NZ715751B2

NZ715751B2 - Sulfonamides as modulators of sodium channels

Info

Publication number: NZ715751B2
Application number: NZ715751A
Authority: NZ
Inventors: Corey Anderson; Vijayalaksmi Arumugam; Brian Richard Bear; Ruah Sara Sabina Hadida; James Philip Johnson; Paul Krenitsky; Andreas P Termin
Original assignee: Vertex Pharmaceuticals Incorporated
Priority date: 2013-07-19
Filing date: 2014-07-18
Publication date: 2022-01-06

Abstract

The invention relates to compounds of formula I or pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels: (I). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders, including pain. tment of various disorders, including pain.

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 itions comprising the compounds of the ion and s of using the compositions in the treatment of various disorders including pain.

BACKGROUND OF THE INVENTION Pain is a protective mechanism that allows healthy animals 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. Neuropathic 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 neuropathic pain conditions in the general population. Pain, 2008. : p. 681—8). athic pain can be divided into two categories, pain caused by generalized metabolic damage to the nerve and pain caused by a te nerve injury. The metabolic neuropathies e post herpetic neuropathy, diabetic neuropathy, and nduced neuropathy. Discrete nerve injuries indications include post amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like neuropathic back pain.

Voltage—gated sodium channels (NaV’s) play a critical role 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 role of these ls in normal physiology, the pathological states arising from mutations in sodium channel genes, preclinical work in animal , and the clinical pharmacology of known sodium channel modulating agents all point to the central role of NaV’s in pain sensation (Rush, A.M. and TR. Cummins, Painful Research: Identiﬁcation ofa Molecule Inhibitor that Selectively Targets NaVI.8 Sodium Channels. Mol Interv, 2007. 7(4): p. 192—5); England, S., Voltage—gated sodium channels: the search for subtype—selective analgesics. Expert Opin Investig Drugs 17 (12), p. 1849—64 ; Krafte, D. S. and Bannon, A. W., Sodium ls and nociception: recent concepts and therapeutic opportunities. Curr Opin Pharmacol 8 (l), 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 table Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Because of the role NaV’s play in the initiation and propagation of neuronal signals, antagonists that reduce NaV currents can prevent or reduce neural signaling and NaV channels have 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., e—gated sodium channels in neurological disorders. CNS Neural Disord Drug Targets 7 (2), p. 144—58 (2008)). Several clinically useful analgesics have been identified as tors of NaV channels.

The local anesthetic drugs such as lidocaine block pain by inhibiting NaV ls, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants that have proven effective at reducing pain have also been suggested to act by sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur JPain 6 Suppl A, p. 3—9 ; Wang, G. K., Mitchell, J., and Wang, S. Y., Block of tent 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 Nav1.1 9. The tissue localizations of the nine isoforms vary y. Navl.4 is the primary sodium channel of al muscle, and Nav1.5 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 r but distinct in the specifics 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 ).

Immediately upon their discovery, NaV1.8 ls 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 s. Nature, 1996. 379(6562): p. 257— 62). Since then, NaV1.8 has been shown to be the most significant carrier of the sodium t that maintains action potential firing in small DRG neurons (Blair, NT. and BF. Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ t in the action potentials of nociceptive sensory neurons. JNeurosci., 2002. 22(23): p. 10277—90).

NaV1.8 is essential for spontaneous firing in damaged neurons, like those that drive neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol, 2003. 550(Pt WO 10065 2014/047265 3): p. 921—6; Jarvis, M.F., et al., A—803467, a potent and selective NaV1.8 sodium channel blocker, attenuates athic and inﬂammatory pain in the rat. Proc Natl Acad Sci. U S A, 2007. 104(20): p. 8520—5; Joshi, S.K., et al., Involvement of the TTX—resistant sodium channel Navl .8 in inﬂammatory and neuropathic,but not post-operative, pain . Pain, 2006. 123(1— 2): pp. 75-82; Lai, J., et al., Inhibition of neuropathic pain by sed expression of the otoxin-resistant sodium channel, Navl.8. Pain, 2002. 95(1—2): p. 143—52; Dong, X.W., et al., Small interfering RNA-mediated selective knockdown ofNa(V)l .8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience, 2007. 146(2): p. 8l2-2l; Huang, H.L., et al., Proteomic proﬁling of neuromas reveals alterations in protein composition and local n synthesis in hyper—excitable nerves. Mol Pain, 2008. 4: p. 33; Black, J.A., et al., Multiple sodium channel isoforms and mitogen-activated protein s are present in painful human neuromas. Ann Neurol, 2008. 64(6): p. 644—53; , K., et al., Immunolocalization of SNS/PN3 and S2 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 l 18 (NaV1.8) mRNA accumulation to c nerve injury-induced painful neuropathy in rats. J Biol Chem. 286(46): p. 39836—47). The small DRG neurons where NaV1.8 is expressed include the nociceptors critical for pain signaling. NaV1.8 is the primary channel that mediates large ude action potentials in small neurons of the dorsal root ganglia , N.T. and BF.

Bean, Roles of otoxin (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). Navl.8 is necessary for rapid repetitive action potentials in nociceptors, and for spontaneous activity of damaged neurons. (Choi, J.S. and S.G. Waxman, Physiological interactions between NaV1.7 and NaV1.8 sodium channels: a computer simulation study. J hysiol. 106(6): p. 3173—84; Renganathan, M., T.R. Cummins, and S.G. Waxman, Contribution ofNa(V)l .8 sodium channels to action potential electrogenesis in DRG neurons. J Neurophysiol, 2001. 86(2): p. 629—40; Roza, C., et al., The tetrodotoxin-resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice.

JPhysiol, 2003. 550(Pt 3): p. 921—6). In depolarized or damaged DRG neurons, NaV1.8 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 , NaV1.8 mRNA expression levels have been shown to increase in the DRG (Sun, W., et al., Reduced conduction failure of the main 2014/047265 axon of polymodal nociceptive C-fibres contributes to painful diabetic athy in rats. Brain. 135(Pt 2): p. ; Strickland, I.T., et al., Changes in the expression of NaVl.7, NaVl.8 and NaVl.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 NaVl.8 and NaVl .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 NaV inhibitors is their poor eutic window, and this is likely a consequence of their lack of isoform selectivity. Since NaVl.8 is primarily restricted to the neurons that sense pain, selective NaVl.8 blockers are unlikely to induce the e events common to non—selective NaV blockers. Accordingly, there remains a need to p additional NaV channel antagonists preferably those that are more NaVl .8 selective 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 have the general formula I: N S\ H 0/, NH2 R3 o R5 R5' R6 R6' or a pharmaceutically acceptable salt thereof.

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

Detailed Description of the Invention In one aspect, the invention provides compounds of formula 1: O” N H2 RS on RR5 R5' R6 R6' or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: R1 is H, Cl, CH3, CF3 or cyclopropyl; R2 is H, F, Cl, CN, CH3, CF3 or CHFZ; R3 is H, F, 01, CN, CF3, OCF3 or CF2CF3; R4 is H; R5 is H, F, Cl, CH3, OCH3, OCHZCH3, ZCHg or OCHFZ; R5' is H, F, Cl, CH3, OCH3, OCHzCHg, OCHzCHzCHg or OCHFZ; R6 is H, F or Cl; R6, is H, F or Cl; and R7 is H, F, 01, OCH3, OCF3, OCHZCHg, OCH(CH3)2 or OCHFz, provided that R1, R2, and R3 are not simultaneously hydrogen; and that R5, R5,, R6, R6,, and R7 are not aneously hydrogen.

For purposes of this invention, the chemical elements are identiﬁed in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. onally, general principles of organic try are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, ito: 1999, and “March’s ed Organic Chemistry,” 5th Ed., Ed.: Smith, MB. 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 exempliﬁed by particular classes, subclasses, and species of the invention. As described herein, the variables in aI encompass speciﬁc 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 result 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, ion, and ably their ry, purification, and use for one or more of the es disclosed herein. In some embodiments, a stable compound or ally feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

The phrase “optionally substituted” may be used interchangeably with the phrase “substituted or unsubstituted.” In l, 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. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof Unless otherwise ted, an ally substituted group can have 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 oned by this invention are those combinations that result in the ion of stable or chemically feasible compounds.

The phrase “up to,” as used herein, refers to zero 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, l, 2, 3, and 4.

The term “aliphatic,” “aliphatic group” or “alkyl” as used , means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely ted or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1 — 20 aliphatic carbon atoms. In some embodiments, tic 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. le aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups.

The terms “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 molecule.

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 have 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 , means F, Cl, Br or I.

Unless otherwise speciﬁed, the term “heterocycle,” “heterocyclyl,” "heterocycloaliphatic,” ocycloalkyl,” or “heterocyclic” as used herein means non— aromatic, monocyclic, bicyclic, or tricyclic ring s 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 rated bonds. In some embodiments, the “heterocycle,” “heterocyclyl,” “heterocycloaliphatic,” “heterocycloalkyl,” or ocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from , sulfur, en, 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 quaternized form of any basic nitrogen or; a substitutable nitrogen of a cyclic ring, for example N (as in 3,4- dihydro-2H—pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).

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

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 xyalkyl,” 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 e all isomeric (e. g., enantiomeric, diastereomeric, and geometric (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 chemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Thus, included within the scope of the invention are ers of compounds of a I. The structures also include rionic 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 have one or more atoms replaced by an atom having an atomic mass or mass number usually found in nature. Examples of isotopes present in compounds of formulaI include isotopes of hydrogen, carbon, en, , phosphorus, ﬂuorine and ne, such as, but not limited to, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 358 and 18F. Certain isotopically-labeled compounds of formula I, in addition to being useful as as uetic agents, are also useful in drug and/or substrate tissue distribution assays, as analytical tools or as probes in other biological assays. In one aspect of the present invention, ted (e. g., 3 H) and carbon—l4 (e. g., 14C) isotopes are useful given their ease of ability.

In another aspect of the present invention, ement 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 definitions, n R1 is H. In another embodiment, R1 is Cl. In another embodiment, R1 is CH3. In another embodiment, R1 is CF3. In another embodiment, R1 is WO 10065 cyclopropyl. In another ment, 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 deﬁnitions, wherein R2 is H. In another embodiment, 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 CHFz. In another embodiment, R2 is H, CF3 or Cl. In another embodiment, R2 is H or CF3_ In another embodiment, the invention features a nd of formula I and the attendant definitions, 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 . In another embodiment, R3 is H, CF3, C1 or OCF3. In another embodiment, R3 is H, CF3 or C1.

In another embodiment, the invention features a compound of formula I and the attendant definitions, n R5 is H. In another embodiment, R5 is F. In another ment, R5 is Cl. In another embodiment, R5 is CH3. In another ment, R5 is OCH3. In another embodiment, R5 is OCHzCH3. In another embodiment, R5 is OCHZCHZCH3. In r embodiment, R5 is OCHFz.

In r embodiment, the invention features a nd of formula I and the attendant definitions, 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 OCHzCH3. In r embodiment, R5, is OCHZCHZCH3. In another embodiment, R5, is OCHFz.

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

In r ment, the invention features a compound of formula I and the attendant definitions, 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 3. In another embodiment, R7 is OCH(CH3)2. In another ment, R7 is OCHFZ. In another ment, R7 is F, Cl, OCH3 or OCF3. In another embodiment, R7 is F or OCH3.

In another , the invention provides a compound of formula LA: R2\©5‘\ //O N \ H O]; NH2 or a pharmaceutically acceptable salt f, n, independently for each occurrence: R2 is F, 01, CN, CH3, 01:3 or CHFZ; and R7 is F, Cl, OCH3, OCF3, OCHZCH3, OCH(CH3)2 or OCHFz.

In one embodiment, the invention features a compound of formula I-A and the attendant definitions, 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 CHFz.

In another embodiment, the invention features a compound of formula I—A and the attendant definitions, wherein R7 is F. In another embodiment, R7 is Cl. In another ment, R7 is OCH3. In another embodiment, R7 is OCF3, In another embodiment, R7 is OCHZCH3. In another ment, R7 is OCH(CH3)2. In another embodiment, R7 is OCHFZ.

In another aspect, the invention provides a compound of formula I-B: CWm 0’§\NH2 or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: R3 is F, Cl, CN, CF3, OCF3 or CFZCF3; and R7 is F, Cl, OCH3, OCF3, OCH2CH3, OCH(CH3)2 01' OCHFz.

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

In r embodiment, the invention features a compound of formula LB and the ant definitions, 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 3. In another embodiment, R7 is OCH(CH3)2. In r embodiment, R7 is OCHFZ.

In another aspect, the ion provides a compound of formula I-C: R1 o H 0/)S\NH2 or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: R1 is Cl, CH3, CF3 or cyclopropyl; R5 is F, Cl, CH3, OCH3, OCHZCH3, OCHZCHZCH3 or OCHFZ; and R7 is F, Cl, OCH3, OCHZCHg, OCH(CH3)2 or OCHFZ.

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

In another embodiment, the invention features a compound of formula I-C and the attendant tions, 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 OCHZCH3. In another embodiment, R5 is OCHZCHZCH3. In another embodiment, R5 is OCHFZ.

In another embodiment, the invention es a compound of formula LC and the attendant deﬁnitions, wherein R7 is F. In another embodiment, R7 is Cl. In another embodiment, R7 is OCH3. In another embodiment, R7 is OCHZCH3. In another embodiment, R7 is OCH(CH3)2. In r embodiment, R7 is OCHFZ.

In r aspect, the invention provides a compound of formula I-D: R2 ”O H 0/5 \N H2 or a pharmaceutically acceptable salt thereof, wherein, independently for each ence: R2 is F, C1, CN, CH3, CF3 or CHFZ; R5 is F, C1, CH3, OCH3, OCHZCH3, OCHZCHZCH3 or OCHFZ; and R7 is F, Cl, OCH3, OCF3, OCHZCH3, OCH(CH3)2 or OCHFZ.

In one embodiment, the invention features a compound of formula 1-D and the attendant definitions, n R2 is F. In another embodiment, R2 is Cl. In another embodiment, R2 is CN. In another ment, R2 is CH3. In another embodiment, R2 is CF3. In another embodiment, R2 is CHFZ. In another embodiment, R2 is C1 or CF3.

In another embodiment, the invention features a compound of formula 1-D and the attendant definitions, wherein R5 is F. In another embodiment, R5 is Cl. In another embodiment, R5 is CH3. In r embodiment, R5 is OCH3. In r embodiment, R5 is OCHZCH3. In another embodiment, R5 is OCHZCHZCH3. In another embodiment, R5 is OCHFZ. In r embodiment, R5 is F, C1, CH3 or OCH3.

In another embodiment, the invention features a compound of formula 1-D and the attendant definitions, n 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 OCHZCH3. In another embodiment, R7 is OCH(CH3)2. In another embodiment, R7 is OCHFZ. In another embodiment, R7 is F, CI, OCH3 or OCF3.

In r aspect, the invention provides a compound of formula LE: N \ H 0’§ NH2 or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: R3 is F, CI, CN, CF3, OCF3 or CF2CF3; R5 is F, CI, CH3, OCH3, OCHZCH3, OCHZCHZCH3 or OCHFZ; and R7 is F, Cl, OCH3, OCF3, OCH2CH3, OCH(CH3)2 or OCHFz.

In one embodiment, the invention features a compound of formula I-E and the attendant defInitions, 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 ment, R3 is CF2CF3. In r embodiment, R3 is Cl, CF3 or OCF3.

In r embodiment, the invention features a compound of formula I-E and the attendant defInitions, wherein R5 is F. In another embodiment, R5 is Cl. In another embodiment, R5 is CH3. In another ment, R5 is OCH3. In another ment, R5 is OCHZCH3. In r embodiment, R5 is OCHZCHZCH3. In another embodiment, R5 is OCHFZ. In another embodiment, R5 is F, CI, CH3 or OCH3.

In another embodiment, the invention features a compound of formula I-E and the attendant defInitions, wherein R7 is F. In r embodiment, R7 is Cl. In another embodiment, R7 is OCH3. In another embodiment, R7 is OCF3. In another embodiment, R7 is OCHZCH3. In another embodiment, R7 is OCH(CH3)2. In another embodiment, R7 is OCHFZ. In another embodiment, R7 is F, CI, OCH3 or OCF3.

In another aspect, the ion provides a compound of formula LE or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: R1 is Cl, CH3, CF3 or cyclopropyl; R3 is F, C1, CN, CF3, ocr3 or ; and R7 is F, Cl, OCH3, OCF3, OCHZCH3, OCH(CH3)2 or OCHFz.

In one embodiment, the invention features a compound of formula I-F and the attendant definitions, wherein R1 is Cl. In r 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 definitions, wherein R3 is F. In another embodiment, R3 is Cl. In another ment, R3 is CN. In r 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-F and the attendant tions, wherein R7 is F. In another embodiment, R7 is Cl. In another embodiment, R7 is OCH3. In another ment, R7 is OCF3. In another embodiment, R7 is OCHZCH3. In another embodiment, R7 is OCH(CH3)2. In another embodiment, R7 is OCHFZ.

In another aspect, the invention provides a compound of formula LG: Rzﬁ ’/0 N \ H o];3 NH2 or a pharmaceutically acceptable salt thereof, wherein, ndently for each occurrence: R2 is F, C1, CN, CH3, CF3 or CHFZ; R3 is F, C1, CN, CF3, OCF3 or CFZCF3; and R7 is F, Cl, OCH3, OCF3, OCH2CH3, OCH(CH3)2 or OCHFZ.

In one embodiment, the invention features a compound of formula I-G and the attendant definitions, 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 CHFz.

In another embodiment, the ion features a compound of formula LG and the attendant definitions, 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 r embodiment, the invention features a compound of formula LG and the attendant definitions, 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 OCHZCH3. In another embodiment, R7 is OCH(CH3)2. In another embodiment, R7 is OCHFZ.

In another aspect, the invention es a compound of a I-H: R1 o IZ 0’33‘NH2 or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: R1 is Cl, CH3, CF3 or ropyl; R3 is F, C1, CN, CF3, OCF3 or ; R5 is F, C1, CH3, OCH3, OCHZCH3, OCHZCHZCH3 or OCHFZ; and R7 is F, Cl, OCH3, OCF3, OCH2CH3, OCH(CH3)2 01' OCHF2.

In one embodiment, the invention es a nd of formula 1-H and the attendant deﬁnitions, wherein R1 is Cl. In another ment, 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-H and the attendant definitions, 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 r embodiment, R3 is .

In another embodiment, the invention es a compound of formula 1-H and the attendant definitions, 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 OCHZCHZCH3. In another embodiment, R5 is OCHFZ.

In another embodiment, the invention features a compound of formula 1-H and the attendant definitions, 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, R7 is OCF3. In another embodiment, R7 is OCHZCH3. In another embodiment, R7 is OCH(CH3)2. In another ment, R7 is OCHFz.

In another aspect, the invention provides a compound of a I-J: R2 ”O H 0’; ‘NH2 or a ceutically acceptable salt thereof, wherein, independently for each ence: R2 is F, C1, CN, CH3, CF3 or CHFz; R3 is F, C1, CN, CF3, OCF3 or CF2CF3; R5 is F, C1, CH3, OCH3, OCHZCH3, OCHZCHZCH3 or OCHFz; and R7 is F, Cl, OCH3, OCF3, OCH2CH3, OCH(CH3)2 01' OCHF2.

In one embodiment, the invention features a compound of formula LI and the attendant definitions, wherein R2 is F. In another embodiment, R2 is Cl. In another embodiment, R2 is CN. In another embodiment, R2 is CH3. In r embodiment, R2 is CF3. In another embodiment, R2 is CHFz.

In r embodiment, the invention features a compound of formula LI and the attendant definitions, wherein R3 is F. In another embodiment, R3 is Cl. In another ment, 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 LI and the ant definitions, 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 OCHZCH3. In another embodiment, R5 is ZCH3. In another ment, R5 is OCHFZ.

In r embodiment, the invention es a compound of formula LI and the ant definitions, 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 OCHZCH3. In another embodiment, R7 is OCH(CH3)2. In another embodiment, R7 is OCHFZ.

In another aspect, the invention provides a compound of formula I-K or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: R1 is Cl, CH3, CF3 or ropyl; and R5 is F, Cl, CH3, OCH3, OCHZCH3, OCHZCHZCH3 or OCHFz; In another embodiment, the invention es a compound of formula I-K and the attendant definitions, wherein R1 is Cl. In another embodiment, R1 is CH3. In another embodiment, R1 is CF3. In another ment, R1 is cyclopropyl.

In another embodiment, the invention features a compound of formula I-K and the attendant deﬁnitions, 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 OCHZCH3. In another embodiment, R5 is OCHZCHZCH3. In another embodiment, R5 is OCHFZ.

In another aspect, the invention provides a compound of formula I-L or a pharmaceutically acceptable salt thereof, n, independently for each occurrence: R3 is F, 01, CN, CF3, ocr3 or CF2CF3; R6 is F or Cl; and R7 is F, Cl, OCH3, OCF3, OCHZCH3, 3)2 or OCHFz.

In r embodiment, the invention es a compound of formula I-L and the attendant definitions, wherein R3 is F. In another embodiment, R3 is Cl. In another embodiment, R3 is CN. In r embodiment, R3 is CF3. In another embodiment, R3 is OCF3. In another embodiment, R3 is CFzCF3_ In another embodiment, the invention features a compound of formula I-L and the attendant definitions, n R6 is F. In another embodiment, R6 is C1.

In another embodiment, the invention features a compound of formula I-L and the attendant definitions, wherein R7 is F. In another embodiment, R7 is Cl. In r embodiment, R7 is OCH3. In another embodiment, R7 is OCF3. In another embodiment, R7 is OCHZCH3. In another embodiment, R7 is OCH(CH3)2. In another embodiment, R7 is OCHF2_ In another aspect, the invention es a compound of formula I-M WO 10065 or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: R3 is F, C1, CN, CF3, OCF3 or CF2CF3; and R5 is F, Cl, CH3, OCH3, OCHZCH3, OCHZCHZCH3 or OCHFZ.

In another embodiment, the invention features a compound of formula I—M and the attendant def1nitions, wherein R3 is F. In another embodiment, R3 is Cl. In another ment, 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 a I—M and the attendant def1nitions, wherein R5 is F. In another embodiment, R5 is Cl. In another embodiment, R5 is CH3. In r embodiment, R5 is OCH3. In another embodiment, R5 is OCHZCH3. In another embodiment, R5 is OCHZCHZCH3. In another embodiment, R5 is OCHFZ.

In r aspect, the invention provides a compound of formula I-N or a pharmaceutically acceptable salt thereof, n, independently for each occurrence: R3 is F, C1, CN, CF3, OCF3 or CF2CF3; R5 is F, C1, CH3, OCH3, OCHZCH3, OCHZCHZCH3 or OCHFZ; and R6 is F or Cl.

In another ment, the invention features a compound of formula I—N and the attendant deﬁnitions, 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—N and the attendant definitions, 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 OCHZCH3. In r embodiment, R5 is OCHZCHZCH3. In another embodiment, R5 is OCHFZ.

In another embodiment, the invention features a compound of formula I—N and the attendant definitions, wherein R6 is F. In another embodiment, R6 is C1.

In another aspect, the invention provides a compound of formula 1-0 or a pharmaceutically acceptable salt thereof, wherein, independently for each ence: R1 is Cl, CH3, CF3 or cyclopropyl; R3 is F, 01, CN, CF3, OCF3 or CF2CF3; R6 is F, or Cl; and R7 is F, Cl, OCH3, OCF3, 3, 3)2 or OCHFz.

In another embodiment, the invention features a compound of formula I-0 and the attendant definitions, 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 a I-0 and the attendant definitions, wherein R3 is F. In another ment, R3 is Cl. In r embodiment, R3 is CN. In another embodiment, R3 is CF3. In another ment, R3 is OCF3. In another embodiment, R3 is CFzCF3_ In another embodiment, the invention features a compound of formula I-0 and the attendant deﬁnitions, wherein R6 is F. In another embodiment, R6 is C1.

