect, the invention features a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subséquent to treatment with an effective amount of a compound, a pharmaceutically acceptable sait thereof or a pharmaceutical composition of the compounds of formula I. In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject an effective amount of a compound, a pharmaceutically acceptable sait thereof or a pharmaceutical composition of the compounds of formula I. In another aspect, the voltage-gated sodium channel is Navl.8.

In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a biological sample comprising contacting the biological sample with an effective amount of a compound, a pharmaceutically acceptable sait thereof or a pharmaceutical composition of the compounds of formula I. In another aspect, the voltage-gated sodium channel is Navl.8.

In another aspect, the invention features a method of treating or lessening the severity in a subject of acute pain, chronic pain, neuropathie pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatrie disorders, anxiety, dépréssion, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, viscéral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, stroke, cérébral ischemia, traumatic brain injury, amyotrophie latéral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility, comprising administering an effective amount of a compound, a pharmaceutically acceptable sait thereof or a pharmaceutical composition of the compounds of formula I.

In another aspect, the invention features a method of treating or lessening the severity in a subject of fémur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathie low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic viscéral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache, cluster headaches; chronic and acute neuropathie pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathie pain; radiotherapy-induced neuropathie pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex régional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury 48 pain; exercise pain; acute viscéral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hemias; chest pain, cardiac pain; pelvic pain, rénal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, bum and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anémia; acute pancreatitis; breakthrough pain; orofacial pain including sinusitis pain, dental pain; multiple sclerosis (MS) pain; pain in dépréssion; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogénital disease, including, urinary incontinence; hyperactivity bladder; painful bladder syndrome; interstitial cyctitis (IC); prostatitis; complex régional pain syndrome (CRPS), type I and type II; widespread pain, paroxysmal extreme pain, pruritis, tinnitis, or angina-induced pain, comprising administering an effective amount of a compound, a pharmaceutically acceptable sait thereof or a pharmaceutical composition of the compounds of formula I.

In another aspect, the invention features a method of treating or lessening the severity in a subject of neuropathie pain comprising administering an effective amount of a compound, a pharmaceutically acceptable sait thereof or a pharmaceutical composition of the compounds of formula I. In one aspect, the neuropathie pain is selected from postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, buming mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton’s neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury, brachial plexus avulsion, complex régional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomie cephalalgia.

Manufacture of Médicaments

In one aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a médicament for use in inhibiting a voltage-gated sodium channel. In another aspect, the voltage-gated sodium channel is Navl.8.

In yet another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a médicament for use in treating or lessening the severity in a subject of chronic pain, gut pain, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia.

In yet another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a médicament for use in treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain or interstitial cystitis pain.

In yet another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a médicament for use in a treating or lessening the severity in a subject of neuropathie pain, wherein neuropathie pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, buming mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex régional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomie cephalalgia.

In yet another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a médicament for use in treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, bum pain or dental pain.

In yet another aspect, the invention the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a médicament for use in treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia.

In yet another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a médicament for use in treating or 50 lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

In yet another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a médicament in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subséquent to treatment with the compound or pharmaceutical composition.

In another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a médicament for use in treating or lessening the severity of acute pain, chronic pain, neuropathie pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatrie disorders, anxiety, dépréssion, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, viscéral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, stroke, cérébral ischemia, traumatic brain injury, amyotrophie latéral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility.

In another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a médicament for use in treating or lessening the severity of fémur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathie low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic viscéral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache, including, cluster headaches; chronic and acute neuropathie pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; CharcotMarie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathie pain; radiotherapy-induced neuropathie pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex régional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury/exercise pain; acute viscéral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hemias; chest pain, cardiac pain; pelvic pain, rénal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, bum and trauma pain; acute intermittent pain, endometriosis; acute heipes zoster pain; sickle cell anémia; acute pancreatitis; breakthrough pain; orofacial pain including sinusitis pain, dental pain; multiple sclerosis (MS) pain; pain in dépréssion; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogénital disease, including, urinary incontinence; hyperactivity bladder; painful bladder syndrome; interstitial cyctitis (IC); prostatitis; complex régional pain syndrome (CRPS), type I and type II; widespread pain, paroxysmal extreme pain, pruritis, tinnitis, or angina-induced pain.

