Alkyldihydroquinoline sulfonamide compounds

Abstract

The present invention relates to alkyl dihydroquinoline sulfamide compounds. The present invention provides compounds of Formula I, and pharmaceutically acceptable salts thereof, which are inhibitors of voltage-gated sodium channels, particularly Nav1.7. The compounds are useful for treating diseases associated with the activity of sodium channels, such as pain conditions, cough, and itch. Also provided are pharmaceutical compositions containing the compounds of the present invention.

Description

[0001] This application is a divisional application of the invention patent filed on December 19, 2016, with application number 201680074274.2 and invention title "alkyl dihydroquinoline sulfonamide compound".

[0002] Related applications

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 269,518, filed December 18, 2015, the description of which is hereby incorporated by reference in its entirety. Technical Field

[0004] This invention provides compounds that act as inhibitors of voltage-gated sodium channels (Nav), specifically Nav1.7, and can be used to treat diseases such as pain conditions that can be treated by inhibiting sodium channels. Pharmaceutical compositions containing the compounds of this invention are also provided. Background Technology

[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, as defined, involves abnormal electrical spikes in neurons along the pain pathway: peripheral sensory neurons, spinal cord neurons, neurons in the brain's pain matrix (e.g., somatosensory cortex, insular cortex, anterior cingulate cortex), and / or neurons in the brainstem. While the firing of these neurons is regulated and managed by many different receptors, enzymes, and growth factors, in most neurons, the rapid rising phase 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 ed. 2001). Nine different isoforms (Nav1.1-Nav1.9) of voltage-gated sodium channels exist, and they exhibit different expression patterns in tissues, including neurons, cardiac muscle, and skeletal muscle (Goldin, 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).

[0006] 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, epilepsy is caused by a certain loss of function due to mutations in Nav1.1, 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, while inhibition of Nav1.1 may be useful for treating pain, it may also be undesirable and may lead to anxiety and hyperexcitability. Nav1.3 is mainly expressed in the fetal central nervous system and has been found to be upregulated in rats after nerve damage (Hains, BD et al., J. Neuroscience (2030) 23(26): 8881-8892). Nav1.4 is primarily expressed in skeletal muscle. Mutations in the gene and its products have significant effects on muscle function, including paralysis (Tamaoka A., Internal Medicine (2003), (9):769-770). Nav1.5 is primarily expressed in cardiomyocytes, including atria, ventricles, sinoatrial node, atrioventricular node, and cardiac Purkinje fibers. The rapid ascending phase of the cardiac action potential and rapid impulse conduction through cardiac tissue are generated by the opening of Nav1.5 channels. Mutations in Nav1.5 channels cause arrhythmia 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 primarily expressed in sensory ganglia of the peripheral nervous system, such as the dorsal root ganglion. No Nav1.8 mutations producing altered pain responses have been identified in humans. Nav1.8 differs from most neuronal Nav isotypes because it is insensitive to inhibition by tetrodotoxin. Similar to Nav1.8, Nav1.9 is also a tetrodotoxin-insensitive sodium channel primarily expressed in dorsal root ganglion neurons (Dib-Hajj, SD et al., Proc. Natl. Acad. Sci. USA (1998), 95(15): 8963-8968).

[0007] Recent evidence from several independent genetic studies suggests that the sensation of pain requires tetrodotoxin-sensitive voltage-gated sodium channel Nav 1.7 (SCN9A). Several rare genetic forms of severe chronic pain, primary erythema exacerbation and paroxysmal excruciating pain, 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 asodium 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).Conversely, two separate clinical studies have identified the genetic disorder congenital inability to experience pain (CIP) as stemming from a loss of function of Nav1.7 caused by mutations that truncate the protein and disrupt 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 underlie congenital indifference to pain in multiple human populations,” Clin Genet 71:311-319, 2007). The disorder is inherited with 100% penetrance in a Mendelian recessive manner. The phenotypes associated with CIP are extreme: reported affected individuals experienced painless burns, childbirth, appendicitis, and fractures, and were insensitive to clinical measures of pain such as needle pricks or tendon pressure. Sensory, motor, voluntary, and other measured functions were normal, with the only reported abnormality being anosmia (inability to smell). These studies suggest that Nav1.7 manages one or more control points important for pain perception among many potential targets in the pain pathway.

[0008] Non-selective sodium channel inhibitors such as lidocaine, mexiletine, and carbamazepine have shown clinical efficacy in chronic pain, including neuropathic pain, but their dosage and use are limited, likely due to their effects on sodium channels outside the pain pathway. Lidocaine is used by local anesthesiologists for minor surgeries. Dentists use novocaine. However, these compounds do not differentiate between various sodium channel subtypes, making them unsuitable for use as systemic analgesics. “If a drug that blocks Nav1.7 but also Nav1.5 is given, the patient will die of heart failure,” says Glenn F. King, a professor at Australia’s University of Queensland who studies poisons that block ion channels. “It’s a completely painless death, but the patient will still die.” Therefore, selectivity for Nav1.7, and especially beyond Nav1.5, is needed. Researchers have been working to find molecules that inhibit or block the activity of Nav1.7 only. Complicating this problem is that the identity, location, function, and / or tertiary structure of each subtype of voltage-gated sodium channel protein are unknown or not fully understood.

[0009] Currently, numerous researchers are attempting to identify small-molecule inhibitors of Nav1.7. For example, Chafeev et al. disclosed spiro-hydroxyindole compounds for the treatment and / or prevention of sodium channel-mediated diseases such as pain in U.S. Patent No. 8,101,647. International publications WO 2013 / 134518 and WO 2014 / 201206 disclose sulfonamide derivatives different from the sulfonamide derivatives of this invention. Therefore, there is a need to identify Nav1.7 inhibitors with selectivity exceeding at least Nav1.5 for the treatment of pain. This invention provides compounds as selective inhibitors of Nav1.7 with selectivity exceeding at least Nav1.5. Invention Overview

[0010] In embodiment 1, the present invention provides compounds of formula (I), their enantiomers, diastereomers, transisomers, mixtures thereof, or pharmaceutically acceptable salts thereof.

[0011]

[0012] in:

[0013] R 1 It is (a)C 1-8 Alkyl, wherein the C 1-8 Alkyl groups are selected from hydroxyl, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl group, -OC (=O)C 1-4 Alkyl or -N(C) 1-4 Alkyl)C1-4 The alkyl group is substituted with 0, 1, 2, or 3 groups; or

[0014] (b)C 1-8 Halogenated alkyl groups;

[0015] R 2 It is H, halogenated group, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0016] R 3 It is C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl or –CN;

[0017] R 4 It is a 5- to 6-membered heteroaryl group;

[0018] R 6 and R 7 Each of them is hydrogen; and

[0019] R 5a ;R 5b ;R 5c ;R 5d ; and R 5e Each of them is either a hydrogen or a halide group.

[0020] In embodiment 2, the present invention provides a compound of formula (I), its enantiomers, diastereomers, transisomers, mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 1 It is C 4-8 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Haloalkyl is C 1-6 Fluorinated alkyl groups.

[0021] In embodiment 3, the present invention provides a compound of formula (I), its enantiomers, diastereomers, transisomers, mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 1 Selected from -CH2-CF3, -CH2-CH2-CF3, -CH2-CH2-CH2-CF3, -CH2-CH(CH3)-CF3, -CH2-CF2-CF3, -CH2-C(CH3)2-CF3, -C(CH3)2-CH2-CF3, -CF2-CH2-CF3, or -CH2-CH2-CHF2.

[0022] In embodiment 4, the present invention provides a compound of formula (I), its enantiomers, diastereomers, transisomers, mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R2 It is H, fluorine, chlorine, methyl, CF3, CHF2 or CH2F.

[0023] In embodiment 5, the present invention provides a compound of formula (I), its enantiomers, diastereomers, transisomers, mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 2 It is H or fluorine. In a sub-implementation of implementation scheme 5, R 2 It's fluorine.

[0024] In embodiment 6, the present invention provides a compound of formula (I), its enantiomers, diastereomers, transisomers, mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 3 It is a methoxy group.

[0025] In embodiment 7, the present invention provides a compound of formula (I), its enantiomers, diastereomers, transisomers, mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 4 It is a 5-membered heteroaryl group.

[0026] In embodiment 8, the present invention provides a compound of formula (I), its enantiomers, diastereomers, transisomers, mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 4 It is a 6-membered heteroaryl group.

[0027] In embodiment 9, the present invention provides a compound of formula (I), its enantiomers, diastereomers, transisomers, mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 4 It is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl. In a sub-implementation of embodiment 8, R 4 It is isoxazolyl or pyridazinyl. In another sub-implementation of embodiment 8, R 4 It is an isoxazolyl group.

[0028] In embodiment 10, the present invention provides a compound of formula (I), its enantiomers, diastereomers, transisomers, mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 5a ;R 5b ;R 5c ;R 5d ; and R 5e Each of them is hydrogen.

[0029] In embodiment 11, the present invention provides a compound of formula (I), its enantiomers, diastereomers, transisomers, mixtures thereof, or pharmaceutically acceptable salts thereof, which are:

[0030]

[0031]

[0032]

[0033] In embodiment 11a, the present invention provides a compound of formula (I), or an enantiomer, diastereomer, transisomer, mixture thereof, or a pharmaceutically acceptable salt thereof, which is 1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-3-isooxazolyl-2-oxo-1,2-dihydro-6-quinoline sulfonamide.

[0034] In embodiment 11b, the present invention provides a compound of formula (I), or an enantiomer, diastereomer, transisomer, mixture thereof, or a pharmaceutically acceptable salt thereof, which is 1-(5-chloro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-3-isooxazolyl-2-oxo-1,2-dihydro-6-quinoline sulfonamide.

[0035] In embodiment 11c, the present invention provides a compound of formula (I), or an enantiomer, diastereomer, transisomer, 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.

[0036] In embodiment 11d, the present invention provides a compound of formula (I), or an enantiomer, diastereomer, transisomer, 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-isooxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide.

[0037] In embodiment 11e, the present invention provides a compound of formula (I), or an enantiomer, diastereomer, transisomer, 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-isooxazolyl-2-oxo-1,2-dihydro-6-quinoline sulfonamide.

