Heteroalkyldihydroquinoline sulfonamide compounds

Abstract

The present invention relates to heteroalkyldihydroquinoline sulfonamide compounds of formula I which are inhibitors of voltage-gated sodium channels, particularly Nav1.7. TIFF2024514990000039.tif78170 and pharma- ceutically acceptable salts thereof are provided. The compounds are useful for treating diseases associated with sodium channel activity, such as pain disorders, cough, and pruritus. Pharmaceutical compositions containing the compounds of the invention are also provided.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 037,000, filed on 10 June 2020.

[0002] The present invention provides heteroalkyldihydroquinoline sulfonamide compounds that are inhibitors of voltage-gated sodium channels (Nav), particularly Nav1.7, and are useful for treating diseases that can be treated by inhibiting sodium channels, such as pain disorders. Pharmaceutical compositions containing the compounds of the present invention are also provided. [Background technology]

[0003] A 2011 report by the Institute of Medicine estimated that approximately 30% of the population, or 100 million adults in the United States, suffer from chronic pain (C&E News, Bethany Halford, “Changing the Channel”, published 3-24). By definition, chronic pain involves the abnormal electrical spiking of neurons in the pain pathway: peripheral sensory neurons, spinal cord neurons, neurons in the pain matrix of the brain (e.g., somatosensory cortex, insular cortex, anterior cingulate cortex), and / or neurons in the brainstem. The firing of these neurons is regulated and controlled by many different receptors, enzymes, and growth factors, but in most neurons, the rapid upstroke of the electrical spike is caused by the influx of sodium ions through voltage-gated sodium channels (Hille B, Ion Channels of Excitable Membranes. Sinauer Associates, Inc.: Sunderland MA, 3). rd(Ed. 2001). There are nine different isoforms of voltage-gated sodium channels (Nav1.1 to Nav1.9), which have different expression patterns in neurons and tissues including cardiac and skeletal muscle (Goldin, AL, “Resurgence of sodium channel research,” Ann Rev Physiol 63:871-894, 2001; Wood, J. Nand, Boorman, J. “Voltage-gated sodium channel blockers; target validation and therapeutic potential,” Curr. Top Med. Chem. 5:529-537, 2005).

[0004] Nav1.1 and Nav1.2 are highly expressed in the brain (Raymond, CK, et al., J. Biol. Chem. Chem. (2004) 279(44):46234-41) and are essential for normal brain function. Some loss of function resulting from Nav1.1 mutations in humans is presumed to lead to epilepsy 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 nervous system, and inhibition of Nav1.1 in the periphery may lead to pain relief. Therefore, while inhibition of Nav1.1 may be useful in treating pain, it may also cause anxiety and hyperexcitability, which may be undesirable. Nav1.3 is primarily expressed in the embryonic central nervous system, and its expression has been found to be upregulated after nerve injury in rats (Hains, BD, et al., J. Neuroscience (2030) 23(26):8881-8892). Nav1.4 is primarily expressed in skeletal muscle. Mutations in its 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 those in the atria, ventricles, sinoatrial node, atrioventricular node, and cardiac Purkinje fibers. Rapid upstroke of cardiac action potentials and rapid conduction of excitation through cardiac tissue are attributed to the opening of Nav1.5 channels. Mutations in the Nav1.5 channel have been associated with arrhythmic syndromes, including QTc prolongation, Brugada syndrome (BS), sudden nocturnal death syndrome (SUNDS), and sudden infant death syndrome (SIDS) (Liu, H., et al., Am.J. Pharmacogenomics (2003), 3(3):173-179). Nav1.6 is a widely distributed voltage-gated sodium channel expressed throughout the central and peripheral nervous systems. Nav1.8 is primarily expressed in sensory ganglia of the peripheral nervous system, such as the dorsal root ganglia. No Nav1.8 mutations that produce diverse pain responses have been identified in humans.Nav1.8 differs from most neuronal Nav isotypes in that it is insensitive to inhibition by tetrodotoxin. Nav1.9, like Nav1.8, is also a tetrodotoxin-insensitive sodium channel mainly expressed in dorsal root ganglion neurons (Dib-Hajj, SD, et al., Proc. Natl. Acad. Sci. USA (1998), 95(15):8963-8968).

[0005] Recent evidence from several independent genetic studies suggests that the tetrodotoxin-sensitive voltage-gated sodium ion channel Nav1.7 (SCN9A) is required for pain perception. Rare genotypes of primary erythromelalgia and paroxysmal erythromelalgia, severe chronic pain conditions, 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 a sodium channel alpha subunit, in patients with primary erythermalgia,” J.Med.Genet. 41:171-174, 2004; Drenth JPH, te Morsche RHM, Guillet G., Taieb A., et al., “SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels,”J Invest Dermatol 124:1333-1338).Conversely, two separate clinical studies have identified the underlying cause of congenital insensitivity to pain (CIP), a genetic disorder, as loss of function in Nav1.7 via mutations that truncate and disrupt the function of the protein (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). This disorder is inherited in a Mendelian recessive manner with 100% penetrance. The phenotype associated with CIP is extreme. Specifically, affected individuals not only experience painless burns, childbirth, appendicitis, and fractures, but are also reported to be insensitive to clinical measurements of pain, such as pin stimulation or tendon compression. Nevertheless, sensory, motor, autonomic, and other measured functions are normal, and the only abnormality reported is anosmia (inability to smell). These studies indicate that Nav1.7 controls one or more control points critical to pain perception among many possible targets in the pain pathway.

[0006] Non-selective sodium channel inhibitors such as lidocaine, mexiletine, and carbamazepine show clinical efficacy in chronic pain, including neuropathic pain, but their dosage and use are limited because they may affect sodium channels other than those in the pain pathway. Lidocaine is a local anesthetic used by physicians for minor surgery. Dentists use novocaine. However, these compounds are unsuitable for use as systemic analgesics because they do not distinguish between various sodium channel subtypes. Glenn F. King, a professor at the University of Queensland in Australia who studies ion channel-blocking venom, states, "If you give a drug that blocks Nav1.7 but also blocks Nav1.5, the patient will die of heart failure. It may be a completely painless death, but the patient will still die." Therefore, selectivity for Nav1.7, especially more so than Nav1.5, is desirable. Researchers have been working to find molecules that inhibit or block the activity of Nav1.7 only. Complicating this issue is that the properties, all locations, all functions, and / or tertiary structures of each subtype of voltage-gated sodium channel proteins are unknown or not fully understood.

[0007] As a result, numerous researchers have attempted to identify small molecule inhibitors of Nav1.7. For example, Chafeev et al. disclose a spiro-oxindole compound for the treatment and / or prevention of sodium channel-mediated disorders such as pain in U.S. Patent No. 8,101,647. International Publication Brochures 2013 / 134518 and 2014 / 201206 disclose sulfonamide derivatives different from the sulfonamide derivative of the present invention. Therefore, there is a need to identify a Nav1.7 inhibitor that is at least more selective to Nav1.5 than to Nav1.5 in order to treat pain. The present invention provides a compound that is an inhibitor that is at least more selective to Nav1.7 than to Nav1.5. [Prior art documents] [Patent Documents]

[0008]

Patent Document 1

Patent document 2

Patent document 3

Non-licensed literature

[0009] [Non-licensed document 1] C & E News, Bethany Halford, “Changing the Channel,” published 3-24

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-Patent Document 14

Non-Patent Document 15

Summary of the Invention

Means for Solving the Problems

[0010] In Embodiment 1, the present invention relates to a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof

Chemical Formula

[0011] In the sub-embodiment 1a of Embodiment 1, the compound of formula (I) has sub-formula (Ia), where R 1 is -C 0~2 alk-OC 1~3 It is alk; and R 4 These are isoxazolyl or pyrimidyl.

[0012] In a more preferred sub-embodiment 1a of Embodiment 1, R 1 is -CH2-O-CF3 or -O-CF3; R 2 is F or Cl; and R 4 It is isoxazolyl.

[0013] In the most preferred sub-embodiment 1a of Embodiment 1, R 1 is -CH2-O-CF3; R2 is F; and R 4 It is isoxazolyl.

[0014] In the sub-embodiment 1b of Embodiment 1, the compound of formula (I) has sub-formula (Ib), where R 1 is -C 0~2 alk-SC1~2 It is alk; and R 4 These are isoxazolyl or pyrimidyl.

[0015] In a more preferred sub-embodiment 1b of Embodiment 1, R 1 -S-CF3 or -S-CH2CF3 is;R 2 is F, Cl, or methyl; and R 4 These are isoxazolyl or pyrimidyl.

[0016] In the most preferred sub-embodiment 1b of Embodiment 1, each R 1 is -S-CF3;R 2 is F; and R 4 It is isoxazolyl.

[0017] In Embodiment 2, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, R 1 is, -OC 1~8 alk, -CH2-OC 1~8 alk, -SC 1~8 alk, -CH2-SC 1~8 alk, or -CH(CH3)-SC 1~8 alk, and the C 1~8 alk is substituted with 1, 2, 3, or 4 hydroxyls or halos.

[0018] In Embodiment 3, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, R 1 The following are selected from -O-CF3, -O-CH2-CF3, -O-CH2-CH2-CF3, -O-CH(CH3)-CF3, -CH2-O-CF3, -S-CF3, or -S-CH2-CF3.

[0019] In the sub-embodiment 3a of Embodiment 3, R 1It is either -CH2-O-CF3 or -S-CF3.

[0020] In the sub-embodiment 3b of Embodiment 3, R 1 It is -CH2-O-CF3.

[0021] In the sub-embodiment 3c of Embodiment 3, R 1 It is -S-CF3.

[0022] In Embodiment 4, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, R 2 These are H, fluoro, chloro, methyl, CN, CF3, CHF2, or CH2F.

[0023] In Embodiment 5, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, R 2 The element is H, fluoro, chloro, or methyl.

[0024] In Embodiment 6, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, R 2 is either H or fluoro.

[0025] In Embodiment 7, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, R 3 It is methoxy.

[0026] In Embodiment 8, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, R 4 It is a 5-membered heteroaryl compound.

[0027] In Embodiment 9, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, R 4 It is a 6-membered heteroaryl compound.

[0028] In Embodiment 10, the present invention provides a compound of formula (I), its enantiomer, diastereoisomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, R 4 These are isoxazolyl, pyridadinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.

[0029] In Embodiment 11, the present invention provides a compound of formula (I), its enantiomer, diastereoisomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, R 4 These are isoxazolyl or pyrimidinyl.

[0030] In a sub-embodiment 11a of embodiment 11, R 4 It is isoxazolyl.

[0031] In another sub-embodiment 11b of embodiment 11, R 4 It is pyrimidinyl.

[0032] In Embodiment 12, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, R 5a ;R 5b ;R 5c ;R 5d ; and R 5e Each of them is hydrogen.

[0033] In Embodiment 13, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, R 5a is F; and R 5b ;R 5c;R 5d ; and R 5e Each of them is hydrogen.

[0034] In Embodiment 14, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, R 5c is F; and R 5a ;R 5b ;R 5d ; and R 5e Each of them is hydrogen.

[0035] In Embodiment 15, the present invention provides a compound of formula (I), its enantiomer, diastereoisomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein this compound is (P)-1-(5-chloro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; (P)-1-(5-chloro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; (P)-1-(5-chloro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; (P)-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; (P)-1-(5-fluoro-2-methoxy-4-((2,2,2-trifluoroethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; (P)-4-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or Selected from (P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-((trifluoromethyl)thio)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0036] In Embodiment 16, the present invention provides a compound of formula (I) having the subformula (Ia) specified above, its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound is (P)-1-(5-chloro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; (P)-1-(5-chloro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; (P)-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or Selected from (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0037] In a sub-embodiment 16a of Embodiment 16, the present invention provides a compound of formula (I) having the sub-formula (Ia) specified above, its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-chloro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0038] In a sub-embodiment 16b of Embodiment 16, the present invention provides a compound of formula (I) having the sub-formula (Ia) specified above, its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-chloro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0039] In a sub-embodied embodiment 16c of Embodiment 16, the present invention provides a compound of formula (I) having the sub-formula (Ia) specified above, its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-chloro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0040] In a sub-embodiment 16d of Embodiment 16, the present invention provides a compound of formula (I) having the sub-formula (Ia) specified above, its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0041] In Embodiment 17, the present invention provides a compound of formula (I) having the subformula (Ib) specified above, its enantiomer, diastereoisomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the compound is (P)-1-(5-chloro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; (P)-1-(5-fluoro-2-methoxy-4-((2,2,2-trifluoroethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; (P)-4-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or Selected from (P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-((trifluoromethyl)thio)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0042] In a sub-embodiment 17a of Embodiment 17, the present invention provides a compound of formula (I) having the sub-formula (Ib) specified above, its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-chloro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0043] In a sub-embodiment 17b of Embodiment 17, the present invention provides a compound of formula (I) having the sub-formula (Ib) specified above, its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-fluoro-2-methoxy-4-((2,2,2-trifluoroethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0044] In a sub-embodiment 17c of Embodiment 17, the present invention provides a compound of formula (I) having the sub-formula (Ib) specified above, its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0045] In a sub-embodiment 17d of Embodiment 17, the present invention provides a compound of formula (I) having the sub-formula (Ib) specified above, its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-4-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0046] In a sub-embodiment 17e of Embodiment 17, the present invention provides a compound of formula (I) having the sub-formula (Ib) specified above, its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-N-(isoxazole-3-yl)-1-(2-methoxy-5-methyl-4-((trifluoromethyl)thio)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0047] In Embodiment 18, the present invention provides the P-atrop isomers of each of the individual compounds listed in Embodiments 1 to 17 (including any one of their sub-embodiments), or pharmaceutically acceptable salts thereof.

[0048] In Embodiment 19, the present invention independently provides the M-atrop isomers of each of the individual compounds listed in Embodiments 1 to 17 (including any one of their sub-embodiments), or pharmaceutically acceptable salts thereof.

[0049] In Embodiment 20, the present invention provides a pharmaceutical composition comprising a compound according to any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 (including any one of its sub-embodiments), an enantiomer thereof, a diastereoisomer, an atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0050] In Embodiment 21, the present invention provides a method for treating pain, cough, or itching, comprising administering to a patient in need a therapeutically effective amount of a compound according to any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 (including any one of its sub-embodiments), its enantiomer, diastereoisomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

[0051] In Embodiment 22, the present invention provides the method of Embodiment 21, 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, diabetic peripheral neuropathy, and neuropathic low back pain.

[0052] In Embodiment 23, the present invention provides the method of Embodiment 21, wherein the cough is selected from post-viral cough, viral cough, or acute viral cough. See Dib-Hajj et al., “The NaV1.7 sodium channel: from molecule to man”, Nature Reviews Neuroscience (2013), 14, 49-62.

[0053] In Embodiment 24, the present invention provides a method for preparing an intermediate compound used in the preparation of a compound of formula (I). [Modes for carrying out the invention]

[0054] The present invention provides compounds of formula (I) as defined above, their enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions comprising compounds of formula (I), their enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and methods for treating diseases and / or conditions such as pain using compounds of formula (I), their enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0055] "C α~β The term "alk" refers to an alkyl group containing a minimum of α carbon atoms and a maximum of β carbon atoms in a branched or linear chain, or any combination thereof, where α and β are integers. The notation C0alk indicates a direct bond. 1~6 Examples of alk include:

Chem.

[0056] The term "halo" or "halogen" means a halogen atom selected from F, Cl, Br, or I.

[0057] “C α~β haloalk” means an alk group as defined herein in which at least one hydrogen atom is replaced by a halo atom as defined herein. A general C α~β haloalk group is a C 1~3 fluoroalk. An example of a general C 1~3 fluoroalk group is -CF3.

[0058] As used herein, the term "heteroatom" means an oxygen, nitrogen, or sulfur atom.