In another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a médicament for use in treating or lessening the severity of neuropathie pain. In one aspect, the neuropathie pain is selected from post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, buming mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton’s neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury, brachial plexus avulsion, complex régional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomie cephalalgia.

Administration of Pharmaceutically Acceptable Salts and Compositions

In certain embodiments of the invention an “effective amount” of the compound, a pharmaceutically acceptable sait thereof or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of chronic pain, gut pain, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia.

The compounds and compositions, according to the method of the invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the pain or non-pain diseases recited herein. The exact amount required will vary from subject to subject, depending on the species, âge, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrète unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The spécifie effective dose level for any particular subject or organism will dépend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the spécifie compound employed; the spécifie composition employed; the âge, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excrétion of the spécifie compound employed; the duration of the treatment; drugs used in combination or coincidental with the spécifie compound employed, and like factors well known in the medical arts. The terni “subject” or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can be administered to humans and other animais orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

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

Injectable préparations, for example, stérile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The stérile injectable préparation may also be a stérile injectable solution, suspension or émulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonie sodium chloride solution. In addition, stérile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the préparation of injectables.

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

In order to prolong the effect of a compound of the invention, it is often désirable to slow the absorption of the compound from subeutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then dépends upon its rate of dissolution that, in tum, may dépend upon crystal size and crystalline form. Altematively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodégradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodégradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

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

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffm, f) absorption accelerators such as quatemary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stéarate, magnésium stéarate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

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

The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnésium stéarate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under stérile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the invention contemplâtes the use of transdermal patches, which hâve the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate 56 controlling membrane or by dispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds and compositions of the invention are inhibitors of Nayl.8 and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of Nayl.8 is implicated in the disease, condition, or disorder. When activation or hyperactivity of Nayl.8 is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a “Nayl.8 -mediated disease, condition or disorder.” Accordingly, in another aspect, the invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of Nayl.8 is implicated in the disease State.

The activity of a compound utilized in this invention as an inhibitor of Nayl .8 may be assayed according to methods described generally in the Examples herein, or according to 15 methods available to one of ordinary skill in the art.

Additional Therapeutic Agents

It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the invention can be employed in combination thérapies, that is, the 20 compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subséquent to, one or more other desired therapeutics or medical procedures. In one embodiment, the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subséquent to treatment with the compound or pharmaceutical composition of formula I of the présent invention.

The particular combination of thérapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the thérapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” For example, exemplary additional therapeutic agents include, but are not limited to: nonopioid analgésies (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such sa Nabumetone; oxicams such as Piroxicam; para-aminophenol dérivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Aspirin, Choline magnésium trisalicylate, Diflunisal; fenamates such as meelofenamie acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprénorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgésie approaches may be utilized in conjunction with administration of one or more compounds of the invention. For example, anesthesiologic (intraspinal infusion, neural blockade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologie (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition, Ed. Robert S.. Porter and Justin L. Kaplan, Merck Sharp &Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

In another embodiment, the additional therapeutic agent is anNav 1.7 inhibitor. Nav 1.7 and Nav 1 -8 ion channels are both highly expressed in the sensory neurons of the dorsal root ganglion, where pain signais originate, but the distinct functional behavior of the two channels leads them to fulfill distinct and complementary rôles in neuronal excitability. Nav 1.7 Controls the general sensitivity of nociceptive neurons, and initiating the painful signal in a nociceptor. Navl .8 amplifies and sustains the pain signal once it has been initiated. Because of these distinct rôles, inhibiting both channels should increase the effectiveness of pain relief. Preclinical genetic knockout mice support this idea, as double knockouts of Navl.7 and Navl.8 channels in the sensory DRG neurons 58 surprisingly diminish nociceptive behaviors to a greater degree than knockout of either channel alone.

