BR112018012298B1 - SULFONAMIDE COMPOUNDS, PHARMACEUTICAL COMPOSITION COMPRISING SAID COMPOUND AND USE THEREOF - Google Patents

Abstract

ALKYL DIHYDROQUINOLINE SULFONAMIDE COMPOUNDS. The present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, which are inhibitors of voltage-gated sodium channels, in particular, Nav1.7. The compounds are useful for treating diseases associated with sodium channel activity, such as pain, cough, and itching disorders. Pharmaceutical compositions containing compounds of the present invention are also provided.

Description

RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62/269,518, filed on December 18, 2015, the specification of which is incorporated herein by reference in its entirety.

FIELD OF INVENTION

[0001] The present invention provides compounds that are inhibitors of voltage-dependent sodium channels (Nav), in particular Nav 1.7, and are useful for the treatment of diseases treatable by inhibition of sodium channels, such as pain disorders. Pharmaceutical compositions containing compounds of the present invention are also provided.

BASICS OF THE INVENTION

[0002] A 2011 Institute of Medicine report estimates that 100 million U.S. adults, about 30% of the population, suffer from chronic pain (C&E News, Bethany Halford, “Changing the Channel,” published on 3- 24). Chronic pain, by definition, involves abnormal electrical addition of neurons in pain pathways: peripheral sensory neurons, spinal cord neurons, neurons in the pain matrix of the brain (e.g., somatosensory cortex, insular cortex, anterior cingulate cortex), and /or neurons in the brain stem. Although the firing of these neurons is modulated and governed by many different receptors, enzymes, and growth factors, in most neurons the rapid upward movement of the electrical spike is produced by the entry of sodium ions through voltage-gated sodium channels (Hille B , Ion Channels of Excitable Membranes. Sinauer Associates, Inc.:Sunderland MA, 3rd Ed. 2001). There are nine different isoforms of voltage-gated sodium channels (Nav 1.1- Nav 1.9), and they have distinct expression patterns in tissues including neurons and cardiac and skeletal muscle (Goldin, A. L, “Resurgence of sodium channel research, ” Ann Rev Physiol 63:871-894, 2001; Wood, J. N. and Boorman, J. “Voltage-gated sodium channel blockers; target validation and therapeutic potential” Curr. Top Med. Chem. 5:529-537, 2005).

[0003] NaV1.1 and NaV1.2 are highly expressed in the brain (Raymond, C. K., et al., J. Biol. Chem. (2004), 279(44):46234-41) and are vital for brain function normal. Some loss of function due to Nav 1.1 mutations in humans has resulted in epilepsy, presumably because these channels are expressed in inhibitory neurons (Yu, F. H., et al., Nat. Neuroscience (2006), 9 (9) 1142-1149). Nav1.1 is also expressed in the peripheral nervous system and inhibition of Nav1.1 in the periphery can provide pain relief. Thus, although Nav1.1 inhibition may provide pain treatment use, it may also be undesirable, possibly leading to anxiety and excess excitability. Nav1.3 is primarily expressed in the fetal central nervous system, and expression was found to be upregulated after nerve injury in rats (Hains, B. D., et al., J. Neuroscience (2030) 23(26):8881-8892). Nav1.4 is mainly expressed in skeletal muscle. Mutations of the gene and its product have a significant impact on muscle function, including paralysis (Tamaoka A., Internal Medicine (2003), (9):769-770). Nav1.5 is mainly expressed in cardiac myocytes, including atria, ventricles, sinoatrial node, atrioventricular node, and cardiac Purkinje fibers. The rapid upward course of the cardiac action potential and the rapid conduction of the impulse through cardiac tissue are due to the opening of the Nav1.5 channel. Mutations of the Nav1.5 channel have resulted in arrhythmic syndromes, including QTc prolongation, Brugada syndrome (BS), sudden unexpected nocturnal death syndrome (SUNDS), and sudden infant death syndrome (SIDS) (Liu, H., et al. , Am. J. Pharmacogenomics (2003), 3(3):173-179). Nav1.6 is a widely distributed voltage-gated sodium channel expressed throughout the central and peripheral nervous system. Nav1.8 is mainly expressed in sensory ganglia of the peripheral nervous system, such as the dorsal root ganglia. There are no mutations in Nav1.8 identified that produce varying pain responses in humans. Nav1.8 differs from most neuronal isotopes of Nav in that it is insensitive to inhibition by tetrodotoxin. Nav1.9, similar to Nav1.8, is also insensitive to tetrodotoxin, a sodium channel expressed primarily in dorsal root ganglia neurons (Dib-Hajj, S. D., et al. Proc. Natl. Acad. Sci. USA (1998 ), 95(15):8963-8968).

[0004] Recent evidence from several independent genetic studies has shown that the tetrodotoxin-sensitive voltage-gated sodium ion channel Nav 1.7 (SCN9A) is required to detect pain. Rare genetic forms of severe chronic pain, Primary Erythromelalgia and Paroxysmal Extreme Pain Disorder, result from mutations that increase the activity of Nav 1.7 (Fertleman C. R., Baker M. D., Parker K. A., Moffatt S., et al. “SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes,” Neuron 52:767-774, 2006; Yang Y., Wang Y., Li S, et al., “Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia," J. Med. Genet. 41:171-174, 2004; Drenth J. P. H., te Morsche R. H. M., Guillet G., Taieb A., et al., "SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels,” J Invest Dermatol 124:1333-1338). On the other hand, two separate clinical studies have determined that the root cause of the genetic disorder Congenital Indifference to Pain (CIP) is a loss of function of Nav 1.7 through mutations that truncate the protein and destroy function (Cox J. J.,Reimann F, Nicholas A. K., et al. “An SCN9A channelopathy causes congenital inability to experience pain,” Nature 444:894-898, 2006; Goldberg Y. P., MacFarlane J., MacDonald M. L., Thompson J., et al. “Loss-of-function mutations in the Nav1.7 gene underlies congenital indifference to pain in multiple human populations,” Clin Genet 71:311-319, 2007). The disorder is inherited in a Mendelian recessive manner with 100% penetration. The phenotype associated with CIP is extreme: Affected individuals have reported experiencing painless burns, childbirth, appendicitis, and bone fractures, as well as having insensitivity to clinical measures of pain such as pin prick or tendon pressure. However, sensory, motor, autonomic functions, and other measures are normal, with the only reported abnormality being anosmia (inability to smell). These studies indicate that among the many possible targets in the pain pathway, Nav 1.7 governs one or more control points critical for pain perception.

[0005] Non-selective sodium channel inhibitors such as lidocaine, mexiletine and carbamazepine show clinical efficacy in chronic pain, including neuropathic pain, but are limited in dose and use, probably due to effects on sodium channels outside the pain pathway. Lidocaine is a local anesthetic used by doctors for minor surgeries. Dentists use novocaine. However, these compounds do not distinguish between the various subtypes of sodium channels, making them unsuitable for use as systemic analgesics. "If you give a drug that blocks Nav1.7 but also blocks Nav1.5, the patient will die of heart failure," says Glenn F. King, a professor at the University of Queensland in Australia who studies poisons that block ion channels. “It will be a completely painless death, but the patient will die anyway.” Thus, selectivity for Nav1.7 is desired, particularly over Nav1.5. Researchers have adapted their efforts to find a molecule that inhibits or blocks the activity of just Nav1.7. Compounding this problem, the identity, all locations, all functions and/or tertiary structures of each subtype of voltage-gated sodium channel proteins are not known or completely understood.

[0006] Consequently, several researchers are trying to identify small molecule inhibitors of Nav1.7. For example, Chafeev et al. disclose a spiro-oxindole compound for the treatment and/or prevention of sodium channel-mediated diseases, such as pain, in U.S. Patent No. 8,101,647. International Publications WO 2013/134518 and WO 2014/201206 disclose sulfonamide derivatives that are different from the sulfonamide derivatives of the present invention. Thus, there is a need to identify selective Nav1.7 inhibitors in place of at least Nav1.5 to treat pain. The present invention provides compounds that are selective inhibitors of Nav 1.7. instead of at least Nav1.5.

SUMMARY OF THE INVENTION

[0007] In embodiment 1, the present invention provides a compound of formula (I), an enantiomer, diastereoisomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is a (a) C1-8alq wherein said C1-8alq is substituted by 0, 1, 2 or 3 selected hydroxy groups, -OC1-4alq, -NH2, -NHC1-4alq, -OC(= O)C1-4alq, or -N(C1-4alq)C1-4alq; or (b) C1-8haloalq; R2 is H, halo, C1-6alq, or C1-6haloalq; R3 is Ci-6alq, Ci-6haloalq, -O-Ci—6alq, or -CN; R4 is a 5- to 6-membered heteroaryl; Each of R6 and R7 is hydrogen; and Each of R5a; R5b; R5c; R5d; and R5e is independently hydrogen or halo.

[0008] In embodiment 2, the current invention provides compounds of formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, in which R1 is C4-8alq or C1-6haloalq, in that said C1-6haloalq is C1-6fluoroalkyl.

[0009] In embodiment 3, the present invention provides compounds of formula (I), an enantiomer, diastereomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from -CH2-CF3, -CH2 -CH2-CF3, -CH2-CH2-CH2-CF3, -CH2-CH(CH3)-CF3, -CH2-CF2- CF3, -CH2-C(CH3)2-CF3, -C(CH3)2-CH2 -CF3, -CF2-CH2-CF3, or -CH2-CH2-CHF2.

[0010] In embodiment 4, the present invention provides compounds of Formula (I), an enantiomer, diastereomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R2 is H, fluorine, chlorine, methyl, CF3 , CHF2, or CH2F.

[0011] In embodiment 5, the present invention provides compounds of Formula (I), an enantiomer, diasteomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R2 is H or fluorine. In the submodality of modality 5, R2 is fluorine.

[0012] In embodiment 6, the present invention provides compounds of Formula (I), an enantiomer, diasteomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R3 is methoxy.

[0013] In embodiment 7, the present invention provides compounds of Formula (I), an enantiomer, diasteoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R4 is a 5-membered heteroaryl.

[0014] In embodiment 8, the present invention provides compounds of Formula (I), an enantiomer, diasteoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R4 is a 6-membered heteroaryl.

[0015] In embodiment 9, the present invention provides compounds of Formula (I), an enantiomer, diasteoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl or pyrimidinyl. In a submodality of embodiment 8, R4 is isoxazolyl or pyridazinyl. In another embodiment of embodiment 8, R4 is isoxazolyl.

[0016] In embodiment 10, the present invention provides compounds of Formula (I), an enantiomer, diasteomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each of R5a; R5b; R5c; R5d;e R5eis hydrogen.

[0017] In embodiment 11, the present invention provides compounds of Formula (I), an enantiomer, diasteoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is: what is:

[0018] In embodiment 11a, the present invention provides a compound of formula (I), which is 1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-3- isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide, or an enantiomer, diastereomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0019] In modality 11b, the present invention provides a compound of formula (I), which is 1-(5-chloro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-3- isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide, or an enantiomer, diasteomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0020] In modality 11c, the present invention provides a compound of formula (I), which is 1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-2-oxo- N-3-pyridazinyl-1,2-dihydro-6-quinolinesulfonamide, or an enantiomer, diasteomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0021] In modality 11d, the present invention provides a compound of formula (I), which is 1-(5-fluoro-2-methoxy-4-((2R)-3,3,3-trifluoro-2-methylpropyl )phenyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide, or an enantiomer, diastereomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0022] In modality 11e, the present invention provides a compound of formula (I), which is 1-(5-fluoro-2-methoxy-4-((2S)-3,3,3-trifluoro-2-methylpropyl )phenyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide, or an enantiomer, diastereomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0023] In modality 11f, the present invention provides a compound of formula (I), which is 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)- N-3- isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide, or an enantiomer, diastereomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0024] In modality 11g, the present invention provides a compound of formula (I), which is 1-(5-fluoro-2-methoxy-4-(4,4,4-trifluorobutyl)phenyl)- N-3- isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide, or an enantiomer, diastereomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0025] In modality 11h, the present invention provides a compound of formula (I), which is 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)- N-3- isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide, or an enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0026] In modality 11i, the present invention provides a compound of formula (I), which is 1-(5-fluoro-2-methoxy-4-(2,2,3,3,3-pentafluoropropyl)phenyl)- N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, or an enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0027] In embodiment 11j, the present invention provides a compound of formula (I), which is 1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoro-2,2-dimethylpropyl)phenyl )-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, or an enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0028] In modality 11k, the present invention provides a compound of formula (I), which is 1-(5-fluoro-2-methoxy-4-(4,4,4-trifluoro-2-methylbutan-2-yl )phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, or an enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0029] In embodiment 11l, the present invention provides a compound of formula (I), which is 1-(5-fluoro-2-methoxy-4-(1,1,3,3,3-pentafluoropropyl)phenyl)- N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, or an enantiomer, diastereoisomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0030] In embodiment 12, the present invention provides a P atropisomer of each individual compound, independently, or a mixture thereof, or pharmaceutically acceptable salts thereof, recited in embodiments 11a to 11l.