In another embodiment, the invention features a compound of formula I-0 and the attendant definitions, n R7 is F. In another ment, R7 is Cl. In r embodiment, R7 is OCH3. In another embodiment, R7 is OCF3. In r embodiment, R7 is OCHZCH3. In another embodiment, R7 is OCH(CH3)2. In another embodiment, R7 is OCHFZ.

In another embodiment, the invention features a compound of formula I, wherein the compound or a ceutically acceptable salt 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 1o\\S,/o 05°4N 2-(4-ﬂuorophenoxy)-N—(3- 2-(2-chloroﬂuorophenoxy) sulfamoylphenyl) cyano-N—(3- triﬂuorometh rélide sulfarno 1 hen lbenzarnide -chloro(4-ﬂuorophenoxy)-N— 2-(2,4-diﬂuorophenixny-(3- (3sulfarnoylphenyl)obenzoarnide sulfarnoylphenyl) O\\800 3 Q {Elm 2-(2,4-diﬂuorophenoxy)-N—(3- sulfamoylphenyl) 2-(4-ﬂuorophenoxy)-N—(3- (triﬂuoromethy1)benzarnide sulfamoylphenyl) rorneth 1 benzamide 2014/047265 7 03°//N 10 05°4N FOHNO F£10mOCH3 4-chloro(4-ﬂuorophenoxy}5- INI methyl-N—(3- 4-cyano(4-ﬂuoro sulfarno lohen lbenzarnide methoxyphenoxy)-N—(3- 8 sulfarno 1 hen lbenzarnide 4chloro2(2Chclloro4- hloroﬂuorophenoxy) ﬂuorophenoxy)-N—(3- cyano-N—(3- su amoy p1f 1 henyDboenzarm'de sulfamoylpheny1)benzarnide 12 Osv/PN 2-(4-ﬂuoromethy1phenoxy)-N— (3-sulfamoylphenyl) 4-c—y-ano(4-ﬂuoro (triﬂuoromethy1)benzarnide methylphenoxy)-N-(3- sulfarno lohen lbenzarnide WO 10065 2014/047265 13 Q¢49 16 O\\ //O 3\ S\ [ :] NHZ [ j NH2 HN O HN O Fif OCH3 F OCH3 CI 2-(4-ﬂuoro-Z-methoxyphenoxy)- 5-chloro(4-ﬂuoro N—(3-sulfarnoy1pheny1) methoxyphenoxy)-N—(3- (triﬂuorornethyl)benzarnide sulfarno lohen lbenzarnide 14 chp O\\ //o NH2 [2/ s‘NHZ HN o HN o F’ : :OCH3 F CI CI CF3 5-chloro(2-chloro-4_ 2-(4-ﬂuoro-Z-methoxyphenoxy)- ﬂuorophenoxy)—N—(3- N—(3-sulfarnoy1pheny1) sulfarno lohen lbenzarnide triﬂuororneth 1 benzamide O\\ //O O\\ 00 [ j NH2 HN 0 HN o F£10 :OCH3 CH3 F’ : CF3 CI 2-(4-ﬂu0r0rnethylphenoxy)-N- 4-chlor0(4-ﬂuoro (3-sulfamoylphenyl) methoxyphenoxy)-N-(3- triﬂuororneth 1 benzarnide sulfarno lohen lbenzarnide 19 O\\S40 22 : £126 @0055: 2-(4-methoxyphenoxy)—N—(3- 4-ch10ro(4-ﬂuoro sulfarnoylphenyl) methylphenoxy)-N-(3- sulfarno lohen 1 benzarnide 23 (triﬂuorornethyl)benzamoide OS\\00 2° m |:5-ch101ro(4-ﬂuoro 2-(4-ethoxyphenoxy)—N—(3- sulfamoylphenyl) methylphenoxy)-N-(3- (triﬂuorornethyl)benzamide 24 O\\S//O 2-(4-chlorophenoxy)-N-(3- -ﬂuoro(4-ﬂuoro sulfamoylphenyl) methylphenoxy)-N-(3- no lohen lbenzarnide (triﬂuoromethy1)benzaglide 2-(4-ﬂu0r0rnethy1phenoxy)—N— 29 O\\ 00 (3-sulfarnoylphenyl) triﬂuororneth lbenzamide 26 QS\NH2 HN O OCH3 F O 2-(3-ﬂuoromethoxyphenoxy)— N—(3-sulfamoylphenyl) (triﬂuoromethy1)benzarnide 2-(2-chloroﬂuorophenoxy)-N- 30 O\\ 00 (3-sulfarnoylphenyl) S\NH2 triﬂuororneth lbenzamide \NHZ HN o HN O OCH3 CI CF3 O 2-(4-ch10r0rnethy1phenoxy)-N— famoylphenyl) F CF3 (triﬂuorornethyl)benzamide 2-(4-ﬂuoromethoxyphenoxy)- 31 O\\ 00 N—(3-sulfamoy1pheny1) S‘NHZ triﬂuororneth mide 28 Q§gp \NHz HN o HN 0 H300 CF3 FU\éO 2-(2-chloromethoxyphenoxy)- N—(3-sulfamoylphenyl) H3CO CF3 (triﬂuorornethyl)benzamide 2-(3-ﬂuor0methoxyphenoxy)- 32 O o N—(3-sulfamoy1pheny1) \NHZ triﬂuororneth 1 benzamide HN 0 WO 10065 N-(3-su1farn0y1phenyl)—2-(o- 36 tolyloxy) OS\\//(:l triﬂuororneth 1 benzargide OCHsoCOHEZ H3CO CF3 2-(2,4-dimethoxyphenoxy)-N-(3- oylphenyl) 2-(2|:-chloroﬂuorophenoxy)-N- 37 (triﬂuoromethy1)benéamide (3-sulfarn0ylphenyl) OS\\//N triﬂuororneth lbenzgmide OCH3O0:92 2-(4-isopropoxyphenoxy)-N-(3- oylphenyl) 2-(2-methoxyphenoxy)-N-(3- 38 (triﬂuoromethy1)benzaronide sulfamoylphenyl) Osv/PN triﬂuororneth lbenzamide OS\\//O {El 2-(2-chloroﬂuorophenoxy) methyl-N-(3- sulfarno lohen lbenzarnide 2-(4-Ich-10ro2-methoxyphenoxy)- N-(3-sulfamoylpheny1) triﬂuororneth lbenzamide N—(3-sulfarn0ylphenyl)(4- 43 O\\ //o (triﬂuoromethoxy)phenoxy)-5 - s triﬂuororneth 1 benzamide E 2/ \NH2 E P/ \NHZ HN 0 HN 0 H300 F 2-(3-ﬂuoromethoxyphenoxy)— F N—(3-sulfarn0ylphenyl) F triﬂuororneth 1 benzarnide 2-(2-chloroﬂuorophenoxy) O\\ //o (diﬂuorornethyl)—N—(3- s sulfarnoylphenyl)benzarnide E 2/ \NH2 HN 0 OCH3 2-(2-rnethoxyphenoxy)—N—(3- sulfamoylphenyl) 2-(4-(diﬂuoromethoxy)phenoxy)- triﬂuororneth 1 benzarnide ulfamoylpheny1) O\\ //O (triﬂuorornethyl)benzarnide 8\ [ j NH2 42 O\\ oo E 2/ \NHZ HN 0 HN O OCH3 EtOOD 2-(4-ethoxyphenoxy)—N—(3- CF3 sulfamoylphenyl) h10r0methoxyphenoxy)- triﬂuororneth 1 benzarnide N—(3-sulfarnoylpheny1) triﬂuororneth 1 benzamide wo 2015/010065 PCT/USZOl4/047265 46 0\\SON 49 0\\800 H3CO 2-(2-pr0p0xyphenoxy)-N-(3- 2-(4-meth0xyrnethylphenoxy)- sulfamoylphenyl) N—(3-sulfarn0ylphenyl) triﬂuororneth lbenzamide triﬂuororneth 1 benzarnide 47 OS\\//N OCH30 H3CO N—(3-sulfarnoy1ph:nyl)(o- 2-(2,4-dimethoxyphenoxy)-N-(3- tolyloxy) sulfamoylphenyl) triﬂuororneth lbenzamide triﬂuororneth 1 nide 48 O\\S/xo OS\\//O Q: QT” 65 F3066 CF3 CF3 2-(2-ch10r0methoxyphenoxy)- N—(3 -sulfarn0ylpheny1)(4- ulfamoylpheny1)—4- (triﬂuorornethoxy)phenoxy)—4- triﬂuororneth 1 benzamide triﬂuororneth 1 benzarnide 52 O\\ //o 55 s O\\S//O E 2/ \NHZ HN O OCH3 F o 2-(3-ﬂuoro-Z-methoxyphenoxy)- 2-(4-ﬂuorophenoxy)—N—(3- N—(3-sulfarnoy1pheny1) sulfamoylphenyl) triﬂuororneth 1 benzamide triﬂuorornethox benzarnide 2-(4-isopropoxyphenoxy)-N—(3- 2-(2-chloroﬂuorophenoxy)-N— sulfamoylphenyl) (3-sulfamoylpheny1)_4_ HN o OCH3 OCF3 2-(2-rnethoxyphenoxy)—N—(3- sulfamoylphenyl) 2-(4-ﬂuoro-Z-methoxyphenoxy)- triﬂuororneth 1 nide N—(3-sulfarnoy1pheny1) rornethox benzarnide 2014/047265 58 OO N—(3-sulfarn0ylphenyl) triﬂuororneth 1 benzarnide O\\ //o E 2/ \NHZ HN 0 h10r0rnethy1phenoxy)-N— (3 -su1farn0ylphenyl) H300 triﬂuororneth 1 benzamide OCF3 9 2-(2-chloromethoxyphenoxy)- N—(3-sulfarn0ylphenyl) triﬂuorornethox benzarnide 2-(3-ﬂuor0rnethy1phenoxy)—N— (3-sulfarnoylphenyl) triﬂuororneth lbenzamide 60 0\\ //o E 2/ \NHZ 2-(2-chlorophenoxy)-N-(3- sulfamoylphenyl) HN 0 (triﬂuorornethoxy)benzarnide O\\ //O CF3 E 2/ \NHZ F300 N—(3-sulfarn0ylphenyl)(4- (triﬂuorornethoxy)phenoxy) triﬂuororneth 1 benzamide 2-(2-(diﬂuorornethoxy)phenoxy)— N—(3-sulfarn0ylphenyl) triﬂuorornethox benzarnide W0 2015/010065 PCT/USZOl4/047265 65 OS\\//C:I 68 OS\\//N HN HN OCH3OCOHEZ OCH3O0::H2 OCF3 2-(4-ch10r0meth0xyphenoxy)- 2-(3-chloromethoxcyl:phenoxy)- N—(3-sulfarnoylpheny1)—4- N—(3-sulfarnoylphenyl) triﬂuorornethox benzarnide triﬂuororneth 1 lide 66 O\\300 00F3 2-(3-ch10r0rneth0xyphenoxy)- 2-(4-ﬂuorophenoxy) N—(3-sulfarnoylpheny1) rornethox benzarnide (perﬂuoroethyl)—N—(3- sulfarno lohen lbenzarnide 67 O\\S/xo [W QT”HN H315‘5 OCH3O 2-(3-ch10r0rneth0xyphenoxy)- F3C F N—(3-sulfarnoylpheny1)—4- 2-(4-ﬂu0r0methoxyphenoxy)— triﬂuororneth 1 ide 4-(perﬂuoroethyl)-N—(3- sulfarno lohen lbenzarnide 71 O\\S//O 74 O\\S/,O Q“ QM H N O HN O OCH3 CI CI 06ch F hlorophenoxy)-N-(3 - F30 F sulfamoylphenyl) 2-(4-ch10r0methoxyphenoxy)- (triﬂuoromethy1)benzarnide 4-(perﬂuoroethyl)-N-(3- 75 O\\ //O sulfarnoylphenyl)benzarnide S‘NHZ 72 O\\S,/O E 2/ \NHZ HN 0 HN o 0 060% H300 2-(2-chloromethoxyphenoxy)- H300 F u1farn0ylphenyl) (triﬂuoromethy1)benzarnide F30 F 76 o o 2-(2-ch10r0methoxyphenoxy)- \\// \NH2 4-(perﬂuoroethyl)-N-(3- sulfarnoylphenyl)benzarnide [2/ s 73 O\\ //o s HN o E 2/ \NH2 OCH3 HN 0 CI H300 CI 0 CI 4,5-dichlor0(2,4- dimethoxyphenoxy)-N—(3- sulfarno 1 hen lbenzarnide 2-(2-chlorophenoxy)-N—(3- sulfamoylphenyl) triﬂuororneth 1 benzamide HN HN OCH3OO:::H OCH3O0::\:-I2 chloro(4-Cﬂu010 4,5-dichloro(4-chloro methoxyphenoxy)-N-(3- methoxyphenoxy)-N—(3- sulfarno lohen lbenzarnide sulfarno lohen lbenzarnide 78 O\\SOC; H3CO FOHNEOIHZ‘0 4,5-dichloro(4- 4,5-dichloro(2-ﬂuoro henoxy)-N—(3- methoxyphenoxy)-N—(3- 79 sulfarnoylphenyl)begzaméde sulfamoylpheny1)begzaméde OS\\//0 OS\\//O Q?“ W 1:13{EL {EL 4,5-dichloro(3-ﬂuloro 4,5-dichloro(2-chloro methoxyphenoxy)-N-(3- methoxyphenoxy)-N—(3- sulfarno lohen lbenzarnide sulfarno lohen lbenzarnide WO 10065 83 Q§§9 86 Q§§p Q“ Q“ HN o HN 0 CH3 CI 0 O F CI H3CO Cl C 4,5-dichlor0-2—(4-ﬂuor0 4-chlor0(2-chloro methylphenoxy)-N-(3- methoxyphenoxy)-N—(3- sulfarno lohen lbenzarnide sulfarno lohen lbenzarnide 84 O\\S//O HN O OCH3 H300 4-ch10r0(2,4- 4-chlor0(4- dimethoxyphenoxy)—N—(3- isopropoxyphenoxy)-N-(3- sulfarnoylphenyl)benzarnide sulfamoylpheny1)benzarnide 85 O O O O Q“? \/ s \S< E 2/ \NH2 NH2 HN 0 OCH3 O CF3 C 93% CI CF3 4-chlor0(4-chloro uorophenoxy)—N—(3- methoxyphenoxy)-N-(3- sulfarnoylphenyl)-4,6- sulfarno lohen lbenzarnide ' triﬂuororneth lbenzamide 89 OS\\//O 92 OS\\//O m? Q‘TNH Q OCH3Q 2-(4-ﬂuoromethoxyphenoxy)- 2-(5-ﬂuorometho:3yphenoxy)- N—(3-sulfam0ylphenyl)-4,6- N—(3-sulfam0ylphenyl)-4,6- bis triﬂuororneth 1 nide ' triﬂuororneth lbenzamide OS\\//O 2-(3-ﬂuoromethoxyphenoxy)- 2-(4-ﬂuorornethy1plFienoxy)-N- N—(3-sulfam0ylphenyl)-4,6- (3-sulfarnoylpheny1)—4,6- bis triﬂuororneth 1 benzarnide OS\\//O 2-(2-ﬂuoromethoxyphenoxy)- 2,4-dich10r0(4- N—(3-sulfam0ylphenyl)-4,6- ﬂuorophenoxy)—N—(3- bis triﬂuororneth 1 nide sulfamoylpheny1)benzarnide 95 o\\ 00 98 0\\ 40 QS\ QS\ HN o HN 0 OCH3 OCH3 0 CI 0 CI F CI CI CI 2,4-dichlor0(4-ﬂuoro-Z- 2,4-dichlor0(4-chloro methoxyphenoxy)-N-(3- methoxyphenoxy)-N—(3- no lohen lbenzarnide sulfarno 1 hen rnide 96 0°st [ j NH2 HN 0 0 CI 2,4-dichlor0(4-ﬂuoro-Z- 2,4-dichlor0(2-ﬂu0r0 methylphenoxy)-N-(3- methoxyphenoxy)-N—(3- sulfarnoylphenyl)benzarnide sulfamoylpheny1)benzarnide 97 O O O O \S<\/ \\// [ j NH2 HN o H300 F CF3 2,4-dichloro-N—(3- 2-cyclopropyl(3-ﬂuoro sulfarnoylphenyl)(4- methoxyphenoxy)-N—(3- (triﬂuorornethoxy)phenoxy)benza sulfamoylphenyl) mide (triﬂuoromethy1)benzarnide In one embodiment, the compound is uorophenoxy)—N—(3- sulfamoylphenyl)(triﬂuoromethyl)benzamide or a pharmaceutically able salt thereof.

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

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

In another embodiment, the compound is 2-(4-ﬂuorophenoxy)—N—(3- oylphenyl)(triﬂuoromethyl)benzamide or a pharmaceutically acceptable salt thereof In another embodiment, the compound is 2-(2-chloroﬂuorophenoxy)-N-(3- sulfamoylphenyl)(triﬂuoromethyl)benzamide or a pharmaceutically acceptable salt thereof In another embodiment, the compound is hloroﬂuorophenoxy) (diﬂuoromethyl)-N—(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof In another embodiment, the compound is 2-(4-ﬂuorophenoxy)—4- (perﬂuoroethyl)-N—(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof In another embodiment, the compound is 2—(4-chloromethoxyphenoxy) (perﬂuoroethyl)-N—(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof In another embodiment, the compound is 2-(4-ﬂuoro methoxyphenoxy)-N—(3-sulfamoylphenyl)(triﬂuoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the nd is 5-chloro(4-ﬂuoro-2— methylphenoxy)—N—(3-sulfamoylphenyl)benzamide or a ceutically acceptable salt thereof In another embodiment, the compound is 4,5-dichloro(4-ﬂuoro methoxyphenoxy)-N—(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof In another embodiment, the nd is 2,4-dichloro(4-chloro methoxyphenoxy)-N—(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof.

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

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

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

In another embodiment, the compound is ro(2-chloro ﬂuorophenoxy)-N—(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof In another embodiment, the compound is 2-(4-ﬂuoro yphenoxy)-N—(3-sulfamoylphenyl)(triﬂuoromethoxy)benzamide or a pharmaceutically acceptable salt f.

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

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

] In another embodiment, the compound is 5-ﬂuoro(4-ﬂuoro-2— methylphenoxy)—N—(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof WO 10065 2014/047265 ] In another embodiment, the nd is 2-(2-chloro ﬂuorophenoxy)cyano-N-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof.

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

Salts, Compositions, Uses, Formulation,Administration and onal Agents Pharmaceutically acceptable salts and itions As discussed herein, the invention provides compounds that are tors of voltage-gated sodium channels, and thus the present compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inﬂammatory pain, cancer pain, idiopathic pain, multiple sis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia. Accordingly, in r aspect of the invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a ceutically acceptable carrier, adjuvant or vehicle. In certain ments, 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 salt thereof of and one or more pharmaceutically acceptable carriers or vehicles.

It will also be appreciated that n of the compounds of invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof According to the invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically able salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a subject in need is capable of providing, directly or indirectly, a nd as otherwise described herein, or a metabolite or residue thereof As used herein, the term “pharmaceutically acceptable salt” 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 animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable t/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a nd of this ion that, upon administration to a recipient, is e of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term itorily active metabolite or residue thereof ’ means that a metabolite or residue thereof is also an inhibitor of a voltage-gated sodium channel.

Pharmaceutically able 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, l-l9, incorporated herein by reference. Pharmaceutically acceptable salts of the nds of this invention include those derived from le 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 hloric acid, romic acid, phosphoric acid, sulﬁaric 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, te, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, ionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2—naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, ate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, anate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1_4 alkyl)4 salts. This invention also ons 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 ization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic um, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lkyl sulfonate and aryl sulfonate.

As described herein, the pharmaceutically acceptable compositions of the invention onally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid e, dispersion or suspension aids, surface active agents, isotonic 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 n, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically able compositions and known techniques for the preparation thereof.

Except insofar as any conventional carrier medium is incompatible with the compounds of the ion, 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 d to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, e, sorbic acid, or potassium e, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal , magnesium trisilicate, nyl pyrrolidone, rylates, 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 derivatives such as sodium carboxymethyl cellulose, ethyl ose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; ents such as cocoa butter and itory waxes; oils such as peanut oil, cottonseed oil; safﬂower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; ing agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic ible lubricants such as sodium lauryl e and magnesium stearate, as well as ng , releasing agents, coating , sweetening, ng and perfuming agents, preservatives and antioxidants can also be present 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 salt f of the compounds of formula I and one or more pharmaceutically acceptable carriers or vehicles.

Uses ofCompounds and Pharmaceutically Acceptable Salts 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 salt thereof or a pharmaceutical composition thereof. In another aspect, the e-gated sodium channel is Navl .8.

In yet another aspect, the invention features a method of ng or lessening the severity in a subject of chronic pain, gut pain, neuropathic 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 salt 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, athic pain, musculoskeletal pain, acute pain, inﬂammatory pain, cancer pain, thic pain, multiple sis, Charcot- Marie-Tooth syndrome, incontinence or cardiac arrhythmia sing administering an effective amount of a compound or a pharmaceutically able salt thereof or a pharmaceutical ition 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 e pain, Crohn’s disease pain or interstitial is pain.

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

In yet another aspect, the ion 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, burn 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 ng or lessening the ty in a subject of inﬂammatory pain wherein inﬂammatory pain comprises rheumatoid arthritis pain or vulvodynia.

In yet r aspect, the invention features a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic 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 salt thereof or a pharmaceutical composition of the compounds of formula I with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent 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 ceutically acceptable salt 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 ty in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning 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 regional pain syndrome, drug y induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, thic small-ﬁber neuropathy, idiopathic sensory athy or trigeminal autonomic cephalalgia n said method comprises administering an effective amount of a compound, a pharmaceutically acceptable salt 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 oskeletal pain, wherein oskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain n said method comprises administering an ive amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I.

In yet another aspect, the ion es a method of treating or lessening the severity in a subject of inﬂammatory pain, wherein atory pain ses rheumatoid arthritis pain or vulvodynia wherein said method comprises administering an ive amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I.

In yet another aspect, the invention es a method of treating or lessening the severity in a subject of idiopathic pain, wherein thic pain comprises f1bromyalgia pain wherein said method comprises stering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I.

In yet another aspect, the invention features a method wherein the t is treated with one or more additional therapeutic agents administered rently with, prior to, or subsequent to treatment with an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I.

In another aspect, the invention es a method of inhibiting a e-gated sodium channel in a subject comprising administering to the subject an effective amount of a compound, a pharmaceutically able salt thereof or a pharmaceutical composition of the compounds of formula I. In another , the voltage-gated sodium channel is Navl .8.

In r aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a biological sample comprising contacting the biological sample with an ive amount of a compound, a pharmaceutically acceptable salt 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, neuropathic pain, inﬂammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, sy, epilepsy ions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, r disorder, myotonia, arrhythmia, movement disorders, ndocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic athy, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility, comprising stering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a ceutical 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 femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; rthritis; spinal stenosis; athic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic Visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; ne; tension headache, cluster hes; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; inal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; ectopic al and distal discharges; lopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional 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 pain; exercise pain; acute Visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelVic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inﬂammatory, burn and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain including sinusitis pain, dental pain; multiple sclerosis (MS) pain; pain in sion; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; in-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital e, including, urinary incontinence; hyperactivity bladder; painﬁll bladder syndrome; interstitial cyctitis (IC); prostatitis; complex regional pain syndrome , type I and type II; Widespread pain, paroxysmal extreme pain, pruritis, is, or angina-induced pain, comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical ition of the compounds of formula I.