[0059] As used herein, the term "monocyclic ring" means a group having one monocyclic ring. The monocyclic ring may be a carbocyclic ring (all atoms of the ring are carbon) or a heterocyclic ring (the atoms of the ring include, in addition to carbon atoms, for example, 1, 2, or 3 heteroatoms, such as N, O, or S). Examples of monocyclic compounds include, but are not limited to, cyclobutyl, cyclopentyl, or cyclohexyl.

[0060] As used herein, the term “bicyclic ring” means a group comprising two linked rings. A bicyclic ring may be a carbocyclic ring (where all atoms in the ring are carbon) or a heterocyclic ring (where the atoms in the ring consist of, for example, one, two, or three heteroatoms, such as N, O, or S, in addition to carbon atoms). Both rings may be aliphatic (e.g., decalin and norbornane), aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin). Bicyclic rings include: (a) spirocyclic compounds, where the two rings share only a single atom (i.e., a spiro atom), which is usually a quaternary carbon. Examples of spirocyclic compounds include: [ka] These include, but are not limited to; (b) A fused bicyclic compound in which two rings share two adjacent atoms. In other words, the rings share one covalent bond; that is, the bridgehead atoms are directly connected (e.g., α-thugen and decalin). Examples of fused bicyclic rings include: [ka] These include, but are not limited to, these; and (c) A bridged bicyclic compound in which two rings share three or more atoms, and the two bridgehead atoms are separated by a bridge containing at least one atom. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be thought of as a pair of cyclopentane rings, each sharing three of its five carbon atoms. Examples of bridged bicyclic rings include: [ka] These include, but are not limited to, the following:

[0061] The term "aryl" refers to a cyclic aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Typical aryl groups have a 6- to 13-membered ring.

[0062] The term "heteroaryl" refers to a cyclic aromatic hydrocarbon in which one or more carbon atoms of an aryl group are replaced by heteroatoms. If a heteroaryl group contains two or more heteroatoms, these heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, indolyl, triazolyl, pyridadinyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, naphthylidinyl, quinoxalinyl, isothiazolyl, and benzo[b]thienyl. Common heteroaryl groups are 5- to 13-membered rings containing 1 to 4 heteroatoms. Heteroaryl groups that are 5- and 6-membered rings containing 1 to 3 heteroatoms are particularly common.

[0063] The terms "saturated, partially saturated, or unsaturated" include substituents saturated with hydrogen, substituents not fully saturated with hydrogen, and substituents partially saturated with hydrogen.

[0064] The term "pharmaceutically acceptable salt" refers to salts prepared by conventional means and is well known to those skilled in the art. Examples of "pharmaceutically acceptable salts" include, but are not limited to, basic salts of inorganic and organic acids, including, 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, and mandelic acid. For additional examples of "pharmaceutically acceptable salts," see Berge et al., J. Pharm. Sci. 66:1 (1977).

[0065] The term "substitution" means that a hydrogen atom on a molecule or group is replaced by another group or atom. Typical substituents include halogens and carbon atoms. 1~8 Alkyl, hydroxyl, C 1~8 Alkoxy, -NR x R x, nitro, cyano, halo, or perhalo 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 are mentioned, and each R x is independently hydrogen or C 1~8 alkyl. It should be noted that when the substituent is -NR x R x , the R x group may be linked with the nitrogen atom to form a ring.

[0066] A group or atom that replaces a hydrogen atom is also called a substituent.

[0067] Any specific molecule or group may have one or more substituents depending on the number of hydrogen atoms that can be replaced.

[0068] The term "unsubstituted" means a hydrogen atom on a molecule or group. The term "substituted" means that a hydrogen atom on a molecule or group is replaced by a group or atom. Typical substituents include halogen, C1-8 alkyl, hydroxyl, C1-8 alkoxy, -NR x R x , nitro, cyano, halo, or perhalo C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -SR x , -S(=O)2R x , -C(=O)OR x , -C(=O)R x are mentioned, and each R x is independently hydrogen or C1-C8 alkyl. It should be noted that when the substituent is -NR x R x , the R x group may be linked with the nitrogen atom to form a ring.

[0069] The symbol "-" represents a covalent bond and can be used to indicate a bond to another group in a radical group. In chemical structures, this symbol is commonly used to represent a methyl group in a molecule.

[0070] 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 metallic agent such as a boronic acid or boronate 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, triflates, and tosylates. Preferred leaving groups are shown herein as appropriate.

[0071] The term “protecting group” generally refers to a group well known in the art used to prevent unwanted reactions such as nucleophilicity, electrophilicity, oxidation, and reduction of selected reactive groups such as carboxy, amino, hydroxy, and mercapto. Preferred protecting groups are shown herein as appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, and silyl. Examples of aralkyl groups include, but are not limited to, benzyl, ortho-methylbenzyl, trityl, and benzhydryl (which may be optionally substituted with halogens, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl, and salts such as phosphonium and ammonium salts). Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenantrenyl, and durenyl. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl groups (preferably having 6 to 10 carbon atoms) include, but are not limited to, cyclohexenylmethyl. Suitable acyl, alkoxycarbonyl, and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, and phthaloyl. The same amino group can be protected using a mixture of protecting groups; for example, a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups can also form heterocyclic rings with the nitrogen to which they are bonded, such as 1,2-bis(methylene)benzene, phthaliumidyl, succinimidyl, and maleimidyl, and these heterocyclic groups may further include adjacent aryl and cycloalkyl rings. In addition, the heterocyclic groups may be monosubstituted, disubstituted, or trisubstituted, such as nitrophthaliumidyl.Amino groups can also be protected from undesirable reactions such as oxidation through the formation of addition salts such as hydrochloride, toluenesulfonic acid, and trifluoroacetic acid. Many amino protecting groups are also suitable for protecting carboxy, hydroxy, and mercapto groups. For example, aralkyl groups. Alkyl groups such as tert-butyl are also suitable for protecting hydroxy and mercapto groups.

[0072] Protecting groups are removed under conditions that do not affect the rest of the molecule. These methods are well known in the art and include acid hydrolysis and hydrolysis. Preferred methods include the removal of protecting groups, such as the removal of benzyloxycarbonyl groups by hydrolysis using palladium carbon in a suitable solvent system such as alcohol, acetic acid, or a mixture 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. Carboxylated protecting groups such as methyl, ethyl, benzyl, tert-butyl, and 4-methoxyphenylmethyl can be removed under hydrolysis and hydrolysis conditions well known to those skilled in the art.

[0073] Prodrugs of the compounds of the present invention are also intended by the present invention. Prodrugs are active or inactive compounds that are chemically modified by in vivo physiological actions such as hydrolysis and metabolism, and become the compounds of the present invention after administration to a patient. The suitability and methods related to the preparation and use of prodrugs are well known to those skilled in the art. For a general consideration of prodrugs containing 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). The amine is masked as an arylcarbonyloxymethyl-substituted derivative that is cleaved in vivo by esterase to release the free drug and formaldehyde (Bundgaard J. Med. Chem. 2503 (1989)). Additionally, drugs containing acidic NH groups, such as imidazoles, imides, and indoles, are masked with an N-acyloxymethyl group (Bundgaard Design of Prodrugs, Elsevier (1985)). The hydroxyl group is masked as an ester and an ether. European Patent No. 039,051 (Sloan and Little, 4 / 11 / 81) discloses Mannich base hydroxamic acid prodrugs, their preparation, and use.

[0074] The term "therapeutic dose" means the amount of a compound that improves, reduces or eliminates one or more symptoms of a particular disease or condition, or the amount of a compound that prevents or delays the onset of one or more symptoms of a particular disease or condition.

[0075] The term "patient" refers to animals such as dogs, cats, cows, horses, sheep, and humans. Certain patients are mammals. The term "patient" includes both males and females.

[0076] The term "pharmaceutically acceptable" means that the referenced substance (e.g., a compound of formula I, a salt of a compound of formula I, a formulation containing a compound of formula I, or a specific excipient) is suitable for administration to a patient.

[0077] Terms such as "to treat," "to treat," or "treatment" include preventative (e.g., prophylactic) treatment and palliative treatment.

[0078] The term "excipients" refers to any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other component other than the active ingredient (API), which are typically included for formulation and / or administration to a patient.

[0079] The compounds of the present invention are administered to patients in therapeutically effective doses. The compounds may be administered alone or as part of a pharmaceutically acceptable composition or formulation. Furthermore, the compounds or compositions may be administered entirely at once, for example by bolus injection, in multiple doses, for example by a series of tablets, or substantially uniformly over a period of time using transdermal delivery. It should also be noted that the dose of the compounds may vary over time.

[0080] In addition, the compounds of the present invention may be administered alone, in combination with other compounds of the present invention, or together with other pharmaceutically active compounds. The other pharmaceutically active compounds may be intended to treat the same disease or condition as the compounds of the present invention, or to treat a different disease or condition. If a patient is administered or has been administered multiple pharmaceutically active compounds, these compounds may be administered simultaneously or sequentially. For example, in the case of tablets, the active compound may be found in one tablet or in separate tablets, and these separate tablets may be administered at once or sequentially in any order. Furthermore, it should be recognized that the composition may be in various forms. For example, one or more compounds may be delivered by tablet, while other compounds may be administered by injection or orally as a syrup. All combinations, delivery methods, and administration sequences are contemplated.

[0081] The compounds of the present invention may be used in the manufacture of pharmaceuticals for the treatment of diseases and / or conditions mediated by Nav1.7, such as pain, chronic cough, or itching.

[0082] Pain is usually classified into two main types based on its duration: chronic pain and acute pain. Chronic pain typically lasts longer than three 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 for which the cause is not identified. An example of idiopathic pain is fibromyalgia.

[0083] Another type of pain is nociceptive pain. Nociceptive pain is caused by the stimulation of peripheral nerve fibers in response to highly noxious events such as thermal, mechanical, or chemical stimuli.

[0084] Another type of pain is neuropathic pain. Neuropathic pain is pain caused by injury or disease affecting a part of the nervous system. Phantom limb pain is a type of neuropathic pain. In phantom limb pain, the body perceives pain from a part of the body that no longer exists. For example, a person who has had a lower limb amputated may feel pain in the lower limb even though the limb no longer exists.

[0085] 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 embodiment, the chronic pain is associated with, but is 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 disorder, and migraine, primary erythromelalgia, and paroxysmal severe pain.Other indications for Nav1.7 inhibitors include depression (Morinville et al., J Comp Neurol., 504:680-689 (2007)), bipolar disorder and other CNS disorders (Ettinger and Argoff, Neurotherapeutics, 4:75-83 (2007)), epilepsy (ibid., and Gonzalez, Termin, Wilson, Methods and Principles in Medicinal Chemistry, 29:168-192 (2006)), multiple sclerosis (Waxman, Nature Neurosci. 7:932-941 (2006)), and Parkinson's disease (Do and Bean, Neuron 39:109-120 (2003); Puopolo et al.) al., J. Neurosci. 27:645-656 (2007), lower limb restlessness syndrome, ataxia, tremor, muscle weakness, dystonia, tetanus (Hamann M., et.al., Exp. Neurol. 184(2):830-838, 2003), anxiety, depression (McKinney BC, et.al., Genes Brain Behav. 7(6):629-638, 2008), learning and memory, cognition (Woodruff-Pak DS, et.al., Behav. Neurosci. 120(2):229-240, 2006), cardiac arrhythmias and fibrillation, contractility, congestive heart failure, sick sinus syndrome (Haufe V., et.al., J Mol. Cell) Examples of conditions requiring treatment include, but are not limited to, Cardiol. 42(3):469-477, 2007, schizophrenia, neuroprotection after stroke, drug and alcohol abuse (Johannessen LC, CNS Drugs 22(1)27-47, 2008), Alzheimer's disease (Kim DY, et.al., Nat. Cell. Biol. 9(7):755-764, 2007), and cancer (Gillet L., et.al., J Biol Chem 2009, Jan 28 (epub)).

[0086] Another aspect of the present invention relates to acute and / or chronic inflammatory and neuropathic pain, toothache, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes. The present invention relates to a method for treating tension headache, general inflammation, arthritis, rheumatic diseases, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorder, inflammatory eye disorder, inflammatory or unstable bladder disorder, psoriasis, skin diseases caused by inflammatory components, chronic inflammatory states, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetic nerve-dependent pain, afferent blockade pain syndrome, asthma, epithelial tissue damage or dysfunction, herpes simplex, visceral motility disorders in the respiratory, genitourinary, gastrointestinal, or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulcer formation, duodenal ulcers, diarrhea, gastric lesions induced by necrotizing substances, hair growth, vasomotor or allergic rhinitis, bronchial disorders, or bladder disorders, comprising the step of administering a compound according to the present invention. The preferred type of pain to be treated is chronic neuropathic pain. Another preferred type of pain to be treated is chronic inflammatory pain.

[0087] In another aspect of the present invention, the compounds of the present invention may be used in combination with other compounds used for the treatment of pain. Examples of such other compounds include, but are not limited to, aspirin, celecoxib, hydrocodone, oxycodone, codeine, fentanyl, ibuprofen, ketoprofen, naproxen, acetaminophen, gabapentin, and pregabalin. Examples of classes of pharmaceuticals containing compounds that may be used in combination with the compounds of the present invention include nonsteroidal anti-inflammatory drugs (NSAIDS), steroidal compounds, cyclooxygenase inhibitors, and opioid analgesics.

[0088] The compounds of the present invention may also be used to treat diabetes, obesity, and / or to promote weight loss.

[0089] The compounds of the present invention may be used in combination with other pharmaceutically active compounds. It should be noted that the term "pharmaceutically active compounds" may include biologics such as proteins, antibodies, and peptides.

[0090] Since one aspect of the present invention intends to treat a disease / condition by a combination of pharmaceutically active compounds that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions into a kit. The kit comprises two separate pharmaceutical compositions, namely the compound of the present invention and a second pharmaceutical compound. The kit includes a container for housing the separate compositions, such as a divided bottle or a divided metal foil wrapper. Further examples of containers include syringes, boxes, and bags. Typically, the kit includes instructions for the use of the separate components. The kit form is particularly advantageous when these separate components are preferably administered in different dosage forms (e.g., orally and parenterally), at different dosing intervals, or when a prescribing physician or veterinarian desires to set the dosages of the individual components of this combination.

[0091] One example of such a kit is the so-called blister pack. Blister packs are well-known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). A blister pack generally consists of a sheet of a relatively rigid material covered with a foil, preferably made of transparent plastic material. During the packaging process, a recess is formed in the plastic foil. This recess has the size and shape of the tablet or capsule to be packaged. Next, the tablet or capsule is placed in this recess, and the relatively rigid sheet seals the plastic foil with the side of the foil opposite to the direction in which the recess was formed. As a result, the tablet or capsule is sealed within the recess between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablet or capsule can be removed from the blister pack by applying pressure to the recess by hand, thereby forming an opening in the sheet at the location of the recess. The tablet or capsule can then be removed through the opening.

[0092] It may be desirable to include memory aids on the kit (for example, in the form of numbers next to the tablets or capsules) (the numbers corresponding to the days of the regimen on which the designated tablets or capsules should be taken). Another example of such a memory aid is a calendar printed on a card, for example, "Week 1, Monday, Tuesday, ... etc... Week 2, Monday, Tuesday, ..." Other variations of memory aids will readily become apparent. The "daily dose" may be a single tablet or capsule, or multiple pills or capsules to be taken on the designated days. Also, the daily dose of the compound of the present invention may consist of one tablet or capsule, while the daily dose of a second compound may consist of multiple tablets or capsules, and vice versa. The memory aid should reflect this and assist in the correct administration of the activator.