[0038] In embodiment 11f, the present invention provides a compound of formula (I), or an enantiomer, diastereomer, transisomer, mixture thereof, or a pharmaceutically acceptable salt thereof, which is 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-3-isooxazolyl-2-oxo-1,2-dihydro-6-quinoline sulfonamide.

[0039] In embodiment 11g, the present invention provides a compound of formula (I), or an enantiomer, diastereomer, transisomer, mixture thereof, or a pharmaceutically acceptable salt thereof, which is 1-(5-fluoro-2-methoxy-4-(4,4,4-trifluorobutyl)phenyl)-N-3-isooxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide.

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

[0041] In embodiment 11i, the present invention provides a compound of formula (I), or an enantiomer, diastereomer, transisomer, mixture thereof, or a pharmaceutically acceptable salt thereof, which is 1-(5-fluoro-2-methoxy-4-(2,2,3,3,3-pentafluoropropyl)phenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0042] In embodiment 11j, the present invention provides a compound of formula (I), or an enantiomer, diastereomer, transisomer, 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-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0043] In embodiment 11k, the present invention provides a compound of formula (I), or an enantiomer, diastereomer, transisomer, mixture thereof, or a pharmaceutically acceptable salt thereof, which is 1-(5-fluoro-2-methoxy-4-(4,4,4-trifluoro-2-methylbutane-2-yl)phenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0044] In embodiment 111, the present invention provides a compound of formula (I), or an enantiomer, diastereomer, transisomer, mixture thereof, or a pharmaceutically acceptable salt thereof, which is 1-(5-fluoro-2-methoxy-4-(1,1,3,3,3-pentafluoropropyl)phenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0045] In embodiment 12, the present invention provides a p-transisomer of each of the individual compounds, or mixtures thereof, or pharmaceutically acceptable salts thereof listed in embodiments 11a to 11l.

[0046] In embodiment 13, the present invention provides an M-restricted transisomer of each of the individual compounds, or mixtures thereof, or pharmaceutically acceptable salts thereof listed in embodiments 11a to 11l.

[0047] In embodiment 14, the present invention provides a pharmaceutical composition comprising a compound, or an enantiomer, diastereomer, transisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11a-11l, 12 and 13 thereof, and a pharmaceutically acceptable excipient thereof.

[0048] In embodiment 15, the present invention provides a method for treating pain, cough, or itching, the method comprising administering to a patient in need a therapeutically effective amount of a compound, or an enantiomer, diastereomer, transisomer, mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11a-11l, 12, and 13 thereof.

[0049] 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, or pain associated with cancer or diabetes.

[0050] In embodiment 17, the present invention provides the method of embodiment 15, wherein the cough is selected from postviral cough, viral cough, or acute viral cough. See Dib-Hajj. et al., "The Na V 1.7 sodium channel: from molecule to man”, Nature Reviews Neuroscience (2013), 14, 49-62. Invention Details

[0051] This invention provides compounds of formula (I) as defined above, their enantiomers, diastereomers, transisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. This invention also provides pharmaceutical compositions comprising compounds of formula (I), their enantiomers, diastereomers, transisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and methods of using compounds of formula (I), their enantiomers, diastereomers, transisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, to treat diseases and / or symptoms such as pain.

[0052] “C α-β "Alkyl" refers to an alkyl group containing at least α and at most β carbon atoms in a branched or straight-chain relationship, or any combination of both, where α and β represent integers. The C0 alkyl nomenclature indicates a direct bond. 1-6 Examples of alkyl groups include, but are not limited to, the following:

[0053]

[0054] The term “halogen” or “halogen” refers to a halogen atom selected from F, Cl, Br and I.

[0055] Term "C" α-β "Haloalkyl" means an alkyl group as defined herein, wherein at least one hydrogen atom is replaced by a halo group atom, as defined herein. Common C α-β The alkyl halogroup is C 1-3 Fluoroalkyl groups. Common C 1-3 Examples of fluoroalkyl groups are _ CF3.

[0056] As used in this article, the term "heteroatom" refers to an oxygen atom, a nitrogen atom, or a sulfur atom.

[0057] The term "aryl" refers to a cyclic aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Common aryl groups are six- to thirteen-membered rings.

[0058] The term "heteroaryl" refers to a cyclic aromatic hydrocarbon in which one or more carbon atoms of the aryl group have been replaced by heteroatoms. If a heteroaryl contains more than one heteroatom, the heteroatoms can be the same or different. Examples of heteroaryl groups include pyridinyl, pyrimidinyl, imidazolyl, thiopheneyl, furanyl, pyrazinyl, pyrroleyl, indolyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinazinyl, isoquinolinyl, quinolinyl, naphthidyl, quinoxalinyl, isothiazolyl, and benzo[b]thiopheneyl. Common heteroaryl groups are five- to thirteen-membered rings containing one to four heteroatoms. Five- and six-membered heteroaryl groups containing one to three heteroatoms are particularly common.

[0059] The term "pharmaceutically acceptable salt" means a salt prepared by conventional means and well known to those skilled in the art. "Pharmaceutically acceptable salt" includes basic 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, etc. Further examples of "pharmaceutically acceptable salt" can be found in Berge et al., J. Pharm. Sci. 66:1 (1977).

[0060] The term "substituted" means that a hydrogen atom in a molecule or group is replaced by a group or atom. Typical substituents include: halogens, C... 1-8 Alkyl, hydroxyl, C 1-8 Alkyl, –NR x R x Nitro, cyano, halogenated, or fully halogenated C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, –SR x –S(=O)2R x –C(=O)OR x –C(=O)R x , where each R x It is independently hydrogen or C1-C8 alkyl. Note that when the substituent is –NR… x R x At that time, R x Groups can be linked to nitrogen atoms to form rings.

[0061] A group or atom that replaces a hydrogen atom is also called a substituent.

[0062] Depending on the number of hydrogen atoms that can be substituted, any particular molecule or group may have one or more substituents.

[0063] The term "unsubstituted" refers to a hydrogen atom in a molecule or group. The term "substituted" refers to a hydrogen atom in a molecule or group being replaced by a group or atom. Typical substituents include: halogens, C... 1-8 Alkyl, hydroxyl, C 1-8 Alkyl, –NR x R x Nitro, cyano, halogenated, or fully halogenated C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, –SR x –S(=O)2R x –C(=O)OR x –C(=O)R x , where each Rx It is independently hydrogen or C1-C8 alkyl. Note that when the substituent is –NR… x R x At that time, R x Groups can be linked to nitrogen atoms to form rings.

[0064] The symbol "-" represents a covalent bond and can also be used in groups to indicate a point where a group is attached to another group. In chemical structures, this symbol is often used to represent methyl groups in a molecule.

[0065] The term "leaving group" generally refers to a group that can be readily replaced by a nucleophile (such as an amine, thiol, or alcohol nucleophile) or by a metal reagent (such as boric acid or borates) 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, trifluoromethanesulfonates, toluenesulfonates, etc. Where appropriate, preferred leaving groups are indicated herein.

[0066] The term "protecting group" generally refers to a group well known in the art that is used to prevent selected reactive groups (such as carboxyl, amino, hydroxyl, mercapto, etc.) from undergoing undesirable reactions (such as 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, cycloalkenyl and substituted cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl, etc. Examples of aralkyl groups include, but are not limited to, benzyl, o-methylbenzyl, triphenylmethyl and diphenylmethyl, which may optionally be substituted with halogens, alkyl, alkoxy, hydroxyl, nitro, acylamino, acyl, etc., and salts such as phosphonium salts and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracene, 9-(9-phenylfluorenyl), phenanthryl, durenyl, etc. Examples of cycloalkenylalkyl or substituted cycloalkenylalkyl groups preferably have 6-10 carbon atoms, including but not limited to cyclohexenylmethyl. Suitable acyl, alkoxycarbonyl, and arylalkoxycarbonyl groups include benzyloxycarbonyl, tert-butoxycarbonyl, isobutoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, etc. Mixtures of protecting groups can be used to protect the same amino group; for example, a primary amino group can be protected by both an arylalkyl group and an arylalkoxycarbonyl group. The amino protecting group can also form a nitrogen-containing heterocycle, wherein the amino protecting group is attached to a nitrogen, such as 1,2-bis(methylene)benzene, phthalimide, succinimide, maleimide, etc., and wherein these heterocyclic groups may also contain linked aryl and cycloalkyl rings. In addition, the heterocyclic group can be monosubstituted, disubstituted, or trisubstituted, such as nitrophthalimide. Amino groups can also be protected from unwanted reactions, such as oxidation, by forming addition salts (such as hydrochlorides, toluenesulfonic acids, trifluoroacetic acids, etc.). Many amino protecting groups are also suitable for protecting carboxyl, hydroxyl, and mercapto groups. For example, aralkyl groups. Alkyl groups are also suitable for protecting hydroxyl and mercapto groups, such as tert-butyl groups.

[0067] Protecting groups are removed without affecting the remainder of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis, etc. Preferred methods involve the removal of protecting groups, such as the removal of benzyloxycarbonyl groups by hydrogenolysis using palladium / carbon in a suitable solvent system such as alcohols, acetic acid, or mixtures thereof. Tert-butoxycarbonyl protecting groups can be removed using inorganic or organic acids (such as HCl or trifluoroacetic acid) in a suitable solvent system such as dioxane or methylene chloride. The resulting amino salt can be readily neutralized to yield a free amine. Carboxyl protecting groups (such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl, etc.) can be removed under hydrolytic and hydrogenolytic conditions well known to those skilled in the art.

[0068] It should be noted that the compounds of the present invention may contain groups that can exist in tautomeric form, such as cyclic and acyclic amidine and guanidine groups, heteroatom-substituted aromatic heterocyclic groups (Y' = O, S, NR), etc., as illustrated in the following examples:

[0069]

[0070] Furthermore, although this document names, describes, displays and / or claims one form, all tautomers are intended to be inherently included in this name, description, display and / or claim.

[0071] This invention also contemplates prodrugs of the compounds of the invention. A prodrug is a chemically modified, active or inactive compound of the compounds of the invention through in vivo physiological processes such as hydrolysis and metabolism after administration to a patient. The suitability and techniques involved in the preparation and use of 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, which are cleaved in vivo by esterases, releasing free drug and formaldehyde (Bundgaard J. Med. Chem. 2503 (1989)). In addition, drugs containing acidic NH groups such as imidazole, imide, and indole have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups have been masked into esters and ethers. EP 039,051 (Sloan and Little, 4 / 11 / 81) discloses the prodrug of Mannich base hydroxamic acid, its preparation, and its uses.