[0031] In embodiment 13, the present invention provides an atropisomer M of each individual compound, independently, or a mixture thereof, or pharmaceutically acceptable salts, recited in embodiments 11a to 11l.

[0032] In embodiment 14, the present invention provides pharmaceutical compositions comprising a compound, an enantiomer, diasteomer, atropisomer, or a mixture thereof, or acceptable pharmaceutical salts, according to any of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11a-11l, 12 and 13, and a pharmaceutically acceptable excipient.

[0033] In embodiment 15, the present invention provides methods of treating pain, coughing, or itching, the methods comprising administering to a patient in need of an effective therapeutic amount of a compound, an enantiomer thereof, diastereoisomer, atropisomer, or a mixture thereof, or pharmaceutically acceptable salts thereof, according to any of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11a-11l, 12 and 13.

[0034] In modality 16, the current invention provides methods of modality 15 in which the pain is selected from chronic pain, acute pain, neuropathic pain, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, pain associated with cancer, cancer , or pain associated with diabetes.

[0035] In modality 17, the current invention provides methods of modality 15 where the cough is selected from post-viral cough, viral cough, or acute viral cough. See Dib-Hajj. et. al. “The NaV1.7 sodium channel: from molecule to man”, Nature Reviews Neuroscience (2013), 14, 49-62.

DETAILED DESCRIPTION OF THE INVENTION

[0036] The present invention provides compounds of Formula (I), as defined above, an enantiomer, diastereoisomer, atropisomer, or a mixture thereof, or pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions that include a compound of formula (I), compound, an enantiomer, diastereomer, atropisomer, or a mixture thereof, or pharmaceutically acceptable salts, and methods of treating diseases and/or conditions, such as pain , using compounds of formula (I), compounds, enantiomers, diastereoisomers, atropisomers, or a mixture thereof, or their pharmaceutically acceptable salts.

[0037] The term "Ca-ßalq” means an alkyl group comprising a minimum of a and a maximum of ß carbon atoms in a branched or linear relationship or any combination of the two, where a and ß represent integers. A designation of C0alq indicates a direct bond. Examples of C1-6alq include, but are not limited to, the following

[0038] The term “halo” or “halogen” means a halogen atom selected from F, Cl, Br or I.

[0039] The term "Ca-ßhaloalkyl" means an alk group, as defined herein, in which at least one of the hydrogen atoms has been replaced by a halogen atom, as defined herein. Common Ca-ßhaloalq groups are C1-3fluoroalq. An example of a common C1-3fluoroalq group is _CF3.

[0040] The term "heteroatom", as used herein, means an atom of oxygen, nitrogen or sulfur.

[0041] The term "aryl" means a cyclic aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Common aryl groups are rings of six to thirteen members.

[0042] The term "heteroaryl" means a cyclic aromatic hydrocarbon in which one or more carbon atoms of an aryl group have been replaced by a heteroatom. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, indolyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, naphthyridinyl, quinoxalinyl, isothiazolyl and benzo[b]thienyl. Common heteroaryl groups are five- to thirteen-membered rings that contain 1 to 4 heteroatoms. Heteroaryl groups which are five- and six-membered rings containing 1 to 3 heteroatoms are particularly common.

[0043] The term "pharmaceutically acceptable salt" means a salt prepared by conventional means and is known to those skilled in the art. "Pharmacologically acceptable salts" include basic salts of organic and inorganic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. For additional examples of "pharmacologically acceptable salts", and Berge et al., J. Pharm. Sci. 66:1 (1977).

[0044] The term “substituted” means that a hydrogen atom in a molecule or group is replaced by a group or atom. Typical substituents include: halogen, C1-8alkyl, hydroxyl, C1-8alkoxy, -NRxRx, nitro, cyano, halo or perhaloC1-8alkyl, C2-8alkenyl, C2-8alkynyl, -SRx, -S(=O)2Rx, -C (=O)ORx, -C(=O)Rx, where each Rx is independently hydrogen or C1-C8 alkyl. Note that when the substituent is -NRxRx, the Rx groups can be joined with the nitrogen atom to form a ring.

[0045] A group or atom that replaces a hydrogen atom is also called a substituent.

[0046] Any particular molecule or group may have one or more substituents depending on the number of hydrogen atoms that can be replaced.

[0047] The term "unsubstituted" means a hydrogen atom in a molecule or group. The term “substituted” means that a hydrogen atom in a molecule or group is replaced by a group or atom. Typical substituents include: halogen, C1-8alkyl, hydroxyl, C1-8alkoxy, -NRxRx, nitro, cyano, halo or perhaloC1-8alkyl, C2-8alkenyl, C2- salkynyl, -SRx, -S(=O)2Rx, -C (=O)ORx, -C(=O)Rx, where each Rx is independently hydrogen or C1-C8alkyl. Note that when the substituent is -NRxRx, the Rx groups can be joined with the nitrogen atom to form a ring.

[0048] The symbol "-" represents a covalent bond and can also be used in a radical group to indicate the connection point to another group. In chemical structures, the symbol is commonly used to represent a methyl group in a molecule.

[0049] The term "leaving group" generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile, or by a metallic agent such as boronic acids or boronates under catalyzed coupling conditions. by transition metals. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates, and the like. Preferential labile groups are indicated in this document where applicable.

[0050] The term "protecting group" generally refers to groups known in the art, which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from subjecting undesirable reactions, such as nucleophilic , electrophilic substitution, oxidation, reduction and the like. Preferred protection groups are indicated in this document where applicable. Examples of amino acid protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples of aralkyl include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which may be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts such as phosphonium salt and ammonium. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples of substituted cycloalkenylalkyl or cycloalkylenylalkyl radicals, preferably having 6 to 10 carbon atoms, include, but are not limited to, methyl cyclohexenyl and the like. Acceptable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthaloyl and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups may also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl and the like, and these heterocyclic groups may further include aryl and adjacent cycloalkyl. Furthermore, heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl. Amino acid groups can also be protected against undesirable reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like. Many of the protective amino acid groups are also suitable for protecting carboxy, hydroxy, and mercapto groups. For example, aralkyl groups. Alkyl groups are also groups suitable for protecting hydroxy and mercapto groups, such as tert-butyl.

[0051] Protecting groups are removed under conditions that will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removing a protecting group, such as removing a benzyloxycarbonyl group by hydrogenolysis using palladium on carbon in a suitable solvent system such as an alcohol, acetic acid and the like or mixtures thereof. A tert-butoxycarbonyl protecting group can be removed using an organic or inorganic acid, such as HCl or trifluoroacetic acid, in an appropriate solvent system, such as dioxane or methylene chloride. The resulting amino salt can be readily neutralized to yield the free amine. Protective carboxy group, such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.

[0052] Note that the compounds of the invention may contain groups that may exist in tautomeric forms, such as cyclic and acyclic amidine and guanidine groups, aromatic heterocyclyl groups with substituted heteroatoms (Y' = O, S, NR) and the like. , which are illustrated in the following examples: and although a form is called, described, displayed or claimed herein, all tautomeric forms are intended to be inherently included in such name, description, display and/or claim.

[0053] Examples of compounds of this invention are also contemplated by this invention. A prodrug is an active or inactive compound, which is chemically modified through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention after administration of the prodrug to a patient. The suitability and techniques involved in making and using the examples are well known to those skilled in the art. For a general discussion of examples involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters such as alkyl (e.g., methyl, ethyl), cycloalkyl (e.g., cyclohexyl), aralkyl (e.g., benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (e.g., pivaloyloxymethyl). . Amines have been masked as substituted arylcarbonyloxymethyl derivatives that are cleaved by esterases in vivo, releasing free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Likewise, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich base hydroxamic acid prodrugs, their preparation, and use.

[0054] The term "therapeutically effective amount" means an amount of a compound, which improves, attenuates or eliminates one or more symptoms of a specific disease or condition or prevents or delays the onset of one of more symptoms of a specific disease or condition .

[0055] The term "patient" means animals, such as dogs, cats, cows, horses, sheep and humans. Specific patients are mammals. The term patient includes males and females.

[0056] The term "pharmaceutically acceptable" means that the referenced substance, such as a compound of Formula I, or a salt of a compound of Formula I, or a formulation containing a compound of Formula I, or a particular excipient, are suitable for administration to a patient.

[0057] The terms "treating", "treating" or "treatment" and the like include preventive (e.g., prophylactic) and palliative treatment.

[0058] The term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), that is normally included in the formulation and/or administration to a patient.

[0059] The compounds of the present invention are administered to a patient in a therapeutically effective amount. The compounds may be administered alone or as part of a pharmaceutically acceptable composition or formulation. Furthermore, the compounds or compositions may be administered all at once, such as, for example, by a bolus injection, several times, such as by a series of tablets, or distributed substantially uniformly over a period of time. , such as using transdermal delivery. It should also be noted that the dose of the compound may vary over time.

[0060] Furthermore, the compounds of the present invention can be administered alone, in combination with other compounds of the present invention or with other pharmaceutically active compounds. The other pharmaceutically active compounds may be intended to treat the same disease or condition as the compounds of the present invention or a different disease or condition. If the patient is to receive or is receiving multiple pharmaceutically active compounds, the compounds may be administered simultaneously or sequentially. For example, in the case of tablets, the active compounds can be found in one tablet or in separate tablets, which can be administered all at once or sequentially in any order. Furthermore, it must be recognized that the compositions can be of different shapes. For example, one or more compounds may be administered by a tablet, while another is administered by injection or orally as a syrup. All combinations, delivery methods and administration sequences are contemplated.

[0061] The compounds of the present invention can be used in the manufacture of a medicine for the treatment of a disease and/or condition mediated by Nav 1.7, such as pain, chronic cough or itching.

[0062] Pain is typically divided into primary types: chronic and acute pain based on the duration of the pain. Typically, chronic pain lasts more than 3 months. Examples of chronic pain include pain associated with rheumatoid arthritis, osteoarthritis, lumbosacral radiculopathy, or cancer. Chronic pain also includes idiopathic pain, which is pain that has no identified cause. An example of idiopathic pain is fibromyalgia.

[0063] Another type of pain is nociceptive pain. Nociceptive pain is caused by the stimulation of peripheral nerve fibers that respond to highly noxious events, such as thermal, mechanical or chemical stimuli.

[0064] Yet another type of pain is neuropathic pain. Neuropathic pain is pain caused by damage or disease affecting a part of the nervous system. Phantom limb pain is a type of neuropathic pain. In phantom limb pain, the body detects pain from a part of a body that no longer exists. For example, a person who has had a leg amputated may experience leg pain even though the leg is no longer there.

[0065] In one embodiment of the treatment methods provided by the present invention using the compounds of Formula (I), or their pharmaceutically acceptable salts, the disease is chronic pain. In another aspect, chronic pain is associated with, but is not limited to, postherpetic neuralgia (shingles), rheumatoid arthritis, osteoarthritis, diabetic neuropathy, complex regional pain syndrome (CRPS), cancer or chemotherapy-induced pain, chronic pain, phantom limb pain, trigeminal neuralgia, HIV-induced neuropathy, cluster headache disorders, and migraine, primary erythromelalgia, and paroxysmal extreme pain disorder. Other indications for Nav 1.7 inhibitors include, but are not limited to, depression (Morinville et al., J Comp Neurol., 504:680-689 (2007)), bipolar and other CNS disorders (Ettinger and Argoff, Neurotherapeutics, 4: 75-83 (2007)), epilepsia:ibid., and Gonzalez, Termin, Wilson, methods and principles in Medicinal Chemistry, 29:168-192 (2006)), multiple sclerosis (Waxman, Nature Neurosci. 7:932 -941 (2006)), Parkinson's (Do and Bean, Neuron 39:109-120 (2003); Puopolo et al., J. Neurosci. 27: 645-656 (2007)), restless legs syndrome, ataxia, tremor , muscle weakness, dystonia, tetanus (Hamann M., et. al. Exp. Neurol. 184 (2): 830-838, 2003), anxiety, depression: McKinney B. C, et. al., Genes Brain Behavior. 7 (6): 629-638, 2008), learning and memory, cognition (Woodruff-Pak D. S., et. al., Behav. Neurosci. 120 (2): 229-240, 2006), cardiac arrhythmia and fibrillation, contractility , congestive heart failure, sick sinus syndrome (Haufe V., et. Al., J Mol. Cell Cardiol. 42 (3): 469-477, 2007), schizophrenia, neuroprotection after stroke, drug and alcohol abuse (Johannessen L. C., CNS Drugs 22(1)27-47, 2008), Alzheimer's (Kim D. Y., et. al., Nat. Cell. Biol. 9 (7): 755-764, 2007) and cancer (Gillet L. , et al., J Biol Chem 2009, January 28 (epub)).