[0093] In another specific embodiment of the present invention, a dispenser is provided that is designed to dispense daily doses one at a time in the order of their intended use. Preferably, to further facilitate adherence to the regimen, the dispenser is equipped with a memory aid. An example of such a memory aid is a mechanical counter that indicates the number of daily doses dispensed. Another example of such a memory aid is a battery-powered microchip memory, linked to a liquid crystal readout or audible reminder signal, which reads the date the last daily dose was taken and / or reminds the patient of the date the next dose should be taken.

[0094] The compounds of the present invention and other pharmaceutically active compounds may be administered to a patient as needed, orally, rectally, parenterally (e.g., intravenously, intramuscularly, or subcutaneously), intracisionally, intravaginally, intraperitoneally, intravesically, topically (e.g., as a powder, ointment, or infusion), or as an oral or nasal spray. All methods used by those skilled in the art for administering pharmaceutically active agents are intended.

[0095] Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as propylene glycol, polyethylene glycol, and glycerol), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Adequate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0096] These compositions may also contain auxiliary agents such as preservatives, humectants, emulsifiers, and dispersants. Microbial contamination can be prevented by adding various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbic acid. It may also be desirable to include isotonic agents, such as sugars and sodium chloride. Sustained absorption of the injectable pharmaceutical composition can be achieved by using absorption-delaying agents, such as aluminum monostearate and gelatin.

[0097] Examples of solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is composed of at least one inert conventional excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate), or (a) fillers or bulking agents (e.g., starch, lactose, sucrose, mannitol, and silicic acid); (b) binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic); (c) humectants (e.g., glycerol); (d) disintegrants (e.g., agar, calcium carbonate, potato starch). (i)

[0098] Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol, etc.

[0099] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules may be prepared using coatings and shells, such as enteric coatings, and others well known in the art. They may also contain opacifiers and may be compositions that release the active compound in a delayed manner in a specific part of the intestinal tract. Examples of embedding compositions that may be used are polymeric substances and waxes. The active compound may also be in microencapsulated form, where appropriate, containing one or more of the above excipients.

[0100] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures thereof.

[0101] In addition to such inert diluents, the composition may also contain auxiliary agents such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and fragrances. In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or mixtures thereof.

[0102] A composition for rectal administration is a preferred suppository that can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at normal room temperature but liquid at body temperature, and therefore melts in the rectum or vaginal cavity to release the active ingredient.

[0103] Dosage forms for topical administration of the compounds of the present invention include ointments, powders, sprays, and inhalants. The active compound or a suitable compound is mixed under sterile conditions with a physiologically acceptable carrier and, if necessary, a preservative, buffer, or propellant. Eye drops, eye ointments, powders, and solutions are also considered to be within the scope of the present invention.

[0104] The compounds of the present invention can be administered to patients at therapeutically effective dose levels. The specific doses and dose ranges that may be used depend on several factors, including the patient's requirements, the condition or severity of the disease being treated, and the pharmacological activity of the administered compound.

[0105] The compounds of the present invention may be administered as pharmaceutically acceptable salts, cocrystals, esters, amides, or prodrugs. The term "salt" refers to inorganic and organic salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in free base or free acid form with a suitable organic or inorganic base or acid separately, and then isolating the salts thus formed. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. Salts may contain cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. See, for example, SMBerge, et al., “Pharmaceutical Salts,” J Pharm Sci, 66:1-19 (1977).

[0106] 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 arylalkyl esters such as benzyl. C1-C4 alkyl esters are commonly used. Esters of the compounds of the present invention can be prepared according to methods well known in the art.

[0107] Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, primary C1-C8 alkylamines, and secondary C1-C8 dialkylamines. In the case of secondary amines, the amine may also be in the form of a 5-membered or 6-membered heterocycloalkyl group containing at least one nitrogen atom. Amides derived from ammonia, C1-C3 primary alkylamines, and C1-C2 dialkyl secondary amines are commonly used. Amides of the compounds of the present invention can be prepared according to methods well known in the art.

[0108] The term "prodrug" refers to a compound that is converted in vivo to produce the compound of the present invention. Conversion can occur through various mechanisms, including hydrolysis in the blood. Considerations of the use of prodrugs are provided in T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACSSymposium Series, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0109] For example, if the compound of the present invention contains a carboxylic acid functional group, the prodrug may have hydrogen atoms of the acid group converted to (C1-C8) alkyl, (C2-C 12) Alkanoyloxymethyl, 1-(alkanoyloxy)ethyl with 4-9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl with 5-10 carbon atoms, alkoxycarbonyloxymethyl with 3-6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl with 4-7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl with 5-8 carbon atoms, N-(alkoxycarbonyl)aminomethyl with 3-9 carbon atoms, 4-10 carbon atoms It may include esters formed by substituting groups such as 1-(N-(alkoxycarbonyl)aminomethyl, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-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 piperidino-, pyrrolidino-, or morpholino-(C2~C3)alkyl.

[0110] Similarly, if the compound of the present invention contains an alcohol functional group, the prodrug can be formed by replacing the hydrogen atoms of the alcohol group with groups 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, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from naturally occurring L-amino acids, -P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2, or glycosyl (a group resulting from the removal of a hydroxyl group from the hemiacetal form of a carbohydrate).

[0111] In addition, if the compound of the present invention contains 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.

[0112] The compounds of the present invention also include tautomerized forms of prodrugs.

[0113] The compounds of the present invention may contain chiral or asymmetric centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds, including racemic mixtures and mixtures thereof, are intended to form part of the present invention. In addition, the present invention intends all geometric and positional isomers. For example, if the compound contains a double bond, both cis and trans forms (denoted by S and E, respectively), as well as mixtures thereof, are intended.

[0114] Mixtures of stereoisomers, such as diastereomer mixtures, can be separated into their individual stereochemical components based on their physicochemical differences by known methods such as chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomer mixture into a diastereomer mixture through reaction with a suitable optically active compound (e.g., an alcohol), separating the diastereomers, and converting the individual diastereomers back into their corresponding pure enantiomers (e.g., by hydrolysis).

[0115] Compounds of general formula (I) can also exist in the form of atropisomers. Atropisomers are compounds that have the same structural formula but possess a specific spatial configuration resulting from rotation around a single bond being restricted by significant steric hindrance on both sides of this single bond. Atropisomerism is independent of the presence of chiral elements such as chiral carbons. The terms "P atropisomer" or "M atropisomer" are used herein to allow for the clear naming of two atropisomers of the same pair. For example, the following intermediate B1, the compound from step 1 having the following structure, can be separated into a pair of atropisomers P and M via a chiral column. [ka]

[0116] The compounds of the present invention may exist in a non-solvated form and in a solvated form with a pharmaceutically acceptable solvent such as water (hydrate) or ethanol. The present invention intends to encompass both solvated and non-solvated forms.

[0117] Furthermore, the compounds of the present invention may exist in various tautomerized forms. All tautomers of the compounds of the present invention are intended. For example, all tautomerized forms of the tetrazole moiety are included in the present invention. Also, for example, all keto-enol or imine-enamine forms of the compounds are included in the present invention. Other examples of tautomerism are as follows: [ka]

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

[0119] The present invention is also intended to encompass compounds synthesized in vitro using laboratory methods, such as those well known to synthetic chemists, or in vivo using methods such as those involving metabolism, fermentation, or digestion. It is also intended that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo methods.

[0120] The present invention also includes isotope-labeled compounds, which are identical to those enumerated herein, except that one or more atoms are replaced with atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 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 is an example. In another embodiment, the compound of the present invention contains one or more deuterium atoms (2H) instead of one or more hydrogen atoms.

[0121] Compounds of the present invention containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Specific isotope-labeled compounds of the present invention, for example, 3 H and 14 Those incorporating radioactive isotopes such as 13C are useful for drug and / or substrate tissue distribution assays. Tritiation (i.e., 3 H) isotopes, and carbon-14 (i.e., 14 C) Isotopes are particularly preferred due to the ease of their preparation and detection. Furthermore, deuterium, i.e. 2Substitution with relatively heavy isotopes such as 1H can result in certain therapeutic advantages, such as increased in vivo half-life or reduced required dose, which may be preferable in some situations due to higher metabolic stability. The isotope-labeled compounds of the present invention can generally be prepared by using readily available isotope-labeling reagents in place of non-isotope-labeling reagents.

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

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

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

[0125] Note that when percentage (%) is used for liquids, it refers to a volume percentage relative to the solution. When used for solids, it refers to a percentage relative to the composition of that solid. Materials obtained from commercial suppliers were usually used without further purification. Reactions involving reagents sensitive to air or moisture were usually carried out under a nitrogen or argon atmosphere. Purity was measured using a high-performance liquid chromatography (HPLC) system with UV detection at 254 nm and 215 nm (System A: HALO C8, 3.0 × 50 mm, 2.7 μm, 5–95% CH3CN in H2O containing 0.1% TFA at 2.0 mL / min for 2.0 minutes) (Agilent Technologies, Santa Clara, CA). Silica gel chromatography was generally performed using pre-packed silica gel cartridges (Biotage, Uppsala, Sweden or Teledyne-Isco, Lincoln, NE). 1 ¹H NMR spectra were recorded at ambient temperature using a Bruker AV-400 (400 MHz) spectrometer (Bruker Corporation, Madison, WI) or a Varian (Agilent Technologies, Santa Clara, CA) 400 MHz spectrometer. All observed protons are reported as parts per million (ppm) low magnetic field from tetramethylsilane (TMS) or other internal standards in the indicated appropriate solvent. Data are reported as follows: chemical shift, multiplicity (s=singleline, d=doubleline, t=tripline, q=quadline, br=broad, m=multiline), coupling constant, and proton number. Low-resolution mass spectral (MS) data were determined on an Agilent 1100 series LC / MS (Agilent Technologies, Santa Clara, CA) with UV detection at 254 nm and 215 nm and low-resonance electrospray mode (ESI).

[0126] This specification may use the following abbreviations. 2-PrOH isopropanol Acetic acid (ACOH) AgOTf Silver(I) Trifluoromethanesulfonate AIBN Azobisisobutyronitrile aq. water-based Bu butyl ca. approx. cm centimeters CPhos 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl DAST Diethylaminosulfur Trifluoride Dba dibenzylideneacetone DCM Dichloromethane Deoxy-Fluor bis(2-methoxyethyl)aminosulfur trifluoride DIPEA N,N-diisopropylethylamine DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) ESI or ES electrospray ionization Et ethyl Et2O Diethyl ether HCl ethyl acetate EtOH Ethanol G grams H time HOAc Acetic Acid HPLC (High-Pressure Liquid Chromatography) IPA 2-propanol Kilogram L (liters) LCMS (Liquid Chromatography Mass Spectrometry) LHMDS Lithium Hexamethyl Disilazide M moles m / z mass-to-charge ratio Me methyl MeOH methanol Mg milligrams MHz (megahertz) Minutes mL or ml (milliliter) Mmol (millimole) Mol MTBE methyl t-butyl ether N regulations NaOMe Sodium Methoxy n-Bu n-butyl NEt3 Triethylamine NMR nuclear magnetic resonance OAc Acetate OTf Trifluoromethanesulfonate PFP-OH Perfluorophenol Ph Phenyl PhMe Toluene PMB 4-methoxybenzyl Ppm parts per million Pr Propyl RT or rt Room temperature sat. saturation SFC Supercritical Fluid Chromatography TBAF Tetra-n-butylammonium fluoride TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) Ti(OiPr)4 Titanium(IV) Isopropoxide TLC (Thin-Layer Chromatography) TMS-CF3 (trifluoromethyl)trimethylsilane wt% weight% XantPhos 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene XtalFluor-M Difluoro(morpholino)sulfonium tetrafluoroborate

[0127] The following compounds presented herein as examples of the present invention, and their intermediates as components for preparing the compounds provided by the present invention, can be prepared by various methods and synthetic strategies taught herein below. These compounds, and others provided by the present invention, can also be prepared using the methods described in International Publication No. 2014 / 201206, filed on 12 June 2014, and International Publication No. 2017 / 106871, filed on 19 December 2016 (these specifications are incorporated herein by reference in their entirety).

[0128] Intermediate A1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] Process 1: 4-bromo-2-iodoaniline To a solution of 4-bromoaniline (500 g, 2.90 mol, 2.0 equivalent, Saibain Chem) in cyclohexane (2.5 L), iodine (368 g, 1.45 mol, 1.0 equivalent, Qualigens) was added, and the mixture was heated at 50°C. After 30 minutes, the reaction mixture became homogenized. 30% aqueous hydrogen peroxide solution (250 mL, Spectrochem) was added to the reaction mixture. The reaction mixture was heated at 50°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5.0 L), and washed with aqueous sodium sulfite solution (2.5 kg in 4.0 L). The organic layer was washed with water (3.0 L) and brine (3.0 L), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by column chromatography (silica gel; mesh size 60-120, elution 0-20% ethyl acetate and hexane) to obtain 4-bromo-2-iodoaniline (650 g, 75.0%) as a grayish-white solid. TLC solvent system: 100% hexane. R of the product f :0.6. MS (ESI, cation) m / z:297.0 (M+1). 1 H NMR(400MHz,CDCl3)δ 7.72(d,J=2.5Hz,1H),7.23(dd,J=8.4,2.1Hz,1H),6.62(d,J=8.3Hz,1H),4.09(s,2H).

[0129] Step 2: (E)-3-(2-amino-5-bromophenyl)ethyl acrylate To a solution of 4-bromo-2-iodoaniline (750 g, 2.51 mol, 1.0 equivalent) in DMF (5.0 L), ethyl acrylate (277 g, 2.76 mol, 1.1 equivalent, Avra) and sodium bicarbonate (680 g, 6.29 mol, 2.5 equivalents) were added. The reaction mixture was degassed under nitrogen for 20 minutes, and then palladium acetate (28.8 g, 128.27 mol, 0.05 equivalent, Hindustan Platinum) was added. The reaction mixture was heated at 70°C for 3 hours. The reaction product was filtered through CELITE® and the CELITE® bed was washed with ethyl acetate (2 × 500 mL). The filtrate was concentrated under reduced pressure to obtain a crude residue, which was purified by column chromatography (silica gel; mesh size 60-120, elution 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. R of the product f :0.4. MS (ESI, cation) m / z; 270.2 (M+1). 1 H NMR(400MHz,DMSO)δ 7.75(d,J=16.1Hz,1H),7.57(d,J=2.0Hz,1H),7.16(dd,J=9.1,2.4Hz,1H),6.66(d,J=8.6 Hz,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). [ka]

[0130] Step 3: (E)-3-(2-amino-5-(benzylthio)phenyl)ethyl acrylate To a solution of (E)-3-(2-amino-5-bromophenyl)ethyl acrylate (620 g, 2.29 mol, 1.0 equivalent) in 1,4-dioxane (4.0 L), DIPEA (1.26 L, 8.88 mol, 3.9 equivalents, GLR) was added, and the mixture was degassed with nitrogen for 20 minutes. XantPhos (92.9 g, 106 mmol, 0.05 equivalents, GLR) and Tris(dibenzylideneacetone)dipalladium (84 g, 91.0 mmol, 0.04 equivalents, Hindustan Platinum) were added to the reaction mixture. The mixture was purged with nitrogen and heated to 80°C for 30 minutes. The reaction mixture was cooled to room temperature, benzyl mercaptan (455.5 g, 3.67 mol, 1.6 equivalents, Alfa Aesar) was added, and the reaction mixture was heated further at 80°C for 4 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (4.0 L). The mixture was filtered through CELITE® and the CELITE® bed was washed with ethyl acetate (2 × 1.0 L). The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by chromatography (silica gel; mesh size 60-120, elution 0-40% ethyl acetate and petroleum ether) to obtain (E)-3-(2-amino-5-(benzylthio)phenyl)acrylate ethyl (520 g, 72.0%) as a yellow solid. TLC solvent system: 30% ethyl acetate in hexane. f :0.4. MS (ESI, cation) m / z; 314.1 (M+1). 1 H NMR(400MHz,DMSO)δ 7.79(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). [ka]

[0131] Step 4: 1-Bromo-2-fluoro-4-iodo-5-methoxybenzene To a solution of 2-bromo-1-fluoro-4-methoxybenzene (500.0 g, 2.44 mol, 1.0 equivalent) in DCM (5.0 L), silver trifluoromethanesulfonate (686.0 g, 2.68 mol, 1.1 equivalent, Angene) was added, and the reaction mixture was stirred for 20 minutes. Iodine (678.0 g, 2.68 mol, 1.1 equivalent) was added to the reactant, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM (3.0 L) and filtered through CELITE®. The CELITE bed was washed with DCM (2 × 1.0 L), and the filtrate was washed with 20% sodium thiosulfate aqueous solution (3.0 L) and saturated sodium bicarbonate aqueous solution (3.0 L). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by chromatography (silica gel; mesh size 60-120, elution 0-5% ethyl acetate and petroleum ether) to obtain 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (720 g, 87%) as a grayish-white solid. TLC solvent system: 100% hexane. Product R f :0.6. MS (ESI, cation) m / z:331.0 (M+1). 1 H NMR(400MHz,CDCl3)δ 7.55(d,J=7.2Hz,1H),6.95(d,J=5.6Hz,1H),3.89(s,3H).