[0072] The term "therapeutic effective amount" refers to the 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.

[0073] The term "patient" refers to animals such as dogs, cats, cows, horses, sheep, and humans. Specifically, patients are mammals. The term "patient" includes both males and females.

[0074] The term “pharmaceutical acceptable” means that the substance mentioned (such as a compound of formula I, or a salt of a compound of formula I, or a preparation containing a compound of formula I, or a particular excipient) is suitable for administration to a patient.

[0075] The terms “treating,” “treat,” or “treatment” include preventative (e.g., preventative) and remission treatments.

[0076] 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 the purpose of formulation and / or administration to a patient.

[0077] The compounds of the present invention are administered to patients in therapeutically effective amounts. The compounds may be administered alone or as part of a pharmaceutically acceptable composition or formulation. Furthermore, the compounds or compositions may be administered, for example, in a single injection, for example, in multiple administrations via a series of tablets, or, for example, in a substantially uniform manner over a period of time using transdermal delivery. It should also be noted that the dosage of the compounds may vary over time.

[0078] Furthermore, 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. These other pharmaceutically active compounds can treat the same disease or condition as, or different diseases or conditions as, the compounds of the present invention. If a patient will receive or is receiving multiple pharmaceutically active compounds, the compounds can be administered simultaneously or sequentially. For example, in the case of tablets, the active compounds can be contained in a single tablet or individual tablets, which can be administered once or in any order. Additionally, it should be recognized that the compositions can be in different forms. For example, one or more compounds may be delivered by tablets, while another may be administered by injection or orally as a syrup. All combinations, delivery methods, and administration sequences should be considered.

[0079] The compounds of the present invention may be used in the manufacture of medicaments for treating Nav1.7-mediated diseases and / or symptoms such as pain, chronic cough or itching.

[0080] Pain is typically categorized into two main types based on its duration: chronic pain and acute pain. Chronic pain usually 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 a definitive cause. An example of idiopathic pain is fibromyalgia.

[0081] Another type of pain is nociceptive pain. Nociceptive pain is caused by stimulation of peripheral nerve fibers that respond to highly harmful events, such as thermal, mechanical, or chemical stimuli.

[0082] Another type of pain is neuropathic pain. Neuropathic pain is caused by damage or disease affecting a part of the nervous system. Phantom limb pain is a type of neuropathic pain. In phantom limb pain, the body detects pain from a body part that no longer exists. For example, a person who has had a leg amputated may feel pain in their leg, even though the leg no longer exists.

[0083] In one embodiment of the treatment method provided by the present invention using a compound of formula (I) or a pharmaceutically acceptable salt thereof, the disease is chronic pain. In another aspect, chronic pain is associated with, but not limited to, postherpetic neuralgia (herpes zoster), 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 syndrome, and migraine, primary erythromelalgia, and paroxysmal excruciating pain syndrome.Other indications for Nav1.7 inhibitors include, but are not limited to, depression (Morinville et al., J Comp Neurol., 504:680-689 (2007)), bipolar disorder and other CNS disorders (Ettinger and Argoff, Neurootherapeutics, 4:75-83 (2007)), epilepsy: ibid., and Gonzalez, Termin, Wilson, Methods and Principles in Medicinal Chemistry, 29:168-192 (2006)), and multiple sclerosis (Waxman, Nature). Neurosci. 7:932-941 (2006)), Parkinson's disease (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 and congestive heart failure, sick sinus syndrome (Haufe V. et al., J Mol. Cell Cardiol. 42(3):469-477, 2007), schizophrenia, neuroprotection after stroke and alcoholism (Johannessen L.C., CNSDrugs 22(1):27-47, 2008), Alzheimer's disease (Kim D.Y. et al., Nat. Cell. Biol. 9(7):755-764, 2007), and cancer (Gillet L. et al., J Biol. 7(6):629-638, 2008). Chem, January 28, 2009 (electronic release)).

[0084] Another aspect of the present invention relates to a method for treating the following conditions: acute and / or chronic inflammatory and neuropathic pain, toothache, general headache, migraine, cluster headache, mixed vascular and nonvascular syndrome, tension headache, general inflammation, arthritis, rheumatic diseases, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, inflammatory eye disease, inflammatory or unstable bladder disease, psoriasis, skin discomfort with inflammatory components, chronic inflammatory symptoms, inflammatory pain and associated hyperalgesia and atypical pain, neuropathic pain and associated hyperalgesia. And for atypical pain, diabetic neuropathy pain, burning pain, sympathetic maintenance pain, blockade pain syndrome, asthma, epithelial tissue damage or dysfunction, herpes simplex, respiratory, genitourinary, gastrointestinal or vascular visceral motility disorders, trauma, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulcer formation, duodenal ulcers, diarrhea, gastric lesions induced by necrotizing agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, the method comprising the step of administering the compound according to the 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.

[0085] In another aspect of the invention, the compounds of the invention can be used in combination with other compounds used to treat pain. Examples of such other compounds include, but are not limited to, aspirin, celecoxib, hydrocodone, oxycodone, codeine, fentanyl, ibuprofen, ketoprofen, naproxen, acetaminophen, gabapentin, and pregabalin. Examples of pharmaceutical classes containing compounds that can be used in combination with the compounds of the invention include nonsteroidal anti-inflammatory compounds (NSAIDs), steroidal compounds, cyclooxygenase inhibitors, and opioid analgesics.

[0086] The compounds of this invention can also be used to treat diabetes, obesity, and / or promote weight loss.

[0087] The compounds of this invention can be used in combination with other pharmaceutically active compounds. It should be noted that the term "pharmaceutically active compound" can include biological agents such as proteins, antibodies, and peptides.

[0088] Because one aspect of the invention contemplates the use of combinations of pharmaceutically active compounds that can be administered individually to treat diseases / symptoms, the invention also relates to combining individual pharmaceutical compositions in the form of a kit. The kit contains two separate pharmaceutical compositions: a compound of the present invention and a second pharmaceutical compound. The kit includes a container for containing the individual compositions, such as spaced-apart bottles or spaced-apart foil packets. Other examples of containers include syringes, boxes, and bags. Typically, the kit includes instructions for use of the individual components. The kit format is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dose intervals, or when a prescribing physician or veterinarian desires a titration protocol for the combined individual components.

[0089] An example of this kit is so-called blister packaging. Blister packaging is well-known in the packaging industry and is widely used for packaging unit dosage forms of pharmaceuticals (tablets, capsules, etc.). Blister packaging typically consists of a sheet of relatively rigid material covered with a foil, preferably a transparent plastic material. During the packaging process, a notch is formed in the plastic foil. The notch is sized and shaped to accommodate the tablet or capsule to be packaged. The tablet or capsule is then placed in the notch, and the plastic foil is sealed with the sheet of relatively rigid material on the side of the foil opposite to the direction in which the notch is formed. As a result, the tablet or capsule is sealed in the notch between the plastic foil and the sheet. Preferably, the sheet is strong enough that the tablet or capsule can be removed from the blister package by manually applying pressure to the notch to create an opening at the location of the notch in the sheet. The tablet or capsule can then be removed through the opening.

[0090] It may be desirable to provide a memory aid on the kit, for example, in the form of a number close to the tablet or capsule, whereby the number corresponds to the number of days in the prescribed regimen in which the tablet or capsule should be taken. Another example of such a memory aid is a calendar printed on a card, for example, as follows: "Week 1, Monday, Tuesday, ... etc... Week 2, Monday, Tuesday, ... " etc. Other variations of the memory aid will be readily apparent. A "daily dose" can be a single tablet or capsule to be taken on a given day, or several tablets or capsules. Alternatively, the daily dose of the compound of the present invention may consist of one tablet or capsule, while the daily dose of the second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this daily dose and aid in the proper administration of the active agent.

[0091] In another specific embodiment of the invention, a dispenser is provided designed to dispense one daily dose at a time according to the intended order of use. The dispenser is preferably equipped with a memory aid to further facilitate adaptability to the regimen. One 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 external liquid crystal readings or audible reminders, which, for example, reads the date of the last daily dose taken and / or reminds when the next dose is to be taken.

[0092] If desired, the compounds of the present invention and other pharmaceutically active compounds may be administered to patients orally, rectally, parenterally (e.g., intravenously, intramuscularly, or subcutaneously), intracerebrospinally, intravaginally, intraperitoneally, intrabladderly, topically (e.g., as powders, ointments, or drops), or as oral or nasal sprays. All methods used by those skilled in the art to administer pharmaceutically active agents are to be considered.

[0093] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or mediators 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 flowability may be maintained, for example, by using a coating such as lecithin, in the case of dispersions by maintaining a desired particle size, and by using surfactants.

[0094] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Microbial contamination can be prevented by adding various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. Isotonic agents, such as sugars and sodium chloride, may also be desired. Prolonged absorption of injectable pharmaceutical compositions can be achieved by using agents that delay absorption (e.g., aluminum monostearate and gelatin).

[0095] 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, starch, lactose, sucrose, mannitol, and silica; (b) binders, such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as, for example, glycerin; (d) disintegrants, such as, for example, agar, calcium carbonate, potato or cassava starch, alginate, certain silicate complexes, and sodium carbonate; (e) slow solvents, such as, for example, paraffin; (f) absorption enhancers, 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 glycol, sodium dodecyl sulfate, or mixtures thereof. In the case of capsules and tablets, the dosage form may also contain a buffer.

[0096] In soft and hard filled gelatin capsules that use such excipients as lactose and high molecular weight polyethylene glycol, similar types of solid compositions can also be used as fillers.

[0097] Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in the art. They may also contain light-blocking agents and may be compositions that release one or more active compounds in a delayed manner in certain portions of the intestine. Examples of usable encapsulation compositions are polymeric substances and waxes. The active compound may also be in microencapsulated form, and where appropriate, may contain one or more of the excipients described above.

[0098] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils, specifically cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and black sesame oil, glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, or mixtures of these substances.

[0099] In addition to such inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aroma agents. Besides the active compound, the suspension may also contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyethylene glycol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum, or mixtures of these substances.

