Alkyl dihydroquinoline sulfonamide compounds

Abstract

The present invention provides a compound of formula I, and a pharmaceutically acceptable salt thereof, which is an inhibitor of voltage-gated sodium channels, specifically Nav1.7. The compound can be used to treat diseases associated with the activity of sodium channels, such as pain disorders, cough and itching. A pharmaceutical composition containing the compound of the present invention is also provided.

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 269,518, filed December 18, 2015, the specification of which is hereby incorporated by reference in its entirety. Field of the Invention

[0003] The present invention provides compounds that are inhibitors of voltage-gated sodium channels (Nav), in particular Nav1.7, and are useful in treating diseases treatable by inhibition of sodium channels, such as pain disorders. Also provided are pharmaceutical compositions containing the compounds of the invention. Background of the Invention

[0005] A 2011 report by the Institute of Medicine estimated that 100 million adults in the United States (approximately 30% of the population) suffer from chronic pain (C&E News, Bethany Halford, "Changing the Channel", published 3-24). Chronic pain by definition involves abnormal electrical spikes in neurons in the pain pathway: 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 brainstem. Although the excitation of these neurons is regulated and managed by many different receptors, enzymes, and growth factors, in most neurons, the rapid ascending branch of the electrical spike is generated by the entry of sodium ions through voltage-gated sodium channels (Hille B, Ion Channels of Excitable Membranes. Sinauer Associates, Inc.: Sunderland MA, 3rd edition 2001). There are nine different isoforms of voltage-gated sodium channels (Nav1.1-Nav1.9), and they have different expression patterns in tissues including neurons as well as cardiac and skeletal muscle (Goldin,

[0006] AL, "Resurgence of sodium channel research," Ann Rev Physiol 63:871-894, 2001; Wood, JN, and Boorman, J. "Voltage-gated sodium channel blockers; target validation and therapeutic potential" Curr. Top Med. Chem. 5:529-537, 2005).

[0007] Nav1.1 and Nav1.2 are highly expressed in the brain (Raymond, CK et al., J.Biol.Chem. (2004) 279 (44): 46234-41) and are important for normal brain function. In humans, a certain loss of function caused by Nav 1.1 mutations causes epilepsy, presumably because these channels are expressed in inhibitory neurons (Yu, FH et al., Nat.Neuroscience (2006), 9 (9) 1142-1149). Nav1.1 is also expressed in the peripheral neuronal system, and inhibition of Nav1.1 in the periphery may provide pain relief. Therefore, although inhibition of Nav1.1 may provide for the treatment of pain, it may also be undesirable and may cause anxiety and overexcitement. Nav1.3 is mainly expressed in the fetal central nervous system, and is found to be upregulated in rats after nerve damage (Hains, BD et al., J.Neuroscience (2030) 23 (26): 8881-8892). Nav1.4 is mainly expressed in skeletal muscle. Mutations in the gene and its product have significant effects on muscle function, including paralysis (Tamaoka A., Internal Medicine (2003), (9): 769-770). Nav1.5 is mainly expressed in myocardial cells, including atria, ventricles, sinoatrial nodes, atrioventricular nodes, and cardiac Purkinje fibers. The rapid rise of cardiac action potentials and the rapid impulse conduction through cardiac tissue are caused by the opening of Nav1.5 channels. Mutations in Nav1.5 channels cause arrhythmic syndromes, including QTc prolongation, Brugada syndrome (BS), sudden 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 systems. Nav1.8 is mainly expressed in sensory ganglia such as dorsal root ganglia of the peripheral nervous system. No Nav1.8 mutations that produce changes in pain response have been identified in humans. Nav1.8 is different from most neuronal Nav isoforms because it is insensitive to inhibition by tetrodotoxin. Similar to Nav1.8, Nav1.9 is also a tetrodotoxin-insensitive sodium channel (Dib-Hajj, SD et al., Proc. Natl. Acad. Sci. USA (1998), 95 (15): 8963-8968) that is mainly expressed in dorsal root ganglion neurons.

[0008] Recent evidence from several independent genetic studies shows that the tetrodotoxin-sensitive voltage-gated sodium channel Nav1.7 (SCN9A) is required for pain perception. Several rare inherited forms of severe chronic pain, primary erythromelalgia and paroxysmal hyperalgesia, are caused by mutations that increase the activity of Nav1.7 (Fertleman CR, Baker MD, Parker KA, 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 sodium channel alpha subunit, in patients with primary erythermalgia,” J. Med. Genet. 41:171-174, 2004; Drenth JPH, te Morsche RHM, 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).In contrast, two separate clinical studies have determined that the genetic disorder congenital insensitivity to pain (CIP) is rooted in the loss of function of Nav1.7 by mutations that truncate the protein and destroy its function (Cox JJ, Reimann F, Nicholas AK et al. "An SCN9A channelopathy causes congenital inability to experience pain," Nature 444: 894-898, 2006; Goldberg YP, MacFarlane J., MacDonald ML, Thompson J. et al. "Loss-of-function mutations in the Nav1.7 gene underlying 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% penetrance. The phenotype associated with CIP is extreme: affected individuals report experiencing painless burns, childbirth, appendicitis, and fractures, and have insensitivity to clinical measures of pain such as pinpricks or tendon pressure. While sensory, motor, autonomic, and other measured functions are normal, the only abnormality reported is anosmia (inability to smell). These studies indicate that among many possible targets in the pain pathway, Nav1.7 regulates one or more control points important for pain perception.

[0009] Non-selective sodium channel inhibitors such as lidocaine, mexiletine and carbamazepine show clinical efficacy in chronic pain (including neuropathic pain), but they are limited in dosage and use, probably due to the influence on sodium channels outside the pain pathway. Lidocaine is used by local anesthesia doctors for minor surgery. Dentists use novocaine. However, these compounds do not distinguish between various sodium channel subtypes, 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," said Glenn F. King, a professor at the University of Queensland, Australia, who studies poisons that block ion channels. "This is a completely painless death, but the patient will still die." Therefore, selectivity for Nav1.7, especially over Nav1.5, is needed. Researchers have worked hard to find molecules that only inhibit or block the activity of Nav1.7. Complicating this issue is that the identity, location, function, and / or tertiary structure of each isoform of the voltage-gated sodium channel protein is unknown or not fully understood.

[0010] Currently, a large number of researchers are trying to identify small molecule inhibitors of Nav1.7. For example, Chafeev et al. disclose spiro-oxindole compounds for treating and / or preventing 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 different from the sulfonamide derivatives of the present invention. Therefore, it is necessary to identify Nav1.7 inhibitors that have selectivity exceeding at least Nav1.5 to treat pain. The present invention provides compounds that are selective inhibitors of Nav1.7 that have selectivity exceeding at least Nav1.5. SUMMARY OF THE INVENTION

[0012] In embodiment 1, the present invention provides a compound of formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0013]

[0014] in:

[0015] R 1 Yes (a) C 1-8 Alkyl, wherein the C 1-8 The alkyl group is selected from hydroxyl, -OC 1-4 Alkyl, -NH 2 、-NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl or -N(C1-4 Alkyl)C 1-4 0, 1, 2 or 3 groups of the alkyl group are substituted; or

[0016] (b)C 1-8 Haloalkyl;

[0017] R 2 is H, halide, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0018] R 3 It is C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl or –CN;

[0019] R 4 is a 5- to 6-membered heteroaryl group;

[0020] R 6 and R 7 each of is hydrogen; and

[0021] R 5a ; R 5b ; R 5c ; R 5d ; and R 5e Each of is independently hydrogen or halo.

[0022] In embodiment 2, the present invention provides a compound of formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 It is C 4-8 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Haloalkyl is C 1-6 Fluorinated alkyl.

[0023] In embodiment 3, the present invention provides a compound of formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from -CH 2 -CF 3 、-CH 2 -CH 2 -CF 3 、-CH 2 -CH 2 -CH 2 -CF 3 、-CH 2 -CH(CH 3 )-CF 3 、-CH2 -CF 2 -CF 3 、-CH 2 -C(CH 3 ) 2 -CF 3 、-C(CH 3 ) 2 -CH 2 -CF 3 , -CF 2 -CH 2 -CF 3 or -CH 2 -CH 2 -CHF 2 .

[0024] In embodiment 4, the present invention provides a compound of formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 It is H, fluorine, chlorine, methyl, CF 3 , CHF 2 or CH 2 F.

[0025] In embodiment 5, the present invention provides a compound of formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is H or fluorine. In a sub-embodiment of embodiment 5, R 2 It's fluorine.

[0026] In embodiment 6, the present invention provides a compound of formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 It's a methoxy group.

[0027] In embodiment 7, the present invention provides a compound of formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 It is a 5-membered heteroaryl.

[0028] In embodiment 8, the present invention provides a compound of formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 It is a 6-membered heteroaryl.

[0029] In embodiment 9, the present invention provides a compound of formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl or pyrimidinyl. In a subembodiment of embodiment 8, R 4 In another sub-embodiment of embodiment 8, R 4 It is isoxazolyl.

[0030] In embodiment 10, the present invention provides a compound of formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5a ; R 5b ; R 5c ; R 5d ; and R 5e Each of them is hydrogen.

[0031] In embodiment 11, the present invention provides a compound of formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is:

[0032]

[0033]

[0034]

[0035] In embodiment 11a, the present invention provides a compound of formula (I), or an enantiomer, a diastereomer, a rotation isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is 1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide.

[0036] In embodiment 11b, the present invention provides a compound of formula (I), or an enantiomer, a diastereomer, a rotation isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is 1-(5-chloro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide.

[0037] In embodiment 11c, the present invention provides a compound of formula (I), or an enantiomer, a diastereomer, a rotation isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is 1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-2-oxo-N-3-pyridazinyl-1,2-dihydro-6-quinolinesulfonamide.

[0038] In embodiment 11d, the present invention provides a compound of formula (I), or an enantiomer, diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, 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.

[0039] In embodiment 11e, the present invention provides a compound of formula (I), or an enantiomer, a diastereomer, a rotation isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, 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.