[0132] Step 5: (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)ethyl acrylate (E)-3-(2-amino-5-(benzylthio)phenyl)ethyl acrylate (300 g, 958.1 mmol, 1.0 equivalent) and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (348.0 g, 1051.6 mmol, 1.1 equivalent) were dissolved in toluene (2.5 L), to which Cs2CO3 (468 g, 1436.3 mmol, 1.5 equivalent, Spectrochem) was added, and the mixture was degassed under nitrogen for 20 minutes. Pd2(dba)3 (35 g, 38.2 mmol, 0.04 equivalent, Hindustan Platinum) and XantPhos (44.6 g, 76.4 mmol, 0.08 equivalent, GLR) were added to the reaction mixture, and the mixture was heated at 110°C for 5 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (2.0 L), and filtered through CELITE®. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by stirring with 5% ethyl acetate in hexane (3.0 L) for 30 minutes and filtered to obtain (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)ethyl acrylate (350 g, 71%) as a yellow solid. TLC solvent system: 30% ethyl acetate in hexane. Product R f :0.5. MS (ESI, cation) m / z; 516.2 (M+1). 1 1H NMR (400MHz, DMSO) δ 7.73-7.61 (m, 3H), 7.34-7.15 (m, 6H), 7.02 (d, J=11.4Hz, 1H), 6.60 (d, J=21.2Hz, 1H), 6.33 (d, J=14.1Hz, 1H), 4.26 (s, 2H), 4.16-4.09 (m, 2H), 3.81 (s, 3H), 1.22 (t, J=7.2Hz, 3H). Note: No protons were observed in NH. [ka]

[0133] Step 6: 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinoline-2(1H)-one To a solution of (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)ethyl acrylate (250.0 g, 484.0 mmol, 1.0 equivalent) in methanol (2.5 L), tri(n-butyl)phosphine (50% solution in ethyl acetate, 48.9 mL, 96.8 mmol, 0.2 equivalent, Spectrochem) was added, and the reaction mixture was heated at 70°C for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product, which was purified by stirring with 5% ethyl acetate in hexane (1.0 mL), filtered, and obtained as a grayish-white solid 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinoline-2(1H)-one (201.0 g, 88%). TLC solvent system: 30% ethyl acetate in hexane. f :0.3. MS (ESI, cation) m / z; 470.0 (M+1). 1 H NMR(400MHz,DMSO)δ 7.92(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).

[0134] Steps 7 and 8: 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl 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), acetic acid (200 mL) and water (130 mL) were added. The resulting mixture was cooled to 0°C, and 1,3-dichloro-5,5-dimethylimidazolidined-2,4-dione (188.5 g, 956.7 mmol, 1.8 equivalent, Aldrich) was added in small amounts over 20 minutes while maintaining the internal temperature below 5°C. The resulting suspension was stirred under nitrogen at 0-5°C for 45 minutes. Next, a solution of pentafluorophenol (127.2 g, 690.95 mmol, 1.3 equivalents, Apollo) in acetonitrile (200 mL) was added over 5 minutes, and then NEt3 (307.7 mL, 2.12 mol, 4.0 equivalents) was added over 20 minutes while maintaining the internal temperature below 5°C. The mixture was stirred continuously at 0-5°C for 30 minutes. Water (4.0 L) was added and extracted with ethyl acetate (2 × 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 the crude product, which was purified by stirring with isopropyl alcohol:hexane (1:1, 1.0 L), filtered, and obtained racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (190 g, 60%) as a white solid. TLC solvent system: 30% ethyl acetate in petroleum ether, product R f :0.4. MS (ESI, cation) m / z; 594.2 (M+1). 1 H-NMR(400MHz,DMSO)δ 8.60(d,J=2.0Hz,1H),8.26(d,J=9.8Hz,1H),7.95(dd,J=2.2,9.1Hz,1H),7.70(t,J=8.6Hz,2H),6.95-6.88(m,2H),3.72(s,3H).

[0135] Step 9: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl Racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (see intermediate A1 above, 76.90 g) was separated via Chiralcel OJ column (40% MeOH / 60% CO2) to obtain (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl and (M)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl as pale yellow, cotton-like solids. Peak 1 data: m / z (ESI) 594.0 (M+H) + Peak 2 data: m / z (ESI) 594.0 (M+H) + .

[0136] Step 10: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] A 250 mL round-bottom flask was filled with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (see step 1 of intermediate B1 above, 11.34 g, 19.08 mmol) and N-(4-methoxybenzyl)isoxazole-3-amine (4.09 g, 20.04 mmol), and then purged with nitrogen. Tetrahydrofuran (191 mL) was introduced, and the resulting brown solution was cooled to 0°C. A solution of lithium bis(trimethylsilyl)amide (1.0 M, 21.0 mL, 21.0 mmol) in THF was added dropwise to the stirred reaction mixture over 10 minutes using a syringe. After 15 minutes, 1.0 N HCl (100 mL) was introduced, and the resulting reaction mixture was warmed to room temperature. The mixture was diluted with RINKAN (100 mL), the layers were separated, and the aqueous layer was further extracted with RINKAN (2 × 100 mL). Next, the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by flash column chromatography (100-g Biotage column, eluate: gradient, 0-100% RINKAN in heptane with 10% CH2Cl2 as an additive) to obtain (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (9.54 g, 15.53 mmol, yield 81%) as a white amorphous solid. 1 H NMR(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,1H),7.63(d, J=8.5Hz,1H),7.26(d,J=7.9Hz,2H),6.91-6.78(m,4H),6.74(d,J=2.0Hz, 1H),4.92(s,2H),3.73-3.69(m,6H),3.32(s,1H).m / z(ESI)615.1(M+H)+.

[0137] Intermediate B1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] Step 1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl Racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (see intermediate A1 above, 76.90 g) was separated via Chiralcel OJ column (40% MeOH / 60% CO2) to obtain (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl and (M)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl as pale yellow, cotton-like solids. Peak 1 data: m / z (ESI) 594.0 (M+H) + Peak 2 data: m / z (ESI) 594.0 (M+H) + . [ka]

[0138] Step 2: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 250 mL round-bottom flask containing a 200 mL solution of (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (6.00 g, 10.10 mmol) and 3-aminoisoxazole (0.821 mL, 11.11 mmol) in THF 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. The yellow solution was stirred at 0°C for 15 minutes, then quenched with 1N HCl at 0°C and extracted three times with siRNA. The organic extracts were combined, dried over MgSO4, filtered, and concentrated to obtain a pale yellowish-brown residue. Et2O was added, the slurry was tritulate, and sonicated. A grayish-white solid was obtained by filtration, which was washed twice with Et2O and dried in vacuum to obtain 3.88 g of the product as a grayish-white solid. The filtrate was concentrated in vacuum and purified by column chromatography (12 g silica gel, 35%~100% siRNA / heptane gradient) to obtain an additional 1.36 g of the product as a pale yellow, cotton-like solid. A total of 5.24 g of (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide was obtained. m / z(ESI) 494.1(M+H) + .

[0139] Intermediate C1: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] Step 1: (E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)ethyl acrylate (E)-3-(2-amino-5-(benzylthio)phenyl)ethyl 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) were dissolved in toluene (1.5 L), to which cesium carbonate (357.5 g, 1100 mmol, 2.0 equivalents) was added, and the mixture was degassed under nitrogen for 20 minutes. Pd2(dba)3 (12.5 g, 13.0 mmol, 0.025 equivalents) and XantPhos (15.8 g, 27.2 mmol, 0.05 equivalents) were added to the reaction mixture, and the mixture was heated at 110°C for 5 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (1.0 L), and filtered through Celite. The filtrate was concentrated under reduced pressure to obtain the crude substance, which was purified by stirring with 5% ethyl acetate in hexane (1.5 L) for 30 minutes. The mixture was then filtered to obtain (E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)ethyl acrylate (290 g, 85%) as a yellow solid. m / z(ESI) 532.2(M+H) + . [ka]

[0140] Step 2: 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinoline-2(1H)-one To a solution of (E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)ethyl acrylate (300.0 g, 5630.0 mmol, 1.0 equivalent) in methanol (3.0 L), tri(n-butyl)phosphine (50% solution in ethyl acetate, 56.2 mL, 1126 mmol, 0.2 equivalents) was added, and the reaction mixture was heated at 70°C for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product, which was purified by stirring with 5% ethyl acetate in hexane (1.0 mL), filtered, and obtained 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) + .

[0141] Step 3: 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinoline-2(1H)-one (400.0 g, 824.9 mmol, 1.0 equivalent) was dissolved in acetonitrile (2.5 L) and THF (2.5 L), to which acetic acid (1.0 L) and water (700 mL) were added. The resulting mixture was cooled to 0°C, and 1,3-dichloro-5,5-dimethylimidazolidined-2,4-dione (292 g, 1484.8 mmol, 1.8 equivalents) was added in small amounts over 30 minutes while maintaining the internal temperature below 5°C. The resulting suspension was stirred under nitrogen at 0°C for 45 minutes. Next, a solution of pentafluorophenol (197.4 g, 1072.3 mmol, 1.3 equivalents) in acetonitrile (500 mL) was added over 5 minutes, and then triethylamine (477 mL, 3299 mmol, 4.0 equivalents) was added over 30 minutes while maintaining the internal temperature below 5°C. The mixture was stirred at 0°C for 50 minutes. Water (4.0 L) was added and extracted with ethyl acetate (3 × 2.0 L). The organic layer was washed with brine (2.0 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by stirring with isopropyl alcohol:hexane (1:1, 2.0 L), filtered, and obtained 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (360 g, 72%) as a white solid. m / z(ESI) 610.6(M+H) + . [ka]

[0142] Step 4: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl and (M)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl 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 obtain (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (72.66 g, yield 93%) and (M)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (76.13 g, yield 98%) as white solids. m / z(ESI) 610.6(M+H) + .

[0143] Step 5: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (2.56 g, 4.19 mmol) was added to a 100 mL RB flask. The flask was placed under nitrogen, and then THF (41.9 ml) and isoxazole-3-amine (0.423 g, 5.03 mmol) were added. The mixture was cooled to 0°C for 10 minutes, and then 1.0 M LHMDS (8.80 ml, 8.80 mmol) in THF was added dropwise over 5 minutes. The reaction mixture was stirred for 2 hours. While still cold, 1N HCl (50 mL) and RINKAN (50 mL) were added. The layers were separated, and the organic layer was washed again with 1N HCl. The combined aqueous layer was extracted with RINKAN (2 × 50 mL). All combined organic matter was dried over sodium sulfate, filtered, and concentrated. This substance was purified by chromatography using silica gel (40-100% Â / heptane) to obtain (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (2.03 g, 3.97 mmol, yield 95%) 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=8.95,2.20Hz,1 H),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)+.

[0144] Intermediate D1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl [ka] Step 1: 4-Bromo-5-fluoro-2-iodoaniline N-iodosuccinimide (710 g, 3158 mmol) was added in small amounts at 10-15°C to a solution of 4-bromo-3-fluoroaniline (500 g, 2631 mmol) in acetic acid (4000 mL). The reaction mixture was stirred at room temperature for 1 hour. Next, the reaction mixture was quenched with ice water (7 L), and the precipitated solid was filtered. The solid was washed with 5% sodium thiosulfate solution (6 L) and water (4 L), dried, and obtained as a brown solid 4-bromo-5-fluoro-2-iodoaniline (750 g, 2374 mmol, yield 90%). 1 H NMR (400MHz, DMSO-d6): δ ppm 7.76(d,J=7.8Hz,1H),6.68(d,J=11.5Hz,1H),5.68(s,2H).

[0145] Step 2: (E)-3-(2-amino-5-bromo-4-fluorophenyl) ethyl acrylate 4-bromo-5-fluoro-2-iodoaniline (500 g, 1583 mmol) was stirred in isopropanol (2550 mL), to which triethylamine (331 mL, 2374 mmol) was added at room temperature. The reaction mixture was degassed under nitrogen for 20 minutes. Tris(dibenzylideneacetone)dipalladium(0) (36.2 g, 39.6 mmol) was added, and then ethyl acrylate (162 g, 1614 mmol) was slowly added under a nitrogen atmosphere. Next, the reaction mixture was heated to 70°C and stirred for 6 hours. After completion, the reaction mixture was filtered through Celite and washed with dichloromethane (2 L). The filtrate was concentrated under reduced pressure to obtain the crude residue. The crude residue was stirred in 3% ethyl acetate in petroleum ether (6 L) and filtered. The obtained solid was washed with 3% ethyl acetate in petroleum ether (2 L) and dried to obtain ethyl (E)-3-(2-amino-5-bromo-4-fluorophenyl)acrylate (433 g, 1505 mmol, 95% yield) as a yellow solid. MS (ESI, cation) m / z: 288.0 (M+1). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.69-7.98(m,2H),6.61(d,J=11.4Hz,1H),6.45(d,J=15.6Hz,1H),6.12(s,2H),4.17(q,J=7.1Hz,2H),1.26(t,J=7.1Hz,3H).

[0146] Step 3: (E)-3-(2-amino-5-(benzylthio)-4-fluorophenyl) ethyl acrylate To a solution of (E)-3-(2-amino-5-bromo-4-fluorophenyl)ethyl acrylate (500.0 g, 1735 mmol) in 1,4-dioxane (2500 mL), N-ethyl-N-isopropylpropan-2-amine (449 g, 3471 mmol) was added, and the mixture was degassed under nitrogen for 20 minutes. (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphan) (50.2 g, 87 mmol) and tris(dibenzylideneacetone)dipalladium(0) (39.7 g, 43.4 mmol) were added to the reaction mixture. The mixture was purged with nitrogen and heated to 80°C for 10 minutes. The reaction mixture was cooled to room temperature, and phenylmethanethiol (237 g, 1909 mmol) was added. The reaction mixture was heated at 90°C for 12 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (1000 mL). The mixture was filtered through Celite, and the Celite bed was washed with ethyl acetate (2500 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel; mesh size 60-120, gradient elution 0-15% ethyl acetate and petroleum ether) to obtain (E)-3-(2-amino-5-(benzylthio)-4-fluorophenyl)ethyl acrylate (300.0 g, 905 mmol, yield 52%) as a yellow solid. MS (ESI, cation) m / z: 332.1 (M+1). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.72(d,J=15.7Hz,1H),7.41(d,J=8.5Hz,1H),7.01-7.32(m,5H),6.38-6.55(m,1H),6.24(d, J=15.7Hz,1H),6.11(s,2H),4.17(q,J=7.1Hz,2H),3.89-4.07(m,2H),1.26(t,J=7.1Hz,3H).