In another embodiment, additional appropriate therapeutic agents are selected from the following:

(1) an opioid analgésie, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaïne, codeine, dihydrocodéine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprénorphine, butorphanol, nalbuphine or pentazocine;

(2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meelofenamie acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

(3) a barbiturate sédative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phénobarbital, secobarbital, talbutal, thiamylal or thiopental;

(4) a benzodiazépine having a sédative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazépam, oxazepam, temazepam or triazolam;

(5) a histamine (Hi) antagonist having a sédative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

(6) a sédative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;

(7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

(8) an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-Nmethylmorphinan) or its métabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4- hydroxy-l- piperidinyl]-l-hydroxyethyl-3,4-dihydro-2(lH)-quinolinone;

(9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-l, 2,3,4- tetrahydroisoquinolin-2-yl)-5-(2-pyridyl) quinazoline;

(10) a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;

(11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;

(12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,l 1 -tetrahydro-9-methyl-5-(4methylphenyl)-7H-[l,4]diazocino[2,l-g][l,7]-naphthyridine-6-13-dione (TAK-637), 5[[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

(13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

(14) a COX-2 sélective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

(15) a coal-tar analgésie, in particular paracétamol;

(16) a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, rispéridone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;

(17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) or antagonist (e.g. capsazepine, GRC-15300);

(18) a beta-adrenergic such as propranolol;

(19) a local anaesthetic such as mexiletine;

(20) a corticosteroid such as dexamethasone;

(21) a 5-HT receptor agonist or antagonist, particularly a 5-HTib/id agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

(22) a 5-HT2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-l-[2-(4fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

(23) a cholinergic (nicotinic) analgésie, such as ispronicline (TC-1734), (E)-N-methyl-4(3-pyridinyl)-3-buten-l-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

(24) Tramadol, Tramadol ER (Ultram ER®), Tapentadol ER (Nucynta®);

(25) a PDE5 inhibitor, such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl-sulphonyl)phenyl]-lmethyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R, 12aR)- 2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2',r:6,l]-pyrido[3,4-b]indole-l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4ethyl-piperazin-l-yl-l-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,lf][l,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(l-ethyl-3azetidinyl)-2,6-dihydro-7/f- pyrazolo[4,3-if]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3pyridinyl)-3-ethyl-2-(I-isopropyl-3-azetidinyl)-2,6-dihydro-7//-pyrazolo[4,3-iZ]pyrimidin7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-l-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2methoxyethyl]-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pynOlidin-l-yl]-N-(pyrimidin-2ylmethyl)pyrimidine-5-carboxamide, 3-(l- methyl-7-oxo-3-propyl-6,7-dihydro-lHpyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4propoxybenzenesulfonamide;

(26) an alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methyl gabapentin, (l[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4 (3-fluorobenzyl)-proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)-4H-[l,2,4]oxadiazol-5-one, C-[l-(lH-tetrazol-5ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

(27) a cannabinoid such as KHK-6188;

(28) metabotropic glutamate subtype 1 receptor (mGluRl) antagonist;

(29) a serotonin reuptake inhibitor such as sertraline, sertraline métabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl métabolite), fluvoxamine, paroxetine, citalopram, citalopram métabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;

(30) a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion métabolite hydroxybupoprion, nomifensine and viloxazine (Vivalan®), especially a sélective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)reboxetine;

(31) a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine métabolite O-desmethylvenlafaxine, clomipramine, clomipramine métabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran and imipramine;

(32) an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(l- iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)-amino]ethyl]-4,4-dioxo-Lcysteine, S-[2-[(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l(5- thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5thiazolyl) butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-462 hydroxy-l-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyldisulfide;

(33) an acetylcholinesterase inhibitor such as donepezil;

(34) a prostaglandin E2 subtype 4 (EP4) antagonist such as 7V-[({2-[4-(2-ethyl-4,6dimethyI-lH-imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl}amino)-carbonyl]-4methylbenzenesulfonamide or 4-[(15)-l-({[5-chloro-2-(3-fluorophenoxy)pyridin-3yl]carbonyl}amino)ethyl]benzoic acid;

(35) a leukotriene B4 antagonist; such as l-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7yl)-cyclopentanecarboxylic acid (CP- 105696), 5-[2-(2-Carboxyethyl)-3-[6-(4methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870;

(36) a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-l-methyl-2-quinolone (ZD-2138), or 2,3,5trimethyl-6-(3-pyridylmethyl)-l,4-benzoquinone (CV-6504);

(37) a sodium channel blocker, such as lidocaine, lidocaine plus tetracaine cream (ZRS201) or eslicarbazepine acetate;

(38) anNayl.7 blocker, such as XEN-402 and such as those disclosed in

WO2011/140425; WO2012/106499; WO2012/112743; WO2012/125613;

WO2013067248 or PCT/US2013/21535 the entire contents of each application hereby incorporated by reference.