[0066] Another aspect of the invention relates to a method of treating acute and/or chronic inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed vascular and non-vascular syndromes, tension headache , general inflammation, arthritis, rheumatic diseases, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory diseases, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentiation pain syndromes, asthma, epithelial tissue injury or dysfunction, herpes simplex, visceral motility disorders in respiratory, genitourinary, gastrointestinal or vascular regions , wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcer, diarrhea, gastric lesions induced by necrotizing agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders comprising the step of administering a compound according to the present invention. A preferred type of pain to be treated is chronic neuropathic pain. Another preferred type of pain to be treated is chronic inflammatory pain.

[0067] In another aspect of the invention, the compounds of the present invention can be used in combination with other compounds that are used to treat pain. Examples of such other compounds include, but are not limited to, aspirin, celecoxib, hydrocodone, oxycodone, codeine, fentanyl, ibuprofen, ketoprofen, naproxen, acetaminophen, gabapentin, and pregabalin. Examples of drug classes containing compounds that can be used in combination with the compounds of the present invention include non-steroidal anti-inflammatory compounds (NSAIDS), steroid compounds, cyclooxygenase inhibitors and opioid analgesics.

[0068] The compounds of the present invention can also be used to treat diabetes, obesity and/or to facilitate weight loss.

[0069] The compounds of the present invention can be used in combination with other pharmaceutically active compounds. Note that the term "pharmaceutically active compounds" may include biological products such as proteins, antibodies and peptibodies.

[0070] Since one aspect of the present invention contemplates the treatment of disease/conditions with a combination of pharmaceutically active compounds that can be administered separately, the invention further relates to the combination of separate pharmaceutical compositions in the form of a kit. The kit comprises two separate pharmaceutical compositions: a compound of the present invention, and a second pharmaceutical compound. The kit comprises a container for containing the separate compositions, such as a split bottle or split foil package. Additional examples of containers include syringes, boxes, and bags. Typically, the kit comprises instructions for using the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the physician or attending veterinarian.

[0071] An example of this kit is a so-called honeycomb packaging. Honeycomb packaging is well known in the packaging industry and is widely used for packaging pharmaceutical unit dosage forms (tablets, capsules and the like). Honeycomb packaging generally consists of a laminated sheet of relatively rigid material covered with a sheet of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic sheet. The recesses are the size and shape of the tablets or capsules to be packaged. Next, the tablets or capsules are placed in the recesses and the laminated sheet of relatively rigid material is sealed against the plastic sheet on the face of the sheet that is opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic sheet and the laminated sheet. Preferably, the strength of the laminated sheet is such that the tablets or capsules can be removed from the blister packaging by applying manual pressure to the recesses, whereby an opening is formed in the laminated sheet in place of the recess. The tablet or capsule can then be removed through said opening.

[0072] It may be desirable to provide a memory aid in the kit, for example, in the form of numbers next to the tablets or capsules, whereby the numbers correspond to the days of the regimen which tablets or capsules are to be taken in the specified manner. Another example of this memory aid is a calendar printed on the card, for example, as follows, "First week, Monday, Tuesday, etc., etc. Second week, Monday, Tuesday, . . . " etc. Other variations of memory aids will be readily evident. A "daily dose" may be a single pill or capsule or multiple pills or capsules to be taken on a given day. Furthermore, a daily dose of a compound of the present invention may consist of one tablet or capsule, while a daily dose of the second compound may consist of several tablets or capsules and vice versa. The memory aid should reflect this and assist in the correct administration of active agents.

[0073] In another specific embodiment of the invention, a dispenser designed to dispense daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory aid to further facilitate compliance with the regimen. An example of this memory aid is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of such a memory aid is a battery-powered microchip memory coupled to a liquid crystal reader, or audible reminder signal that, for example, reads the date the last daily dose was taken and/or reminds you of a when the next dose must be taken.

[0074] The compounds of the present invention and other pharmaceutically active compounds, if desired, can be administered to a patient either orally, rectally, parenterally (e.g., intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, local (e.g. powders, ointments or drops) or as a mouth or nasal spray. All methods that are used by those skilled in the art to administer a pharmaceutically active agent are contemplated.

[0075] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0076] These compositions may also contain adjuvants, such as preserving, humidifying and dispersing agents. Contamination by microorganisms can be avoided by the addition of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of injectable pharmaceutical compositions can be caused by the use of absorption delaying agents, for example, aluminum monostearate and gelatin.

[0077] Solid dosage forms for oral administration include capsules, tablets, powders and granules. In such solid dosage forms, the active compound is mixed with at least one usual inert excipient (or carrier), such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, such as, for example, starches, lactose, sucrose, mannitol and silicic acid; (b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, such as, for example, glycerol; (d) disintegrating agents, such as, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution retardants, such as paraffin; (f) absorption accelerators, such as, for example, quaternary ammonium compounds; (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin and bentonite; and (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules and tablets, the dosage forms may also comprise buffering agents.

[0078] Solid compositions of a similar type can also be used as fillers in soft or hard gelatin capsules filled using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

[0079] Solid dosage forms, such as tablets, tablets, capsules, pills and granules, can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and may also be of such composition that they release the active compound or compounds in a particular part of the intestinal tract in a delayed manner. Examples of incorporated compositions that can be used are polymeric substances and waxes. The active compounds may also be in microencapsulated form, if appropriate, with one or more of the excipients mentioned above.

[0080] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and seed oil of sesame, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, or mixtures of these substances, and the like.

[0081] In addition to these inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. Suspensions, in addition to the active compound, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances. , and the like.

[0082] Compositions for rectal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature common, but liquids at body temperature, and therefore melt in the rectum or vaginal cavity and release the active component.

[0083] Dosage forms for topical administration of a compound of the present invention include ointments, powders, sprays and inhalants. The active compound or suitable compounds are mixed under sterile conditions with a physiologically acceptable carrier, and any preservatives, buffers or pressurizers that may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

[0084] The compounds of the present invention can be administered to a patient at dosage levels ranging from about 0.1 to about 3,000 mg per day. For a normal adult human with a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight is normally sufficient. The specific dosage and dosage range that can be used depend on a number of factors, including the patient's requirements, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. Determining optimal dosage ranges and dosages for a particular patient is within the ordinary skill of the art.

[0085] The compounds of the present invention can be administered as pharmaceutically acceptable salts, co-crystals, esters, amides or prodrugs. The term "salts" refers to inorganic and organic salts of compounds of the present invention. Salts may be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its base or free acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glyco salts. -heptonate, lactobionate and laurylsulfonate, and the like. Salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J Pharm Sci, 66:1-19 (1977).

[0086] Examples of pharmaceutically acceptable esters of the compound of the present invention include C1-C8 alkyl esters. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylakyl esters such as benzyl. C1-C4 alkyl esters are commonly used. Esters of the compounds of the present invention can be prepared according to methods that are well known in the art.

[0087] Examples of pharmaceutically acceptable amides of the compounds of the present invention include ammonia-derived amides, C1-C8 primary alkylamines, and C1-C8 secondary dialkylamines. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycloalkyl group containing at least one nitrogen atom. Ammonia-derived amides, C1-C3 primary alkylamines, and C1-C2 secondary dialkylamines are commonly used. The amides of the compounds of the present invention can be prepared according to methods well known to those skilled in the art.

[0088] The term "prodrug" means compounds that are transformed in vivo to produce a compound of the present invention. Transformation can occur by several mechanisms, such as through hydrolysis in the blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0089] To illustrate, if the compound of the invention contains a carboxylic acid functional group, a prodrug may comprise an ester formed by replacing the hydrogen atom of the acid group with a group, such as (C1-alkyl C8, (C2-C12) alkanoyloxymethyl, 1-(alkanoyloxy) ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy) ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 atoms carbon, 1-(alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms carbon, 1-(N-(alkoxycarbonyl) aminomethyl having from 4 to 10 carbon atoms, 3-phthalidil, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N-(C1-C2) alkylamino (C2 -C3) alkyl (such as ß-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino (C2- 3) alkyl.

[0090] Similarly, if a compound of the present invention comprises an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as (C1-C6) alkanoyloxymethyl, 1 - ( (C1-C6) alkanoyloxy) ethyl, 1-methyl-1 - ((C1-C6) alkanoyloxy) ethyl, (C1-C6) alkoxycarbonyloxymethyl, N- (C1-C6) alkoxycarbonylaminomethyl, succinoyl, (C1-C6) alkanoyl, a-amino (C1-C4) alkanoyl, arylacyl and a-aminoacyl, or a-aminoacyl- a-aminoacyl, where each a-aminoacyl group is independently selected from naturally occurring acids L-amino acids, -P(O) (OH)2, -P (O) (O (C1-C6) alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group from the hemiacetal form of a carbohydrate).

[0091] Furthermore, if a compound of the present invention comprises a sulfonamide moiety, a prodrug can be formed by replacing the sulfonamide N(H) with a group such as -CH2P(O)(O(C1-C6) alkyl)2 or -CH2OC(O)(C1-C6)alkyl.

[0092] The compounds of the present invention also include tautomeric forms of prodrugs.

[0093] The compounds of the present invention may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds, as well as mixtures thereof, including racemic mixtures, form part of the present invention. Furthermore, the present invention contemplates all geometric and positional isomers. For example, if the compound contains a double bond, both cis and trans forms (designated as S and E, respectively), as well as mixtures, are contemplated.

[0094] The mixture of stereoisomers, such as diastereomeric mixtures, can be separated into their individual stereochemical components based on their physicochemical differences by known methods, such as chromatography and/or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reacting with an appropriate optically active compound (e.g., an alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. .

[0095] Compounds of general formula (I) can also exist in the form of atropisomers. Atropisomers are compounds with identical structural formulas, but which have a particular spatial configuration resulting from a restricted rotation around a single bond, due to an important steric hindrance on both sides of this single bond. Atropisomerism is independent of the presence of stereogenic elements, such as an asymmetric carbon. The terms "P atropisomer" or "M atropisomer" are used here to be able to clearly name two atropisomers of the same pair. For example, the following compound from Intermediate B1, Step 1, with the structure below, can be separated into the pair of P and M atropisomers through a chiral column:

[0096] The compounds of the present invention can exist in unsolvated forms, as well as solvated with pharmaceutically acceptable solvents, such as water (hydrate), ethanol and the like. The present invention contemplates and encompasses both solvated and unsolvated forms.

[0097] It is also possible that compounds of the present invention may exist in different tautomeric forms. All tautomers of the compounds of the present invention are contemplated. For example, all tautomeric forms of the tetrazole moiety are included in this invention. Furthermore, for example, all keto-enol or imine-enamine forms of the compounds are included in this invention. Other examples of tautomerism are the following:

[0098] Those skilled in the art will recognize that the names and structures of the compounds contained herein may be based on a specific tautomer of a compound. Although the name or structure for only a particular tautomer may be used, it is intended that all tautomers are encompassed by the present invention unless otherwise indicated.

[0099] The present invention is also intended to cover compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion and the like. It is also contemplated that the compounds of the present invention can be synthesized using a combination of in vitro and in vivo techniques.

[00100] The present invention also includes isotopically labeled compounds, which are identical to those reported herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or number of mass generally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 16O, 17O, 31P, 32P, 35S, 18F , and 36Cl. In another aspect, the compounds of the present invention contain one or more deuterium (2H) atoms instead of one or more hydrogen atoms.