[0147] Step 4: (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-4-fluorophenyl)ethyl acrylate Cesium carbonate (39.3 g, 121 mmol) was added to a 250 mL three-necked round-bottom flask filled with ethyl (E)-3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate (10 g, 30.2 mmol) and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (10.48 g, 31.7 mmol) in toluene (100 mL). The mixture was degassed under nitrogen for 15 minutes. Tris(dibenzylideneacetone)dipalladium(0) (1.105 g, 1.207 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphan) (1.397 g, 2.414 mmol) were added to the reaction mixture, and the mixture was heated at 110 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (200 mL), and filtered through Celite. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by stirring with methanol (250 mL) for 1 hour and then filtered. The cake was washed with methanol (100 mL), dried, and obtained as a yellow solid (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-4-fluorophenyl) ethyl acrylate (13.5 g, 25.3 mmol, yield 84%). MS (ESI, cation) m / z: 534.0 (M+1). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.97(s,1H),7.75(d,J=8.4Hz,1H),7.66(d,J=15.9Hz,1H),7.05-7.43(m,6H),6.77(d,J=11.1Hz,1H),6.63(d, J=10.2Hz,1H),6.52(d,J=15.9Hz,1H),4.25(s,2H),4.16(q,J=7.1Hz,2H),3.82(s,3H),1.23(t,J=7.1Hz,3H).

[0148] Step 5: 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoroquinoline-2(1H)-one A 500 mL three-necked round-bottom flask was packed with (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-4-fluorophenyl)ethyl acrylate (13.5 g, 25.3 mmol) in methanol (140 mL), and tributylphosphan (50% solution in ethyl acetate) (3.74 mL, 7.58 mmol) was added. The reaction mixture was heated at 70 °C for 5 hours. The reaction mixture was cooled to 15 °C, filtered, washed with cold methanol (100 mL), and dried to obtain 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoroquinoline-2(1H)-one (9.5 g, 19.45 mmol, yield 77%) as a yellow solid. MS (ESI, cation) m / z: 488.0 (M+1). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.88-8.02(m,2H),7.64(d,J=6.3Hz,1H),7.56(d,J=8.6Hz,1H),7.20-7.38(m ,5H),6.64(d,J=9.6Hz,1H),6.48(d,J=11.3Hz,1H),4.23(s,2H),3.71(s,3H).

[0149] Steps 6 and 7: 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl A 250 mL three-necked round-bottom flask filled with 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoroquinoline-2(1H)-one (9.5 g, 19.45 mmol) in acetonitrile (95 mL) was filled with acetic acid (6.4 mL) and water (4.13 mL). The resulting mixture was cooled to 0-5°C, and 1,3-dichloro5,5-dimethylimidazolidined-2,4-dione (6.13 g, 31.1 mmol) was added in small amounts over 10-20 minutes while maintaining the internal temperature below 5-10°C. The resulting suspension was stirred under nitrogen at 5-10°C for 45 minutes. Next, a solution of 2,3,4,5,6-pentafluorophenol (7.16 g, 38.9 mmol) in acetonitrile (10 mL) was added over 10-15 minutes, followed by the addition of triethylamine (13.54 mL, 97 mmol) over 20 minutes while maintaining the internal temperature below 5-10°C. The mixture was stirred continuously at 5-10°C for 30 minutes. Ice water (200 mL) was added, the precipitated solid was filtered, and washed with water (100 mL). The crude substance was purified by stirring with methanol (50 mL), filtered, washed with MeOH (50 mL), and dried to obtain 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (9.5 g, 15.52 mmol, yield 80%) as a grayish-white solid. MS (ESI, cation) m / z; 612.0 (M+1). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.53(d,J=7.4Hz,1H),8.20(d,J=9.8Hz,1H),7.67(dd,J=16.2,7.4Hz,2H),6.99(d,J=12.1Hz,1H),6.83(d,J=9.8Hz,1H),3.74(s,3H).

[0150] Step 8: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate (135 g, 220 mmol) was purified by SFC using a Regis Whelk-O s,s 5×15 cm, 5 μm column with a mobile phase of 50% dichloromethane at a flow rate of 350 mL / min to give (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate (49.2 g, 80.4 mmol, 36% yield). MS (ESI, positive ion) m / z: 612.7 (M+1).

[0151] Intermediate E1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [Chemical formula] A 100 mL round-bottom flask was charged with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (6.01 g, 9.82 mmol) and N-(4-methoxybenzyl)isoxazol-3-amine (2.48 g, 12.14 mmol). The flask was purged with nitrogen for 5 minutes and then tetrahydrofuran (20 mL) was added. After cooling the mixture to -78 °C, a 30% solution of sodium tert-pentoxide in THF (6 mL, 15.00 mmol) was added dropwise. After 15 minutes, the reaction was quenched with 5 M aqueous ammonium chloride and then warmed to ambient temperature. The mixture was extracted with EtOAc (twice), the organic layer was separated and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage Isolera One, Biotage Sfar silica HC D 20um 50 g, 0 - 80% ethyl acetate in heptane containing 10% dichloromethane as additive) to give (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide as a white solid (5.0 g, 7.91 mmol, 81% yield). m / z (ESI, cation) 634.0 (M+H) + .

[0152] Example 1 (P)-1-(5-chloro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [Chemical formula] Step 1: To a solution of (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (20 g, 32.7 mmol) and N-(4-methoxybenzyl)isoxazole-3-amine (7.36 g, 36.0 mmol) in 2-methyltetrahydrofuran (99 mL), cooled to -0.8 °C in a brine ice bath, a solution of sodium tert-pentoxide (1.4 M in THF, 28.1 mL, 39.3 mmol) was added dropwise at a rate such that the internal reaction temperature did not exceed 3 °C. After stirring for 1 hour, the solution was transferred to another refrigerator containing 100 mL of 2N HCl aqueous solution and 100 mL of RINKAN. The layers were separated, and the aqueous layer was extracted with RINKAN. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was diluted with 2-propanol (500 mL) to precipitate a white solid. The mixture was stirred overnight at ambient temperature, and the solid was isolated by filtration. It was washed with 2-propanol to obtain (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (16.5 g, 26.2 mmol, yield 80%) as a grayish-white solid. m / z(ESI) 631.4(M+H) + .

[0153] Step 2: A round-bottom flask was filled with (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (6.39 g, 10.1 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(ii)methanesulfonate (1.29 g, 1.52 mmol), potassium phosphate (6.45 g, 30.4 mmol), and dibutyl vinylboronate (3.73 g, 4.47 mL, 20.3 mmol). Next, ethanol (10.1 mL), water (20.3 mL), and toluene (70.9 mL) were introduced, and the resulting reaction mixture was aerated with nitrogen for 10 minutes, then heated to 45°C. After about 5 hours, the reaction mixture was cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-50% ethyl acetate / EtOH (3:1) in heptane to obtain (P)-1-(5-chloro-2-methoxy-4-vinylphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (3.78 g, 6.54 mmol, yield 65%). m / z(ESI)579.0(M+H)+.

[0154] Step 3: To a solution of (P)-1-(5-chloro-2-methoxy-4-vinylphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (3.78 g, 6.54 mmol) in water (9.34 mL) and acetone (56.1 mL), 4-methylmorpholine 4-oxide (1.19 g, 9.81 mmol) and potassium osmite dihydrate (0.022 g, 0.065 mmol) were added at ambient temperature. The resulting reaction mixture was stirred for 16 hours, after which a solution of sodium periodate (2.80 g, 13.1 mmol) in water (8.9 mL) was introduced. The resulting reaction mixture was stirred at ambient temperature for 1.5 hours. Next, the reaction mixture was diluted with dichloromethane, the layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting under a gradient of 0–60% Â / EtOH in heptane to obtain (P)-1-(5-chloro-4-formyl-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (3.40 g, 5.86 mmol, 90% yield). m / z(ESI) 581.0(M+H)+.

[0155] Step 4: A 250 mL round-bottom flask was packed with (P)-1-(5-chloro-4-formyl-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (3.78 g, 6.52 mmol), methanol (21.7 mL), and tetrahydrofuran (21.7 mL). Sodium borohydride (0.264 g, 6.84 mmol) was added to the reaction mixture in small amounts at 0°C. After stirring at 0°C for 1 hour, the reaction mixture was quenched with water and saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain (P)-1-(5-chloro-4-(hydroxymethyl)-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (3.34 g, 5.74 mmol, yield 88%). m / z(ESI) 582.0(M+H)+.

[0156] Step 5: A 40 mL vial was filled with (P)-7-fluoro-1-(5-fluoro-4-(hydroxymethyl)-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (3.33 g, 5.72 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diiumtetrafluoroborate (3.04 g, 8.58 mmol). The vial was transferred to a glove box, and then potassium fluoride (997 mg, 17.2 mmol) and silver(I) trifluoromethanesulfonate (2.94 g, 11.44 mmol) were added. Next, the vial was capped and removed from the glove box, and then ethyl acetate (14.3 mL), 2-fluoropyridine (1.11 g, 0.985 mL, 11.4 mmol), and trimethyl(trifluoromethyl)silane (1.63 g, 1.69 mL, 11.4 mmol) were added. The resulting mixture was stirred at ambient temperature for 96 hours. After this time, the reaction mixture was filtered through a silica gel plug and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with a gradient of 0-30% Â-EtOH (3:1) in heptane to obtain (P)-1-(5-chloro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.30 g, 2.00 mmol, yield 35.0%). m / z(ESI) 650.0(M+H)+.

[0157] Step 6: A round-bottom flask was filled with (P)-1-(5-chloro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.30 g, 2.00 mmol), dichloromethane (8.0 mL), and trifluoroacetic acid (13.1 g, 8.82 mL, 114 mmol). The reaction mixture was stirred at ambient temperature. After 16 hours, the reaction mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography eluting with a gradient of 0-75% Â-EtOH (3:1) in heptane to obtain (P)-1-(5-chloro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.05 g, 1.98 mmol, 99% yield). 1H NMR(500MHz,DMSO-d6)δ 11.64(br s,1H),8.72(d,J=1.82Hz,1H),8.37(d,J=2.21Hz,1H),8.22(d,J=9.60Hz,1H),7.85(dd,J=8.95,2.21Hz,1H),7.68(s,1H),7.50- 7.64(m,1H),6.79(dd,J=9.28,4.87Hz,2H),6.44(d,J=1.82Hz,1H),5.28-5.35(m,2H),3.67-3.76(m,3H).m / z(ESI)530.0(M+H)+.

[0158] Example 2 (P)-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] Step 1: A 40 mL vial was filled with (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (824 mg, 1.31 mmol), 2-di-t-butylphosphino-2,4,6-tri-i-propyl-1,1-biphenyl (555 mg, 1.31 mmol), and (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(ii) (508 mg, 1.31 mmol). The vial was purged with nitrogen for 10 minutes, and then tetrahydrofuran (6.53 mL) was added. The vial was capped, and the reaction mixture was stirred at ambient temperature. After 16 hours, (trifluoromethylthio)silver (355 mg, 1.70 mmol) was added to the reaction mixture all at once. The resulting reaction mixture was stirred at ambient temperature. After 1 hour, 1.0 g of Silicycle SiliaMetS® DMT metal scavenger was introduced, the mixture was diluted with dichloromethane, filtered with Celite®, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain (P)-1-(5-chloro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, which was used in the next step without further purification. m / z(ESI) 653.6(M+H)+.

[0159] Step 2: A 40 mL vial was filled with (P)-1-(5-chloro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, triethylsilane (759 mg, 1.06 mL, 6.53 mmol), and trifluoroacetic acid (6.53 mL). The reaction mixture was stirred at ambient temperature. After 16 hours, the solvent was removed under reduced pressure. The residue was purified by reverse-phase HPLC to obtain (P)-1-(5-chloro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (323 mg, total yield 47%) as an orange solid. 1 H NMR(500MHz,DMSO-d6)δ 8.70(s,1H),8.37(d,J=2.1Hz,1H),8.23(d,J=9.7Hz,1H),7.92(s,1H),7.86(dd,J=9.0,2.2Hz,1H), 7.78(s,1H),6.80(dd,J=9.2,7.4Hz,2H),6.43(d,J=1.7Hz,1H),3.75(s,3H).m / z(ESI)532.8(M+H)+.

[0160] Example 3 (P)-1-(5-chloro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] Step 1: A 250 mL three-necked round-bottom flask equipped with a Claisen adapter, nitrogen inlet, thermocouple, overhead stirrer, and addition funnel was filled with (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (20.0 g, 32.7 mmol) and N-(4-methoxybenzyl)isoxazole-3-amine (7.36 g, 36.0 mmol). The flask was evacuated, refilled with nitrogen three times, and then 2-methyltetrahydrofuran (99.0 mL) was introduced to cool the resulting solution to -0.8°C. A 1.4 M solution of sodium tert-pentoxide in THF (28.1 ml, 39.3 mmol) was transferred to the addition funnel and then added dropwise at a rate not exceeding 3°C in internal reaction temperature. After the addition was complete, the solution was siphoned into another refrigerated container containing 100 mL of 2.0 N HCl aqueous solution and 100 mL of Â. The layers were separated, and the aqueous layer was extracted with  (twice). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was diluted with IPA (500 mL) to form a white solid precipitate. The mixture was stirred overnight, and the solid was isolated by filtration. The isolated product was washed once with IPA and dried to obtain (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (16.5 g, 26.2 mmol, yield 80%) as a grayish-white solid. m / z(ESI) 631.4(M+H)+.

[0161] Step 2: Potassium hydroxide (548 mg, 9.76 mmol), 1,4-dioxane (6.00 mL), and water (2.00 mL) were added to a vial containing [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(ii)methanesulfonate (278 mg, 0.33 mmol) and 1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (2.05 g, 3.25 mmol). The reaction mixture was stirred at 80°C. After 2 hours, the reaction mixture was partitioned between DCM and water. The layers were separated, and the aqueous layer was extracted by DCM (twice). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluate: 0-60% ethyl acetate in heptane) to obtain (P)-1-(5-chloro-4-hydroxy-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.52 g, 2.67 mmol, yield 82%). m / z(ESI) 568.0(M+H)+.

[0162] Step 3: In a glove box filled with nitrogen, in a 40 mL vial, add silver(I) trifluoromethanesulfonate (1.81 g, 7.04 mmol), 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (998 mg, 2.82 mmol), N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (888 mg, The vials were filled with 2.82 mmol of cesium fluoride (1.28 g, 8.45 mmol), 2,6-di-tert-butylphenol (581 mg, 2.82 mmol), and 1-(5-chloro-4-hydroxy-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (800 mg, 1.41 mmol). After removing the vials from the glove box, toluene (7.1 mL), benzotrifluoride (14.2 mL), 2-fluoropyridine (684 mg, 606 μL, 7.04 mmol), and trimethyl(trifluoromethyl)silane (1.00 g, 1.04 mL, 7.04 mmol) were sequentially introduced under an argon atmosphere. The resulting reaction mixture was stirred at ambient temperature for 36 hours. After this time, the reaction mixture was filtered through a silica gel plug and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, eluate: 0-40% siRNA / EtOH (3:1) in heptane containing 10% dichloromethane as an additive) to obtain (P)-1-(5-chloro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (254 mg, 0.40 mmol, yield 28.4%). m / z(ESI) 635.8(M+H)+.