[0040] In embodiment 11f, the present invention provides a compound of formula (I), or an enantiomer, a diastereomer, a rotation isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide.

[0041] In embodiment 11g, the present invention provides a compound of formula (I), or an enantiomer, a diastereomer, a rotation isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is 1-(5-fluoro-2-methoxy-4-(4,4,4-trifluorobutyl)phenyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide.

[0042] In embodiment 11h, the present invention provides a compound of formula (I), or an enantiomer, a diastereomer, a rotation isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide.

[0043] In embodiment 11i, the present invention provides a compound of formula (I), or its enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, 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.

[0044] In embodiment 11j, the present invention provides a compound of formula (I), or an enantiomer, a diastereomer, a rotation isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, 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.

[0045] In embodiment 11k, the present invention provides a compound of formula (I), or an enantiomer, a diastereomer, a rotation isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, 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.

[0046] In embodiment 111, the present invention provides a compound of formula (I), or its enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, 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.

[0047] In embodiment 12, the present invention provides atropisomers of each individual compound listed in embodiments 11a to 111 independently, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0048] In embodiment 13, the present invention provides an M atropisomer of each individual compound listed in embodiments 11a to 111 independently, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0049] In embodiment 14, the present invention provides a pharmaceutical composition comprising a compound according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11a-111, 12 and 13, or an enantiomer, a diastereomer, a rotation isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0050] In embodiment 15, the present invention provides a method of treating pain, cough or itching, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11a-111, 12 and 13, or an enantiomer, a diastereomer, a transisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0051] In embodiment 16, the present invention provides the method of embodiment 15, wherein 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.

[0052] In embodiment 17, the present invention provides a method according to embodiment 15, wherein the cough is selected from post-viral cough, viral cough or acute viral cough. See Dib-Hajj et al., "The NaV1.7sodium channel: from molecule to man", Nature Reviews Neuroscience (2013), 14, 49-62. DETAILED DESCRIPTION OF THE INVENTION

[0054] The present invention provides a compound of formula (I) as defined above, its enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition comprising a compound of formula (I), a compound, its enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a method of using a compound of formula (I), a compound, its enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof to treat a disease and / or condition such as pain.

[0055] “C α-β "Alkyl" means an alkyl group containing a minimum of α and a maximum of β carbon atoms in branched or linear relationship or any combination of the two, wherein α and β represent integers. 0 Alkyl nomenclature indicates a direct bond. 1-6 Examples of alkyl groups include, but are not limited to, the following:

[0056]

[0057] The term "halo" or "halogen" refers to a halogen atom selected from F, Cl, Br and I.

[0058] The term "C α-β "Haloalkyl" means an alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halo atom, as defined herein. Common C α-β A haloalkyl group is C 1-3 Fluorinated alkyl. Common C 1-3 An example of a fluoroalkyl group is _CF 3 .

[0059] The term "heteroatom" as used herein means an oxygen atom, a nitrogen atom or a sulfur atom.

[0060] The term "aryl" means a cyclic aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Common aryl groups are six- to thirteen-membered rings.

[0061] The term "heteroaryl" means a cyclic aromatic hydrocarbon in which one or more carbon atoms of the aryl group have been replaced with 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, furanyl, 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 containing 1 to 4 heteroatoms. Five- and six-membered rings containing 1 to 3 heteroatoms are particularly common.

[0062] The term "pharmaceutically acceptable salt" means a salt prepared by conventional means and is well known to those skilled in the art. "Pharmaceutically acceptable salts" include alkaline salts of inorganic and organic 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 "pharmaceutically acceptable salts", see Berge et al., J. Pharm. Sci. 66: 1 (1977).

[0063] The term "substituted" means that a hydrogen atom on a molecule or group is replaced with a group or atom. Typical substituents include: halogen, C 1-8 Alkyl, hydroxyl, C 1-8 Alkoxy, –NR x R x , nitro, cyano, halo or perhalogenated C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, –SR x , –S(=O) 2 R x 、–C(=O)OR x , –C(=O)R x , where each R x are independently hydrogen or C 1 -C 8 Alkyl. It should be noted that when the substituent is –NR x R x When R x The groups may be linked together with the nitrogen atom to form a ring.

[0064] The group or atom replacing a hydrogen atom is also called a substituent.

[0065] Any particular molecule or group may have one or more substituents, depending on the number of hydrogen atoms that may be replaced.

[0066] The term "unsubstituted" refers to a hydrogen atom on a molecule or group. The term "substituted" refers to a hydrogen atom on a molecule or group replaced with a group or atom. Typical substituents include: halogen, C 1-8 Alkyl, hydroxyl, C 1-8 Alkoxy, –NR x R x , nitro, cyano, halo or perhalogenated C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, –SR x , –S(=O) 2 R x 、–C(=O)OR x , –C(=O)R x , where each R x are independently hydrogen or C 1 -C 8 Alkyl. It should be noted that when the substituent is –NR x R x When R x The groups may be linked together with the nitrogen atom to form a ring.

[0067] The symbol "-" represents a covalent bond and may also be used in a group to indicate the point of attachment to another group. In chemical structures, the symbol is often used to represent a methyl group in a molecule.

[0068] The term "leaving group" generally refers to a group that can be easily replaced by a nucleophile (such as an amine, thiol or alcohol nucleophile) or by a metal reagent (such as boric acid or borate) under transition metal catalyzed coupling conditions. 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, triflate, tosylate, etc. Where appropriate, preferred leaving groups are indicated herein.

[0069] The term "protecting group" generally refers to a group known in the art for preventing a selected reactive group (such as a carboxyl, amino, hydroxyl, sulfhydryl, etc.) from undergoing an unwanted reaction (such as a nucleophilic, electrophilic, oxidative, reductive, etc.). Where appropriate, preferred protecting groups are indicated herein. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkyloxycarbonyl, silanyl, etc. Examples of aralkyl include, but are not limited to, benzyl, o-methylbenzyl, trityl and diphenylmethyl, which may be optionally substituted with halogen, alkyl, alkoxy, hydroxyl, nitro, acylamino, acyl, etc., and salts such as phosphonium salts and ammonium salts. Examples of aryl include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl, etc. Examples of cycloalkenylalkyl or substituted cycloalkenylalkyl preferably have 6-10 carbon atoms, including but not limited to cyclohexenylmethyl, etc. Suitable acyl, alkoxycarbonyl and aralkyloxycarbonyl include benzyloxycarbonyl, tert-butoxycarbonyl, isobutoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, etc. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkyloxycarbonyl group. The amino protecting group can also form a nitrogen-containing heterocycle, wherein the amino protecting group is connected to nitrogen, such as 1,2-bis(methylene)benzene, phthalimide, succinimidyl, maleimide, etc., and wherein these heterocyclic groups can also include connected aryl and cycloalkyl rings. In addition, the heterocyclic group can be monosubstituted, disubstituted or trisubstituted, such as nitrophthalimide. Amino groups can also be protected to avoid unwanted reactions such as oxidation by forming addition salts (such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid, etc.). Many amino protecting groups are also suitable for protecting carboxyl, hydroxyl and sulfhydryl groups. For example, aralkyl groups. Alkyl groups are also suitable for protecting hydroxyl and sulfhydryl groups, such as tert-butyl.

[0070] The protecting group is removed under the condition that does not affect the remainder of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis, etc. A preferred method relates to removing the protecting group, such as removing the benzyloxycarbonyl by hydrogenolysis in a suitable solvent system such as alcohol, acetic acid, etc. or its mixture using palladium / carbon. The tert-butoxycarbonyl protecting group can be removed using an inorganic acid or an organic acid (such as HCl or trifluoroacetic acid) in a suitable solvent system such as dioxane or methylene chloride. The resulting amino salt can be easily neutralized to obtain free amine. The carboxyl protecting group (such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl, etc.) can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.

[0071] It should be noted that the compounds of the present invention may contain groups that can exist in tautomeric forms, such as cyclic and acyclic amidine and guanidine groups, heteroatom-substituted aromatic heterocyclyl groups (Y'=O, S, NR), etc., which are illustrated in the following examples:

[0072]

[0073] And although one form is named, described, shown, and / or claimed herein, all tautomeric forms are intended to be inherently encompassed by such name, description, showing, and / or claiming.

[0074] The present invention also contemplates prodrugs of the compounds of the present invention. Prodrugs are active or inactive compounds that are chemically modified to compounds of the present invention by physiological effects in vivo such as hydrolysis and metabolism after administration to a patient. The suitability and techniques involved in preparing and using prodrugs are well known to those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of masked carboxylate anions include various 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 into arylcarbonyloxymethyl-substituted derivatives that are cleaved by esterases in vivo, releasing free drug and formaldehyde (Bundgaard J. Med. Chem. 2503 (1989)). In addition, drugs containing acidic NH groups such as imidazole, imide, indole, etc. have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl 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.

[0075] The term "therapeutically effective amount" means an amount of a compound that improves, alleviates or eliminates one or more symptoms of a particular disease or condition, or prevents or delays the onset of one or more symptoms of a particular disease or condition.

[0076] The term "patient" means animals such as dogs, cats, cows, horses, sheep and humans. Particular patients are mammals. The term patient includes males and females.

[0077] The term "pharmaceutically acceptable" means that the substance in question (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 specific excipient) is suitable for administration to a patient.

[0078] The terms "treating," "treat," or "treatment" and the like include preventative (eg, prophylactic) and palliative treatment.

[0079] The term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant or other ingredient other than the active pharmaceutical ingredient (API), which is typically included for formulation and / or administration to a patient.

[0080] The compounds of the present invention are administered to the patient in a therapeutically effective amount. The compounds may be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds or compositions may be administered all at once, for example, by a single injection, for example, by multiple administrations of a series of tablets, or for example, by transdermal delivery, generally uniformly over a period of time. It should also be noted that the dosage of the compound may vary over time.