[00101] Compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example, those in which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated isotopes, i.e., 3H, and carbon-14, i.e., 14C, are particularly preferred for their ease of preparation and detection. Furthermore, substitution with heavier isotopes, such as deuterium, i.e., 2H, may generate certain therapeutic advantages that result from greater metabolic stability, e.g., longer in vivo half-life or lower dosage requirements, and consequently may be preferred in some circumstances. The isotopically labeled compounds of the present invention can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[00102] The compounds of the present invention can exist in various solid states, including crystalline states and as an amorphous state. The different crystalline states, also called polymorphs, and the amorphous states of the present compounds are contemplated as part of this invention.

[00103] All patents and other publications referred to in this document are incorporated in their entirety by reference.

[00104] The examples presented below illustrate specific embodiments of the present invention. These examples are intended to be representative and are not intended to limit the scope of the claims in any way.

[00105] Note that when one percent (%) is used with respect to a liquid, it is one percent by volume with respect to the solution. When used with a solid, that is the percentage with respect to the solid composition. Materials obtained from commercial suppliers were typically used without further purification. Reactions involving air- or moisture-sensitive reagents were typically carried out under a nitrogen or argon atmosphere. Purity was measured using a high performance liquid chromatography (HPLC) system with UV detection at 254 nm and 215 nm (System A:Agilent Zorbax Eclipse XDB-C8 4.6 x 150 mm, 5 µm, 5 to 100% CH3CN in H2O with 0.1% TFA for 15 min at 1.5 mL/min; System B:Zorbax SB-C8, 4.6 x 75 mm, 10 to 90% CH3CN in H2O with 0.1% formic acid for 12 min at 1.0 mL/min) (Agilent Technologies, Santa Clara, CA). Silica gel chromatography was generally performed with prepackaged silica gel cartridges (Biotage, Uppsala, Sweden or Teledyne-Isco, Lincoln, NE). 1H NMR spectra were recorded on a Bruker AV-400 (400 MHz) spectrometer (Bruker Corporation, Madison, WI) or a Varian (Agilent Technologies, Santa Clara, CA) 400 MHz spectrometer at room temperature. All protons observed are referred to as parts per million (ppm) of tetramethylsilane (TMS) or other internal reference in the appropriate solvent indicated. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants, and number of protons. Low-resolution mass spectral (MS) data were determined on an Agilent 1100 Series LC/MS (Agilent Technologies, Santa Clara, CA) with UV detection at 254 nm and 215 nm and a low resonance absorption (ESI) mode. .

SYNTHETIC EXAMPLES

[00106] The following list of abbreviations used or commonly used throughout the specification represents the following and should aid in understanding the invention:

[00107] The following preparations of compounds of Formula (I) and intermediate compounds are given to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

[00108] INTERMEDIATE A1: RACEMIC PERFLUORPHENIL 1- (4-BROMO-5-FLUORINE-2-METHOXYPHENYL)-2-OXO-1,2-DIHYDRO 6-SULFONATE

STAGE 1:4-BROMO-2-IODOANILINE

[00109] To a solution of 4-bromo-aniline (500 g, 2.90 mol, 2.0 equiv, Saibain Chem) in cyclohexane (2.5 L) was added iodine (368 g, 1.45 mol, 1.0 equiv. Qualigens) and the mixture was heated to 50 °C. After 30 min, the reaction mixture became homogeneous. 30% aqueous hydrogen peroxide solution (250 mL, Spectrochem) was added to the reaction mixture. The reaction was heated for 4 h at 50 °C. The reaction was cooled to room temperature, diluted with ethyl acetate (5.0 L) and washed with aqueous sodium sulfite solution (2.5 kg in 4.0 L). The organic layer was washed with water (3.0 L) and brine (3.0 L), dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain crude material which was purified by column chromatography (silica gel ; mesh size 60-120, elution 0-20% ethyl acetate and hexanes) to obtain 4-bromo-2-iodoaniline (650 g, 75.0%) as an off-white solid. TLC solvent system: 100% hexanes. Product RF: 0.6. MS (ESI, positive ion) m/z:297.0 (M+1). 1H NMR (400 MHz, CDCl3) d 7.72 (d, J = 2.5 Hz, 1H), 7.23 (dd, J = 8.4, 2.1 Hz, 1H), 6.62 (d , J = 8.3 Hz, 1H), 4.09 (s, 2H).

STEP 2: ETHYL (E)-3-(2-AMINO-5-BROMOPHENYL)ACRYLATE

[00110] To a solution of 4-bromo-2-iodoaniline (750 g, 2.51 mol, 1.0 equiv) in DMF (5.0 L) was added ethyl acrylate (277 g, 2.76 mol, 1.1 equiv, Avra) and sodium bicarbonate (680 g, 6.29 mol, 2.5 equiv). The reaction mixture was degassed with nitrogen for 20 min followed by the addition of palladium acetate (28.8 g, 128.27 mmol, 0.05 equiv, Hindustan Platinum). The reaction mixture was heated at 70 °C for 3 hours. The reaction was filtered through CELITE® and the CELITE® bed was washed with ethyl acetate (2 x 500 mL). The filtrate was concentrated under reduced pressure to obtain the crude residue which was purified by column chromatography (silica gel; 60-120 mesh size, elution 0-20% ethiol acetate in hexanes) to obtain ( E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g, 77.0%), as a yellow solid. TLC solvent system: 20% ethyl acetate in hexanes. Product Rf: 0.4MS (ESI, positive ion) m/z: 270.2 (M+1). 1H NMR (400 MHz, DMSO) d 7.75 (d, J = 16.1 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 9 .1, 2.4 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 6.43 (d, J = 8.6 Hz, 1H), 5.81 (s, 2H ), 4.20 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H).

STEP 3: ETHYL (E)-3-(2-AMINO-5-(BENZYLTIO)PHENYL)ACRYLATE (THE SCHEMATIC ABOVE NEEDED TO BE REDESIGNED)

[00111] To a solution of (E)-ethyl 3-(2-amino-5-bromophenyl) acrylate (620 g, 2.29 mol, 1.0 equiv) in 1,4-dioxane (4.0 L) DIPEA (1.26 L, 8.88 mol, 3.9 equiv, GLR) was added and degassed with nitrogen for 20 min. XantPhos (92.9 g, 106 mmol, 0.05 equiv, GLR) and tris(dibenzylideneacetone)dipalladium (84 g, 91.0 mmol, 0.04 equiv, Hindustan Platinum) were added to the reaction mixture. The mixture was purged with nitrogen and heated at 80 °C for 30 min. The reaction mixture was cooled to RT and benzyl mercaptan (455.5 g, 3.67 mol, 1.6 equiv. Alfa Aesar) was added and the reaction mixture was heated to 80 °C for an additional 4 h . The reaction was cooled to room temperature and diluted with ethyl acetate (4.0 L). The mixture was filtered through CELITE® and the CELITE® bed was washed with ethyl acetate (2 x 1.0 L). The filtrate was concentrated under reduced pressure to obtain crude material which was purified by chromatography (silica gel; 60-120 mesh size, 0-40% ethyl acetate and petroleum ether elution) to obtain (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (520 g, 72.0%) as a yellow solid. TLC solvent system:30% ethyl acetate in hexanes. Product Rf: 0.4MS (ESI, positive ion) m/z; 314.1 (M+1). 1H NMR (400 MHz, DMSO) d 7.79 (d, J = 16.1 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.25 - 7.17 (m , 5H) 7.10 (dd, J = 8.4, 2.1 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 6.32 (d, J = 15.2 Hz, 1H), 5.75 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 4.01 (s, 2H), 1.27 (t, J = 7.2 Hz, 3H).

STEP 4:1-BROMO-2-FLUORINE-4-IODO-5-METHOXYBENZENE

[00112] To a solution of 2-bromo-1-fluoro-4-methoxybenzene (500.0 g, 2.44 mol, 1.0 equiv) in DCM (5.0 L) was added silver trifluoromethane sulfonate (686.0 g, 2.68 mol, 1.1 equiv, Angene) and the reaction mixture was stirred for 20 min. Iodine (678.0 g, 2.68 mol, 1.1 equiv.) was added to the reaction and the mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM (3.0 L) and filtered through CELITE®. The CELITE bed was washed with DCM (2 x 1.0 L) and the filtrate was washed with 20% aqueous sodium thiosulfate (3.0 L) and saturated aqueous sodium bicarbonate solution (3.0 L). The organic layer was dried over solid sulfate, filtered and concentrated under reduced pressure to obtain crude material which was purified by chromatography (silica gel; 60-120 mesh size, elution of 0-5% sodium acetate). ethyl and petroleum ether) to obtain 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (720 g, 87%) as an off-white solid. TLC solvent system: 100% hexanes. Product Rf:0.6MS (ESI, positive ion) m/z:331.0 (M+1). 1H NMR (400 MHz, CDCl3) d 7.55 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 5.6 Hz, 1H), 3.89 (s, 3H). STEP 5: ETHYL (E)-3-(5-(BENZYLTHIUM)-2-((4-BROMO-5-FLUORINE-2- METHOXYPHENYL)AMINO)PHENYL) ACRYLATE

[00113] To a solution of (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (300 g, 958.1 mmol, 1.0 equiv) and 1-bromo-2-fluoro- 4-iodo-5-methoxybenzene (348.0 g, 1051.6 mmol, 1.1 equiv) in toluene (2.5 L) was added Cs2CO3 (468 g, 1436.3 mmol, 1.5 equiv, Spectrochem) and the mixture was degassed with nitrogen for 20 min. Pd2(dba)3 (35 g, 38.2 mmol, 0.04 equiv, Hindustan Platinum) and XantPhos (44.6 g, 76.4 mmol, 0.08 equiv, GLR) were added to the reaction mixture and the mixture was heated at 110 °C for 5 h. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane (2.0 L) and filtered through CELITE®. The filtrate was concentrated under reduced pressure to obtain crude material which was purified by stirring with 5% ethyl acetate in hexane (3.0 L) for 30 min and filtered to obtain (E)-ethyl 3-(5-(benzylthio )-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (350 g, 71%) as yellow solid. TLC solvent system:30% ethyl acetate in hexanes. Product RF: 0.5. MS (ESI, positive ion) m/z: 516.2 (M+1). 1H NMR (400 MHz, DMSO) d 7.73 - 7.61 (m, 3H), 7.34 - 7.15 (m, 6H), 7.02 (d, J = 11.4 Hz, 1H) , 6.60 (d, J = 21.2 Hz, 1H), 6.33 (d, J = 14.1 Hz, 1H), 4.26 (s, 2H), 4.16 - 4.09 ( m, 2H), 3.81 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H). Note: NH proton not observed.

STEP 6:6-(BENZYLTHIUM)-1-(4-BROMO-5-FLUORINE-2- METHOXYPHENYL)QUINOLIN-2(1H)-ONE

[00114] To a solution of (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (250.0 g, 484, 0 mmol, 1.0 equiv) in methanol (2.5 L) tri(n-butyl)phosphine (50% solution in ethyl acetate, 48.9 mL, 96.8 mmol, 0.2 equiv) was added. Spectrochem) and the reaction mixture was heated at 70 °C for 5 h. The reaction mixture was allowed to cool to RT, concentrated under reduced pressure to obtain crude material which was purified by stirring with 5% ethyl acetate in hexanes (1.0 mL) and filtered to obtain 6-(benzylthio) -1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one (201.0 g, 88%) as an off-white solid. TLC solvent system:30% ethyl acetate in hexanes. Product RF: 0.3. MS (ESI, positive ion) m/z: 470.0 (M+1). 1H NMR (400 MHz, DMSO) d 7.92 (d, J = 9.1 Hz, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.65 (d, J = 6 .1 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.40 - 7.22 (m, 6H), 6.68 (d, J = 9.6 Hz, 1H ), 6.56 (d, J = 8.8 Hz, 1H), 4.24 (s, 2H), 3.69 (s, 3H).