[0163] Procedure 4: A solution of (P)-1-(5-chloro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (254 mg, 0.40 mmol) and triethylsilane (203 mg, 280 μL, 1.75 mmol) in TFA (1.18 mL) was stirred at 50 °C for 2 h. Next, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, eluent: 0 - 40% EtOAc / EtOH (3:1) in heptane containing 10% dichloromethane as an additive) to give (P)-1-(5-chloro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (122 mg, 0.237 mmol, 16.8% yield). 1 H NMR (500 MHz, methanol-d4) δ 8.44 (d, J = 1.69 Hz, 1H), 8.32 (d, J = 2.08 Hz, 1H), 8.12 (d, J = 9.60 Hz, 1H), 7.92 (dd, J = 8.95, 2.21 Hz, 1H), 7.62 (s, 1H), 7.35 - 7.38 (m, 1H), 6.86 (d, J = 8.95 Hz, 1H), 6.83 (d, J = 9.73 Hz, 1H), 6.48 (d, J = 1.82 Hz, 1H), 3.77 (s, 3H). m / z (ESI) 515.8 (M + H)+.

[0164] Example 4 (P)-1-(5-Fluoro-2-methoxy-4-((trifluoromethoxy) methyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

Chemical Structure

[0165] Step 2: A 1 L round-bottom flask was filled with (P)-1-(5-fluoro-2-methoxy-4-vinylphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (14.0 g, 24.9 mmol), water (35.6 mL), and acetone (214 mL). 4-methylmorpholine 4-oxide (4.38 g, 37.4 mmol) and potassium dioxide dioxoosmium dihydrate (0.092 g, 0.249 mmol) were introduced, and the resulting reaction mixture was stirred at room temperature. After 21 hours, a solution of sodium periodate (10.7 g, 49.8 mmol) in water (250 mL) was added to the reaction mixture. After 20 minutes, an additional 500 mL of water was added, and the solid precipitate was collected by filtration. The solid was washed with water and dried under vacuum to obtain (P)-1-(5-fluoro-4-formyl-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (13.8 g, 24.4 mmol, 98% yield) as a grayish-white solid, which was used without further purification. 1H NMR(500MHz,CDCl3)δ:10.44(s,1H),8.24(d,1H,J=1.82Hz),7.84(d,1H,J=2.08H z),7.72(d,1H,J=9.73Hz),7.52-7.61(m,2H),7.32-7.39(m,2H),7.16(d,1H,J=9 .21Hz),6.83(d,1H,J=9.60Hz),6.74-6.81(m,2H),6.71(d,1H,J=1.69Hz),6.63( d,1H,J=8.95Hz),4.95(s,2H),3.79(s,3H),3.77(s,3H).m / z(ESI)564.2(M+H)+.

[0166] Step 3: A 1 L round-bottom flask was packed with (P)-1-(5-fluoro-4-formyl-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (24.4 g, 43.2 mmol), methanol (216 mL), and tetrahydrofuran (216 mL). After cooling to 0°C, sodium borohydride was added in small amounts over 5 minutes (1.72 g, 45.4 mmol). After the addition, the reaction mixture was stirred for 10 minutes, and then aqueous ammonium chloride solution (5 M) was introduced. The resulting mixture was extracted with ethyl acetate (3 times). The combined organic layers were washed with a 5M aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (P)-1-(5-fluoro-4-(hydroxymethyl)-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (23.3 g, 41.2 mmol, yield 95%) as a white solid, which was used without further purification. 1H NMR(500MHz,DMSO-d6)δ:8.79(s,1H),8.35(s,1H),8.14(d,1H,J=9.7Hz),7.78(br d,1H,J=9.1Hz),7.37(br d,1H,J=6.2Hz),7.21-7.33(m,3H),6.79-6.88(m,3H),6.72(s,1H),6.72(d,1H,J=6.3Hz),5.47(t,1H,J =5.4Hz),4.92(s,2H),4.60-4.69(m,2H),3.72(s,3H),3.70(s,3H),3.30(s,1H).m / z(ESI)566.2(M+H)+.

[0167] Step 4: A 250 mL round-bottom flask was packed with (P)-1-(5-fluoro-4-(hydroxymethyl)-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (8.05 g, 14.2 mmol) and carbon tetrabromide (5.66 g, 17.1 mmol). Next, dichloromethane (71.2 mL) was added, and after the reaction mixture was cooled to 0°C, triphenylphosphine (4.85 g, 18.5 mmol) was added all at once. After 20 minutes, water was introduced, and the mixture was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (Biotage, 100 g silica cartridge, 100% heptane per column volume, then 0-45% ethyl acetate in heptane (containing 10% dichloromethane additive) per column volume, then 45-65% ethyl acetate in heptane (containing 10% dichloromethane additive) per column volume) to obtain (P)-1-(4-(bromomethyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (7.20 g, 11.5 mmol, yield 80%) as a white solid. 1H NMR(500MHz,CDCl3)δ:8.25(d,1H,J=1.8Hz),7.84(d,1H,J=2.2Hz),7.71(d,1H,J=9.6Hz),7.58(dd,1H,J=9.0,2.2Hz),7.35-7.40(m,2H),7.16(d,1H,J=6.4Hz),7.01(d,1H,J=8.8Hz),6.77-6.86(m,3H),6.68-6.75(m,2H),4.96(s,2H),4.65(d,1H,J=10.5Hz),4.53(d,1H,J=10.6Hz),3.78(s,3H),3.77(s,3H).m / z(ESI)629.8(M+H)+.

[0168] Step 5: Trifluoromethyl triflate (10.2 g, 10.2 mL, 46.8 mmol) was quickly transferred to a 250 mL three-necked round-bottom flask, and the reaction vessel was immediately cooled in a dry ice acetone bath. Next, the flask was connected to an oil bubbler via a Teflon tube, and its outlet was connected to a 6 M potassium hydroxide solution. Next, a solid addition funnel filled with silver(I) fluoride (6.05 g, 47.7 mmol) was attached to the reaction vessel. Next, the reaction vessel was purged with nitrogen for 5 minutes. Acetonitrile (90 mL) was introduced, and the resulting two-phase mixture was heated to 0°C in an ice bath. Next, silver(I) fluoride (6.05 g, 47.7 mmol) was added to the reaction mixture in small amounts at a rate that controlled gas release. After the addition, the reaction mixture was stirred for 30 minutes to obtain an AgOCF3 aqueous solution, which was used without further manipulation. In another 500 mL round-bottom flask, (P)-1-(4-(bromomethyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (8.90 g, 14.2 mmol) was packed, purged with nitrogen for 5 minutes, and then packed with acetonitrile (70.8 mL). Next, the previously prepared AgOCF3 solution was added dropwise to the stirred reaction mixture via a cannula. After addition, the nitrogen inlet line was removed and the reaction mixture was stirred at ambient temperature. After 19 hours, a saturated aqueous solution of sodium bicarbonate was introduced, and the resulting mixture was diluted with dichloromethane.The resulting two-phase mixture was filtered, the organic layer was separated using an Isolute® phase separator, concentrated under reduced pressure, and purified by flash column chromatography (Biotage, 350 g silica cartridge, eluate: 100% heptane per column volume, 0-40% ethyl acetate in heptane (containing 10% dichloromethane additive) per 0.5 column volume, then 40-65% ethyl acetate in heptane (containing 10% dichloromethane additive) per 8 column volumes) to obtain (P)-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (7.83 g, 12.4 mmol, yield 87%) as a white solid. 1 H NMR(500MHz,CDCl3)δ:8.24(d,1H,J=1.8Hz),7.84(d,1H,J=2.2Hz),7.71(d,1H,J=9.6H z),7.57(dd,1H,J=9.0,2.1Hz),7.36(d,2H,J=7.4Hz),7.17(d,1H,J=6.1Hz),7.04(d,1 H,J=9.0Hz),6.76-6.85(m,3H),6.72(d,1H,J=1.8Hz),6.67(d,1H,J=9.0Hz),5.22(d,1 H,J=12.2Hz),5.10(d,1H,J=12.2Hz),4.95(s,2H),3.77(s,6H).m / z(ESI)634.0(M+H)+.

[0169] Step 6: A 100 mL round-bottom flask was filled with (P)-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (6.0 g, 9.47 mmol) and triethylsilane (5.51 g, 7.56 mL, 47.4 mmol). 1,1,1-trifluoroacetic acid (32.4 g, 21.9 mL, 284 mmol) was added dropwise to the reaction mixture at ambient temperature. The resulting reaction mixture was heated to 40°C. After 8 hours, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (Biotage, 100g silica cartridge, eluate: 0-20% ethyl ethyl in DCM) to obtain (P)-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (4.00g, 7.79 mmol, yield 82%) as a grayish-white solid. 1 H NMR(500MHz,DMSO-d6)δ:11.63(s,1H),8.73(d,1H,J=1.8Hz),8.37(d,1H,J=2.2Hz),8.22(d,1H,J=9.6Hz),7.85(dd,1H,J=9.0,2.2Hz),7.54(d, 1H,J=6.4Hz),7.50(d,1H,J=9.5Hz),6.79(dd,2H,J=9.3,4.7Hz),6.44(d,1H,J=1.8Hz),5.27-5.34(m,2H),3.69(s,3H).m / z(ESI)514.0(M+H)+.

[0170] Example 5 (P)-1-(5-fluoro-2-methoxy-4-((2,2,2-trifluoroethyl)thio)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] Step 1: A microwave vial was filled with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.00 g, 1.63 mmol), tris(dibenzylideneacetone)dipalladium (0) (59.6 mg, 0.07 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (75.4 mg, 0.13 mmol), and 1,4-dioxane (4.00 mL). After aeration of the reaction mixture with nitrogen, diisopropylethylamine (420 mg, 566 μL, 3.25 mmol) and 2,2,2-trifluoroethane-1-thiol (226 mg, 174 μL, 1.95 mmol) were introduced. Next, nitrogen was passed through the reaction mixture, the lid was closed, and the mixture was irradiated at 125°C for 1 hour. Then, the reaction mixture was filtered through a Celite® pad, and the filtrate cake was rinsed with ethyl acetate. The filtrate was partitioned between ethyl acetate and water, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, eluate: 0-30% ethyl acetate in heptane / EtOH (3:1)) to obtain racemic 1-(5-fluoro-2-methoxy-4-((2,2,2-trifluoroethyl)thio)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (625 mg, 0.96 mmol, yield 59%) as a pale yellow solid. m / z(ESI) 649.8(M+H)+.

[0171] Step 2: A solution of 1-(5-fluoro-2-methoxy-4-((2,2,2-trifluoroethyl)thio)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (625 mg, 0.96 mmol) and trifluoroacetic acid (2.0 mL) was stirred at ambient temperature. After 16 hours, the reaction mixture was concentrated under reduced pressure to obtain 1-(5-fluoro-2-methoxy-4-((2,2,2-trifluoroethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide as a mixture of atrop isomers.

[0172] Step 3: Racemic 1-(5-fluoro-2-methoxy-4-((2,2,2-trifluoroethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide was separated by chiral SFC chromatography via a Regis Whelk-O S,S, 3×15cm, 5μm column, 35% 1:1 methanol / DCM mobile phase, and a flow rate of 160 mL / min. The first elution peak was concentrated to obtain (P)-1-(5-fluoro-2-methoxy-4-((2,2,2-trifluoroethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (248 mg, 0.47 mmol, 48.6% yield in 2 steps) as a white solid. The second elution peak was concentrated separately to obtain (M) atrop isomer. 1 H NMR(400MHz,DMSO-d6)δ:11.64(s,1H),8.72(d,J=1.76Hz,1H),8.36(d,J=2.18Hz,1H),8.21(d,J=9.54Hz,1H),7.84(dd,J=8.91,2.28Hz ,1H),7.44-7.51(m,2H),6.79(dd,J=9.28,2.02Hz,2H),6.44(d,J=1.76Hz,1H),4.15-4.27(m,2H),3.70(s,3H).m / z(ESI)559.8(M+H)+.

[0173] Example 6 (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0174] Step 1: In a 100 mL round-bottom flask, (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (2.00 g, 3.16 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1, The mixture was packed with 1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(ii)methanesulfonate (0.402 g, 0.474 mmol), potassium phosphate (2.01 g, 9.49 mmol), dibutyl vinylboronate (1.164 g, 1.39 mL, 6.32 mmol), ethanol (3.16 mL), water (6.32 mL), and toluene (22.1 mL). The reaction mixture was stirred at 50°C for 2 hours. After this time, the reaction mixture was diluted with water and extracted with butyl (3 times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a gradient of 0-40% ethyl acetate / EtOH (3:1) in heptane to obtain (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-vinylphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.60 g, 2.76 mmol, yield 87%). m / z(ESI) 580.8(M+H)+.

[0175] Step 2: A 40 mL vial was filled with (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-vinylphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (570 mg, 0.98 mmol), N-methylmorpholine N-oxide (NMO) (173 mg, 1.48 mmol), and potassium osmate dihydrate (1.62 mg, 4.92 μmol). The resulting reaction mixture was stirred at room temperature for 48 hours. After this time, the solution was treated with a solution of sodium periodate (421 mg, 1.97 mmol) in water (15.8 mL). The resulting reaction mixture was stirred at room temperature for 1.5 hours. Next, the reaction mixture was diluted with dichloromethane, the layers were separated, and the aqueous layer was further extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (RediSep 40 g, 3-50% Â(3:1) in heptane with 10% dichloromethane as an additive) to obtain (P)-7-fluoro-1-(5-fluoro-4-formyl-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.435 g, 0.748 mmol, yield 76%) as a yellow solid. m / z(ESI) 582.8(M+H)+.

[0176] Step 3: A vial containing (P)-7-fluoro-1-(5-fluoro-4-formyl-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (785 mg, 1.35 mmol), methanol (6.75 mL), and dichloromethane (5 mL) was cooled to 0°C. Sodium tetrahydroborate (51.1 mg, 1.35 mmol) was then added in small amounts to the stirred reaction mixture. The resulting reaction mixture was stirred at 0°C for 5 minutes, then at ambient temperature for 10 minutes. The reaction mixture was quenched with water, extracted with dichloromethane, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (RediSep 24g, 0-50% RINKAN / EtOH (3:1) in heptane containing 10% dichloromethane as an additive), (P)-7-fluoro-1-(5-fluoro-4-(hydroxymethyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (524 mg, 0.897 mmol, yield 67%) was obtained as a white solid. m / z(ESI) 584.8(M+H)+.

[0177] Step 4: A 40 mL vial was filled with (P)-7-fluoro-1-(5-fluoro-4-(hydroxymethyl)-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (524 mg, 0.897 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diiumtetrafluoroborate (477 mg, 1.35 mmol). The vial was then transferred to a glove box, after which potassium fluoride (209 mg, 3.59 mmol) and silver(I) trifluoromethanesulfonate (692 mg, 2.69 mmol) were added. Next, the vial was capped and removed from the glove box, and ethyl acetate (4.49 mL), 2-fluoropyridine (261 mg, 232 μL, 2.69 mmol), and trimethyl(trifluoromethyl)silane (383 mg, 398 μL, 2.69 mmol) were added. The resulting reaction mixture was stirred at room temperature for 16 hours. After this time, ethyl acetate (10 mL) was added, and the mixture was passed through a silica gel plug. The silica gel plug was washed with ethyl acetate (20 mL). The filtrate was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (RediSep 24g, 2-40% siRNA / EtOH (3:1) in heptane containing 10% dichloromethane as an additive) to obtain (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (274 mg, 0.421 mmol, yield 47%) as a white solid. m / z(ESI) 652.8(M+H)+.