(39) an Nayl.8 blocker, such as those disclosed in WO2008/135826 and WO2006/011050 the entire contents of each application hereby incorporated by reference.

(40) a combined Nayl.7 and Nayl.8 blocker, such as DSP-2230 or BL-1021;

(41) a 5-HT3 antagonist, such as ondansetron;

(42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®, Qutenza®); and the pharmaceutically acceptable salts and solvatés thereof;

(43) a nicotinic receptor antagonist, such as varenicline;

(44) an N-type calcium channel antagonist, such as Z-160;

(45) a nerve growth factor antagonist, such as tanezumab;

(46) an endopeptidase stimulant, such as senrebotase;

(47) an angiotensin II antagonist, such as EMA-401;

In one embodiment, the additional appropriate therapeutic agents are selected from V116517, Pregabalin, controlled release Pregabalin, Ezogabine (Potiga®).

Ketamine/amitriptyline topical cream (Amiket®), AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561or ARC-4558.

The amount of additional therapeutic agent présent in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the presently disclosed compositions will range from about 10% to 100% of the amount normally présent in a composition comprising that agent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artifîcial valves, vascular grafts, stents and cathéters. Accordingly, the invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the invention includes an implantable device coated with a composition comprising a compound of the invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general préparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be fiirther covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting Nayl.8 activity in a biological sample or a subject, which method comprises administering to the subject, or contacting said biological sample with a compound of formula I or a composition comprising said compound. The term “biological sample,” as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of Nayl .8 activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of sodium channels in biological and pathological phenomena; and the comparative évaluation of new sodium channel inhibitors.

Claims

We claim:

A compound of formula I

R⁴

R⁵' or a pharmaceutically acceptable sait thereof, wherein, independently for each occurrence:

R¹ is H, Cl, CH3, CF3 or cyclopropyl;

R² is H, F, Cl, CN, CH₃, CF₃ or CHF₂;

R³ is H, F, Cl, CN, CF₃, OCF₃ or CF₂CF₃;

R⁴ is H;

R⁵ is H, F, Cl, CH₃, OCH3, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂;

R⁵' is H, F, Cl, CH₃, OCH3, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂;

R⁶ is H, F or Cl;

R⁶' is H, F or Cl; and

R⁷ is H, F, Cl, OCH3, OCF3, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂, provided that R¹, R², and R³ are not simultaneously hydrogen; and that R⁵, R⁵, R⁶, R⁶, and R⁷ are not simultaneously hydrogen..
2-cyclopropyl-6-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

or a pharmaceutically acceptable sait thereof.

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable sait thereof of any one of daims 1-8 and one or 5 more pharmaceutically acceptable carriers or vehicles.

10. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject a compound or a pharmaceutically acceptable sait thereof of any one of daims 1-8 or a pharmaceutical composition according to daim 21.

11. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathie pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia

149 comprising administering an effective amount of a compound or a pharmaceutically acceptable sait thereof of any one of daims 1-8 or a pharmaceutical composition of claim 9.

12. The method according to claim 10 or 11, wherein said subject is treated with one or

2,4-dichloro-6-(2-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; and

2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

H₃CO

nh₂

Cl

Cl

2,4-dichloro-N-(3-sulfamoylphenyl)-6-(4-(trifluoromethoxy)phenoxy)benzamide;

Cl

148

2,4-dichloro-6-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfarnoylphenyl)benzarnide;

Cl

2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

Cl 2,4-dichloro-6-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

147

Ο .

Cl

2-(5-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

O. _ZO w

CF₃

2-(2-fluoiO-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

146

F CF₃

2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

O. ,0

CF₃

2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

CF₃2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

141

Ο. .ο χχζ

2-(2-chloro-4-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide;

NH₂ cf₃

2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide;

2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide;

140

2-(3-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(3-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

139

Ο. .0 XVz

cf₃

2-(3-chioro-2-methoxyphenoxy)-N-(3-sulfamoylphenyi)-4-(trifluoromethoxy)benzamide;