STAGE 7 AND 8: PERFLUORPHENYL 1-(4-BROMO-5-FLUORINE-2- METHOXYPHENYL)-2-OXO-1,2-DIHYDRO QUINOLINE-6-SULFONATO

[00115] To a solution of 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one (250.0 g, 531.5 mmol, 1.0 equiv) in acetonitrile (2.5 L) were added acetic acid (200 mL) and water (130 mL). The resulting mixture was cooled to 0°C and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (188.5 g, 956.7 mmol, 1.8 equiv, Aldrich) was added in portions to over 20 min, keeping the internal temperature below 5oC. The resulting suspension was stirred at 0-5oC under nitrogen for 45 min. Then, a solution of pentafluorophenol (127.2 g, 690.95 mmol, 1.3 equiv, Apollo) in acetonitrile (200 mL) was added over 5 min, followed by NEt3 (307.7 mL, 2. 12 mol, 4.0 equiv) over 20 min maintaining the internal temperature below 5 °C. The mixture was continued to be stirred at 0-5 oC for 30 min. Water (4.0 L) was added and extracted with ethyl acetate (2 x 2.0 L). The organic layer was washed with brine (1.0 L), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material which was purified by stirring with isopropyl alcohol:hexanes (1:1.1. 0 L) and filtered to obtain racemic perfluorophenyl 1-(4-Bromo-5-fluoro-2-methoxyphenyl) 2-oxo-1,2-dihydroquinoline-6-sulfonate (190 g, 60%) as white solid. TLC solvent system: 30% ethyl acetate in petroleum ether, product Rf: 0.4 MS (ESI, positive ion) m/z; 594.2 (M+1). 1H-NMR (400 MHz, DMSO) d 8.60 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 9.8 Hz, 1H), 7.95 (dd, J = 2.2, 9.1 Hz, 1H), 7.70 (t, J = 8.6 Hz, 2H), 6.95 - 6.88 (m, 2H), 3.72 (s, 3H). INTERMEDIATE B1:(P)-1-(4-BROMO-5-FLUORINE-2-METHOXYPHENYL)-N- (ISOXAZOLE-3-IL)-2-OXO-1,2-DIHYDROQUINOLINE-6-SULFONAMIDE

STEP 1:(P)-PERFLUORPHENYL 1-(4-BROMO-5-FLUORINE-2- METHOXYPHENYL)-2-OXO-1,2-DI-HYDROQUINOLINE-6-SULFONATE

[00116] Racemic perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (see intermediate A1 above, 76.90 g) was separated through the Chiralcel Jo column (40% MeOH/60% CO2) for 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate and (M)-perfluorophenyl 1- (4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate as pale yellow flocculent solids. Data for peak 1: m/z (ESI) 594.0 (M+H)+. Data for peak 2: m/z (ESI) 594.0 (M+H)+.

STEP 2:(P)-1-(4-BROMO-5-FLUORINE-2-METHOXYPHENYL)-N-(ISOXAZOLE- 3-YL)-2-OXO-1,2-DIHYDROQUINOLINE-6-SULFONAMIDE

[00117] A THF solution (200 ml) of (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (6.00 g, 10.10 mmol) and 3-aminoisoxazole (0.821 ml, 11.11 mmol) in a 250 ml round bottom flask was cooled to 0 °C, and lithium bis(trimethylsilyl)amide, 1.0 M solution in THF (21.20 ml, 21.20 mmol) was added dropwise. After stirring the yellow solution at 0°C for 15 min, it was quenched at 0°C with 1N HCl and extracted three times with EtOAc. The organic extracts were combined, dried over MgSO4, filtered and concentrated to a light brown residue. Et2O was added and the suspension was titrated and sonicated. Filtration gave an off-white solid, which was washed twice with Et2O and dried under vacuum to give 3.88 g of product as an off-white solid. The filtrate was concentrated in vacuo and purified via column chromatography (12 g silica gel, 35% to 100% EtOAc gradient/hept) to provide a further 1.36 g of product as a pale yellow flocculent solid. A total of 5.24 g of (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6- sulfonamide was obtained. m/z (ESI) 494.1 (M+H)+. INTERMEDIATE C1:(P)-1-(4-BROMO-5-fluoro-2-methoxyphenyl)-N-(ISOXAZOL-3-yl)-N-(4-methoxyBENZyl)-2-OXO-1,2-DIhydroquinoline -6- SULfonamide

[00118] A 250 ml round bottom flask was charged with (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (see Step 1 of Intermediate B1 above, 11.34 g, 19.08 mmol), and N-(4-methoxybenzyl)isoxazol-3-amine (4.09 g, 20.04 mmol), then purged with nitrogen. Tetrahydrofuran (191 mL) was introduced and the resulting brown solution was cooled to 0°C. A solution of lithium bis(trimethylsilyl)amide in THF (1.0 M, 21.0 mL, 21.0 mmol), through a syringe, to the reaction mixture stirred for 10 min. After 15 min, 1.0 N HCl (100 mL) was introduced and the resulting reaction mixture was allowed to warm to RT. The mixture was diluted with EtOAc (100 mL) and the layers were separated and the aqueous layer was further extracted with EtOAc (2 x 100 mL). The combined organic layers were then washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by flash column chromatography (100 g Biotage column, eluent:gradient 0 to 100% EtOAc in heptane with 10% CH2Cl2 as additive) to yield (P)-1-(4-bromo- 5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1, 2-dihydroquinoline-6-sulfonamide (9.54 g, 15, 53 mmol, 81% yield) as a white amorphous solid. 1H NMR (400MHz, DMSO-d6) d = 8.82 (d, J=2.0 Hz, 1H), 8.38 (d, J=2.3 Hz, 1H), 8.17 (d, J =9.4 Hz, 1H), 7.76 (t, J=5.1 Hz, 1H), 7.68 (d, J=6.1 Hz, 1H), 7.63 (d, J=8 .5Hz, 1H), 7.26 (d, J=7.9Hz, 2H),6.91 - 6.78 (m, 4H), 6.74 (d, J=2.0Hz, 1H ), 4.92 (s, 2H), 3.73 - 3.69 (m, 6H), 3.32 (s, 1H). m/z (ESI) 615.1 (M+H)+. INTERMEDIATE D1:(P)- 1-(4-BROMO-5-CHLORO-2-METHOXYPHENIL)- N-(ISOXAZOL-3-IL)-2-OXO-1,2-DIHYDROQUINOLINE-6-SULFONAMIDE

STEP 1: ETHYL (E)-3-(5-(BENZYLTHIO)-2-((4-BROMO-5-CHLORO-2- METHOXYPHENYL)AMINO)PHENYL) ACRYLATE

[00119] To a solution of ethyl (E)-3-(2-amino-5-(benzylthio)phenyl)acrylate (175 g, 555.0 mmol, 1.0 equiv) and 1-bromo-2-chloro -4-iodo-5-methoxybenzene (231.3 g, 666.2 mmol, 1.1 equiv) in toluene (1.5 L) was added cesium carbonate (357.5 g, 1100 mmol, 2.0 equiv ) and the mixture was degassed with nitrogen for 20 min. Pd2(dba) 3 (12.5 g, 13.0 mmol, 0.025 equiv.) and xantphos (15.8 g, 27.2 mmol, 0.05 equiv.) were added to the reaction mixture and the mixture was heated to 110 °C for 5 h. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane (1.0 L) and filtered through celite. The filtrate was concentrated under reduced pressure to obtain crude material which was purified by stirring with 5% ethyl acetate in hexane (1.5 L) for 30 min and filtered to obtain (E)-3-(5-( benzylthio)-2-((4-Bromo-5-chloro-2-methoxyphenyl)amino)phenyl) ethyl acrylate (290 g, 85%) as a yellow solid. m/z (ESI) 532.2 (M+H)+.

STAGE 2:6-(BENZYLTHIO)-1-(4-BROMO-5-CHLORO-2- METHOXYPHENYL)QUINOLIN-2(1H)-ONE

[00120] To a solution of (E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)ethyl acrylate (300.0 g, 5630 .0 mmol, 1.0 equiv) in methanol (3.0 L) tri(n-butyl)phosphine (50% solution in ethyl acetate, 56.2 mL, 1126 mmol, 0.2 equiv) was added and the reaction mixture was heated at 70 °C for 5 h. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure to obtain crude material which was purified by stirring with 5% ethyl acetate in hexane (1.0 mL) and filtered to obtain 6-(benzylthio) -1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)-one (210.0 g, 76.6%) as an off-white solid. m/z (ESI) 486.0 (M+H)+.

STEP 3: PERFLUORPHENYL 1-(4-BROMO-5-FLUORINE-2-METHOXYPHENYL)-2-OXO-1,2-QUINOLINE DIHYDRO-6-SULFONATO

[00121] To a solution of 6-(benzylthio)-1-(4-Bromo-5-chloro-2-methoxyphenyl)hydroxy-2(1H)-one (400.0 g, 824.9 mmol, 1.0 equivalent) in acetonitrile (2.5 L) and THF (2.5 L) acetic acid (1.0 L) and water (700 mL) were added. The resulting mixture was cooled to 0°C and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (292 g, 1484.8 mmol, 1.8 equiv.) was added in portions over 30 min keeping the internal temperature below 5 °C. The resulting suspension was stirred at 0 °C under nitrogen for 45 min. Then a solution of pentafluorophenol (197.4 g, 1072.3 mmol, 1.3 equiv) in acetonitrile (500 mL) was added over 5 min, followed by triethylamine (477 mL, 3299 mmol, 4.0 equiv). ) over 30 min, keeping the internal temperature below 5 °C. The mixture continued to be stirred at 0°C for 50 min. Water (4.0 L) was added and extracted with ethyl acetate (3 x 2.0 L). The organic layer was washed with brine (2.0 L), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product which was purified by stirring with isopropyl alcohol:hexane (1:1, 2.0 L) and filtered to obtain perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (360 g, 72%) as a white solid. m/z (ESI) 610.6 (M+H)+.

STEP 4: (P)- PERFLUORPHENIL 1-(4-BROMO-5-FLUORINE-2-METHOXYPHENYL)- 2-OXO-1,2-DIHYDRO QUINOLINE-6-SULFONATE & (M)- PERFLUORPHENIL 1-(4-BROMINE -5-FLUORINE-2-METHOXYPHENYL)-2-OXO-1,2- QUINOLINE DIHYDRO-6-SULFONATE

[00122] 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (156 g, 255 mmol) was purified by chiral SFC chromatography ((S, S) Whelk-O, 45% isopropanol) to give (P)-perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (72.66 g, 93% yield) and (M)-perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (76.13 g, 98% yield) as white solids. m/z (ESI) 610.6 (M+H)+.

STEP 5:(P)- 1-(4-BROMO-5-CHLORO-2-METHOXYPHENYL)-N- (ISOXAZOLE-3-YL)-2-OXO-1,2-DIHYDROQUINOLINE-6-SULFONAMIDE

[00123] To a 100 mL RB flask was added (P)-perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (2.56 g, 4.19 mmol). The flask was placed under nitrogen, then THF (41.9 mL) and isoxazol-3-amine (0.423 g, 5.03 mmol) were added. The mixture was cooled to 0°C over 10 min, then 1.0 M LHMDS in THF (8.80 mL, 8.80 mmol) was added dropwise over 5 min. The reaction was then stirred for two hours. While still cold, 1N HCl (50 mL) and EtOAc (50 mL) were added. The layers were separated and the organic layer was washed again with 1N HCl. Aqueous layers combined and extracted with EtOAc (2x50 mL). All combined organics were dried with sodium sulfate, filtered and concentrated. The material was purified by silica gel chromatography (40-100% EtOAc/heptane) to provide (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl) -2-oxo-1,2-dihydroquinoline-6-sulfonamide (2.03 g, 3.97 mmol, 95% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) d = 11.66 (br. s. .1 H), 8.69 (d, J=1.47 Hz, 1 H), 8.35 (d, J= 2.15 Hz, 1 H), 8.22 (d, J=9.59 Hz, 1 H), 7.83 (dd, J=8.95, 2.20 Hz, 1 H), 7.77 (s, 1 H) 7.70 - 7.74 (m, 1 H), 6.85 (d, J=8.90 Hz, 1 H), 6.79 (d, J=9.59 Hz, 1 H), 6.42 (d, J=1.76 Hz, 1 H), 3.72 (s, 3 H). m/z (ESI) 511.0 (M+H)+. INTERMEDIATE E1:(M)- 1-(4-BROMO-5-CHLORO-2-METHOXYPHENIL)- N-(ISOXAZOL-3-IL)-2-OXO-1,2-DIHYDROQUINOLINE-6-SULFONAMIDE

[00124] The title compound was prepared according to the method of Intermediate D1, except that (M)-perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline -6-sulfonate was used instead of (P)-perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate to yield (M)-1 -(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) d = 11.66 (br. s. .1 H), 8.69 (d, J=1.47 Hz, 1 H), 8.35 (d, J= 2.15 Hz, 1 H), 8.22 (d, J=9.59 Hz, 1 H), 7.83 (dd, J=8.95, 2.20 Hz, 1 H), 7.77 (s, 1 H) 7.70 - 7.74 (m, 1 H), 6.85 (d, J=8.90 Hz, 1 H), 6.79 (d, J=9.59 Hz, 1 H), 6.42 (d, J=1.76 Hz, 1 H), 3.72 (s, 3 H). m/z (ESI) 511.0 (M+H)+.