[0178] Step 5: A 20 mL vial was filled with (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (274 mg, 0.421 mmol) and trifluoroacetic acid (4.0 mL). The reaction mixture was stirred at 48°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (RediSep 12g, 2-45% siRNA / EtOH (3:1) in heptane containing 10% dichloromethane as an additive) to obtain (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (158 mg, 0.297 mmol, yield 71%) as a grayish-white solid. 1 H NMR(CDCl3,500MHz)δ 8.75(br s,1H),8.24(d,J=1.4Hz,1H),8.1-8.2(m,1H),7.79(d,J=9.7Hz,1H),7.18(d,J=6.1Hz,1H),7.03(d,J=8.8Hz,1H),6 .81(d,J=9.7Hz,1H),6.55(d,J=1.6Hz,1H),6.4-6.5(m,1H),5.1-5.3(m,2H),3.7-3.8(m,3H).m / z(ESI)532.8(M+H)+

[0179] Example 7 (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] Step 1: A 40 mL vial was filled with (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II) (0.246 g, 0.632 mmol), di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (0.295 g, 0.696 mmol), (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (2.00 g, 3.16 mmol), and toluene (16 mL). The reaction mixture was aerated with nitrogen for 15 minutes, and then heated at 50°C for 45 minutes to obtain a homogeneous solution. Another 40 mL vial was filled with phenyltriethylammonium iodide (1.25 g, 4.11 mmol) and silver(I) trifluoromethylthiolate (859 mg, 4.11 mmol). After purging the vial with nitrogen for 15 minutes, the solution from the first vial was transferred to the second vial using a cannula, and the resulting mixture was vigorously stirred at 50°C. After 45 minutes, the mixture was cooled to room temperature, filtered through a Celite pad, and the filtered cake was washed with toluene (10 mL). The filtrate was concentrated under vacuum, and the residue was purified by flash column chromatography (ISCO CombiFlash, 24g silica cartridge, eluate: 0-50% ethyl ethyl heptane) to obtain (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.74g, 2.66 mmol, yield 84%) as a white solid. m / z(ESI) 654.0(M+H)+.

[0180] Step 2: A 250 mL round-bottom flask equipped with a reflux condenser was filled with (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (23.2 g, 35.5 mmol), triethylsilane (26.3 mL, 177 mmol), and trifluoroacetic acid (81 mL, 1.05 mol). The resulting mixture was heated to 50°C for 6 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate (200 mL) was added. The resulting mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was azeotropically removed from heptane (3 × 70 mL), and the residue was purified by flash column chromatography (Biotage, 200 g silica cartridge, eluate: gradient of 0-60% ethyl acetate / ethanol (3:1 mixture) in heptane / DCM (9:1 mixture)). The fractions containing the product were combined and concentrated under reduced pressure. The resulting solid was purified by SFC via Regis Whelk-O s,s, 3 × 15 cm, 5 μm column; 35% methanol mobile phase, 180 mL / min flow rate to obtain (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (13.7 g, 25.6 mmol, yield 72%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ:12.02(br s,1H),8.73(d,J=1.6Hz,1H),8.49(d,J=7.8Hz,1H),8.26(d,J=9.7Hz,1H),7.73(d,J=8.4Hz,1H),7.68(d,J=6.2H) z,1H),6.77(d,J=9.7Hz,1H),6.63(d,J=11.8Hz,1H),6.38(d,J=1.7Hz,1H),3.74(s,3H).m / z(ESI)534.0(M+H)+.

[0181] Example 8 (P)-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] Step 1: A 500 mL round-bottom flask was packed with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.30 g, 2.12 mmol), 2-di-t-butylphosphino-2,4,6-tri-i-propyl-1,1-biphenyl (898 mg, 2.12 mmol), and (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(ii) (823 mg, 2.12 mmol). The flask was purged with nitrogen for 30 minutes, then tetrahydrofuran (21.2 mL) was introduced, and the reaction mixture was stirred at ambient temperature. After 21 hours, ((trifluoromethyl)thio)silver (575 mg, 2.75 mmol) was introduced all at once into the stirred reaction mixture. After 1.5 hours, Silicycle SiliaMetS® DMT metal scavenger (9.0 g) was introduced, and the mixture was diluted with dichloromethane. Next, the mixture was filtered through a Celite® plug and eluted with 10% MeOH in dichloromethane. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (220 g silica gel column, eluted with 0-50% siRNA / EtOH (3:1) in heptane (containing 10% dichloromethane)) to obtain (P)-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.19 g, 1.87 mmol, yield 88%) as a brown foam. m / z(ESI) 636.0(M+H)+.

[0182] Step 2: A 20 mL vial was filled with (P)-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.19 g, 1.87 mmol) and trifluoroacetic acid (19.2 g, 12.9 mL, 169 mmol). The reaction mixture was stirred at 40°C for 1.5 hours. After concentrating the reaction mixture under reduced pressure, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with dichloromethane. The combined organic layers were concentrated and subjected to reverse-phase MPLC purification with elution in a 30-75% acetonitrile aqueous solution (0.1% formic acid) to obtain (P)-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.58 g, 1.13 mmol, yield 60%) as a beige solid. 1 H NMR(CDCl3,500MHz)δ 8.28(d,J=1.8Hz,1H),8.21(br s,1H),8.1-8.2(m,1H),7.81(t,J=10.5Hz,2H),7.38(d,J=5.8Hz,1H),7.16(d,J=7.7Hz,1H),6.87( d,J=9.6Hz,1H),6.72(d,J=9.0Hz,1H),6.62(d,J=1.8Hz,1H),3.77(s,3H).m / z(ESI)516.7(M+H)+.

[0183] Example 9 (P)-1-(5-fluoro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] Step 1: A vial containing [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(ii)methanesulfonate (278 mg, 0.33 mmol) and (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (2.00 g, 3.25 mmol) was mixed with potassium hydroxide (548 mg, 9.76 mmol) in water (2.00 mL) and 1,4-dioxane (6.00 mL). The resulting reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was then cooled to ambient temperature and partitioned between DCM and water. The pH of the aqueous phase was adjusted to approximately 7 with an aqueous HCl solution (1.0N), and extracted with DCM (twice). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, eluate: 0-50% ethyl acetate / EtOH (3:1) in heptane (containing 10% DCM)) to obtain (P)-1-(5-fluoro-4-hydroxy-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.67 g, 3.03 mmol, yield 93%). m / z(ESI) 552.0(M+H)+.

[0184] Step 2: In a glove box filled with nitrogen, add silver(I) trifluoromethanesulfonate (1.17 g, 4.53 mmol), 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diiumtetrafluoroborate (0.64 g, 1.81 mmol), and N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (0.57 g, 1 The vials were filled with 0.81 mmol of cesium fluoride (0.83 g, 5.44 mmol), 2,6-di-tert-butylphenol (0.37 g, 1.81 mmol), and 1-(5-fluoro-4-hydroxy-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.50 g, 0.91 mmol). The vials were removed from the glove box and toluene (4.58 mL), benzotrifluoride (9.16 mL), 2-fluoropyridine (0.44 g, 0.39 mL, 4.53 mmol), and trimethyl(trifluoromethyl)silane (0.64 g, 0.67 mL, 4.53 mmol) were introduced under an argon atmosphere. The resulting reaction mixture was stirred at ambient temperature. After 16 hours, the reaction mixture was filtered through a silica gel plug and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, eluate: 0-100% ethyl acetate / EtOH (3:1) in heptane (containing 10% DCM)) to obtain (P)-1-(5-fluoro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (126 mg, 0.20 mmol, yield 22.4%). m / z(ESI) 620.0(M+H)+.

[0185] Step 3: A mixture of (P)-1-(5-fluoro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (126 mg, 0.20 mmol), triethylsilane (0.212 g, 0.29 mL, 1.82 mmol), and 2,2,2-trifluoroacetic acid (1.76 g, 1.15 mL, 15.4 mmol) was stirred at 50°C. After 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, eluate: 0-60% ethyl acetate / EtOH (3:1) in heptane (containing 10% DCM)) to obtain (P)-1-(5-fluoro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (22.2 mg, 0.044 mmol, yield 22.2%). 1 H NMR(500MHz,DMSO-d6)δ:11.64(bs,1H),8.72(d,J=1.69Hz,1H),8.37(d,J=2.08Hz,1H),8.23(d,J=9.73Hz,1H),7.84(dd,J=8.95,2.21Hz,1H),7.77(d ,J=10.38Hz,1H),7.54(d,J=7.14Hz,1H),6.85(d,J=8.95Hz,1H),6.80(d,J =9.60Hz,1H),6.44(d,J=1.82Hz,1H),3.71(s,3H).m / z(ESI)500.0(M+H)+.

[0186] Example 10 (P)-1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethoxy) Phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] Step 1: (P)-1-(5-fluoro-4-hydroxy-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (300 mg, 0.54 mmol) and cesium carbonate (532 mg, 1.63 mmol) were dissolved in tetrahydrofuran (1.00 mL), to which 2,2,2-trifluoroethyl triflate (252 mg, 1.09 mmol) was added. The resulting reaction mixture was purged with nitrogen and heated to 50°C. After 6 hours, the reaction mixture was concentrated under reduced pressure, and the residue was partitioned between DCM and water. The organic layer was concentrated to obtain 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethoxy)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. m / z(ESI) 634.1(M+H)+.

[0187] Step 2: A solution of 1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethoxy)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide in TFA (0.5 mL) was stirred at 50°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chiral SFC chromatography using a Regis Whelk-O1 S,S, 21 × 250 mm, 5 μm column, 30% methanol mobile phase, and a flow rate of 80 mL / min to obtain (P)-1-(5-fluoro-2-methoxy-4-(2,2,2-trifluoroethoxy)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (81.3 mg, 0.16 mmol, 29.1% yield in two steps) as a white solid. 1H NMR(600MHz,DMSO-d6)δ 11.62(br s,1H),8.72(d,J=1.73Hz,1H),8.35(d,J=2.09Hz,1H),8.19(d,J=9.63Hz,1H),7.84(dd,J=8.99,2.18Hz,1H),7.45(d,J=11.08Hz,1H),7.24(d, J=7.72Hz,1H),6.81(d,J=8.99Hz,1H),6.78(d,J=9.63Hz,1H),6.44(d,J=1.73Hz,1H),4.97-5.06(m,2H),3.69(s,3H).m / z(ESI)514.0(M+H)+.

[0188] Examples 11-26: The following compounds were prepared in the same manner as described in Examples 1-10 above.

[0189] [Table 1]

[0190] [Table 2]

[0191] [Table 3]

[0192] [Table 4]

[0193] [Table 5]

[0194] Biological examples The following assays were used to test exemplary compounds of the present invention. The data for those examples, tested according to the following procedure, are shown in Table 1 below.

[0195] IONWORKS BARRACUDA Automated Patch Clamp Assay (Same protocol for both human and mouse) The currents of human Nav1.7 cells were recorded in population patch-clamp mode using an IWB automated electrophysiology system (Molecular Devices, LLC, Sunnyvale, CA). Spiking HEK cells (without Kir2.1 transfection) were recorded as previously described for the IonWorks Quattro trial. 1 Cells were cultured and prepared for recording purposes. The external solution consisted of 320 mOsmol of NaCl 140, KCl 5, CaCl22, MgCl21, HEPES 10, and glucose 11 (units mM), pH 7.4, containing N-methyl-D-glucamine. The internal solution consisted of 300 mOsmol of KCl 70, KF 70, MgCl20.25, HEDTA 5, and HEPES 10 (units mM), pH 7.25, containing N-methyl-D-glucamine. Current was induced by a series of 26 depolarizations from a holding potential of -110 mV to -20 mV at a frequency of 5 Hz for a duration of 150 ms. The cells were then clamped to -20 mV for 4 minutes in the presence of a single concentration of the test compound. After this compound incubation period, the cells were clamped to -110mV for 3 seconds to restore unbound channels and subjected to the same 26-pulse voltage protocol as above. The inhibition rate was determined by dividing the peak inward current during the 26th pulse to -20mV in the presence of the compound by the peak inward current induced by the 26th pulse to -20mV in the absence of the compound. A concentration-response curve of the inhibition rate as a function of concentration was constructed and IC was calculated as described in Kornecook, TJ; Yin, R.; Altmann, S.; et al. Pharmacologic Characterization of AMG8379, a Potent and Selective Small Molecule Sulfonamide Antagonist of the Voltage-Gated Sodium Channel NaV1.7.J.Pharmacol.Exp.Ther.2017,362,146-160. 50 The value was calculated.

[0196] Microsome-specific clearance assay The objective of this assay was to determine the intrinsic clearance of the test compound in microsomes derived from preclinical species and humans by monitoring the time course of the test substance's disappearance in liver microsomes. Microsomes in 20 mg / mL stock form, stored at -80°C, were used. The chemicals used were: (1) test substance, 10 mM stock (DMSO) or powder from a sample bank; (2) verapamil, 10 mM stock; (3) NADPH, powder (Sigma); (4) potassium phosphate buffer, 100 mM, pH 7.4; and (5) tolbutamide (or equivalent). The final incubation concentrations were 0.25 mg / mL of microsomal protein and 0.5 μM of test substance, and incubation was performed in triplicate. Typical time points for the assay were 1, 5, 10, 20, 30, and 40 minutes. The assay was performed in a 96-well format, with samples continuously taken from 400 μL of incubation. At the appropriate time, the incubation was quenched with acetonitrile containing an internal standard (tolbutamide). Tolbutamide was the initial internal standard because it has a signal by cation or anion mass spectrometry. Verapamil was the positive control for the microsome intrinsic clearance assay. Samples were subjected to LC-MS / MS analysis, and the relative amount of the compound was calculated by the peak area of ​​the compound normalized to the peak area of ​​the internal standard (A / IS). Intrinsic clearance was calculated using Galileo.

[0197] procedure: Remove the microsomes from the -80°C freezer. Thaw them at room temperature or in a 37°C water bath. After thawing, store them on ice. Add the microsomes (0.53 mg / mL) to 0.1 M phosphate buffer and take 250 μL for each reaction. Prepare a 10 mM stock of the test substance in DMSO. Dilute to 1 / 100 with 50:50 acetonitrile:water to prepare a 100 μM stock. Add approximately 2.5 μL of the 100 μM stock of the test substance to each reaction to achieve a final substrate concentration of 1.05 μM. (Note: At this stage, the concentration is approximately twice as high as the final incubation conditions, taking into account dilution with NADPH at approximately 1:1).

[0198] A 1.9 mM NADPH solution is prepared in 0.1 mM phosphate buffer. Prepare four 250 μL replication wells containing 1.05 μM substrate and 0.53 mg / mL protein, each containing substrate and microsomes. Prepare three replication wells containing 210 μL of 1.90 mM NADPH, and one well containing buffer (-NADPH). Pre-incubate the microsomes, 0.1 M phosphate buffer, and test substance at 37°C for 5 minutes. To initiate the reaction, add 190 μL of substrate to the NADPH-containing well to a final concentration of 0.25 mg / mL microsomes, 0.5 μM test substance, and 1 mM NADPH. Take 35 μL at 1, 5, 10, 20, 30, and 40 minutes. Quench 1:1 with acetonitrile containing an internal standard. Vortex and centrifuge. Transfer for biological analysis by LC-MS / MS.

[0199] Spontaneous motility in open fields in mice On the day of the test, C57Bl / 6 male mice were orally administered either the Nav1.7 compound or a solvent control formulation at a dose of 10 ml / kg. The solvents used were 2% HPMC / 1% Tween 80 pH10 containing NaOH; DI water pH10 containing NaOH; or 2% HPMC / 1% Tween 80 pH2.2.

[0200] Two to three hours after treatment with the test substance, animals were placed in an open-field chamber according to the cmax of each Nav1.7 test compound of the present invention, and their behavior was monitored for 30 minutes. For the experiments at Thousand Oaks, a 16" × 16" open-field chamber (KINDER SCIENTIFIC®, San Diego, CA) was used. For the experiments at Cambridge Massachusetts, a 16" × 16" open-field chamber (SAN DIEGO INSTRUMENTS®, San Diego, CA) was used. Spontaneous motor activity (horizontal movement and standing behavior) parameters were automatically measured by blocking the infrared light beam.