[0100] The composition for rectal administration is preferably a suppository, which can be prepared by mixing the compound of the invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or suppository paraffin, which is solid at normal room temperature but liquid at body temperature, and thus melts and releases the active ingredient in the rectum or vaginal cavity.

[0101] The compounds of this invention are intended for topical application in dosage forms including ointments, powders, sprays, and inhalers. The active or suitable compound is mixed under sterile conditions with a physiologically acceptable carrier and any necessary preservatives, buffers, or propellants. Ophthalmic preparations, ointments, powders, and solutions are also contemplated within the scope of this invention.

[0102] The compounds of the present invention can be administered to patients at dose levels ranging from about 0.1 to about 3,000 mg per day. For a normal adult weighing about 70 kg, a dose ranging from about 0.01 to about 100 mg per kilogram of body weight is generally sufficient. Specific doses and dose ranges 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 compound being administered. Determining the dose range and optimal dose for a particular patient is a matter of general skill in the art.

[0103] The compounds of this invention can be administered as pharmaceutically acceptable salts, cocrystals, esters, amides, or prodrugs. The term "salt" refers to both inorganic and organic salts of the compounds of this invention. The salts can be prepared on-site during the final separation and purification of the compound, or by reacting the purified compound, in its free base or acid form, alone with a suitable organic or inorganic base or acid and separating the resulting salt. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, methanesulfonate, gluconate, lactobionate, and dodecyl sulfonate, etc. The salts may include cations based on alkali metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. See, for example, SMBerge et al., “Pharmaceutical Salts,” JPharm Sci, 66:1-19 (1977).

[0104] Examples of pharmaceutically acceptable esters of the compounds of the present invention include C1-C8 alkyl esters. Acceptable esters also include C5-C7 cycloalkyl esters, and aryl esters such as benzyl esters. C1-C4 alkyl esters are commonly used. Esters of the compounds of the present invention can be prepared according to methods well known in the art.

[0105] Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, C1-C8 alkyl primary amines, and C1-C8 dialkyl secondary amines. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocyclic alkyl group containing at least one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines, and C1-C2 dialkyl secondary amines are commonly used. The amides of the compounds of the present invention can be prepared according to methods well known to those skilled in the art.

[0106] The term "prodrug" means a compound that is transformed in the body to produce the compound of the present invention. This transformation can occur through various matrices, such as through hydrolysis in the blood. Discussions of the uses of prodrugs are provided in: T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," ACSSymposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0107] For illustration, if the compound of the present 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: (C1-C8 alkyl, (C2-C12) alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having 5 to 8 carbon atoms. Carbonyloxy)ethyl, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)aminomethyl having 4 to 10 carbon atoms, 3-phthaloyl, 4-crotonic lactone, γ-butyrolactone-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidinyl-, pyrrolidine- or morpholino (C 2-3 )alkyl.

[0108] Similarly, if the compounds of the present invention contain an alcohol functional group, the prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanoyl, aromatic acyl and α-aminoacyl or α-aminoacyl-α-aminoacyl, wherein each α-aminoacyl is independently selected from: naturally occurring L-amino acids, –P(O)(OH)2, –P(O)(O(C1-C6)alkyl)2 or glycosyl (a group generated by removing a hydroxyl group from a carbohydrate hemiacetal).

[0109] Additionally, if the compounds of the present invention contain a sulfonamide moiety, the prodrug can be formed by replacing the sulfonamide N(H) with a group such as -CH2P(O)(O(C1-C6)alkyl)2 or -CH2OC(O)(C1-C6)alkyl.

[0110] The compounds of the present invention also include prodrugs in tautomer form.

[0111] The compounds of this invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds, as well as mixtures thereof (including racemic mixtures), constitute part of this invention. Furthermore, this invention considers all geometric and positional isomers. For example, if the compound contains a double bond, the cis and trans forms (designated S and E, respectively), as well as mixtures, are considered.

[0112] Mixtures of stereoisomers (such as diastereomer mixtures) can be separated into their individual stereochemical components by known methods such as chromatography and / or stepwise crystallization based on their physicochemical differences. Enantiomers can also be separated by reacting an enantiomer mixture with a suitable optically active compound (e.g., an alcohol) to convert the enantiomer mixture into a diastereomer mixture, separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into their corresponding pure enantiomers.

[0113] Compounds of general formula (I) can also exist as trans-isomers. Trans-isomers are compounds with the same structural formula, but with a specific spatial configuration resulting from restricted rotation around the single bond due to predominant steric hindrance on either side of the single bond. Trans-isomerism is independent of the presence of stereoisomers such as asymmetric carbon. The terms “P-trans-isomer” or “M-trans-isomer” are used herein to allow for naming of two trans-isomers of the same pair. For example, the following compound of step 1, intermediate B1, having the structure described below, can be separated into a pair of trans-isomers, P and M, by a chiral column:

[0114]

[0115] The compounds of this invention can exist in both non-solventized and solvated forms in pharmaceutically acceptable solvents (such as water (hydrate), ethanol, etc.). This invention considers and covers both solvated and non-solventized forms.

[0116] The compounds of the present invention may also exist in different tautomer forms. Consider all tautomers of the compounds of the present invention. For example, the present invention includes all tautomer forms of the tetrazolium moiety. For example, the present invention also includes all keto-enol or imine-enamine forms of the compounds. Other examples of tautomerism are as follows:

[0117]

[0118] Those skilled in the art will recognize that the compound names and structures contained herein may be based on specific tautomers of the compounds. While only the names or structures of specific tautomers may be used, this invention is intended to cover all tautomers unless otherwise stated.

[0119] This invention is also intended to cover 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 compounds of this invention may be synthesized using a combination of in vitro and in vivo techniques.

[0120] This invention also includes isotopically labeled compounds, which are identical to those described herein, except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this 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 present invention contain one or more deuterium atoms (2H) in place of one or more hydrogen atoms.

[0121] Compounds of the present invention containing other isotopes of the aforementioned isotopes and / or other atoms are within the scope of the present invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (such as...) 3 H and 14 Those in category C) can be used for drug and / or matrix tissue distribution determination. Tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are particularly preferred because they are easy to prepare and detect. Additionally, isotopes such as deuterium (i.e., 2 Heavy isotope substitution of H) can provide certain therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and is therefore preferred in some cases. The isotope-labeled compounds of the present invention can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents.

[0122] The compounds of this invention can exist in various solid states, including crystalline and amorphous states. Different crystalline states (also called polymorphs) and amorphous states of the compounds of this invention are considered as part of this invention.

[0123] All patents and other publications mentioned herein are hereby incorporated in their entirety by reference.

[0124] The embodiments presented below illustrate specific implementations of the invention. These embodiments are representative and are not intended to limit the scope of the claims in any way.

[0125] It should be noted that when referring to the percentage (%) used in liquids, it is a volume percentage of the solution. When used in the case of solids, it is a percentage of the solid composition. Materials obtained from commercial suppliers are generally used without further purification. Reactions involving air- or moisture-sensitive reagents are generally performed under nitrogen or argon conditions. Purity is measured using a high-performance liquid chromatography (HPLC) system in the case of UV detection at 254 nm and 215 nm (System A: Agilent Zorbax Eclipse XDB-C8 4.6 x 150 mm, 5 μm, 5% to 100% CH3CN in H2O, using 0.1% TFA, sustained at 1.5 mL / min for 15 min; System B: Zorbax SB-C8, 4.6 x 75 mm, 10% to 90% CH3CN in H2O, using 0.1% formic acid, sustained at 1.0 mL / min for 12 min) (Agilent Technologies, Santa Clara, CA). Pre-packaged silica gel sleeves (Biotage, Uppsala, Sweden, or Teledyne-Isco, Lincoln, NE) are typically used for silica gel chromatography. Recordings are performed at ambient temperature on a Bruker AV-400 (400MHz) spectrometer (Bruker Corporation, Madison, WI) or a Varian (Agilent Technologies, Santa Clara, CA) 400MHz spectrometer. 1 1H NMR spectra. All observed protons are reported as parts per million (ppm) of downshift from tetramethylsilane (TMS) or other internal standards in the indicated appropriate solvent. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quadruplet, br = broad peak, m = multiplet), coupling constant, and number of protons. Low-resolution mass spectrometry (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 ionization (ESI) mode.

[0126] Synthesis Examples

[0127] The following list of abbreviations used or commonly used throughout this specification represents the following and should aid in understanding the invention:

[0128] ACN, MeCN acetonitrile

[0129] Aq., aq. water-based

[0130] Argon (gas)

[0131] BOP Benzotriazole-1-yl-oxyhexafluorophosphate

[0132] Butyllithium (BuLi)

[0133] Cs2CO3 (cesium carbonate)

[0134] CHCl3 chloroform

[0135] CH2Cl2, DCM dichloromethane, methylene chloride

[0136] Cu(1)I Copper Iodide(1)

[0137] DCC Dicyclohexylcarbodiimide

[0138] DIC 1,3-Diisopropylcarbodiimide

[0139] DIEA, DIPEA (diisopropylethylamine)

[0140] DME dimethoxyethane

[0141] DMF (dimethylformamide)

[0142] DMAP 4-Dimethylaminopyridine

[0143] DMS dimethyl sulfide

[0144] DMSO (dimethyl sulfoxide)

[0145] EDC, EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide

[0146] Et2O diethyl ether

[0147] EtOAc (ethyl acetate)

[0148] FBS Fetal Bovine Serum

[0149] G, gm gram

[0150] h, hr hours

[0151] H2 hydrogen gas

[0152] H2O water

[0153] HCl hydrochloric acid

[0154] HOAc acetic acid

[0155] HPLC (High-Performance Liquid Chromatography)

[0156] IPA, IpOH, Isopropanol

[0157] K2CO3 (potassium carbonate)

[0158] KI potassium iodide

[0159] LG leaving group

[0160] LDA (Lithium diisopropylamino)

[0161] LiOH (Lithium hydroxide)

[0162] MgSO4 Magnesium sulfate

[0163] MS or m / z mass spectrometry

[0164] MeOH (methanol)

[0165] N2 nitrogen gas

[0166] NaCNBH3 Sodium cyanoborohydride

[0167] Na2CO3 (Sodium carbonate)

[0168] NaHCO3 (Sodium bicarbonate)

[0169] Sodium hydride (NaH)

[0170] Sodium iodide (NaI)

[0171] NaBH4 sodium borohydride

[0172] NaOH (sodium hydroxide)

[0173] Na2SO4 Sodium sulfate

[0174] NH4Cl ammonium chloride

[0175] NH4OH ammonium hydroxide

[0176] P(t-bu)3 tri(tert-butylphosphine)

[0177] PBS (Phosphate Buffered Saline)

[0178] Pd / C Palladium / Carbon

[0179] Pd(PPh3)4 Palladium(0)tetra(triphenylphosphine)

[0180] Pd(dppf)Cl2palladium(1,1-bis(diphenylphosphine ferrocene))(II) chloride

[0181] Pd(PhCN)₂Cl₂ Palladium dicyanophenyl dichloride

[0182] Pd(OAc)2 Palladium acetate

[0183] Pd2(dba)3 Tris(dibenzylacetone)dipalladium

[0184] RT, rt room temperature

[0185] RBF, rbf round-bottom flask

[0186] TLC, TLC thin-layer chromatography

[0187] TEA, Et3N Triethylamine

[0188] TFA (trifluoroacetic acid)

[0189] THF Tetrahydrofuran

[0190] The following preparation methods for compounds and intermediates of formula (I) are given to enable those skilled in the art to better understand and practice the invention. They should not be considered as limiting the scope of the invention, but only as illustrative and representative of the invention.