EXAMPLES

[00125] EXAMPLE 1: (P)-1-(5-FLUORINE-2-METHOXY-4-(3,3,3-TRIFLUORPROPYL)PHENYL)-N-(ISOXAZOL-3-YL)-2-OXO-1 ,2- DIHYDROQUINOLINE-6-SULFONAMIDE

[00126] A vial was charged with activated zinc (Rieke Zinc) (4.38 mL, 3.35 mmol) and cooled to 0 °C. 1,1,1-trifluoro-3-iodopropane (0.268 mL, 2.233 mmol) was added slowly dropwise and the reaction was warmed to room temperature and stirred for one hour. Pale (II) acetate (2.73 mg, 0.012 mmol), 2'-(dicyclohexylphosphine)-N2,N2,N6,N6-tetramethyl-[1,1'-biphenyl]-2,6-diamine (CPhos) (10.60 mg, 0.024 mmol), and 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6 - sulfonamide (See above, Intermediate B1, 0.100 g, 0.202 mmol) and the reaction was stirred for two hours at 50 ºC. The reaction was diluted with ethyl acetate and washed twice with 1N HCl solution. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified via column chromatography (RediSep Gold 40g, 0-100% gradient elution in EtOAc:Heptane) to yield (P)-1-(5-fluoro-2-methoxy-4-(3,3, 3-trifluoropropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.067 g, 0.131 mmol, 64.8% yield) as a white solid . 1H NMR (400 MHz, DMSO-d6) d = 2.64 - 2.78 (m, 2 H) 2.87 - 3.03 (m, 2 H) 3.66 (s, 3 H) 6.44 (d, J=1.81 Hz, 1 H) 6.77 (dd, J=15.32, 9.30 Hz, 2 H) 7.30 - 7.41 (m, 2 H) 7.84 ( dd, J=8.97, 2.23 Hz, 1 H) 8.21 (d, J=9.69 Hz, 1 H) 8.36 (d, J=2.18 Hz, 1 H) 8, 73 (d, J=1.76 Hz, 1 H) 11.65 (s, 1 H). m/z (ESI) 512.2 (M+H)+. EXAMPLE 2:(P)-1-(5-CHLORO-2-METHOXY-4-(3,3,3-TRIFLUORPROPYL)PHENYL)-N-(ISOXAZOL-3-YL)-2-OXO-1,2- DIHYDROQUINOLINE-6-SULFONAMIDE

[00127] The title compound was prepared according to the method of example 1, except that (P)- 1-(4-bromo-5-chloro-2-methoxyphenyl)-N- (isoxazol-3-yl)- 2-oxo-1,2-dihydroquinoline-6-sulfonamide (see Intermediate D1 above) was used in place of Intermediate B1 to yield (P)-1-(5-chloro-2-methoxy-4-(3,3 ,3-trifluoropropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.25 g, 0.047 mmol, 24.19% yield) as a solid white. 1H NMR (400 MHz, DMSO-d6) d = 2.62 - 2.78 (m, 2 H) 2.97 - 3.09 (m, 2 H) 3.69 (s, 3 H) 6.44 (d, J=1.71 Hz, 1 H) 6.77 (dd, J=14.25, 9.33 Hz, 2 H) 7.43 (s, 1 H) 7.55 (s, 1 H ) 7.84 (dd, J=8.97, 2.12 Hz, 1 H) 8.21 (d, J=9.69 Hz, 1 H) 8.36 (d, J=2.02 Hz, 1 H) 8.73 (d, J=1.71 Hz, 1 H) 11.66 (s, 1 H). m/z (ESI) 528.0 (M+H)+. EXAMPLE 3:(P)-1-(5-FLUORINE-2-METHOXY-4-(3,3,3-TRIFLUORPROPYL)PHENYL)-2-OXO-N-(PYRDAZIN-3-YL)-1,2- DIHYDROQUINOLINE-6-SULFONAMIDE

STAGE 1: (P)-PERFLUORPHENYL 1-(5-FLUORY-2-METHOXY-4-(3,3,3- TRIFLUORPROPYL)PHENYL)-2-OXO-1,2-DIHYDROQUINOLINE-6- SULFONATE

[00128] A vial was charged with activated zinc (Rieke zinc) (6.61 mL, 5.05 mmol) and cooled to 0 °C. 3-Bromo-1,1,1-trifluoropropane (0.358 mL, 3.37 mmol) was slowly added dropwise. The reaction was warmed to room temperature and stirred for one hour. (P)-fluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (See Step 1 of Intermediate Intermediate B1 above, 0.500 g, 0.841 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.043 g, 0.084 mmol) were added and the reaction was stirred for one hour at 50 °C. The reaction was filtered through a CELITE® pad, which was washed with ethyl acetate. The filtrate was washed with water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified via column chromatography (RediSep Gold 40g, 0-50% EtOAc:Heptane elution gradient) to provide (P)-perfluorophenyl 1-(5-fluoro-2-methoxy-4-(3,3 ,3-trifluoropropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.104, 0.170 mmol, 20.22% yield) as a white solid. m/z (ESI) 612.0 (M+H)+.

STEP 2:(P)-1-(5-FLUORINE-2-METHOXY-4-(3,3,3-TRIFLUORPROPYL)PHENYL)-2-OXO-N-(PYRDAZIN-3-YL)-1,2- DIHYDROQUINOLINE-6-SULFONAMIDE

[00129] A round bottom flask was charged with pyridazin-3-amine (10.11 mg, 0.106 mmol) and DMSO (0.204 mL) to give a solution. (P)-perfluorophenyl 1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.050 g, 0.082 mmol) and THF (0.613 mL) were added. The vial was cooled in an ice bath for 5 minutes, then LHMDS (1M in THF) (0.188 mL, 0.188 mmol) was added dropwise. The reaction was stirred for 15 minutes. The reaction was diluted with ethyl acetate and washed twice with 1N HCl solution. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified via column chromatography (RediSep Gold 40g, gradient elution 10-75% [3:1 EtOAc/EtOH]:heptane) to yield (P)-1-(5-fluoro-2-methoxy-4- (3,3,3-trifluoropropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (0.036 g, 0.069 mmol, 84% yield) as a solid white. 1H NMR (400 MHz, DMSO-d6) d = 2.62 - 2.79 (m, 2 H) 2.89 - 3.04 (m, 2 H) 3.66 (s, 3 H) 6.67 (d, J=8.86 Hz, 1 H) 6.76 (d, J=9.59 Hz, 1 H) 7.30 - 7.40 (m, 2 H) 7.68 (dd, J= 9.43, 3.73 Hz, 1 H) 7.84 (d, J=7.98 Hz, 1 H) 7.93 (d, J=9.23 Hz, 1 H) 8.18 (d, J=9.64 Hz, 1 H) 8.25 - 8.38 (m, 2 H) 14.49 (br. s., 1 H). m/z (ESI) 523.0 (M+H)+. EXAMPLE 4:(P)-1-(5-FLUORINE-2-METHOXY-4-(3,3,3-TRIFLUORY-2- METHYLPROPYL)PHENYL)-N-(ISOXAZOL-3-YL)-2-OXO- 1,2- DIHYDROQUINOLINE-6-SULFONAMIDE

STAGE 1: (3,3,3-TRIFLUOR-2-METHYLPROPYL)ZINC(II) BROMIDE (0.033 M)

[00130] An oven-dried round bottom flask equipped with a magnetic stir bar and a rubber septum was charged with lithium chloride (0.888 g, 20.94 mmol). The container was heated with a heat gun for 10 min under high vacuum and filled with nitrogen after cooling to room temperature. Zinc (1.369 g, 20.94 mmol) was added. The container was heated again with a heat gun for 10 min under high vacuum and filled with nitrogen after cooling to room temperature. THF (13.96 mL) and 1,2-dibromoethane (0.045 mL, 0.524 mmol) were added via syringe and the reaction mixture was heated to 60°C until bubbling occurred. After cooling to room temperature, TMS-Cl (0.040 mL, 0.314 mmol) and a solution of iodine (0.027 g, 0.105 mmol) in THF (0.2 mL) were added via syringe. The reaction mixture was heated to 60 °C for 20 min and then cooled to room temperature. 3-Bromo-1,1,1-trifluoro-2-methylpropane (1.361 mL, 10.47 mmol) was added and the reaction was stirred at 50 °C for 48 h. The reaction mixture was left to stand at room temperature for 1 hour and the solution was collected in a syringe and transferred to an oven-dried screw-capped vial with a Teflon septum. The solution was titrated by dropwise addition to a 0°C solution of iodine (0.0067 g, 0.026 mmol) in lithium chloride, 0.5 M in anhydrous tetrahydrofuran (1.0 ml, 0.500 mmol) until orange color disappear. 0.8 mL of solution was used, corresponding to a concentration of 0.033 M.

STEP 2:(P)-1-(5-FLUORINE-2-METHOXY-4-(3,3,3-TRIFLUORY-2- METHYLPROPYL)PHENYL)-N-(ISOXAZOL-3-YL)-2-OXO- 1,2- DIHYDROQUINOLINE-6-SULFONAMIDE

[00131] A vial was charged with palladium(ii) acetate (3.27 mg, 0.015 mmol), 2'-(dicyclohexylphosphine)-N2,N2,N6,N6-tetramethyl-[1,1'-biphenyl] -2,6-diamine (CPhos) (0.013 g, 0.029 mmol), and (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl )-2-oxo-1,2-dihydroquinoline-6-sulfonamide (see above Intermediate B1, 0.120 g, 0.243 mmol). (3,3,3-Trifluoro-2-methylpropyl)zinc(II) bromide (0.033 M in THF) (18.39 mL, 0.607 mmol) was added and the reaction mixture was stirred for one hour at 50° W. The reaction was diluted with ethyl acetate and washed with 1N aqueous HCl solution. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified via column chromatography (RediSep Gold 40g, gradient elution 0-50% [3:1 EtOAc/EtOH]:heptane) to yield (P)-1-(5-fluoro-2-methoxy-4- (3,3,3-trifluoro-2-methylpropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.103 g, 0.196 mmol, 81% yield ) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) d = 1.09 (dd, J=6.79, 2.54 Hz, 3 H) 2.69 - 2.77 (m, 1 H) 2.85 (br .s. H) 6.74 - 6.81 (m, 2 H) 7.29 - 7.41 (m, 2 H) 7.84 (dd, J=9.17, 2.23 Hz, 1 H) 8, 21 (d, J=9.64 Hz, 1 H) 8.36 (d, J=2.18 Hz, 1 H) 8.72 (d, J=1.76 Hz, 1 H) 11.65 ( s, 1H). m/z (ESI) 526.0 (M+H)+. EXAMPLE 5:(P)-1-(5-FLUORINE-2-METHOXY-4-(4,4,4-TRIFLUORBUTYL)PHENYL)-N-(ISOXAZOL-3-YL)-2-OXO-1,2- DIHYDROQUINOLINE-6-SULFONAMIDE

[00132] The title compound was prepared according to the method of Example 1, except that 1,1,1-trifluoro-4-iodobutane was used instead of 1,1,1-trifluoro-3-iodopropane to yield ( P)-1-(5-fluoro-2-methoxy-4-(4,4,4-trifluorobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6- sulfonamide (43.4 mg, 0.083 mmol, 100% yield) was obtained as a brown solid. 1H NMR (400 MHz, DMSO-d6) d = 11.65 (s, 1 H), 8.71 (d, J=1.66 Hz, 1 H), 8.35 (d, J=2.18 Hz, 1 H), 8.20 (d, J=9.64 Hz, 1 H), 7.83 (dd, J=9.02, 2.18 Hz, 1 H), 7.31 (d, J=9.74 Hz, 1 H), 7.25 (d, J=6.84 Hz, 1 H), 6.76 - 6.80 (m, 2 H), 6.43 (s, 1 H ), 2.80 (t, J=7.88 Hz, 2 H), 2.32 - 2.45 (m, 2 H), 1.84 - 1.92 (m, 2 H). m/z (ESI) 526.0 (M+H)+. EXAMPLES 6A and 6B: RACEMIC- E (P)-1-(5-FLUORINE-2-METHOXY-4- (2,2,2-TRIFLUORETHYL)PHENYL)-N-(ISOXAZOL-3-YL)-2-OXO -1,2- DIHYDROQUINOLINE-6-SULFONAMIDE, RESPECTIVELY.