In another aspect, the invention features a method of treating or lessening the severity in a subject of neuropathic pain sing administering an effective WO 10065 amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I. In one aspect, the neuropathic pain is selected from post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal gia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton’s neuroma, nerve entrapment injury, spinal is, carpal tunnel syndrome, lar pain, sciatica pain, nerve avulsion injury, brachial plexus avulsion, complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy d neuralgia, post spinal cord injury pain, idiopathic small-ﬁber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic algia.

Manufacture ofMedl'caments In one aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the cture of a medicament 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 ition bed herein for the manufacture of a medicament for use in treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inﬂammatory pain, cancer pain, idiopathic pain, multiple sis, 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 medicament for use in ng 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 medicament for use in a treating or lessening the ty in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, ic neuralgia, painful HIV-associated y athy, trigeminal neuralgia, burning 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 regional pain syndrome, drug y induced neuralgia, cancer chemotherapy induced gia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic algia.

In yet another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or ing the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn 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 medicament 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 , the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the ty in a subject of idiopathic pain, wherein idiopathic pain comprises ﬁbromyalgia pain.

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

In another aspect, the invention provides the use of a compound or pharmaceutical ition described herein for the manufacture of a medicament for use in treating or lessening the ty of acute pain, chronic pain, neuropathic pain, inﬂammatory pain, arthritis, migraine, r headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, sion, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, , le sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, rpetic 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, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility.

In another aspect, the invention es the use of a compound or pharmaceutical composition bed herein for the manufacture of a ment for use in treating or lessening the severity of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; c visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache, including, cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic athy; 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 neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional 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 al pain; pyelonephritis; appendicitis; cholecystitis; inal obstruction; hernias; chest pain, c pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inﬂammatory, burn and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell ; acute pancreatitis; breakthrough pain; ial pain including tis pain, dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; d syndrome; erythromelalgia pain; Fabry's e pain; bladder and urogenital disease, including, y incontinence; hyperactivity bladder; painﬁll bladder syndrome; interstitial is (1C); prostatitis; complex regional pain syndrome (CRPS), type I and type II; Widespread pain, paroxysmal extreme pain, pruritis, tinnitis, or angina-induced pain.

In another aspect, the invention es the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or ing the severity of neuropathic pain. In one aspect, the neuropathic pain is ed from erpetic neuralgia, diabetic gia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning 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 on , brachial plexus avulsion, complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, post spinal cord injury pain, idiopathic small-ﬁber athy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

Administration ofPharmaceutically Acceptable Salts and Compositions In certain embodiments of the invention an “effective amount” of the compound, a pharmaceutically able salt thereof or pharmaceutically acceptable ition is that amount effective for treating or lessening the severity of one or more of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inﬂammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia.

The compounds and itions, according to the method of the invention, may be stered 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 s, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.

The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the subject to be d. It will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending ian within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the speciﬁc compound employed; the speciﬁc composition ed; the age, body weight, general health, sex and diet of the subject; the time of stration, route of administration, and rate of excretion of the speciﬁc compound employed; the duration of the treatment; drugs used in combination or coincidental with the speciﬁc compound employed, and like s well known in the medical arts. The term “subject” or nt,” 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 animals orally, rectally, parenterally, intracistemally, aginally, intraperitoneally, topically (as by s, ointments, or drops), y, as an oral or nasal spray, or the like, ing 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 ably 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, ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert ts commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsiﬁers such as ethyl alcohol, isopropyl alcohol, ethyl ate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene , l,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), ol, tetrahydrofurﬁlryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, ﬂavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous sions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile inj ectable solution, suspension or emulsion in a nontoxic parenterally WO 10065 2014/047265 acceptable diluent or solvent, for example, as a solution in l,3-butanediol. Among the acceptable vehicles and solvents that may be ed are water, ’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, ﬁxed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland ﬁxed oil can be employed including synthetic mono- or erides. In addition, fatty acids such as oleic acid are used in the preparation of inj ectables.

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

In order to prolong the effect of a compound of the invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of lline or amorphous al with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon l size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by ving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in radable 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 biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot inj ectable 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 ed by mixing the compounds of this invention with suitable non-irritating ents or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and ore 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) s or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, n, nylpyrrolidinone, sucrose, and acacia, c) ants such as ol, 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 paraffin, f) tion accelerators such as quaternary 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 te, magnesium stearate, solid hylene 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 lled gelatin capsules using such ents 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 n part of the intestinal tract, optionally, in a delayed manner. Examples of embedding itions that can be used e 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 ents 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 e, 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 magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and 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 d manner. Examples of embedding itions that can be used include polymeric nces and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include nts, pastes, , lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable r and any needed preservatives or s as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the invention contemplates the use of transdermal s, which have the added advantage of ing lled 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 controlling ne 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 ofNaVl .8 and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or ing the severity of a disease, condition, or disorder where activation or hyperactivity ofNaVl .8 is implicated in the e, condition, or disorder. When activation or hyperactivity ofNaVl .8 is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a “NaVl .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 ofNaVI .8 is implicated in the disease state.

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

Additional Therapeutic Agents It will also be iated that the compounds and pharmaceutically acceptable compositions of the invention can be employed in combination therapies, that is, the nds and pharmaceutically acceptable compositions can be stered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. In one embodiment, the subject is treated with one or more onal therapeutic agents administered concurrently with, prior to, or uent to treatment with the compound or pharmaceutical composition of formula I of the present invention. The particular combination of therapies peutics or procedures) to employ in a combination regimen will take into account compatibility of the desired eutics and/or procedures and the desired therapeutic effect to be achieved. It will also be iated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional eutic 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 analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such sa Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, fen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Aspirin, Choline magnesium trisalicylate, Diﬂunisal; fenamates such as meclofenamic acid, Mefenamic acid; and les such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, dine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, orphine, Butorphanol, Dezocine, Nalbuphine, and ocine). Additionally, nondrug analgesic approaches may be ed 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 cutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or ches 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 an NaV l.7 tor. NaV 1.7 and NaV 1.8 ion channels are both highly expressed in the sensory neurons of the dorsal root ganglion, where pain signals originate, but the distinct ﬁanctional or of the two channels leads them to fulﬁll distinct and complementary roles in neuronal excitability. NaVl .7 controls the general sensitivity of nociceptive neurons, and initiating the painﬁJl signal in a nociceptor. NaVl .8 ampliﬁes and sustains the pain signal once it has been initiated. Because of these distinct roles, inhibiting both channels should increase the effectiveness of pain relief. Preclinical genetic knockout mice support this idea, as double knockouts ofNaVl .7 and NaVl .8 channels in the sensory DRG s surprisingly diminish nociceptive ors to a greater degree than knockout of either channel alone.

In another embodiment, additional riate therapeutic agents are selected from the following: (1) an opioid analgesic, e. g. morphine, heroin, hydromorphone, phone, levorphanol, levallorphan, methadone, meperidine, fentanyl, e, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, orphine, hanol, nalbuphine or pentazocine; (2) a nonsteroidal antiinﬂammatory drug (NSAID), e. g. aspirin, diclofenac, diﬂunisal, etodolac, fenbufen, fenoprofen, ﬂufenisal, ﬂurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroﬂurbiprofen, olsalazine, zin, phenylbutazone, piroxicam, alazine, sulindac, tolmetin or zomepirac; (3) a barbiturate sedative, e. g. bital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, exital, pentobarbital, phenobarbital, secobarbital, talbutal, lal or thiopental; (4) a iazepine having a sedative , e. g. chlordiazepoxide, clorazepate, diazepam, ﬂurazepam, lorazepam, oxazepam, temazepam or triazolam; (5) a histamine (H1) antagonist having a sedative , e. g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; (6) a sedative 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 - hydroxy-N— methylmorphinan) or its metabolite dextrorphan -hydroxy-N- methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis (phosphonomethyl) piperidinecarboxylic acid, budipine, EN—323l (MorphiDeX®), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or fotel including an NRZB antagonist, e.g. odil, traxoprodil or ) {2-[4-(3- ﬂuorophenyl)hydroxy-l- piperidinyl]-l-hydroxyethyl-3 ,4-dihydro-2(lH)-quinolinone; (9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, etomidine, modaﬁnil, or 4-amino-6,7-dimethoxy(5-methane- sulfonamido-l, 2,3,4- tetrahydroisoquinolinyl)—5-(2-pyridyl) quinazoline; (10) a tricyclic antidepressant, e. g. amine, imipramine, amitriptyline or nortriptyline; (ll) 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-l antagonist, e.g. (alphaR,9R)—7-[3,5-bis(triﬂuoromethyl)benzyl]-8,9,lO,ll -tetrahydro methyl(4- methylphenyl)-7H-[l,4]diazocino[2,l-g] [l,7]-naphthyridine l 3-dione (TAK- 637), 5- [[(2R,3S)-2—[(lR)-l-[3,5-bis(triﬂuoromethyl)phenyl]ethoxy(4-ﬂuorophenyl)—4- morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4-triazolone (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-n1ethoxy(triﬂuoroniethoxy)phenyl]-n1ethylan1ino]phenylpiperidine (2S ,3 S); (13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, uni chloride, darifenacin, solifenacin, temiverine and ipratropiuni; (14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; (15) a coal-tar analgesic, in particular paracetamol; ] (16) a eptic such as idol, chlorproniazine, haloperidol, perphenazine, thioridazine, mesoridazine, triﬂuoperazine, ﬂuphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, ine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rinionabant, n1eclinertant, on® or sarizotan; (17) a oid receptor agonist (e.g. resinferatoxin or civaniide) or antagonist (e.g. capsazepine, GRC-15300); ] (18) a beta-adrenergic such as nolol; (19) a local anaesthetic such as niexiletine; (20) a corticosteroid such as ethasone; (21) a 5-HT receptor agonist or antagonist, particularly a 5-HTlB/1D t such as eletriptan, sumatriptan, naratriptan, zolniitriptan or rizatriptan; (22) a 5-HT2A receptor antagonist such as R(+)—alpha-(2,3-din1ethoxy- phenyl)-l- [2-(4-ﬂuorophenylethyl)] piperidinen1ethanol (MDL-100907); (23) a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-n1ethyl(3-pyridinyl)buten-l-an1ine (RJR—2403), (R)—5-(2-azetidinyln1ethoxy)—2- pyridine (ABT-594) or nicotine; (24) Tramadol, Tramadol ER (Ultrani ER®), Tapentadol ER (Nucynta®); (25) a PDES inhibitor, such as thoxy(4-methyl-l-piperazinylsulphonyl )phenyl]-l-methyln-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone (sildenaﬁl), (6R, l2aR)— 2,3 ,6,7, 12, l 2a-hexahydromethyl(3 ,4-methylenedioxyphenyl)- pyrazino[2',l':6,l]-pyrido[3,4-b]indole-l,4-dione (IC-3Sl or tadalaﬁl), thoxy(4-ethylpiperazin-l-yl-l-sulphonyl )-phenyl] methylpropyl-3H-imidazo [5 ,l-f] [l,2,4]triazinone (vardenaﬁl), 5-(5 -acetylbutoxypyridinyl)ethyl(l-ethylazetidinyl)-2,6-dihydro- 7H- pyrazolo[4,3-d]pyrimidinone, 5 -(5-acetylpropoxy-3 -pyridinyl)ethyl(l- isopropylazetidinyl)-2,6-dihydro-7H—pyrazolo[4,3-d]pyrimidinone, 5-[2-ethoxy(4- ethylpiperazin-l-ylsulphonyl)pyridinyl]ethyl[2-methoxyethyl]-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidinone, 4-[(3-chloromethoxybenzyl)amino][(2S) (hydroxymethyl)pyrrolidin-l-yl]-N-(pyrimidinylmethyl)pyrimidinecarboxamide, 3-(l- methyloxopropyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidinyl)—N—[2-(l- pyrrolidinyl)ethyl]propoxybenzenesulfonamide; (26) an alphadelta ligand such as ntin (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, )aminomethylmethyl-heptanoic acid, (3S,5R)—3-aminomethyl- heptanoic acid, (3S,5R)—3-aminomethyl-octanoic acid, (2S,4S)(3- chlorophenoxy)proline, (2S,4S)—4-(3-ﬂuorobenzyl)—proline, [(lR,5R,6S)—6- (aminomethyl)bicyclo[3.2.0]heptyl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)-4H- [l,2,4]oxadiazolone, C-[l-(lH-tetrazol-S-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(l- aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)aminomethylmethyl- octanoic acid, )—3-aminomethyl-nonanoic acid, (3S,5R)—3-aminomethyl-octanoic acid, (3R,4R,5R)—3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)amino-4,5- dimethyl-octanoic acid; (27) a cannabinoid such as KHK-6188; (28) metabotropic ate subtype 1 receptor (mGluRl) antagonist; (29) a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, ﬂuoxetine, norﬂuoxetine (ﬂuoxetine desmethyl metabolite), ﬂuvoxamine, paroxetine, pram, citalopram lite desmethylcitalopram, escitalopram, nﬂuramine, tine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone; (30) a noradrenaline inephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupoprion, nomifensine and Viloxazine (Vivalan®), especially a ive noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)- reboxetine; (3 l) a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran and imipramine; (32) an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2- inoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)-amino]ethyl]-4,4-dioxo-L- ne, S-[2-[(l-iminoethyl)amino]ethyl]methyl-L-cysteine, (2S,5Z)aminomethyl [(l-iminoethyl)amino]heptenoic acid, 2-[[(lR,3S)aminohydroxy-l-(5-thiazolyl)- butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(lR,3S)aminohydroxy-l-(5- thiazolyl)butyl]thio]chlorobenzonitrile, (ZS,4R)amino[[2-chloro (triﬂuoromethyl)phenyl]thio]thiazolebutanol, 2-[[(lR,3S)aminohydroxy-l-(5- thiazolyl) butyl]thio](triﬂuoromethyl)pyridinecarbonitrile, 2-[[(lR,3S)amino hydroxy- l -(5 -thiazolyl)butyl]thio] -5 -chlorobenzonitrile, N— [4-[2-(3 - chlorobenzylamino)ethyl]phenyl]thiophenecarboxamidine, 2, or guanidinoethyldisulﬁde; (33) an acetylcholinesterase inhibitor such as donepezil; (34) a prostaglandin E2 subtype 4 (EP4) antagonist such as N—[( {2-[4- (2-ethyl-4,6- dimethyl-lH-imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl} amino)-carbonyl] methylbenzenesulfonamide or 4-[( l 5)-l-( { [5-chloro(3-ﬂuorophenoxy)pyridin yl]carbonyl} amino)ethyl]benzoic acid; (35) a leukotriene B4 nist; such as l-(3-biphenylylmethyl hydroxy-chromanyl)-cyclopentanecarboxylic acid (CP- 105696), 5-[2-(2-Carboxyethyl)—3- [6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-Valeric acid 057) or DPC-11870; (36) a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-ﬂuoro[4- methoxy-3 ,4,5 ,6- tetrahydro-2H-pyranyl])phenoxy-methyl]-l-methylquinolone (ZD- 2138), or 2,3,5- trimethyl(3 -pyridylmethyl)-l,4-benzoquinone (CV-6504); (37) a sodium channel r, such as lidocaine, lidocaine plus tetracaine cream (ZRS-201) or eslicarbazepine acetate; ] (38) an NaV1.7 blocker, such as XEN—402 and such as those disclosed in WO2011/140425; WO2012/106499; WO2012/112743; WO2012/125613; WO2013067248 or the entire contents of each ation hereby incorporated by reference. (39) an NaV1.8 blocker, such as those disclosed in WO2008/135826 and WO2006/011050 the entire contents of each application hereby incorporated by reference. ] (40) a combined NaV1.7 and NaV1.8 blocker, such as DSP-2230 or BL- 1021; (41) a 5-HT3 antagonist, such as ondansetron; (42) a TPRV 1 receptor agonist, such as cin (NeurogesX®, a®); and the ceutically acceptable salts and solvates 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 V-116517, Pregabalin, controlled release Pregabalin, Ezogabine a®).

Ketamine/amitriptyline topical cream (Amiket®), AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-95456lor ARC-4558.

The amount of onal therapeutic agent present 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 % to 100% of the amount normally t in a composition comprising that agent as the only eutically active agent.

The compounds of this invention or pharmaceutically acceptable compositions thereofmay also be incorporated into compositions for coating an table medical device, such as prostheses, artiﬁcial valves, vascular grafts, stents and catheters.

Accordingly, the invention, in another , includes a ition for coating an implantable device comprising a nd of the invention as described lly 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 ion as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 562; 5,886,026; and 5,304,121. The gs are typically patible polymeric materials such as a hydrogel polymer, thyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further 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 NaV1.8 activity in a biological sample or a subject, which method comprises administering to the subject, or contacting said ical 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 ts thereof.

Inhibition ofNavl .8 ty 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 ative evaluation of new sodium l inhibitors.

SCHEMES AND EXAMPLES ] The following deﬁnitions describe terms and abbreviations used herein: Ac acetyl Bu butyl Et ethyl Ph phenyl Me methyl THF tetrahydrofuran DCM dichloromethane CHzClz dichloromethane EtOAc ethyl acetate CH3CN acetonitrile MeCN acetonitrile ACN acetonitrile EtOH ethanol EtzO diethyl ether MeOH methanol i-PrOH isopropyl alcohol MTBE methyl tert-butyl ether DMF N,N—dimethylformamide DMA N,N—dimethylacetamide DMSO dimethyl sulfoxide HOAc acetic acid NMP N—methylpyrrolidinone TEA triethylamine TFA triﬂuoroacetic acid TFAA triﬂuoroacetic anhydride Eth or NEtg triethylamine DIPEA or DIEA diisopropylethylamine K2C03 potassium carbonate N32C03 sodium carbonate g sodium thiosulfate C82C03 cesium carbonate NaHCOg sodium bicarbonate NaOH sodium hydroxide Na2S04 sodium sulfate MgSO4, magnesium sulfate K3P04 potassium phosphate NH4Cl ammonium chloride SOzClz thionyl chloride KMnO4 potassium ganate DMAP N,N-dimethylaminopyridine HATU l - [bis(dimethylamino)methylene] - l H- l ,2,3 -triazolo [4,5 -b]pyridinium-3 -oxid hexaﬂuorophosphate EDCI N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride HOBT oxybenzotriazole hydrate HCl hydrochloric acid H20 water Pd/C palladium on carbon NaOAc sodium e H2804 sulfuric acid N2 nitrogen gas H2 hydrogen gas n-BuLi n-butyl lithium Pd(OAc)2 palladium(II)acetate PPh3 triphenylphosphine NBS N—bromosuccinimide 3)P]4 tetrakis(triphenylphosphine)palladium(0) LC/MS liquid chromatography/mass spectra GCMS gas chromatography mass spectra HPLC high performance liquid chromatography GC gas tography LC liquid chromatography IC ion chromatography Hr or h hours min minutes atm atmospheres rt or RT room temperature TLC thin layer chromatography SM starting material EquiV. or Eq. equivalents aq aqueous N normal L liters mL milliliters uL microliters M molar uM micromolar nM nanomolar N normal mol moles mmol millimoles g grams mg milligrams ug micrograms 1H-NMR proton nuclear magnetic resonance MHz megahertz Hz hertz CDC13 deutero form DMSO-d6 deutero dimethyl sulfoxide MeOD deutero methanol CD301) deutero methanol Ki dissociation constant IC50 half maximal inhibitory concentration The compounds of the invention may be prepared readily using the following methods. Illustrated below in Schemes 1-3 are general methods for preparing the compounds of the present invention.

Scheme 1: General Preparation of nds of Formula I R5 R5' R6 R6, R1 0 R2 R7 R2 OH S’NH2 R2 Q,NH2 N —> H 0” \‘O —> H (a) R3 F (c) R3 0 R5' (d) R6 R7 (a) 3-aminophenyl sulfonamide, coupling agent (i.e. HATU, EDCI, HOBT), base (i.e. N- methylmorpholine), solvent (i.e. DMF, dichloromethane); (b) ophenyl sulfonamide, base (i.e. pyridine, C82C03), solvent (i.e. dichloromethane, DMF); (c) base (i.e. NaH, C82C03, N32C03, ), solvent (DMF, NMP, dioxane), AT; (d) SOzClz, DMF in a solvent (i.e. dichloromethane).

Scheme 2: General Preparation of nds of Formula I R5 R5 R6 R6 R1 0 R7 R1 O OH R2 NH2 R3 F ” ‘\ R3 (a) O R5' M O O R4 R3 R4 o R5 R5 R6' R4 R5 R6 R6 R7 R6 R7 R2 CN R3 F (a) i) base (i.e. NaH, C82C03, N32C03, NaHC03), solvent (DMF, NMP, dioxane), AT; ii) oxidation conditions (i.e. KMnO4 or sodium dihydrogen phosphate, 2-methylbutene and sodium chlorite) in a solvent (water, tBuOH and acetonitrile); (b) i) base (i.e.

NaH, C82C03, N32C03, NaHCOg), solvent (DMF, NMP, dioxane), AT; ii) Hydrolysis conditions (i.e. aqueous HBr); (c) ophenyl sulfonamide, coupling agent (i.e.

HATU, EDCI, HOBT), base (i.e. N—methylmorpholine), solvent (i.e. DMF, romethane).

Scheme 3: General Preparation of nds of Formula I R _' // \\ (a) 1 ' O O R5 R5 O R5 R5 R6 R6 7 R6 R6 (a) R3-B(OH)2 (i.e. MeB(OH)2, Pd catalyst (i.e. (PPh3)4Pd), solvent (i.e. dimethoxyethane), base (i.e. N32C03).

Scheme 3 above may be used to insert a variety of R1, R2, R3 and R4 groups ng with the aryl bromide. The scheme above shows the presence of, for instance, an R1 group and an aryl bromide which is reacted with a suitable boronic acid under Suzuki type conditions to replace the bromide group with an R3 moiety. One of skill in the art would recognize that a variety of R1 through R4 groups could be inserted from the starting aryl bromide through this ure.

EXAMPLES General methods. 1H NMR (400 MHz) a were obtained as ons in an appropriate deuterated solvent such as dimethyl sulfoxide-d6 (DMSO). Mass spectra (MS) were obtained using an Applied Biosystems API EX LC/MS system.

Compound purity and retention times were determined by reverse phase HPLC using a Kinetix C18 column (50 X 2.1 mm, 1.7 um particle) from Phenomenex (pn: 00BAN)), and a dual gradient run from 1-99% mobile phase B over 3 minutes. Mobile phase A = H20 (0.05 % CF3C02H). Mobile phase B = CH3CN (0.05 % CF3C02H). Flow rate = 2 mL/min, injection volume = 3 uL, and column temperature = 50 CC. Silica gel chromatography was performed using silica gel-60 with a particle size of 0 mesh. Pyridine, dichloromethane, tetrahydrofuran, dimethylformamide, acetonitrile, methanol, 1,4-dioxane and other commonly used solvetns were from, for example, Baker or Aldrich and in some cases the reagents were Aldrich Sure-Seal bottles kept under dry nitrogen. All reactions were stirred magnetically unless otherwise noted.

EXAMPLE 1 ation of 2-ﬂuoro-N—(3-sulfamoylphenyl)(triﬂuoromethyl)benzamide o o F3C O F3C ,NH2 CI NH N S F O 0 F To a solution of 3-aminobenzenesulfonamide (18.77 g, 109.0 mmol) and pyridine (88.16 mL, 1.090 mol) in dichloromethane (247.0 mL) at 0 0C was added dropwise 2-ﬂuoro(triﬂuoromethyl)benzoyl chloride (24.7 g, 109.0 mmol). The e was allowed to warm to room temperature and was stirred for 18 hours. The on mixture was diluted with dichloromethane and water. The layers were separated and the c layer washed with aqueous 1N HCl (2x). The c layer was dried over sodium sulfate, ﬁltered and concentrated under reduced re. The residue was triturated with dichloromethane and ﬁltered. The white solid was washed with diethyl ether and was collected via vacuum ﬁltration to give 2-ﬂuoro-N—(3-sulfamoylphenyl)(triﬂuoromethyl)benzamide (23.83 g, 60%) as a white solid. ESI-MS m/z calc. , found 363.3 (M+1) +; Retention time: 1.37 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) 5 10.91 (s, 1H), 8.30 (s, 1H), 8.15 - 8.07 (m, 1H), 8.06 = 9.2 Hz, 1H), 7.62 - 7.97 (m, 1H), 7.89 - 7.83 (m, 1H), 7.64 (t, J - 7.54 (m, 2H), 7.42 (s, 2H) ppm.