[0191] Intermediate A1: Racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate perfluorophenyl ester

[0192]

[0193] Step 1: 4-Bromo-2-iodoaniline

[0194] Iodine (368 g, 1.45 mol, 1.0 equivalent, Qualigens) was added to a solution of 4-bromoaniline (500 g, 2.90 mol, 2.0 equivalent, Saibain Chem) in cyclohexane (2.5 L), and the mixture was heated at 50 °C. After 30 min, the reaction mixture became homogeneous. A 30% aqueous hydrogen peroxide solution (250 mL, Spectrochem) was added to the reaction mixture. The reaction mixture was heated at 50 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5.0 L), and washed with an aqueous sodium sulfite solution (2.5 kg in 4.0 L). The organic layer was washed with water (3.0 L) and brine (3.0 L), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude material. This crude material was purified by column chromatography (silica gel; sieve size 60-120, elution 0%-20% ethyl acetate and hexane) to give 4-bromo-2-iodoaniline (650 g, 75%) as a grayish-white solid. TLC solvent system: 100% hexane. The product's R... f : 0.6. MS (ESI, cation) m / z: 297.0 (M+1). 1HNMR (400MHz, CDCl3) δ7.72 (d, J = 2.5 Hz, 1H), 7.23 (dd, J = 8.4, 2.1 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 4.09 (s, 2H).

[0195] Step 2: Ethyl (E)-3-(2-amino-5-bromophenyl)acrylate

[0196] Ethyl acrylate (277 g, 2.76 mol, 1.0 equivalent) and sodium bicarbonate (680 g, 6.29 mol, 2.5 equivalent) were added to a solution of 4-bromo-2-iodoaniline (750 g, 2.51 mol, 1.0 equivalent) in DMF (5.0 L). 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 equivalent, Hindustan Platinum). The reaction mixture was heated at 70 °C for 3 h. The reactants were then subjected to... 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; sieve size 60-120, eluting 0%-20% ethyl acetate in hexane) to obtain ethyl (E)-3-(2-amino-5-bromophenyl)acrylate (620 g, 77.0%) as a yellow solid. TLC solvent system: 20% ethyl acetate in hexane. The product's R... f : 0.4. MS (ESI, cation) 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).

[0197]

[0198] Step 3: (E)-3-(2-amino-5-(benzylthio)phenyl)ethyl acrylate (The above scheme needs to be redrawn)

[0199] DIPEA (1.26 L, 8.88 mol, 3.9 equivalence, GLR) was added to a solution of (E)-3-(2-amino-5-bromophenyl)acrylate (620 g, 2.29 mol, 1.0 equivalence) in 1,4-dioxane (4.0 L), and the mixture was degassed with nitrogen for 20 min. XantPhos (92.9 g, 106 mmol, 0.05 equivalence, GLR) and tris(dibenzylacetone)palladium (84 g, 91.0 mmol, 0.04 equivalence, Hindustan Platinum) were added to the reaction mixture. The mixture was purged with nitrogen and heated to 80 °C for 30 min. The reaction mixture was cooled to RT and benzyl mercaptan (455.5 g, 3.67 mol, 1.6 equivalence, AlfaAesar) was added, and the mixture was heated again at 80 °C for 4 h. The reactants were cooled to room temperature and diluted with ethyl acetate (4.0 L). The mixture was then passed through... 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; sieve size 60-120, elution 0%-40% ethyl acetate and petroleum ether) to obtain ethyl (E)-3-(2-amino-5-(benzylthio)phenyl)acrylate (520 g, 72.0%) as a yellow solid. TLC solvent system: 30% ethyl acetate in hexane. The product's R... f : 0.4. MS (ESI, cation) 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).

[0200]

[0201] Step 4: 1-Bromo-2-fluoro-4-iodo-5-methoxybenzene

[0202] Silver trifluoromethanesulfonate (686.0 g, 2.68 mol, 1.1 equivalent, Angene) was added to a solution of 2-bromo-1-fluoro-4-methoxybenzene (500.0 g, 2.44 mol, 1.0 equivalent) in DCM (5.0 L), and the reaction mixture was stirred for 20 min. Iodine (678.0 g, 2.68 mol, 1.1 equivalent) was added to the reactants, and the mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM (3.0 L) and... Filtration. The CELITE bed was washed with DCM (2 x 1.0 L) and the filtrate was washed with 20% aqueous sodium thiosulfate (3.0 L) and saturated aqueous sodium bicarbonate solution (3.0 L). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude material, which was purified by chromatography (silica gel; sieve size 60-120, elution 0%-5% ethyl acetate and petroleum ether) to give 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (720 g, 87%) as a grayish-white solid. TLC solvent system: 100% hexane. R of the product f : 0.6. MS (ESI, cation) m / z: 331.0 (M+1). 1 HNMR (400MHz, CDCl3) δ7.55 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 5.6 Hz, 1H), 3.89 (s, 3H).

[0203] Step 5: Ethyl (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate

[0204] Cs₂CO₃ (468 g, 1436.3 mmol, 1.5 equivalence) was added to a solution of (E)-3-(2-amino-5-(benzylthio)phenyl)acrylate (300 g, 958.1 mmol, 1.0 equivalence) and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (348.0 g, 1051.6 mmol, 1.1 equivalence) in toluene (2.5 L), and the mixture was degassed with nitrogen for 20 min. Pd₂(dba)₃ (35 g, 38.2 mmol, 0.04 equivalence, Hindustan Platinum) and XantPhos (44.6 g, 76.4 mmol, 0.08 equivalence, 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 subjected to... Filtration. 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 then filtered to obtain ethyl (E)-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. R of the product f : 0.5. MS (ESI, cation) m / z: 516.2 (M+1). 1 ¹H NMR (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.

[0205]

[0206] Step 6: 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinoline-2(1H)-one

[0207] A solution of (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (250.0 g, 484.0 mmol, 1.0 equivalent) in methanol (2.5 L) was added to tris(n-butyl)phosphine (50% solution in ethyl acetate, 48.9 mL, 96.8 mmol, 0.2 equivalent, 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 obtain a crude material. This crude material was purified by stirring with 5% ethyl acetate in hexane (1.0 mL) and filtered to obtain 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinoline-2(1H)-one (201.0 g, 88%) as a grayish-white solid. TLC solvent system: 30% ethyl acetate in hexane. The product's R... f : 0.3. MS (ESI, cation) 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).

[0208] Steps 7 and 8: 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate perfluorophenyl ester

[0209] Acetic acid (200 mL) and water (130 mL) were added to a solution of 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinoline-2(1H)-one (250.0 g, 531.5 mmol, 1.0 equivalent) in acetonitrile (2.5 L). 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 equivalent, Aldrich) was added in portions over 20 min, keeping the internal temperature below 5 °C. The resulting suspension was stirred under nitrogen at 0 °C–5 °C for 45 min. Then, a solution of pentafluorophenol (127.2 g, 690.95 mmol, 1.3 equivalents, Apollo) in acetonitrile (200 mL) was added over 5 min, followed by the addition of NEt3 (307.7 mL, 2.12 mol, 4.0 equivalents) over 20 min, while maintaining the internal temperature below 5 °C. The mixture was stirred for another 30 min at 0 °C–5 °C. Water (4.0 L) was added and the mixture was extracted with ethyl acetate (2 x 2.0 L). The organic layer was washed with brine (1.0 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by stirring with isopropanol:hexane (1:1, 1.0 L) and filtered to obtain 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, cation) m / z: 594.2 (M+1). 1 H-NMR (400MHz, DMSO) δ8.60 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 9.8 Hz, 1H), 7.95 (dd, J = 2.2, 9.1 Hz, 1H), 7.70 (t, J = 8.6 Hz, 2H), 6.95-6.88 (m, 2H), 3.72 (s, 3H).

[0210] Intermediate B1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0211]

[0212] Step 1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate perfluorophenyl ester

[0213] 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) was separated by chiral OJ column (40% MeOH / 60% CO2) to give (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 pale yellow flocculent solids. Peak 1 data: m / z (ESI) 594.0 (M+H) + Peak 2 data: m / z (ESI) 594.0 (M+H) + .

[0214]

[0215] Step 2: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0216] A 250 mL round-bottom flask containing perfluorophenyl (4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (6.00 g, 10.10 mmol) and 3-aminoisoxazole (0.821 mL, 11.11 mmol) in THF (200 mL) 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 stirring the yellow solution at 0 °C for 15 min, it was quenched with 1 N HCl at 0 °C and extracted three times with EtOAc. The organic extracts were combined, dried over MgSO4, filtered, and concentrated to a light brown residue. Et2O was added, and the slurry was ground and sonicated. The product was filtered to obtain a grayish-white solid, which was washed twice with Et₂O and dried under vacuum to give 3.88 g of the product as a grayish-white solid. The filtrate was concentrated under vacuum 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 pale yellow flocculent solid. A total of 5.24 g of (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide was obtained. m / z (ESI) 494.1 (M+H) + .

