Cyclopropyl dihydroquinoline sulfonamide compound

Abstract

To provide cyclopropyl dihydroquinoline sulfonamide compounds.SOLUTION: The present invention provides a compound of Formula (I), an enantiomer, diastereoisomer or atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof. The compound inhibits voltage-gated sodium channels, in particular NaV1.7, and is useful for treatment of diseases such as pain disorders, cough and itch.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention provides a compound that is an inhibitor of voltage-opening sodium channels (NaV), particularly NaV 1.7, and is useful for treating diseases that can be treated by inhibiting sodium channels, such as pain disorders. A pharmaceutical composition containing the compound of the present invention is also provided. [Background technology]

[0002] 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 generated by the influx of sodium ions through voltage-opening 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 (NaV 1.1 to NaV 1.9), and they 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).

[0003] NaV1.1 and NaV1.2 are highly expressed in the brain (Raymond, CK, et al., J. Biol. Chem. (2004) 279(44):46234-41) and are essential for normal brain function. Some loss of function resulting from NaV 1.1 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 result in pain reduction. Therefore, while inhibition of NaV1.1 may be useful in treating pain, it may also be undesirable as it can cause anxiety and hyperexcitability. 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, such as paralysis (Tamaoka A., Internal Medicine (2003), (9):769-770). NaV1.5 is primarily expressed in cardiomyocytes, including the atria, ventricles, sinoatrial node, atrioventricular node, and cardiac Purkinje fibers. Rapid upstroke of cardiac action potentials and rapid action potential conduction through cardiac tissue are due to the opening of NaV1.5 channels. Mutations in the NaV1.5 channel have caused 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-opening sodium channel expressed throughout the central and peripheral nervous systems. NaV1.8 is mainly expressed in sensory ganglia of the peripheral nervous system, such as the dorsal root ganglia. No NaV1.8 mutations resulting in 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. Like NaV1.8, NaV1.9 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).

[0004] Recent evidence from several independent genetic studies has shown that the tetrodotoxin-sensitive potential-opening sodium ion channel NaV 1.7 (SCN9A) is required for sensory pain. Rare genotypes of primary erythromelalgia and paroxysmal severe pain, both severe chronic pain, are caused by mutations that increase the activity of NaV 1.7 (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 identified that the underlying cause of congenital insensitivity to pain (CIP), a genetic disorder, is loss of function in NaV 1.7 via mutations that cleave the protein and disrupt its function (Cox JJ, Reimann F, Nicholas AK, et al. “An SCN9A channelopathy causes congenital inability to experience pain,” Nature 444:894-898, 2006; Goldberg YP, MacFarlane J., MacDonald ML, Thompson J., et al. “Loss-of-function mutations in the NaV1.7 gene underlie congenital indifference to pain in multiple human populations,” Clin Genet 71:311-319, 2007). This disorder is inherited in a Mendelian recessive manner with 100% penetrance. The phenotype associated with CIP is extreme: affected individuals have reported experiencing painless burns, childbirth, appendicitis, and fractures, and being insensitive to clinical pain measurements such as pin stimulation or tendon compression. However, sensory, motor, autonomic, and other measured functions are normal, and the only abnormality reported is anosmia (inability to smell). These studies suggest that NaV 1.7 controls one or more control points of significant importance to pain perception among many possible targets in the pain pathway.

[0005] 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 topical anesthetic used by physicians for minor surgery. Dentists use novocaine. However, these compounds do not distinguish between various sodium channel subtypes, making them unsuitable for use as systemic analgesics. 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, particularly for NaV1.7 rather than NaV1.5, is desirable. Researchers have been working to discover molecules that inhibit or block the activity of NaV1.7 only. Complicating this issue is that the identification information, all locations, all functions, and / or three-dimensional structures of each subtype of voltage-opening sodium channel proteins are unknown or not fully understood.

[0006] As a result, several 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 selective to at least NaV1.5 for the treatment of pain. The present invention provides a compound that is a selective inhibitor of NaV 1.7 with respect to at least NaV1.5. [Prior art documents] [Patent Documents]

[0007] [License 1] U.S. Patent No. 8,101,647 [License 2] International Publication No. 2013 / 134518 [License 3] International Publication No. 2014 / 201206 [License 4] European Patent No. 039,051 [Patent Document 5] U.S. Patent and Trademark Office Publication No. 2014 / 042055 [License 6] U.S. Patent and Trademark Office Publication No. 2016 / 067617 [Non-licensed literature]

[0008] [Non-licensed Document 1] C & E News, Bethany Halford, “Changing the Channel,” published 3-24 [Non-licensed Document 2] Hille B, Ion Channels of Excitable Membranes. Sinauer Associates, Inc.: Sunderland MA, 3rd Ed. 2001 [Non-licensed Document 3] Goldin, AL, "Resurgence of sodium channel research," Ann Rev Physiol 63:871-894, 2001 [Non-licensed Document 4] Wood, JNand, Boorman, J. "Voltage-gated sodium channel blockers; target validation and therapeutic potential" Curr.Top Med.Chem.5:529-537, 2005 [Non-licensed Document 5] Raymond,CK,et al.,J.Biol.Chem.(2004)279(44):46234-41

Non-licensed Document 6

Non-licensed Document 7

Non-licensed Document 8

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-Patent Document 39

Summary of the Invention

Means for Solving the Problems

[0009] In Embodiment 1, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof

Chemical Formula

[0010] In the sub-embodiment 1a of Embodiment 1, the compound of formula (I) is a sub-formula of (Ia): [ka] (In the formula, R 1a It contains (which is fluoro, methyl, -O-CF3, -CH2-O-CF3, CF3, cyclopropyl, or phenyl).

[0011] In a more preferred lower embodiment 1a of Embodiment 1, R 1a is methyl, CF3, or phenyl; and R 4 These are isoxazolyl or pyridazinyl.

[0012] In the most preferred lower embodiment 1a of Embodiment 1, R 1a is CF3; R 2 is F; and R 4 It is isoxazolyl.

[0013] In the sub-embodiment 1b of Embodiment 1, the compound of formula (I) is the sub-formula of (Ib): [ka] (In the formula, R1a R is fluoro, methyl, or CF3. In a further lower embodiment 1b of Embodiment 1, 1a It is either fluoro or methyl.

[0014] In a sub-embodiment 1c of Embodiment 1, the compound of formula (I) is a sub-formula of (Ic): [ka] (In the formula, R 1a R is fluoro, methyl, or CF3. In a further lower embodiment 1c of Embodiment 1, 1a This is CF3.

[0015] In the sub-embodiment 1d of Embodiment 1, the compound of formula (I) is the sub-formula of (Id): [ka] (In the formula, R 1a (is fluoro, methyl, or CF3). In a further lower embodiment 1d of Embodiment 1, R 1a This is CF3.

[0016] 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 1a The base is Halo, C 1~8 alk, -OC 1~4 alk, C 1~8 Selected from haloalk, cyclopropyl, or phenyl; the C 1~8 Haloalk is C 1~8 It is a fluoroalkyl group.

[0017] 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 1is a cyclopropyl ring; or a 4, 5, or 6-membered bicyclic ring; the bicyclic ring contains 0 N, O, and S atoms; the cyclopropyl ring or bicyclic ring contains 1, 2, or 3 R selected from F, -CF3, -O-CF3, -C(CH3)3, cyclopropyl, or phenyl. 1a It is replaced by the base.

[0018] 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 1 is a cyclopropyl ring or a bicyclo[1.1.0]butan-1-yl ring; each ring is substituted with one or two F or -CF3 atoms.

[0019] 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 1 is a cyclopropyl ring substituted with one or two F or -CF3 groups; the cyclopropyl ring is a trans isomer.

[0020] 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 1 This is a bicyclo[1.1.0]butane-1-yl ring substituted with one or two F or -CF3 molecules.

[0021] 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 2 is H, fluoro, chloro, CN, methyl, CF3, CHF2, or CH2F. In a lower embodiment 7a of Embodiment 7, R 2 It is fluoro.

[0022] 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 2 The element is H, fluoro, chloro, CN, or methyl.

[0023] 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 2 is either H or fluoro.

[0024] In Embodiment 10, 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.

[0025] In Embodiment 11, 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.

[0026] 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 4 It is a 6-membered heteroaryl compound.

[0027] 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 4 isoxazolyl, pyridadinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl. In a lower embodiment of Embodiment 13a of Embodiment 13, R 4 isoxazolyl, pyridadinyl, or pyrimidyl. In another sub-embodied embodiment 13b of Embodiment 13, R 4It is isoxazolyl.

[0028] 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, a)R 5a ;R 5b ;R 5c ;R 5d ; and R 5e Each of them is hydrogen; b) R 5a is F; and R 5b ;R 5c ;R 5d ; and R 5e Each of them is hydrogen; or c)R 5d is F; and R 5a ;R 5b ;R 5c ; and R 5e Each of them is hydrogen.

[0029] In Embodiment 14a, 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.

[0030] In Embodiment 14b, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, R 5a is F; and R 5b ;R 5c ;R 5d ; and R 5e Each of them is hydrogen.

[0031] In Embodiment 14c, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, R 5d is F; and R 5a ;R5b ; R 5c ; and R 5e each of which is hydrogen.

[0032] In Embodiment 15, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is of formula (Ia):

Chemical formula

[0033] In Embodiment 15a, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a is CF3 or methyl; the cyclopropyl ring is the trans isomer; R 2 is H or F; R 4 is isoxazolyl, pyridazinyl, thiazolyl, or thiadiazolyl; and R 5a is H or F.

[0034] In Embodiment 15b, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a is CF3 or methyl; the cyclopropyl ring is the cis isomer; R 2 is H or F; R 4 is isoxazolyl, pyridazinyl, thiazolyl, or thiadiazolyl; and R 5a is H or F.

[0035] In Embodiment 15c, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1aCF3 is the cyclopropyl ring; the cyclopropyl ring is a trans isomer; R 2 H is; R 4 isoxazolyl, pyridazinyl, thiazolyl, or thiadiazolyl; and R 5a is F. In a lower embodiment of Embodiment 15c, preferably R 4 It is isoxazolyl.

[0036] In Embodiment 15d, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, R 1a CF3 is the cyclopropyl ring; the cyclopropyl ring is a trans isomer; R 2 F is; R 4 isoxazolyl, pyridazinyl, thiazolyl, or thiadiazolyl; and R 5a H is H. In a lower embodiment of Embodiment 15d, preferably R 4 It is isoxazolyl.

[0037] In Embodiment 16, the present invention provides a compound of formula (I), its enantiomer, diastereoisomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is an atropisomer and also a p-atropisomer.

[0038] In Embodiment 17, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the compound being selected from the following:

[0039] [Table 1]

[0040] [Table 2]

[0041] [Table 3]

[0042] In Embodiment 18, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the compound being selected from the following:

[0043] [Table 4]

[0044] [Table 5]

[0045] In Embodiment 18a, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0046] In Embodiment 18b, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0047] In Embodiment 18c, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-methylcyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0048] In Embodiment 18d, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-phenylcyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0049] In Embodiment 18e, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-phenylcyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0050] In Embodiment 18f, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide.

[0051] In Embodiment 18g, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0052] In Embodiment 18h, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(1,2,4-thiadiazole-5-yl)-1,2-dihydroquinoline-6-sulfonamide.

[0053] In Embodiment 18i, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-cyano-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0054] In Embodiment 18j, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0055] In Embodiment 18k, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0056] In Embodiment 18, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(1,3,4-thiadiazole-2-yl)-1,2-dihydroquinoline-6-sulfonamide.

[0057] In Embodiment 18m, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-6-(benzylthio)-1-(5-fluoro-2-hydroxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one.

[0058] In Embodiment 18n, the present invention provides a compound of formula (I), 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-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0059] In Embodiment 18o, the present invention provides a compound of formula (I), 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-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0060] In Embodiment 18p, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the compound being (P)-7-fluoro-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0061] In Embodiment 19, the present invention provides the P-atrop isomers, individually or in mixtures thereof, or pharmaceutically acceptable salts thereof of each of the individual compounds listed in Embodiments 18a to 18p.

[0062] In Embodiment 20, the present invention provides the M atrop isomers, individually or in mixtures thereof, or pharmaceutically acceptable salts thereof of each of the individual compounds listed in Embodiments 18a to 18p.

[0063] In Embodiment 21, the present invention provides a compound of formula (I), its enantiomer, diastereoisomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is of formula (Ia): [ka] The compound is selected from the following:

[0064] [Table 6]

[0065] [Table 7]

[0066] In Embodiment 22, the present invention provides a pharmaceutical composition comprising a compound according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or any one of its subordinate embodiments, an enantiomer, diastereoisomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0067] In Embodiment 23, 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 Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or any one of its subordinate embodiments, its enantiomer, diastereoisomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

[0068] In Embodiment 24, the present invention provides the method of Embodiment 23, 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.

[0069] In Embodiment 25, the present invention provides the method of Embodiment 23, wherein the cough is selected from post-infectious cough, viral cough, or acute viral cough. Dib-Hajj et al., “The Na V See "1.7 sodium channel: from molecule to man", Nature Reviews Neuroscience (2013), 14, 49-62.

[0070] In Embodiment 26, the present invention relates to formula (A): [ka] (In the formula, R is a halo or base [ka] A method for preparing the compound of (which is); 1) Formula (B): [ka] (In the formula, R is a halo or base [ka] And; and R 1 The process involves reacting a transolefin compound (which is C1-C6 alkyl) with UV light or near-UV light to form a cisolefin compound (C); and 2) The present invention provides a method comprising reacting compound (C) with a chiral acid in an organic solvent to form the compound of formula (A).

[0071] In Embodiment 27, the present invention provides the method of Embodiment 26, wherein the chiral acid is a phosphochiral acid.

[0072] In Embodiment 28, the present invention provides that the chiral acid is of formula: [ka] The method of Embodiment 26 is provided, which is a (S)-TRIP having

[0073] In Embodiment 29, the present invention provides the method of Embodiment 26, wherein the organic solvent is dichloromethane.

[0074] In Embodiment 30, the present invention provides the method of Embodiment 26, wherein R is bromo.

[0075] In Embodiment 31, the present invention is based on R [ka] The present invention provides the method of embodiment 26.

[0076] In Embodiment 32, the present invention relates to the R 1 is ethyl; the compound of formula (B) is of formula: [ka] The present invention provides a method according to embodiment 26, which has the following characteristics:

[0077] In Embodiment 33, the present invention provides the method of Embodiment 26, wherein the P-atrop isomer of the compound of formula (A) is selectively formed in reaction (2).

[0078] In Embodiment 34, the present invention relates to a compound of formula (A) being a compound of formula (I): [ka] ; or its pharmaceutically acceptable salt (In the formula, R 1 is a cyclopropyl ring; or a 4, 5, 6, 7, or 8-membered bicyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; and the cyclopropyl ring or bicyclic ring is hydroxyl, halo, C 1~8 alk, C 1~8 Haloalk, -OC 1~4 alk, -OC 1~8 Haloalk, -C(=O)C 1~4 alk, -OC(=O)C 1~4 alk, -NH2, -NHC 1~4 alk, -N(C 1~4 alk)C 1~4 0, 1, 2, or 3 R selected from alk, 3, 4, or 5-membered cycloalkyl, or 6-membered aryl 1a Substituted by the group; R 2H, Haro, CN, C 1~6 alk, or C 1~6 It is Haloalk; R 3 C 1~6 alk, C 1~6 Haloalk, -OC 1~6 It is alk, -O-cyclopropyl, or -O-cyclobutyl; 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 used as an intermediate compound in the preparation of hydrogen or halo. The present invention provides a method according to Embodiment 26 in which the P-atrop isomer of the compound of formula (I) is selectively formed. [Modes for carrying out the invention]

[0079] 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.

[0080] The term “C α~β As used herein, "alk" means an alkyl group containing a minimum of α carbon atoms and a maximum of β carbon atoms in a branched or linear linkage or any combination thereof, where α and β are integers. The designation C0alk indicates a direct linkage. 1~6 Examples of alk include: [ka] These include, but are not limited to, the following:

[0081] The term "halo" or "halogen" refers to a halogen atom selected from F, Cl, Br, or I.

[0082] As used herein, the term "C α~β "Halo-alk" means an alk group as defined herein, in which at least one hydrogen atom is replaced by a halo atom as defined herein. α~β The haloalk group is C 1~3 It is fluoroalk. A common C 1~3 An example of a fluoroalk group is -CF3.

[0083] As used herein, the term "cycloalkyl" means a cyclic non-aromatic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may contain one or more double bonds. Examples of cycloalkyl groups containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cyclobutadienyl. Common cycloalkyl groups are C 3~8 It is a cycloalkyl group.

[0084] As used herein, the term "aryl" refers to a cyclic aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Typical aryl groups are rings with 6 to 13 members.

[0085] The term “Embodiment” includes all subordinate embodiments, including those labeled “a,” “b,” “c,” and so on. For example, Embodiment 18 includes all subordinate embodiments 18a to 18p.

[0086] As used herein, the term "heteroaryl" means a cyclic aromatic hydrocarbon in which one or more carbon atoms of an aryl group are substituted with heteroatoms. When a heteroaryl group contains two or more heteroatoms, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, indolyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, naphthyridinyl, quinoxalinyl, isothiazolyl, and benzo[b]thienyl. A typical heteroaryl group is a 5- to 13-membered ring containing 1 to 4 heteroatoms. Heteroaryl groups that are 5- and 6-membered rings containing 1 to 3 heteroatoms are particularly common.

[0087] As used herein, the term "heteroatom" means an oxygen, nitrogen, or sulfur atom.

[0088] As used herein, the term "monocyclic ring" means a group having one monocyclic ring. The monocyclic ring can be a carbocyclic ring (all ring atoms are carbon) or a heterocyclic ring (the ring atoms include at least one heteroatom in addition to carbon atoms, such as 1, 2, or 3 heteroatoms such as N, O, or S). Examples of monocyclic rings include, but are not limited to, cyclobutyl, cyclopentyl, or cyclohexyl.

[0089] As used herein, the term "bicyclic ring" means a group having two fused rings. The bicyclic ring can be a carbocyclic ring (all ring atoms are carbon) or a heterocyclic ring (the ring atoms include at least one heteroatom in addition to carbon atoms, such as 1, 2, or 3 heteroatoms such as N, O, or S). Both rings can be aliphatic (e.g., decalin and norbornane), aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin). The bicyclic ring is (a) Spirocyclic compounds (the two rings share only one atom, which is usually a quaternary carbon spiro atom. Examples of spirocyclic compounds include,

Chem.

Chem.

Chem.

[0090] The term "saturated, partially saturated or unsaturated" includes substituents saturated with hydrogen, substituents not completely saturated with hydrogen and substituents partially saturated with hydrogen.

[0091] The term "pharmaceutically acceptable salt" refers to salts prepared by conventional means and is well known to those skilled in the art. "Pharmacologically 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).

[0092] The term "substituted" means that a hydrogen atom on a molecule or group is replaced by a group or atom other than hydrogen. 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 Alkenil, C 2~8 Alkinil, -SR x -S(=O)2R x , -C(=O)OR x -C(=O)R x These are listed, and each R x These are, independently, hydrogen or C 1~8 It is alkyl. The substituent is -NR x R x When R x It is recognized that a group can be bonded to a nitrogen atom to form a ring. A group or atom that substitutes a hydrogen atom is also called a substituent.

[0093] Any particular molecule or group may have one or more substituents depending on the number of hydrogen atoms that can be substituted.

[0094] The term "unsubstituted" refers to a hydrogen atom on a molecule or group.

[0095] The symbol "-" represents a covalent bond and can be used to indicate a bond to another group in a radical group. In chemical structures, the symbol is commonly used to represent a methyl group in a molecule.

[0096] The term "leaving group" generally refers to a group that can be readily substituted 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.

[0097] The term "protecting group" generally refers to a group well known in the art that is used to protect selected reactive groups, such as carboxy, amino, hydroxy, and mercapto, from undesirable reactions such as nucleophilic, electrophilic, oxidation, and reduction. 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 cycloalkenyl, alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, and silyl. Examples of aralkyl groups include, but are not limited to, halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, and acyl, as well as benzyl, ortho-methylbenzyl, trityl, and benzhydryl, which can be optionally substituted with 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 include, but are not limited to, cyclohexenylmethyl and have 6 to 10 carbon atoms. Suitable acyl, alkoxycarbonyl, and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, and phthaloyl. A mixture of protecting groups can be used to protect the same amino group; 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, phthalimidyl, succinimidyl, and maleimidyl, and these heterocyclic groups may further include adjacent aryl and cycloalkyl rings. In addition, heterocyclic groups may be monosubstituted, disubstituted, or trisubstituted, such as nitrophthalimidyl. The amino group 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.

[0098] 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.

[0099] 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 physiological processes in vivo, such as hydrolysis and metabolism, to become the compounds of the present invention after administration to a patient. The suitability and methods involved in the preparation and use of prodrugs are well known to those skilled in the art. For a general discussion of prodrugs including esters, see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of masked carboxylate anions include various esters such as alkyl (e.g., methyl, ethyl), cycloalkyl (e.g., cyclohexyl), aralkyl (e.g., benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (e.g., pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl-substituted derivatives that are cleaved by esterases that release free drugs and formaldehyde in the body (Bundgaard J. Med. Chem. 2503 (1989)). Furthermore, drugs containing acidic NH groups, such as imidazoles, imides, and indoles, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups have been masked as esters and ethers. European Patent No. 039,051 (Sloan and Little, 4 / 11 / 81) discloses Mannich base hydroxamic acid prodrugs, their preparation and use.