EXAMPLE 2 Preparation of 2-ﬂuoro-N—(3-sulfamoylphenyl)(triﬂuoromethyl)benzamide 136 O 0 CI + Q NH2 NH N 8’ F3C F H2N 8’ 2 —’ d“ ’/\\ 0” “o 0 0 F30 F To a solution of 3-aminobenzenesulfonamide (3.8 g, 22.07 mmol) and o(triﬂuoromethyl)benzoyl chloride (5 g, 22.07 mmol) in dichloromethane (90 mL) was added pyridine (10.7 mL, 132.4 mmol) and the mixture was stirred at room temperature for 15 hours. Water (50 mL) was added to the reaction and the product crashed out. The solid was ed by ﬁltration, washed with water (2 x 75 mL), and dried under vacuum to yield 2- ﬂuoro-N—(3-sulfamoylphenyl)(triﬂuoromethyl)benzamide (4.43 g) as a cream solid. The solvent was evaporated under reduced pressure. Water was added and the mixture was set aside. After a few minutes, solid precipitated. The solid was isolated by ﬁltration, washed with water (2 x 30 mL), and dried under vacuum to yield a second crop of the d product (2.7 g). The two crops were combined to yield 2-ﬁuoro-N-(3-sulfamoylphenyl) (triﬁuoromethyl)benzamide (7.13g, 88%) as a solid. ESI-MS m/z calc. 362.03, found 363.3 (M+1) +; Retention time: 1.63 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 5 .93 (s, 1H), 8.35 = 8.0 - 8.27 (m, 1H), 7.99 - 7.88 (m, 2H), 7.88 - 7.80 (m, 1H), 7.76 (d, J Hz, 1H), 7.65 - 7.51 (m, 2H), 7.43 (s, 2H) ppm.

EXAMPLE 3 WO 10065 2014/047265 Preparation of 4-chloroﬂuoro-N-(3-sulfamoylphenyl)benzamide /©\)l\ NH Cl 2 + HNOS,NH CI F 0800* (“dagOx/S\O\ Pyridine (939.0 uL, 11.61 mmol) was added slowly to a solution of 4- chloroﬂuoro-benzoyl chloride (1.1 g, 5.81 mmol) and 3-aminobenzenesulfonamide (1 g, .81 mmol) in dichloromethane (5 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was ﬁltered and the precipitate was washed with romethane and water to give 4-chloroﬂuoro-N—(3-sulfamoylphenyl)benzamide (1.8 g, 92.2%) as a white solid. ESI-MS m/z calc. 328.01, found 329.1 (M+1)+; Retention time: 1.47 minutes (3 minutes run). 1H NMR (400 MHZ, DMSO-d6) 5 10.78 (s, 1H), 8.31 (s, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.66 (dd, J = 10.0, 1.9 Hz, 1H), 7.57 (m, 2H), 7.46 (dd, J = 8.3, 1.9 Hz, 1H), 7.41 (s, 2H) ppm.

EXAMPLE 4 Preparation of roﬂuoro-N-(3-sulfamoylphenyl)benzamide OﬁOI—I'l‘ Q/NHZ —> CI\©ELN/©\OS//\\O//S\\ H2 O 0 A mixture of 5-chloroﬂuoro-benzoic acid (349.1 mg, 2.0 mol), 3- aminobenzenesulfonamide (413.3 mg, 2.4 mmol), HATU (608.4 mg, 1.6 mmol), and N- methylmorpholine (439.8 uL, 4.0 mmol) in DMF (4 mL) was stirred at 40 CC for 1 hour. The reaction mixture was poured into water, the pH was adjusted to 4, and the mixture was extracted with ethyl acetate (3x). The organics were combined, washed with water, brine, dried over Na2S04, ﬁltered and evaporated to dryness to give 5-chloroﬂuoro-N—(3- oylphenyl)benzamide (0.36 g, 55%) as an pale yellow solid. ESI-MS m/z calc. 328.01, found 329.1 (M+1)+; Retention time: 1.41 minutes (3 minutes run).

EXAMPLE 5 Preparation of 2-ﬂuoromethyl-N—(3-sulfamoylphenyl)benzamide CI + O NH N S’ F O 0 F Pyridine (1.0 mL, 12.98 mmol) was added se to a mixture of 2- ﬂuoromethyl-benzoyl chloride (2.24 g, 12.98 mmol), 3-aminobenzenesulfonamide (2.235 g, 12.98 mmol) and dichloromethane (40.32 mL) at room temperature. The mixture was allowed to stir at room temperature for 2.5 hours before water (150 mL) was added. The mixture was ﬁltered and the solid was collected by vacuum ﬁltration. The solid was slurried with l ether (30 mL) and ﬁltered (twice). The solid was placed in a vacuum oven at 40 CC overnight to give 2-ﬂuoromethyl-N—(3 -sulfamoylphenyl)benzamide (1.81 g, 45%) as an off-white solid. ESI-MS m/z calc. 308.06, found 309.5 (M+1) +; Retention time: 1.42 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 8 10.61 (s, 1H), 8.32 (s, 1H), 7.89 - 7.80 (m, 1H), 7.62 - 7.51 (m, 3H), 7.39 (s, 2H), 7.24 - 7.11 (m, 2H), 2.39 (s, 3H) ppm.

Preparation of 4-cyanoﬂuoro-N—(3-sulfamoylphenyl)benzamide O 0 £1 1:6 ,NH2 OH * /£::]\ NH N _ 8\ ,3; 2 1:6 o”‘o NC F 0 0 NC F ] A solution of 4-cyanoﬂuoro-benzoic acid (495.4 mg, 3.0 mmol), 3- aminobenzenesulfonamide (516.6 mg, 3.0 mmol), EDCI (575.1 mg, 3.0 mmol), HOBT (405.4 mg, 3.0 mmol) and N—methylmorpholine (659.7 uL, 6.0 mmol) in DMF (4 mL) was stirred at °C for 16 hours. The reaction mixture was poured into 1N HCl and extracted with ethyl acetate (3x). The organics were combined and washed with 1N HCl (3x), water, brine, dried over Na2S04, d through a short plug of silica and evaporated to dryness to yield 4- cyanoﬂuoro-N—(3-sulfamoylphenyl)benzamide (860 mg, 90%) as a white solid that was 2014/047265 used in the next steps without ﬁarther puriﬁcation. ESI-MS m/z calc. 319.04, found 320.1 (M+1): Retention time: 1.04 minutes (3 minutes run).

EXAMPLE 7 Preparation of oﬂuoro-N—(3-sulfamoylphenyl)benzamide NC@ NC NH2 OH "' O H N 2 ,8” H2“ oSSN ’ H 0’ “o F 0 0 F A solution of 5-cyanoﬁuoro-benzoic acid (165.1 mg, 1.0 mmol), 3- aminobenzenesulfonamide (206.6 mg, 1.20 mmol), HATU (342.2 mg, 0.90 mmol) and N- methylmorpholine (219.9 uL, 2.0 mmol) in DMF (2 mL) was stirred at 25 CC for 4 hours. The reaction e was poured into water and extracted with ethyl acetate (3x). The organics were combined, washed with water, acidiﬁed to pH ~ 4 with 1N HC1 and ted with ethyl acetate (3x). The organics were combined, washed with water, brine, dried with NaZSO4, ﬁltered and evaporated to dryness to give 5-cyanoﬁuoro-N-(3-sulfamoylphenyl)benzamide (150 mg, 47%) that was used in the next steps without further puriﬁcation. ESI-MS m/z calc. 319.04, found 320.1 (M+1) ; Retention time: 0.97 minutes (3 minutes run).

EXAMPLE 8 Preparation of 2,4-diﬂuoro-N-(3-sulfamoylphenyl)benzamide ,NH2 CI + O NH N S F F O O F F To a mixture of 2,4-diﬁuorobenzoyl chloride (2.0 g, 11.33 mmol), 3- aminobenzenesulfonamide (1.95 g, 11.33 mmol) and romethane (36.0 mL) was added pyridine (3.7 mL, 45.32 mol) at 25 CC . The mixture was allowed to stir at 25 CC for 18h before it was washed with 1N HC1 and water. The organic layer was dried over sodium sulfate, ﬁltered and concentrated. The e was subjected to column chromatography (0- 100% ethyl acetate/hexanes) to give 2,4-diﬁuoro-N—(3-sulfamoylphenyl)benzamide (2.0 g, 57%) . ESI-MS m/z calc. 312.04, found 313.1 (M+1) +; Retention time: 1.31 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 5 10.73 (s, 1H), 8.31 (s, 1H), 7.89 - 7.74 (m, 2H), 7.62 - 7.52 (m, 2H), 7.51 - 7.42 (m, 1H), 7.41 (s, 2H), 7.26 (td, J = 8.4, 2.2 Hz, 1H) ppm.

Preparation of 2,5-diﬂuoro-N-(3-sulfamoylphenyl)benzamide O 0 O F@ F ,NH2 “2“ as; 2 H 0”‘o F 0 0 F To a solution of 3-aminobenzenesulfonamide (1.0 g, 5.81 mmol) and pyridine (4.7 mL, 58.07 mmol) in dichloromethane (10.3 mL) at 0 0C was added dropwise 2,5-diﬂuorobenzoyl chloride (719.3 uL, 5.81 mmol). The mixture was allowed to warm to 25 °C and was stirred for 72 hours. The on mixture was diluted with ethyl acetate and water. The layers were separated and the organic layer washed with brine (2x). The organic layer was dried over sodium sulfate, ﬁltered and concentrated under reduced pressure to give a clear oil that crystallized upon standing. The solid was re-dissolved in ethyl acetate and washed with 1N HCl (3x). The organic layer was dried with MgSO4, ﬁltered and ated to yield 2,5-diﬂuoro-N—(3-sulfamoylphenyl)benzamide (1.17 g, 64%) as a white solid. ESI- MS m/Z calc. 312.04, found 313.3 (M+1) +; Retention time: 1.31 minutes (3 minutes run). 1H NMR (400 MHz, 6) 5 10.81 (s, 1H), 8.31 (s, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.59 - 7.54 (m, 3H), 7.50 - 7.39 (m, 4H) ppm.

EXAMPLE 10 Preparation of 2,5-diﬂuoromethyl-N—(3 -sulfamoylphenyl)benzamide F F 011,NH2 F O O F A solution of 3-aminobenzenesulfonamide (413.3 mg, 2.40 mmol), 2,5- diﬂuoromethyl-benzoic acid (344.3 mg, 2.0 mmol), HATU (684.4 mg, 1.80 mmol) and N- methylmorpholine (439.8 uL, 4.0 mmol) in DMF (2 mL) was d at 40 CC for 2 hours. The reaction was poured into 1N HCl and extracted with ethyl acetate (3x). The organics were combined, washed with water, brine, dried with Na2S04 and evaporated to dryness to give 2,5-diﬂuoromethyl-N—(3-sulfamoylphenyl)benzamide (610 mg, 94%) as a solid that was used in the next step without further puriﬁcation. ESI-MS m/z calc. 326.05, found 327.3 (M+1) +; Retention time: 1.25 minutes (3 s run).

EXAMPLE 11 Preparation of 2-ﬂuoro-N—(3-sulfamoylphenyl)(triﬂuoromethyl)benzamide CF30 CF30 o”S“o NH2 NH2 —> (380\\O To a solution of 3-aminobenzenesulfonamide (760.1 mg, 4.41 mmol) in romethane (10 mL) was added 2-ﬂuoro(triﬂuoromethyl)benzoyl chloride (1 g, 4.41 mmol), 3-aminobenzenesulfonamide (760.1 mg, 4.41 mmol) and pyridine (1.1 mL, 13.24 mmol) and the mixture was d at 25 CC for 12 hours. The reaction was diluted with dichloromethane and water. The 2 layers were separated and the organic layer washed with water and 1N HCl. The organics were combined and evaporated to yield 2-ﬂuoro-N—(3- sulfamoylphenyl)(triﬂuoromethyl)benzamide (600 mg, 37%) a s a light pink solid. ESI-MS m/z calc. 362.03, found 363.3 (M+1)+; Retention time: 1.39 s (3 minutes run). 1H NMR (400 MHz, CD3CN) 8 9.18 (s, 1H), 8.31 (t, J = 1.9 Hz, 1H), 7.83 - 7.43 (m, 6H), 5.75 (s, 2H) ppm.

EXAMPLE 12 Preparation of 5-(diﬂuoromethyl)ﬂuorobenzoic acid F HC2 \OkaH 2-Fluoromethyl-benzoic acid (2 g, 12.98 mmol), NBS (6.0 g, 33.75 mmol) and benzoyl peroxide (157.2 mg, 0.65 mmol) in CC14 (30 mL) was heated at reﬂux for 48 hours. The solids were ﬁltered off and washed with dichloromethane. The solvent was evaporated and the residue was taken up in l (30 mL) and heated to 50 °C. A solution of silver nitrate (2.20 g, 12.98 mmol) in 5 ml water was added drop wise. The mixture was 2014/047265 stirred for 45 minutes, cooled to 25 0C, then poured into 1N HCl. The solids were ﬁltered off and washed with EtOH. The EtOH was removed and the aqueous layer was extracted with ethyl acetate (3x). The organics were combined, washed with brine, dried over Na2S04 and evaporated to dryness. ation by column chromatography using a gradient of ethyl acetate in hexanes (0 - 50%) gave oformyl-benzoic acid (0.33 g, 15%) as a light yellow solid. ESI-MS m/z calc. 168.02, found 169.1 (M+1)+; Retention time: 0.49 minutes (3 minutes run). 1H NMR (400 MHz, 6) 5 13.64 (s, 1H), 10.03 (s, 1H), 8.43 (dd, J = 7.2, 2.2 Hz, 1H), 8.17 (ddd, J = 8.4, 4.7, 2.2 Hz, 1H), 7.56 (dd, J = 10.6, 8.6 Hz, 1H) ppm.

Deoxoﬁuor (566.8 uL, 3.07 mmol) was added to methyl 2-ﬁuoro formyl-benzoate (280 mg, 1.54 mmol) followed by 2 drops of ethanol and the reaction mixture was stirred at 25 0C for 4 hours. More deoxoﬁuor (100 uL, 0.54 mmol) was added and the reaction mixture was stirred for an additional hour. The mixture was carefully quenched with saturated aqueous solution of sodium bicarbonate and then ted with ethyl acetate (3x). The organics were combined, washed with water, brine, dried over Na2S04, ﬁltered and evaporated to dryness. Puriﬁcation by column chromatography using a gradient of ethyl acetate in hexanes (0 - 20%) gave methyl 5-(diﬂuoromethyl)ﬁuoro-benzoate (230 mg, 73%) as a clear oil. ESI-MS m/z calc. 204.04, found 204.9 (M+1)+; Retention time: 1.31 minutes (3 minutes run). 1H NMR (400 MHZ, CDClg) 5 8.26 - 8.05 (m, 1H), 7.81 - 7.58 (m, 1H), 7.29 - 7.19 (m, 1H), 6.66 (t, J = 56.1 Hz, 1H), 3.96 (s, 3H) ppm.

To a solution of methyl 5-(diﬂuoromethyl)ﬂuoro-benzoate (230 mg, 1.127 mmol) in THF (4 mL) was added a solution of LiOH (269.9 mg, 11.27 mmol) in water (1 mL) and the reaction mixture was stirred at 25 CC for 4 hours. The reaction was brought to pH 4 with 4N HCl and then extracted with ethyl acetate (3x). The organics were combined, washed with water, brine, dried over Na2S04, ﬁltered and evaporated to dryness to give 5- (diﬂuoromethyl)ﬂuoro-benzoic acid (187 mg, 87%) as a white solid. ESI-MS m/z calc. 190.02, found 191.3 ; Retention time: 1.0 s (3 minutes run).

E 13 Preparation of 5-(diﬂuoromethyl)ﬂuoro-N-(3-sulfamoylphenyl)benzamide o o FZHCCEK F2HC ,NH2 OH + O NH N ,S\ W as; 2 —’ H 0’ ‘o F 0 O F To a solution of 5-(diﬂuoromethyl)—2-ﬂuoro-benzoic acid (95.1 mg, 0.50 mmol), 3-aminobenzenesulfonamide (94.7 mg, 0.55 mmol), and N-methylmorpholine (109.9 uL, 1.0 mmol) in DMF (1 mL) was added HATU (209 mg, 0.55 mmol) and the reaction mixture was stirred at 25 CC for 1 hour. The on was poured into 1N HCl and extracted with ethyl acetate (3x). The organics were combined, washed with water (2x), brine, dried with Na2S04, ﬁltered and evaporated to dryness. Puriﬁcation by silica gel column chromatography using a 20 - 80% gradient of ethyl acetate in hexanes gave 5- romethyl)ﬂuoro-N-(3-sulfamoylphenyl)benzamide (202 mg, >100%) that was used in the next step without further puriﬁcation. ESI-MS m/z calc. 344.04, found 345.3 (M+1)+; Retention time: 1.19 minutes (3 minutes run).

EXAMPLE 14 Preparation of 5-bromochloroﬂuoro-N—(3-sulfamoylphenyl)benzamide O 0 0 BrKL + 0 Br ,NH2 OH NH N S as; 2 H2N ULH o” *0 CI F 0 0 CI F To 5-bromochloroﬂuoro-benzoic acid (5.0 g, 19.73 mmol), 3- aminobenzenesulfonamide (5.1 g, 29.60 mmol), 1-hydroxybenzotriazole (2.93 g, 21.70 mmol), 3-(ethyliminomethyleneamino)-N,N-dimethyl-propanamine hydrochloride (4.2 g, 21.70 mmol), and N,N-dimethylformamide (80 mL), triethyl amine (5.5 mL, 39.46 mmol) was added and stirred at room temperature for 18 hours. The solvent was evaporated. The reaction was washed with a 1M solution of hydrochloric acid (3 x 50 mL), a ted aqueous solution of sodium onate (3 x 50 mL), and a saturated s on of sodium chloride (3 x 50 mL). The organic layer was dried over sodium sulfate, ﬁltered, and evaporated to dryness. The crude product was dissolved in dichloromethane and the precipitate was isolated by ﬁltration to yield 5-bromochloroﬂuoro-N—(3- sulfamoylphenyl)benzamide (4.0 g, 35%) as a grey solid. The product was used in the next step without further puriﬁcation. ESI-MS m/z calc. 405.92, found 407.0 (M+1)+; Retention time: 1.7 s (3 minutes run). 1H NMR (400 MHz, 6) 5 10.84 (s, 1H), 8.32 - 8.24 (m, 1H), 8.13 (d, J = 7.0 Hz, 1H), 7.90 (d, J = 9.7 Hz, 1H), 7.86 - 7.81 (m, 1H), 7.61 - 7.53 (m, 2H), 7.42 (s, 2H) ppm.

EXAMPLE 15 Preparation of 2-ﬂuoro-N—(3-sulfamoylphenyl)(triﬂuoromethoxy)benzamide ’xS\\,NH2 OS’x\\O H2 F300 0 O F3CO To 2-ﬂuoro(triﬂuoromethoxy)benzoic acid (5 g, 22.31 mmol) in thionyl de (2.43 mL, 33.46 mmol) was added N,N-dimethylformamide (491.6 uL, 6.38 mmol). The reaction mixture was stirred at room temperature for 17 hours. Excess thionyl chloride and methyl formamide were removed in vacuo to yield 2-ﬂuoro (triﬁuoromethoxy)benzoyl chloride that was used in the next step without further puriﬁcation.

To obenzenesulfonamide (4.79 g, 27.83 mmol) was added potassium carbonate (3.85 g, 27.82 mmol), methyl tert-butyl ether (27.0 mL) and water (27.0 mL). The reaction was cooled to 0 0C. To the vigorously d reaction was added 2-ﬂuoro- 4-(triﬂuoromethoxy)benzoyl chloride (5.4 g, 22.26 mmol) in dichloromethane (13.5 mL). The reaction was stirred at room temperature for 30 hours. The reaction was a slurry. The product was isolated by ion using ether. The t was loaded onto celite and puriﬁed by silica gel chromatography utilizing a gradient of 0-50% ethyl acetate in dichloromethane to yield 3 g (35%) of 2-ﬁuoro-N—(3-sulfamoylphenyl)(triﬂuoromethoxy)benzamide. 1H NMR (400 MHz, DMSO-d6) 5 10.83 (s, 1H), 8.38 - 8.25 (m, 1H), 7.90 - 7.78 (m, 2H), 7.66 - 7.52 (m, 3H), 7.47 - 7.36 (m, 3H) ppm. ESI-MS m/z calc. 378.03, found 379.4 (M+1)+; Retention time: 1.56 minutes (3 minutes run).

EXAMPLE 16 Preparation of 2-ﬂuoro(perﬂuoroethyl)-N—(3-sulfamoylphenyl)benzamide I \ C2F5 0’ \0 C2F5 To a stirred solution of 4-bromoﬂuoro-benzoic acid (3.0 g, 13.70 mmol) and copper (8.70 g, 137.0 mmol) in DMSO (56.3 mL) in a bomb, 1,1,1,2,2- pentaﬂuoroiodo-ethane (23.6 g, 95.90 mmol) was bubbled through. The vessel was sealed and heated at 120 CC for 72 hours. The reaction mixture was diluted with water and ﬁltered h a plug of silica and then extracted with ethyl acetate (4x). The organics were WO 10065 combined, washed with brine, dried (Na2SO4) and evaporated to dryness. ation by column chromatography using a gradient of 0-40% ethyl acetate in hexanes gave o (1,1,2,2,2-pentaﬁuoroethyl)benzoic acid (1.81 g, 51%) as white solid. ESI-MS m/z calc. 258.01, found 259.3 (M+1)+; Retention time: 1.45 s.

A solution of 2-ﬂuoro(1 ,1,2,2,2-pentaﬁuoroethyl)benzoic acid (516.2 mg, 2.0 mmol), 3-aminobenzenesulfonamide (378.9 mg, 2.20 mmol), HATU (836.5 mg, 2.20 mmol) and N—methylmorpholine (439.8 uL, 4.0 mmol) in DMF (6 mL) was stirred at room temperature for 16 hours. The reaction mixture was poured into water, the pH adjusted to 4 with 1N HCl and extracted with ethyl acetate (3x). The organics were combined, washed with water, brine, dried over Na2S04 and evaporated to dryness. Puriﬁcation by column chromatography using a gradient of 0 - 50% ethyl acetate in hexanes gave o (1,1,2,2,2-pentaﬂuoroethyl)-N-(3-sulfamoylphenyl)benzamide (710 mg, 86%) as a white solid. ESI-MS m/z calc. 412.03165, found 413.3 (M+1)+; Retention time: 1.5 minutes.