[0217] Intermediate C1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazo-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0218]

[0219] A 250-mL round-bottom flask was filled with perfluorophenyl (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (see step 1 above for intermediate B1, 11.34 g, 19.08 mmol) and N-(4-methoxybenzyl)isoxazol-3-amine (4.09 g, 20.04 mmol), and then purged with nitrogen. Tetrahydrofuran (191 mL) was introduced, and the resulting brown solution was cooled to 0 °C. Over 10 min, 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 using a syringe. After 15 min, 1.0 N HCl (100 mL) was introduced, and the resulting reaction mixture was heated to RT. The mixture was diluted with EtOAc (100 mL) and the layers were separated. 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 rapid column chromatography (100-g Biotage column, eluent: gradient, 0% to 100% EtOAc in heptane, with 10% CH2Cl2 as an additive) to give (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazo-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 HNMR (400MHz, DMSO-d6) 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, 1 H),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)+.

[0220] Intermediate D1: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0221]

[0222] Step 1: Ethyl (E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate

[0223] Cesium carbonate (357.5 g, 1100 mmol, 2.0 equivalent) was added to a solution of ethyl (E)-3-(2-amino-5-(benzylthio)phenyl)acrylate (175 g, 555.0 mmol, 1.0 equivalent) and 1-bromo-2-chloro-4-iodo-5-methoxybenzene (231.3 g, 666.2 mmol, 1.1 equivalent) in toluene (1.5 L), and the mixture was degassed with nitrogen for 20 min. Pd2(dba)3 (12.5 g, 13.0 mmol, 0.025 equivalent) and xantphos (15.8 g, 27.2 mmol, 0.05 equivalent) 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 diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain a crude material, which was purified by stirring with 5% ethyl acetate in hexane (1.5 L) for 30 min and then filtered to obtain ethyl (E)-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) + .

[0224]

[0225] Step 2: 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinoline-2(1H)-one

[0226] A solution of (E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate (300.0 g, 5630.0 mmol, 1.0 equivalent) in methanol (3.0 L) was supplemented with tris(n-butyl)phosphine (50% solution in ethyl acetate, 56.2 mL, 1126 mmol, 0.2 equivalent), 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 obtain a crude material. This crude material was purified by stirring with 5% ethyl acetate in hexane (1.0 mL) and filtered to obtain 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinoline-2(1H)-one (210.0 g, 76.6%) as a grayish-white solid. m / z (ESI) 486.0 (M+H) + .

[0227] Step 3: 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate perfluorophenyl ester

[0228] Acetic acid (1.0 L) and water (700 mL) were added to a solution of 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinoline-2(1H)-one (400.0 g, 824.9 mmol, 1.0 equivalent) in acetonitrile (2.5 L) and THF (2.5 L). The resulting mixture was cooled to 0 °C and 1,3-dichloro-5,5-dimethylimidazolium-2,4-dione (292 g, 1484.8 mmol, 1.8 equivalent) was added in portions over 30 min, keeping the internal temperature below 5 °C. The resulting suspension was stirred at 0 °C under nitrogen for 45 min. Then, a solution of pentafluorophenol (197.4 g, 1072.3 mmol, 1.3 equivalents) in acetonitrile (500 mL) was added over 5 min, followed by the addition of triethylamine (477 mL, 3299 mol, 4.0 equivalents) over 30 min, while maintaining the internal temperature below 5 °C. The mixture was stirred at 0 °C for 50 min. Water (4.0 L) was added and the mixture was extracted with ethyl acetate (3 x 2.0 L). The organic layer was washed with brine (2.0 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by stirring with isopropanol:hexane (1:1, 2.0 L) and filtered to obtain perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (360 g, 72%) as a white solid. m / z (ESI) 610.6 (M+H) + .

[0229]

[0230] Step 4: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate perfluorophenyl ester and (M)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate perfluorophenyl ester

[0231] 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (156 g, 255 MMOL) was purified by chiral SFC chromatography ((S,S)Whelk-O, 45% isopropanol) to give (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate perfluorophenyl ester (72.66 g, 93% yield) and (M)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate perfluorophenyl ester (76.13 g, 98% yield) as white solids. m / z (ESI) 610.6 (M+H) + .

[0232] Step 5: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0233] Add (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (2.56 g, 4.19 mmol) to a 100 mL RB flask. Place the flask under nitrogen atmosphere, then add THF (41.9 mL) and isoxazol-3-amine (0.423 g, 5.03 mmol). Cool the mixture to 0 °C for 10 min, then add 1.0 M LHMDS in THF (8.80 mL, 8.80 mmol) dropwise over 5 min. Stir the reaction mixture for two hours. While still relatively cool, add 1 N HCl (50 mL) and EtOAc (50 mL). Separate the layers and wash the organic layer again with 1 N HCl. Combine the aqueous layers and extract with EtOAc (2 x 50 mL). Dry all combined organic compounds with sodium sulfate, filter, and concentrate. The material was purified by chromatography on silica gel (40%-100% EtOAc / heptane) to give (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (2.03 g, 3.97 mmol, 95% yield) as a grayish-white solid. 1H NMR (400MHz, DMSO-d6) 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=8.9 5,2.20Hz,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)+.

[0234] Intermediate E1: (M)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0235]

[0236] 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-sulfonate perfluorophenyl ester was used instead of (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate perfluorophenyl ester to give (M)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate as a grayish-white solid. 1 HNMR (400MHz, DMSO-d6) 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

[0237] Example 1: (P)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0238]

[0239] Fill the vial with active zinc (Rieke zinc) (4.38 ml, 3.35 mmol) and cool to 0°C. Slowly add dropwise 1,1,1-trifluoro-3-iodopropane (0.268 ml, 2.233 mmol) and slowly heat the reaction mixture to room temperature while stirring for one hour. Add 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), and stir the reaction mixture at 50°C for two hours. The reactants were 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 40 g, gradient elution 0%-100% EtOAc:heptane) to give (P)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-(isoxazo-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(400MHz, DMSO-d6)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) + .

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

[0241]

[0242] The title compound was prepared according to the method of Example 1, except that (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (see intermediate D1 above) instead of intermediate B1 to give (P)-1-(5-chloro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-(isoxazo-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(400MHz, DMSO-d6)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)7.55(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) + .

[0243] 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

[0244]

[0245] Step 1: (P)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate perfluorophenyl ester

[0246] Fill a vial with active zinc (Rieke zinc) (6.61 ml, 5.05 mmol) and cool to 0°C. Slowly add dropwise 3-bromo-1,1,1-trifluoropropane (0.358 ml, 3.37 mmol). Heat the reaction mixture to room temperature and stir for one hour. Add (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, 0.500 g, 0.841 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.043 g, 0.084 mmol), and stir the reaction mixture at 50°C for one hour. The reaction is then passed through... Pad filtration, to the 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, 0.170 mmol, 20.22% yield) as a white solid. m / z (ESI) 612.0 (M+H) + .

[0247] 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

[0248] A round-bottom flask was filled with pyridazine-3-amine (10.11 mg, 0.106 mmol) and DMSO (0.204 mL) 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 (0.050 g, 0.082 mmol) and THF (0.613 mL) were added. The flask was cooled in an ice bath for 5 minutes, and then LHMDS (1 M, in THF) (0.188 mL, 0.188 mmol) was added dropwise. The reaction mixture was stirred for 15 minutes. The reaction mixture was diluted with ethyl acetate and washed twice with 1 N 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 40 g, gradient elution 10%-75% [3:1EtOAc / EtOH]:heptane) to give (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. 1H NMR(400MHz, DMSO-d6)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) + .

[0249] Example 4: (P)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoro-2-methylpropyl)phenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0250]

[0251] Step 1: (3,3,3-trifluoro-2-methylpropyl)zinc bromide(II) (0.033M)

[0252] A round-bottom flask equipped with a magnetic stir bar and a rubber diaphragm, dried in an oven, was filled with lithium chloride (0.888 g, 20.94 mmol). The container was heated under high vacuum with a hot air gun for 10 min and then backfilled with nitrogen after cooling to room temperature. Zinc (1.369 g, 20.94 mmol) was added. The container was again heated under high vacuum with a hot air gun for 10 min and then backfilled with nitrogen after cooling to room temperature. THF (13.96 mL) and 1,2-dibromoethane (0.045 mL, 0.524 mmol) were added via syringe, and the reaction mixture was heated at 60 °C until bubbling occurred. After cooling to room temperature, TMS-Cl (0.040 mL, 0.314 mmol) and a solution of iodine (0.027 g, 0.105 mmol) in THF (0.2 mL) were added via syringe. The reaction mixture was heated at 60 °C for 20 min and then cooled to room temperature. Add 1.361 mL of 3-bromo-1,1,1-trifluoro-2-methylpropane (10.47 mmol) and stir the reaction mixture at 50 °C for 48 h. Allow the reaction mixture to stand at room temperature for 1 h, and pipette the solution into a syringe and transfer it to an oven-dried screw-top vial with a PTFE diaphragm. Titrate the solution dropwise with a 0 °C solution of iodine (0.0067 g, 0.026 mmol) in lithium chloride in anhydrous tetrahydrofuran (1.0 mL, 0.500 mmol) at 0.5 M until the orange color disappears. Use 0.8 mL of the solution, corresponding to a concentration of 0.033 M.

[0253]

[0254] Step 2: (P)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoro-2-methylpropyl)phenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0255] The vial was filled with palladium acetate (ii) (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). Zinc bromide (II) (3,3,3-trifluoro-2-methylpropyl)bromide (II) (0.033 M in THF) (18.39 mL, 0.607 mmol) was added, and the reaction mixture was stirred at 50 °C for one hour. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl aqueous solution. The organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (RediSep Gold 40 g, gradient elution 0%-50% [3:1EtOAc / EtOH]:heptane) to give (P)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoro-2-methylpropyl)phenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.103 g, 0.196 mmol, 81% yield) as a pale yellow solid. 1 HNMR(400MHz, DMSO-d6)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) + .

[0256] Example 5: (P)-1-(5-fluoro-2-methoxy-4-(4,4,4-trifluorobutyl)phenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0257]

[0258] 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-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (43.4 mg, 0.083 mmol, 100% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6) 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),6.4 3(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)+.

[0259] Examples 6A and 6B: racemic- and (P)-1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamides, respectively.