[0081] In addition, the compounds of the present invention can be administered alone, in combination with other compounds of the present invention, or in combination with other pharmaceutically active compounds. The other pharmaceutically active compounds can be used to treat the same disease or condition as the compounds of the present invention or different diseases or conditions. If the patient will receive or is receiving multiple pharmaceutically active compounds, the compounds can be administered simultaneously or continuously. For example, in the case of tablets, the active compound can be placed in one tablet or in a separate tablet, and the tablet can be administered once or sequentially in any order. In addition, it should be recognized that the composition can be in different forms. For example, one or more compounds can be delivered by tablets, while another can be administered by injection or orally as a syrup. All combinations, delivery methods, and administration sequences are considered.

[0082] The compounds of the invention may be used in the manufacture of a medicament for treating Nav1.7 mediated diseases and / or conditions such as pain, chronic cough or itching.

[0083] Pain is usually divided into two main types based on the duration of the pain: chronic pain and acute pain. Typically, chronic pain lasts longer 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 without an identified cause. An example of idiopathic pain is fibromyalgia.

[0084] Another type of pain is nociceptive pain. Nociceptive pain results from the stimulation of peripheral nerve fibers in response to highly noxious events, such as thermal, mechanical, or chemical stimuli.

[0085] Yet another type of pain is neuropathic pain. Neuropathic pain is pain caused by damage or disease that affects 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 the body that is no longer there. For example, a person who has had a leg amputated may feel pain in the leg even though the leg is no longer there.

[0086] In one embodiment of the method of treatment provided by the present invention using a compound of formula (I) or a pharmaceutically acceptable salt thereof, the disease is chronic pain. On the other hand, chronic pain is associated with, but is not limited to, post-herpetic neuralgia (shingles), rheumatoid arthritis, osteoarthritis, diabetic neuropathy, complex regional pain syndrome (CRPS), cancer or chemotherapy-induced pain, chronic back pain, phantom limb pain, trigeminal neuralgia, HIV-induced neuropathy, cluster headache disorders, and migraine, primary erythromelalgia, and paroxysmal pain.Other indications for Nav1.7 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)), epilepsy: 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 Behav. 7 (6): 629-638, 2008), learning and memory, cognition (Woodruff-Pak D.S. et al., Behav. Neurosci. 120 (2): 229-240, 2006), arrhythmias and fibrillation, systolic, 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 LC, CNS Drugs 22(1)27-47, 2008), Alzheimer's disease (Alzheimer's) (Kim DY et al., Nat. Cell. Biol. 9(7):755-764, 2007), and cancer (Gillet L. et al., J Biol Chem 2009 January 28 (Epub)).

[0087] 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 syndrome, tension headache, general inflammation, arthritis, rheumatic diseases, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin disorders with an inflammatory component, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetic maintenance pain, block pain syndrome, asthma, epithelial tissue damage or dysfunction, herpes simplex, respiratory, urogenital, gastrointestinal or vascular area visceral motility disorder, trauma, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulcer formation, duodenal ulcer, diarrhea, gastric lesions induced by necrotic agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, the method 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.

[0088] In another aspect of the present invention, the compound of the present invention can be used in combination with other compounds for the treatment of 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 compound of the present invention include non-steroidal anti-inflammatory compounds (NSAIDS), steroidal compounds, cyclooxygenase inhibitors and opioid analgesics.

[0089] The compounds of the present invention may also be used to treat diabetes, obesity and / or promote weight loss.

[0090] The compounds of the present invention may be used in combination with other pharmaceutically active compounds.It should be noted that the term "pharmaceutically active compound" may include biologics such as proteins, antibodies and peptibodies.

[0091] Because one aspect of the present invention contemplates the use of combinations of pharmaceutically active compounds that can be administered separately to treat diseases / conditions, the present invention also relates to combining separate pharmaceutical compositions in kit form. 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 separated bottle or a separated foil packet. Other examples of containers include syringes, boxes, and bags. Typically, the kit comprises instructions for use of the separate components. The kit form is particularly advantageous when the independent components are preferably administered in different dosage forms (e.g., oral and parenteral), when administered at different dosage intervals, or when the prescribing physician or veterinarian desires a titration regimen for the separate components of the combination.

[0092] The example of this kit is so-called blister pack. Blister pack is well known in the packaging industry and is widely used for packaging drug unit dosage forms (tablets, capsules, etc.). Blister pack is usually composed of a sheet of relatively hard material covered with a foil that is preferably a transparent plastic material. A recess is formed in the plastic foil during the packaging process. The recess has the size and shape of the tablet or capsule to be packaged. Next, the tablet or capsule is placed in the recess and sealed with a sheet of relatively hard material at the face of the foil opposite to the direction in which the recess is formed. As a result, the tablet or capsule is sealed in the recess between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablet or capsule can be removed from the blister pack by manually applying pressure on the recess to form an opening at the position of the recess of the sheet. The tablet or capsule can then be removed by the opening.

[0093] It may be desirable to provide a memory aid on the kit, for example, in the form of a number near the tablet or capsule, whereby the number corresponds to the number of days of the regimen on which the tablet or capsule so specified should be ingested. Another example of such a memory aid is a calendar printed on a card, for example, as follows "First week, Monday, Tuesday, ... etc. ... Second week, Monday, Tuesday, ... " etc. Other variations of memory aids will be apparent. A "daily dose" can be a single tablet or capsule to be taken on a given day, or several pills or capsules. In addition, the daily dose of a compound of the present invention can be composed of one tablet or capsule, while the daily dose of a second compound can be composed of several tablets or capsules, and vice versa. The memory aid should reflect this daily dose and help to correctly administer the active agent.

[0094] In another specific embodiment of the present invention, a dispenser designed to dispense one daily dose at a time in the expected order of use of the daily dose is provided. The dispenser is preferably equipped with a memory aid to further facilitate adaptability to the regimen. An example of such a memory aid is a mechanical counter that indicates the number of daily doses dispensed. Another example of such a memory aid is a battery-powered microchip memory with an additional liquid crystal readout or audible reminder signal that, for example, reads out the date of the last daily dose taken and / or reminds when to take the next dose.

[0095] If desired, the compounds of the present invention and other pharmaceutically active compounds can be administered to the patient orally, rectally, parenterally (e.g., intravenous, intramuscular or subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, topically (e.g., powders, ointments or drops), or as an oral or nasal spray. All methods used by those skilled in the art to administer pharmaceutically active agents are contemplated.

[0096] Compositions suitable for parenteral injection may include 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, etc.), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using a surfactant to maintain.

[0097] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Microbial contamination may be prevented by adding various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical compositions may be produced by using agents that delay absorption (e.g., aluminum monostearate and gelatin).

[0098] 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 of the following inert conventional excipients (or carriers): 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, polyvinyl pyrrolidone, 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 silicate complexes and sodium carbonate; (e) solubilizing agents, such as, for example, paraffin; (f) absorption promoters, such as, for example, quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as, for example, 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 form may also comprise buffering agents.

[0099] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose (milk sugar) as well as high molecular weight polyethylene glycols.

[0100] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the art. They may also contain opacifiers and may also be such compositions that release one or more active compounds in a delayed manner in certain parts of the intestinal tract. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compound may also be in microencapsulated form, where appropriate, with one or more of the above-mentioned excipients.

[0101] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, specifically cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and black sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters or mixtures of these substances, etc.

[0102] In addition to such inert diluents, the composition may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. In addition to the active compounds, the suspension may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or mixtures of these substances, etc.

[0103] 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 suppository waxes which are solid at ordinary room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredients.

[0104] The compounds of the present invention are used in dosage forms for topical administration including ointments, powders, sprays and inhalants. The active compound or suitable compound is mixed with a physiologically acceptable carrier and any preservative, buffer or propellant that may be required under aseptic conditions. Ophthalmic preparations, eye ointments, powders and solutions are also considered within the scope of the present invention.

[0105] The compounds of the present invention can be administered to patients at dosage levels ranging from about 0.1 to about 3,000 mg per day. For normal adults weighing about 70 kg, a dosage ranging from about 0.01 to about 100 mg per kilogram of body weight is generally sufficient. The specific dose and dosage range that can be used depend on several factors, including the patient's needs, the severity of the condition or disease being treated, and the pharmacological activity of the administered compound. The determination of the dosage range and optimal dose for a particular patient belongs to the general technology of the art.

[0106] The compounds of the present invention can be used as pharmaceutically acceptable salts, co-crystals, esters, amides or prodrugs. The term "salt" refers to inorganic and organic salts of the compounds of the present invention. The salt can be prepared on the spot during the final separation and purification of the compound, or by reacting the purified compound in the form of free alkali or acid with a suitable organic or inorganic base or acid alone and separating the salt thus formed. Representative salts include hydrobromate, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthyl acid salt, mesylate, gluconate, lactobionate and dodecylsulfonate etc. The salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, etc., and non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. See, e.g., SM Berge et al., "Pharmaceutical Salts," J Pharm Sci, 66: 1-19 (1977).

[0107] Examples of pharmaceutically acceptable esters of the compounds of the present invention include C 1 -C 8 Alkyl esters. Acceptable esters also include C 5 -C 7 Cycloalkyl esters, and aryl esters such as benzyl. 1 -C 4 Alkyl Esters. Esters of the compounds of the present invention can be prepared according to methods well known in the art.

[0108] Examples of pharmaceutically acceptable amides of the compounds of the present invention include those derived from ammonia, C 1 -C 8 Alkyl primary amine and C 1 -C 8 Amides of 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. 1 -C 3 Alkyl primary amine and C 1 -C 2 Amides of Secondary Dialkylamines Amides of the compounds of the present invention can be prepared according to methods well known to those skilled in the art.

[0109] The term "prodrug" means a compound that is transformed in vivo to produce a compound of the invention. The transformation can occur through various substrates, such as by 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," Volume 14 of the ACSSymposium Series, and in Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987.