[0100] The term "therapeutic dose" means the amount of a compound that causes one or more symptoms of a particular disease or condition to go into remission, be reduced, or be eliminated, or the amount of a compound that prevents or delays the onset of one of several symptoms of a particular disease or condition.

[0101] The term "patient" means animals such as dogs, cats, cows, horses, sheep, and humans. A particular patient is a mammal. The term "patient" includes both males and females.

[0102] The term "pharmaceutically acceptable" means that the substance being referred to (e.g., a compound of formula (I), or a salt of a compound of formula (I), a formulation containing a compound of formula (I), or a particular excipient) is suitable for administration to a patient.

[0103] The terms "treating", "treat", or "treatment" etc. include prophylactic (e.g., preventive) treatment and palliative treatment.

[0104] The term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other component other than the active ingredient (API), and these are typically included for formulation and / or administration to a patient.

[0105] The compounds of the present invention are administered to a patient in a therapeutically effective amount. This compound can be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, this compound or composition can be administered all at once, for example, by bolus injection, or can be administered multiple times, for example, by a series of tablets, or can be delivered substantially uniformly over a period of time, for example, using transdermal delivery. It should also be noted that the dosage of this compound can be varied over time.

[0106] 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 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 others may be administered by injection or orally as a syrup. All combinations, delivery methods, and administration sequences are contemplated.

[0107] The compounds of the present invention may be used in the manufacture of pharmaceuticals for the treatment of diseases and / or conditions mediated by NaV 1.7, such as pain, chronic cough, or itching.

[0108] Pain is usually divided into two main types based on its duration: chronic 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 pain of unknown cause, which is pain without an identified cause. An example of pain of unknown cause is fibromyalgia.

[0109] 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.

[0110] Another type of pain is neuropathic pain. Neuropathic pain is pain caused by a disorder or disease that affects a part of the nervous system. Phantom limb pain is a type of neuropathic pain. In phantom limb pain, the body 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.

[0111] In one embodiment of a therapeutic 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, 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 signs of NaV 1.7 inhibitor use 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, depressive state (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), arrhythmia 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)).

[0112] 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 nonvascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorder, inflammatory eye disorder, inflammatory or unstable bladder disorder, psoriasis, skin diseases due to inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, and diabetic neuropathy. The present invention relates to a method for treating pain, causalgia, sympathetic-dependent pain, afferent blockade pain syndrome, asthma, epithelial tissue injury or dysfunction, herpes simplex, visceral motility disorders in the respiratory, genitourinary, gastrointestinal, or vascular regions, wounds, burns, allergic skin reactions, itching, vitiligo, general gastrointestinal disorders, gastric ulcers, 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. A preferred type of pain to be treated is chronic neuropathic pain. Another preferred type of pain to be treated is chronic inflammatory pain.

[0113] In another aspect of the present invention, the compounds of the present invention may be used in combination with other compounds used to treat pain. Examples of such other compounds include, but are not limited to, aspirin, celecoxib, hydrocodone, oxycodone, codeine, fentanyl, ibuprofen, ketoprofen, naproxen, acetaminophen, gabapentin, and pregabalin. Examples of classes of pharmaceuticals containing compounds that may be used in combination with the compounds of the present invention include nonsteroidal anti-inflammatory drugs (NSAIDS), steroid compounds, cyclooxygenase inhibitors, and opioid analgesics.

[0114] The compounds of the present invention may also be used to treat diabetes, obesity, and / or to promote weight loss.

[0115] The compounds of the present invention may be used in combination with other pharmaceutically active compounds. The term "pharmaceutically active compounds" may include biological products such as proteins, antibodies, and peptide bodies.

[0116] Since one aspect of the present invention aims 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: a compound of the present invention and a second pharmaceutical compound. The kit includes a container for containing 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. This kit configuration is particularly advantageous when these separate components are administered, preferably 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.

[0117] An 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, and the like). 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 depression is formed in the plastic foil. This depression has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in this depression, and the relatively rigid sheet seals the plastic foil with the foil side opposite to the direction in which the depression was formed. As a result, the tablet or capsule is sealed within the depression between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablet or capsule can be removed from the blister pack by manually applying pressure to the depression, thereby forming an opening in the sheet at the location of the depression. The tablet or capsule can then be removed through the opening.

[0118] It may be desirable to include a memory aid in numerical form on the kit (for example, next to the tablets or capsules) (the numbers correspond to the number of days in 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 a 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.

[0119] 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, for example, a battery-powered microchip memory with a liquid crystal readout or audible reminder signal that reads the date the last daily dose was taken and / or reminds the patient of the date the next dose should be taken.

[0120] The compounds of the present invention and other pharmaceutically active compounds may be administered to a patient as needed by oral, rectal, parenteral (e.g., intravenous, intramuscular, or subcutaneous), intracisional, intravaginal, intraperitoneal, intravesical, topical administration (e.g., powder, ointment, or infusion), or oral or nasal spray. All methods used by those skilled in the art for administering pharmaceutically active agents are intended.

[0121] 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.

[0122] These compositions may also contain adjuvants 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 (e.g., sugars, sodium chloride). Sustained absorption of the injectable pharmaceutical composition can be achieved by using absorption-delaying agents (e.g., aluminum monostearate and gelatin).

[0123] Examples of solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound may be at least one inert conventional additive (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 acacia); (c) humectants (e.g., glycerol); (d) disintegrants (e.g., agar, calcium carbonate, potato methionine). (e) Pun or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) dissolution retarders (e.g., paraffin); (g) absorption enhancers (e.g., quaternary ammonium compounds); (g) wetting agents (e.g., cetyl alcohol and glycerol monostearate); (h) adsorbents (e.g., kaolin and bentonite); and (i) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate), or mixtures thereof, which may be mixed with the pharmacopoeia. In the case of capsules and tablets, the dosage form may also contain buffers.

[0124] Similar 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.

[0125] 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 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, optionally containing one or more of the above excipients.

[0126] 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 (e.g., 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.

[0127] In addition to such inert diluents, the composition may also contain adjuvants 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 and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or mixtures thereof.

[0128] A composition for rectal administration is a preferred suppository that can be prepared by mixing the compound of the present disclosure with a suitable non-irritating additive 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.

[0129] Dosage forms for topical administration of the compounds of the present invention include ointments, powders, sprays, and inhalants. The active compound or 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.

[0130] 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 severity of the condition or disease being treated, and the pharmacological activity of the administered compound.

[0131] 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 acid form with a suitable organic or inorganic acid separately and isolating the salt thus produced. 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).

[0132] 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.

[0133] 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- 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.

[0134] 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. Discussions 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.

[0135] For example, if the compound of the present invention contains a carboxylic acid functional group, the prodrug is (C1-C8 alkyl, (C2-C12) alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4-9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having 5-10 carbon atoms, alkoxycarbonyloxymethyl having 3-6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4-7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5-8 carbon atoms, N having 3-9 carbon atoms This may include esters formed by substitution with groups such as -(alkoxycarbonyl)aminomethyl, 1-(N-(alkoxycarbonyl)aminomethyl) having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4-yl, di-N,N-(C1~C2)alkylamino(C2~C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1~C2)alkyl, N,N-di(C1~C2)alkylcarbamoyl-(C1~C2)alkyl, and piperidino-, pyrrolidino-, or morpholino-(C2~C3)alkyl.

[0136] Similarly, if the compound of the present invention contains an alcohol functional group, the prodrug may be formed by substituting 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).

[0137] In addition, if the compound of the present invention contains a sulfonamide moiety, the prodrug can be formed by substituting the sulfonamide N(H) with a group such as -CH2P(O)(O(C1~C6)alkyl)2 or -CH2OC(O)(C1~C6)alkyl.

[0138] The compounds of the present invention also include tautomerized forms of prodrugs.

[0139] The compounds of the present invention may have chiral or asymmetric centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds and mixtures thereof, including racemic mixtures, are intended to form part of the present invention. In addition, the present invention intends all geometric and positional isomers. For example, if a compound contains a double bond or a disubstituted cycloalkyl group, both cis and trans isomers (unless a specific isomer is specified), as well as mixtures, are intended. In disubstituted cycloalkyl-containing compounds, cis and trans isomers refer to the relative positional relationships of the substitutions. for example: [ka] (A) represents the trans-cyclobutyl isomer because the -CF3 group is facing upwards while the -CH3 group is facing downwards, while (B) represents the cis-cyclobutyl isomer because both the -CF3 and -CH3 groups are facing downwards.

[0140] 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).

[0141] Compounds of general formula (I) may 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. Atropisomers do not depend on the presence of chiral elements such as asymmetric 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 of step 1 having the structure shown below, can be separated into a pair of atropisomers P and M via a chiral column: [ka]

[0142] 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.

[0143] 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]

[0144] Those skilled in the art will recognize that the names and structures of 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.

[0145] This disclosure is also intended to encompass compounds synthesized in vitro using laboratory methods, such as those well known to synthetic chemists; or compounds synthesized 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.

[0146] The present invention also includes isotope-labeled compounds, which are identical to those enumerated herein, except that one or more atoms are replaced by 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.

[0147] 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 Products incorporating radioactive isotopes such as 13C are useful for drug and / or substrate tissue distribution assays. Tritiated isotopes (i.e., 3 H isotopes and carbon-14 isotopes (i.e.) 14 14C 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 lead to certain therapeutic benefits resulting from higher metabolic stability, such as an increased in vivo half-life or a reduced dosage requirement, and may therefore be preferable. The isotope-labeled compounds of the present invention can generally be prepared by replacing non-isotopically labeled reagents with readily available isotope-labeling reagents.

[0148] 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.

[0149] All patents and other publications cited herein are incorporated herein by reference as a whole.

[0150] The following embodiments illustrate specific examples of the present invention. These embodiments are representative and are not intended to limit the scope of the claims in any way. [Examples]

[0151] When percentage (%) is used in relation to liquids, it is recognized as a percentage by volume relative to the solution. When used with solids, it is a percentage relative to the solid composition. Materials obtained from private manufacturers are 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 over 2.0 minutes at 2.0 mL / min) (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 on 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) of low magnetic field from tetramethylsilane (TMS) or other internal standards in a specified appropriate solvent. The data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quadruplet, br=broad, m=multilet), coupling constant, and number of protons. Low-resolution mass spectral (MS) data were determined on an Agilent 1100 series (Agilent Technologies, Santa Clara, CA) LC / MS with UV detection at 254 nm and 215 nm and low-resonance electrospray mode (ESI).

[0152] The following abbreviations may be used in this specification.

[0153] 2-PrOH isopropanol AgOTf Silver(I) Trifluoromethanesulfonate AIBN Azobisisobutyronitrile aq. Water-based Bu butyl ca. approx. Cm (centimeter) 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 HPLC (High-Pressure Liquid Chromatography) IPA 2-propanol Kilogram L (liters) LCMS (Liquid Chromatography Mass Spectrometry) LHMDS Lithium Hexamethyl Disilazide M molar concentration Mass divided by m / z charge Me methyl MeOH methanol Me-THF (methyltetrahydrofuran) Mg milligrams MHz (megahertz) Minutes mL or ml (milliliter) Mmol (millimole) Mol MTBE methyl tert-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 Rac Race Semi 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 percentage) XantPhos 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene XtalFluor-M Difluoro(morpholino)sulfonium tetrafluoroborate

[0154] 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 below herein. 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 June 12, 2014, the specification of which is incorporated herein by reference in whole.

[0155] In addition, the inventors have developed a photochemical atrop-selective ring closure that forms an N-arylquinolinone compound. Specifically, P-atrop isomer compound 3 is selectively formed in the photochemical reaction of the present invention. A general description of the photochemical step of the present invention is given below. [ka]

[0156] The reaction relies on UV or near-UV light to excite olefin 1; R is a halo or group. [ka] And; and R 1 It is a C1-C6 alkyl group; and it induces cis-trans isomerization to transiently form 2; and each R and R 1 It is as defined above. Preferably, R 1 is ethyl. Next, cisolefin 2 can be activated with chiral acid (S)-TRIP to form a ring-closed quinolinone 3 asymmetrically, where R is as defined above. Preferably, R is Br or [ka] The selection of chiral phosphoric acid revealed that (S)-TRIP is the preferred chiral acid. The preferred organic solvent is dichloromethane. The photochemical reaction has been prepared to 1 g in a batch reactor and demonstrated in a small photochemical flow reactor.

[0157] This photochemical process can operate well without the presence of bulky rotational barrier substituents such as tert-butyl groups in the starting materials. Rather, this novel photochemical process was demonstrated in the presence of much smaller methoxy groups in the starting materials. Mild reaction conditions further enable compounds with low rotational barriers that will be prepared in a stereoselective manner.

[0158] 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 below herein. These compounds, and others provided by the present invention, can also be prepared using the methods described in PCT / U.S. Patent Application Publication No. 2014 / 042055, filed on 18 December 2014, or PCT / U.S. Patent Application Publication No. 2016 / 067617, filed on 19 December 2016, which is incorporated herein by reference in whole.

[0159] Intermediate A: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] [ka]

[0160] Step 1: 4-Bromo-2-iodoaniline To a solution of 4-bromo-aniline (500 g, 2.90 mol) in cyclohexane (2.5 L), iodine (368 g, 1.45 mol) was added, and the mixture was heated at 50°C. After 30 minutes, the reaction mixture became homogenized, and 30% aqueous hydrogen peroxide (250 mL) was added to the reaction mixture. The reaction was heated at 50°C for 4 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (5.0 L), and washed with aqueous sodium sulfite solution (2.5 kg in 4.0 L). The organic layer was washed with water (3.0 L) and brine (3.0 L), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the initial product, which 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%) as a grayish-white solid. TLC solvent system: 100% hexane. Product R 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).

[0161] Step 2: (E)-3-(2-amino-5-bromophenyl)ethyl acrylate To a solution of 4-bromo-2-iodoaniline (750 g, 2.51 mol) in DMF (5.0 L), ethyl acrylate (277 g, 2.76 mol) and sodium bicarbonate (680 g, 6.29 mol) were added. The reaction mixture was degassed under nitrogen for 20 minutes, and then palladium acetate (28.8 g, 128.27 mmol) 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 residue, which was purified by column chromatography (silica gel; mesh size 60-120, elution 0-20% ethyl acetate in hexane) to obtain 3-(2-amino-5-bromophenyl)acrylate(E)-ethyl (620 g, 77%) as a yellow solid. TLC solvent system: 20% ethyl acetate in hexane. f :0.4. MS (ESI, cation) m / z; 270.2 (M+1). 1 ¹H 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=8.6Hz, 1H), 6.43 (d, J=8.6Hz, 1H), 5.81 (s, 2H), 4.20 (q, J=7.2Hz, 2H), 1.27 (t, J=7.2Hz, 3H). Different esters can be obtained by using other acrylate salts instead of ethyl acrylate. For example, methyl acrylate, propyl acrylate, butyl acrylate, and others can be used instead of ethyl acrylate.

[0162] Step 3: (E)-3-(2-amino-5-(benzylthio)phenyl)ethyl acrylate To a solution of ethyl 3-(2-amino-5-bromophenyl)acrylate (E) (620 g, 2.29 mol) 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 under nitrogen for 20 minutes. XantPhos (92.9 g, 106 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (84 g, 91.0 mmol) were added to the reaction mixture. The mixture was purged under 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) 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 initial product, which was purified by chromatography (silica gel; mesh size 60-120, elution 0-40% ethyl acetate and petroleum ether) to obtain 3-(2-amino-5-(benzylthio)phenyl)acrylate(E)-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).

[0163] 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) in DCM (5.0 L), silver trifluoromethanesulfonate (686.0 g, 2.68 mol) was added, and the reaction mixture was stirred for 20 minutes. Iodine (678.0 g, 2.68 mol) was added to the reaction mixture, 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 initial product, which 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. 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).

[0164] Step 5: (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)ethyl acrylate To a solution of 3-(2-amino-5-(benzylthio)phenyl)acrylate(E)-ethyl (300 g, 958.1 mmol) and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (348.0 g, 1051.6 mmol) in toluene (2.5 L), Cs2CO3 (468 g, 1436.3 mmol) was added, and the mixture was degassed under nitrogen for 20 minutes. Pd2(dba)3 (35 g, 38.2 mmol) and XantPhos (44.6 g, 76.4 mmol) 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 initial product, which was purified by stirring with 5% ethyl acetate in hexane (3.0 L) for 30 minutes and filtered to obtain 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (E)-ethyl (350 g, 71%) as a yellow solid. TLC solvent system: 30% ethyl acetate in hexane. R of the product f :0.5. MS (ESI, cation) m / z; 516.2 (M+1). 1 1H NMR (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.

[0165] Step 6: 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinoline-2(1H)-one To a solution of 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate(E)-ethyl (250.0 g, 484.0 mmol) in methanol (2.5 L), tri(n-butyl)phosphine (50% solution in ethyl acetate, 48.9 mL, 96.8 mmol) 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 initial 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).

[0166] 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) 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) 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) in acetonitrile (200 mL) was added over 5 minutes, followed by the addition of NEt3 (307.7 mL, 2.12 mol) 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 as a white solid 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (190 g, 60%). 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 ppm 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).

[0167] Step 9: 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-perfluorophenyl Racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (76.90 g) was separated via Chiralcel OJ column (40% MeOH / 60% CO2) to obtain 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-perfluorophenyl and 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (M)-perfluorophenyl as pale yellow, villi-like solids. Data for peak 1: m / z (ESI) 594.0 (M+H) + Data for Peak 2: m / z (ESI) 594.0 (M+H) + .

[0168] Step 10: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A solution of 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-perfluorophenyl (6.00 g, 10.10 mmol) and 3-aminoisoxazole (0.821 mL, 11.11 mmol) in THF (200 mL) in a 250 mL round-bottom flask was cooled to 0°C, and lithium bis(trimethylsilyl)amide (1.0 M 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% Â / heptane gradient) to obtain an additional 1.36 g of the product as a pale yellow, villi-like solid. A total amount 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) + .

[0169] Intermediate B: 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] A solution of 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (9.45 g, 15.90 mmol) and 3-aminoisoxazole (1.292 mL, 17.49 mmol) in THF (159 mL) in a 500 mL round-bottom flask was cooled to 0°C, and lithium bis(trimethylsilyl)amide (1.0 M in THF, 33.4 mL, 33.4 mmol) was added dropwise. After stirring the solution at 0°C for 1 hour, it was quenched with 1N HCl at 0°C and extracted three times with ELISA. The organic extracts were combined, dried over MgSO4, filtered, and concentrated to obtain a pale yellowish-brown residue, yielding 3.81 g of product. The filtrate contained the product obtained by LC-MS and was therefore concentrated under vacuum and purified via column chromatography (120 g silica gel, 20%-80% siRNA / heptane gradient) to obtain an additional 1.01 g of product. 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (4.82 g, 9.75 mmol, yield 61.3%) was obtained as a grayish-white solid. m / z(ESI)494.1(M+H) + .

[0170] Intermediate C: 1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0171] Step 1: 3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl)acrylate(E)-ethyl A round-bottom flask was packed with ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (E)-(2.39 g, 7.63 mmol), 4-bromo-1-iodo-2-methoxybenzene (2.86 g, 9.15 mmol), XantPhos (0.221 g, 0.381 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.175 g, 0.191 mmol), and cesium carbonate (4.97 g, 15.25 mmol) was added. A reflux condenser was attached, and the flask was lowered into a 110°C hot bath. After 2 hours, the additional portion of cesium carbonate (1.4 g) was added, and the bath temperature was raised to 120°C. The mixture was heated for a further 2 hours, then cooled to room temperature, diluted with ethyl phosphate, and filtered through ethyl phosphate into a CELITE filter. The filtrate was concentrated. The oily residue was dissolved in 2-PrOH. The mixture was concentrated to obtain a yellow solid along with some oily solid present. The mixture was dissolved in 2-PrOH to obtain a suspension, which was stirred for 16 hours. The mixture was filtered, and the filtered solid was washed with 2-PrOH(3x). The recovered solid was dried on a filter under N2 flow for 15 minutes to obtain 3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl)acrylate(E)-ethyl (3.136 g, 6.29 mmol, yield 83%) as a golden-yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.72(d,J=16.0Hz,1H),7.68(d,J=2.2Hz,1H),7.47(s,1H),7.37-7.19(m,6H),7.13(d,J=2.2Hz,1H),6.94(dd,J=2.2,8.4Hz,1H),6.86(d,J= 8.5Hz,1H),6.55(s,1H),6.52(d,J=7.7Hz,1H),4.24(s,2H),4.15(q,J=7.1Hz,2H),3.82(s,3H),1.23(t,J=7.1Hz,3H).m / z(ESI)498.0(M+H) + .