[0260]

[0261] Step 1: 1-(5-fluoro-2-methoxy-4-vinylphenyl)-N-(isoxazo-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0262] The vial was filled with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazo-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 vinylborate (0.812 mL, 3.66 mmol) were added. The reaction mixture was heated to 100 °C and stirred for two hours. The reaction mixture 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 40 g, gradient elution 0%-100% EtOAc:heptane) to give 1-(5-fluoro-2-methoxy-4-vinylphenyl)-N-(isoxazo-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) + .

[0263] Step 2: 1-(5-fluoro-4-formyl-2-methoxyphenyl)-N-(isoxazo-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0264] 1-(5-fluoro-2-methoxy-4-vinylphenyl)-N-(isoxazo-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.652 g, 1.161 mmol) was dissolved in acetonitrile (9.95 mL) and water (1.659 mL). Ruthenium(III) chloride dihydrate (0.05 M aqueous solution) (1.161 mL, 0.058 mmol) was added, followed by the addition of sodium periodate (0.129 mL, 2.322 mmol) in portions. The reaction mixture was stirred at room temperature for one hour. The reaction mixture was quenched with aqueous sodium thiosulfate and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (RediSep Gold 40 g, gradient elution 0%-100% EtOAc:heptane) to give 1-(5-fluoro-4-formyl-2-methoxyphenyl)-N-(isoxazo-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) + .

[0265]

[0266] Step 3: 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-N-(isoxazo-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0267] A round-bottom flask was filled with 1-(5-fluoro-4-formyl-2-methoxyphenyl)-N-(isoxazo-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.100 g, 0.177 mmol) and THF (0.887 mL). Trifluoromethyltrimethylsilane (0.045 mL, 0.302 mmol) and TBAF (1.0 M in THF) (0.018 mL, 0.018 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for three hours. 1N HCl (1.242 mL, 1.242 mmol) was added, and the reaction mixture was stirred for one hour. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (Biotage SNAP 25g column, gradient elution 0%-75% EtOAc:heptane) to give 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-N-(isoxazo-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) + .

[0268] Step 4: OO-(2,2,2-trifluoro-1-(2-fluoro-4-(6-(N-(isoxazo-3-yl)-N-(4-methoxybenzyl)aminosulfonyl)-2-oxoquinoline-1(2H)-yl)-5-methoxyphenyl)ethyl)phenyl thiocarbonate

[0269] 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-N-(isoxazo-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 sieve (0.100 g, 0.155 mmol) and DMAP (0.038 g, 0.309 mmol) were added, and the mixture was vigorously stirred. Phenyl thiochloroformate (0.043 ml, 0.309 mmol) was slowly added, resulting in a thick slurry. The reaction mixture was stirred at 60 °C for two hours. The reaction mixture was then passed through… Filter, to the Washed with DCM. The filtrate was concentrated and purified by column chromatography (RediSep Gold 12g, gradient elution 0%-100% EtOAc:heptane) to give OO-(2,2,2-trifluoro-1-(2-fluoro-4-(6-(N-(isoxazo-3-yl)-N-(4-methoxybenzyl)aminosulfonyl)-2-oxoquinoline-1(2H)-yl)-5-methoxyphenyl)ethyl)phenyl thiocarbonate as a white solid (0.106 g, 0.138 mmol, 89% yield). m / z (ESI) 770.0 (M+H) + .

[0270]

[0271] Step 5: 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-(isoxazo-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0272] 0.106 g (0.138 mmol) of OO-(2,2,2-trifluoro-1-(2-fluoro-4-(6-(N-(isoxazo-3-yl)-N-(4-methoxybenzyl)aminosulfonyl)-2-oxoquinoline-1(2H)-yl)-5-methoxyphenyl)ethyl)phenyl thiocarbonate was dissolved in toluene (2.75 mL) and cooled to -78 °C. A solution of tri-n-butyltin hydride (0.182 mL, 0.689 mmol) and triethylborane in hexane (0.138 mL, 0.138 mmol) was added, and the solution was bubbled through with an air-filled syringe to produce a bright pink solution. The reaction mixture was stirred at -78 °C for 30 min. The reaction mixture 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-(isoxazo-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.076g, 0.123mmol, 89% yield) as a white solid. m / z (ESI) 618.0 (M+H) + .

[0273] Step 6: 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (Example 6a)

[0274] 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-(isoxazo-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 reactants were concentrated and purified by column chromatography (RediSepGold 40 g, gradient elution 0%-75% [3:1EtOAc / EtOH]:heptane) to give 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.061 g, 0.123 mmol, 100% yield) as a grayish-white solid. m / z (ESI) 498.0 (M+H) + .

[0275]

[0276] Step 7: (P)-1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (Example 6B)

[0277] Racemic 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-(isoxazo-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-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.027 g, 0.054 mmol, 44.1% yield) as a grayish-white solid. 1 HNMR(500MHz,DMSO-d6)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) + .

[0278] The following compounds can be prepared from suitable starting materials similar to those used to prepare the compounds exemplified above.

[0279]

[0280]

[0281] Biological Examples

[0282] The following measurements were used to test exemplary compounds of the present invention. Data from those embodiments tested according to the procedures described below are presented in Table 1 below.

[0283] In vivo assay of Nav1.7 or Nav1.5 IWQ

[0284] HEK 293 cells stably transfected with Nav 1.7 or Nav 1.5 were used according to the manufacturer's instructions. The Quattro automated electrophysiology system (Molecular Devices, LLC, Sunnyvale, CA) recorded data in group patch-clamp mode. Sodium channel currents were measured in response to a series of depolarizations induced by successive inductions of greater inactivation.

[0285] Cells were held at a holding voltage of -15 mV to -110 mV for three seconds (Nav 1.7) or half a second (Nav 1.5), then subjected to a series of 26 pulses at a frequency of 5 Hz for a duration of 150 msec, down to -20 mV. The cells were then left unclamped for 3 to 8 minutes while a single concentration of the test compound was added. The cells were then clamped and subjected to the same voltage protocol. Leakage current was corrected by subtracting the current at the end of the 26th pulse down to -20 mV from the peak current excited by the 26th pulse down to -20 mV. The percentage of blockade was calculated in duplicate for each concentration, and IC50 was used to calculate the percentage of blockade. 50 The curve is fitted to the percentage of blockade as a function of concentration.

[0286] Nav 1.7 in vitro PX assay

[0287] HEK 293 cells stably transfected with human Nav1.7 were recorded in whole-cell voltage-clamp mode using a PatchXpress automated electrophysiology system (Molecular Devices, LLC, Sunnyvale, CA). The effects of compounds on the partially inactivated state of sodium channels were measured. Cells were clamped to produce a hold potential of 20% to 50% inactivation. To induce sodium current, the channels were activated by pulse to -10 mV for 20 msec. This voltage protocol was repeated at a rate of 0.1 Hz throughout the experiment. A single concentration of the test compound was applied to the cells for a duration of 3 minutes. The peak sodium current was 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 IC50 was measured. 50 The curves were fitted as a function of concentration to the percentage of inhibition. Data representing the compounds of this invention are presented in the tables herein.

[0288] Nav 1.5 in vitro PX assay

[0289] 293 cells stably transfected with Nav 1.5 were recorded in whole-cell voltage-clamp mode using a PatchXpress automated electrophysiology system (Molecular Devices, LLC, Sunnyvale, CA) according to the manufacturer's instructions. Cells were held at a hold potential of -50 mV to inactivate sodium channels. To induce sodium current, the voltage was changed to -120 mV to allow partial channel recovery, followed by a 20 msec test pulse 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 current was measured at the end of the compound addition period to determine the percentage of inhibition. At least two cells were tested for each concentration. IC50 was then applied to the cells. 50 The curves were fitted as a function of concentration to the percentage of inhibition. Data representing the compounds of this invention are presented in the tables herein.

[0290] The compounds of the present invention can also be tested in the following in vivo assays.

[0291] Formalin model of persistent pain in rats

[0292] On the day of testing, 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). All animals can be housed in captivity under a 12 / 12h light / dark cycle with the light on at 06:00. Rodents can be housed in pairs in solid-bottom cages lined with corncob, with free access to food and water. Animals should be allowed to acclimatize to their enclosure for at least five days prior to the start of the test and should be brought to the testing room at least 30 minutes before administration. Animals are pretreated with the appropriate test compound via oral tube feeding or intraperitoneal injection at the required pretreatment time (usually two hours before the start of the test) and then returned to their living cages. Animals can be acclimatized to their individual testing rooms after administration and at least 30 minutes before the start of the test. At the time of testing, each animal can be gently wrapped in a towel with its left hind paw exposed. A diluted formalin (2.5%) solution in phosphate-buffered saline was subcutaneously injected into the dorsal side of the left hind paw using a 30g needle at a volume of 50 μL. Immediately after injection, a small metal band was attached to the plantar side of the left hind paw with a drop of LOCTITE (adhesive). The animal was then placed in a testing chamber, and the number of withdrawals was recorded between 10 and 40 minutes after formalin injection. Withdrawal was defined as a rapid, spontaneous movement of the injected hind paw not associated with gait. Withdrawal was quantified with the aid of an Automated Nociception Analyzer established at the University of California, San Diego Department of Anesthesiology. Individual data can be expressed as the % Maximum Potential Effect (%MPE) calculated using the following formula: (-(Individual Score - Mean Media Score) / Mean Media Score))*100=%MPE

[0293] Statistical analysis of significant primary effects was performed using analysis of variance (ANOVA) along with post-hoc analysis using Bonferroni, comparing the media group to the media group. Data can be expressed as mean %MPE + / - standard error for each group.

[0294] Open field test of rats

[0295] On the day of testing, 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). All animals can be housed in captivity under a 12 / 12h light / dark cycle with the light on at 06:00. Rodents can be housed in pairs in solid-bottom cages lined with corncob, with free access to food and water. Animals should be allowed to acclimatize to the enclosure for at least five days prior to the start of the test and should be brought to the testing room at least 30 minutes before administration. In a separate room from the testing room, animals can be pretreated with the appropriate test compound via oral tube feeding or intraperitoneal injection at the required pretreatment time (usually two hours before the start of the test) and then returned to their living cages after pretreatment. At the time of testing, animals can be transferred to the open testing room in their living cages. Each animal can be placed in a separate testing room with a motion tracking system activated. The indoor lighting in the testing room should be turned off, and animals should be allowed to explore the new area for 30 minutes at the beginning. Animal movement can be detected by using an automated motion tracker manufactured by San Diego Instruments, Inc. (San Diego Instruments, San Diego, CA) with the aid of an infrared beam to capture animal exploration. These behaviors include basic movement and standing upright, which can be used as the primary endpoint of this assay. At the end of the test, the indoor lighting can be turned on, and the animals should be removed from the testing equipment. Data can be expressed as a percentage change relative to the medium control using the following equation.