[0201] Human CYP 3A4 induction assay Cryopreserved human hepatocytes were seeded at a rate of 70,000 cells per well in hepatocyte plating medium (HPM, final concentration: 1× Dulbecco's modified Eagle medium, 0.1 μM dexamethasone, 10% fetal bovine serum, 1× ITS, 1× PSG) on 96-well collagen-coated plates. The plates were then incubated at 37°C under 5% CO2 and 90% relative humidity for 2 days to form a confluent layer of hepatocytes. On day 3, the hepatocytes were treated with either a test compound prepared in hepatocyte incubation medium (HIM, final concentration: 1× William's medium E, 0.1 μM dexamethasone, 1× ITS, 1× PSG) or rifampin (20 μM, positive control for CYP3A induction). The treatment was performed for 72 hours with either two concentrations (2 μM or 10 μM) or a certain concentration range (0.001 μM to 100 μM) of the test compound to obtain a complete dose-response curve. Fresh medium containing the appropriate concentration of the test compound was changed daily until the sample was treated. After 72 hours of incubation, the sample was treated for mRNA analysis using bDNA technology according to the manufacturer's instructions (Affymetrix, Fremont, CA). Cell viability was tested at the end of the experiment using an MTT assay kit (Roche Diagnostics, Basel, Switzerland). Data were analyzed and expressed as a percentage of control (POC), and, where appropriate, E obtained according to the guidelines of the Center for Drug Evaluation and Research (CDER), 2006, Guidance for Industry, Drug Interaction Studies - Study Design, Data Analysis, and Implications for Dosing and Labeling. max and EC 50 This was shown as follows.

[0202] Cryopreserved human hepatocytes were seeded at a rate of 70,000 cells per well in hepatocyte plating medium (HPM, final concentration: 1× Dulbecco's modified Eagle medium, 0.1 μM dexamethasone, 10% fetal bovine serum, 1× ITS, 1× PSG) on 96-well collagen-coated plates. The plates were then incubated at 37°C under 5% CO2 and 90% relative humidity for 2 days to form a confluent layer of hepatocytes. On day 3, the hepatocytes were treated with either a test compound prepared in hepatocyte incubation medium (HIM, final concentration: 1× William's medium E, 0.1 μM dexamethasone, 1× ITS, 1× PSG) or rifampin (20 μM, positive control for CYP3A induction). The treatment was performed for 72 hours with either two concentrations (2 μM or 10 μM) or a certain concentration range (0.001 μM to 100 μM) of the test compound to obtain a complete dose-response curve. Fresh medium containing the appropriate concentration of the test compound was changed daily until the samples were treated. After 72 hours of incubation, the samples were processed for mRNA analysis using bDNA technology according to the manufacturer's instructions (Affymetrix, Fremont, CA). Cell viability was tested at the end of the experiment using an MTT assay kit (Roche Diagnostics, Basel, Switzerland). The data were analyzed and expressed as a percentage relative to control (POC), and where appropriate, as E obtained as described in Halladay, J. et al, 2012, An “all-inclusive” 96-well cytochrome P450 induction method: Measuring enzyme activity, mRNA levels, protein levels, and cytotoxicity from one well using cryopreserved human hepatocytes, Pharmacological and Toxicological Methods, 66:270-275. max and EC 50 This was shown as follows.

[0203] The compounds of the present invention can also be tested in the following in vivo assays.

[0204] Rat formalin model of persistent pain On the day of the experiment, animals (naive, male Sprague Dolly rats) weighing 260-300g at the start of the experiment can be obtained from Harlan (Indianapolis, IN). All animals can be housed under a 12 / 12 hour light / dark cycle with the lights turned on at 6:00. Rodents can be housed two per cage in sturdy cages with corn cobs as the flooring, and food and water can be freely accessed. Animals must be acclimatized in their enclosures for at least 5 days before the start of the experiment and placed in the laboratory at least 30 minutes before administration. At the desired pre-treatment time (typically 2 hours before the start of the experiment), animals are pre-treated with the appropriate test compound by either forced oral administration or intraperitoneal injection, and then returned to their home cages. Animals can be acclimatized to their respective test chambers after administration and at least 30 minutes before the start of the experiment. During the experiment, each animal can be lightly wrapped in a towel with its left hind leg exposed. A diluted solution of formalin (2.5%) in phosphate-buffered saline can be subcutaneously injected into the dorsal surface of the left hind limb in volumes of up to 50 μL using a 30 g needle. Immediately after injection, a small metal band can be attached to the sole of the left hind limb using a small amount of LOCTITE (adhesive). The animal can then be placed in a test chamber, and the number of flinches can be recorded for 10 to 40 minutes after formalin injection. A flinch is defined as a rapid, spontaneous movement of the injected hind limb unrelated to walking. Flinches can be quantified using an automated pain analyzer developed by the Department of Anesthesiology at the University of California, San Diego. Individual data can be expressed as Maximum Potential Effect % (MPE%), which is calculated using the following formula: (-(individual score - solvent mean score) / solvent mean score)) × 100 = MPE%.

[0205] Statistical analysis can be performed using analysis of variance (ANOVA) with a post-hoc analysis using Bonferroni, comparing significant main effects with those of the solvent group. Data can be expressed for each group as mean MPE% ± standard error.

[0206] Rat open-field assay On the day of the test, animals (naive, male Sprague Dolly rats) weighing 260-300g at the start of the test can be obtained from Harlan (Indianapolis, IN). All animals can be housed under a 12 / 12 hour light / dark cycle with lights turned on at 6:00. Rodents can be housed two per cage in sturdy cages with corn cobs as flooring, and food and water can be freely accessed. Animals must be acclimated to their enclosures for at least 5 days before the start of the test and placed in the laboratory at least 30 minutes before administration. In a separate room from the laboratory, animals can be pre-treated with the appropriate test compound by forced oral administration or intraperitoneal injection at the desired pre-treatment time (typically 2 hours before the start of the test), and then returned to their home cages until the pre-treatment period is over. At the time of the test, animals can be moved to an open-field laboratory within their home cages. Each animal can be placed in a separate test chamber, and a motion tracking system is activated. The laboratory house lights must be turned off, and the animals can be allowed to explore a new open field for 30 minutes. An automated motion tracking system, manufactured by San Diego Instruments, San Diego, CA, can be used to capture the animals' exploration using an infrared beam to detect their movements. These movements include basic movements and vertical standing, which can be used as the primary endpoint of this assay. At the end of the test, the house lights can be turned on, and the animals must be removed from the apparatus. The data can be expressed as a percentage change from the solvent control using the following formula: (1 - (Test average / Solvent average)) × 100 = Change %

[0207] Statistical analysis can be performed using analysis of variance (ANOVA) with a post-hoc analysis using Dunnett to track significant main effects.

[0208] Mouse formalin model of persistent pain Mice (naive, male C57Bl / 6) weighing 22–30 g at the start of the study were obtained from Harlan (Indianapolis, IN). All animals were housed under a 12 / 12 hour light / dark cycle with lights turned on at 6:30. Rodents were housed individually in cages with sturdy floors lined with corn cobs, and were given free access to food and water. Animals were acclimatized to their enclosures for at least 5 days prior to the start of the study and introduced to the laboratory at least 30 minutes before administration. At the desired pre-treatment time (typically 2 hours before the start of the study), animals were pre-treated with the appropriate test compound by either forced oral administration or intraperitoneal injection, and then returned to their home cages. Animals were acclimatized to their respective test chambers after administration and at least 5 minutes before the start of the study. During the study, each animal was lightly wrapped in a cloth glove with its left hind limb exposed. A diluted solution of formalin (2%) in phosphate-buffered saline was subcutaneously injected into the dorsal surface of the left hind limb using a 30g needle in volumes up to 20 μL. The animals were then placed in an observation chamber, and their behavior was recorded for 60 minutes after formalin injection. Pain-like behavior was defined as licking and / or unweighting of the injected hind limb that was not associated with walking.

[0209] Statistical analysis was performed using analysis of variance (ANOVA) with a post-hoc analysis employing Dunnett's post-hoc test, comparing all significant main effects with the solvent group. Data are presented as mean ± standard error for each group.

[0210] Table 1 provides data and priority documents relating to the compounds illustrated in this application as representative compounds of the present invention, as follows: Compound name (named using Chem Draw Ultra version 15.1); and in vitro Nav1.7 IWQ data (IC in uM units). 50), and, where available, biological data including in vitro human CYP3A4 mRNA induction data (percentage (POC) (%) relative to control at 2uM and 10uM). Ex.# refers to the example number. ND means no data is available. The representative compound of the present invention exhibits lower human CYP3A4 mRNA induction data compared to comparative compound A. The representative compound of the present invention preferably exhibits lower human CYP3A4 mRNA induction data and preferred in vitro human Nav1.7 IWQ data activity compared to compound A. Comparative compound A is named (P)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)-N-(1,2-oxazole-3-yl)-2-oxo-1,2-dihydro-6-quinoline sulfonamide and has the following structure: [ka] It holds.

[0211] Compound A was illustrated in International Publication No. 2017 / 106871.

[0212] [Table 6]

[0213] The invention described above is described in some detail by examples and embodiments for the purpose of clarification and understanding. Those skilled in the art will understand that changes 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 limiting. Accordingly, 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 entire scope of equivalents to which such claims are entitled.

[0214] All patents, patent applications, and publications cited herein are incorporated herein by reference in whole for all purposes to the same extent that each individual patent, patent application, or publication is so individually indicated.

Claims

1. Compounds of formula I, or their enantiomers, diastereoisomers, or atropisomers, or pharmaceutically acceptable salts thereof. 【Chemistry 1】 (In the formula, R １ is, -C ０～４ alk-O-C １～８ alk, -C ０～４ alk-S-C １～８ alk, or -C ０～４ alk-NH(C) １～８ (alk) is; Said C １～８ Alk is substituted with 0, 1, 2, 3, 4, 5, or 6 halo groups; R ２ is H, halo, -CN, C １～６ alk, or C １～６ haloalk; R ３ It is -O-C 1-6 alk; R ４ It is a 5-6 member heteroaryl; R ６ and R ７ Each of them is hydrogen; and R ５ａ ;R ５ｂ ;R ５ｃ ;R ５ｄ ; and R ５ｅ Each of these is independently either hydrogen or a halo.

2. R １ However, -O-C １～８ alk, -CH ２ -O-C １～８ alk, -S-C １～８ alk, -CH ２ -S-C １～８ alk, or -CH(CH ３ )-S-C １～８ It is alk, and the above C １～８ The compound according to claim 1, wherein alk is substituted with one, two, three, or four halo groups, or its enantiomer, diastereoisomer, or atropisomer, or a pharmaceutically acceptable salt thereof.

3. R １ However, -O-CF ３ , -O-CH ２ -CF ３ , -O-CH ２ -CH ２ -CF ３ , -O-CH(CH ３ ) - CF ３ ien-CH ２ -O-CF ３ , -S-CF ３ , or -S-CH ２ -CF ３ A compound according to claim 1 or 2, selected from, or an enantiomer, diastereoisomer, or atropisomer thereof, or a pharmaceutically acceptable salt thereof.

4. R ２ However, H, fluoro, chloro, methyl, CN, CF ３ CHF ２ , or CH ２ F is a compound according to any one of claims 1 to 3, or an enantiomer, diastereoisomer, or atropisomer thereof, or a pharmaceutically acceptable salt thereof.

5. R ２ The compound according to any one of claims 1 to 4, wherein the compound is H, fluoro, chloro, or methyl, or its enantiomer, diastereoisomer, or atropisomer, or a pharmaceutically acceptable salt thereof.

6. R ２ The compound according to any one of claims 1 to 5, wherein the compound is H or fluoro, or its enantiomer, diastereoisomer, or atropisomer, or a pharmaceutically acceptable salt thereof.

7. R ３ The compound according to any one of claims 1 to 6, wherein the compound is methoxy, or its enantiomer, diastereoisomer, or atropisomer, or a pharmaceutically acceptable salt thereof.

8. R ４ The compound according to any one of claims 1 to 7, which is a five-membered heteroaryl compound, or its enantiomer, diastereoisomer, or atropisomer, or a pharmaceutically acceptable salt thereof.

9. R ４ The compound according to any one of claims 1 to 7, which is a six-membered heteroaryl compound, or its enantiomer, diastereoisomer, or atropisomer, or a pharmaceutically acceptable salt thereof.

10. R ４ The compound according to any one of claims 1 to 7, wherein the compound is isoxazolyl, pyridadinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl, or its enantiomer, diastereoisomer, or atropisomer, or a pharmaceutically acceptable salt thereof.

11. R ４ The compound according to any one of claims 1 to 7, wherein the compound is isoxazolyl or pyrimidinyl, or its enantiomer, diastereoisomer, or atropisomer, or a pharmaceutically acceptable salt thereof.

12. R ４ The compound according to any one of claims 1 to 7, wherein the compound is isoxazolyl, or its enantiomer, diastereoisomer, or atropisomer, or a pharmaceutically acceptable salt thereof.

13. R ５ａ ;R ５ｂ ;R ５ｃ ;R ５ｄ ; and R ５ｅ A compound according to any one of claims 1 to 12, wherein each of the isomers is hydrogen, or an enantiomer, diastereoisomer, or atropisomer thereof, or a pharmaceutically acceptable salt thereof.

14. R ５ａ However, F is R ５ｂ ;R ５ｃ ;R ５ｄ ; and R ５ｅ A compound according to any one of claims 1 to 12, wherein each of the isomers is hydrogen, or an enantiomer, diastereoisomer, or atropisomer thereof, or a pharmaceutically acceptable salt thereof.

15. R ５ｃ However, F is; R ５ａ ;R ５ｂ ;R ５ｄ ; and R ５ｅ A compound according to any one of claims 1 to 12, wherein each of the isomers is hydrogen, or an enantiomer, diastereoisomer, or atropisomer thereof, or a pharmaceutically acceptable salt thereof.

16. a) (P)-1-(5-chloro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; b) (P)-1-(5-chloro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; c) (P)-1-(5-chloro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; d) (P)-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; e) (P)-1-(5-fluoro-2-methoxy-4-((2,2,2-trifluoroethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; f) (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; g) (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; h)(P)-4-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or i) A compound according to claim 1, selected from the group consisting of (P)-N-(isoxazole-3-yl)-1-(2-methoxy-5-methyl-4-((trifluoromethyl)thio)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, or a pharmaceutically acceptable salt thereof.

17. a) (P)-1-(5-chloro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; b) (P)-1-(5-chloro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; c) (P)-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or d) A compound according to claim 1, selected from (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-1-(5-chloro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

19. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-1-(5-chloro-2-methoxy-4-(trifluoromethoxy)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethoxy)methyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

21. a) (P)-1-(5-chloro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; b) (P)-1-(5-fluoro-2-methoxy-4-((2,2,2-trifluoroethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; c) (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; d) (P)-4-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or e) A compound according to claim 1, selected from (P)-N-(isoxazole-3-yl)-1-(2-methoxy-5-methyl-4-((trifluoromethyl)thio)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-1-(5-chloro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

23. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-1-(5-fluoro-2-methoxy-4-((2,2,2-trifluoroethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

24. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

25. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-4-fluoro-1-(5-fluoro-2-methoxy-4-((trifluoromethyl)thio)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

26. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-N-(isoxazole-3-yl)-1-(2-methoxy-5-methyl-4-((trifluoromethyl)thio)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

27. The compound according to any one of claims 1 to 26, wherein the atrop isomer is the P-atrop isomer, or its enantiomer, diastereoisomer, or atrop isomer, or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

29. A drug for use in a method for treating pain, cough, or itching, wherein the drug comprises a therapeutically effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, and the method comprises administering the drug to a patient in need thereof.

30. The agent according to claim 29, 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, diabetic peripheral neuropathy, and neuropathic low back pain.

31. The agent according to claim 29, wherein the cough is selected from post-viral infection cough, viral cough, or acute viral cough.

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