[0172] Step 2: 6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)quinoline-2(1H)-one A round-bottom flask was packed with 3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl)acrylate(E)-ethyl (3.13 g, 6.28 mmol) and MeOH (31.4 mL) to obtain a yellow suspension. Sodium methoxide (25 wt% of MeOH, 0.271 mL, 1.256 mmol) was added. A reflux condenser was attached, and the flask was lowered into a 75°C hot bath. The bath was rapidly increased to approximately 80-85°C, but was returned to 70-75°C after 30 minutes. The reaction mixture was stirred for 16 hours, diluted with DCM, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 25-g silica gel loading column, 10-60% siRNA / heptane) to obtain 6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)quinoline-2(1H)-one (1.95 g, 4.31 mmol, yield 69%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.94(d,J=9.5Hz,1H),7.78(d,J=2.2Hz,1H),7.50(d,J=2.1Hz,1H),7.43-7.16(m,8H),6. 66(d,J=9.6Hz,1H),6.47(d,J=8.8Hz,1H),4.23(s,2H),3.69(s,3H).m / z(ESI)452.0(M+H) + .

[0173] Step 3: 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl A round-bottom flask was filled with 6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)quinoline-2(1H)-one (1.777 g, 3.93 mmol), acetonitrile (18.49 mL), acetic acid (0.693 mL), and water (0.462 mL) to obtain the solution. The flask was cooled in an ice-water bath for 10 minutes, after which 1,3-dichloro-5,5-dimethylimidazolidined-2,4-dione (0.813 g, 4.12 mmol) was added all at once. After 20 minutes, the remaining portion of 1,3-dichloro-5,5-dimethylimidazolidined-2,4-dione (0.813 g, 4.12 mmol) was added all at once. After another 20 minutes, 2,3,4,5,6-pentafluorophenol (1.085 g, 5.89 mmol) was added, and the mixture was stirred for 5 minutes. Triethylamine (2.190 mL, 15.71 mmol) was added dropwise over 30 minutes, and the mixture was then stirred for 20 minutes. The reaction mixture was diluted with water and extracted with DCM (3×). The combined organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 25-g silica gel loading column, 10-60% ethyl acetate / heptane). Perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (1.644 g, 2.85 mmol, yield 72.6%) was isolated as a white foam. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.59(d,J=2.2Hz,1H),8.24(d,J=9.6Hz,1H),7.95(dd,J=2.3,9.1Hz,1H),7.56(d,J=1.9H z,1H),7.44-7.26(m,2H),6.86(dd,J=9.4,13.7Hz,2H),3.72(s,3H).m / z(ESI)575.9(M+H) + .

[0174] Step 4: 1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A round-bottom flask was filled with 1.070 g, 1.857 mmol of 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl, 0.158 mL, 2.135 mmol of isoxazole-3-amine, and 12 mL of THF to obtain a clear solution. The flask was cooled in an ice-water bath for 10 minutes, and then lithium bis(trimethylsilyl)amide (1 M in THF, 3.90 mL, 3.90 mmol) was added dropwise. After 10 minutes, the mixture was diluted with ethyl acetate and washed with 1 N aqueous HCl solution. The aqueous layer was washed with ethyl acetate. The combined organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (50-g SNAP Ultra column, 25-g silica gel loading column, 0-5% MeOH / DCM) to obtain 1-(4-bromo-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.867g) as a yellowish-brown foam with approximately 90% purity. m / z(ESI)476.1(M+H) + .

[0175] Step 5: (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide Racemic 1-(4-bromo-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (400 mg) was purified using a (S,S)Whelk-O, 2 × 15 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 60% isopropanol; flow rate: 80 mL / min. The first eluting peak was assigned to (M)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (150 mg). The second peak to elute was assigned to (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (154 mg). Data for peak 1: 1 H NMR(400MHz,acetonitrile-d3)δ ppm 8.65-8.94(m,1H),8.37(d,J=1.9Hz,1H),8.23(d,J=2.3Hz,1H),7.97(d,J=9.3Hz,1H),7.78(dd,J=8.9,2.3Hz,1H),7.43(d,J=2.1Hz,1H) ),7.34(dd,J=8.3,2.1Hz,1H),7.16(d,J=8.3Hz,1H),6.70-6.80(m,2H),6.45(d,J=1.9Hz,1H),3.69(s,3H).m / z(ESI,cation)476.0(M+H) + Data regarding Peak 2: 1 H NMR(400MHz,acetonitrile-d3)δ ppm 8.72-8.87(m,1H),8.37(d,J=1.7Hz,1H),8.23(d,J=2.1Hz,1H),7.97(d,J=9.5Hz,1H),7.78(dd,J=9.0,2.2Hz,1H),7.43(d,J=2.1Hz,1H) ),7.34(dd,J=8.3,1.9Hz,1H),7.16(d,J=8.3Hz,1H),6.69-6.80(m,2H),6.45(d,J=1.9Hz,1H),3.69(s,3H).m / z(ESI,cation)476.0(M+H) + .

[0176] Intermediate D: N-(4-methoxybenzyl)isoxazole-3-amine [ka] In a 20 L round-bottom flask, isoxazole-3-amine (150 g, 1784 mmol) and 4-methoxybenzaldehyde (274 g, 2016 mmol) were added to methanol (9000 mL), water (150 mL), and acetic acid (101 mL), and the mixture was stirred at room temperature for 15 minutes. Next, molybdenum dichloride dioxide (17.74 g, 89 mmol) and phenylsilane (193 g, 1784 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mass was concentrated, diluted with dichloromethane (5000 mL), and washed with saturated aqueous solution of NaHCO3 (2000 mL). The organic layer was washed with water (2000 mL) and dried over Na2SO4. The solution was filtered and concentrated under vacuum to obtain the first product as an orange solid. The initial product was adsorbed onto a silica gel plug and purified by column chromatography (silica gel, 60-120 mesh) eluting under a gradient of 0%-30% siRNA in hexane to obtain N-(4-methoxybenzyl)isoxazole-3-amine (272 g, 1332 mmol, 75% yield) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.36(d,J=1.8Hz,1H),7.16-7.37(m,2H),6.71-6.97(m,2H),6.56(t,J=6.0Hz,1H),5 .97(d,J=1.8Hz,1H),4.18(d,J=6.0Hz,2H),3.73(s,3H).m / z(ESI,cation)205.1(M+H) + .

[0177] Intermediate E: (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 packed with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-perfluorophenyl (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 in THF, 21.0 mL, 21.0 mmol) was added dropwise to the stirred reaction mixture via syringe over 10 minutes. 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 ppm 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) + .

[0178] Intermediate F: (P)-1-(5-fluoro-2-methoxy-4-vinylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] The vial was filled with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.300 g, 0.607 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.056 g, 0.061 mmol), 2-(dicyclohexylphosphino)-2',4',6'-tri-i-propyl-1,1'-biphenyl (0.058 g, 0.121 mmol), and potassium carbonate (0.419 g, 3.03 mmol). DMSO (3.0 mL) and dibutyl vinylboronate (0.40 mL, 1.8 mmol) were added. The reaction mixture was heated to 100°C and stirred for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with 1N HCl solution. The aqueous layer was extracted with ethyl acetate, the combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (RediSep Gold 40g column, gradient elution 0-50% [3:1 siRNA / EtOH]:heptane) to obtain (P)-1-(5-fluoro-2-methoxy-4-vinylphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.206 g, 0.467 mmol, yield 77%) as a pale yellow solid. m / z (ESI, cation) 442.0 (M+H) + .

[0179] Intermediate G: 1-bromo-2-chloro-4-iodo-5-methoxybenzene [ka] To a solution of 2-bromo-1-chloro-4-methoxybenzene (500 g, 2258 mmol) in dichloromethane (7500 mL), silver(I) trifluoromethanesulfonate (638 g, 2483 mmol) was added under nitrogen conditions at ambient temperature. The reaction mixture was stirred at ambient temperature for 20 minutes, and iodine (630 g, 2483 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 hours. Next, the mixture was diluted with DCM (4500 mL) and filtered through CELITE. The CELITE bed was washed with DCM (2 × 1.0 L). The filtrate was washed with 20% sodium thiosulfate aqueous solution (5.0 L) and saturated sodium bicarbonate aqueous solution (5.0 L). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the initial product, which was purified by column chromatography (silica gel; mesh size 60-120, elution 0-5% ethyl acetate and petroleum ether) to obtain 1-bromo-2-chloro-4-iodo-5-methoxybenzene (610 g, 1756 mmol, yield 78%) as a grayish-white solid. 1 H NMR(400MHz,CDCl3)δ ppm 7.83(s,1H),7.03(s,1H),3.89(s,3H).

[0180] Intermediate H:N-(4-methoxybenzyl)pyrimidine-2-amine [ka] In a 50 mL microwave vial, the compounds were successively dissolved in EtOH (20 mL), 2-chloropyrimidine (1.5 g, 13.10 mmol), (4-methoxyphenyl)methaneamine (2.15 g, 15.72 mmol), and triethylamine (2.65 g, 26.2 mmol). The reaction tube was sealed and irradiated for 1 hour in the cavity of a microwave reactor at a maximum power of 80 W and a ceiling temperature of 120 °C. After cooling the reaction mixture with an airflow for 15 minutes, it was diluted with water (100 mL), extracted with CH₂Cl₂ (2 × 150 mL), and dried over Na₂SO₄. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic extract was washed with saturated aqueous solution of NaCl (1 × 50 mL) and dried over Na₂SO₄. The solution was filtered and concentrated under vacuum to obtain the initial product as a yellow oil. The initial product was adsorbed onto a silica gel plug and purified by chromatography via a Redi-Sep pre-packed silica gel column (12g) eluting under a 20%-30% siRNA gradient in hexane to obtain N-(4-methoxybenzyl)pyrimidine-2-amine (1.5g, 6.97 mmol, 53% yield) as a grayish-white solid. m / z(ESI)216.2(M+H) + .

[0181] Intermediate I: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka]

[0182] Step 1: Acrylic acid (E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl) To a solution of ethyl (E)-3-(2-amino-5-(benzylthio)phenyl)acrylate (175 g, 555.0 mmol) and 1-bromo-2-chloro-4-iodo-5-methoxybenzene (231.3 g, 666.2 mmol) in toluene (1.5 L), cesium carbonate (357.5 g, 1100 mmol) was added, and the mixture was degassed under nitrogen for 20 minutes. Tris(dibenzylideneacetone)dipalladium(0) (12.5 g, 13.0 mmol) and XantPhos (15.8 g, 27.2 mmol) 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 initial product, which was purified by stirring with 5% ethyl acetate in hexane (1.5 L) for 30 minutes. The product was then filtered to obtain (E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)ethyl acrylate (290 g, 85% yield) as a yellow solid. m / z(ESI) 532.2(M+H) + .

[0183] 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) in methanol (3.0 L), tri(n-butyl)phosphine (50% solution in ethyl acetate, 56.2 mL, 1126 mmol) 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 initial product, which was purified by stirring with 5% ethyl acetate in hexane (1.0 mL), filtered, and yielded 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) + .

[0184] Step 3: 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-chloro-2-methoxyphenyl)quinoline-2(1H)-one (400.0 g, 824.9 mmol) in acetonitrile (2.5 L) and THF (2.5 L), acetic acid (1.0 L) and water (700 mL) were added. The resulting mixture was cooled to 0°C, and 1,3-dichloro-5,5-dimethylimidazolidined-2,4-dione (292 g, 1484.8 mmol) 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) in acetonitrile (500 mL) was added over 5 minutes, followed by the addition of triethylamine (477 mL, 3299 mmol) 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 the mixture was 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. This was purified by stirring with isopropyl alcohol and 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) + .

[0185] Step 4: 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-perfluorophenyl and 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (M)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (156 g, 255 mmol) was purified by chiral SFC chromatography ((S,S)Whelk-O, 45% isopropanol) to obtain 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-perfluorophenyl (72.66 g, yield 93%) and 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (M)-perfluorophenyl (76.13 g, yield 98%) as white solids. m / z(ESI)610.6(M+H) + .

[0186] Step 5: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide N-(4-methoxybenzyl)pyrimidine-2-amine (9.72 g, 45.1 mmol) and 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-perfluorophenyl (25.06 g, 41.0 mmol) were added to a 500 mL flask. The flask was flushed with a stream of N2, followed by the addition of tetrahydrofuran (136 mL), and the reaction mixture was cooled to 2°C under N2. Sodium tert-pentoxide (30% solution in THF, 197 mL, 492 mmol) was added over 30 minutes via an addition funnel while maintaining an internal temperature of approximately 5°C, and the pale yellow solution turned orange upon addition. The reaction mixture was stirred in an ice bath for 30 minutes. Next, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl and diluted with ethyl acetate. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic materials were dried over Na2SO4, filtered, and evaporated. IPA was added, and a white precipitate formed. The solvent was evaporated to approximately 100 mL, followed by the addition of IPA, and the reaction mixture was stirred for 18 hours. The slurry was filtered, and the solid was washed with IPA. The solid was dissolved in 150 mL of MTBE and heated at 40°C for 2 hours. The slurry was cooled to ambient temperature, filtered, and a white solid was obtained. The impure material was dissolved in 500 mL of 10% MeOH / DCM and stirred with 500 mL of saturated NaHCO3 aqueous solution for 30 minutes. The layers were separated, and the aqueous layer was extracted twice with 10% MeOH / DCM. The combined organic layer was dried and evaporated. The filtrates from IPA and MTBE titrations were combined and loaded onto a 25 g silica cartridge for purification by column chromatography (RediSep Rf Gold 120 g column, gradient elution in heptane with 10% dichloromethane additive, 10%-50% 3:1 siRNA:EtOH). The pure product from the column and the product from the NaHCO3 extraction were combined to obtain (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (16.94 g, 26.4 mmol, yield 64%) as a pale yellow foam. 1H NMR(500MHz,DMSO-d6)δ ppm 8.58(d,J=4.9Hz,2H),8.39(d,J=2.1Hz,1H),8.13(d,J=9.6Hz,1H),7.96(d d,J=9.1,2.3Hz,1H),7.76(s,1H),7.73(s,1H),7.29(d,J=8.8Hz,2H),7.13( t,J=4.9Hz,1H),6.87(d,J=8.8Hz,2H),6.78(d,J=9.6Hz,1H),6.74(d,J=9. 1Hz,1H),5.36(s,2H),3.72(s,3H),3.71(s,3H).m / z(ESI,cation)642.8(M+H) + .

[0187] Intermediate J: N-(4-methoxybenzyl)pyridazine-3-amine [ka] In a 25 mL round-bottom flask, 1.00 g (7.34 mmol) of 4-methoxybenzaldehyde and 0.838 g (8.81 mmol) of pyridazine-3-amine were added in 10 mL of tetrahydrofuran. Next, 6.46 mL (22.03 mmol) of titanium(IV) isopropoxide was added, and the reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was then cooled to 0°C, and sodium borohydride (0.556 g (14.69 mmol) was added in small amounts. The reaction mixture was then stirred at 0°C for 2 hours. The reaction mixture was diluted with water (20 mL) and filtered. The filtrate was then extracted with dimethylammonium phosphate (3 × 50 mL). The organic extract was washed with saturated aqueous solution of NaCl (30 mL) and dried over Na₂SO₄. The solution was filtered and concentrated under vacuum to obtain the initial product as an orange oil. The initial product was adsorbed onto a silica gel plug and purified by chromatography via a Redi-Sep pre-packed silica gel column (40g) eluted with 0%-15% MeOH in CH2Cl2 to obtain N-(4-methoxybenzyl)pyridazine-3-amine (0.680g, 3.16 mmol, yield 43.0%) as a yellow solid. m / z(ESI, cation) 216.2(M+H) + .

[0188] Intermediate K: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazine-3-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] A 100 mL recovery flask containing (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (5.00 g, 8.41 mmol) and N-(4-methoxybenzyl)pyridazine-3-amine (1.902 g, 8.83 mmol) was flushed with nitrogen and subsequently packed with THF (34 mL). The solution was cooled to 0°C, and sodium tert-pentoxide (8.4 mL, 11.78 mmol, 1.4 M in THF) was slowly added. The pale yellow solution was stirred at 0°C for 15 minutes, and then volatile substances were removed under vacuum. Water was added, resulting in the formation of a white precipitate. This precipitate was isolated, dissolved in dichloromethane, and treated with heptane to form a white precipitate of (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (4.20 g, 6.71 mmol, yield 80%). m / z(ESI, cation) 625.0(M+H) + .

[0189] Intermediate L: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl [ka]

[0190] Step 1: 3-(5-(benzylthio)-2-((4-bromo-2-methoxy-5-methylphenyl)amino)phenyl)acrylate(E)-ethyl A round-bottom flask was filled with 3-(2-amino-5-(benzylthio)phenyl)acrylate(E)-ethyl (4.729 g, 15.09 mmol), 1-bromo-4-iodo-5-methoxy-2-methylbenzene (5.18 g, 15.84 mmol), XantPhos (0.437 g, 0.754 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.345 g, 0.377 mmol), and cesium carbonate (9.83 g, 30.2 mmol), and toluene (30 mL) was added. A reflux condenser was attached, and the mixture was heated to reflux. After 4 hours, the additional portions of tris(dibenzylideneacetone)dipalladium(0) (172 mg) and XantPhos (213 mg) were added. After 2 hours, an additional portion of cesium carbonate (approximately 2 g) and 1-bromo-4-iodo-5-methoxy-2-methylbenzene (600 mg) were added. After refluxing for a further 30 minutes, the mixture was cooled and filtered through CELITE. The filter pad was washed with ELISA (3×). The filtrate was concentrated. The residue was concentrated from MeOH and dissolved in MeOH. The resulting suspension was heated to a boil, followed by sonication and cooling to room temperature. The mixture was filtered, the recovered solid was washed with MeOH (3×), and dried under N2 flow for 48 hours to obtain 3-(5-(benzylthio)-2-((4-bromo-2-methoxy-5-methylphenyl)amino)phenyl)acrylate (E)-ethyl (5.21 g, 10.17 mmol, yield 67.4%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.75(d,J=15.9Hz,1H),7.66(d,J=2.1Hz,1H),7.42(s,1H),7.37-7.20(m,6H),7.14(s,1H),6.85(d,J=8.5Hz,1H),6.62(s,1H),6 .51(d,J=15.9Hz,1H),4.23(s,2H),4.15(q,J=7.0Hz,2H),3.78(s,3H),2.14(s,2H),1.23(t,J=7.1Hz,3H).m / z(ESI)512.2(M+H) + .

[0191] Step 2: 6-(benzylthio)-1-(4-bromo-2-methoxy-5-methylphenyl)quinoline-2(1H)-one A round-bottom flask was packed with 3-(5-(benzylthio)-2-((4-bromo-2-methoxy-5-methylphenyl)amino)phenyl)acrylate(E)-ethyl (5.12 g, 9.99 mmol) and MeOH (50.0 mL) to obtain a yellow suspension. Sodium methoxide (25 wt% of MeOH, 0.432 mL, 1.998 mmol) was added. A reflux condenser was attached, and the flask was lowered into a 70°C hot bath. After 1 hour, an additional portion of MeOH (25 mL) and sodium methoxide solution (approximately 0.85 mL) were added in sequence. After 7 hours, the mixture was cooled and concentrated under vacuum. The residue was purified by chromatography on silica gel (80-g, Redi-Sep column, 25-g silica gel loading column, loaded as a solution in MeOH-DCM, followed by elution with 25-75% ethyl / heptane containing 10% DCM). The fractions containing the product were combined and concentrated to obtain 6-(benzylthio)-1-(4-bromo-2-methoxy-5-methylphenyl)quinoline-2(1H)-one (4.233 g, 9.08 mmol, 91% yield) as a yellowish-brown solid. m / z(ESI)466.1(M+H) + .

[0192] Step 3: 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl A round-bottom flask was filled with 6-(benzylthio)-1-(4-bromo-2-methoxy-5-methylphenyl)quinoline-2(1H)-one (4.23 g, 9.07 mmol), DCM (71.1 mL), acetic acid (2.67 mL), and water (1.778 mL) to obtain a clear, pale brown solution. The flask was cooled in an ice-water bath for 10 minutes, after which 1,3-dichloro-5,5-dimethylimidazolidined-2,4-dione (3.66 g, 18.59 mmol) was added all at once. After 40 minutes, the additional oxidized portion (850 mg) was added. The mixture was stirred for a further 20 minutes, after which 2,3,4,5,6-pentafluorophenol (2.504 g, 13.60 mmol) and triethylamine (5.06 mL, 36.3 mmol) were added in order. After 20 minutes, the mixture was diluted with water. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (80 g, Redi-Sep Gold column, 25 g silica gel loading column, heptane with 10-60% Â1 / 10% DCM) to obtain 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (3.37 g, 5.71 mmol, yield 63%). m / z(ESI) 590.0(M+H) + .

[0193] Step 4: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (22.896 g, 38.79 mmol) was purified using a (S,S)Whelk-O, 5 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 50% dichloromethane; flow rate: 350 mL / min. The first eluting peak was assigned to (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (10.425 g). The second peak to elute was assigned to (M)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (10.76 g). Data for peak 1: m / z (ESI) 590.0 (M+H) + Data for Peak 2: m / z (ESI) 590.0 (M+H) + .