STEP 1:1-(5-FLUORINE-2-METHOXY-4-VINYLPHENYL)-N-(ISOXAZOL-3- IL)-N-(4-METHOXYBENZYL)-2-OXO-1,2-DIHYDROQUINOLINE-6- SULFONAMIDE

[00133] A vial was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2- dihydroquinoline-6-sulfonamide (see above Intermediate C1, 0.750 g, 1.221 mmol), Pd2 (dba) 3 (0.112 g, 0.122 mmol), dicyclohexyl(2',6'-dimethoxy-[1,1' -biphenyl] -2-yl)phosphine (SPhos) (0.100 g, 0.244 mmol) and potassium carbonate (0.843 g, 6.10 mmol). DMSO (6.10 mL) and vinylboronic acid dibutyl ester (0.812 mL, 3.66 mmol) were added. The reaction was heated to 100°C and stirred for two hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The material was purified via column chromatography (RediSep Gold 40g, gradient elution 0-100% EtOAc:Heptane) to provide 1-(5-fluoro-2-methoxy-4-vinylphenyl)-N-(isoxazol-3-yl )-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.652 g, 1.161 mmol, 95% yield) as a light yellow solid. m/z (ESI) 562.0 (M+H)+.

STEP 2: 1-(5-FLUORO-4-FORMYL-2-METHOXYPHENYL)-N- (ISOXAZOL-3-YL)-N-(4-METHOXYBENZYL)-2-OXO-1,2-DI-HYDROQUINOLINE- 6 -SULFONAMIDE

[00134] 1-(5-fluoro-2-methoxy-4-vinylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6 -sulfonamide (0.652 g, 1.161 mmol) was dissolved in acetonitrile (9.95 mL) and water (1.659 mL). Ruthenium(III) chloride dihydrate (0.05 M aqueous solution) (1.161 mL, 0.058 mmol) was added, followed by the addition, in portions, of sodium periodate (0.129 mL, 2.322 mmol). The reaction was stirred for one hour at room temperature. The reaction was quenched with aqueous sodium thiosulfate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified via column chromatography (RediSep Gold 40g, gradient elution 0-100% EtOAc:Heptane) to provide 1-(5-fluoro-4-formyl-2-methoxyphenyl)-N-(isoxazol-3-yl )-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.251 g, 0.445 mmol, 38.4% yield) as a white oily solid. m/z (ESI) 564.0 (M+H)+.

STEP 3: 1-(5-FLUORO-2-METHOXY-4-(2,2,2-TRIFLUORO-1- HYDROXYETHYL)PHENYL)-N-(ISOXAZOL-3-YL)-N-(4-METHOXYBENZYL)- 2-OXO- 1,2-DI-HYDROQUINOLINE-6-SULFONAMIDE

[00135] A round bottom flask was charged with 1-(5-fluoro-4-formyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1 ,2-dihydroquinoline-6-sulfonamide (0.100 g, 0.177 mmol) and THF (0.887 mL). (trifluoromethyl)trimethylsilane (0.045 mL, 0.302 mmol) and TBAF (1.0 M in THF) (0.018 mL, 0.018 mmol) were added in succession and the reaction was stirred for three hours at room temperature. 1N HCl (1.242 mL, 1.242 mmol) was added and the reaction was stirred for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified via column chromatography (Biotage SNAP 25g column, gradient elution 0-75% EtOAc:Heptane) to provide 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoro-1 -hydroxyethyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.098 g, 0.155 mmol, 87% yield ) as a white solid. m/z (ESI) 634.0 (M+H)+.

STEP 4: O-PHENYL O-(2,2,2-TRIFLUORO-1-(2-FLUORO-4-(6-(N-(ISOXAZOL-3-YL)-N-(4-METHOXYBENZYL)SULFAMOYL)- 2-OXOQUINOLIN- 1(2H)-IL)-5-METHOXYPHENYL)ETHYL) CARBONOTHIOATE

[00136] 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)- N-(isoxazol-3-yl)-N-(4-methoxybenzyl)- 2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.098 g, 0.155 mmol) was dissolved in toluene (2.210 mL). 4 A molecular sieves (0.100 g, 0.155 mmol) and DMAP (0.038 g, 0.309 mmol) were added and the mixture was stirred vigorously. Phenyl chlorothionoformate (0.043 mL, 0.309 mmol) was added slowly, resulting in a thick suspension. The reaction was then stirred at 60 °C for two hours. The reaction was filtered through CELITE®, which was washed with DCM. The filtrate was concentrated and purified via column chromatography (RediSep Gold 12 g, elution gradient 0-100% EtOAc:Heptane) to yield O-phenyl O-(2,2,2-trifluoro-1-(2-fluoro- 4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)ethyl)carbonthioate (0.106 g, 0.138 mmol, 89% yield) as a white solid. m/z (ESI) 770.0 (M+H)+.

STEP 5: 1-(5-FLUORO-2-METHOXY-4-(2,2,2- TRIFLUOROETHYL)PHENYL)-N-(ISOXAZOL-3-YL)-N-(4-METHOXYBENZYL)-2- OXO- 1,2-DI-HYDROQUINOLINE-6-SULFONAMIDE

[00137] O-phenyl O-(2,2,2-trifluoro-1-(2-fluoro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)- 2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)ethyl)carbonthioate (0.106 g, 0.138 mmol) was dissolved in toluene (2.75 mL) and cooled to -78 °C. Tin tri-n-butylhydride (0.182 mL, 0.689 mmol) and triethylborane, 1.0 M solution in hexanes (0.138 mL, 0.138 mmol) were added, then a syringe filled with air was bubbled through the solution, resulting in a bright pink solution. The reaction was stirred for 30 minutes at -78°C. The reaction was quenched with water and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified via column chromatography (RediSep Gold 12g gradient elution 0-100% EtOAc:Heptane) to provide 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)- N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.076 g, 0.123 mmol, 89% yield) as a white solid. m/z (ESI) 618.0 (M+H)+.

STEP 6: 1-(5-FLUORO-2-METHOXY-4-(2,2,2- TRIFLUOROETHYL)PHENYL)-N-(ISOXAZOL-3-YL)-2-OXO-1,2- DIHYDROQUINOLINE-6- SULFONAMIDE (EXAMPLE 6A)

[00138] 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo- 1,2-dihydroquinoline-6-sulfonamide (0.076 g, 0.123 mmol) was dissolved in TFA (1.0 ml, 12.98 mmol) and heated at 50 °C for two hours. The reaction was concentrated and purified via column chromatography (RediSep Gold 40g, gradient elution 0-75% [3:1 EtOAc/EtOH]:Heptane) to provide 1-(5-fluoro-2-methoxy-4-(2, 2,2-trifluoroethyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.061 g, 0.123 mmol, 100% yield) as a white solid . m/z (ESI) 498.0 (M+H)+.

STEP 7: 1-(5-FLUORO-2-METHOXY-4-(2,2,2-TRIFLUOROETHYL)PHENYL)-N-(ISOXAZOL-3-IL)-2-OXO-1,2-DI-IDROQUINOLINE- 6-SULFONAMIDE (EXAMPLE 6B)

[00139] 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6- Racemic sulfonamide (0.061 g, 0.123 mmol) was purified by chiral SFC (Regis Whelk-O s,s, 25% methanol) to provide (P)-1-(5-fluoro-2-methoxy-4-(2 ,2,2-trifluoroethyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.027 g, 0.054 mmol, 44.1% yield) as white solid . 1H NMR (500 MHz, DMSO-d6) d ppm 3.66 (s, 3 H) 3.82 (d, J=11.42 Hz, 2 H) 6.35 (br. s. .1 H) 6 .71 (d, J=8.50 Hz, 1 H) 6.77 (d, J=9.28 Hz, 1 H) 7.41 (d, J=5.84 Hz, 1 H) 7.46 (d, J=9.28 Hz, 1 H) 7.82 (d, J=8.69 Hz, 1 H) 8.19 (d, J=9.60 Hz, 1 H) 8.30 (br . s. ,1 H) 8.59 (br. s. ,1 H). m/z (ESI) 498.0 (M+H)+.

[00140] The following compounds can be prepared from appropriate starting materials, analogous to the methods for preparing the compounds exemplified above.

BIOLOGICAL EXAMPLES

[00141] The following assays were used in testing the exemplary compounds of the invention. Data for the examples tested according to the procedures described below are presented in Table 1 below. In Vitro Nav 1.7 or Nav 1.5 IWQ Assay

In Vitro Nav 1.7 or Nav 1.5 IWQ Assay

[00142] HEK 293 cells stably transfected with Nav 1.7 or Nav 1.5 were recorded in population patch-clamp mode with the IonWorks®Quattro automated electrophysiology system, according to the manufacturer's specifications (Molecular Devices, LLC, Sunnyvale, CA) . Sodium channel currents were measured in response to a series of depolarizations that induced successively greater inactivation.

[00143] Cells were held at -110 mV for three seconds (Nav1.7) or half a second (Nav1.5) from a holding voltage of -15 mV, then subjected to a series of 26 pulses of 150 ms duration at -20 mV at a frequency of 5 Hz. Cells were then left unattached for a period of 3 to 8 minutes while a single concentration of test compound was added. The cells were then refixed and placed on the same voltage protocol. The current at the end of the 26th pulse at -20 mV was subtracted from the peak current evoked by the 26th pulse at -20 mV to correct for leakage current. Percent blocking was calculated for each concentration in duplicate, and IC50 curves were fitted to percent blocking as a function of concentration.

Nav 1.7 PX In Vitro Assay

[00144] HEK 293 cells stably transfected with human Nav1.7 were recorded in whole-cell voltage clamp mode with the PatchXpress automated electrophysiology system (Molecular Devices, LLC, Sunnyvale, CA). Composite effects were measured in a partially inactivated state of the sodium channel. Cells were fixed at a holding potential that yields 20 to 50% inactivation. To elicit the sodium current, the channels were activated by pulsing at -10 mV for 20 msec. This voltage protocol was repeated at a rate of 0.1 Hz throughout the experiment. A single concentration of the test compound was applied to the cells over a period of 3 minutes. The maximum sodium current was measured at the end of the compound addition period to determine the percentage of inhibition. Three to five cells were tested per concentration, and IC50 curves were fitted to percent inhibition as a function of concentration. Data for representative compounds of the invention are presented in the Tables presented herein.

Nav 1.5 PX In Vitro Assay

[00145] 293 cells stably transfected with Nav1.5 were recorded in whole-cell voltage clamp mode with the PatchXpress automated electrophysiology system according to the manufacturer's specifications (Molecular Devices, LLC, Sunnyvale, CA). Cells were maintained at a holding potential of −50 mV to inactivate sodium channels. To elicit the sodium currents, the voltage was changed to -120 mV to recover a portion of the channels, followed by the delivery of 20 ms long test pulses at 0 mV, at 0.1 Hz. A single concentration of the sodium compound test was applied to cells over a period of 5 minutes. The maximum sodium current was measured at the end of the compound addition period to determine the percentage of inhibition. A minimum of two cells were tested per concentration. IC50 curves were fitted to percent inhibition as a function of concentration. Data for representative compounds of the invention are presented in the Tables presented herein.

[00146] The compounds of the present invention can also be tested in the following in vivo assays.

Rat Formalin Model of Persistent Pain

[00147] On the day of the test, animals (Naïve, male Sprague Dawley rats) weighing between 260-300g at the start of the test can be obtained from Harlan (Indianapolis, IN). All animals can be housed under a 12/12h light/dark cycle with lights on at 0600. Rodents can be housed in solid bottom cages with corncob bedding and can have access to food and water ad libitum . Animals must be allowed to habituate to the vivarium for at least five days before starting the test and must be taken to the testing room at least 30 minutes before dosing. Animals are pretreated with the appropriate test compound by oral gavage or intraperitoneal injection at the desired pretreatment time (typically two hours before the start of the test) and then returned to their home cages. After administration and at least 30 minutes before testing begins, animals can be acclimatized to the individual testing chambers. At the time of testing, each animal can be gently wrapped in a towel with the left hind paw exposed. A diluted solution of formalin (2.5%) in phosphate-buffered saline can be injected subcutaneously into the dorsal surface of the left hind paw in a volume of 50 µL with a 30 g needle. Immediately after the injection, a small metal strip can be affixed to the plantar side of the left hind paw with a drop of LOCTITE (adhesive). The animals can then be placed in the testing chambers and the number of twitches can be recorded between 10 to 40 minutes after the formalin injection. A twitch is defined as a rapid, spontaneous movement of the injected hind paw not associated with ambulation. Twitching can be quantified with the help of the Automated Nociception Analyzer, built by the Department of Anesthesiology at the University of California, San Diego. Individual data can be expressed as a % Maximum Potential Effect (% MPE) calculated with the following formula: (- (Individual Score - Average Vehicle Score)/Average Vehicle Score)) * 100 = % MPE

[00148] Statistical analysis can be performed by analysis of variance (ANOVA), with Bonferroni post-hoc analysis using in comparison with the vehicle group for a significant main effect. Data can be represented as the mean %MPE +/- the standard error for each group.