[0296] (1 - (test average value / media average value)) * 100 = change.

[0297] Statistical analysis can be performed using analysis of variance (ANOVA), along with post-hoc analysis using Dunnett, to track significant major effects.

[0298] Formalin model of persistent pain in mice

[0299] Mice (first contact experiment, male C57Bl / 6) weighing between 22 and 30 g at the start of the test were obtained from Harlan (Indianapolis, IN). All animals were housed in captivity under a 12 / 12h light / dark cycle with the light on at 06:30. The rodents were individually housed in solid-bottom cages lined with corncob and given free access to food and water. Animals were allowed to acclimatize to their housing for at least five days prior to the start of the test and were brought to the test chamber at least 30 minutes before administration. Animals were pretreated with the appropriate test compound via oral tube feeding or intraperitoneal injection at the required pretreatment time (usually two hours before the start of the test) and then returned to their living cages. Animals were allowed to acclimatize to their individual test chambers after administration and at least 5 minutes before the start of the test. At the time of the test, each animal was gently wrapped in a cloth glove with its left hind paw exposed. A diluted solution of formalin (2%) in phosphate-buffered saline was subcutaneously injected in 20 μL volume into the dorsal side of the left hind paw using a 30 g needle. The animals were then placed in an observation room, and their behavior was recorded for 60 minutes following the formalin injection. Pain-related behaviors were defined as licking of the hind paws and / or non-weight-bearing that were not associated with walking.

[0300] Statistical analysis for any significant primary effect can be performed by analysis of variance (ANOVA), along with post-hoc analysis using Dunnett's post-hoc test, comparing the media group to the media group. Data are expressed as mean + / - standard error for each group.

[0301] Mouse Open Field Test

[0302] Mice (first exposure experiment, male C57Bl / 6) weighing between 22-30g were obtained from Harlan (Indianapolis, IN). All animals were housed in captivity under a 12 / 12h light / dark cycle with light on at 06:30. Rodents were individually housed in solid-bottom cages lined with corncob and had free access to food and water. Animals were allowed to acclimatize to their housing for at least five days prior to the start of the test and were brought to the test chamber at least 30 minutes before administration. In a separate chamber from the test chamber, animals were pretreated with the appropriate test compound via oral tube feeding or intraperitoneal injection for the required pretreatment time (usually two hours before the start of the test) and then returned to their living cages after pretreatment. At the test time, animals were transferred to the open test chamber in their living cages. Each animal was placed in an individual test chamber and the movement tracking system was turned on. The indoor lighting in the test chamber was turned off, and animals were allowed to explore the novel opening for 30 minutes. Animal movement was detected by capturing animal exploration using an automated motion tracker manufactured by Kinder Scientific, Poway, CA, aided by an infrared beam. These behaviors included basic movement and standing upright, which served as the primary endpoint of the assay. At the end of the test, indoor lighting was turned on and the animal was removed from the testing equipment.

[0303] Statistical analyses for any significant primary effect can be performed by analysis of variance (ANOVA), along with post-hoc analyses using Dunnett post-hoc tests, comparing the data to the media group. Data are expressed as the mean plus or minus the standard error for each group. Data are also expressed as percentage changes relative to the media control using the following equation:

[0304] (1 - (test average value / media average value)) * 100 = change.

[0305] CFA - Thermal Measurement

[0306] 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). All animals can be housed in captivity under a 12 / 12h light / dark cycle with light on at 06:00. Rodents can be housed in pairs in solid-bottom cages lined with corncob, with free access to food and water. Animals can be allowed to acclimatize to the enclosure for at least five days prior to the start of the test and can be brought to the testing room at least 30 minutes before administration. The Complete Freund's Adjuvant (CFA) thermometry can be performed using a three-day testing schedule consisting of an acclimatization day, a baseline day, and a test day. On Day 1, animals can be brought to the testing room, tagged, and placed in their individual test kits on their testing equipment. Animals can be allowed to explore the environment for at least one hour without actual testing. After acclimatization, animals can be returned to their living cages and to the enclosure. On day 2, the animal can be brought back to the testing room and placed on the testing equipment and sedated (usually for 30-45 minutes). The baseline thermal threshold should then be determined using the following procedure: Once sedated, place the Ugo Basile foot device under the animal's left hind paw; press the start button to activate a steadily increasing heat source and timer; when the animal reaches its thermal threshold, it will retract its hind paw, stopping the timer and heat stimulation. This retraction delay can be recorded three times for each animal, with at least 5 minutes between tests, and the average score can be used as the animal's baseline threshold. After testing, 25 μg / 50 μl of complete Freund's adjuvant can be injected intraplantarly into the animal's left hind paw. The animal is then returned to its living cage and back to its enclosure. On the day of testing, the animal can be placed on the thermal testing equipment again, and its post-CFA baseline can be obtained using the procedure summarized above. The animal can be pretreated with the appropriate test compound via oral tube feeding or intraperitoneal injection at the desired pretreatment time (usually two hours before the start of testing) and then returned to its living cage. Thirty minutes before the test, the animal can be placed back on the device. Once the pretreatment time is over, the animal can be tested again using the above procedure. Data can be expressed as the percentage of the maximum potential effect using the following formula:

[0307] ((Post-drug mean – Pre-drug mean) / (Baseline mean – Pre-drug mean)) * 100 = %MPE

[0308] Statistical analysis of significant primary effects was performed using analysis of variance (ANOVA) along with post-hoc analysis using Bonferroni, comparing the media group to the media group. Data can be expressed as mean %MPE + / - standard error for each group.

[0309] Spinal nerve ligation (Chung)

[0310] Animals weighing between 150-200g at the start of the first test (first contact experiment, male Sprague Dawley rats) were available from Harlan (Indianapolis, IN). All animals were kept in captivity under a 12 / 12h light / dark cycle with the light on at 06:00. Rodents were kept in pairs in solid-bottom cages lined with corncobs, with free access to food and water. Animals were allowed to acclimatize to the enclosure for at least five days before the start of the test. Surgery was then performed based on the method described by Kim and Chung (1992). In short, the animals were placed under isoflurane anesthesia in a sterile surgical area. The lumbar region was excised, exposing the spinal nerves at L4-L5. The L5 spinal nerve was identified and tightly ligated with 5-0 sutures. The muscles were closed with absorbable sutures, and the skin was closed with wound clamps. Animals were returned to the enclosure for 7-14 days and monitored daily. On the day of testing, animals are brought to the testing chamber and placed on a metal mesh floor in an individual testing chamber. Animals are allowed to acclimatize to the chamber until they are calm. A series of Semimes-Weinstein monofilaments (von Frey hairs) with calibrated bending forces are then applied to establish a baseline of pain sensitivity according to the method outlined by Chaplan et al. (1994). In short, the monofilaments are applied with increasing force (if there is no response to a previous stimulus) or decreasing force (if there is a response to a previous stimulus) until the baseline is reached. Animals are then pretreated with the appropriate test compound via oral tube feeding or intraperitoneal injection at the desired pretreatment time (usually two hours before the start of testing) and then returned to their living cages. Thirty minutes before testing, the animals are placed back on the equipment. After the pretreatment time, the above procedure is repeated to determine drug efficacy. Data can be expressed as mean gram force for inducing nociceptive pain. Statistical analysis for significant primary effects can be performed by analysis of variance (ANOVA) compared to the mediator group, along with post-hoc analysis using Bonferroni.

[0311] Table 1 provides data for the compounds exemplified in this application and its priority documents as representative compounds of the present invention, as follows: compound name (as named by ACD software, version 12; while the compound names in the written examples presented herein are named using ChemDraw Ultra version 12); and biological data, including, where available, in vitro Nav 1.7PX data (IC in μM). 50 Nav 1.7IWQ data (IC in μM) 50HLM in vitro data (μL / (min·mg)) and human PXRPOC S (%) at 2 μM. Ex.# refers to the example number. The compounds of the present invention show favorable activity against hNav1.7 and HLM and human PXR data.

[0312] Table 1: Biological Data

[0313]

[0314] For purposes of clarity and understanding, the foregoing invention has been described in detail through illustration and examples. Those skilled in the art will understand that variations and modifications may be made within the scope of the appended claims. Therefore, it should be understood that the above description is intended to be illustrative and not restrictive. Consequently, the scope of the invention should not be determined by reference to the above description, but rather by reference to the following appended claims together with the full scope of the equivalents of the claims.

[0315] All patents, patent applications and publications cited in this article are hereby incorporated in their entirety by reference, to the extent that each individual patent, patent application or publication is so individually indicated.

Claims

1. A compound of formula I, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, (I)； in: R 1 Selected from -CH2-CF3 or -CH2-CH2-CF3; R 2 It is a halogenated group; R 3 It is a methoxy group; R 4 It is an isoxazolyl group; R 6 and R 7 Each of them is hydrogen; and R 5a ;R 5b ;R 5c ;R 5d ; and R 5e Each of them is hydrogen.

2. The compound according to claim 1, or its transisomer, or its pharmaceutically acceptable salt, wherein R 2 It is either fluorine or chlorine.

3. The compound according to claim 1, or its transisomer, or its pharmaceutically acceptable salt, wherein R 2 It's fluorine.

4. The compound according to claim 1, or its transisomer, or its pharmaceutically acceptable salt, is: 1-(5-chloro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinoline sulfonamide, or 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethyl)phenyl)-N-(isoxazo-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

5. The compound according to any one of claims 1-4, or its transisomer, or its pharmaceutically acceptable salt, wherein, when present, the transisomer is a P-transisomer.

6. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

7. Use of the compound, or its transisomer, or its pharmaceutically acceptable salt, according to any one of claims 1-5, in the preparation of a medicament for treating Nav1.7-mediated pain.

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

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