[0194] Intermediate M: N-(2,4-dimethoxybenzyl)isoxazole-3-amine [ka] To a solution of isoxazole-3-amine (100 g, 1190 mmol) in a mixture of methanol (6500 mL), acetic acid (67.0 mL), and water (100 mL), 2,4-dimethoxybenzaldehyde (223 g, 1340 mmol) was added under a nitrogen atmosphere at ambient temperature. The reaction mixture was stirred at ambient temperature for 15 minutes, and molybdenum dichloride dioxide (11.82 g, 59.5 mmol) was added, followed by phenylsilane (218 ml, 1784 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. Next, the reaction product was concentrated under reduced pressure. The residue was diluted with dichloromethane (5000 mL), washed with saturated aqueous solution of NaHCO3 (2 × 2000 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain an orange solid. The solid was purified by chromatography (60-120 mesh silica, gradient elution 0-30% siRNA:hexane) to obtain N-(2,4-dimethoxybenzyl)isoxazole-3-amine (170 g, 726 mmol, yield 61%).

[0195] Intermediate N:(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] A 250 mL round-bottom flask was sequentially filled with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (2.00 g, 3.37 mmol), tetrahydrofuran (16.8 mL), and N-(2,4-dimethoxybenzyl)isoxazole-3-amine (0.828 g, 3.53 mmol), and the resulting solution was cooled to 0°C. Next, lithium bis(trimethylsilyl)amide (3.70 mL, 3.70 mmol, 1.0 M in THF) was added dropwise to the stirred reaction mixture. After 15 minutes, aqueous HCl (1.0 M, 100 mL) and HCl (100 mL) were added to the reaction mixture, and the mixture was subsequently warmed to ambient temperature. The layers were separated, and the aqueous layer was extracted with HCl (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, gradient elution, 0-100% Â: heptane with 10% CH2Cl2 as co-eluate) to obtain (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.50 g, 2.33 mmol, yield 69%) as a white solid. m / z (ESI, cation) 644.0 (M+H) + .

[0196] Intermediate O: Racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl [ka]

[0197] 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 initial 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%) as a grayish-white solid. TLC solvent system: 100% hexane. 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).

[0198] 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 mixture 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 3-(2-amino-5-bromophenyl)acrylate(E)-ethyl (620 g, 77.0%) as a yellow solid. TLC solvent system: 20% ethyl acetate in hexane. 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).

[0199] [ka] Step 3: (E)-3-(2-amino-5-(benzylthio)phenyl)ethyl acrylate To a solution of ethyl 3-(2-amino-5-bromophenyl)acrylate (E) (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 under 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 initial product, which was purified by chromatography (silica gel; mesh size 60-120, elution 0-40% ethyl acetate and petroleum ether) to obtain 3-(2-amino-5-(benzylthio)phenyl)acrylate(E)-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).

[0200] [ka] 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 initial product, which 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. 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).

[0201] [ka] Step 5: (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)ethyl acrylate To a solution of 3-(2-amino-5-(benzylthio)phenyl)acrylate(E)-ethyl (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) in toluene (2.5 L), 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 initial product, which was purified by stirring with 5% ethyl acetate in hexane (3.0 L) for 30 minutes and filtered to obtain 350 g, 71% ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (E)-ethyl as a yellow solid. TLC solvent system: 30% ethyl acetate in hexane. 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.

[0202] [ka] Step 6: 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinoline-2(1H)-one To a solution of 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate(E)-ethyl (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 initial 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).

[0203] 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 equivalents, 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, followed by the addition of NEt3 (307.7 mL, 2.12 mol, 4.0 equivalents) 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 the mixture was 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 as a white solid racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (190 g, 60%). 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).

[0204] Intermediate P: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide Step 1: 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-perfluorophenyl Racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (see steps 7 and 8 of intermediate O above, 76.90 g) was separated via Chiralcel OJ column (40% MeOH / 60% CO2) to obtain 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-perfluorophenyl and 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (M)-perfluorophenyl as pale yellow, villi-like solids. Data for peak 1: m / z (ESI) 594.0 (M+H) + Data for Peak 2: m / z (ESI) 594.0 (M+H) + .

[0205] Step 2: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] A 250 mL round-bottom flask was packed with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-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 via syringe over 10 minutes. 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=2.0H z,1H),4.92(s,2H),3.73-3.69(m,6H),3.32(s,1H).m / z(ESI)615.1(M+H) + .

[0206] Examples Example 1: (P)-1-(4-(2,2-dimethylcyclopropyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] A 5 mL vial was filled with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (150 mg, 0.303 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane adduct (49.6 mg, 0.061 mmol), and (2,2-dimethylcyclopropyl)boronic acid (69.2 mg, 0.607 mmol). Next, 1,4-dioxane (3 mL) and an aqueous solution of sodium carbonate (1 mL, 1.9 M) were sequentially added to the reaction vessel via syringe. The vial was sealed with a PTFE-lined cap, and the resulting red mixture was aerated with nitrogen for 10 minutes. The reaction mixture was heated to 50°C. After 16 hours, the mixture was allowed to cool to ambient temperature, and 1 M HCl was carefully added, followed by siRNA. The layers were separated, and the aqueous layer was extracted with siRNA. The combined organic layers were concentrated to dryness. The brown residue was purified by reverse-phase HPLC using an XBridge Prep Shield RP18 19 × 100 mm column. The mobile phase was run under gradient elution; acetonitrile with 35–85% water / 0.1% trifluoroacetic acid; flow rate: 40 mL / min. This yielded (P)-1-(4-(2,2-dimethylcyclopropyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.029 g, 0.060 mmol, yield 20%) as a brown solid. 1H NMR(400MHz,DMSO-d6)δ ppm 11.65(s,1H),8.74(d,J=1.9Hz,1H),8.36(s,1H),8.15-8.27(m,1H),7.81 -7.88(m,1H),7.29(dd,J=8.6,1.1Hz,1H),6.94-7.04(m,1H),6.76-6.80( m,1H),6.67-6.73(m,1H),6.45(s,1H),3.65(s,3H),1.90-1.98(m,1H),1. 28(s,3H),1.05-1.18(m,1H),0.87-0.95(m,4H).m / z(ESI, anion)482.0(MH) + .

[0207] Example 2: (P)-1-(4-(2,2-dimethylcyclopropyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] A 5 mL vial was filled with (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (150 mg, 0.303 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(ii) dichloride dichloromethane adduct (51.4 mg, 0.063 mmol), and (2,2-dimethylcyclopropyl)boronic acid (71.8 mg, 0.630 mmol). Next, 1,4-dioxane (3 mL) and an aqueous solution of sodium carbonate (1 mL, 1.9 M) were sequentially added to the reaction vessel via syringe. The vial was sealed with a PTFE-lined cap, and the resulting red mixture was aerated with nitrogen for 10 minutes. The reaction mixture was heated to 50°C. After 16 hours, the mixture was allowed to cool to ambient temperature, and 1 M HCl was carefully added, followed by siRNA. The layers were separated, and the aqueous layer was extracted with siRNA. The combined organic layers were concentrated to dryness. The brown residue was purified by reverse-phase HPLC using an XBridge Prep Shield RP18 19 × 100 mm column. The mobile phase was run under gradient elution; acetonitrile with water / 0.1% trifluoroacetic acid; flow rate: 40 mL / min. This yielded (P)-1-(4-(2,2-dimethylcyclopropyl)-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.024 g, 0.052 mmol, yield 16%) as a brown solid. 1H NMR(400MHz,DMSO-d6)δ ppm 11.62(s,1H),8.72(d,J=1.9Hz,1H),8.34(d,J=2.3Hz,1H),8.18(d,J=9.7Hz,1H),7.82(dd,J=8.9,2. 1Hz,1H),7.14(d,J=7.9Hz,1H),7.04(dd,J=14.0,1.6Hz,1H),6.90(ddd,J=10.9,8.1,1.3Hz,1H),6.77 (d,J=9.7Hz,1H),6.67(d,J=8.9Hz,1H),6.44(d,J=1.9Hz,1H),3.65(s,3H),1.99(dd,J=8.2,6.1Hz,1H ),1.25(s,3H),0.96-1.03(m,1H),0.91(s,3H),0.85(dd,J=8.5,4.8Hz,1H).m / z(ESI, anion)464.0(MH) + .

[0208] Examples 3, 4, and 5: trans-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, and (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] The vials were filled with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (intermediate A) (0.200 g, 0.405 mmol), trans-6-methyl-2-[2-(trifluoromethyl)cyclopropyl]-1,3,6,2-dioxazabolocan-4,8-dione (0.322 g, 1.214 mmol), chloro-(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-t-butyl ether adduct (0.066 g, 0.081 mmol), and potassium carbonate (0.224 g, 1.618 mmol). 1,4-dioxane (1.5 mL) and water (0.5 mL) were added, the vial was flushed with argon, and the reaction mixture was heated at 130°C for 6 hours. Next, the reaction mixture was diluted with ethyl acetate and washed twice with 1N HCl solution. The aqueous layer was extracted with ethyl acetate, the combined organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (RediSep Gold 40 g column, gradient elution 0-75% [3:1 ethyl acetate / EtOH]:heptane) to obtain trans-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.072 g, 0.138 mmol, yield 34%) as a grayish-white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 11.52-11.84(m,1H),8.72(d,J=1.6Hz,1H),8.35(d,J=2.1Hz,1H),8.20(d,J=9.6Hz,1H),7.83(dt,J=9.0,2.6Hz,1H),7.36(d,J=9.9Hz,1H),7 .00(t,J=6.0Hz,1H),6.73-6.85(m,2H),6.44(d,J=1.3Hz,1H),3.66(s,3H),2.53-2.67(m,2H),1.43-1.62(m,2H).m / z(ESI,cation)523.8(M+H) + .

[0209] Diastereoisomers and atropisomers were separated from trans-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (63 mg) using two consecutive chiral SFC chromatography steps. For the first separation, a (S,S)Whelk-O, 2 × 15 cm column was used. The mobile phase was flowed under homogeneous solvent conditions; supercritical CO2 with 30% methanol; flow rate: 80 mL / min. Next, the first peak eluted from this separation was further separated using a Chiralcel OJ 2 × 25 cm column. The mobile phase was flowed under homogeneous solvent conditions; supercritical CO2 with 20% ethanol; flow rate: 65 mL / min. The first eluting peak was assigned to (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (16 mg), and the second eluting peak was assigned to (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (12 mg). Both materials were isolated as white solids. Data for peak 1: 1 H NMR(500MHz,DMSO-d6)δ ppm 11.48-11.87(m,1H),8.71(d,J=1.3Hz,1H),8.34(d,J=1.8Hz,1H),8.20(d,J=9.6Hz,1H),7.83(dd,J=8.8,1.8Hz,1H),7.36(d,J=10.1Hz,1H), 6.99(d,J=6.7Hz,1H),6.69-6.85(m,2H),6.43(d,J=1.6Hz,1H),3.66(s,3H),2.52-2.59(m,2H),1.53-1.63(m,2H).m / z(ESI,cation)524.0(M+H) + Data regarding Peak 2: 1H NMR(500MHz,DMSO-d6)δ ppm 11.49-11.76(m,1H),8.72(d,J=1.3Hz,1H),8.35(d,J=1.8Hz,1H),8.20( d,J=9.9Hz,1H),7.82(dd,J=9.1,2.1Hz,1H),7.36(d,J=9.9Hz,1H),7.00( d,J=6.7Hz,1H),6.78(dd,J=9.1,7.0Hz,2H),6.44(d,J=1.3Hz,1H),3.66 (s,3H),2.53-2.63(m,2H),1.48-1.63(m,2H).m / z(ESI,cation)524.0(M+H) + .

[0210] Examples 6 and 7: (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-methylcyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-methylcyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] A 40 mL vial was filled with tris(dibenzylideneacetone)dipalladium (0) (22 mg, 0.024 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (23 mg, 0.049 mmol), (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (300 mg, 0.488 mmol), potassium phosphate (518 mg, 2.441 mmol), trans-2-methylcyclopropylboronic acid pinacol ester (116 mg, 0.635 mmol), 1,4-dioxane (1.0 mL), and water (0.3 mL). The vial was aerated with nitrogen for 30 seconds, followed by heating to 65°C. After stirring for 6 hours, the reaction mixture was filtered through a phase separator and washed with dichloromethane. The filtrate was concentrated under vacuum, the residue was dissolved in dichloromethane (1 mL), and treated with trifluoromethanesulfonic acid (0.13 mL, 1.5 mmol). After stirring for 2 hours, volatile substances were removed under vacuum, and the residue was purified using a Chiralcel OJ-H 2 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 25% methanol; flow rate: 80 mL / min. The first peak to elute was assigned to (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-methylcyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (20 mg). The second eluting peak was assigned to (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-methylcyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (16 mg). Data for peak 1: 1H NMR (500MHz, methanol-d4) δ ppm 8.43(br s,1H),8.29(br s,1H),8.07(d,J=9.6Hz,1H),7.87(br d,J=8.6Hz,1H),7.01(d,J=9.6Hz,1H),6.81(br dd,J=14.5,9.1Hz,2H),6.74(d,J=6.5Hz,1H),6.47(br s,1H),3.64(s,3H),1.81-1.93(m,1H),1.21-1.29(m,4H),1.08-1.18(m,1H),0.82-0.91(m,1H).m / z(ESI,cation)470.0(M+H) + Data regarding Peak 2: 1 H NMR (500MHz, methanol-d4) δ ppm 8.43(br s,1H),8.29(s,1H),8.07(d,J=9.6Hz,1H),7.87(br d,J=8.6Hz,1H),7.01(d,J=9.9Hz,1H),6.83(br d,J=8.6Hz,1H),6.80(d,J=9.6Hz,1H),6.73(d,J=6.5Hz,1H),6.47(br s,1H),3.64(s,3H),1.83-1.91(m,1H),1.22-1.29(m,4H),1.07-1.13(m,1H),0.84-0.91(m,1H).m / z(ESI, cation)470.0(M+H) + .

[0211] Examples 8 and 9: (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-phenylcyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-phenylcyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] The compound of the title was prepared according to the methods of Examples 6 and 7, except that trans-2-phenylcyclopropylboronic acid pinacol ester (155 mg, 0.635 mmol) was used instead of trans-2-methyl-cyclopropylboronic acid pinacol ester. Purification was performed using a Chiralcel OJ-H, 2 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 45% methanol; flow rate: 70 mL / min. The first eluting peak was assigned to (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-phenylcyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (6 mg). The second peak to elute was assigned to (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-phenylcyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (4 mg). Data for peak 1: 1 ¹H NMR (500MHz, chloroform-d) δ ppm 8.27(s,1H), 8.11(d,J=2.1Hz,1H), 7.78(d,J=9.6Hz,1H), 7.74(dd,J=9.0,2.2Hz,1H), 7.31-7.38(m,3H), 7.20-7.25(m,3H), 6.93(d,J=9.3Hz,1H), 6.86(d,J=9.6Hz,1H), 6. 79(d,J=9.1Hz,1H),6.74(d,J=6.2Hz,1H),6.62(s,1H),3.71(s,3H),2.42(td,J=7.4, 4.9Hz,1H),2.35(td,J=7.5,4.8Hz,1H),1.56-1.63(m,2H).m / z(ESI, cation)532.0(M+H) + Data regarding Peak 2: 1H NMR(500MHz,chloroform-d)δ ppm 8.27(br s,1H),8.11(d,J=1.8Hz,1H),7.78(d,J=9.6Hz,1H),7.75(dd,J=9.1,2.1Hz,1H),7.43(br s,1H),7.31-7.38(m,2H),7.23-7.26(m,3H),6.92(d,J=9.3Hz,1H),6.86(d,J=9.6Hz,1H),6.79(d,J=9.1Hz,1H),6.74(d,J=6.5Hz,1H),6.62(br s,1H),3.71(s,3H),2.40-2.48(m,1H),2.32-2.39(m,1H),1.55-1.60(m,2H).m / z(ESI,cation)532.0(M+H) + .

[0212] Examples 10 and 11: (P)-(R)-1-(4-(2,2-difluorocyclopropyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-(S)-1-(4-(2,2-difluorocyclopropyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] Sodium iodide (66.7 mg, 0.445 mmol) was added in small increments to a vial containing (P)-1-(5-fluoro-2-methoxy-4-vinylphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (500 mg, 0.890 mmol) and (trifluoromethyl)trimethylsilane (0.33 mL, 2.2 mmol) in tetrahydrofuran (3.0 mL). After 10 minutes, the reaction mixture was heated to 60°C. After 3 hours, the reaction mixture was cooled to room temperature, and volatile substances were removed under vacuum. The residue was dissolved in trifluoroacetic acid (1 mL) and stirred at 40°C for 4 hours. Next, volatile substances were removed under vacuum, and the residue was purified using a Chiralcel OJ-H, 2 × 15 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 25% methanol; flow rate: 80 mL / min. The first eluted peak was assigned to (P)-(R)-1-(4-(2,2-difluorocyclopropyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide). The second eluted peak was assigned to (P)-(S)-1-(4-(2,2-difluorocyclopropyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide). Data for peak 1: 1 H NMR(500MHz, methanol-d4)δ ppm 8.16-8.34(m,2H),8.07(d,J=9.6Hz,1H),7.81-7.95(m,1H),7.15(d,J=9.3Hz,1H),7.09(d,J=6.2Hz,1H),6.69-6.89(m,2H),6.24(br s,1H),3.70(s,3H),2.98-3.03(m,1H),1.90-2.13(m,2H).m / z(ESI,cation)491.8(M+H) + Data regarding Peak 2: 1H NMR (500MHz, methanol-d4) δ ppm 8.43(br s,1H),8.30(s,1H),8.09(d,J=9.6Hz,1H),7.89(br d,J=8.8Hz,1H),7.17(d,J=9.3Hz,1H),7.09(d,J=6.5Hz,1H),6.76-6.84(m,2H),6.47(br s,1H),3.70(s,3H),2.98-3.09(m,1H),1.91-2.10(m,2H).m / z(ESI,cation)491.8(M+H) + .

[0213] Examples 12 and 13: (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka]

[0214] Step 1: trans-(P)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide A 40 mL vial was filled with RuPhos Pd fourth-generation pre-catalyst (372 mg, 0.438 mmol), potassium phosphate (864 mg, 4.38 mmol), (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (937 mg, 1.46 mmol), and trans-6-methyl-2-(2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazavolocan-4,8-dione (696 mg, 2.63 mmol). The vial was capped and refilled with nitrogen. 1,4-dioxane (4.5 mL) and water (1.5 mL) were added, and the reaction mixture was aerated with nitrogen for 15 minutes. Next, the vial was heated to 100°C for 4 hours, followed by 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and quenched with water. The layers were separated, and the aqueous extract was extracted three times with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (gradient elution 20-80% [3:1 ethyl acetate:EtOH]:heptane) to obtain trans-(P)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (401 mg, 0.598 mmol, yield 41%). m / z (ESI, cation) 671.0 (M+H) + .

[0215] Step 2: (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide trans-(P)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (401 mg, 0.598 mmol) was dissolved in dichloromethane (5 mL), cooled to 0°C, and trifluoromethanesulfonic acid (250 μL, 2.82 mmol) was added. After stirring at 0°C for 30 minutes, the reaction was quenched by dropwise addition of the reaction mixture to vigorously stirred saturated NaHCO3. After gas generation ceased, the mixture was extracted four times with dichloromethane. The organic extracts were combined, washed with brine, dried over Na2SO4, and concentrated. The residue was purified using a (S,S)Whelk-O, 2 × 15 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 40% methanol; flow rate: 80 mL / min. The first peak was further purified using a Chiralcel OJ-H, 3 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 20% ethanol; flow rate: 120 mL / min. The first peak to elute was assigned to (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (43 mg). The second peak to elute was assigned to (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (37 mg). Data for peak 1: 1H NMR(500MHz,DMSO-d6)δ ppm 11.59-12.12(m,1H),8.49(d,J=4.7Hz,2H),8.45(d,J=1.8Hz,1H),8.23(d,J=9.6Hz,1H),7.96(dd,J=9.0,2.2Hz,1H),7.55(s,1H),7.03(br s,1H),7.00(s,1H),6.76(d,J=9.6Hz,1H),6.73(d,J=9.1Hz,1H),3.69(s,3H),2.58-2.67(m,1H ),2.52-2.55(m,1H),1.59-1.71(m,1H),1.49(dt,J=9.5,5.8Hz,1H).m / z(ESI, cation)551.0(M+H) + Data regarding Peak 2: 1 H NMR(500MHz,DMSO-d6)δ ppm 11.71-12.06(m,1H),8.41-8.54(m,3H),8.23(d,J=9.6Hz,1H),7.95(dd,J=9.0,2.2Hz,1H),7.54(s,1H),6.93- 7.09(m,2H),6.65-6.83(m,2H),3.68(s,3H),2.55-2.68(m,2H),1.45-1.60(m,2H).m / z(ESI,Cation)551.0(M+H) + .

[0216] Examples 14 and 15: (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide [ka]

[0217] Step 1: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide A 100 mL round-bottom flask was packed with 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-perfluorophenyl (5.00 g, 8.19 mmol) and N-(4-methoxybenzyl)pyridazine-3-amine (1.939 g, 9.01 mmol). The flask was flushed with nitrogen and packed with tetrahydrofuran (54.6 mL). After all solids had dissolved, the reaction mixture was cooled to 0°C, and sodium tert-pentoxide (6.7 mL, 9.4 mmol, 1.4 M in THF) was added dropwise over 5-10 minutes. After 1.5 hours, the reaction mixture was quenched by adding saturated aqueous solution of ammonium chloride. The heterogeneous mixture was diluted with water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated. The resulting dark crude oil was purified by silica gel chromatography (gradient elution 20-100% [3:1 siRNA:EtOH]:heptane) to obtain (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (2.84 g, 4.42 mmol, yield 54%). m / z (ESI, cation) 641.0 (M+H) + .