Rat Open Field Trial

[00149] On the day of the test, animals (Naïve, male Sprague Dawley rats) weighing between 260-300g at the start of the test can be obtained from Harlan (Indianapolis, IN). All animals can be housed under a 12/12h light/dark cycle with lights on at 0600. Rodents can be housed in solid bottom cages with corncob bedding and can have access to food and water ad libitum . Animals must be allowed to habituate to the vivarium for at least five days before starting the test and must be taken to the testing room at least 30 minutes before dosing. In a room separate from the testing room, animals can be pretreated with the appropriate test compound by oral gavage or intraperitoneal injection at the desired pretreatment time (generally two hours before the start of testing) and then returned to their cages until the pre-treatment has expired. At the time of testing, the animal can be transferred to the open field testing room in its home cages. Each animal can be placed in a separate test chamber and the motion tracking system is started. The house lights in the testing room should be turned off and the animals are allowed to explore the new open field for 30 minutes. An automatic motion tracker, manufactured by San Diego Instruments in San Diego, California, can be used to capture animal exploration with the help of infrared rays to detect the movement of animals. These behaviors include basic movement and standing on hind legs, which can be used as primary assessment criteria for this trial. At the end of the test, the housing lights can be turned on and the animals must be removed from the testing apparatus. The data can be expressed as a percentage change in vehicle control using the following equation.

[00150] (1-(test average/vehicle average)) * 100 = % Change.

[00151] Statistical analysis can be performed by analysis of variance (ANOVA), with Dunnett's post-hoc analysis used to track significant main effects.

Rat Formalin Model of Persistent Pain

[00152] Mice (Naïve, male C57BI/6) weighing between 22-30 g at the start of testing were obtained from Harlan (Indianapolis, IN). All animals were housed under a 12/12 h light/dark cycle with lights on at 0630. Rodents were individually housed in solid-bottom cages with corncob bedding and had access to food and water ad libitum. The animals were allowed to habituate to the vivarium for at least five days before the start of the test and were taken to the testing room at least 30 minutes before dosing. Animals were pretreated with the appropriate test compound by oral gavage or intraperitoneal injection at the desired pretreatment time (typically two hours before the start of the test) and then returned to their home cages. After administration and at least 5 minutes before the start of testing, animals were acclimatized to the individual testing chambers. During testing, each animal was gently wrapped in a cloth glove with the left hind paw exposed. A diluted solution of formalin (2%) in phosphate-buffered saline was injected subcutaneously into the dorsal surface of the left hind paw in a volume up to 20 µL with a 30 g needle. The animals were then placed in the observation chambers and behaviors were recorded for 60 minutes after the formalin injection. A pain behavior was defined as licking and/or not supporting the injected hind paw not associated with ambulation.

[00153] Statistical analysis was performed by analysis of variance (ANOVA), with post-hoc analysis using Dunnett's post-hoc test compared with vehicle group for any significant main effect. Data were represented as the mean +/- standard error for each group.

Rat Open Field Trial

[00154] Mice (Naïve, male C57BI/6) weighing between 22-30 g at the start of testing were obtained from Harlan (Indianapolis, IN). All animals were housed under a 12/12 h light/dark cycle with lights on at 0630. Rodents were individually housed in solid-bottom cages with corncob bedding and had access to food and water ad libitum. The animals were allowed to habituate to the vivarium for at least five days before the start of the test and were taken to the testing room at least 30 minutes before dosing. In a room separate from the testing room, animals were pretreated with the appropriate test compound by oral gavage or intraperitoneal injection at the desired pretreatment time (generally two hours before the start of testing) and then returned to their rooms. their cages until the pre-treatment has expired. At the time of testing, the animal was transferred to the open field testing room in its home cages. Each animal was placed in a separate testing chamber and the motion tracking system was started. The house lights in the testing room were turned off and the animals were allowed to explore the new open field for 30 minutes. An automated motion tracker, made by Kinder Scientific, Poway, CA, was used to capture animal exploration with the aid of infrared rays to detect the animals' movement. These behaviors include basic movement and standing on hind legs, which were used as primary assessment criteria for this trial. At the end of the test, the compartment lights were turned on and the animals were removed from the testing apparatus.

[00155] Statistical analysis was performed by analysis of variance (ANOVA), with post-hoc analysis using Dunnett's post-hoc test compared with vehicle group for any significant main effect. Data were represented as the mean +/- standard error for each group. Data was expressed as a percentage change in vehicle control using the following equation:

[00156] (1-(test average/vehicle average)) * 100 = % Change.

CFA Thermal Test

[00157] Animals (Naïve, male Sprague Dawley rats) weighing between 260-300g at the start of the test can be obtained from Harlan (Indianapolis, IN). All animals can be housed under a 12/12h light/dark cycle with lights on at 0600. Rodents can be housed in solid bottom cages with corncob bedding with access to food and water ad libitum. Animals may be allowed to habituate to the vivarium for at least five days before testing begins and may be brought into the testing room at least 30 minutes before dosing. The Complete Freund's Adjuvant (CFA) thermal assay may use a continuous three-day testing schedule, consisting of a habituation day, a baseline day, and a test day. On day 1, animals can be brought into the testing room, labeled, and placed in their individual testing boxes in the testing apparatus. Animals can explore this environment for at least an hour without actually being tested. After habituation, the animals can be placed back in their cages and returned to the vivarium. On day 2, animals can be brought back to the testing room and placed in the testing apparatus and allowed to calm (typically 30-45 minutes). A basal thermal threshold should be taken with the following procedure: once calm, an Ugo Basile plantar device is placed under the animals left hind paw; the start button is pressed, turning on a constantly growing thermal source and a timer; When the animal reaches its thermal limit, it will withdraw its hind leg, stopping the timer and the thermal stimulus. This latency to retreat can be recorded three times for each animal, with at least 5 minutes between trials, and the average score can be used as the animal's baseline threshold. After testing, animals can be injected intraplantarly with 25 µg/50 µl of complete Freund's adjuvant in the left hind paw. The animals are then returned to their cages and returned to the vivarium. On the day of testing, animals can be placed back into the thermal testing apparatus and their post-CFA baselines obtained with the procedure described above. Animals can be pretreated with the appropriate test compound by oral gavage or intraperitoneal injection at the desired pretreatment time (typically two hours before the start of the test) and then returned to their home cages. Thirty minutes before the test, the animals can be placed in the apparatus again. Once the pre-treatment time has elapsed, the animals can be retested using the above procedure. The data can be expressed as a maximum percentage potential effect with the following formula:

[00158] ((Post-Drug Average - Pre-Drug Average)/(Baseline Average - Pre-Drug Average)) * 100 = % MPE

[00159] Statistical analysis can be performed by analysis of variance (ANOVA), with Bonferroni post-hoc analysis using in comparison with the vehicle group for a significant main effect. Data can be represented as the mean %MPE +/- the standard error for each group.

Spinal Nerve Ligation (Chung)

[00160] Animals (Naïve, male Sprague Dawley rats) weighing between 150-200g at the first start of the test can be obtained from Harlan (Indianapolis, IN). All animals can be housed under a 12/12h light/dark cycle with lights on at 0600. Rodents can be housed in solid bottom cages with corncob bedding with access to food and water at libitum. Animals are allowed to habituate to the vivarium for at least five days before the test begins. Surgery can then be performed based on the method described by Kim and Chung (1992). Briefly, animals can be placed under isoflurane anesthesia and placed in a sterile surgical field. The lumbar spine area is excised and the spinal nerves at L4-L5 are exposed. The L5 spinal nerve is identified and firmly ligated with 50 silk suture. The muscle can be closed with absorbable suture and the skin with wound clip. Animals can be returned to the vivarium for 7-14 days and monitored daily. On the day of testing, animals can be taken to the testing room and placed on a wire mesh floor in individual testing chambers. They can get used to the chambers until they are calm. A series of Semmes-Weinstein monofilaments (von Frey hairs) with calibrated bending forces are then applied to determine a hyperalgesic baseline following the method established by Chaplan et al. (1994). Briefly, the filaments are applied with increasing force (if there was no reaction to the previous stimulus) or decreasing force (if there was a reaction to the previous stimulus) until a reference value is reached. Animals are then pretreated with the appropriate test compound by oral gavage or intraperitoneal injection at the desired pretreatment time (typically two hours before the start of the test) and then returned to their home cages. Thirty minutes before the test, the animals are placed in the apparatus again. After the pre-treatment time, the above procedure is repeated to determine the effectiveness of the medicine. The data can be expressed as the average grammatical strength to elicit nociceptive behavior. Statistical analysis can be performed by analysis of variance (ANOVA), with Bonferroni post-hoc analysis using comparison with the vehicle group for a significant main effect.

[00161] Table 1 provides data for compounds exemplified in the present application and its priority document, as representative compounds of the present invention, as follows: compound name (as named by ACD software, version 12; while compound names in written examples presented here were named using version 12 of ChemDraw Ultra); and biological data, including in vitro Nav 1.7 PX data (IC50 in uM), Nav 1.7 IWQ data (IC50 in uM), in vitro HLM data (µL/(min • mg)) and Human PXR @ 2 µM POC S ( %), when available. Ex. # refers to Example No. Compounds of the present invention show favorable activities against Nav1.7 as well as human HLM and PXR data. TABLE 1: Biological data

[00162] The preceding invention has been described in detail by way of illustration and example, for purposes of clarity and understanding. Those skilled in the art understand that changes and modifications can be made within the scope of the attached claims. Therefore, it is necessary to understand that the description above is for illustrative purposes, not restrictive. The scope of the invention must therefore be determined not with reference to the above description, but rather must be determined with reference to the claims appended below, together with the full scope of equivalents to which these claims are entitled.

[00163] All publications and patent documents cited in this application are incorporated by reference for all purposes, to the same extent that each individual publication or patent document is then individually noted.

Claims (15)

1. Compound of Formula I or a pharmaceutically acceptable salt thereof characterized by having the formula: where: R1 is C2-8haloalq; R2 is H, halo, C1-6alq, or C1-6haloalq; R3 is Ci-6alq, Ci-6haloalq, -O-Ci—6alq, or -CN; R4 is a 5- to 6-membered heteroaryl; each of R6 and R7 is hydrogen; and each of R5a; R5b; R5c; R5d; and R5e is independently hydrogen or halo. 2. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R1 is C2-6haloalq, wherein said C2-6haloalq is C2-6fluoroalkyl. 3. Compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that R1 is selected from -CH2-CF3, -CH2-CH2-CF3, -CH2-CH2-CH2-CF3, - CH2- CH(CH3)-CF3, -CH2-CF2-CF3, -CH2-C(CH3)2-CF3, -C(CH3)2-CH2-CF3, -CF2- CH2-CF3, or -CH2-CH2 -CHF2. 4. Compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that R2 is H, fluorine, chlorine, methyl, CF3, CHF2 or CH2F. 5. Compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that R2 is fluorine. 6. Compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that R3 is methoxy. 7. Compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that R4 is a 5-membered heteroaryl. 8. Compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, characterized in that R4 is a 6-membered heteroaryl. 9. Compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, characterized in that R4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl or pyrimidinyl. 10. Compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, characterized in that each of R5a; R5b; R5c; R5d;e R5eis hydrogen. 11. Compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, characterized in that it is 12. Compound according to any one of claims 1 to 11, enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, characterized by the fact that said atropisomer is a P atropisomer. 13. Pharmaceutical composition characterized by comprising a compound, as defined in any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 14. Use of a compound as defined in any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, characterized in that it is in the manufacture of a medicament for treating pain, cough or itching in a patient in need thereof. 15. Use according to claim 14, characterized by the fact that a) the pain is selected from chronic pain, acute pain, neuropathic pain, pain associated with rheumatoid arthritis, pain associated with osteoarthritis or pain associated with cancer ; b) the cough is selected from post-viral cough, viral cough or acute viral cough.