EXAMPLE 17 Preparation of 4,5-dichloroﬁuoro-N-(3- sulfamoylphenyl)benzamide FJ\OHHZ 00830 H2 ,NH2 _>::j(\:ﬁLN/©\O/ :0,8 \ A solution of 3-aminobenzenesulfonamide (271.9 mg, 1.58 mmol), 4,5- dichloroﬂuoro-benzoic acid (300 mg, 1.43 mmol), and HATU (654.8 mg, 1.72 mmol) in DMF (3.12 mL) was treated with ylmorpholine (315.5 uL, 2.87 mmol) and stirred at 40 0C for 16 hours. The reaction was diluted with ethyl acetate and water and the organic layer separated. The organic layer was washed with 1 N HCl, water (3 x 50 mL), and brine, then dried over Na2S04, ﬁltered, and concentrated. The residue was slurried in romethane to form a white precipitate. The precipitate was ﬁltered and washed with dichloromethane to provide 4,5-dichloroﬂuoro-N-(3-sulfamoylphenyl)benzamide (422 mg, 81%) as a white powder. 1H NMR (400 MHz, DMSO-d6) 8 10.85 (s, 1H), 8.32 - 8.25 (m, 1H), 8.03 (d, J = 6.7 Hz, 1H), 7.93 (d, J = 9.5 Hz, 1H), 7.83 (dt, J = 6.8, 2.2 Hz, 1H), 7.64 - 7.52 (m, 2H), 7.42 (s, 2H) ppm. ESI-MS m/z calc. 361.96948, found 364.7 (M+1)+; Retention time: 1.4 minutes (3 minutes run).

EXAMPLE 18 WO 10065 ation of o-N—(3-sulfamoylphenyl)-4,6-bis(triﬁuoromethyl)benzamide CF30 CF30 o”S‘b,NH2 08/,30 H2 To 3-aminobenzenesulfonamide (300.8 mg, 1.75 mmol) in methyl-tert- butylether (2.8 mL) was added K2C03 (689.9 mg, 5.0 mmol) in water (2.8 mL). The reaction was stirred at room temperature and 2-ﬁuoro-4,6-bis(triﬁuoromethyl)benzoyl de (490 mg, 1.66 mmol) in methyl-tert-butylether (2.8 mL) was added dropwise. The reaction was stirred at room temperature for 40 minutes. Ethyl acetate (50ml) was added and the organic layer was separated, washed with brine, and concentrated to yield 2-ﬂuoro-N—(3- oylphenyl)-4,6-bis(triﬁuoromethyl)benzamide (162 mg, 23%) as a pink solid that was used in the next step without further puriﬁcation. 1H NMR (400 MHz, DMSO-d6) 5 11.27 (s, 1H), 8.49 - 8.35 (m, 1H), 8.31 = 7.5, 1.9 Hz, 1H), 7.69 - 8.08 (m, 2H), 7.74 (dt, J - 7.54 (m, 2H), 7.46 (s, 2H) ppm.

EXAMPLE 19 Preparation of 2,4-dichloroﬁuoro-N—(3-sulfamoylphenyl)benzamide NH2 ,8\ To a solution of 2,4-dichloroﬁuoro-benzoic acid (400 mg, 1.91 mmol), 3-aminobenzenesulfonamide (329.6 mg, 1.91 mmol), and HATU (727.8 mg, 1.91 mmol) in DMF (4 mL) was added N—methylmorpholine (210.4 uL, 1.91 mmol) and thereaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 1N HCl and extracted with ethyl acetate (3x). The organics were combined, washed with 1N HCl, water, brine, dried over Na2S04, ﬁltered and evaporated to dryness.

Puriﬁcation by column chromatography using a gradient of ethyl acetate in hexanes 1 - 50% gave 2,4-dichloroﬁuoro-N—(3-sulfamoylphenyl)benzamide (420 mg, 60%) as a white solid.

EXAMPLE 20 Preparation of 2-cyclopropylﬁuoro-N-(3-sulfamoylphenyl) (triﬁuoromethyl)benzamide F3C F O’/ \\0 F3C F To a mixture of 2,6-diﬁuoro(triﬁuoromethyl)benzoic acid (500 mg, 2.21 mmol) in THF (4.0 mL) was slowly added bromo(cyclopropyl)magnesium (12.0 mL of 0.5 M, 6.00 mmol). The reaction was stirred at room temperature for one hour then at 55 0C for one hour. To the reaction was added additional bromo(cyclopropyl)magnesium (8.84 mL of 0.5 M, 4.42 mmol) and the reaction was d at 55°C for 12 additional hours. The on mixture was carefully poured into 50ml of saturated NH4C1 and was extracted with ethyl acetate. The organic layer was washed with water. The combined water layers were acidiﬁed to pH=3 using 1N HCl and were ted with ethyl acetate (2 X 50ml), dried over sodium sulfate, ﬁltered and concentrated to provide 2-cyclopropylﬁuoro (triﬂuoromethyl)benzoic acid (345 mg, 63%) that was used in the next step withourt further puriﬁcation. ESI-MS m/z calc. 248.05, found 249.15 (M+1)+; Retention time: 0.59 minutes (1 minute run). 1H NMR (400 MHz, DMSO-d6) 8 7.91 - 7.43 (m, 1H), 7.12 (s, 1H), 2.04 (tt, J = 8.4, 5.2 Hz, 1H), 1.09 - 0.98 (m, 2H), 0.89 - 0.80 (m, 2H) ppm. 2-Cyclopropylﬁuoro(triﬁuoromethyl)benzoic acid (345 mg, 1.39 mmol), toluene (3.4 mL) and pyridine (5.6 uL, 0.069 mmol) were added to a reaction vessel and the mixture was heated to 60°C under an inert atmosphere. To the reaction mixture was added SOClz (202.8 uL, 2.780 mmol)and the mixture was stirred for 90 s. onal SOClz (900 ul, 12.34 mmol) was added and the mixture was concentrated in vacuo. Toluene was added and the mixture concentrated again to give a product that was used in the next step without r puriﬁcation.

To 3-aminobenzenesulfonamide (271.4 mg, 1.576 mmol) in methyl-t- butyl ether (1.99 mL) and DMF (1 mL) was added K2C03 (544.4 mg, 3.94 mmol) in water (1.99 mL). The on was stirred at room temperature and opropylﬁuoro (triﬁuoromethyl)benzoyl chloride (350 mg, 1.31 mmol) in methyl-t-butyl ether (1.99 mL) was added dropwise. The reaction was stirred at room temperature overnight after which 50ml of ethyl acetate were added. The 2 layers were separated and the organic layer was washed with brine, dried with MgSO4, ﬁltered and concentrated to yield 2-cyclopropylﬁuoro-N—(3- sulfamoylphenyl)(triﬁuoromethyl)benzamide (220 mg, 42%) as a pink solid that was used in the next step without further puriﬁcation. ESI-MS m/z calc. 402.07, found 403.1 (M+1)+; Retention time: 0.59 minutes (1 minute run).

E 21 Preparation of 2-(2-chloroﬁuorophenoxy)-N—(3-sulfamoylphenyl) oromethyl)benzamide (33) (3km ,NH2 O”S‘b To a solution of 2-chloroﬁuoro-phenol (21 g, 143.1 mmol) and 2- ﬂuoro(triﬁuoromethyl)benzaldehyde (25 g, 130.1 mmol) in DMF (125.0 mL) was added Cs2C03 (46.6 g, 143.1 mmol) and the reaction mixture was d at 100 CC for 1 hour. The mixture was poured into water (500 ml) and extracted with ethyl acetate (3 x 150 ml). The organics were combined, washed with water, brine (2x), dried over Na2S04, ﬁltered and evaporated to give a red oil that ﬁed after standing over night. The material was then triturated with hot hexanes and cooled to 25 oC. The slurry was ﬁltered and washed with cold hexanes to give 2-(2-chloroﬁuoro-phenoxy)(triﬁuoromethyl)benzaldehyde (32.7 g, 79%) as an off-white solid. 1H NMR (400 MHZ, DMSO-d6) 5 10.61 (s, 1H), 7.84 - 7.70 (m, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.47 (dd, J = 9.0, 5.3 Hz, 1H), 7.42 = - 7.32 (m, 1H), 7.12 (d, J 8.3 Hz, 1H) ppm.

To a solution of 2-(2-chloroﬁuoro-phenoxy) oromethyl)benzaldehyde (31 g, 97.3 mmol) in tBuOH (155.0 mL), water (100.8 mL), CH3CN (155.0 mL) and 2-methylbutene (51.45 mL, 486.4 mmol) was added sodium dihydrogen ate (18.3 mL, 291.9 mmol) and the mixture was cooled to 0 oC. Sodium chlorite (26.40 g, 291.9 mmol) was added in one portion and the mixture was stirred at 25 CC for 1 hour. The pH of the mixture was adjusted to 2-3 with 1N HCl and the layers separated.

The aqueous was extracted with ethyl acetate (3 X). All organic layers were combined, and in the separatory funnel, solid sodium sulﬁte (~5 g) was added followed by brine (50 ml) and 1N NaOH (10 ml) and the mixture was shaken until the yellow color was gone. The layers were separated and the organic was washed with brine, dried with Na2S04, ﬁltered through a short plug of silica gel and evaporated to dryness to give 2-(2-chloroﬂuoro-phenoxy) (triﬂuoromethyl)benzoic acid (40 g, 98%) as an oil that was used in the next step without ﬁthher puriﬁcation. ESI-MS m/z calc. , found 335.1 (M+1)+; Retention time: 1.78 minutes (3 minutes run).

To a stirred solution of 2-(2-chloroﬂuoro-phenoxy) (triﬂuoromethyl)benzoic acid (20 g, 47.81 mmol) in NMP (110 mL) was added HATU (16.36 g, 43.03 mmol) followed by 3-aminobenzenesulfonamide (9.88 g, 57.37 mmol) and N- morpholine (10.51 mL, 95.60 mmol) and the mixture was heated to 80 CC and stirred at this temperature for 4 hours. The on was recharged with 3-aminobenzenesulfonamide (4.12 g, 23.91 mmol) was stirred at 80 CC for 13 hours. The mixture was poured into 1N HCl (400 ml) and extracted with ethyl acetate (3 x 200 ml). The organics were combined, washed with 1N HCl (2 x 400 ml), water (2 x 400 ml), brine and then dried with Na2S04, ﬁltered and ated to dryness to yield a crude mixture that was purified by silica gel column tography using a gradient of ethyl acetate and hexanes (0 - 50%) to give the desired t as a white foam. After drying under vacuum, 2-(2-chloroﬂuoro-phenoxy)—N—(3- sulfamoylphenyl)(triﬂuoromethyl)benzamide (33) (14 g, 60%) was obtained as a white solid. ESI-MS m/z calc. 488.02, found 489.3 (M+1)+; Retention time: 1.57 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 5 11.02 (s, 1H), 8.29 (s, 1H), 7.73 (d, J = 7.3 Hz, 1H), 7.69 - 7.60 (m, 3H), 7.59 - 7.51 (m, 2H), 7.41 (s, 2H), 7.38 - 7.29 (m, 2H), 7.10 (d, J = 7.3 Hz, 1H) ppm.

EXAMPLE 22 Preparation of 2-(4-ﬂuoromethoxyphenoxy)-N—(3-sulfamoylphenyl) (triﬂuoromethyl)benzamide (13) CF30 o”S*0 2-Fluoro-N-(3-sulfamoylphenyl)(triﬂuoromethyl)benzamide (l30 mg, 0.36 mmol), 4-ﬂuoromethoxy-phenol (204.5 uL, 1.8 mmol) and CS2C03 (584.5 mg, 1.8 mmol) in NMP (1 mL) was stirred at 90 0C for 4 hours. The reaction e was poured into 1N HCl and extracted with ethyl acetate (3x). The organics were combined, washed with water, brine, dried with Na2S04 and evaporated to dryness. Puriﬁcation by reverse-phase HPLC using a gradient of (1-99% ACN in water (HCl modiﬁer)) gave 2-(4-ﬂuoromethoxy- phenoxy)-N—(3-sulfamoylphenyl)(triﬂuoromethyl)benzamide (13) (25.6 mg, 14%) as a white solid. ESI-MS m/z calc. 484.07, found 485.3 (M+1)+; Retention time: 1.61 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 5 10.98 (s, 1H), 8.33 (s, 1H), 7.79 - 7.72 (m, 1H), 7.61 = 8.9, 5.9 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 - 7.48 (m, 4H), 7.40 (s, 2H), 7.20 (dd, J Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.84 (td, J = 8.4, 2.8 Hz, 1H), 3.77 (s, 3H) ppm.

Following a similar ure as described above for nd (13), the following compounds were prepared from 2-ﬂuoro-N-(3-sulfamoylphenyl) (triﬂuoromethyl)benzamide and a phenol. _MNo. 2-(4-ﬂuoromethylphenoxy)-N—(3- 4-ﬂuoromethylphenol sulfamoylphenyl) (triﬂuoromethyl)benzamide ethoxyphenoxy)—N—(3- 2-methoxyphenol oylphenyl) triﬂuorometh l benzamide 58 2-(4-chloromethylphenoxy)-N-(3- 4-chloromethylphenol sulfamo lohen l triﬁuorometh l benzamide 2-(3-ﬁuoromethylphenoxy)-N—(3- 3-ﬁuoromethylphenol sulfamoylphenyl) (triﬁuoromethyl)benzamide 60 ulfamoylphenyl)(4- 4-(triﬁuoromethoxy)phenol (triﬁuoromethoxy)phenoxy)—6- triﬁuorometh l benzamide 61 2-(3-ﬁuoromethoxyphenoxy)-N-(3- 3-ﬁuoromethoxyphenol sulfamoylphenyl) triﬁuorometh l benzamide 74 2-(2-chlorophenoxy)-N—(3- 2-chlorophenol sulfamoylphenyl) triﬁuorometh l ide 75 2-(2-chloromethoxyphenoxy)-N-(3- romethoxyphenol sulfamoylphenyl) (triﬁuoromethyl)benzamide EXAMPLE 23 Preparation of 2-(4-ﬁuorophenoxy)-N-(3-sulfamoylphenyl)(triﬁuoromethyl)benzamide (1) ] 2-Fluoro-N-(3-sulfamoylphenyl)(triﬁuoromethyl)benzamide (32.2 mg, 0.1 mmol), 4-ﬁuorophenol (112.1 mg, 1 mmol) were dissolved in DMF (1 mL). CS2C03 (325.8 mg, 1 mmol) was added and the reactions was heated at 100 0C for 1 hour. The reaction was ﬁltered and puriﬁed by reverse phase preparative HPLC utilizing a gradient of -99% acetonitrile in water (HCl as a modiﬁer) to yield 2-(4-ﬁuorophenoxy)—N—(3- sulfamoylphenyl)(triﬁuoromethyl)benzamide (1) (25.6 mg, 56%). ESI-MS m/z calc. 454.06, found 455.3 (M+1)+; Retention time: 1.96 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 8 10.84 (s, 1H), 8.34 = 7.9 Hz, 1H), 7.82 - 8.24 (m, 1H), 7.88 (d, J - 7.72 (m, 1H), 7.64 (dd, J = 7.9, 0.8 Hz, 1H), 7.60 - 7.47 (m, 2H), 7.40 (s, 2H), 7.32 - 7.25 (m, 2H), 7.25 - 7.18 (m, 2H), 7.15 (s, 1H) ppm. ing a r procedure as described above for compound (1), the following compounds were prepared starting from 2-ﬂuoro-N—(3-sulfamoylphenyl)—4- (triﬂuoromethyl)benzamide and the ing phenols.

Cmpd. Product name Phenol 2 2-(2,4-diﬂuorophenoxy)-N—(3- 2,4-diﬂuorophenol sulfamoylphenyl)—4- (triﬂuoromethyl)benzamide 14 2-(4-ﬂuoromethoxyphenoxy)—N— 4-ﬂuoromethoxyphenol (3-sulfamoylphenyl) triﬂuorometh l benzamide 18 2-(4-ﬂuoromethylphenoxy)-N—(3- 4-ﬂuoromethylphenol sulfamoylphenyl)—4- triﬂuorometh l benzamide 42 2-(4-chloromethoxyphenoxy)-N— 4-chloromethoxyphenol (3-sulfamoylphenyl) rometh l benzamide 43 2-(3-ﬂuoromethoxyphenoxy)—N— 3-ﬂuoromethoxyphenol (3-sulfamoylphenyl) (triﬂuoromethyl)benzamide 44 2-(2-methoxyphenoxy)—N—(3- 2-methoxyphenol sulfamoylphenyl)—4- triﬂuorometh l benzamide 45 2-(4-ethoxyphenoxy)-N—(3- 4-ethoxyphenol sulfamoylphenyl)—4- triﬂuorometh l ide 46 2-(2-propoxyphenoxy)—N—(3- 2-(2-propoxy)phenol sulfamoylphenyl)—4- triﬂuorometh l benzamide 47 N—(3-sulfamoylphenyl)(o- 2-methylphenol tolyloxy) oromethyl)benzamide 48 2-(2-chloromethoxyphenoxy)-N— 2-chloromethoxyphenol (3-sulfamoylphenyl) triﬂuorometh l benzamide 49 2-(4-methoxymethylphenoxy)-N- 4-methoxymethylphenol (3-sulfamoylphenyl) triﬂuorometh l benzamide 50 2-(2,4-dimethoxyphenoxy)-N-(3- methoxyphenol sulfamoylphenyl)—4- triﬂuorometh l benzamide 51 N—(3-sulfamoylphenyl)(4- 4-(triﬂuoromethoxy)phenol (triﬂuoromethoxy)phenoxy) (triﬂuoromethyl)benzamide 2014/047265 52 2-(3-ﬁuoromethoxyphenoxy)—N— 3-ﬁuoromethoxyphenol (3-sulfamoylphenyl) triﬁuorometh l benzamide 53 2-(4-isopropoxyphenoxy)-N—(3- 4-isopropoxyphenol sulfamoylphenyl)—4- triﬁuorometh l benzamide 67 2-(3-chloromethoxyphenoxy)-N— romethoxyphenol (3-sulfamoylphenyl) triﬁuorometh l benzamide 68 2-(3-chloromethoxyphenoxy)-N— 3-chloromethoxyphenol (3-sulfamoylphenyl) oromethyl)benzamide 73 2-(2-chlorophenoxy)-N-(3- 2-chlorophenol sulfamoylphenyl)—4- triﬁuorometh l benzamide E 24 Preparation of 5-chloro(4-ﬁuorophenoxy)-N—(3-sulfamoylphenyl)benzamide (5) CIﬁn ,NH2 O”S‘b roﬁuoro-N—(3-sulfamoylphenyl)benzamide (32.8 mg, 0.1 mmol), 4-ﬂuorophenol (35.8 mg, 0.3 mmol) were dissolved in NMP (0.5 mL). CS2C03 (98 mg, 0.3 mmol) was added and the reactions was heated at 90 0C for 6 hour. The reaction was ﬁltered and puriﬁed by reverse phase preparative HPLC utilizing a gradient of 10-99% acetonitrile in water (HCl as a modiﬁer) to yield 5-chloro(4-ﬁuorophenoxy)-N—(3- sulfamoylphenyl)benzamide (5) (10.2 mg, 24%). ESI-MS m/z calc. 420.03, found 42l.l (M+l)+; Retention time: 1.70 minutes (3 minutes run).

Following a similar procedure as described above for compound (5), the following compounds were prepared. 16 5-chloro(4-ﬂuoro 5-chloroﬂuoro-N—(3- o methoxyphenoxy)—N—(3- sulfamoylphenyl)benzamide methoxyphenol sulfamo lohen lbenzamide 17 5-chloro(2-chloro 5-chloroﬂuoro-N—(3- 2-chloro ﬁuorophenoxy)—N-(3- sulfamoylphenyl)benzamide ﬂuorophenol sulfamo lohen lbenzamide 5-chloro(4-ﬂuoro 5-chloroﬂuoro-N—(3- 4-ﬁuoro methylphenoxy)-N-(3- sulfamoylphenyl)benzamide methylphenol sulfamo lohen lbenzamide EXAMPLE 25 Preparation of 2-(2-chloroﬂuorophenoxy)methyl-N-(3-sulfamoylphenyl)benzamide (38) N s’NH2 H ’/\\ o o To a solution of 2-ﬂuoromethyl-benzaldehyde (1.1 g, 7.75 mmol) and 2-chloroﬂuoro-phenol (817.7 uL, 7.75 mmol) in DMF (9.2 mL) was added cesium carbonate (2.5 g, 7.75 mmol) and the mixture was heated at 100 CC for 1 hour. The mixture was cooled to room temperature before it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organics were washed with brine, dried over sodium sulfate, ﬁltered and concentrated. The residue was puriﬁed by column tography using a gradient of ethyl acetate in hexanes (0-100%) to yield hloroﬁuoro-phenoxy)methyl-benzaldehyde (1.05 g, 51%). ESI- MS m/z calc. 264.03, found 265.1 (M+1)+; Retention time: 2.02 minutes (3 minutes run).

To a solution of hloroﬂuoro-phenoxy)methyl-benzaldehyde (1.05 g, 3.97 mmol) in t—BuOH (10.50 mL), water (6.6 mL) and acetonitrile (6.6 mL) was added sodium dihydrogen phosphate (745.7 uL, 11.90 mmol), 2-methylbutene (2.1 mL, 19.83 mmol) and sodium chlorite (1.08 g, 11.90 mmol). The reaction mixture was stirred at CC for 1h. The reaction mixture was acidiﬁed with 1N HCl and was diluted with ethyl acetate. Sodium sulﬁte was added to remove the faint yellow color. The two layers were separated and the aqueous layer was ted with ethyl e (3x). The organics were combined, washed with brine, dried over sodium e, ﬁltered and concentrated to give 2- (2-chloroﬂuoro-phenoxy)methyl-benzoic acid (1.06 g, 95%). ESI-MS m/z calc. 280.03, found 281.5 (M+1)+; Retention time: 1.7 minutes (3 s run).

DMF (1.4 uL, 0.018 mmol) was added to a mixture of hloro ﬂuoro-phenoxy)methyl-benzoic acid (100 mg, 0.36 mmol), CHzClz (2.0 mL) and SOClz (33.8 uL, 0.46 mol) at room temperature. The mixture was allowed to stir for 1.5 hours before it was concentrated under reduced pressure. The residue was placed under high vacuum for 30 minutes before it was taken up in CHzClz (2.0 mL) and added to a mixture of 3-aminobenzenesulfonamide (92.0 mg, 0.53 mmol), Eth (86.5 uL, 1.07 mmol) and CHzClz (2.0 mL) at room temperature. The mixture was allowed to stir for 2h at room temperature before it was partitioned between 1N HCl and CHZClz. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was ted to preparatory-HPLC (10-90% ACN/water with 0.01% HCl) to give hloroﬂuoro-phenoxy)methyl-N-(3- sulfamoylphenyl)benzamide (38) (6.5 mg, 4%). ESI-MS m/z calc. 434.05, found 435.5 (M+1)+; Retention time: 1.72 s (3 minutes run). 1H NMR (400 MHZ, DMSO-d6) 5 .83 (s, 1H), 8.41 = 7.1, 2.0 Hz, 1H), 7.63 - 8.36 (m, 1H), 7.76 (dt, J - 7.51 (m, 3H), 7.39 (s, 2H), 7.34 - 7.25 (m, 3H), 7.12 - 7.07 (m, 1H), 6.61 (t, J = 8.0 Hz, 1H), 2.35 (s, 3H) ppm.

EXAMPLE 26 Preparation of 2-(4-ﬂuorophenoxy)-N-(3-sulfamoylphenyl)-5 -(triﬂuoromethyl)benzamide (3) O JCL FC3 ﬂ” ,NH2 008% A mixture of 2-ﬂuoro-N—(3-sulfamoylphenyl) (triﬂuoromethyl)benzamide (9.0 g, 24.8 mmol), 4-ﬂuorophenol (8.4 g, 74.5 mmol), cesium carbonate (24.3 g, 74.5 mmol) and DMF (225.0 mL) was heated at 100 0C for 0.5 hours. The mixture was cooled to room temperature before it was partitioned between ethyl acetate and water. The layers were separated and the s layer was extracted with ethyl e (3x).

The combined organics were washed with saturated aqueous NH4C1, water and brine. The WO 10065 organics were dried over sodium sulfate, ﬁltered and concentrated under reduced pressure.