[0218] Step 2: trans-(P)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide A 40 mL vial was filled with RuPhos Pd fourth-generation pre-catalyst (0.331 g, 0.389 mmol), potassium phosphate (0.992 g, 4.67 mmol), (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (1.00 g, 1.56 mmol), and trans-6-methyl-2-(2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazabolocan-4,8-dione (0.743 g, 2.80 mmol). The vial was capped and refilled with nitrogen. 1,4-dioxane (5.8 mL) and water (1.9 mL) were added, and the reaction mixture was aerated with nitrogen for 15 minutes. Next, the vial was heated to 80°C for 16 hours. The reaction mixture was cooled to room temperature, followed by the addition of trans-6-methyl-2-(2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazabolocan-4,8-dione (0.200 g, 0.744 mmol) and RuPhos Pd fourth-generation pre-catalyst (0.100 g, 0.118 mmol). After stirring at 100°C for a further 5 hours, the reaction was quenched with water and extracted three times with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and concentrated. The residue was purified via silica gel chromatography (gradient elution 55-85% [3:1 siRNA:EtOH]:heptane) to obtain trans-(P)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (450 mg, 0.671 mmol, yield 43%). m / z(ESI, cation) 671.0(M+H) + .

[0219] Step 3: (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide trans-(P)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (450 mg, 0.671 mmol) was dissolved in dichloromethane (0.5 mL), cooled to 0°C, and trifluoroacetic acid (1.8 mL) was added. The mixture was stirred at room temperature for 1 hour, followed by 1 hour at 40°C. The reaction mixture was then cooled to room temperature, diluted with dichloromethane, and quenched by dropwise addition of the reaction mixture to vigorously stirred saturated NaHCO3. After gas generation ceased, the mixture was extracted three times with dichloromethane. The organic extracts were combined, washed with brine, dried over Na2SO4, and concentrated. The residue was purified using a (S,S)Whelk-O, 2 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 50% methanol; flow rate: 80 mL / min. The first peak was further purified using a Chiralcel OJ-H, 3 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 25% methanol; flow rate: 80 mL / min. The first peak to elute was assigned to (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (51 mg). The second peak to elute was assigned to (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (50 mg). Data for peak 1:1 H NMR(500MHz,DMSO-d6)δ ppm 14.17-14.77(m,1H),8.33(d,J=2.1Hz,1H),8.28-8.32(m,1H),8.18(d,J=9.6Hz,1H),7.86- 7.95(m,1H),7.83(dd,J=9.0,2.2Hz,1H),7.67(dd,J=9.5,4.0Hz,1H),7.54(s,1H),7.00(s,1 H),6.75(d,J=9.6Hz,1H),6.69(d,J=9.1Hz,1H),3.69(s,3H),2.58-2.65(m,1H),2.51-2.54 (m,1H),1.64(dt,J=8.8,6.2Hz,1H),1.49(dt,J=9.3,5.7Hz,1H).m / z(ESI,cation)551.0(M+H) + Data regarding Peak 2: 1 H NMR(600MHz,DMSO-d6)δ ppm 13.96-14.63(m,1H),8.29-8.35(m,2H),8.17(d,J=9.8Hz,1H),7.82(br dd,J=8.9,1.3Hz,2H),7.60-7.68(m,1H),7.52(s,1H),7.01(s,1H),6.74(d,J=9.4Hz,1H),6.70 (d,J=9.1Hz,1H),3.69(s,3H),2.55-2.69(m,2H),1.44-1.59(m,2H).m / z(ESI,cation)551.0(M+H) + .

[0220] Examples 16 and 17: (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] A 40 mL vial was filled with Pd-171 (80 mg, 0.12 mmol), (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (500 mg, 0.799 mmol), potassium phosphate (509 mg, 2.40 mmol), and trans-6-methyl-2-(2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazavolocan-4,8-dione (318 mg, 1.20 mmol), 1,4-dioxane (3.0 mL), and water (1.0 mL). The vial was aerated with nitrogen and subsequently heated to 95°C. After stirring for 6 hours, the mixture was filtered through a phase separator and washed with dichloromethane. Volatile substances were removed under vacuum. The residue was dissolved in dichloromethane (1 mL) and treated with trifluoromethanesulfonic acid (0.2 mL, 2.4 mmol). After heating at 50°C for 1 hour, volatile substances were removed, and the product was purified using a (S,S)Whelk-O 2 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 40% methanol; flow rate: 80 mL / min. The first peak was further purified using a Chiralcel OJ-H, 3 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 25% methanol; flow rate: 80 mL / min. The first eluting peak was assigned to (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (31 mg). The second eluting peak was assigned to (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (37 mg). Data for Peak 1: 11H NMR (500 MHz, methanol-d4) δ ppm 8.34(d,J=2.1Hz,1H),8.18-8.29(m,1H),8.11(d,J=9.6Hz,1H),7.87-7.97(m ,2H),7.59(dd,J=9.6,4.2Hz,1H),7.12(d,J=9.6Hz,1H),6.96(d,J=6.5Hz,1H ),6.82(d,J=8.8Hz,1H),6.80(d,J=9.6Hz,1H),3.69(s,3H),2.59(dt,J=8.8, 6.0Hz,1H),2.20-2.28(m,1H),1.45-1.53(m,2H).m / z(ESI,cation)535.0(M+H) + Data regarding Peak 2: 1 H NMR(500MHz, methanol-d4)δ ppm 8.33(d,J=2.1Hz,1H),8.20-8.29(m,1H),8.10(d,J=9.6Hz,1H),7.83-7.96 (m,2H),7.58(dd,J=9.5,4.3Hz,1H),7.11(d,J=9.6Hz,1H),6.94(d,J=6.5H z,1H),6.82(d,J=9.1Hz,1H),6.79(d,J=9.6Hz,1H),3.69(s,3H),2.53-2.6 4(m,1H),2.21-2.34(m,1H),1.42-1.53(m,2H).m / z(ESI, cation)535.0(M+H) + .

[0221] Examples 18 and 19: (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0222] Step 1: 6-(benzylthio)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one A 40 mL vial was filled with 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinoline-2(1H)-one (1.50 g, 3.08 mmol), trans-6-methyl-2-(2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazavolocan-4,8-dione (1.23 g, 4.62 mmol), potassium phosphate (1.96 g, 9.24 mmol), and RuPhos Pd fourth-generation pre-catalyst (0.786 g, 0.924 mmol). The vial was capped and refilled with nitrogen, after which 1,4-dioxane (15.4 mL) and water (5.1 mL) were added. The reaction mixture was vigorously stirred and aerated with nitrogen. After heating to 80°C for 16 hours, an additional RuPhos Pd fourth-generation pre-catalyst (150 mg, 0.176 mmol) was added, and the reaction mixture was heated to 100°C for 8 hours. After cooling to room temperature, the reaction mixture was poured into a mixture of ethyl acetate and water and extracted three times with ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (gradient elution 10-75% ethyl acetate:heptane) to obtain 6-(benzylthio)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (1.00 g, 1.94 mmol, yield 63%). 1H NMR(500MHz,DMSO-d6)δ ppm 7.94(d,J=9.6Hz,1H),7.78(d,J=2.1Hz,1H),7.48(d,J=2.3Hz,1H),7.38(ddd,J=8.8, 5.2,2.1Hz,1H),7.31-7.35(m,2H),7.26-7.31(m,2H),7.19-7.25(m,1H),6.99(d,J=6 .2Hz,1H),6.66(d,J=9.6Hz,1H),6.48(dd,J=8.7,6.9Hz,1H),4.23(s,2H),3.69(s,3H) ),2.53-2.66(m,2H),1.53-1.66(m,1H),1.45-1.52(m,1H).m / z(ESI, cation)516.0(M+H) + .

[0223] Step 2: trans-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl A 25 mL round-bottom flask was filled with trans-6-(benzylthio)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (1.00 g, 1.94 mmol), followed by acetonitrile (6.1 mL), water (0.15 mL), and acetic acid (0.23 mL). This solution was cooled to 0°C, and 1,3-dichloro-5,5-dimethyl-2,4-imidazolidinedione (0.382 g, 1.94 mmol) was added. After 90 minutes at 0°C, an additional 1,3-dichloro-5,5-dimethyl-2,4-imidazolidinedione (0.191 g, 0.969 mmol) was added. After 15 minutes, pentafluorophenol (0.428 g, 2.34 mmol) was added, followed by the dropwise addition of triethylamine (1.1 mL, 7.8 mmol). After 30 minutes at 0°C, the reaction mixture was warmed to room temperature and diluted with ethyl acetate (25 mL) and 1:1 water:saline solution (50 mL). After briefly stirring the mixture, it was extracted three times with ethyl acetate. The combined organic matter was washed with saline solution, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (gradient elution 0-35% [3:1 ethyl acetate:EtOH]:heptane) to obtain trans-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (760 mg, 1.19 mmol, yield 61%). 1 H NMR(500MHz,DMSO-d6)δ ppm 8.54-8.69(m,1H),8.24(d,J=9.9Hz,1H),7.96(ddd,J=9.0,4.3,2.3Hz,1H),7.63(d,J=1.6Hz,1H),7.04(d,J=3.4Hz,1H ),6.80-6.91(m,2H),3.71(s,3H),2.53-2.67(m,2H),1.54-1.69(m,1H),1.47-1.54(m,1H).m / z(ESI,Cation)639.9(M+H) + .

[0224] Step 3: (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 40 mL vial was filled with trans-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (781 mg, 1.22 mmol) and isoxazole-3-amine (123 mg, 1.47 mmol). Tetrahydrofuran (8.1 mL) was added via syringe, and the reaction mixture was cooled to 0°C. Lithium bis(trimethylsilyl)amide (1.5 mL, 1.5 mmol, 1.0 M in THF) was added dropwise via syringe. After stirring at 0°C for 1 hour, an additional lithium bis(trimethylsilyl)amide (1.2 mL, 1.2 mmol, 1.0 M in THF) was added, and the reaction mixture was stirred at 0°C for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted four times with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (gradient elution 10-65% [3:1 Â:EtOH]:heptane) to obtain trans-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (611 mg, 1.13 mmol, yield 93%). This product was further purified using a (S,S)Whelk-O, 2 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 50% methanol; flow rate: 80 mL / min. The first peak was further purified using two parallel Chiralcel OJ-H, 3 × 25 cm and Chiralcel OJ-H, 3 × 15 cm columns. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 30% methanol; flow rate: 80 mL / min. The first peak to elute was assigned to (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (70 mg).The second eluting peak was assigned to (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (70 mg). Data for peak 1: 1 1H NMR (500MHz, DMSO-d6) δ ppm 11.64(s,1H),8.71(d,J=1.8Hz,1H),8.34(d,J=2.3Hz,1H),8.20(d,J=9.6Hz,1H) ,7.83(dd,J=9.0,2.2Hz,1H),7.56(s,1H),7.00(s,1H),6.77(dd,J=9.3,6.2Hz,2 H),6.43(d,J=1.8Hz,1H),3.69(s,3H),2.58-2.66(m,1H),2.51-2.54(m,1H),1.6 4(dt,J=8.9,6.2Hz,1H),1.50(dt,J=9.5,5.8Hz,1H).m / z(ESI,cation)540.0(M+H) + Data regarding Peak 2: 1 H NMR(500MHz,DMSO-d6)δ ppm 11.64(s,1H),8.71(d,J=1.8Hz,1H),8.35(d,J=2.3Hz,1H),8.20(d,J=9.6Hz,1H),7.82(dd,J=9.0,2.2Hz,1H),7.56(s,1H),7.01 (s,1H),6.71-6.88(m,2H),6.43(d,J=1.8Hz,1H),3.69(s,3H),2.55-2.67(m,2H),1.46-1.60(m,2H).m / z(ESI,cation)540.0(M+H) + .

[0225] Examples 20 and 21: (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] A 40 mL vial was filled with Pd-171 (80 mg, 0.12 mmol), (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (500 mg, 0.799 mmol), potassium phosphate (509 mg, 2.40 mmol), and trans-6-methyl-2-(2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazavolokano-4,8-dione (318 mg, 1.20 mmol), 1,4-dioxane (3.0 mL), and water (1.0 mL). The vial was aerated with nitrogen and subsequently heated to 95°C. After stirring for 6 hours, the mixture was filtered through a phase separator and washed with dichloromethane. Volatile substances were removed under vacuum. The residue was dissolved in dichloromethane (1 mL) and treated with trifluoromethanesulfonic acid (0.2 mL, 2.4 mmol). After heating at 50°C for 1 hour, volatile substances were removed, and the product was purified using a (S,S)Whelk-O 2 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 40% methanol; flow rate: 80 mL / min. The first peak was further purified using a Chiralcel OJ-H, 3 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 25% methanol; flow rate: 80 mL / min. The second and third eluting peaks were isolated, dissolved in PhMe (1 mL), and heated to 100°C for 1 hour. The solvent was then removed.

[0226] The second peak was further purified using a (S,S)Whelk-O1, 2.1 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 35% methanol; flow rate: 80 mL / min. The first eluting peak was assigned to (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (14.3 mg). 1 H NMR(500MHz,chloroform-d)δ ppm 10.89-11.97(m,1H),8.65(d,J=4.9Hz,2H),8.42(d,J=1.8Hz,1H),8.06(dd,J=8.8,2 .1Hz,1H),7.85(d,J=9.9Hz,1H),7.01(t,J=4.8Hz,1H),6.96(d,J=9.3Hz,1H),6.84(d ,J=9.6Hz,1H),6.69-6.78(m,2H),3.69(s,3H),2.48-2.58(m,1H),2.03(dq,J=8.8,5 .8Hz,1H),1.50(dt,J=9.7,5.6Hz,1H),1.32-1.41(m,1H).m / z(ESI, cation)534.9(M+H) + .

[0227] The third peak derived from the above was further purified using a (S,S)Whelk-O1, 2.1 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 40% methanol; flow rate: 80 mL / min. The first peak to elute was assigned to (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (13.7 mg). 1¹H NMR (500 MHz, chloroform-d) δ ppm 10.75-12.14(m,1H),8.65(d,J=4.7Hz,2H),8.42(d,J=1.6Hz,1H),8.05(dd,J=8 .8,1.8Hz,1H),7.85(d,J=9.6Hz,1H),7.01(t,J=4.8Hz,1H),6.95(d,J=9.3Hz,1H ),6.85(d,J=9.6Hz,1H),6.70-6.78(m,2H),3.70(s,3H),2.45-2.63(m,1H),1.9 7-2.14(m,1H),1.45-1.55(m,1H),1.32-1.42(m,1H).m / z(ESI, cation)535.0(M+H) + .

[0228] Example 22: (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0229] Step 1: (P)-6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropane-1-en-2-yl)phenyl)quinoline-2(1H)-one A 100 mL round-bottom flask was packed with (P)-6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinoline-2(1H)-one (2.00 g, 4.25 mmol), potassium phosphate (2.71 g, 12.8 mmol), and bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.602 g, 0.850 mmol). After flushing the vial with nitrogen, 1,4-dioxane (18 mL), water (6.1 mL), and 1-(trifluoromethyl)vinylboronic acid hexylene glycol ester (1.1 mL, 5.3 mmol) were added. The container was heated to 50°C and stirred at this temperature for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography (gradient elution 5-60% Â:heptane) yielded (P)-6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropane-1-en-2-yl)phenyl)quinoline-2(1H)-one (1.80 g, 3.71 mmol, yield 87%). 1 H NMR(500MHz,DMSO-d6)δ ppm 7.96(d,J=9.3Hz,1H),7.80(d,J=2.3Hz,1H),7.49(d,J=9.6Hz,1H),7.4 2(dd,J=8.8,2.3Hz,1H),7.32-7.35(m,2H),7.26-7.31(m,2H),7.19-7.2 6(m,2H),6.68(d,J=9.6Hz,1H),6.50(d,J=8.8Hz,1H),6.43(d,J=1.0Hz,1H),6.18(s,1H),4.24(s,2H),3.69(s,3H).m / z(ESI,cation)486.0(M+H) + .

[0230] Step 2: (P)-6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one A 40 mL vial was filled with (P)-6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropane-1-en-2-yl)phenyl)quinoline-2(1H)-one (516 mg, 1.06 mmol), triethylammonium bis(catecholato)iodomethylsilicate (1.30 g, 2.67 mmol), and 2,4,5,6-tetrakis(carbazole-9-yl)-1,3-dicyanobenzene (85 mg, 0.11 mmol). After flushing the vial with nitrogen, DMSO (11 mL) was added. The mixture was aerated with nitrogen and irradiated in a Penn OC photoreactor m1 at 5% brightness with a blue LED, stirring at 1000 rpm, and a blower speed of 4500 rpm for 6 hours, followed by 2.5 hours at 50% brightness, stirring at 1000 rpm, and a blower speed of 4500 rpm. The reaction product was diluted with ethyl acetate and washed three times with 2N NaOH. The organic extract was washed with water followed by brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (gradient elution 10-60% ethyl acetate:heptane) to obtain (P)-6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (193 mg, 0.386 mmol, yield 36%). 1 H NMR(500MHz,DMSO-d6)δ ppm 7.95(d,J=9.3Hz,1H),7.79(d,J=2.3Hz,1H),7.42(dd,J=8.8,2.1Hz,1H) ,7.39(d,J=9.6Hz,1H),7.31-7.36(m,3H),7.26-7.30(m,2H),7.19-7.25 (m,1H),6.67(d,J=9.6Hz,1H),6.45(d,J=8.8Hz,1H),4.23(s,2H),3.69( s,3H),1.44-1.53(m,2H),1.28-1.36(m,2H).m / z(ESI,cation)500.0(M+H) + .

[0231] Step 3: (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl A 40 mL vial was filled with (P)-6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (560 mg, 1.12 mmol), acetonitrile (4.25 mL), water (0.11 mL), and acetic acid (0.16 mL). After cooling the solution to 0°C, 1,3-dichloro-5,5-dimethyl-2,4-imidazolidinedione (331 mg, 1.68 mmol) was added in two parts. After 1 hour, pentafluorophenol (248 mg, 1.35 mmol), followed by triethylamine (0.625 mL, 4.48 mmol), was added sequentially. After 5 minutes, the reaction was quenched by adding 1N HCl and extracted five times with ethylethanol. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (gradient elution 25-50% ethyl heptane) to obtain (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (403 mg, 0.646 mmol, yield 58%). 1 H NMR(500MHz,DMSO-d6)δ ppm 8.60(d,J=2.3Hz,1H),8.26(d,J=9.6Hz,1H),7.99(dd,J=9.1,2.3Hz,1H),7.53(d,J=9.9Hz,1H),7.40(d,J=6.5Hz,1H),6. 89(d,J=9.6Hz,1H),6.82(d,J=9.1Hz,1H),3.71(s,3H),1.45-1.54(m,2H),1.27-1.36(m,2H).m / z(ESI, cation)624.0(M+H) + .

[0232] Step 4: (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide Two drum vials were filled with isoxazole-3-amine (0.019 mL, 0.28 mmol), (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (150 mg, 0.241 mmol), and THF (1.6 mL). The vials were cooled to 0°C, and sodium tert-pentoxide (0.34 mL, 0.48 mmol, 1.4 M in THF) was added. The resulting yellow solution was stirred at 0°C for 1 hour. Next, the reaction mixture was diluted with ethyl acetate, quenched by adding 1N HCl, and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (gradient elution 20-70% ethyl heptane) to obtain (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (54 mg, 0.10 mmol, yield 43%). 1 H NMR(500MHz,DMSO-d6)δ ppm 11.65(s,1H),8.72(d,J=1.6Hz,1H),8.36(d,J=2.1Hz,1H),8.22(d,J=9.6H z,1H),7.85(dd,J=9.0,2.2Hz,1H),7.45(d,J=9.9Hz,1H),7.36(d,J=6.2Hz, 1H),6.80(d,J=9.6Hz,1H),6.74(d,J=9.1Hz,1H),6.44(d,J=1.8Hz,1H),3. 69(s,3H),1.44-1.53(m,2H),1.24-1.37(m,2H).m / z(ESI,cation)524.0(M+H) + .

[0233] Example 23: (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] Two drum vials were filled with 2-pyrimidineamine (26 mg, 0.28 mmol), (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (150 mg, 0.241 mmol), and THF (1.6 mL). The vials were cooled to 0°C, and sodium tert-pentoxide (0.34 mL, 0.48 mmol, 1.4 M in THF) was added. The resulting yellow solution was stirred at 0°C for 1 hour. Next, the reaction mixture was diluted with ethyl acetate, quenched by adding 1N HCl, and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (gradient elution 20-70% ethyl heptane) to obtain (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (60 mg, 0.11 mmol, yield 47%). 1 H NMR(500MHz,DMSO-d6)δ ppm 11.62-12.01(m,1H),8.50(d,J=4.7Hz,2H),8.47(d,J=1.8Hz,1H),8.25(d,J=9.6Hz,1 H),7.99(dd,J=9.0,2.2Hz,1H),7.44(d,J=9.9Hz,1H),7.36(d,J=6.5Hz,1H),7.05(br s,1H),6.78(d,J=9.6Hz,1H),6.71(d,J=8.8Hz,1H),3.68(s,3H),1.42-1.54(m,2H),1.23-1.35(m,2H).m / z(ESI,cation)535.0(M+H) + .