[0110] To illustrate, if the compound of the invention contains a carboxylic acid functional group, the prodrug may comprise an ester formed by replacing the hydrogen atom of the acid group with a group such as: (C 1 -C 8 Alkyl, (C 2 -C1 2 )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 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)aminomethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactone, γ-butyrolactone-4-yl, di-N,N-(C 1 -C 2 ) alkylamino (C 2 -C 3 ) alkyl (such as β-dimethylaminoethyl), carbamoyl-(C 1 -C 2 ) alkyl, N,N-di(C 1 -C 2 )alkylcarbamoyl-(C 1 -C 2 )alkyl and piperidino-, pyrrolidino- or morpholino (C 2-3 )alkyl.

[0111] Similarly, if the compound of the invention contains an alcohol functional group, a prodrug may be formed by replacing the hydrogen atom of the alcohol group with a group such as: (C 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6)alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 -C 6 ) alkoxycarbonyloxymethyl, N-(C 1 -C 6 ) alkoxycarbonylaminomethyl, succinyl, (C 1 -C 6 ) alkanoyl, α-amino (C 1 -C 4 )alkanoyl, aroyl and α-aminoacyl or α-aminoacyl-α-aminoacyl, wherein each α-aminoacyl group is independently selected from: naturally occurring L-amino acids, –P(O)(OH) 2 , –P(O)(O(C 1 -C 6 )alkyl) 2 or a glycosyl group (a group derived from the hemiacetal form of a carbohydrate by removal of a hydroxyl group).

[0112] Additionally, if the compounds of the invention contain a sulfonamide moiety, the prodrug may be prepared by using, for example, -CH 2 P(O)(O(C 1 -C 6 )alkyl) 2 or -CH 2 OC(O)(C 1 -C 6 )alkyl group instead of the sulfonamide N(H) to form.

[0113] The compounds of the present invention also include prodrugs in tautomeric forms.

[0114] 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 and mixtures thereof (including racemic mixtures) form part of the present invention. In addition, the present invention contemplates all geometric and positional isomers. For example, if the compound contains a double bond, cis and trans forms (named S and E, respectively) and mixtures are contemplated.

[0115] Mixtures of stereoisomers, such as diastereomeric mixtures, can be separated into their individual stereochemical components on the basis of their physical chemical 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 reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.

[0116] Compounds of formula (I) may also exist as atropisomers. Atropisomers are compounds with the same structural formula, but the compounds have a specific spatial configuration caused by restricted rotation around the single bond due to major steric hindrance on either side of the single bond. Atropisomerism is independent of the presence of stereogenic elements such as asymmetric carbon. The terms "P atropisomer" or "M atropisomer" are used herein so that two atropisomers of the same pair can be named. For example, the following compound of step 1, intermediate B1 having the structure below can be separated into a pair of atropisomers P and M by a chiral column:

[0117]

[0118] The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrate), ethanol, etc. Both solvated and unsolvated forms are contemplated and encompassed by the present invention.

[0119] The compounds of the present invention may also 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 the present invention. For example, all keto-enol or imine-enamine forms of the compounds are also included in the present invention. Other examples of tautomerism are as follows:

[0120]

[0121] Those skilled in the art will recognize that the compound names and structures contained herein may be based on specific tautomers of the compounds. Although only the name or structure of a specific tautomer may be used, the present invention is intended to cover all tautomers unless otherwise stated.

[0122] The invention is also intended to encompass compounds synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists, or compounds synthesized using in vivo techniques, such as by metabolism, fermentation, digestion, etc. It is also contemplated that the compounds of the invention may be synthesized using a combination of in vitro and in vivo techniques.

[0123] The present invention also includes isotopically labeled compounds, which are identical to the compounds described 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 mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. 15 N. 16 O. 17 O. 31 P.32 P. 35 S. 18 F and 36 Cl. In another aspect, the compounds of the invention contain one or more deuterium atoms (2H) replacing one or more hydrogen atoms.

[0124] Compounds of the invention containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled compounds of the invention, for example, incorporating radioactive isotopes (such as 3 H and 14 C) can be used for drug and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e., 14 C) isotopes are particularly preferred because they are easy to prepare and detect. 2 Heavy isotope substitution with H) may offer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0125] The compounds of the present invention may exist in various solid states, including crystalline and amorphous forms. Different crystalline states (also known as polymorphs) and amorphous forms of the compounds of the present invention are contemplated as part of the present invention.

[0126] All patents and other publications mentioned herein are hereby incorporated by reference in their entirety.

[0127] The examples presented below illustrate specific embodiments of the invention. These examples are meant to be representative, and are not intended to limit the scope of the claims in any way.

[0128] It should be noted that when a percentage (%) is used in relation to a liquid, it is in relation to the volume percentage of the solution. When used in the case of a solid, it is in relation to the percentage of the solid composition. Materials obtained from commercial suppliers were generally used without further purification. Reactions involving air or moisture sensitive reagents were generally performed under nitrogen or argon atmospheres. 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, at H 2 5% to 100% CH in O 3 CN, 0.1% TFA, 1.5 mL / min for 15 min; System B: Zorbax SB-C8, 4.6 x 75 mm, in H2 10% to 90% CH in O 3 CN with 0.1% formic acid at 1.0 mL / min for 12 min) (Agilent Technologies, Santa Clara, CA). Silica gel chromatography was typically performed using pre-packed silica gel cartridges (Biotage, Uppsala, Sweden or Teledyne-Isco, Lincoln, NE). Data were recorded at ambient temperature on a Bruker AV-400 (400 MHz) spectrometer (Bruker Corporation, Madison, WI) or a Varian (Agilent Technologies, Santa Clara, CA) 400 MHz spectrometer. 1 H NMR spectra. All observed protons are reported as parts per million (ppm) downshifted from tetramethylsilane (TMS) or other internal standards in the appropriate solvents indicated. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant, and number of protons. Low-resolution mass spectral (MS) data were determined on an Agilent 1100 series (Agilent Technologies, Santa Clara, CA) LC / MS using UV detection at 254 nm and 215 nm and low-resonance electrospray mode (ESI).

[0129] Synthesis Example

[0130] The following list of abbreviations used or commonly used throughout the specification represent the following and should aid in understanding the present invention:

[0131] ACN, MeCN Acetonitrile

[0132] Aq., aq. water-based

[0133] Ar Argon (gas)

[0134] BOP Benzotriazol-1-yl-oxyl hexafluorophosphate

[0135] BuLi Butyl lithium

[0136] Cs 2 CO 3 Cesium carbonate

[0137] CHCl 3 Chloroform

[0138] CH 2 Cl 2 , DCM dichloromethane, methylene chloride

[0139] Cu(1)I Copper(1) iodide

[0140] DCC Dicyclohexylcarbodiimide

[0141] DIC 1,3-Diisopropylcarbodiimide

[0142] DIEA, DIPEA Diisopropylethylamine

[0143] DME Dimethoxyethane

[0144] DMF Dimethylformamide

[0145] DMAP 4-dimethylaminopyridine

[0146] DMS Dimethyl sulfide

[0147] DMSO Dimethyl sulfoxide

[0148] EDC, EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

[0149] Et 2 O Diethyl ether

[0150] EtOAc Ethyl acetate

[0151] FBS Fetal Bovine Serum

[0152] G, gm grams

[0153] h, hr hours

[0154] H 2 hydrogen

[0155] H 2 O Water

[0156] HCl

[0157] HOAc Acetic acid

[0158] HPLC High Pressure Liquid Chromatography

[0159] IPA, IpOH Isopropyl alcohol

[0160] K 2 CO 3 Potassium carbonate

[0161] KI Potassium iodide

[0162] LG Leaving Group

[0163] LDA Lithium diisopropylamide

[0164] LiOH Lithium Hydroxide

[0165] MgSO 4 Magnesium sulfate

[0166] MS or m / z mass spectrometry

[0167] MeOH Methanol

[0168] N 2 Nitrogen

[0169] NaCNBH 3 Sodium cyanoborohydride

[0170] Na 2 CO 3 Sodium carbonate

[0171] NaHCO 3 Sodium bicarbonate

[0172] NaH Sodium hydride

[0173] NaI Sodium iodide

[0174] NaBH 4 Sodium borohydride

[0175] NaOH Sodium hydroxide

[0176] Na 2 SO 4 Sodium sulfate

[0177] NH 4 Cl Ammonium chloride

[0178] NH 4 OH Ammonium hydroxide

[0179] P(t-bu) 3 Tri(tert-butyl)phosphine

[0180] PBS Phosphate buffered saline

[0181] Pd / C Palladium / Carbon

[0182] Pd(PPh 3 ) 4 Palladium(0)tetrakis(triphenylphosphine)

[0183] Pd(dppf)Cl 2 Palladium(1,1-bis(diphenylphosphinoferrocene)(II)) chloride

[0184] Pd(PhCN) 2 Cl 2 Palladium dicyanophenyl dichloride

[0185] Pd(OAc) 2 Palladium acetate

[0186] Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium

[0187] RT, rt room temperature

[0188] RBF, rbf round bottom flask

[0189] TLC, tlc thin layer chromatography

[0190] TEA, Et 3 N-Triethylamine

[0191] TFA Trifluoroacetic acid

[0192] THF Tetrahydrofuran

[0193] 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 to limit the scope of the present invention, but should only be considered to illustrate and represent the present invention.

[0194] Intermediate A1: racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0195]

[0196] Step 1: 4-Bromo-2-iodoaniline

[0197] To a solution of 4-bromo-aniline (500 g, 2.90 mol, 2.0 equivalents, Saibain Chem) in cyclohexane (2.5 L) was added iodine (368 g, 1.45 mol, 1.0 equivalents, Qualigens) and the mixture was heated at 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 reactant was heated at 50 ° C for 4 h. The reactant was cooled to room temperature, diluted with ethyl acetate (5.0 L) and washed with aqueous sodium sulfite (2.5 Kg in 4.0 L) solution. 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 the crude material, which was purified by column chromatography (silica gel; mesh size 60-120, elution 0%-20% ethyl acetate and hexanes) to afford 4-bromo-2-iodoaniline (650 g, 75%) as an off-white solid. TLC solvent system: 100% hexanes. R of the product f : 0.6. MS (ESI, positive ion) m / z: 297.0 (M+1). 1HNMR (400MHz, CDCl 3 )δ7.72(d,J=2.5Hz,1H),7.23(dd,J=8.4,2.1Hz,1H),6.62(d,J=8.3Hz,1H),4.09(s,2H).