The residue was puriﬁed by column chromatography (0-100% ethyl acetate/hexanes) to give an off-white solid. The solid was slurried with hexane, then ﬁltered. That solid was slurried in diethyl ether and ﬁltered (2x). The solid was placed under vacuum at 55 0C for 1 hour to give 2-(4-ﬂuorophenoxy)-N—(3-sulfamoylphenyl)(triﬂuoromethyl)benzamide (3) (8.6 g, 77%). ESI-MS m/z calc. 454.06, found 455.5 (M+1)+; Retention time: 1.87 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 8 10.81 (s, 1H), 8.30 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.82 (ddd, J = 8.9, 4.8, 2.2 Hz, 2H), 7.61 - 7.49 (m, 2H), 7.40 (s, 2H), 7.35 - 7.23 (m, 4H), 7.00 (d, J = 8.7 Hz, 1H) ppm.

EXAMPLE 27 Preparation of uoromethylphenoxy)-N-(3-sulfamoylphenyl) (triﬁuoromethyl)benzamide (25) F30 N H2 N ,S: H o’ ‘o To a mixture of 2-ﬂuoro-N—(3-sulfamoylphenyl) (triﬁuoromethyl)benzamide (10 g, 27.60 mmol) in DMF (55.00 mL) was added 4-ﬁuoro methyl-phenol (3.7 g, 28.98 mmol) and cesium carbonate (10.8 g, 33.12 mmol) and the e heated at 100 CC for 1h. The mixture was cooled to ambient temperature and diluted with 300 mL of ice water. The mixture was acidiﬁed with 6N HCl and diluted to a volume of 400 mL with water. The slurry was diluted with 400 mL of ethyl acetate and the c phase separated. The organic phase was washed with 400 mL of water and then 400 mL of brine. The organic phase was dried over MgSO4, d and concentrated in vacuo. The crude solid was diluted with 100 mL of itrile and heated until homogeneous. e stirred at 25 CC, the precipitate was collected by ﬁltration and washed with 25 mL of acetonitrile to yield 2-(4-ﬂuoromethylphenoxy)-N-(3-sulfamoylphenyl) (triﬁuoromethyl)benzamide (25) (4.14 g, 32%). ESI-MS m/z calc. 468.08, found 469.20 (M+1)+; Retention time: 1.81 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 5 2014/047265 .83 (s, 1H), 8.33 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.81 (m, 2H), 7.56 (m, 2H), 7.40 (s, 2H), 7.23 (ddd, J = 13.9, 9.1, 4.0 Hz, 2H), 7.14 (td, J = 8.6, 3.1 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 2.15 (s, 3H) ppm.

EXAMPLE 28 ation of 2-(2-chloroﬂuorophenoxy)-N—(3-sulfamoylphenyl) (triﬁuoromethyl)benzamide (26) O JCL FC3 ﬂ” /NH2 008% A mixture of 2-ﬂuoro-N—(3-sulfamoylphenyl) (triﬁuoromethyl)benzamide (15 g, 41.40 mmol), 2-chloroﬁuoro-phenol (17.35 g, 118.4 mmol), cesium carbonate (40.47 g, 124.20 mmol) and DMF (375.0 mL) was heated at 100 °C for 1 hour and 15 s. The mixture was cooled to room temperature and ﬁltered using ethyl acetate. Water was added to the ﬁltrate. The layers were separated and the aqueous layer was extracted with ethyl e (3 x 100 mL). The ed organics were washed with saturated aqueous solution of NH4C1, water and brine. The organics were dried over sodium sulfate, ﬁltered and concentrated under reduced pressure. The crude product was puriﬁed silica gel chromatography utilizing a gradient of ethyl acetate in dichloromethane (0- %). The fractions containing the d product were concentrated and the resulting solid slurried in ether and hexanes and ﬁltered. The solvent was evaporated under reduced pressure to yield 2-(2-chloroﬂuoro-phenoxy)-N—(3-sulfamoylphenyl)(triﬂuoromethyl)benzamide (26) (10.35 g, 50%) as a light pink solid. ESI-MS m/z calc. 488.02, found 489.2 (M+1)+; Retention time: 2.03 s (3 minutes run). 1H NMR (400 MHZ, DMSO-d6) 5 10.83 (s, 1H), 8.37 - 8.27 (m, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.92 - 7.74 (m, 2H), 7.69 (dd, J = 8.4, 3.0 Hz, 1H), 7.63 = 8.7 Hz, 1H) ppm. - 7.50 (m, 2H), 7.50 - 7.28 (m, 4H), 6.92 (d, J Following a similar procedure as described above for compound (26), the following compounds were prepared starting from 2-ﬂuoro-N—(3-sulfamoylphenyl) (triﬂuoromethyl)benzamide and the phenols listed below.

Cmpd. Product name Phenol 32 N-(3-sulfamoylphenyl)(o-tolyloxy) o-cresol (trifluoromethyl)benzamide 34 2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)- 2-methoxyphenol -(trifluoromethyl)benzamide 22 2-(4-methoxyphenoxy)-N-(3-sulfamoylphenyl)- 4-methoxyphenol fluoromethyl)benzamide 24 2-(4-chlorophenoxy)-N-(3-sulfamoylphenyl) rophenol (trifluoromethyl)benzamide 6 2-(2,4-difluorophenoxy)-N-(3- 2,4-difluorophenol sulfamoylphenyl)(trifluoromethyl)benzamide 23 2-(4-ethoxyphenoxy)-N-(3-sulfamoylphenyl) 4-ethoxyphenol (trifluoromethyl)benzamide 2-(4-chloromethylphenoxy)-N-(3- 4-chloromethylphenol sulfamoylphenyl)(trifluoromethyl)benzamide 29 2-(3-fluoromethoxyphenoxy)-N-(3- 3-fluoromethoxyphenol sulfamoylphenyl)(trifluoromethyl)benzamide 27 2-(4-fluoromethoxyphenoxy)-N-(3- 4-fluoromethoxyphenol sulfamoylphenyl)(trifluoromethyl)benzamide 28 2-(3-fluoromethoxyphenoxy)-N-(3- 3-fluoromethoxyphenol sulfamoylphenyl)(trifluoromethyl)benzamide 37 2-(4-isopropoxyphenoxy)-N-(3- 4-isopropoxyphenol sulfamoylphenyl)(trifluoromethyl)benzamide 36 2-(2,4-dimethoxyphenoxy)-N-(3- 2,4-dimethoxyphenol sulfamoylphenyl)(trifluoromethyl)benzamide hloromethoxyphenoxy)-N-(3- 4-chloro sulfamoylphenyl)(trifluoromethyl)benzamide methoxyphenol 31 2-(2-chloromethoxyphenoxy)-N-(3- 2-chloro sulfamoylphenyl)(trifluoromethyl)benzamide yphenol 41 2-(4-(difluoromethoxy)phenoxy)-N-(3- 4- sulfamoylphenyl)(trifluoromethyl)benzamide (difluoromethoxy)phenol 39 N-(3-sulfamoylphenyl)(4- 4- uoromethoxy)phenoxy) (trifluoromethoxy)phenol (trifluoromethyl)benzamide EXAMPLE 29 Preparation of 5-fluoro(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)benzamide (21) To a solution of 2,5-difluoro-N-(3-sulfamoylphenyl)benzamide (200 mg, 0.64 mmol) in DMF (2 mL) was added 4-fluoromethyl-phenol (72.99 µL, 0.64 mmol) and cesium carbonate (1.0 g, 3.2 mmol) and the mixture was heated at 100 °C for 3 hours.

The reaction was cooled to 25 °C, diluted with ethyl acetate and poured over water. The 2 layers were separated and the s layer was extracted with ethyl acetate (2x). The organics were combined, dried over MgSO4, filtered and evaporated to yield a red oil that was purified by column chromatography using a gradient of ethyl acetate and hexanes to yield -fluoro(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)benzamide (21) (7.2 mg, 3%).

EXAMPLE 30 Preparation of 4-cyano(4-ﬂuoromethoxyphenoxy)-N—(3-sulfamoylphenyl)benzamide (10) To a solution of 4-cyanoﬂuoro-N—(3-sulfamoylphenyl)benzamide (19.2 mg, 0.06 mmol) and 4-ﬂuoromethoxyphenol (42.6 mg, 0.3 mmol) in NMP (0.5 mL) was added C82C03 (97.7 mg, 0.3 mmol) and the mixture was stirred at 90 0C for 4 hours. The reaction was ﬁltered and puriﬁed by reverse phase HPLC using a gradient of acetonitrile in water (l-99%) to give 4-cyano(4-ﬂuoromethoxy-phenoxy)-N—(3- sulfamoylphenyl)benzamide. ESI-MS m/z calc. 441.08, found 442.3 (M+l)+; Retention time: 1.53 minutes (3 s run).

Following a similar procedure as described above for compound (10), the following nds were prepared starting from oﬂuoro-N—(3- sulfamoylphenyl)benzamide and the phenols listed below.

I—mN0. 2-(2-chloroﬂuoro-phenoxy)cyano-N-(3- 2-chloroﬂuorophenol sulfamoylphenyl)benzamide 4-cyano(4-ﬂuoromethyl-phenoxy)—N—(3- 4-ﬂuoromethyl-phenol sulfamo lohen lbenzamide EXAMPLE 31 Preparation of 2-(2-chloroﬂuorophenoxy)—5-cyano-N-(3-sulfamoylphenyl)benzamide (11) NCﬁlm ,NH2 Ol’s‘b To a solution of 5-cyanoﬂuoro-N—(3-sulfamoylphenyl)benzamide (31.9 mg, 0.10 mmol) and 2-chloroﬁuorophenol (44.0 mg, 0.30 mmol) in NMP (0.5 mL) was added CS2C03 (97.7 mg, 0.30 mmol) and the mixture was stirred at 90 0C for 4 hours.

The reaction was ﬁltered and puriﬁed by reverse phase HPLC using a gradient of acetonitrile in water (1-99%) using HCl as a modiﬁer to yield 2-(2-chloroﬂuoro-phenoxy)—5-cyano-N- (3-sulfamoylphenyl)benzamide (11) (5.8 mg, 13%). ESI-MS m/z calc. 445.03, found 446.1 (M+1)+; Retention time: 1.57 s (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 8 .84 (s, 1H), 8.33 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 6.9 Hz, 1H), 7.69 (dd, J = 8.3, 2.8 Hz, 1H), 7.60 = 9.1, 5.2 Hz, 1H), - 7.54 (m, 2H), 7.48 (dd, J 7.44 = 8.7 Hz, 1H) ppm. - 7.34 (m, 3H), 6.88 (d, J E 32 ation of 4-chloro(4-ﬁuorophenoxy)—5-methyl-N-(3-sulfamoylphenyl)benzamide (7) 0 /©\ H3C ,NH2 N ,S\ H o"o CI 0 To a solution of 5-bromochloroﬂuoro-N—(3- sulfamoylphenyl)benzamide (122.3 mg, 0.3 mmol) and ophenol (100.9 mg, 0.9 mmol) in N,N—dimethylformamide (3 mL) was added cesium carbonate (293.2 mg, 0.9 mmol) and the reaction was heated at 100 0C for 2 hours. The reaction was ﬁltered and puriﬁed by reverse phase preparative chromatography utilizing a gradient of 20-99% acetonitrile in water 2014/047265 containing HCl as a modiﬁer to yield 5-bromochloro(4-ﬁuorophenoxy)-N—(3- sulfamoylphenyl)benzamide (59.5 mg, 40%).

] To 5-bromochloro(4-ﬂuorophenoxy)-N—(3- sulfamoylphenyl)benzamide (44 mg, 0.09 mmol), methylboronic acid (7.9 mg, 0.13 mmol), tetrakis(triphenylphosphine)palla-dium (0) (5.3 mg, 0.004 mmol) and 1,2-dimethoxyethane (500 uL) was added sodium carbonate (132.1 uL of 2 M solution, 0.26 mmol) and the reaction was heated at 80 0C for 65 hours. The reaction was ﬁltered and the solvent was evaporated.

The crude product was puriﬁed by reverse phase LCMS using acetonitrile and water containing HCl as a modiﬁer to yield 4-chloro(4-ﬂuorophenoxy)—5-methyl-N-(3- sulfamoylphenyl)benzamide (7) (12.1 mg, 29%) as a yellow solid. ESI-MS m/z calc. 434.05, found 435.15 (M+1)+; ion time: 1.8 s (3 s run). 1H NMR (400 MHz, DMSO-d6) 8 10.65 (s, 1H), 8.30 - 8.24 (m, 1H), 7.81 - 7.72 (m, 1H), 7.68 (s, 1H), 7.58 - 7.48 (m, 2H), 7.38 (s, 2H), 7.29 - 7.18 (m, 2H), 7.18 - 7.09 (m, 2H), 6.98 (s, 1H), 2.36 (s, 3H) ppm.

EXAMPLE 33 ation of 4-chloro(2-chloroﬁuorophenoxy)—N—(3-sulfamoylphenyl)benzamide (8) To a solution of 4-chloroﬁuoro-N—(3-sulfamoylphenyl)benzamide (39.4 mg, 0.12 mmol) and 2-chloroﬁuorophenol (52.8 mg, 0.36 mmol) in DMF (0.8 mL) was added cesium carbonate (117.3 mg, 0.36 mmol) and the reaction was heated at 100 0C for 1 hour. The reaction was ﬁltered and puriﬁed by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HCl as a modiﬁer to yield 4- chloro(2-chloroﬂuorophenoxy)-N—(3 -sulfamoylphenyl)benzamide (8) (1.7 mg, 3%).

ESI-MS m/z calc. , found 455.3 (M+1)+; Retention time: 1.73 minutes (3 minutes run).

Following a similar procedure as described above for compound (8), the following compounds were prepared starting from 4-chloroﬁuoro-N—(3- sulfamoylphenyl)benzamide and the phenols listed below.

Cmpd. Product name Phenol 4-chloro(4-ﬂuoromethoxy-phenoxy)-N-(3- 4-ﬁuoromethoxy- o lohen lbenzamide ohenol 4-chlor0(4-ﬁuoromethyl-phen0xy)-N—(3- 4-ﬁu0r0methyl- sulfamoylphenyl)benzamide phenol 4-chlor0(2,4-dimethoxyphen0xy)-N-(3- 2,4-dimeth0xyphenol sulfamo lohen lbenzamide 4-chlor0(4-chlor0meth0xyphenoxy)-N—(3- 4-chlor0 sulfamoylphenyl)benzamide methoxyphenol 4-chlor0(2-chlor0meth0xyphenoxy)-N—(3- 2-chlor0 o lohen lbenzamide methox ohenol 87 4-chloro(4-isopropoxyphenoxy)—N—(3- 4-isopropoxyphenol sulfamoylphenyl)benzamide E 34 ation of 2-(2-chloroﬁuorophenoxy)(diﬁuoromethyl)-N-(3- sulfamoylphenyl)benzamide (40) 0 £1 HFC2 \CELN NH 00830 2 5-(Diﬁu0r0methyl)ﬁuor0-N—(3-sulfam0ylphenyl)benzamide (75 mg, 0.22 mmol), 2-chloroﬁuoro-phenol (95.7 mg, 0.65 mmol) and cesium carbonate (212.9 mg, 0.65 mmol) in NMP (0.75 mL) was stirred at 90 0C for 2 hours. The reaction mixture was diluted with MeOH, ﬁltered and puriﬁcation by reverse phase HPLC using a gradient of acetonitrile in water ) and HCl as a modiﬁer gave 2-(2-chloroﬁuorophenoxy)—5- (diﬁuoromethyl)-N—(3-sulfam0ylphenyl)benzamide (40) (56 mg, 53%) as a white solid. ESI- MS m/z calc. 470.03, found 471.3 (M+l)+; Retention time: 1.63 minutes (3 minute run). 1H NMR (400 MHz, DMSO-d6) 5 10.77 (s, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 7.85 - 7.78 (m, 1H), 7.72 = 8.1 Hz, 1H), 7.10 - 7.64 (m, 2H), 7.60 - 7.53 (m, 2H), 7.39 (s br, 3H), 7.35 (d, J (t, J = 55.8 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H) ppm.

EXAMPLE 35 Preparation of 2-(4-ﬂuoromethoxyphenoxy)-N—(3-sulfamoylphenyl) (triﬁuoromethoxy)benzamide (54) H o” *0 F3CO o To 2-ﬁuoro-N-(3-sulfamoylphenyl)(triﬂuoromethoxy)benzamide (75.7 mg, 0.2 mmol), 4-ﬂuoromethoxyphenol (68.3 ul, 0.6 mmol), cesium carbonate (195.5 mg, 0.6 mmol) and ylpyrrolidinone (2 mL) were added and the on was stirred at 100 °C for 30 s to 2 hours. The reaction was ﬁltered and mixture was puriﬁed by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HCl as a modiﬁer to yield 2-(4-ﬂuoromethoxyphenoxy)-N-(3- sulfamoylphenyl)(triﬂuoromethoxy)benzamide (54) (27.8 mg, 27%). ESI-MS m/z calc. 500.07, found 501.2 (M+1)+; Retention time: 1.99 minutes (3 minutes run). 1H-NMR (DMSO-d6) 5 10.68 (s, 1H), 8.37 - 8.30 (m, 1H), 7.84 = 8.4 Hz, 1H), - 7.79 (m, 1H), 7.77 (d, J 7.60 - 7.50 (m, 2H), 7.40 (s, 2H), 7.37 - 7.28 (m, 1H), 7.23 - 7.11 (m, 2H), 6.93 - 6.82 (m, 1H), 6.58 - 6.50 (m, 1H), 3.75 (s, 3H) ppm.

The following compounds were prepared using a similar experimental procedure to compound (54) above starting from o-N-(3-sulfamoylphenyl) (triﬂuoromethoxy)benzamide and the phenols listed below. 55 2-(4-ﬂuorophenoxy)—N—(3-sulfamoylphenyl) 4-ﬂuorophenol (triﬂuoromethoxy)benzamide 56 2-(2-chloroﬂuorophenoxy)—N—(3- roﬂuorophenol o l triﬂuoromethox benzamide 2-(2-chloromethoxyphenoxy)—N—(3- 2-chloro sulfamoylphenyl)(triﬂuoromethoxy)benzamide methoxyphenol 2-(2-chlorophenoxy)-N—(3-sulfamoylphenyl) 2-chlorophenol triﬂuoromethox. benzamide. 64 2-(2-(diﬂuoromethoxy)phenoxy)—N—(3- 2- WO 10065 2014/047265 sulfamo lohen l triﬂuoromethox benzamide diﬂuoromethox ohenol 2-(4-chloromethoxyphenoxy)—N—(3 - ro sulfamo lohen l romethox benzamide methox ohenol 2-(3-chloromethoxyphenoxy)—N—(3- 3-chloro sulfamo lohen l triﬂuoromethox benzamide methox ohenol EXAMPLE 36 Preparation of 2-(4-ﬂuoromethoxyphenoxy)—4-(perﬂuoroethyl)-N—(3- sulfamoylphenyl)benzamide (70) d” ,NH2 OOSQO C2F5 O 2-Fluoro(l , l ,2,2,2-pentaﬂuoroethyl)—N—(3- sulfamoylphenyl)benzamide (34.2 mg, 0.1 mmol), the 2-methoxyﬂuorophenol (34.2 ul, 0.3 mmol) and CS2C03 (97.8 mg, 0.3 mmol) in NMP (0.4 mL) was stirred at 80°C for 2 hours.

Puriﬁcation by HPLC using a gradient of 1-99% acetonitrile in water, using HCl as a modiﬁer, gave 2-(4-ﬂuoromethoxyphenoxy)—4-(perﬂuoroethyl)-N—(3- sulfamoylphenyl)benzamide (70) (17.8 mg, 33%). ESI-MS m/z calc. 534.07, found 535.3 (M+1)+; Retention time: 1.78 minutes (3 minutes run).

The following compounds were prepared using a r experimental procedure as used for compound (70) above starting from 2-ﬂuoro(1,1,2,2,2- pentaﬂuoroethyl)-N—(3-sulfamoylphenyl)benzamide and the phenols listed below. mN0. 2-(4-ﬂuorophenoxy)(perﬂuoroethyl)-N—(3- 4-ﬂuorophenol sulfamo lohen lbenzamide 2- 4-chloromethox ohenox 4-chloro WO 10065 (perﬂuoroethyl)—N—(3- methoxyphenol sulfamo lohen lbenzamide hloromethoxyphenoxy) 2-chloro (perﬂuoroethyl)—N—(3- methoxyphenol sulfamo lohen lbenzamide EXAMPLE 37 Preparation of 4,5-dichloro(4-ﬂuoromethoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide (77) O JCL CIﬁn ,NH2 Oos‘b CI 0 4,5-Dichloroﬂuoro-N—(3-sulfamoylphenyl)benzamide (50 mg, 0.14 mmol), 4-ﬂuoromethoxyphenol (17.3 ul, 0.15 mmol), and K2C03 (57.1 mg, 0.41 mmol) were combined in DMF (0.5 mL) and heated at 75 0C for 12 hours. The reaction e was ﬁltered and puriﬁed by reverse phase HPLC using a gradient of acetonitrile in water 10-99% and 5 mM HCl in the mobile phase to e 4,5-dichloro(4-ﬂuoromethoxyphenoxy)— ulfamoylphenyl)benzamide (77) (7.5 mg, 11%). ESI-MS m/z calc. 484.01, found 485.3 (M+1)+; Retention time: 1.74 minutes (3 minutes run). 1H NMR (400 MHZ, DMSO-d6) 5 .70 (s, 1H), 8.33 - 8.26 (m, 1H), 7.93 (s, 1H), 7.80 (dt, J = 6.4, 2.3 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.40 (s, 2H), 7.29 (dd, J = 8.8, 5.8 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 Hz, 1H), 6.89 - 6.79 (m, 2H), 3.76 (s, 3H) ppm.

The following compounds were prepared using a similar experimental procedure as for compound (77) above starting from 4,5-dichloroﬂuoro-N-(3- sulfamoylphenyl)benzamide and the phenols listed below.

Cmpd Product name Phenol 76 4,5-dichloro(2,4-dimethoxyphenoxy)-N—(3- 2,4-dimethoxyphenol sulfamo l hen lbenzamide 78 4,5-dichloro(4-ﬂuorophenoxy)-N-(3- 4-ﬂuorophenol o lohen lbenzamide chloro(3-ﬂuoromethoxyphenoxy)—N— 3-ﬂuoro 3-sulfamo lohen lbenzamide methox ohenol chloro(4-chloromethoxyphenoxy)—N— 4-chloro 3-sulfamo lohen lbenzamide methox ohenol 4,5-dichloro(2-ﬂuoromethoxyphenoxy)—N— 2-ﬂuoro 3-sulfamo lohen lbenzamide methox ohenol 4,5-dichloro(2-chloromethoxyphenoxy)—N— 2-chloro 3-sulfamo lohen lbenzamide methox ohenol 4,5-dichloro(4-ﬂuoromethylphenoxy)-N—(3- 4-ﬂuoro o lohen lbenzamide meth l.henol EXAMPLE 38 Preparation of 2-(4-ﬂuoromethoxyphenoxy)-N—(3-sulfamoylphenyl)-4,6- bis(triﬂuoromethyl)benzamide (89) CF3 o O ,NH2 N ’/S\\ H o o FSC 0 To 2-Fluoro-N-(3-sulfamoylphenyl)—4,6-bis(triﬂuoromethyl)benzamide (70 mg, 0.16 mmol) and omethoxyphenol (20.4 uL, 0.18 mmol) in DMF (68.4 uL) was added K2C03 (67.5 mg, 0.49 mmol). The reaction was stirred at 70°C for 2 hours, then at 100°C for 1 hour. The reaction was cooled to room temperature, d and puriﬁed by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) to yield 2-(4-ﬂuoro methoxyphenoxy)-N—(3-sulfamoylphenyl)—4,6-bis(triﬂuoromethyl)benzamide (89) (44.9 mg, 50%). ESI-MS m/z calc. 552.06, found 553.2 (M+1)+; Retention time: 1.87 minutes (3 minutes run).