[0234] Example 24: (P)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0235] Step 1: (P)-6-(benzylthio)-1-(5-chloro-2-methoxy-4-(3,3,3-trifluoropropane-1-en-2-yl)phenyl)quinoline-2(1H)-one A 250 mL round-bottom flask was packed with (P)-6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinoline-2(1H)-one (3.50 g, 7.19 mmol), potassium phosphate (4.58 g, 21.6 mmol), and bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ii) (1.02 g, 1.44 mmol). After flushing the vial with nitrogen, 1,4-dioxane (27 mL), water (9 mL), and 1-(trifluoromethyl)vinylboronic acid hexylene glycol ester (1.9 mL, 9.4 mmol) were added. The container was heated to 50°C and stirred at this temperature for 1 hour, followed by 15.5 hours at 45°C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography (gradient elution 0-70% siRNA:heptane) yielded (P)-6-(benzylthio)-1-(5-chloro-2-methoxy-4-(3,3,3-trifluoropropane-1-en-2-yl)phenyl)quinoline-2(1H)-one (3.14 g, 6.26 mmol, yield 87%). 1 H NMR(500MHz,DMSO-d6)δ ppm 7.96(d,J=9.6Hz,1H),7.80(d,J=2.3Hz,1H),7.66(s,1H),7.44(dd,J=8.7,2.2Hz,1H),7.32-7.37(m,2H),7.26-7.31(m,3H),7.18-7.2 5(m,1H),6.68(d,J=9.6Hz,1H),6.49(d,J=8.8Hz,1H),6.45(s,1H),6.04(s,1H),4.24(s,2H),3.70(s,3H).m / z(ESI,cation)502.0(M+H) + .

[0236] Step 2: (P)-6-(benzylthio)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one A 40 mL vial was filled with (P)-6-(benzylthio)-1-(5-chloro-2-methoxy-4-(3,3,3-trifluoropropane-1-en-2-yl)phenyl)quinoline-2(1H)-one (1.10 g, 2.19 mmol), triethylammonium bis(catecholato)iodomethylsilicate (3.20 g, 6.57 mmol), and 2,4,5,6-tetrakis(carbazole-9-yl)-1,3-dicyanobenzene (175 mg, 0.349 mmol). After flushing the vial with nitrogen, DMSO (22 mL) was added. The mixture was aerated with nitrogen for 15 minutes and irradiated for 6 hours with a blue LED in a Penn OC photoreactor m1 at 50% brightness, stirring at 1000 rpm, and a blower speed of 4500 rpm. In parallel, two other identical reactions were induced using 150 mg and 915 mg of (P)-6-(benzylthio)-1-(5-chloro-2-methoxy-4-(3,3,3-trifluoropropane-1-en-2-yl)phenyl)quinoline-2(1H)-one (using reagents and solvents of similar stoichiometry and concentrations). The reaction products were combined, diluted with ethyl acetate, cooled using an ice bath, and washed three times with 2N NaOH. The organic extract was washed twice with water followed by brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (gradient elution 0-60% ethyl acetate:heptane) to obtain (P)-6-(benzylthio)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (712 mg, 1.38 mmol, yield 35%). 1H NMR(500MHz,DMSO-d6)δ ppm 7.95(d,J=9.3Hz,1H),7.78(d,J=2.1Hz,1H),7.54(s,1H),7.42(dd,J=8. 8,2.3Hz,1H),7.40(s,1H),7.31-7.35(m,2H),7.26-7.30(m,2H),7.19-7. 25(m,1H),6.67(d,J=9.3Hz,1H),6.44(d,J=8.8Hz,1H),4.23(s,2H),3.71 (s,3H),1.45-1.69(m,2H),1.32-1.41(m,2H).m / z(ESI,cation)516.0(M+H) + .

[0237] Step 3: (P)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl A vial was filled with (P)-6-(benzylthio)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (712 mg, 1.38 mmol), acetonitrile (4.5 mL), water (0.11 mL), and acetic acid (0.17 mL). After cooling the solution to 0°C, 1,3-dichloro-5,5-dimethyl-2,4-imidazolidinedione (408 mg, 2.07 mmol) was added. After 30 minutes, pentafluorophenol (305 mg, 1.66 mmol), followed by triethylamine (0.77 mL, 5.5 mmol), was added sequentially. After 5 minutes, the reaction was quenched by adding 1N HCl and extracted four times with ethylethanol. The combined organic extract was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (gradient elution 10-65% ethyl heptane) to obtain (P)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (624 mg, 0.975 mmol, yield 71%). 1H NMR(500MHz,DMSO-d6)δ ppm 8.60(d,J=2.3Hz,1H),8.25(d,J=9.6Hz,1H),8.00(dd,J=9.1,2.3Hz,1H),7.70(s,1 H),7.46(s,1H),6.89(d,J=9.6Hz,1H),6.82(d,J=9.1Hz,1H),3.74(s,3H),1.57(br t,J=3.1Hz,2H),1.29-1.46(m,2H).m / z(ESI,cation)640.0(M+H) + .

[0238] Step 4: (P)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide Two drum vials were filled with isoxazole-3-amine (0.025 mL, 0.37 mmol), (P)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (203 mg, 0.317 mmol), and THF (2 mL). The vials were cooled to 0°C, and sodium tert-pentoxide (0.40 mL, 0.56 mmol, 1.4 M in THF) was added. The resulting yellow solution was stirred at 0°C for 45 minutes, followed by the addition of the remaining sodium tert-pentoxide (0.10 mL, 0.14 mmol, 1.4 M in THF). The reaction mixture was stirred for 5 minutes, then quenched by adding 1N HCl and water, and extracted three times with dichloromethane. The combined organic extracts were filtered through a phase separator and concentrated under vacuum. The residue was purified using a Torus Diol, 3 × 15 cm column. The mobile phase was run under gradient conditions; supercritical CO2 with 10-30% methanol; flow rate: 100 mL / min. This yielded (P)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (77.5 mg, 0.144 mmol, yield 45%). 1H NMR(600MHz,DMSO-d6)δ ppm 11.64(br s,1H),8.72(d,J=1.8Hz,1H),8.36(d,J=2.2Hz,1H),8.22(d,J=9.8Hz,1H),7.86(dd,J=9.1,2.2Hz,1H),7.62(s,1H),7.43(s,1H),6.80 (d,J=9.4Hz,1H),6.74(d,J=9.1Hz,1H),6.44(d,J=1.8Hz,1H),3.72(s,3H),1.56(s,2H),1.26-1.42(m,2H).m / z(ESI,cation)539.8(M+H) + .

[0239] Example 25: (P)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] Two drum vials were packed with 2-pyrimidineamine (35 mg, 0.37 mmol), (P)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (203 mg, 0.317 mmol), and THF (2 mL). The vials were cooled to 0°C, and sodium tert-pentoxide (0.40 mL, 0.56 mmol, 1.4 M in THF) was added. The resulting yellow solution was stirred at 0°C for 20 minutes, followed by quenching with the addition of 1N HCl and water. The mixture was then extracted three times with dichloromethane. The combined organic extracts were filtered through a phase separator and concentrated under vacuum. The residue was purified using a Torus Diol, 3 × 25 cm column. The mobile phase was run under gradient conditions; supercritical CO2 with 10-30% methanol; flow rate: 100 mL / min. This yielded (P)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (93.0 mg, 0.169 mmol, yield 53%). 1 H NMR(600MHz,DMSO-d6)δ ppm 11.60-12.10(m,1H),8.45-8.60(m,3H),8.25(d,J=9.8Hz,1H),7.99(dd,J=8.7,2.2Hz,1H),7.61(s,1H),7.42(s,1H),7.05(br t,J=4.5Hz,1H),6.78(d,J=9.8Hz,1H),6.71(d,J=9.1Hz,1H),3.71(s,3H),1.56(s,2H),1.30-1.45(m,2H).m / z(ESI,cation)551.0(M+H) + .

[0240] Examples 26 and 27: (P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0241] Step 1: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 40 mL vial was filled with N-(4-methoxybenzyl)isoxazole-3-amine (270 mg, 1.32 mmol), (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (650 mg, 1.10 mmol), and THF (5.6 mL). The reaction mixture was cooled to 0°C, and sodium tert-pentoxide (0.60 mL, 1.5 mmol, 30% of THF) was added dropwise. After 30 minutes, the reaction was quenched by adding saturated aqueous solution of NH4Cl, and extracted four times with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (gradient elution 10-80% [3:1 Â:EtOH]:heptane) to obtain (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (640 mg, 1.05 mmol, yield 95%). 1H NMR(500MHz,DMSO-d6)δ ppm 8.80(d,J=1.8Hz,1H),8.27-8.40(m,1H),8.15(d,J=9.6Hz,1H),7.77(dd,J=9.1,2.3Hz,1H),7.53(s,1H),7.35(s,1H),7.20-7.30(m,2H),6 .84-6.91(m,2H),6.81(d,J=9.6Hz,1H),6.69-6.75(m,2H),4.91(s,2H),3.71(s,3H),3.69(s,3H),2.32(s,3H).m / z(ESI,cation)610.0(M+H) + .

[0242] Step 2: trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 40 mL vial was filled with (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (431 mg, 0.706 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (46 mg, 0.071 mmol), trans-6-methyl-2-(2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazavolocan-4,8-dione (234 mg, 0.883 mmol), and potassium phosphate (599 mg, 2.82 mmol), followed by flushing with nitrogen. Toluene (3.75 mL) and water (0.94 mL) were added, the reaction mixture was aerated with nitrogen, and then heated to 50°C for 22.5 hours. Next, the reaction mixture was poured into a 1:1 brine / water mixture and extracted three times with ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (gradient elution 0-30% [3:1 ethyl acetate:EtOH]:heptane) to obtain trans-(P)-N-(isoxazole-3-yl)-1-(2-methoxy-5-methyl-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (404 mg, 0.632 mmol, yield 89%). 1H NMR(500MHz,DMSO-d6)δ ppm 8.79(dd,J=1.8,0.8Hz,1H),8.33(d,J=2.3Hz,1H),8.12(d,J=9.6Hz,1H),7.76(td,J=8.7,2.3Hz,1H),7 .24(d,J=7.8Hz,2H),7.12(d,J=1.6Hz,1H),6.92(d,J=3.1Hz,1H),6.85(d,J=8.3Hz,2H),6.79(d,J=9.6 Hz,1H),6.72(dd,J=1.8,1.0Hz,1H),6.65(dd,J=9.1,3.9Hz,1H),4.90(s,2H),3.70(s,3H),3.66(s,3H) ,2.44-2.46(m,1H),2.29-2.38(m,4H),1.40-1.46(m,1H),1.23-1.29(m,1H).m / z(ESI,cation)640.0(M+H) + .

[0243] Step 3: (P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 40 mL vial containing trans-(P)-N-(isoxazole-3-yl)-1-(2-methoxy-5-methyl-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (404 mg, 0.632 mmol) was packed with trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 16.75 hours. Next, the reaction mixture was stirred and poured into a saturated aqueous solution of NaHCO3. After gas generation ceased, the mixture was extracted three times with dichloromethane. The combined organic matter was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using a Chiralcel OJ-H, 2 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 30% methanol; flow rate: 60 mL / min. The first eluting peak was assigned to (P)-N-(isoxazole-3-yl)-1-(2-methoxy-5-methyl-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (127.8 mg). The second eluting peak was assigned to (P)-N-(isoxazole-3-yl)-1-(2-methoxy-5-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (123.2 mg). Data for Peak 1: 1 H NMR(600MHz,DMSO-d6)δ ppm 11.61(br s,1H),8.72(d,J=1.5Hz,1H),8.34(d,J=2.2Hz,1H),8.19(d,J=9.8Hz,1H),7.83( dd,J=8.7,2.2Hz,1H),7.11(s,1H),6.91(s,1H),6.77(d,J=9.4Hz,1H),6.71(d,J =8.7Hz,1H),6.44(d,J=1.8Hz,1H),3.65(s,3H),2.42-2.48(m,1H),2.29-2.39(m ,4H),1.49-1.58(m,1H),1.40(dt,J=9.5,5.4Hz,1H).m / z(ESI,cation)520.0(M+H) + Data regarding Peak 2:1 H NMR(600MHz,DMSO-d6)δ ppm 11.60(br s,1H),8.71(d,J=1.5Hz,1H),8.34(d,J=2.2Hz,1H),8.19(d,J=9.8Hz,1 H),7.82(dd,J=8.7,2.2Hz,1H),7.11(s,1H),6.92(s,1H),6.77(d,J=9.8 Hz,1H),6.72(d,J=9.1Hz,1H),6.44(d,J=1.8Hz,1H),3.65(s,3H),2.39- 2.48(m,2H),2.34(s,3H),1.33-1.50(m,2H).m / z(ESI, cation)520.0(M+H) + .

[0244] Examples 28 and 29: (P)-1-(2-methoxy-5-methyl-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(2-methoxy-5-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka]

[0245] Step 1: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide A 40 mL vial was filled with N-(4-methoxybenzyl)pyrimidine-2-amine (284 mg, 1.32 mmol), (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (650 mg, 1.10 mmol), and THF (5.6 mL). The reaction mixture was cooled to 0°C, and sodium tert-pentoxide (0.60 mL, 1.5 mmol, 30% of THF) was added dropwise. After 30 minutes, the reaction was quenched by adding saturated aqueous solution of NH4Cl, and extracted four times with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (gradient elution with heptane, 50-80% [3:1 SiO:EtOH]:15% dichloromethane co-eluate) to obtain (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (299 mg, 0.481 mmol, yield 44%). 1 1H NMR (500MHz, DMSO-d6) δ ppm 8.58(d,J=4.9Hz,2H),8.38(d,J=2.3Hz,1H),8.12(d,J=9.6Hz,1H),7.96(dd, J=9.0,2.2Hz,1H),7.53(s,1H),7.33(s,1H),7.28(d,J=8.8Hz,2H),7.13(t,J= 4.9Hz,1H),6.84-6.90(m,2H),6.77(d,J=9.6Hz,1H),6.67(d,J=9.1Hz,1H),5 .35(s,2H),3.72(s,3H),3.67(s,3H),2.32(s,3H).m / z(ESI,cation)621.0(M+H) + .

[0246] Step 2: trans-(P)-1-(2-methoxy-5-methyl-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide Two drum vials were filled with (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (299 mg, 0.481 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (31 mg, 0.048 mmol), trans-6-methyl-2-(2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazavolocan-4,8-dione (159 mg, 0.601 mmol), and potassium phosphate (408 mg, 1.92 mmol), followed by flushing with nitrogen. Toluene (2.6 mL) and water (0.65 mL) were added, the reaction mixture was aerated with nitrogen, and then heated to 50°C for 16 hours. Next, the reaction mixture was diluted with ethyl acetate and water and extracted three times with ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (gradient elution 30-80% ethyl acetate:heptane) to obtain trans-(P)-1-(2-methoxy-5-methyl-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (307 mg, 0.472 mmol, yield 98%). 1 H NMR(500MHz,DMSO-d6)δ ppm 8.57(d,J=4.7Hz,2H),8.36(t,J=1.9Hz,1H),8.10(d,J=9.9Hz,1H),7.89-8.01(m,1H),7.2 8(dd,J=8.7,1.4Hz,2H),7.06-7.17(m,2H),6.92(d,J=3.9Hz,1H),6.85-6.88(m,2H),6.76( d,J=9.6Hz,1H),6.61(dd,J=9.0,5.6Hz,1H),5.35(s,2H),3.71(s,3H),3.65(s,3H),2.43- 2.48(m,2H),2.34(s,3H),1.37-1.46(m,1H),1.26-1.30(m,1H).m / z(ESI,cation)651.0(M+H) + .

[0247] Step 3: (P)-1-(2-Methoxy-5-methyl-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(2-Methoxy-5-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide A 40 mL vial containing trans-(P)-1-(2-methoxy-5-methyl-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (307 mg, 0.472 mmol) was packed with trifluoroacetic acid (2.4 mL). The reaction mixture was stirred at room temperature for 17.5 hours. Next, the reaction mixture was stirred and poured into a saturated aqueous solution of NaHCO3. After gas generation ceased, the mixture was extracted three times with dichloromethane. The combined organic matter was washed with brine, dried over Na2SO4, and concentrated. The residue was purified using a Chiralpak IG, 2 × 15 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 35% [4:1 EtOH:dichloromethane]; flow rate: 50 mL / min. The first eluting peak was assigned to (P)-1-(2-methoxy-5-methyl-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (76.0 mg). The second eluting peak was assigned to (P)-1-(2-methoxy-5-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidine-2-yl)-1,2-dihydroquinoline-6-sulfonamide (70.1 mg). Data for Peak 1: 1H NMR(500MHz,DMSO-d6)δ ppm 11.57-12.09(m,1H),8.50(d,J=4.9Hz,2H),8.45(d,J=2.1Hz,1H),8.22(d,J=9.6Hz,1H ),7.96(dd,J=9.0,2.2Hz,1H),7.11(s,1H),7.05(t,J=4.7Hz,1H),6.91(s,1H),6.76(d ,J=9.6Hz,1H),6.68(d,J=9.1Hz,1H),3.65(s,3H),2.46(dt,J=9.4,5.7Hz,2H),2.26-2 .37(m,4H),1.48-1.58(m,1H),1.40(dt,J=9.6,5.4Hz,1H).m / z(ESI,cation)531.0(M+H) + Data regarding Peak 2: 1 H NMR(500MHz,DMSO-d6)δ ppm 11.67-12.10(m,1H),8.49(d,J=4.9Hz,2H),8.44(d,J=2.1Hz,1H),8.22(d,J=9.6Hz,1H),7.94(dd,J=9.0,2.2Hz,1H),7.10(s,1H),7.04(br t,J=4.7Hz,1H),6.92(s,1H),6.75(d,J=9.6Hz,1H),6.69(d,J=8.8Hz,1H),3.64(s, 3H),2.40-2.46(m,2H),2.34(s,3H),1.37-1.48(m,2H).m / z(ESI, cation)531.0(M+H) + .

[0248] Examples 30 and 31: (P)-1-(4-((1S,2S)-[1,1'-bi(cyclopropane)]-2-yl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(4-((1R,2S)-[1,1'-bi(cyclopropane)]-2-yl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0249] Step 1: trans-(P)-1-(4-([1,1'-bi(cyclopropane)]-2-yl)-5-fluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide To a vial containing (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (800 mg, 1.24 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (81 mg, 0.12 mmol), potassium phosphate (1.05 g, 4.97 mmol), and trans-1-cyclopropyl-cyclopropyl-2-boronic acid pinacol ester (310 mg, 1.49 mmol), toluene (4.0 mL) and water (1.0 mL) were added. The reaction mixture was flushed with nitrogen and stirred at 50°C for 16 hours. Next, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed twice with water. Next, volatile substances were removed, and the residue was purified by column chromatography (gradient elution, 0-30% [3:1 siRNA / EtOH]:heptane) to obtain 1-(4-([1,1'-bi(cyclopropane)]-2-yl)-5-fluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (589 mg, 0.912 mmol, yield 74%). m / z(ESI, cation) 646.0(M+H) + .

[0250] Step 2: (P)-1-(4-((1S,2S)-[1,1'-bi(cyclopropane)]-2-yl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(4-((1R,2S)-[1,1'-bi(cyclopropane)]-2-yl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide TFA (1 mL) was added to a vial containing (P)-1-(4-([1,1'-bi(cyclopropane)]-2-yl)-5-fluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (500 mg, 0.774 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at 40°C for 4 hours. After removing volatile substances, the residue was purified by reverse-phase HPLC using an XBridge Prep Shield RP18 19 × 100 mm column. The mobile phase was run under gradient elution; acetonitrile with 25-70% water / 0.1% glycerin; flow rate: 40 mL / min. The material was further purified using a Chiralcel OJ-H, 2 × 25 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 30% methanol; flow rate: 60 mL / min. The first eluted peak was assigned to (P)-1-(4-((1S,2S)-[1,1'-bi(cyclopropane)]-2-yl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (101.5 mg). The second eluted peak was assigned to (P)-1-(4-((1R,2S)-[1,1'-bi(cyclopropane)]-2-yl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (136.7 mg). Data for peak 1: 1H NMR(500MHz,chloroform-d)δ ppm 8.77(br s,1H),8.24(s,1H),8.12(d,J=1.8Hz,1H),7.68-7.80(m,2H),6.87(d,J=9.3Hz,1H), 6.84(d,J=9.6Hz,1H),6.76(d,J=8.8Hz,1H),6.51-6.62(m,2H),3.65(s,3H),1.87-1. 98(m,1H),1.20-1.34(m,1H),0.98-1.06(m,1H),0.95(dt,J=8.7,5.3Hz,1H),0.89(dt ,J=8.6,5.5Hz,1H),0.39-0.53(m,2H),0.14-0.28(m,2H).m / z(ESI,cation)496.0(M+H) + Data regarding Peak 2: 1 H NMR(500MHz,chloroform-d)δ ppm 9.01(br s,1H),8.23(s,1H),8.13(d,J=1.6Hz,1H),7.75(dd,J=9.1,1.8Hz,2H),6.85(br dd,J=17.3,9.5Hz,2H),6.77(d,J=8.8Hz,1H),6.44-6.66(m,2H),3.65(s,3H),1.85-1.99(m,1H),1.22-1.36(m,1H),0.98-1.11( m,1H),0.94(dt,J=8.6,5.2Hz,1H),0.88(dt,J=8.6,5.5Hz,1H),0.39-0.57(m,2H),0.16-0.32(m,2H).m / z(ESI,cation)496.0(M+H) + .