[0198] Step 2: (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate

[0199] To a solution of 4-bromo-2-iodoaniline (750 g, 2.51 mol, 1.0 eq.) in DMF (5.0 L) was added ethyl acrylate (277 g, 2.76 mol, 1.1 eq., Avra) and sodium bicarbonate (680 g, 6.29 mol, 2.5 eq.). 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 eq., Hindustan Platinum). The reaction mixture was heated at 70 °C for 3 h. The reactants were stirred for 1 h at room temperature. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was stirred for Filter and The bed was washed with ethyl acetate (2 x 500 mL). The filtrate was concentrated under reduced pressure to obtain a crude residue which was subjected to column chromatography (silica gel; mesh size 60-120, eluting 0%-20% ethyl 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. The R of the product f : 0.4. MS (ESI, positive ion) m / z; 270.2 (M+1). 1 HNMR (400MHz, DMSO) δ7.75(d,J=16.1Hz,1H),7.57(d,J=2.0Hz,1H),7.16(dd,J=9.1,2.4Hz,1H),6.6 6(d,J=8.6Hz,1H), 6.43(d,J=8.6Hz,1H), 5.81(s,2H), 4.20(q,J=7.2Hz,2H), 1.27(t,J=7.2Hz,3H).

[0200]

[0201] Step 3: (E)-3-(2-amino-5-(benzylthio)phenyl) ethyl acrylate (the above scheme needs to be redrawn)

[0202] 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) was added DIPEA (1.26 L, 8.88 mol, 3.9 equiv, GLR) 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 to 80 °C for 30 min. The reactants were cooled to RT and benzyl mercaptan (455.5 g, 3.67 mol, 1.6 equiv, Alfa Aesar) was added and the reactants were heated at 80 °C for another 4 h. The reaction was cooled to room temperature and diluted with ethyl acetate (4.0 L). The mixture was stirred for 2 h. Filter and The bed was washed with ethyl acetate (2 x 1.0 L). The filtrate was concentrated under reduced pressure to obtain a crude material, which was purified by chromatography (silica gel; mesh size 60-120, eluting 0%-40% ethyl acetate and petroleum ether) 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 hexane. The R of the product f : 0.4. MS (ESI, positive ion) m / z; 314.1 (M+1). 1 H NMR(400MHz, DMSO)δ7.79(d,J=16.1Hz,1H),7.37(d,J=2.0Hz,1H),7.25–7.17(m,5H)7.10(dd,J=8.4,2.1Hz,1H),6. 61(d,J=8.3Hz,1H), 6.32(d,J=15.2Hz,1H), 5.75(s,2H), 4.20(q,J=7.2Hz,2H), 4.01(s,2H), 1.27(t,J=7.2Hz,3H).

[0203]

[0204] Step 4: 1-Bromo-2-fluoro-4-iodo-5-methoxybenzene

[0205] To a solution of 2-bromo-1-fluoro-4-methoxybenzene (500.0 g, 2.44 mol, 1.0 eq.) in DCM (5.0 L) was added silver trifluoromethanesulfonate (686.0 g, 2.68 mol, 1.1 eq., Angene) and the reaction mixture was stirred for 20 min. Iodine (678.0 g, 2.68 mol, 1.1 eq.) was added to the reactant and the mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM (3.0 L) and heated to 40 ℃ for 1 h. Filter. The CELITE bed was washed with DCM (2x 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 sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude material, which was purified by chromatography (silica gel; mesh size 60-120, eluted with 0%-5% ethyl acetate 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% hexane. The R of the product f : 0.6. MS (ESI, positive ion) m / z: 331.0 (M+1). 1 HNMR (400MHz, CDCl 3 )δ7.55(d,J=7.2Hz,1H),6.95(d,J=5.6Hz,1H),3.89(s,3H).

[0206] Step 5: (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate

[0207] 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 Cs 2 CO 3 (468 g, 1436.3 mmol, 1.5 eq., Spectrochem) and the mixture was degassed with nitrogen for 20 min. 2 (dba) 3 (35 g, 38.2 mmol, 0.04 eq., Hindustan Platinum) and XantPhos (44.6 g, 76.4 mmol, 0.08 eq., GLR) were added to the reaction mixture and the mixture was heated at 110° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (2.0 L) and stirred for 2 h. The filtrate was concentrated under reduced pressure to obtain a 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 a yellow solid. TLC solvent system: 30% ethyl acetate in hexane. The R of the product f : 0.5. MS (ESI, positive ion) m / z; 516.2 (M+1). 1 HNMR (400 MHz, DMSO) δ 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: No NH protons were observed.

[0208]

[0209] Step 6: 6-(Benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one

[0210] 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) was added tri(n-butyl)phosphine (50% solution in ethyl acetate, 48.9 mL, 96.8 mmol, 0.2 equiv, Spectrochem) and the reaction mixture was heated at 70 °C for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude material which was purified by stirring with 5% ethyl acetate in hexanes (1.0 mL) and filtered to afford 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. R of the product f : 0.3. MS (ESI, positive ion) m / z; 470.0 (M+1). 1HNMR (400MHz, DMSO) δ7.92(d,J=9.1Hz,1H),7.79(d,J=1.7Hz,1H),7.65(d,J=6.1Hz,1H),7.57(d,J=8 .8Hz,1H),7.40–7.22(m,6H),6.68(d,J=9.6Hz,1H),6.56(d,J=8.8Hz,1H),4.24(s,2H),3.69(s,3H).

[0211] Steps 7 and 8: Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate

[0212] 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 eq) in acetonitrile (2.5 L) was 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 eq, Aldrich) was added portionwise over 20 min, keeping the internal temperature below 5°C. The resulting suspension was stirred at 0°C-5°C under nitrogen for 45 min. A solution of pentafluorophenol (127.2 g, 690.95 mmol, 1.3 eq, Apollo) in acetonitrile (200 mL) was then added over 5 min, followed by NEt over 20 min. 3 The mixture was stirred for 30 min at 0 ° C to 5 ° C. (307.7 mL, 2.12 mol, 4.0 equivalents), keeping the internal temperature below 5 ° C. The mixture was stirred for 30 min at 0 ° C to 5 ° C. Water (4.0 L) was added and extracted with ethyl acetate (2x2.0 L). The organic layer was washed with brine (1.0 L), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified and filtered by stirring with isopropanol: hexane (1: 1, 1.0 L) to obtain a racemic 1- (4- bromo-5-fluoro-2-methoxyphenyl) -2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (190 g, 60%) as a white solid. TLC solvent system: 30% ethyl acetate in petroleum ether, R of the product f : 0.4. MS (ESI, positive ion) m / z; 594.2 (M+1). 1H-NMR (400MHz, DMSO) δ8.60(d,J=2.0Hz,1H),8.26(d,J=9.8Hz,1H),7.95(dd,J=2.2,9.1Hz,1H),7.70(t,J=8.6Hz,2H),6.95-6.88(m,2H),3.72(s,3H).

[0213] Intermediate B1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0214]

[0215] Step 1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0216] The precipitate was purified by chiral OJ column (40% MeOH / 60% CO 2 ) was separated from racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (see Intermediate A1 above, 76.90 g) to obtain (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester and (M)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester as light yellow flocculent solids. Peak 1 data: m / z (ESI) 594.0 (M+H) + Peak 2 data: m / z (ESI) 594.0 (M+H) + .

[0217]

[0218] Step 2: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0219] A solution of (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (6.00 g, 10.10 mmol) and 3-aminoisoxazole (0.821 ml, 11.11 mmol) in THF (200 mL) in a 250-mL round-bottom flask was cooled to 0° C., and a 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (21.20 ml, 21.20 mmol) was added dropwise. After the yellow solution was stirred at 0° C. for 15 min, it was quenched with 1N HCl at 0° C. and extracted three times with EtOAc. The organic extracts were combined and purified by MgSO 4 Dry, filter, and concentrate to a light brown residue. Add Et 2 O, and the slurry was ground and sonicated. Filtration gave an off-white solid, which was washed with Et 2 O was washed twice and dried under vacuum to give 3.88 g of the product as an off-white solid. The filtrate was concentrated in vacuo and purified by column chromatography (12 g silica gel, 35% to 100% EtOAc / hept gradient) to give an additional 1.36 g of the product as a light 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) + .

[0220] Intermediate C1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0221]

[0222] A 250-mL round-bottom flask was charged with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (see Step 1 of Intermediate B1 above, 11.34 g, 19.08 mmol) and N-(4-methoxybenzyl)isoxazole-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) was added dropwise to the stirred reaction mixture via a syringe over 10 min. After 15 min, 1.0 N HCl (100 mL) was introduced and the resulting reaction mixture was warmed 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 × 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, 10% CH 2 Cl 2 as an additive) to give (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 anhydrous solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.82(d,J=2.0Hz,1H),8.38(d,J=2.3Hz,1H),8.17(d,J=9.4Hz,1H),7.76(t,J=5.1Hz,1H),7.68(d,J=6.1Hz,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)+.

[0223] Intermediate D1: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0224]

[0225] Step 1: (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate

[0226] To a solution of (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (175 g, 555.0 mmol, 1.0 eq) and 1-bromo-2-chloro-4-iodo-5-methoxybenzene (231.3 g, 666.2 mmol, 1.1 eq) in toluene (1.5 L) was added cesium carbonate (357.5 g, 1100 mmol, 2.0 eq) and the mixture was degassed with nitrogen for 20 min. Pd2(dba)3 (12.5 g, 13.0 mmol, 0.025 eq) and xantphos (15.8 g, 27.2 mmol, 0.05 eq) were added to the reaction mixture and the mixture was heated at 110 °C for 5 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (1.0 L) and filtered through celite. The filtrate was concentrated under reduced pressure to obtain the crude material, which was purified by stirring with 5% ethyl acetate in hexanes (1.5 L) for 30 min and filtered to obtain (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate (290 g, 85%) as a yellow solid. m / z (ESI) 532.2 (M+H) + .