CF₃

2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

O. /0

0CF₃

2-(2-(difluoromethoxy)phenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

138

ocf₃

2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

F

nh₂

0CF₃

2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

ocf₃

2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

137

o_x/o

ocf₃

2-(3-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

NH₂ cf₃ f₃co

N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)benzamide;

HhL ^0

2-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

°_x\ z_z°

136

2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

OCF₃

2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

OCF₃

2-(4-isopropoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

135

ocf₃

2-(3-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(4-methoxy-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

134

Ο. .0

cf₃

N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide;

°\z°

cf₃

2-(4-ethoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

Ο. ,0

cf₃

N-(3-sulfamoylphenyl)-2-(o-tolyloxy)-4-(trifluoromethyl)benzamide;

133

2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

132

C\ /0 χχζ

cf₃

2-(4-(difluoromethoxy)phenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

131

CF₃2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

O. ,O

cf₃

2-(2-chloro-4-fluorophenoxy)-6-methyl-N-(3-sulfamoylphenyl)benzamide;

⁰^//°

N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide;

2-(4-isopropoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

130

I

nh₂ ch₃

F

2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

°^//⁰

2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

0^0

2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

129 och₃

nh₂ cf₃

2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

N-(3-sulfamoylphenyl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide;

HN. .O

Cl

F

2-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(3-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

128

2-(3 -fluoro-4-methoxyphenoxy)-N-(3 -sulfamoylphenyl)-5 -(tri fluoromethyl)benzamide;

2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

O. ,0

2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

127

nh₂ cf₃

2-(4-chlorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-ethoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

^o^//°

2-(4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

EtO

NH₂ cf₃

2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

Cl

2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

°_χ\ //°

Cl

2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

124

Οχ /0 ν_ον

CF₃

2-(2-chloro-4-fluorophenoxy)-5-cyano-N-(3-sulfamoylphenyl)benzamide;

2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

122

2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

°\\ /z°

5-chloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

%//°

2-(2,4-difluorophenoxy)-N-(3 -sul famoylphenyl )-4-(trifluoromethyl)benzamide;

121

2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

O. _ZO w

CF₃

2. The compound or sait according to claim 1, wherein R is H, CF3 or Cl; or R is H, CF3 or Cl; or R³ is H, CF₃, Cl or OCF₃; or R⁵ is H; or R⁶ or R⁶’ is H or F; or R⁷ is F, Cl, OCH3 or

OCF3.

119
3. The compound or sait according to claim l or 2, wherein R¹ is H or CF3; or R² is H or

CF₃; or R³ is H, CF3 or Cl; or R⁵ is H; or R⁶ or R⁶' is H or F; or R⁷ is F or OCH3.

5 4. The compound or sait according claim 1, wherein the compound has formula I-D:

I-D, wherein, independently for each occurrence:

R² is F, Cl, CN, CH₃, CF₃ or CHF₂;

10 R⁵ is F, Cl, CH₃, OCH3, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; and

R⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

5. The compound or sait according to claim 4, wherein R is Cl or CF3; or R is F, Cl, CH₃ or OCH₃; or R⁷ is F, Cl, OCH₃ or OCF₃.

6. The compound or sait according to claim 1, wherein the compound has formula I-E:

I-E, wherein, independently for each occurrence:

120

R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃;

R⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; and

R⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

5 7. The compound or sait according to claim 6, wherein R³ is Cl, CF₃ or OCF₃; or R⁵ is F,

Cl, CH₃ or OCH₃; or R⁷ is F, Cl, OCH₃ or OCF₃.

8. The compound or sait of claim l, wherein the compound or a pharmaceutically acceptable sait thereof, is selected from the group consisting of:

CF₃
4-chloro-2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

145

4-chloro-2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

144

Cl

4,5-dichloro-2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

°xVz°

4,5-dichloro-2-(2-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)-N“(3-sulfamoylphenyl)benzamide;

Cl

143

4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

O. _yO

4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

Cl

4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

142

Cl

4,5-dichloro-2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

°_x<0

5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

126

4-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

0_{K z}0

5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

125

%//°

cf₃

4-cyano-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

123

II N

4-chloro-2-(4-fluorophenoxy)-5-methyl-N-(3-sulfamoylphenyl)benzamide;

Cl
5 more additional therapeutic agents administered concurrently with, prior to, or subséquent to treatment with the compound, sait, or pharmaceutical composition.