[0251] Examples 32 and 33: (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0252] Step 1: (P)-1-(4-(2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide The vials were filled with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (600 mg, 0.976 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (127 mg, 0.195 mmol), tert-butyldiphenyl(((1R,2R)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methoxy)silane (511 mg, 1.172 mmol) and potassium triphosphate (829 mg, 3.91 mmol). The vials were purged with nitrogen, followed by the addition of toluene (3.9 mL) and water (0.98 mL). The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was filtered through a Celiteno plug and concentrated under reduced pressure. The crude mixture was purified on a column to obtain the desired product as a mixture of transcyclopropyl isomers (0.96 g).

[0253] Step 2: (P)-1-(5-fluoro-4-(2-(hydroxymethyl)cyclopropyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide To a solution of (P)-1-(4-(2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (960.1 mg, 1.138 mmol) in tetrahydrofuran (5.7 mL), a solution of tetrabutylammonium in THF (3.4 mL, 3.41 mmol) was added. The mixture was stirred overnight at ambient temperature. After 16 hours, the reaction product was diluted and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude reaction mixture as an oil. The crude product was purified by column chromatography (silica gel: elution of 0-50% heptane (3:1 Â / ethanol)) to obtain the title compound (527 mg, 0.87 mmol, yield 76%) as a grayish-white solid. m / z (ESI, cation) 606.2 (M+H) + .

[0254] Step 3: (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide The vial was filled under a nitrogen stream with potassium fluoride (200 mg, 3.45 mmol), silver trifluoromethanesulfonate (670 mg, 2.6 mmol), selectfluor® (460 mg, 1.3 mmol), and (P)-1-(5-fluoro-4-(2-(hydroxymethyl)cyclopropyl)-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (526 mg, 0.87 mmol). The vial was purged with nitrogen and ethyl acetate (2.18 mL), 2-fluoropyridine (253 mg, 225 μL, 2.61 mmol), and trimethyl(trifluoromethyl)silane (371 mg, 386 μL, 2.61 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered through a Celite plug and washed with ethyl acetate. The filtrate was concentrated, and the product was purified by column chromatography (silica gel: elution 0-40% in heptane (3:1 ethyl acetate / ethanol with 10% DCM)). This material was further purified using a Chiralpak AZ-H, 2 × 25 cm, 5 μm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 30% ethanol; flow rate: 60 mL / min. The first peak to elute was assigned to (P)-1-(5-fluoro-2-methoxy-4-((1s,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (50 mg). The second peak to elute was assigned to (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (50.4 mg). m / z(ESI,cation)674.2(M+H) + .

[0255] Step 4: (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide Separately, (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (50 mg, 0.074 mmol) and (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(( Trifluoromethoxy)methyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (50.4 mg, 0.075 mmol) was dissolved in trifluoroacetic acid (171 mg, 171 μL, 1.5 mmol), and triethylsilane (43 mg, 60 μL, 0.37 mmol) was added to each reactant. The reactants were stirred at 50°C for 4 hours, then poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (silica gel: elution 10% DCM with 0-40% (3:1 ethyl alcohol / ethanol) in heptane) to obtain (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (35.5 mg, 0.064 mmol, yield 86%) and (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (38.7 mg, 0.070 mmol, yield 93%). Data for Peak 1: 1H NMR(500MHz,chloroform-d)δ 8.27(d,J=1.69Hz,1H),8.11(d,J=2.08Hz,1H),7.78(d,J=9.60Hz,1H),7.74(dd,J=2.21 ,8.95Hz,1H),7.42(s,1H),6.92(d,J=9.34Hz,1H),6.85(d,J=9.60Hz,1H),6.76(d,J=8.9 5Hz,1H),6.68(d,J=6.36Hz,1H),6.61(d,J=1.82Hz,1H),4.03-4.11(m,1H),3.95-4.03(m ,1H),3.68(s,3H),2.13-2.19(m,1H),1.64-1.73(m,1H),1.21-1.26(m,1H),1.15(m,1H). m / z (ESI, cation) 554.1 (M+H) + Data regarding Peak 2: 1 1H NMR (500 MHz, chloroform-d)δ 8.27(d,J=1.43Hz,1H),8.11(d,J=2.08Hz,1H),7.69-7.82(m,2H),7.34(s,1 H),6.92(d,J=9.21Hz,1H),6.85(d,J=9.60Hz,1H),6.77(d,J=8.95Hz,1H),6. 66(d,J=6.36Hz,1H),6.62(d,J=1.82Hz,1H),4.03-4.12(m,1H),3.97-4.03( m,1H),3.68(s,3H),2.13-2.22(m,1H),1.63-1.74(m,1H),1.09-1.26(m,2H).

[0256] Example 34: (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(1,2,4-thiadiazole-5-yl)-1,2-dihydroquinoline-6-sulfonamide [ka]

[0257] Step 1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl The vial was filled with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (50 mg, 0.084 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (13 mg, 0.021 mmol), potassium triphosphate (71 mg, 0.34 mmol), and 6-methyl-2-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazavolocan-4,8-dione (45 mg, 0.17 mmol). The vial was flushed with nitrogen, followed by the addition of toluene (450 μL) and water (112 μL). The reaction mixture was aerated with nitrogen, capped, and stirred at 50°C for 14 hours. Next, the reaction mixture was partitioned between a semi-saturated aqueous sodium chloride solution and ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The initial product was adsorbed onto a silica gel plug and eluted with 60% ethyl acetate / heptane. The filtrate was concentrated to obtain (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (59 mg, 0.095 mmol, yield 112%). m / z(ESI, cation)624.0(M+H) + .

[0258] Step 2: (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(1,2,4-thiadiazole-5-yl)-1,2-dihydroquinoline-6-sulfonamide The vial was filled with N-(4-methoxybenzyl)-1,2,4-thiadiazole-5-amine (121 mg, 0.546 mmol) and (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (309.4 mg, 0.496 mmol). The vial was flushed with nitrogen, followed by the addition of tetrahydrofuran (5.0 mL), and the reaction mixture was cooled to 0°C. Sodium tert-pentoxide (1.4 M in THF, 430 μL, 0.60 mmol) was slowly added to the reaction mixture via syringe, and the mixture was stirred at 0°C for 30 minutes. After 30 minutes, the reaction mixture was partitioned between a saturated aqueous solution of ammonium chloride and DCM. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were concentrated, and the crude product was purified by column chromatography (silica gel: elution 20%-80% ethyl ethyl elution in heptane with 10% dichloromethane additive) to obtain (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(1,2,4-thiadiazole-5-yl)-1,2-dihydroquinoline-6-sulfonamide (174 mg, 0.263 mmol, yield 53.0%) as a colorless, waxy solid. m / z(ESI, cation) 660.8(M+H) + .

[0259] Step 3: (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(1,2,4-thiadiazole-5-yl)-1,2-dihydroquinoline-6-sulfonamide To a solution of (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(1,2,4-thiadiazole-5-yl)-1,2-dihydroquinoline-6-sulfonamide (172 mg, 0.260 mmol) in TFA (2.0 mL), triethylsilane (151 mg, 0.21 mL, 1.3 mmol) was added, and the reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography (silica gel: elution 10% to 60% (3:1 ethyl alcohol / ethanol) in heptane with 10% dichloromethane additive) to obtain (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(1,2,4-thiadiazole-5-yl)-1,2-dihydroquinoline-6-sulfonamide (64.7 mg, 0.12 mmol, yield 46%) as a white solid. 1 H NMR (500MHz,DMSO-d6)δ ppm 8.43(s,1H),8.28(d,J=2.21Hz,1H),8.20(d,J=9.60Hz,1H),7.80(dd,J=8.95,2.21Hz,1H),7.34(d,J=9.86Hz,1H),7.00(d,J=6.75Hz,1H),6. 76(d,J=9.60Hz,1H),6.72(d,J=8.95Hz,1H),3.66(s,3H),2.51-2.58(m,2H),1.56-1.61(m,1H),1.46-1.51(m,1H).m / z(ESI,cation)540.8(M+H) + .

[0260] Examples 35 and 36: (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0261] Step 1: (P)-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl))-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide The vial was filled with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(oxazole-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.0 g, 1.7 mmol), 6-methyl-2-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazabolocan-4,8-dione (531 mg, 2.0 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (109 mg, 0.17 mmol), and potassium triphosphate (1.42 g, 6.7 mmol), followed by the addition of toluene (4.0 mL) and water (1.0 mL). The reaction mixture was flushed with nitrogen and stirred overnight at 50°C. After 16 hours, the reaction mixture was partitioned between ethyl acetate and brine, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated, and the crude product was purified by column chromatography (silica gel: elution of 0-30% in heptane (3:1 ethyl acetate / ethanol)) to obtain (P)-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-N-(oxazole-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (780 mg, 1.2 mmol, yield 72%) as a mixture of transcyclopropyl isomers. m / z (ESI, cation) 644.0 (M+H) + .

[0262] Step 2: (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A solution of (P)-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-N-(oxazole-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (780 mg, 1.2 mmol) in TFA (1.0 mL) was flushed with nitrogen and stirred at 50°C for 4 hours. The solvent was removed, and the crude product was redissolved in DMSO and purified as a mixture of transcyclopropyl isomers by RP_HPLC (C18, elution (water / 0.1% formic acid) for 25-70% (ACN / 0.1% formic acid)). The isomers were separated by chiral chromatography using an OHJ 21 × 250 cm, 5 μm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 20% ethanol; flow rate: 40 mL / min. The first eluting peak was assigned to (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(oxazole-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (144 mg, 0.28 mmol, yield 23%). The second eluting peak was assigned to (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(oxazole-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (205 mg, 0.39 mmol, yield 32%). Data for peak 1: 1 H NMR(500MHz,chloroform-d)δ ppm 8.24(br s,1H),7.89(br d,J=8.43Hz,1H),7.77-7.86(m,1H),7.07(s,1H),6.97(br d,J=9.08Hz,1H),6.91(br s,1H),6.84(br d,J=7.66Hz,1H),6.70-6.80(m,2H),3.70(s,3H),2.49-2.58(m,1H),1.99-2 .10(m,1H),1.44-1.54(m,1H),1.27-1.43(m,1H).m / z(ESI, cation)524.2(M+H) + Data regarding Peak 2: 1H NMR(500MHz,chloroform-d)δ ppm 8.24(br s,1H),7.89(br d,J=7.53Hz,1H),7.84(br s,1H),7.08(br s,1H),6.97(br d,J=8.17Hz,1H),6.92(br s,1H),6.84(br s,1H),6.75(br d,J=5.97Hz,2H),3.70(s,3H),2.51-2.59(m,1H),1.98-2.10(m,1H),1.47-1.53(m,1H),1.30-1.45(m,1H).m / z(ESI,cation)524.2(M+H) + .

[0263] Example 37: (P)-1-(5-cyano-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0264] Step 1: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide 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 (7.02 g, 34.4 mmol) in tetrahydrofuran (109 mL) at 0°C, sodium tert-pentoxide (30% solution in THF, 14.4 mL, 36.0 mmol) was added dropwise over 15 minutes. The dark red solution was vigorously stirred at 0°C for 1 hour, and some unreacted starting material was observed. After adding a further 500 mg of N-(4-methoxybenzyl)isoxazole-3-amine, 1.7 mL of sodium tert-pentoxide was added. The mixture was stirred for a further 30 minutes. The reaction was quenched with 100 mL of 2N HCl aqueous solution and 150 mL of siRNA. The layers were separated, and the aqueous layer was extracted with siRNA. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The mixture was diluted with 2-propanol (500 mL), and a white solid precipitated. The mixture was stirred overnight, the precipitate was isolated by vacuum filtration, washed with 2-propanol, and dried under a nitrogen stream to obtain (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (17.1 g, 27.2 mmol, yield 83%) as a grayish-white solid. m / z (ESI, cation) 524.2 (M+H) + .

[0265] Step 2: (P)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide To a solution of (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (500 mg, 0.793 mmol) and 6-methyl-2-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazabolocan-4,8-dione (252 mg, 0.951 mmol), a solution of potassium phosphate (673 mg, 3.2 mmol) in water (1.6 mL) was added, followed by the addition of [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (51.7 mg, 0.079 mmol). The reaction mixture was aerated with argon and stirred at 50°C. After 16 hours, the reaction mixture was partitioned between water and ethyl acetate; the organic layer was concentrated. The crude product was purified by column chromatography (silica gel: elution of 40-100% ethyl acetate in heptane with 10% DCM) to obtain (P)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (400 mg, 0.61 mmol, yield 76%) as a pale yellow oil solidified overnight. m / z (ESI, cation) 659.8 (M+H) + .

[0266] Step 3: (P)-1-(5-cyano-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide To a suspension of (P)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (400 mg, 0.61 mmol), potassium hexacyanoferrate(II) trihydrate (128 mg, 0.30 mmol), and potassium acetate (7.43 mg, 0.076 mmol) in a microwave vial, methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (103 mg, 0.121 mmol) was added. The vial was aerated with argon, capped, and irradiated at 100°C for 30 minutes. After 30 minutes, the reaction mixture was partitioned between water and ethyl acetate; the organic layer was concentrated. The crude product was purified by column chromatography (silica gel: elution of 40-100% ethyl acetate in heptane with 10% DCM) to obtain (P)-1-(5-cyano-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (245 mg, 0.38 mmol, yield 62%) as a mixture of transcyclopropyl isomers. The isomers were separated by chiral chromatography using an ASH 21 × 250 cm, 5 μm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 20% ethanol; flow rate: 40 mL / min. The first peak to elute was assigned to (P)-1-(5-cyano-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (44 mg, 0.068 mmol, yield 18%).The second peak to elute was assigned to (P)-1-(5-cyano-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (38 mg, 0.058 mmol, yield 15%). Data for peak 2: m / z (ESI, cation) 650.8 (M+H). + .

[0267] Step 4: (P)-1-(5-cyano-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A solution of (P)-1-(5-cyano-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (38 mg, 0.058 mmol) in TFA (2 mL) was stirred at 40°C for 2 hours. After 2 hours, the reaction mixture was concentrated, and the crude product was purified by column chromatography (silica gel: elution 10% DCM in 10-60% (3:1 ethyl acetate / ethanol) in heptane to obtain (P)-1-(5-cyano-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide) as a white powder (30 mg, 0.057 mmol, yield 84%). 1H NMR(500MHz,DMSO-d6)δ ppm 11.64(s,1H),8.73(d,J=1.82Hz,1H),8.37(d,J=2.21Hz,1H),8.22(d,J =9.60Hz,1H),7.95(s,1H),7.82(dd,J=8.95,2.21Hz,1H),7.06(s,1H),6 .80(t,J=9.67Hz,2H),6.44(d,J=1.82Hz,1H),3.78(s,3H),2.72-2.79( m,1H),2.63-2.69(m,1H),1.60-1.69(m,2H).m / z(ESI,cation)531.0(M+H) + .

[0268] Examples 38 and 39: (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0269] Step 1: (P)-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide To a solution of (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.90 g, 1.51 mmol) and 6-methyl-2-[(1s,2s)-2-(trifluoromethyl)cyclopropyl]-1,3,6,2-dioxazabolocan-4,8-dione (0.48 g, 1.81 mmol) in toluene (12.00 mL), a solution of tripotassium phosphate (1.28 g, 6.0 mmol) in water (3 mL) was added, followed by the addition of [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.098 g, 0.15 mmol). The reaction mixture was aerated with argon and stirred at 50°C. After 16 hours, the reaction mixture was partitioned between water and ethyl acetate; the organic layer was concentrated. The crude product was purified by column chromatography (silica gel: elution of 40-100% ethyl acetate in heptane with 10% DCM) to obtain (P)-N-(isoxazole-3-yl)-1-(2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.38 g, 0.61 mmol, yield 40.3%) as a mixture of transcyclopropyl isomers. The mixture of isomers was separated by chiral chromatography using an ASH 21 × 250 cm, 5 μm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 15% ethanol; flow rate: 50 mL / min. The first eluting peak was assigned to (P)-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (133 mg, 0.213 mmol, yield 14%). The second eluting peak was assigned to (P)-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (147 mg, 0.235 mmol, yield 16%).

[0270] Step 2: (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide Separately, a solution of (P)-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (133 mg, 0.213 mmol) in TFA (2 mL) and a solution of (P)-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (147 mg, 0.235 mmol) in TFA (2 mL) were stirred at 50°C for 2 hours. After 2 hours, the reaction mixture was concentrated, and the crude product was purified by column chromatography (silica gel: elution 10% DCM with 10-60% (3:1 ethyl acetate / ethanol)) to obtain (P)-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (107 mg, 0.212 mmol, yield 100%) and (P)-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (118 mg, 0.233 mmol, yield 110%) as white powders. Data on (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide: 1H NMR(500MHz,DMSO-d6)δ ppm 11.61(s,1H),8.72(d,J=1.82Hz,1H),8.34(d,J=2.21Hz,1H),8.19(d,J=9.60Hz,1H), 7.82(dd,J=9.02,2.27Hz,1H),7.20(d,J=8.04Hz,1H),7.12(d,J=1.82Hz,1H),6.99(dd ,J=8.04,1.82Hz,1H),6.77(d,J=9.60Hz,1H),6.73(d,J=8.95Hz,1H),6.44(d,J=1.69 Hz,1H),3.67(s,3H),2.42-2.57(m,2H),1.37-1.47(m,2H).m / z(ESI,cation)505.8(M+H) + Data on (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide: 1 H NMR(500MHz,DMSO-d6)δ ppm 11.61(s,1H),8.72(d,J=1.82Hz,1H),8.34(d,J=2.21Hz,1H),8.19(d,J=9.73Hz,1H),7.8 2(dd,J=9.02,2.27Hz,1H),7.20(d,J=8.04Hz,1H),7.11(d,J=1.69Hz,1H),7.00(dd,J=8.0 4,1.82Hz,1H),6.77(d,J=9.60Hz,1H),6.73(d,J=8.95Hz,1H),6.44(d,J=1.82Hz,1H),3.6 7(s,3H)2.52-2.57(m,1H)2.44-2.48(m,1H)1.38-1.48(m,2H).m / z(ESI, cation)505.8(M+H) + .

[0271] Example 40: (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(1,3,4-thiadiazole-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka]

[0272] Step 1: (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(1,3,4-thiadiazole-2-yl)-1,2-dihydroquinoline-6-sulfonamide To a suspension of (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (500 mg, 0.802 mmol) in tetrahydrofuran (10 mL) and 2-amino-1,3,4-thiadiazole (97 mg, 0.962 mmol), sodium tert-pentoxide (0.613 mL, 2.005 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour, then quenched with methanol and adsorbed onto silica gel. The crude product was purified by column chromatography (silica gel: elution (9:1 heptane / DCM) with 0-100% (3:1 ethyl acetate / ethanol)) to obtain (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(1,3,4-thiadiazole-2-yl)-1,2-dihydroquinoline-6-sulfonamide) as a white powder (322 mg, 0.60 mmol, yield 74%). 1 H NMR(500MHz,DMSO-d6)δ ppm 8.70(s,1H),8.24(d,J=2.2Hz,1H),8.18(d,J=9.6Hz,1H),7.77(dd,J=8.9,2.1Hz,1H),7.33(d,J=9.9Hz,1H),6.99(d,J=6.7Hz,1H),6.74 (d,J=9.6Hz,1H),6.70(d,J=9.0Hz,1H),3.66(s,3H),2.52-2.58(m,2H),1.55-1.61(m,1H),1.44-1.52(m,1H).m / z(ESI,cation)541.0(M+H) + .

[0273] Example 41: (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(1,3,4-thiadiazole-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka]

[0274] Step 1: (P)-6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one A 1 L three-necked flask equipped with an overhead stirrer, reflux condenser, and Claisen adapter with a nitrogen inlet was filled with 6-methyl-2-[(1r,2r)-2-(trifluoromethyl)cyclopropyl]-1,3,6,2-dioxazabolocan-4,8-dione (14.9 g, 56.1 mmol), (P)-6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinoline-2(1H)-one (22.0 g, 46.8 mmol), and tripotassium phosphate (39.7 g, 187 mmol). The solids were suspended in toluene (400 mL) and water (100 mL), and the mixture was degassed by bubbling nitrogen for 1 hour. Dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (1.52 g, 2.34 mmol) was added to the reaction mixture, and the reaction mixture was heated to 50°C with vigorous stirring. After 5.5 hours, the reaction mixture was cooled to ambient temperature and filtered through a Celite pad. The filtrate was washed with ethyl acetate (200 mL), and the filtrate layer was separated. The aqueous layer was extracted with ethyl acetate (2 × 100 mL), the combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was suspended in 25 mL of methanol and 5 mL of water, the suspension was stirred overnight, and filtered through a sintered glass filter to obtain (P)-6-(benzylthio)-1-(5-fluoro-2-methoxy-4-((2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (21.81 g, 43.7 mmol, yield 93%) as a mixture of transcyclopropyl isomers. m / z(ESI, cation) 500.2(M+H) + .