[0227]

[0228] Step 2: 6-(Benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)-one

[0229] To a solution of (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate (300.0 g, 5630.0 mmol, 1.0 equiv) in methanol (3.0 L) was added tri(n-butyl)phosphine (50% solution in ethyl acetate, 56.2 mL, 1126 mmol, 0.2 equiv) and the reaction mixture was heated at 70 °C for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude material, which was purified by stirring with 5% ethyl acetate in hexanes (1.0 mL) and filtered to afford 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) + .

[0230] Step 3: Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate

[0231] To a solution of 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)-one (400.0 g, 824.9 mmol, 1.0 eq) in acetonitrile (2.5 L) and THF (2.5 L) was added acetic acid (1.0 L) and water (700 mL). 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 eq) was added portionwise over 30 min, keeping the internal temperature below 5 °C. The resulting suspension was stirred at 0 °C under nitrogen for 45 min. Then add pentafluorophenol (197.4g, 1072.3mmol, 1.3 equivalents) in acetonitrile (500mL) solution in 5min, then add triethylamine (477mL, 3299mol, 4.0 equivalents) in 30min, keep the internal temperature below 5°C. The mixture is stirred for 50min at 0°C. Add water (4.0L) and extract with ethyl acetate (3x 2.0L). The organic layer is washed with brine (2.0L), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude material, which is purified by stirring with isopropanol: hexane (1: 1, 2.0L) and filtered to obtain 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (360g, 72%) as a white solid. m / z (ESI) 610.6 (M+H) + .

[0232]

[0233] Step 4: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester and (M)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0234] 1-(4-Bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (156 g, 255 M MOLE) was purified by chiral SFC chromatography ((S,S) Whelk-O, 45% isopropanol) to give (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (72.66 g, 93% yield) and (M)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (76.13 g, 98% yield) as white solids. m / z (ESI) 610.6 (M+H) + .

[0235] Step 5: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0236] To 100mL RB flask add (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (2.56g, 4.19mmol).Flask is placed under nitrogen, then THF (41.9ml) and isoxazole-3-amine (0.423g, 5.03mmol) are added.Mixture is cooled to 0 ℃, continues 10min, then LHMDS 1.0M in THF (8.80ml, 8.80mmol) is added dropwise in 5min.Reactant is stirred for two hours.When still relatively cold, 1N HCl (50mL) and EtOAc (50mL) are added.Separate each layer, and organic layer is washed again with 1N HCl.Merge water layer and extract with EtOAc (2x50mL).All organics merged are dried with sodium sulfate, filtered and concentrated. The material was purified by chromatography on silica gel (40%-100% EtOAc / heptane) to afford (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. 1 H NMR (400 MHz, DMSO-d 6)δ=11.66(br.s.,1H),8.69(d,J=1.47Hz,1H),8.35(d,J=2.15Hz,1H),8.22(d,J=9.59Hz,1H),7.83(dd,J=8.95,2.20Hz, 1H),7.77(s,1H)7.70-7.74(m,1H),6.85(d,J=8.90Hz,1H),6.79(d,J=9.59Hz,1H),6.42(d,J=1.76Hz,1H),3.72(s,3H). m / z(ESI)511.0(M+H)+.

[0237] Intermediate E1: (M)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0238]

[0239] The title compound was prepared according to the method of Intermediate D1, except that (M)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester was used instead of (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester to give (M)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide as an off-white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ=11.66(br.s.,1H),8.69(d,J=1.47Hz,1H),8.35(d,J=2.15Hz,1H),8.22(d,J=9.59Hz,1H),7.83(dd,J=8.95,2.20Hz, 1H),7.77(s,1H)7.70-7.74(m,1H),6.85(d,J=8.90Hz,1H),6.79(d,J=9.59Hz,1H),6.42(d,J=1.76Hz,1H),3.72(s,3H). m / z(ESI)511.0(M+H)+. Example

[0240] Example 1: (P)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0241]

[0242] The vial was charged with active 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 slowly added dropwise and the reactants were slowly warmed to room temperature and stirred for one hour. Palladium (II) acetate (2.73 mg, 0.012 mmol), 2'-(dicyclohexylphosphino)-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 Intermediate B1 above, 0.100 g, 0.202 mmol) were added and the reactants were stirred at 50°C for two hours. The reactant 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 by column chromatography (RediSep Gold 40g, gradient elution 0%-100% EtOAc: heptane) to obtain (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. 1 H NMR (400 MHz, DMSO-d 6 )δ=2.64-2.78(m,2H)2.87-3.03(m,2H)3.66(s,3H)6.44(d,J=1.81Hz,1H)6.77(dd,J=15.32,9.30Hz,2H)7.30-7.41( m,2H)7.84(dd,J=8.97,2.23Hz,1H)8.21(d,J=9.69Hz,1H)8.36(d,J=2.18Hz,1H)8.73(d,J=1.76Hz,1H)11.65(s,1H). m / z(ESI)512.2(M+H) + .

[0243] Example 2: (P)-1-(5-chloro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0244]

[0245] 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 instead of Intermediate B1 to give (P)-1-(5-chloro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.025 g, 0.047 mmol, 24.19% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=2.62-2.78(m,2H)2.97-3.09(m,2H)3.69(s,3H)6.44(d,J=1.71Hz,1H)6.77(dd,J=14.25,9.33Hz,2H)7.43(s,1H)7.5 5(s,1H)7.84(dd,J=8.97,2.12Hz,1H)8.21(d,J=9.69Hz,1H)8.36(d,J=2.02Hz,1H)8.73(d,J=1.71Hz,1H)11.66(s,1H). m / z(ESI)528.0(M+H) + .

[0246] Example 3: (P)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0247]

[0248] Step 1: (P)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0249] The vial was charged with active 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 added dropwise slowly. The reactants were warmed to room temperature and stirred for one hour. (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (see Step 1 of Intermediate Intermediate B1 above, 0.500 g, 0.841 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.043 g, 0.084 mmol) were added and the reactants were stirred at 50°C for one hour. The reaction was stirred by Filter the pad and The pad 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 by column chromatography (RediSep Gold 40g, gradient elution 0%-50% EtOAc: heptane) to give (P)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (0.104, 0.170mmol, 20.22% yield) as a white solid. m / z(ESI)612.0(M+H) + .

[0250] Step 2: (P)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0251] A round-bottomed flask is charged with pyridazine-3-amine (10.11mg, 0.106mmol) and DMSO (0.204ml) to obtain a solution. (P)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl) phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (0.050g, 0.082mmol) and THF (0.613ml) are added. The flask is cooled in an ice bath for 5 minutes, then LHMDS (1M, in THF) (0.188ml, 0.188mmol) is added dropwise. The reactant is stirred for 15 minutes. The reactant is diluted with ethyl acetate and washed twice with 1NHCl solution. The organic layer is washed with salt water, dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (RediSep Gold 40g, gradient elution 10%-75% [3:1 EtOAc / EtOH]:heptane) to afford (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 white solid. 1 H NMR (400 MHz, DMSO-d 6)δ=2.62-2.79(m,2H)2.89-3.04(m,2H)3.66(s,3H)6.67(d,J=8.86Hz,1H)6.76(d,J=9.59Hz,1H)7.30-7.40(m,2H)7.68(dd, J=9.43, 3.73Hz, 1H) 7.84 (d, J= 7.98Hz, 1H) 7.93 (d, J= 9.23Hz, 1H) 8.18 (d, J= 9.64Hz, 1H) 8.25-8.38 (m, 2H) 14.49 (br.s., 1H). m / z(ESI)523.0(M+H) + .

[0252] Example 4: (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

[0253]

[0254] Step 1: (3,3,3-Trifluoro-2-methylpropyl)zinc(II) bromide (0.033M)

[0255] The oven-dried round-bottom flask equipped with a magnetic stirring bar and a rubber septum is charged with lithium chloride (0.888g, 20.94mmol). The container is heated with a heat gun under high vacuum for 10min and backfilled with nitrogen after cooling to room temperature. Zinc (1.369g, 20.94mmol) is added. The container is heated with a heat gun under high vacuum for 10min again and backfilled with nitrogen after cooling to room temperature. THF (13.96ml) and 1,2- dibromoethane (0.045ml, 0.524mmol) are added by syringe, and the reaction mixture is heated at 60°C until bubbling occurs. After cooling to room temperature, TMS-Cl (0.040ml, 0.314mmol) and iodine (0.027g, 0.105mmol) solution in THF (0.2mL) are added by syringe. The reaction mixture is heated at 60°C for 20min, 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 allowed to stand at room temperature for 1 hour and the solution was drawn up in a syringe and transferred to an oven-dried screw-top vial with a polytetrafluoroethylene septum. The solution was titrated into 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) by dropwise addition until the orange color disappeared. 0.8 mL of solution was used, corresponding to a concentration of 0.033 M.

[0256]

[0257] Step 2: (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

[0258] A vial was charged with palladium(II) acetate (3.27 mg, 0.015 mmol), 2'-(dicyclohexylphosphino)-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 Intermediate B1 above, 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 was stirred at 50° C. for one hour. The reaction was diluted with ethyl acetate and washed with 1N aqueous HCl. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (RediSep Gold 40g, gradient elution 0%-50% [3:1 EtOAc / EtOH]:heptane) to afford (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 pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=1.09(dd,J=6.79,2.54Hz,3H)2.69-2.77(m,1H)2.85(br.s.,1H)3.08(dd,J=12.96,3.84Hz,1H)3.66(s,3H)6.44(d,J=1.76Hz,1H)6.74-6 .81(m,2H)7.29-7.41(m,2H)7.84(dd,J=9.17,2.23Hz,1H)8.21(d,J=9.64Hz,1H)8.36(d,J=2.18Hz,1H)8.72(d,J=1.76Hz,1H)11.65(s,1H). m / z(ESI)526.0(M+H) + .