The following compounds were prepared using a similar experimental procedure as for compound (89) above starting from 2-ﬂuoro-N-(3-sulfamoylphenyl)-4,6- bis(triﬂuoromethyl)benzamide and the phenols listed below.

I—mdNo. 2- 4-ﬂuor0ohenox -N- 3-sulfamo lohen l - 4-ﬂuor0ohenol 4,6-bis triﬁuorometh l benzamide 90 2—(3-ﬁuoromethoxyphenoxy)—N—(3- 3-ﬁuoromethoxyphenol sulfamoylphenyl)—4,6- bis(triﬁuoromethyl)benzamide 91 2-(2-ﬁuoromethoxyphenoxy)—N—(3- 2-ﬁuoromethoxyphenol sulfamoylphenyl)—4,6- bis triﬁuorometh l benzamide 92 2—(5-ﬁuoromethoxyphenoxy)—N—(3- 5-ﬁuoromethoxyphenol oylphenyl)—4,6- bis triﬁuorometh l ide 93 2-(4-ﬁuoromethylphenoxy)-N—(3- 4-ﬁuoromethylphenol sulfamoylphenyl)—4,6- bis rometh l benzamide EXAMPLE 39 Preparation of 2,4-dichloro(4-ﬁuoromethoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide (95) N osgNHz H O 0 CI 0 ] A mixture of 2,4-dichloroﬁuoro-N—(3-sulfamoylphenyl)benzamide (36.3 mg, 0.1 mmol), 4-ﬁuoromethoxyphenol (34.2 11L, 0.30 mmol) and CS2C03 (97.7 mg, 0.3 mmol) in NMP (0.4 mL) was stirred for 1 hour at 80 CC. The reaction mixture was diluted with methanol, ﬁltered and puriﬁed by reverse phase HPLC using a gradient of acetonitrile/water (1-99%) and HCl as a modiﬁer to give 2,4-dichloro(4-ﬁuoro methoxyphenoxy)—N—(3-sulfamoylphenyl)benzamide (95) (6.5 mg, 13%) as a white solid.

ESI-MS m/z calc. 484.01, found 485.5 (M+1)+; Retention time: 1.58 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 8 11.02 (s, 1H), 8.34 (s, 1H), 7.81 - 7.74 (m, 1H), 7.61 - 7.53 (m, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.41 (s, 2H), 7.21 (dd, J = 8.8, 5.8 Hz, 1H), 7.15 (dd, J = .6, 2.9 Hz, 1H), 6.89 — 6.81 (m, 1H), 6.60 (d, J = 1.8 Hz, 1H), 3.78 (s, 3H) ppm.

The following compounds were prepared using a similar experimental ure as for compound (95) above starting from 2,4-dichloroﬂuoro-N—(3- sulfamoylphenyl)benzamide and the phenols listed below.

Cmpd t name Phenol 94 2,4-dichloro(4-ﬂuorophenoxy)—N—(3- 4-ﬂuorophenol sulfamo lohen lbenzamide 2,4-dichloro(4-ﬁuoromethylphenoxy)—N— omethylphenol (3-sulfamoylphenyl)benzamide 2,4-dichloro-N—(3-sulfamoylphenyl)(4- triﬂuoromethox ohenox benzamide 2,4-dichloro(4-chloromethoxyphenoxy)—N— 4-chloro (3-sulfamoylphenyl)benzamide methoxyphenol 2,4-dichloro(2-ﬁuoromethoxyphenoxy)—N— 2-ﬂuoro 3-sulfamo lohen lbenzamide methox ohenol EXAMPLE 40 Preparation of 2-cyclopropyl(3-ﬂuoromethoxyphenoxy)-N—(3-sulfamoylphenyl) (triﬂuoromethyl)benzamide (100) 0 £1 / S: H o’ ‘o F3C o To a mixture of 2-cyclopropylﬁuoro-N—(3-sulfamoylphenyl) (triﬁuoromethyl)benzamide (20 mg, 0.08 mmol) and 3-ﬂuoromethoxyphenol (17.7 mg, 0.12 mmol) in DMF (0.5 mL) was added K2C03 (41.2 mg, 0.3 mmol) and the reaction was d at 100°C for 2 hours, then at 80°C overnight. The reaction was cooled to room temperature, ﬁltered and puriﬁed by reverse phase HPLC using a gradient of acetonitrile in water (1-99%) and HCl as a modiﬁer to yield opropyl(3-ﬁuoromethoxyphenoxy)— ulfamoylphenyl)(triﬂuoromethyl)benzamide (100) (3.69 mg, 9%). ESI-MS m/z calc. 524.10, found 525.2 (M+1)+; Retention time: 1.50 minutes (3 minutes run).

EXAMPLE 41 Analytical data for the compounds of the present invention is provided below in Table 2. Mass Spec (e.g., M+1 data in Table 2), ﬁnal purity and retention times were determined by reverse phase HPLC using a Kinetix C18 column (50 X 2.1 mm, 1.7 um particle) from Phenomenex (pn: 00BAN)), and a dual gradient run from 1-99% mobile phase B over 3 minutes. Mobile phase A = H20 (0.05 % CF3C02H). Mobile phase B = CH3CN (0.05 % CF3C02H). Flow rate = 2 mL/min, ion volume = 3 uL, and column temperature = 50 CC.

] Table 2. Analytical Data cmpd° LCM.S 1H—NMR (400 MHz) N0 Retentlon Tlme 1n. . (M+1) minutes 1 d6) 8 10.84 (s, 1H), 8.34 - 8.24 (m, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.82 - 7.72 (m, 1H), 7.64 1.96 455.3 (dd, J = 7.9, 0.8 Hz, 1H), 7.60 - 7.47 (m, 2H), 7.40 (s, 2H), 7.32 - 7.25 (m, 2H), 7.25 - 7.18 (m, 2H), 7.15 S, 1H 0 0111. 2 473-2— (DMSO-d6) 5 10.81 (S, 1H), 8.30 (S, 1H), 8.01 (d, J = 2.3 HZ, 1H), 7.86 - 7.78 (1’11, 2H), 7.59 - 7.53 (1’11, 1 86' 455 5' 2H), 7.39 (S, 2H), 7.35 - 7.24 (1’11, 4H), 7.00 (d, J = 8.7 HZ, 1H 0 01’11.

\IGUI-b —_—--—1.91 473.3 (DMSO-d6) 8 10.65 (s, 1H), 8.30 — 8.24 (m, 1H), 7.81 — 7.72 (m, 1H), 7.68 (s, 1H), 7.58 — 7.48 (m, 1 8' 435 15' 2H), 7.38 (s, 2H), 7.29 — 7.18 (m, 2H), 7.18 — 7.09 8 —_— 9 —_— 1.53 442.3 11 (DMSO-d6) 5 10.84 (s, 1H), 8.33 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 1.57 446.1 6.9 Hz, 1H), 7.69 (dd, J = 8.3, 2.8 Hz, 1H), 7.60 — 7.54 (m, 2H), 7.48 (dd, J = 9.1, 5.2 Hz, 1H), 7.44 _ 7.34 m, 3H 6.88 , d, J = 8.7 Hz, 1H . .m. 12 —_— Cmpd. LCMS 1 H_NMR (400 MHZ) N0 Retention (M+1) Time in minutes 13 (DMSO-d6) 8 10.98 (s, 1H), 8.33 (s, 1H), 7.79 - 7.72 (m, 1H), 7.61 - 7.48 (m, 4H), 7.40 (s, 2H), 1.61 485.3 7.20 (dd, J = 8.9, 5.9 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.84 (td, J = 8.4, 2.8 Hz, 1H 3.77 , s, 3H . .m. 14 485.3— 451.1— 17 1.76 455.3 18 469-3— 19 435.3— 1.79 435.3 21 (DMSO-d6) 5 10.73 (s, 1H), 8.30 (s, 1H), 7.75 (m, 1H), 7.54 (m, 3H), 7.39 (s, 2H), 7.32 (m, 1H), 7.16 1.85 419.1 (dd, J = 9.4, 2.9 Hz, 1H), 7.04 (td, J = 8.6, 3.2 Hz, 1H), 6.97 (dd, J = 8.8, 5.1 Hz, 1H), 6.84 (dd, J = 9.1, 4.4 Hz, 1H ,2.18 s, 3H “1’11. 22 467.2— 23 481.1— 24 1.82 471.2 (DMSO-d6) 5 10.83 (S, 1H), 8.33 (S, 1H), 8.01 (d, J = 2.1 HZ, 1H), 7.81 (1’11, 2H), 7.56 (1’11, 2H), 7.40 (S, 1.81 469.2 2H), 7.23 (ddd, J = 13.9, 9.1, 4.0 HZ, 2H), 7.14 (td, J = 8.6, 3.1 HZ, 1H), 6.82 (d, J = 8.7 HZ,1H), 2.15 S, 3H 0 01’11. 26 d6) 5 10.84 (S, 1H), 8.32 (d, J = 1.6 HZ, 1H), 8.04 (d, J = 2.1 HZ, 1H), 7.82 (1’11, 2H), 7.69 1.78 489.2 (dd, J = 8.4, 3.0 HZ, 1H), 7.56 (1’11, 2H), 7.47 (dd, J = 9.1, 5.3 HZ, 1H), 7.37 (1’11, 3H), 6.92 (d, J = 8.7 HZ, 1H 0 01’11. 27 (DMSO-d6) 5 10.74 (S, 1H), 8.33 (S, 1H), 7.97 (d, J = 2.2 HZ, 1H), 7.84 (1’11, 1H), 7.77 (dd, J = 8.9, 2.2 HZ, 1H), 7.56 (1’11, 2H), 7.40 (S, 2H), 7.35 (dd, J = 1.79 485.2 8.8, 5.9 HZ, 1H), 7.17 (dd, J =10.7, 2.9 HZ, 1H), 6.88 (td, J = 8.4, 2.9 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H) Rpm. 28 1.73 485.2 29 485.1— 485.2— 31 1.81 501.1 32 2.0 451.1 DMSO-d6 510.82 s, 1H 8.32 , s, 1H 8.01 , s, Cmpd. LCMS 1H—NMR (400 MHz) N0 Retention (M+1) Time in 1H), 7.81 (s, 2H), 7.56 (s, 2H), 7.26 (m, 6H), 6.82 d, J = 8.3 Hz, 1H 2.15 , s, 3H 0 0111. 33 (DMSO-d6) 5 11.02 (s, 1H), 8.32 - 8.25 (m, 1H), 7.73 (dt, J = 7.2, 2.0 Hz, 1H), 7.69 - 7.60 (m, 3H), 7.60 - 7.50 (m, 2H), 7.41 (s, 2H), 7.37 - 7.31 (m, 2H 7.13 - 7.07 , 1’11,1Hn1’n. 34 (DMSO-d6) 5 10.74 (s, 1H), 8.33 (s, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.84 (m, 1H), 7.77 (dd, J = 8.9, 2.3 Hz, 1H), 7.56 (m, 2H), 7.40 (s, 2H), 7.31 (dd, J = 11.5, 4.6 Hz, 2H), 7.23 (m, 1H), 7.05 (td, J = 7.7, 1.5 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 3.74 (s, 3H) ppm.

(DMSO-d6) 5 10.75 (s, 1H), 8.32 (s, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.83 (dt, J = 6.2, 2.4 Hz, 1H), 7.77 (dd, J = 8.9, 2.3 Hz, 1H), 7.56 (m, 2H), 7.40 (s, 2H), 7.31 (dd, J = 5.4, 2.9 Hz, 2H), 7.11 (dd, J = 8.5, 2.4 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 3.77 (s, 36 —_— 37 1.88 495.1 38 (DMSO-d6) 5 10.83 (s, 1H), 8.41 — 8.36 (m, 1H), 7.76 (dt, J = 7.1, 2.0 Hz, 1H), 7.63 — 7.51 (111,3H), 1 72' 435 5' 7.39 (s, 2H), 7.34 — 7.25 (m, 3H), 7.12 — 7.07 (m, 1H), 6.61 (t, J = 8.0 Hz, 1H), 2.35 (s, 3H) ppm. 39 (DMSO-d6) 5 10.83 (S, 1H), 8.31 - 8.23 (1’11, 1H), 8.05 (d, J = 2.3 HZ, 1H), 7.87 (dd, J = 8.8, 2.2 HZ, 2.16 . 1H), 7.82 - 7.75 (1’11, 1H), 7.59 - 7.50 (1’11, 2H), 7.50 - 7.42 (1’11, 2H), 7.39 (S, 2H), 7.35 - 7.26 (1’11, 2H), 7.13 d, J = 8.8 HZ, 1H 0 0111. 40 (DMSO-d6) 5 10.77 (S, 1H), 8.32 (S, 1H), 7.87 (S, 1H), 7.85 - 7.78 (1’11, 1H), 7.72 - 7.64 (1’11, 2H), 7.60 - 7.53 (1’11, 2H), 7.39 (S 131‘, 3H), 7.35 (d, J = 8.1 HZ, 1H), 7.10 (t, J = 55.8 HZ,1H), 6.89 (d, J = 8.5 HZ, 41 (DMSO-d6)510.82 (s, 1H), 8.33- 8.26 (m, 1H), 8.0,3(d J= 2.3Hz,1H), 7.8-8 7.76(rn, 2H), 7.61- 43 (DMSO-d6) 5 ppm10.82 (s, 1H), 8.35- 8.25 (m, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.82 — 7.73 (m, 1H), Cmpd. LCMS 1H—NMR (400 MHz) N0 Retention (M+1) Time in minutes 7.40 (S, 2H), 7.31 - 7.10 (1’11, 3H), 7.06 - 6.94 (1’11, 1H 3.83 , S, 3H 0 0111. 44 —_— 45 --— 46 2.1 495.4 47 —_— 48 —_— 49 2.0 481.3 50 1.97 497.4 51 (DMSO-d6) 5 10.86 (s, 1H), 8.26 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.78 — 7.68 (m, 2H), 7.60 — 7.49 (m, 2 08' 521 4' 2H), 7.45 — 7.38 (m, 4H), 7.36 (s, 1H), 7.26 — 7.19 52 —_— 53 (DMSO-d6) 5 10.82 (S, 1H), 8.36 - 8.28 (1’11, 1H), 7.85 (d, J = 7.8 HZ, 1H), 7.83 - 7.76 (1’11, 1H), 7.61 - 2.05 495.5 7.49 (1’11, 3H), 7.39 (S, 2H), 7.17 - 7.08 (1’11, 2H), 7.07 - 6.93 (1’11, 3H), 4.65 - 4.50 (1’11, 1H), 1.25 (d, J = 6.0 HZ, 6H 0 0111. 54 d6) 8 10.68 (s, 1H), 8.37 - 8.30 (m, 1H), 7.84 - 7.79 (m, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.60 - 501.2 7.50 (m, 2H), 7.40 (s, 2H), 7.37 - 7.28 (m, 1H), 7.23 - 7.11 (m, 2H), 6.93 - 6.82 (m, 1H), 6.58 - 6.50 (m, 1H), 3.75 (s, 3H) Rpm. 55 (DMSO-d6) 5 10.75 (s, 1H), 8.32 - 8.28 (m, 1H), 7.84 - 7.74 (m, 2H), 7.59 - 7.49 (m, 2H), 7.39 (s, 2H), 7.33 - 7.25 (m, 3H), 7.25 - 7.18 (m, 2H), 6.87 - 6.79 (m, 1H) ppm. 56 (DMSO-d6) 5 10.77 (s, 1H), 8.36 — 8.28 (m, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.80 — 7.74 (m, 1H), 7.64 (dd, J = 8.4, 2.9 Hz, 1H), 7.59 — 7.48 (m, 2H), 7.40 (s, 2H), 7.38 = 2.2 Hz, — 7.26 (m, 3H), 6.79 (d, J 58 (DMSO-d6)511.03(s, 1H), 8.29 (t, J—— 1.8 Hz, 1H), 7.72 (dt, J = 73,20 Hz, 1H), 7.67 — 7.50 (m, 4H), 7.43 (d, J = 2.5 Hz, 1H), 7.41 (s, 2H), 7.32 (dd, J—— 86, 27 Hz, 1H), 7.12 — 7.04 (m, 2H), 2.15 Cmpd. LCMS 1H—NMR (400 MHz) N0 Retention (M+1) Time in minutes 4H), 7.41 (s, 2H), 7.30 (td, J = 8.2, 6.5 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.10 - 7.04 (m, 1H), 6.91 d, J = 8.2 Hz, 1H 2.08 , s, 3H 0 01’11. .0 --— 61 1.20 485 62 —_— 63 —_— .4 --— 65 1.96 517.2 66 —_— 67 —_— 68 1.87 501.2 69 1.75 505.3 70 d6) 5 10.83 (s, 1H), 8.35 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.84 — 7.77 (m, 1H), 7.62 — 7.49 (m, 1.78 535.3 3H), 7.40 (s, 2H), 7.32 (dd, J = 8.8, 5.9 Hz, 1H), 7.16 (dd, J = 10.6, 2.8 Hz, 1H), 6.88 (ddd, J = 8.4, 2.8 Hz, 1H 6.76 , s, 1H 3.73 , s, 3H . .m. 71 —_— 72 1.79 551.1 73 (DMSO-d6) 5 10.86 (S, 1H), 8.32 - 8.27 (1’11, 1H), 7.91 (d, J = 7.9 HZ, 1H), 7.81 - 7.73 (1’11, 1H), 7.73 - 1.83 471.3 7.65 (1’11, 1H), 7.61 (dd, J = 8.0, 1.6 HZ, 1H), 7.58 - 7.50 (1’11, 2H), 7.48 - 7.36 (1’11, 3H), 7.32 - 7.21 (1’11, 2H 7.10 , d, J=1.6 HZ, 1H “1’11. 74 —_— 75 (CDsOD) 8 8.31 (t, J = 2.0 Hz, 1H), 7.79 (ddd, J = 8.1, 2.2, 1.1 Hz, 1H), 7.68 (dt, J = 8.1, 1.3 Hz,1H), 1.55 501.3 7.57 - 7.50 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 9.0 Hz, 1H), 7.09 (d, J = 2.9 Hz, 1H), 6.93 dd, J = 9.1, 2.4 Hz, 2H 3.81 , s, 3H 0 0111. 76 (DMSO-d6) 5 10.67 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.86 - 7.79 (m, 1H), 7.58 - 7.51 (m, 2H), 7.40 1.76 498.5 (s, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.78 - 6.71 (m, 2H), 6.59 (dd, J = 8.9, 2.8 Hz, 1H), 3.79 (s, 3H), 3.74 (s, 3H) 9pm. 77 (DMSO-d6) 5 10.70 (s, 1H), 8.33 - 8.26 (m, 1H), 7.93 (s, 1H), 7.80 (dt, J = 6.4, 2.3 Hz, 1H), 7.60 - 1.74 485.3 7.49 (m, 2H), 7.40 (s, 2H), 7.29 (dd, J = 8.8, 5.8 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 Hz, 1H), 6.89 - 6.79 Cmpd. LCMS 1H—NMR (400 MHz) N0 Retention (M+1) Time in minutes 78 (DMSO-d6) 5 10.77 (s, 1H), 8.28 - 8.23 (m, 1H), 7.98 (s, 1H), 7.76 (dt, J = 6.9, 2.1 Hz, 1H), 7.59 - 1.70 455.5 7.49 (m, 2H), 7.39 (s, 2H), 7.26 (t, J = 8.7 Hz, 2H), 7.22 - 7.16 (m, 3H) ppm. 79 d6) 5 10.74 (s, 1H), 8.29 _ 8.23 (m, 1H), 7.96 (s, 1H), 7.77 (dt, J = 7.0, 2.2 Hz, 1H), 7.60 _ 1.70 485.3 7.50 (m, 2H), 7.40 (s, 2H), 7.25 _ 7.14 (m, 3H), 6.97 (dt, J = 9.4, 1.9 Hz, 1H), 3.83 (s, 3H) ppm. 80 (DMSO-d6) 5 10.80 (s, 1H), 8.32 - 8.28 (m, 1H), 7.96 (s, 1H), 7.80 (dt, J = 6.8, 2.2 Hz, 1H), 7.59 - 1.82 503.1 7.51 (m, 2H), 7.40 (s, 2H), 7.29 (t, J = 9.2 Hz, 1H), 7.06 (dd, J = 12.6, 2.9 Hz, 1H), 7.01 (s, 1H), 6.84 ddd, J = 9.1, 3.0, 1.3 Hz, 1H 3.78 , s, 3H 5 m. 81 (DMSO-d6) 5 10.80 (s, 1H), 8.32 - 8.28 (m, 1H), 7.96 (s, 1H), 7.80 (dt, J = 6.8, 2.2 Hz, 1H), 7.61 - 1.72 485.3 7.51 (m, 2H), 7.40 (s, 2H), 7.29 (t, J = 9.2 Hz, 1H), 7.06 (dd, J = 12.6, 2.9 Hz, 1H), 7.01 (s, 1H), 6.84 ddd, J = 9.1,3.0,1.3 Hz, 1H 3.78 5 m. , s, 3H 82 (DMSO-d6) 5 10.77 (s, 1H), 8.33 - 8.28 (m, 1H), 7.98 (s, 1H), 7.79 (dt, J = 6.8, 2.2 Hz, 1H), 7.59 - 18 501.3 7.51 (m, 2H), 7.40 (s, 2H), 7.32 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 3.0 Hz, 1H), 7.02 (dd, J = 9.0, 3.0 Hz, 1H ,6.89 s, 1H ,3.79 s, 3H um. 83 (DMSO-d6) 5 10.78 (s, 1H), 8.31 - 8.27 (m, 1H), 7.97 (s, 1H), 7.77 (dt, J = 7.0, 2.1 Hz, 1H), 7.62 - 1.78 469.3 7.50 (m, 2H), 7.40 (s, 2H), 7.21 (dd, J = 9.4, 2.9 Hz, 1H), 7.15 - 7.04 (m, 2H), 6.95 (s, 1H), 2.17 (s, 3H) ppm. 84 (DMSO-d6) 8 10.55 (s, 1H), 8.32 (s, 1H), 7.82 (d, J = 3.5 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.62 — 7.51 1.65 463.3 (m, 2H), 7.39 (s, 2H), 7.30 — 7.19 (m, 2H), 6.76 (d, J = 2.7 Hz, 1H), 6.60 (dd, J = 8.8, 2.7 Hz, 1H), 6.56 d, J = 1.8 Hz, 1H 3.79 , s, 3H 3.75 , s, 3H . .m. 85 1.71 467.1 86 (DMSO-d6) 8 10.60 (s, 1H), 8.30 (s, 1H), 7.80 (5 br, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.63 — 7.50 (m, 2H), 1.67 467.1 7.39 (s, 2H), 7.32 — 7.20 (m, 3H), 7.13 — 7.05 (m, 1H 6.72 , d, J = 1.8 Hz, 1H 3.77 , s, 3H . .m. 87 —_— 88 (DMSO-d6)511.16(s,1H),8.25(t,J=1.8Hz, 5232 WO 10065 Cmpd. LCMS 1H—NMR (400 MHz) No Retention (M+1) Time in minutes 7.63 — 7.52 (m, 2H), 7.48 (s, 1H), 7.43 (s, 2H), 7.37 89 —_— 9° --— 91 1.87 553.23 92 —_— 93 —_— 94 (DMSO-d6) 5 11.06 (S, 1H), 8.30 (S, 1H), 7.77 - 7.71 (1’11, 1H), 7.59 - 7.52 (1’11, 3H), 7.41 (S, 2H), 1 57' 455 3' 7.29 (dd, J = 8.7 HZ, 2H), 7.25 - 7.19 (1’11, 2H), 6.90 d, J=1.8 HZ, 1H “1’11. 95 (DMSO-d6) 5 11.02 (S, 1H), 8.34 (S, 1H), 7.81 - 7.74 (1’11, 1H), 7.61 - 7.53 (1’11, 2H), 7.48 (d, J = 1.8 1.58 HZ, 1H), 7.41 (S, 2H), 7.21 (dd, J = 8.8, 5.8 HZ, 1H), 7.15 (dd, J = 10.6, 2.9 HZ, 1H), 6.89 - 6.81 (1’11, 1H), 6.60 (d, J = 1.8 HZ, 1H), 3.78 (S, 3H) ppm. 96 1.64 469.3 97 —_— 98 —_— 99 1.58 485.5 100 1.5 525.2 EXAMPLE 42 ASSAYS FOR DETECTINGAND MEASURING NayINHIBITIONPROPERTIES OF COMPOUNDS E-VIPR optical membrane ial assay method with electrical stimulation ] Sodium channels are voltage-dependent proteins that can be activated by inducing membrane voltage changes by applying electric ﬁelds. The electrical stimulation instrument and methods of use are described in Ion Channel Assay Methods PCT/U801/21652, herein incorporated by reference and are referred to as E-VIPR. The instrument comprises a iter plate handler, an optical system for ng the coumarin dye While simultaneously recording the coumarin and oxonol emissions, a waveform generator, a t- or voltage-controlled ampliﬁer, and a device for inserting electrodes in well. Under integrated computer control, this instrument passes user-programmed e1ectrica1 WO 10065 stimulus protocols to cells within the wells of the microtiter plate. 24 hours before the assay on E-VIPR, HEK cells expressing human Nav1.8 were seeded in 384-well poly-lysine coated plates at 15,000-20,000 cells per well.