[0259] Example 5: (P)-1-(5-fluoro-2-methoxy-4-(4,4,4-trifluorobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0260]

[0261] 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 give (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), which was obtained as a brown solid. 1 HNMR (400 MHz, DMSO-d 6 )δ=11.65(s,1H),8.71(d,J=1.66Hz,1H),8.35(d,J=2.18Hz,1H),8.20(d,J=9.64Hz,1H),7.83(dd,J=9.02,2.18Hz,1H),7.31(d,J= 9.74Hz,1H),7.25(d,J=6.84Hz,1H),6.76-6.80(m,2H),6.43(s,1H),2.80(t,J=7.88Hz,2H),2.32-2.45(m,2H),1.84-1.92(m,2H). m / z(ESI)526.0(M+H)+.

[0262] Examples 6A and 6B: rac- and (P)-1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, respectively.

[0263]

[0264] Step 1: 1-(5-fluoro-2-methoxy-4-vinylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0265] 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 Intermediate C1 above, 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 dibutyl vinylboronate (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 by column chromatography (RediSep Gold 40g, gradient elution 0%-100% EtOAc: heptane) to give 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 pale yellow solid. m / z (ESI) 562.0 (M+H) + .

[0266] Step 2: 1-(5-fluoro-4-formyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0267] 1-(5-fluoro-2-methoxy-4-vinylphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.652g, 1.161mmol) was dissolved in acetonitrile (9.95ml) and water (1.659ml). Ruthenium (III) chloride dihydrate (0.05M aqueous solution) (1.161ml, 0.058mmol) was added, followed by sodium periodate (0.129ml, 2.322mmol) in batches. The reactant was stirred at room temperature for one hour. The reactant was quenched with aqueous sodium thiosulfate and extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (RediSep Gold 40g, gradient elution 0%-100% EtOAc:heptane) to give 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) + .

[0268]

[0269] 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-dihydroquinoline-6-sulfonamide

[0270] A round-bottom flask is charged with 1-(5-fluoro-4-formyl-2-methoxyphenyl)-N-(isoxazole-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) are added continuously, and the reactant is stirred at room temperature for three hours. 1N HCl (1.242 ml, 1.242 mmol) is added, and the reactant is stirred for one hour. The reactant is diluted with ethyl acetate and washed with water. The aqueous layer is extracted with ethyl acetate, and the combined organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (Biotage SNAP 25 g column, gradient elution 0%-75% EtOAc:heptane) to give 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) + .

[0271] Step 4: OO-(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)phenylthiocarbonate

[0272] 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). 4A molecular sieves (0.100 g, 0.155 mmol) and DMAP (0.038 g, 0.309 mmol) were added, and the mixture was stirred vigorously. Thiochlorothioate (0.043 ml, 0.309 mmol) was slowly added to produce a thick slurry. The reactants were stirred at 60 ° C for two hours. The reactants were stirred for two hours at 60 ° C. Filter and Washed with DCM. The filtrate was concentrated and purified by column chromatography (RediSep Gold 12g, gradient elution 0%-100% EtOAc:heptane) to give 0-(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)phenylthiocarbonate (0.106 g, 0.138 mmol, 89% yield) as a white solid. m / z (ESI) 770.0 (M+H) + .

[0273]

[0274] Step 5: 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

[0275] Phenyl OO-(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)carbonothioate (0.106 g, 0.138 mmol) was dissolved in toluene (2.75 ml) and cooled to -78°C. Tri-n-butyltin hydride (0.182 ml, 0.689 mmol) and a 1.0 m solution of triethylborane in hexanes (0.138 ml, 0.138 mmol) were added and a syringe filled with air was bubbled through the solution to produce a bright pink solution. The reaction was stirred at -78°C for 30 minutes. 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 by column chromatography (RediSep Gold 12g, gradient elution 0%-100% EtOAc:heptane) to give 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) + .

[0276] 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)

[0277] 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 to 50 °C for two hours. The reaction was concentrated and purified by column chromatography (RediSep Gold 40 g, gradient elution 0%-75% [3:1 EtOAc / EtOH]:heptane) to give 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 an off-white solid. m / z (ESI) 498.0 (M+H) + .

[0278]

[0279] Step 7: (P)-1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (Example 6B)

[0280] Racemic 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) was purified by chiral SFC (Regis Whelk-O s,s, 25% methanol) to give (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 an off-white solid. 1 HNMR (500 MHz, DMSO-d 6 )δppm 3.66 (s, 3H) 3.82 (d, J = 11.42Hz, 2H) 6.35 (br.s., 1H) 6.71 (d, J = 8.50Hz, 1H) 6.77 (d, J = 9.28Hz, 1H) 7.41 (d, J = 5. 84Hz, 1H) 7.46 (d, J = 9.28Hz, 1H) 7.82 (d, J = 8.69Hz, 1H) 8.19 (d, J = 9.60Hz, 1H) 8.30 (br.s., 1H) 8.59 (br.s., 1H). m / z(ESI)498.0(M+H) + .

[0281] The following compounds can be prepared from appropriate starting materials similarly to the methods for preparing the above-exemplified compounds.

[0282]

[0283]

[0284] Biological Examples

[0285] The following assays were used to test exemplary compounds of the invention. The data for those examples tested according to the procedure described below are presented in Table 1 below.

[0286] In vivo assay of Nav1.7 or Nav1.5 IWQ

[0287] HEK 293 cells stably transfected with Nav 1.7 or Nav 1.5 were cultured according to the manufacturer's instructions. Recordings were performed in population patch clamp mode using a Quattro automated electrophysiology system (Molecular Devices, LLC, Sunnyvale, CA). Sodium channel currents were measured in response to a series of depolarizations that successively induced greater inactivation.

[0288] The cells were held at -110 mV for three seconds (Nav 1.7) or half a second (Nav 1.5) from a holding voltage of -15 mV, and then subjected to a series of 26 pulses of 150 msec duration at a frequency of 5 Hz to -20 mV. The cells were then left unclamped for a period of 3 to 8 minutes while a single concentration of the test compound was added. The cells were then re-clamped and subjected to the same voltage protocol. The leakage current was corrected by subtracting the current at the end of the 26th pulse to -20 mV from the peak current excited by the 26th pulse to -20 mV. The percentage of blockade was calculated in duplicate for each concentration, and the IC 50 Curves were fitted to the percentage of blocking as a function of concentration.

[0289] Nav1.7 in vitro PX assay

[0290] HEK 293 cells stably transfected with human Nav1.7 were recorded in whole-cell voltage clamp mode using the PatchXpress automated electrophysiology system (Molecular Devices, LLC, Sunnyvale, CA). The effects of compounds on partially inactivated states of sodium channels were measured. Cells were clamped to a holding potential that produced 20% to 50% inactivation. To elicit sodium currents, channels were activated by pulsing to -10mV for 20msec. This voltage scheme was repeated at a rate of 0.1Hz throughout the experiment. A single concentration of the test compound was applied to the cells for a duration of 3 minutes. Peak sodium currents were measured at the end of the compound addition period to determine the percentage of inhibition. Three to five cells were tested for each concentration, and the IC 50 Curves were fitted to percent inhibition as a function of concentration.Data representative of compounds of the invention are presented in the tables herein.

[0291] Nav 1.5 in vitro PX assay

[0292] 293 cells stably transfected with Nav 1.5 were recorded in whole-cell voltage clamp mode using the PatchXpress automated electrophysiology system (Molecular Devices, LLC, Sunnyvale, CA) according to the manufacturer's instructions. Cells were kept at a holding potential of -50 mV to inactivate sodium channels. To elicit sodium currents, the voltage was changed to -120 mV to allow a portion of the channels to recover, followed by a test pulse of 20 msec duration delivered at 0.1 Hz. A single concentration of the test compound was applied to the cells for a duration of 5 minutes. Peak sodium currents were measured at the end of the compound addition period to determine the percentage of inhibition. A minimum of two cells were tested for each concentration. The IC 50 Curves were fitted to percent inhibition as a function of concentration.Data representative of compounds of the invention are presented in the tables herein.

[0293] The compounds of the invention may also be tested in the following in vivo assays.

[0294] Formalin model of persistent pain in rats

[0295] On the test day, animals weighing between 260-300g at the start of the test can be obtained from Harlan (Indianapolis, IN) (first contact experiment, male Sprague Dawley rats). When the light is turned on at 0600, all animals can be housed under a 12 / 12h light / dark cycle. Rodents can be housed in two cages on a solid bottom cage with corn cob pads, and food and water can be obtained at will. Before the test begins, animals should be allowed to adapt to the breeding house for at least five days, and should be brought to the test room at least 30 minutes before administration. Animals are pretreated with appropriate test compounds by oral gavage or intraperitoneal injection at the required pretreatment time (usually two hours before the test begins), and then returned to their living cages. After administration and at least 30 minutes before the test begins, animals can be adapted to individual test rooms. At test time, each animal can be gently wrapped in a towel, and the left hind paw is exposed. A diluted solution of formalin (2.5%) in phosphate buffered saline can be subcutaneously injected into the back of the left hind paw with a 30g needle in a volume of 50 μL. After injection, a small metal band can be attached to the plantar side of the left hind paw with a drop of LOCTITE (adhesive) immediately. The animal can then be placed in the test room, and the number of flinching can be recorded between 10 minutes and 40 minutes after the formalin injection. Flinching is defined as the rapid and spontaneous movement of the injected hind paw that is not associated with walking. Flinching can be quantified with the help of an automated pain analyzer (Automated Nociception Analyzer) established by the Department of Anesthesiology, University of California, San Diego. Individual data can be expressed as the % maximum potential effect (% MPE) calculated by the following formula: (-(individual score-vehicle average score) / vehicle average score))*100=% MPE

[0296] Statistical analysis can be performed by analysis of variance (ANOVA) for significant main effects compared to the vehicle group, with post hoc analysis using Bonferroni. Data can be expressed as mean % MPE + / - standard error for each group.

[0297] Rat open field assay

[0298] On the day of the test, animals weighing between 260-300g at the start of the test (first contact experiment, male Sprague Dawley rats) can be obtained from Harlan (Indianapolis, IN). When the light is turned on at 0600, all animals can be housed under a 12 / 12h light / dark cycle. Rodents can be housed in two cages on a solid bottom cage with corn cob pads, and food and water can be obtained at will. Before the test begins, animals should be allowed to adapt to the breeding house for at least five days, and should be brought to the test room at least 30 minutes before administration. In a room separated from the test room, animals can be pretreated with appropriate test compounds by oral gavage or intraperitoneal injection at the required pretreatment time (usually two hours before the start of the test), and then can be returned to their living cages after the pretreatment ends. At the test time, animals can be transferred to the open field test room in their living cages. Each animal can be placed in a separate test room and the motion tracking system can be turned on. The indoor lighting in the test room should be turned off, and animals can be allowed to explore the new opening for 30 minutes. The automatic motion tracker manufactured by San Diego Instruments, San Diego, CA can be used to capture animal exploration with the help of infrared beams to detect animal movement. These behaviors include basic movement and vertical standing, which can be used as the primary endpoint of the assay. At the end of the test, the indoor lighting can be turned on and the animals should be removed from the test equipment. Data can be expressed as a percentage change relative to the vehicle control using the following equation.

[0299] (1-(Assay mean / Vehicle mean))*100=% change.

[0300] Statistical analysis can be performed by analysis of variance (ANOVA), with post hoc analysis using Dunnett to follow up on significant main effects.

[0301] Formalin model of persistent pain in mice

[0302] Mice weighing between 22-30 g at the start of the test were obtained from Harlan (Indianapolis, IN) (first exposure experiment, male C57Bl / 6). With the light turned on at 0630, all animals were housed under a 12 / 12h light / dark cycle. Rodents were housed individually in a solid bottom cage with corn cob padding and had free access to food and water. Before the start of the test, animals were allowed to adapt to the breeding house for at least five days and were brought to the test room at least 30 minutes before administration. Animals were pretreated with appropriate test compounds by oral gavage or intraperitoneal injection at the required pretreatment time (usually 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 the test, animals were adapted to individual test rooms. At the test time, each animal was gently wrapped in a cloth glove and the left hind paw was exposed. A diluted solution of formalin (2%) in phosphate buffered saline was subcutaneously injected into the back of the left hind paw with a 30g needle in a volume of 20 μL. The animals were then placed into an observation chamber and behavior was recorded for 60 minutes after formalin injection. Pain-like behavior was defined as licking and / or weight-bearing of the injected hind paw not associated with ambulation.

[0303] Statistical analysis was performed by analysis of variance (ANOVA) with post hoc analysis using Dunnett's post hoc test for any significant main effects compared to the vehicle group. Data are expressed as mean + / - standard error for each group.

[0304] Mouse open field assay

[0305] Mice weighing between 22-30g were obtained from Harlan (Indianapolis, IN) at the beginning of the test (first contact experiment, male C57Bl / 6). When the illumination was turned on at 0630, all animals were housed under a 12 / 12h light / dark cycle. Rodents were housed individually on a solid bottom cage with corncob pads, and food and water were obtained at will. Before the test began, animals were allowed to adapt to the breeding house for at least five days, and were brought to the test room at least 30 minutes before administration. In a room separated from the test room, animals were pretreated with appropriate test compounds by oral gavage or intraperitoneal injection at the required pretreatment time (usually two hours before the test began), and then returned to their home cages after the pretreatment ended. At the test time, animals were transferred to the open-field test room in their home cages. Each animal was placed in a separate test room and the motion tracking system was turned on. The indoor illumination in the test room was turned off, and animals were allowed to explore the novel open field for 30 minutes. Animal movements were detected using an automatic motion tracker manufactured by Kinder Scientific, Poway, CA, which captured animal exploration with the help of an infrared beam. These behaviors included basic movement and upright standing, which served as the primary endpoint of the assay. At the end of the test, the room lighting was turned on and the animals were removed from the test apparatus.

[0306] Statistical analysis was performed by analysis of variance (ANOVA) with post hoc analysis using Dunnett's post hoc test for any significant main effect compared to the vehicle group. Data are expressed as the mean + / - standard error for each group. Data are also expressed as the percentage change relative to the vehicle control using the following equation:

[0307] (1-(Assay mean / Vehicle mean))*100=% change.

[0308] CFA-calorimetry

[0309] Animals weighing between 260-300g at the beginning of the test can be obtained from Harlan (Indianapolis, IN) (first exposure experiment, male Sprague Dawley rats). When the light is turned on at 0600, all animals can be housed under a 12 / 12h light / dark cycle. Rodents can be housed in two cages on a solid bottom cage with corn cob pads, with free access to food and water. Before the test begins, animals can be allowed to adapt to the breeding house for at least five days, and can be brought to the test room at least 30 minutes before administration. Complete Freund's Adjuvant (Complete Freund's Adjuvant, CFA)-thermometry can use a continuous three-day test schedule consisting of an adaptation day, a baseline day, and a test day. On the first day, animals can be brought to the test room, marked and placed in an individual test box on its test equipment. Animals can be allowed to explore the environment for at least one hour without actual testing. After adaptation, animals can be placed back in their living cages and returned to the breeding house. On the second day, the animal can be brought back to the test room and placed on the test device and sedated (usually 30-45 minutes). The following procedure should then be used to take the basal thermal threshold: once sedated, the Ugo Basile plantar device is placed under the animal's left hind paw; press the start button to turn on the steadily increasing heat source and timer; when the animal reaches its thermal threshold, it will withdraw its hind paw, stop the timer and thermal stimulation. The withdrawal delay 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 the test, 25 μg / 50 μl of complete Freund's adjuvant can be used to inject the animal's left hind paw intraplantarly. The animal is then returned to its home cage and returned to the breeding house. On the day of the test, the animal can be placed on the thermal test device again, and its CFA post-baseline is obtained using the procedure outlined above. The animal can be pretreated with an appropriate test compound by oral gavage or intraperitoneal injection at the desired pretreatment time (usually two hours before the start of the test), and then can be returned to its home cage. Thirty minutes before testing, the animals can be placed on the apparatus again. Once the pre-treatment period is over, the animals can be tested again using the above procedure. Data can be expressed as a percentage of the maximum potential effect using the following formula:

[0310] ((Post-drug mean - Pre-drug mean) / (Baseline mean - Pre-drug mean))*100 = % MPE

[0311] Statistical analysis can be performed by analysis of variance (ANOVA) for significant main effects compared to the vehicle group, with post hoc analysis using Bonferroni. Data can be expressed as mean % MPE + / - standard error for each group.

[0312] Spinal Nerve Ligation (Chung)

[0313] Animals weighing between 150-200 g at the start of the first test can be obtained from Harlan (Indianapolis, IN) (first exposure experiment, male Sprague Dawley rats). All animals can be housed under a 12 / 12h light / dark cycle when the light is turned on at 0600. Rodents can be housed in two cages on a solid bottom cage with corn cob padding, with free access to food and water. Before the start of the test, the animals can be allowed to adapt to the breeding house for at least five days. Then surgery can be performed based on the method described by Kim and Chung (1992). In short, the animal can be placed under isoflurane anesthesia and placed in a sterile surgical area. The area of ​​the lumbar spine is excised and the spinal nerves at L4-L5 are exposed. The L5 spinal nerve is identified and tightly ligated with a 5-0 suture. The muscles can be closed with absorbable sutures and the skin can be closed with a wound clamp. The animals can be returned to the breeding house for 7-14 days and monitored every day. On the day of the test, the animals can be brought to the test room and placed on the metal mesh floor in the individual test room. The animals can be allowed to adapt to the room until they are calm. Then a series of Semmes-Weinstein monofilaments (von Frey hair) with calibrated bending force are applied to determine the pain sensitivity baseline according to the method listed by Chaplan et al. (1994). In short, the monofilament is applied to increase the force (if there is no reaction to the previous stimulus) or reduce the force (if there is a reaction to the previous stimulus) until the baseline is reached. The animals are then pretreated with appropriate test compounds by oral gavage or intraperitoneal injection at the required pretreatment time (usually two hours before the start of the test), and then returned to their home cages. Thirty minutes before the test, the animals are placed on the device again. After the pretreatment time ends, the above procedure is repeated to determine the drug efficacy. The data can be expressed as the average gram force to induce nociceptive pain. Statistical analysis can be performed by analysis of variance (ANOVA) for significant main effects compared to the vehicle group, together with post-hoc analysis using Bonferroni.

[0314] Table 1 provides data for compounds exemplified in this application and its priority documents as representative compounds of the invention, as follows: compound names (as named by ACD software, version 12; whereas compound names in the written examples presented herein are named using ChemDraw Ultra version 12); and biological data, including in vitro Nav 1.7PX data (IC in uM) where available. 50 )、Nav 1.7IWQ data (IC in uM 50), HLM in vitro data (μL / (min·mg)) and human PXRPOC S (%) at 2uM. Ex. # refers to Example No. The compounds of the present invention show favorable activity against hNav1.7 as well as HLM and human PXR data.

[0315] Table 1: Biological data

[0316]

[0317] For the purpose of clarity and understanding, the foregoing invention has been described in detail by way of illustration and example. It will be appreciated by those skilled in the art that variations and modifications may be implemented within the scope of the appended claims. Therefore, it should be understood that the above description is intended to be illustrative and not restrictive. Therefore, the scope of the present invention should not be determined with reference to the above description, but instead should be determined with reference to the following appended claims together with the full scope of equivalents to which the claims are entitled.

[0318] All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety to the same extent as if each individual patent, patent application or publication was so individually denoted.

Claims

1. A compound, or an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (P)-1-(5-chloro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, or (P)-1-(5-Fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

2. A pharmaceutical composition comprising the compound according to claim 1, or its enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating Nav1.7-mediated pain, comprising administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

4. The use according to claim 3, wherein the Nav1.7-mediated pain is selected from chronic pain, acute pain, neuropathic pain, pain associated with rheumatoid arthritis, pain associated with osteoarthritis or pain associated with cancer.

Images