HEK cells were grown in media (exact ition is speciﬁc to each cell type and NaV subtype) supplemented with 10% FBS (Fetal Bovine Serum, ed; GibcoBRL #16140- 071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL #15140-122). Cells were grown in vented cap ﬂasks, in 90% humidity and 5% C02. ts and Solutions: 100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO nd Plates: 384-well round bottom plate, e.g. Corning 384-well Polypropylene Round Bottom #3656 Cell Plates: 384-well tissue culture treated plate, e.g. Greiner #781091- 10 mM DiSBAC6(3) (Aurora 0-010) in dry DMSO 10 mM CC2-DMPE a #00008) in dry DMSO 200 mM ABSC1 in H20 Bath1 buffer: Glucose 10mM (1.8g/L), Magnesium Chloride (Anhydrous), 1mM (0.095g/L), Calcium Chloride, 2mM (0.222g/L), HEPES 10mM (2.38g/L), Potassium Chloride, 4.5mM (0.335g/L), Sodium Chloride 160mM (9.35g/L).

Hexyl Dye Solution: Bath1 Buffer + 0.5% B-cyclodextrin (make this prior to use, Sigma #C4767), 8 uM PE + 2.5 uM DiSBAC6(3). To make the solution Added volume of 10% Pluronic F127 stock equal to volumes of CC2-DMPE + DiSBAC6(3).

The order of preparation was ﬁrst mix ic and CC2-DMPE, then added DiSBAC6(3) while vortexing, then added Bath1 + B-Cyclodextrin.

Assay Protocol: 1) Pre-spotted compounds (in neat DMSO) into compound plates.

Vehicle control (neat DMSO), the positive control (20mM DMSO stock tetracaine, 125 uM ﬁnal in assay) and test compounds were added to each well at l60x desired ﬁnal concentration in neat DMSO. Final compound plate volume was 80 [LL (80-fold intermediate on from 1 [LL DMSO spot; l60-fold ﬁnal dilution after transfer to cell plate). Final DMSO concentration for all wells in assay was 0.625%. 2) Prepared Hexyl Dye Solution. 3) Prepared cell plates. On the day of the assay, medium was aspirated and cells were washed three times with 100 [LL of Bathl Solution, maintaining 25 [LL residual volume in each well. 4) Dispensed 25 [LL per well of Hexyl Dye Solution into cell plates.

Incubated for 20-35 minutes at room temp or ambient conditions. 5) Dispensed 80 [LL per well of Bathl into compound plates. Acid Yellow-l7 (1 mM) was added and Potassium Chloride was d from 4.5 to 20 mM depending on the NaV subtype and assay sensitivity. 6) Washed cell plates three times with 100 [LL per well of Bathl, leaving 25 [LL of residual volume. Then transfered 25uL per well from Compound Plates to Cell Plates. Incubated for 20-35 minutes at room temp/ambient condition. 7) Read Plate on . Used the current-controlled ampliﬁer to deliver stimulation wave pulses for 10 seconds and a scan rate of 200Hz. A pre-stimulus recording was performed for 0.5 seconds to obtain the un-stimulated intensities baseline. The stimulatory rm was followed by 0.5 seconds of post-stimulation ing to examine the relaxation to the resting state.

Data Analysis Data was analyzed and reported as ized ratios of emission ities measured in the 460 nm and 580 nm channels. The response as a function of time was reported as the ratios obtained using the following formula:: (intensity 460 nm - ound 460 11m) R(t) = --------------------------------------------- (intensity 580 nm - background 580 nm) The data was further d by calculating the l (R) and ﬁnal (Rf) ratios. These were the average ratio values during part or all of the pre-stimulation period, and during sample points during the stimulation period. The response to the stimulus R = Rf/Ri was then calculated and reported as a function of time.

Control responses were obtained by performing assays in the presence of a nd with the desired ties (positive control), such as aine, and in the absence of cological agents (negative control). Responses to the negative (N) and positive (P) controls were calculated as above. The compound antagonist activity A is deﬁned R _ P A = * 100 N — P where R is the ratio response of the test compound ELECTROPHYSIOLOGYASSA YS FOR NaVACTIVITYAND INHIBITION OF TEST COMPOUNDS Patch clamp ophysiology was used to assess the efﬁcacy and ivity of sodium channel blockers in dorsal root ganglion neurons. Rat neurons were isolated from the dorsal root ganglions and maintained in culture for 2 to 10 days in the presence ofNGF (50 ng/ml) (culture media consisted ofNeurobasalA supplemented with B27, glutamine and antibiotics). Small diameter neurons (nociceptors, 8-12 um in diameter) were ly identiﬁed and probed with ﬁne tip glass electrodes connected to an ampliﬁer (Axon Instruments). The “voltage clamp” mode was used to assess the compound’s IC50 holding the cells at — 60 mV. In addition, the “current clamp” mode was employed to test the efﬁcacy of the compounds in blocking action potential generation in response to current injections. The results of these experiments contributed to the ion of the efﬁcacy proﬁle of the compounds.

The exempliﬁed compounds in Table 1 herein are active against Navl .8 sodium channels as measured using the assays described herein and as presented in Table 3 below.

Table 3. Navl.8 IC50 activity WO 10065 Cmpd.

N0 NaV1.8 IC50 (11M) N0 NaV1.8 IC50 (11M) i 42 DJN 43 44 0.02 ii 45 \]O\ 77 48 0.01 ii 49 HH #0 51 0.014 52 0.011 >—A>—A LAN 53 >—A>—A UI-h 77 56 0.004 >—A>—A \]O\ 57 >—A>—A ©OO 59 60 0.009 NN 77 NDJ 64 0.022 iiUI-b 65 NN \]O\ 77 68 0.009 ii000 69 DJ 0 77 DJ j—A 72 0.02 WU) DJN 73 DJ J; 77 DJ £11 76 0.003 WU) \]O\ 77 WU) \Ooo 77 80 0.004 ii#0 81 N0 Nav1.8 IC50 (uM) N0 EXAMPLE 43 IonWorks assays. This assay was performed to determine the activity for the compounds of the present invention t non NaVl .8 channels. Sodium ts were recorded using the automated patch clamp system, IonWorks (Molecular Devices Corporation, Inc.). Cells expressing NaV subtypes were harvested from tissue culture and placed in sion at 0.5-4 n cells per mL Bathl. The IonWorks instrument measured changes in sodium currents in response to applied voltage clamp similarly to the traditional patch clamp assay, except in a 384-well format. Using the ks, dose-response relationships were determined in voltage clamp mode by depolarizing the cell from the experiment speciﬁc holding potential to a test potential of about 0 mV before and following addition of the test compound. The inﬂuence of the compound on currents were ed at the test potential.

EXAMPLE 44 Human Liver Microsome Assay Protocol: Liver microsomal stability data were generated as follows. Substrates were incubated at 37 0C and shaken for 30 minutes in a phosphate ed on with human liver microsomes and the cofactor NADPH. A time zero control was similarly prepared, however with NADPH ed. The ﬁnal incubation concentrations were 1 uM substrate (0.2% DMSO), 0.5 mg/mL liver microsome, 2 mM NADPH, and 0.1 M phosphate. Reactions were quenched and proteins precipitated with the addition of 2 volume equivalents of ice cold acetonitrile containing an internal standard. ing a centriﬁlgation step, aliquots from the quenched incubations were further diluted with 4 volume equivalents of a 50% s methanol solution and then subjected to LC/MS/MS analysis for quantitation of parent substrate. Microsome stability values were calculated as the percent of substrate remaining after 30 minutes referenced against the time zero control.

Table 4. Human liver ome (HLM) data for selected compounds of the present invention is listed below. The values presented represent the percent of compound remaining after 30 minutes using the protocol described above in Example 44.

Compounds with reported >100% t unchanged after 30 minutes of incubation represent compounds that were not metabolized under the assay conditions. The numbers ing 100% were due to ility in the analytical quantitation of the assay. The abbreviation “ND”stands for no data.

HLM: percent . HLM: percent unchanged after 30 . unchanged after 30 min min ii000\IUJ ilgw —CN \l \1 OO —\l O\ j—AOGOO OO O\ — >—t>—A NH 00 Q 96 CJ; 82 13 78 m- 14 83 >—A>—A GUI 00 )—A 00 O\ >—A>—A OO\] — C 00 )—A C CL NO OO\ 90 N)—A CO\ NN 00 OO —\1N Cmpd. HLM: percent Cmpd. HLM: percent N0. unchanged after 30 N0. unchanged after 30 min min £110 \100 OUIO MOON C>—t U1 O\ O U1 \1 00 mm 000 2U O\ O\ 00 00 #0 av: ooN 2U ii00 ©OO NH O\L OO\ @900 \owq 00 \10 000 Ho O\O\ OOO OO O wow qu \1\1 Ho 0000 >—‘\] \]N 00mm \] D.) ©O\ U‘I\] 2C Many modiﬁcations and variations of the ments described herein may be made Without departing from the scope, as is apparent to those skilled in the art.

The speciﬁc embodiments described herein are d by way of example only.

Claims

We claim :

1. A compound of formula I R1 o N SIP H o” ‘NHZ R3 0 R5 R5 or a ceutically acceptable salt thereof, wherein, independently for each occurrence: R1 is H, Cl, CH3, CF3 or cyclopropyl; R2 is H, F, Cl, CN, CH3, CF3 or CHFZ; R3 is H, F, Cl, CN, CF3, OCF3 or ; R4 is H; R5 is H, F, Cl, CH3, OCH3, OCH2CH3, OCHZCHZCHg or OCHFZ; R5’ is H, F, Cl, CH3, OCH3, OCH2CH3, OCHZCHZCHg or OCHFZ; R6 is H, F or Cl; R6/ is H, F or Cl; and R7 is H, F, Cl, OCH3, OCF3, OCHzCHg, OCH(CH3)2 or OCHFZ, provided that R1, R2, and R3 are not simultaneously hydrogen; and that R5, R5, R6, R6, and R7 are not simultaneously hydrogen.

2. The compound or salt according to claim 1, wherein R1 is H, CF3 or Cl.

3. The compound or salt according to claim 1 or 2, wherein R1 is H or CF3.

4. The nd or salt according to any one of claims 1 to 3, wherein R2 is H, CF3 or

5. The compound or salt according to claim 4, wherein R2 is H or CF3.

6. The compound or salt according to any one of claims 1 to 5, wherein R3 is H, CF3, C1 or OCFg.

7. The compound or salt according to claim 6, wherein R3 is H, CF3 or Cl.

8. The compound or salt according to any one of claims 1 to 7, wherein R5 is H.

9. The compound or salt according to any one of claims 1 to 8, n R6 or R is H or

10. The compound or salt according to claim any one of claims 1 to 9, n R7 is F, Cl, OCH3 OI' OCFg.

11. The compound or salt according to claim 10, wherein R7 is F or OCH3.

12. The compound or salt according claim 1, wherein the compound has formula I-D: R2 ,9 M 0/)S \NH2 I-D, wherein, independently for each occurrence: R2 is F, C1, CN, CH3, CF3 or CHFZ; R5 is F, C1, CH3, OCHg, OCHZCHg, ZCHg or OCHFZ; and R7 is F, Cl, OCHg, OCFg, OCH2CH3, OCH(CH3)2 OI' OCHFz.

13. The compound or salt ing to claim 12, wherein R2 is Cl or CF3.

14. The compound or salt according to claim 12 or 13, wherein R5 is F, Cl, CH3 or OCH3.

15. The compound or salt according to any one of claims 12 to 14, wherein R7 is F, Cl, OCH3 OI' OCFg.

16. The compound or salt according to claim 1, wherein the compound has formula LE: M 0/)S \NH2 I-E, wherein, independently for each occurrence: R3 is F, Cl, CN, CF3, OCF3 or CFZCFg; R5 is F, C1, CH3, OCHg, OCHZCHg, OCHZCHZCHg or OCHFZ; and R7 is F, Cl, OCHg, OCFg, 3, OCH(CH3)2 OI' OCHFz.

17. The compound or salt according to claim 16, wherein R3 is Cl, CF3 or OCF3.

18. The compound or salt according to claim 16 or 17, wherein R5 is F, Cl, CH3 or OCH3.

19. The compound or salt according to any one of claims 16 to 18, wherein R7 is F, Cl, OCH3 or OCF3.

20. The compound or salt of claim 1, wherein the compound, or the pharmaceutically acceptable salt f, is selected from the group consisting of: 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2-chlorofluorophenoxy)cyano-N-(3-sulfamoylphenyl)benzamide; 5-chloro(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide; -difluorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; O O HN O F CH3 4-chloro(4-fluorophenoxy)methyl-N-(3-sulfamoylphenyl)benzamide; O O HN O F Cl ro(2-chlorofluorophenoxy)-N-(3-sulfamoylphenyl)benzamide; 4-cyano(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)benzamide; 4-cyano(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 2-(2-chlorofluorophenoxy)cyano-N-(3-sulfamoylphenyl)benzamide; luoromethylphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; O O HN O F OCH3 4-chloro(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 5-chloro(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; ro(2-chlorofluorophenoxy)-N-(3-sulfamoylphenyl)benzamide; 2-(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; O O HN O F CH3 4-chloro(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)benzamide; ro(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)benzamide; 5-fluoro(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)benzamide; 2-(4-methoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-ethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; hlorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2-chlorofluorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; luoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(3-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-chloromethylphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; N-(3-sulfamoylphenyl)(o-tolyloxy)(trifluoromethyl)benzamide; hlorofluorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; -dimethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-isopropoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2-chlorofluorophenoxy)methyl-N-(3-sulfamoylphenyl)benzamide; ulfamoylphenyl)(4-(trifluoromethoxy)phenoxy)(trifluoromethyl)benzamide; 2-(2-chlorofluorophenoxy)(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide; 2-(4-(difluoromethoxy)phenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(3-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; O O HN O OCH3 ethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-ethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2-propoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; ulfamoylphenyl)(o-tolyloxy)(trifluoromethyl)benzamide; 2-(2-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; ethoxymethylphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; O O HN O F3CO N-(3-sulfamoylphenyl)(4-(trifluoromethoxy)phenoxy)(trifluoromethyl)benzamide; 2-(3-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; O O HN O sopropoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; luorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; 2-(2-chlorofluorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; 2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-chloromethylphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; luoromethylphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; N-(3-sulfamoylphenyl)(4-(trifluoromethoxy)phenoxy)(trifluoromethyl)benzamide; 2-(3-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; 2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; O O HN O F O OCF3 difluoromethoxy)phenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; 2-(4-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; hloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; 2-(3-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(3-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-fluorophenoxy)(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide; luoromethoxyphenoxy)(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide; 2-(4-chloromethoxyphenoxy)(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide; 2-(2-chloromethoxyphenoxy)(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide; O O HN O 2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; hlorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; chloro(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; O O HN O OCH3 F Cl 4,5-dichloro(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; O O HN O F Cl 4,5-dichloro(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide; chloro(3-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 4,5-dichloro(4-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 4,5-dichloro(2-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 4,5-dichloro(2-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; O O HN O F Cl chloro(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)benzamide; 4-chloro(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; ro(4-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 4-chloro(2-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 4-chloro(4-isopropoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; luoromethoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; 2-(3-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; luoromethoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; O O HN O OCH3 O CF3 F CF3 2-(5-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; 2-(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; O O HN O O Cl chloro(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide; O O HN O OCH3 O Cl 2,4-dichloro(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; O O HN O O Cl 2,4-dichloro(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)benzamide; 2,4-dichloro-N-(3-sulfamoylphenyl)(4-(trifluoromethoxy)phenoxy)benzamide; chloro(4-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 2,4-dichloro(2-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; and 2-cyclopropyl(3-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; or a pharmaceutically acceptable salt thereof.

21. The nd of claim 1, wherein the compound is selected from the group consisting of: 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; luorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2-chlorofluorophenoxy)cyano-N-(3-sulfamoylphenyl)benzamide; 5-chloro(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide; 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; O O HN O F CH3 4-chloro(4-fluorophenoxy)methyl-N-(3-sulfamoylphenyl)benzamide; O O HN O F Cl ro(2-chlorofluorophenoxy)-N-(3-sulfamoylphenyl)benzamide; 4-cyano(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)benzamide; 4-cyano(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 2-(2-chlorofluorophenoxy)cyano-N-(3-sulfamoylphenyl)benzamide; luoromethylphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; O O HN O F OCH3 ro(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 5-chloro(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 5-chloro(2-chlorofluorophenoxy)-N-(3-sulfamoylphenyl)benzamide; luoromethylphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; O O HN O F CH3 4-chloro(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)benzamide; 5-chloro(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)benzamide; 5-fluoro(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)benzamide; 2-(4-methoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-ethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; hlorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; hlorofluorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(3-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(3-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-chloromethylphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; ulfamoylphenyl)(o-tolyloxy)(trifluoromethyl)benzamide; 2-(2-chlorofluorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; ethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-isopropoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2-chlorofluorophenoxy)methyl-N-(3-sulfamoylphenyl)benzamide; N-(3-sulfamoylphenyl)(4-(trifluoromethoxy)phenoxy)(trifluoromethyl)benzamide; hlorofluorophenoxy)(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide; 2-(4-(difluoromethoxy)phenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; luoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; O O HN O OCH3 2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; thoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2-propoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; N-(3-sulfamoylphenyl)(o-tolyloxy)(trifluoromethyl)benzamide; 2-(2-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; ethoxymethylphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; O O HN O F3CO ulfamoylphenyl)(4-(trifluoromethoxy)phenoxy)(trifluoromethyl)benzamide; 2-(3-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; O O HN O 2-(4-isopropoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; luorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; 2-(2-chlorofluorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; 2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; hloromethylphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(3-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; N-(3-sulfamoylphenyl)(4-(trifluoromethoxy)phenoxy)(trifluoromethyl)benzamide; 2-(3-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; hloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; 2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; O O HN O F O OCF3 2-(2-(difluoromethoxy)phenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; hloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; 2-(3-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethoxy)benzamide; 2-(3-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(3-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; luorophenoxy)(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide; 2-(4-fluoromethoxyphenoxy)(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide; 2-(4-chloromethoxyphenoxy)(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide; hloromethoxyphenoxy)(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide; O O HN O 2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; hloromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide; 4,5-dichloro(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; O O HN O OCH3 F Cl 4,5-dichloro(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; O O HN O F Cl 4,5-dichloro(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide; chloro(3-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 4,5-dichloro(4-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; chloro(2-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 4,5-dichloro(2-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; O O HN O F Cl 4,5-dichloro(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)benzamide; ro(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 4-chloro(4-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 4-chloro(2-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 4-chloro(4-isopropoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; luorophenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; 2-(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; luoromethoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; 2-(2-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; O O HN O OCH3 O CF3 F CF3 2-(5-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; luoromethylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; O O HN O O Cl 2,4-dichloro(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide; O O HN O OCH3 O Cl 2,4-dichloro(4-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; O O HN O O Cl chloro(4-fluoromethylphenoxy)-N-(3-sulfamoylphenyl)benzamide; 2,4-dichloro-N-(3-sulfamoylphenyl)(4-(trifluoromethoxy)phenoxy)benzamide; 2,4-dichloro(4-chloromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; 2,4-dichloro(2-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; and 2-cyclopropyl(3-fluoromethoxyphenoxy)-N-(3-sulfamoylphenyl)(trifluoromethyl)benzamide.

22. A pharmaceutical composition comprising a therapeutically ive amount of the compound or the pharmaceutically acceptable salt f of any one of claims 1 to 20 or the compound of claim 21 and one or more pharmaceutically acceptable carriers or vehicles.

23. A pharmaceutical composition comprising the compound or the pharmaceutically able salt thereof of any one of claims 1 to 20 or the compound of claim 21 and one or more pharmaceutically acceptable carriers or vehicles.

24. Use of the nd or the pharmaceutically acceptable salt thereof of any one of claims 1 to 20, the compound of claim 21 or the pharmaceutical composition according to claim 22 or 23 in the manufacture of a medicament for inhibiting a voltage-gated sodium channel in a subject.

25. The use of claim 24, wherein the voltage-gated sodium channel is Nav1.8.

26. Use of the nd or the pharmaceutically acceptable salt thereof of any one of claims 1 to 20, the compound of claim 21 or the pharmaceutical composition according to claim 22 or 23 in the manufacture of a ment for treating or lessening the severity in a subject of chronic pain, gut pain, athic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, al pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia.

27. The use of claim 26, wherein the gut pain comprises inflammatory bowel disease pain, s disease pain or interstitial cystitis pain.

28. The use of claim 26, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful a; traumatic neuroma; ’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, antiretroviral therapy induced neuralgia; post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

29. The use of claim 28, wherein neuropathic pain comprises idiopathic fiber neuropathy.

30. The use of claim 28, n neuropathic pain comprises post-herpetic neuralgia.

31. The use of claim 26, wherein the musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.

32. The method of claim 31, n musculoskeletal pain comprises osteoarthritis pain.

33. The use of claim 26, wherein the matory pain comprises rheumatoid arthritis pain or vulvodynia.

34. The use of claim 26, wherein the idiopathic pain comprises fibromyalgia pain.

35. The use of claim 26, wherein the medicament is for treating or lessening the severity in the subject of acute pain.

36. The use of claim 35, n the acute pain comprises acute post-operative pain.

37. The use of claim 26, wherein the ment is for treating or lessening the ty in the subject of postsurgical pain.

38. The use of claim 26, wherein the medicament is for treating or lessening the severity in the subject of visceral pain.

39. The use of claim 26, wherein the medicament is for treating or lessening the severity in the subject of neuropathic pain, wherein the neuropathic pain is diabetic neuropathy.

40. Use of the compound or the pharmaceutically acceptable salt thereof of any one of claims 1 to 20, the compound of claim 21 or the pharmaceutical composition according to claim 22 or 23 in the manufacture of a medicament for treating or lessening the severity in a subject of pain.

41. The use according to any one of claims 24 to 40, wherein the ment is to be administered to said t in conjunction with one or more additional therapeutic agents to be administered concurrently with, prior to, or subsequent to treatment with the medicament comprising the compound, pharmaceutically able salt, or pharmaceutical composition. 42. The compound or the pharmaceutically acceptable salt thereof of any one of claims 1 to 20, the compound of claim 21, or the pharmaceutical composition according to claim 22 or 23, for use as a medicament.

42. The compound according to claim 1, ntially as herein described with reference to any one of the examples thereof.