[0275] Step 2: (P)-6-(benzylthio)-1-(5-fluoro-2-hydroxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one To a solution of (P)-6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (5.0 g, 10.0 mmol) in dichloromethane (100 mL), boron tribromide (1 M solution in DCM, 20 mL, 20 mmol) was added, and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction was quenched with saturated aqueous solution of ammonium chloride (100 mL), diluted with DCM (100 mL), and the phases were separated. The organic layer was concentrated to obtain (P)-6-(benzylthio)-1-(5-fluoro-2-hydroxy-4-((1R,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one as a mixture of transcyclopropyl isomers. The cyclopropyl isomers were separated by chiral chromatography using a Whilk-O(S,S) 30 × 150 cm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 25% methanol; flow rate: 200 mL / min. The first eluting peak was assigned to (P)-6-(benzylthio)-1-(5-fluoro-2-hydroxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (1.60 g, 1.73 mmol, yield 17%). m / z(ESI, cation) 486.0(M+H) + .

[0276] Step 3: (P)-6-(benzylthio)-1-(2-cyclopropoxy-5-fluoro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one A microwave vial was filled with (P)-6-(benzylthio)-1-(5-fluoro-2-hydroxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (0.84 g, 1.73 mmol), N,N-dimethylacetamide (5.8 mL), cesium carbonate (1.7 g, 5.2 mmol), potassium iodide (0.14 g, 0.87 mmol), and bromocyclopropane (0.209 g, 1.73 mmol). The vial was capped and irradiated at 150°C for 24 hours. The vial was cooled to ambient temperature, the reaction mixture was diluted with water (100 mL), and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (silica gel: elution in heptane with 10% DCM and 0-100% ethyl acetate) to obtain 6-(benzylthio)-1-(2-cyclopropoxy-5-fluoro-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (0.65 g, 1.24 mmol, yield 71%) as a grayish-white solid. m / z(ESI, cation) 526.0(M+H) + .

[0277] Step 4: 1-(2-cyclopropoxy-5-fluoro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl To a suspension of 6-(benzylthio)-1-(2-cyclopropoxy-5-fluoro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (0.65 g, 1.24 mmol) in DCM (11.6 mL), acetic acid (0.44 mL), and water (0.29 mL), 1,3-dichloro-5,5-dimethylimidazolidined-2,4-dione (0.61 g, 3.1 mmol) was added all at once at 0°C. The reaction mixture was stirred at 0°C for 15 minutes, followed by the addition of 2,3,4,5,6-pentafluorophenol (0.455 g, 0.26 mL, 2.47 mmol), and then triethylamine (0.313 g, 0.431 mL, 3.09 mmol) dropwise. The reaction mixture was stirred for 2 hours. After 2 hours, the reaction mixture was diluted with DCM (10 mL), the organic layer was separated, and the mixture was concentrated. The crude product was purified by column chromatography (silica gel: elution 0-50% ethyl acetate in heptane) to obtain 1-(2-cyclopropoxy-5-fluoro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (0.562 g, 0.87 mmol, yield 70%) as a grayish-white solid. m / z(ESI, cation)649-8(M+H) + .

[0278] Step 5: (P)-1-(2-cyclopropoxy-5-fluoro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide To a solution of 1-(2-cyclopropoxy-5-fluoro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (0.562 g, 0.87 mmol) and isoxazole-3-amine (0.080 g, 0.95 mmol) in tetrahydrofuran (4.3 mL), sodium tert-pentoxide (0.95 mL, 1.9 mmol) was added dropwise at 0°C. The reaction mixture was stirred for 30 minutes, followed by partitioning between 1N HCl aqueous solution and ethyl acetate. The organic layers were washed with 1N HCl aqueous solution, and the combined aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified via column chromatography (silica gel: elution in 0-10% ethanol in ethyl acetate) to obtain 1-(2-cyclopropoxy-5-fluoro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide) as a pale yellow solid. The atrop isomers were separated by chiral chromatography using a Whilk-O(S,S) 2×15cm, 5μm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 30% methanol; flow rate: 80 mL / min. The first peak to elute was assigned to (P)-6-(benzylthio)-1-(5-fluoro-2-hydroxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (192 mg, 0.35 mmol, yield 37%). 1H NMR(400MHz,DMSO-d6)δ ppm 11.62(s,1H),8.72(d,J=1.76Hz,1H),8.34(d,J=2.18Hz,1H),8.19(d,J=9.64Hz,1 H),7.78-7.87(m,1H),7.36(d,J=9.95Hz,1H),7.25(d,J=6.84Hz,1H),6.76(dd,J= 9.28,5.55Hz,2H),6.42(d,J=1.55Hz,1H),3.84-3.99(m,1H),2.54-2.61(m,2H),1 .42-1.62(m,2H),0.53-0.72(m,2H),0.11-0.41(m,2H).m / z(ESI, cation)549.8(M+H) + .

[0279] Examples 42 and 43: (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (M)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0280] Step 1: 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropane-1-en-2-yl)phenyl)quinoline-2(1H)-one In a 20 mL vial, add 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinoline-2(1H)-one (500 mg, 1.063 mmol), 4,4,6-trimethyl-2-(3,3,3-trifluoropropane-1-en-2-yl)-1,3,2-dioxaborinan (472 mg, 2.126 mmol), and tripotassium phosphate (677 mg, 3.19 mmol). The reaction vessel was filled with 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (151 mg, 0.213 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl)]palladium(II) chloride (151 mg, 0.213 mmol) and purged with nitrogen. Next, the reaction vessel was sequentially filled with dioxane (3.8 mL) and water (1.3 mL) vial using a syringe. The vial was capped and heated to 50°C. After 16 hours, the reaction mixture was allowed to cool to ambient temperature and purged with 1.0 N An aqueous solution of HCl (5 mL) was added, and the mixture was diluted with toluene (5 mL). The layers were separated, and the aqueous layer was extracted with toluene (3 × 5 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellowish-brown oil. This was purified by flash column chromatography (silica gel: elution additive: 0-40% toluene in heptane with 5% CH2Cl2) to obtain 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropane-1-en-2-yl)phenyl)quinoline-2(1H)-one (516 mg, 1.063 mmol, yield 100%) as a yellowish-brown solid. m / z (ESI, cation) 486.0 (M + H) + .

[0281] Step 2: 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole-3-yl)phenyl)quinoline-2(1H)-one To a solution of 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoropropane-1-en-2-yl)phenyl)quinoline-2(1H)-one (506 mg, 1.04 mmol) in DCM (5.2 mL), (trimethylsilyl)diazomethane (2 M in heptane, 1.5 mL, 3.13 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 minutes, at 50°C for 2 hours, and overnight at ambient temperature. After 16 hours, TFA (798 μl, 10.4 mmol) was carefully added to the stirred reaction mixture via pipette. After 30 minutes, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (silica gel: elution 0-30%, Â: DCM) to obtain 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole-3-yl)phenyl)quinoline-2(1H)-one (430 mg, 0.815 mmol, yield 78%) as a pale yellow solid. m / z(ESI, cation) 528.0(M+H) + .

[0282] Step 3: 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one A 140 mL pressure vessel equipped with a pressure relief valve was packed with 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole-3-yl)phenyl)quinoline-2(1H)-one (1.13 g, 2.14 mmol) and 1,2-dichlorobenzene (10.7 mL). The reaction mixture was stirred at 208 °C for 6 hours, followed by 230 °C for a further 9 hours. The brown reaction mixture was cooled to ambient temperature and purified by column chromatography (silica gel: elution 0-75% ethyl ethyl ethyl elution in heptane) to obtain 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (493 mg, 0.99 mmol, yield 46%) as a yellowish-brown solid. m / z (ESI, cation) 500.0 (M+H) + .

[0283] Step 4: 1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl To a solution of 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (440 mg, 0.881 mmol) in DCM (8.3 mL), acetic acid (311 μL), and water (207 μL), 1,3-dichloro-5,5-dimethylimidazolidined-2,4-dione (434 mg, 2.20 mmol) was added at 0°C. The reaction mixture was stirred for 15 minutes, followed by the addition of 2,3,4,5,6-pentafluorophenol (185 μL, 1.76 mmol), and then triethylamine (307 μL, 2.20 mmol) dropwise. The reaction mixture was stirred for 3 hours and then concentrated. The crude product was purified by column chromatography (silica gel: elution 0-50%, ethyl heptane) to obtain 1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (500 mg, 0.80 mmol, yield 91%) as a grayish-white solid. m / z(ESI, cation) 623.8(M+H) + .

[0284] Step 5: (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (M)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide To a solution of isoxazole-3-amine (23 μL, 0.31 mmol) in THF (2.4 mL), 1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (150 mg, 0.24 mmol) was added. The remaining portion of THF (2.4 mL) was added, the solution was cooled to 0°C, and then lithium bis(trimethylsilyl)amide (1 M in THF) (553 μL, 0.553 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes, followed by partitioning between saturated aqueous ammonium chloride and ethyl acetate. The layers were separated, and the aqueous layer was extracted with RINKAN (3 × 5 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was diluted with DMSO and filtered through a 0.45 micron filter. The filtrate was purified by reverse-phase HPLC (C18: 25-85% (ACN / 0.1% formic acid) in water / 0.1% formic acid). The fractions containing the desired product were combined and lyophilized to obtain 1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (30 mg, 0.057 mmol). The atrop isomers were separated by chiral chromatography using a ChiralPak AS-H 2×25 cm, 5 mm column. The mobile phase was run under homogeneous solvent conditions; supercritical CO2 with 20% methanol; flow rate: 80 mL / min. The first eluting peak is assigned to (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (11.9 mg, 0.023 mmol, yield 9%), and the second peak is, (M)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (12.3 mg, 0.024 mmol, yield 10%). (P)-Data on the atrop isomer: 1H NMR(400MHz,acetonitrile-d3)δ ppm 8.37-8.42(m,1H),8.27(d,J=2.28Hz,1H),8.01(d,J=9.64Hz,1H),7.82(dd,J=8.97,2.23Hz,1H),7.36(d,J=6.32Hz,1H),7.15(d,J=9.6 4Hz,1H),6.78(dd,J=9.33,4.87Hz,2H),6.47(d,J=1.87Hz,1H),3.71(s,3H),1.49-1.57(m,2H),1.29(s,2H).m / z(ESI,cation)523.8(M+H) + Data on the (M)-atropisomer: 1 H NMR(400MHz,DMSO-d6)δ ppm 8.36(br s,1H),8.11-8.30(m,3H),7.76(dd,J=8.81,2.07Hz,1H),7.39-7.47(m,1H),7.35(d,J=6.43Hz,1H), 6.72(d,J=9.64Hz,1H),6.60(d,J=8.71Hz,1H),6.22(s,1H),3.69(s,3H),1.43-1.53(m,2H),1.32(br s,2H).m / z(ESI,cation)524.0(M+H) + .

[0285] Example 44: (P)-4-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0286] Step 1: 1-(5-(benzylthio)-2-((5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)amino)phenyl)ethane-1-one A 100 mL round-bottom flask was filled with cesium carbonate (10.13 g, 31.1 mmol), 1-(2-amino-5-(benzylthio)phenyl)ethane-1-one (2 g, 7.77 mmol), 1-fluoro-5-iodo-4-methoxy-2-((1R,2R)-2-(trifluoromethyl)cyclopropyl)benzene (2.80 g, 7.77 mmol), and toluene (25.9 mL). The mixture was aerated with nitrogen for 20 minutes, and then tris(dibenzylideneacetone)dipalladium (0.356 g, 0.389 mmol) and (5-diphenylphosphanyl-9,9-dimethylxanthene-4-yl)-diphenylphosphan (0.450 g, 0.777 mmol). The reaction mixture was stirred at 110 °C for 18 hours. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, filtered through CELITE, and washed with ethyl acetate. The resulting dark solution was evaporated to dryness. Purification by column chromatography (RediSepRf Gold 80g, gradient elution of 10%-60% ethyl acetate in heptane) yielded 1-(5-(benzylthio)-2-((5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)amino)phenyl)ethane-1-one (2.8247g, 5.77 mmol, 74% yield) as a golden-yellow oil. m / z(ESI, cation) 490.0(M+H) + .

[0287] Step 2: 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-4-hydroxyquinoline-2(1H)-one Dimethyl carbonate (2.076 g, 1.940 mL, 23.04 mmol) was added to a slurry of sodium hydride (60% dispersion in mineral oil) (0.922 g, 23.04 mmol) in tetrahydrofuran (57.6 mL). The temperature was raised to 60°C and the reaction mixture was stirred for 20 minutes. A solution of 1-(5-(benzylthio)-2-((5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)amino)phenyl)ethane-1-one (2.82 g, 5.76 mmol) in THF (10 ml) was added, and the reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was cooled to 0°C, and the reaction was quenched by adding water. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (RediSepRf Gold 80g, 10%-80% 3:1 siRNA:EtOH in heptane with 10% dichloromethane as a gradient elution additive) to obtain 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-4-hydroxyquinoline-2(1H)-one (1.666g, 3.23 mmol, yield 56%) as a pale orange solid. m / z(ESI, cation) 515.8(M+H) + .

[0288] Step 3: 6-(benzylthio)-4-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one The PhenoFluor mixture was dried by heating to 140°C for 2 hours under high vacuum. After cooling to ambient temperature under vacuum, 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-4-hydroxyquinoline-2(1H)-one (500 mg, 0.970 mmol), which had been slurryed in dry toluene (9.7 mL), was added to a vial. The reaction mixture was stirred at room temperature for half an hour, followed by 1.5 hours at 100°C under nitrogen. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, filtered through CELITE, and washed with ethyl acetate. The resulting yellowish-brown solution was evaporated to dryness. The residue solid was purified by column chromatography (RediSepRf Gold 40g, gradient elution, 10%-60% ethyl phosphate in heptane with 10% dichloromethane as an additive) to obtain 6-(benzylthio)-4-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (406.8 mg, 0.786 mmol, yield 81%) as a pale green solid. m / z (ESI, cation) 517.8 (M+H) + .

[0289] Steps 4 and 5: 4-Fluoro-1-(5-Fluoro-2-Methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl A slurry of 6-(benzylthio)-4-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)quinoline-2(1H)-one (405 mg, 0.783 mmol) in a 40 mL vial with acetonitrile (2.45 mL), acetic acid (93 μL), and water (61.4 μL) was cooled to 0°C under nitrogen, and 1,3-dichloro-5,5-dimethylhydantoin (308 mg, 1.565 mmol) was added in small increments. The pale green slurry was dissolved, yielding a yellow solution during the addition, and then a white precipitate formed while the reaction mixture was stirred at 0°C for 30 minutes. Perfluorophenol (223 mg, 1.213 mmol) in acetonitrile (0.5 mL) was added, followed by triethylamine (396 mg, 545 μL, 3.91 mmol). The pale green slurry was stirred at 0°C for 15 minutes, followed by 30 minutes at ambient temperature. Next, the reaction mixture was diluted with dichloromethane, filtered through a phase separator cartridge, and concentrated under vacuum to obtain a yellow solid. The crude product was purified by column chromatography (RediSepRf Gold 24g, gradient elution of 10%-60% ethyl acetate in heptane) to obtain a white solid of 4-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (378.4 mg, 0.590 mmol, yield 75%). m / z(ESI, cation) 641.8(M+H) + .

[0290] Step 6: 4-Fluoro-1-(5-Fluoro-2-Methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 40 mL vial was filled with isoxazole-3-amine (73.7 mg, 0.877 mmol) and 4-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (375 mg, 0.585 mmol). The vial was flushed with nitrogen for 10 minutes, and then tetrahydrofuran (1.95 mL) was added. The reaction mixture was cooled to -78°C under nitrogen. A 30% solution of sodium tert-pentoxide in THF (0.491 mL, 1.228 mmol) was slowly added via syringe, and the reaction mixture turned yellow upon addition. The reaction mixture was stirred at -78°C for 15 minutes. Saturated ammonium chloride and dichloromethane were added to the reaction mixture. The layers were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were dried by filtration through a phase separator cartridge and evaporated. The residue was purified by column chromatography (RediSepRf Gold 40g, 10%-40% 3:1 siRNA:EtOH in heptane with 10% dichloromethane as a gradient elution additive) to obtain 4-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (296.1 mg, 0.547 mmol, yield 94%) as a white foam. m / z(ESI, cation) 541.8(M+H) + .

[0291] Step 7: (P)-4-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide 4-Fluoro-1-(5-Fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (296 mg, 0.547 mmol) was purified by SFC using a Regis Whelk-O s,s column (2 × 15 cm, 5 micron) with a mobile phase of 30% methanol at a flow rate of 100 mL / min. This yielded (P)-4-Fluoro-1-(5-Fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (121 mg, 0.223 mmol, yield 41%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 11.70(br s,1H),8.73(d,J=1.69Hz,1H),8.27(d,J=2.08Hz,1H),7.96(dd,J=9.08,2.21Hz ,1H),7.37(d,J=9.86Hz,1H),7.01(d,J=6.75Hz,1H),6.89(dd,J=9.02,1.49Hz,1 H),6.80(d,J=11.68Hz,1H),6.45(d,J=1.82Hz,1H),3.63(s,3H),2.51-2.59(m,2 H),1.55-1.61(m,1H),1.49(dt,J=9.34,5.77Hz,1H).m / z(ESI, cation)541.8(M+H) + .

[0292] Examples 45 and 46: (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0293] Step 1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 100 mL round-bottom flask was packed with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-perfluorophenyl (6.01 g, 9.82 mmol) and N-(4-methoxybenzyl)isoxazole-3-amine (2.48 g, 12.14 mmol). After aerating the flask with nitrogen for 5 minutes, 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 a 5 M aqueous solution of ammonium chloride, followed by warming to ambient temperature. The mixture was extracted with ELISA (2×), the organic layer was separated, and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage Isolera One, Biotage Sfar Silica HCl 20um 50g, 0-80% ethyl acetate in heptane with 10% dichloromethane as an additive) to obtain (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (5.0g, 7.91 mmol, yield 81%) as a white solid. m / z(ESI, cation) 634.0(M+H) + .

[0294] Step 2: trans-(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 100 mL round-bottom flask was filled with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (3.914 g, 6.19 mmol), trans-6-methyl-2-(2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazabolocan-4,8-dione (1.972 g, 7.44 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ii) (0.484 g, 0.743 mmol), and tripotassium phosphate (5.25 g, 24.76 mmol). The flask was capped and purged with nitrogen for 5 minutes, after which toluene (30.9 mL) and water (7.74 mL) were added. The resulting mixture was aerated with nitrogen for 15 minutes, followed by stirring at 50°C. After 16 hours, the reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was separated, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (Biotage Isolera One, Biotage Sfar Silica HCl 25g, eluate 0-70% ethyl acetate in heptane with 10% dichloromethane as an additive) to obtain (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (3.748g, 5.67 mmol, yield 92%) as a grayish-white solid. m / z(ESI, cation) 662.2(M+H) + .

[0295] Step 3: (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (3.748g, 5.67mmol) is used in Chiralpak IE (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.68 g, 2.54 mmol, yield 45%) and (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.75 g, 2.65 mmol, yield 47%).

[0296] Step 4: (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide Two 40 mL vials were filled with either (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.68 g, 2.54 mmol) or (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.75 g, 2.65 mmol). Next, 1,1,1-trifluoroacetic acid (23.84 g, 16 mL, 209 mmol) was added.

[0297] The resulting mixture was stirred at 40°C for 2.5 hours. The reaction mixture was cooled, and excess TFA was removed under vacuum. The obtained residue was subjected to reverse-phase purification (ISCO, water, 25-70% acetonitrile in 0.1% formic acid additive), and after freeze-drying, (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.9991 g, 1.845 mmol, yield 73%) and (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.1023 g, 2.036 mmol, yield 80%) were obtained as white powders. 1 H NMR(500MHz,DMSO-d6)δ ppm 11.96(br s,1H),8.72(d,J=1.8Hz,1H),8.45(d,J=7.8Hz,1H),8.22(d,J=9.7Hz,1H),7.35(d,J=9.9Hz,1H),6.99(d,J=6.7Hz,1H),6.74(d,J=9.6Hz,1 H),6.53(d,J=11.9Hz,1H),6.38(d,J=1.8Hz,1H),3.68(s,3H),2.5-2.6(m,2H),1.5-1.6(m,1H),1.48(td,J=5.9,9.3Hz,1H),m / z(ESI, cation) 542.0 (M+H) + and 1 H NMR(500MHz,DMSO-d6)δ ppm 11.96(br s,1H),8.72(d,J=1.8Hz,1H),8.45(d,J=7.8Hz,1H),8.21(d,J=9.7Hz,1H),7.34(d,J=9.9Hz,1H),7.00(d,J=6.7Hz,1H),6.74(d,J=9.6Hz,1 H),6.55(d,J=11.9Hz,1H),6.38(d,J=1.8Hz,1H),3.68(s,3H),2.6-2.6(m,1H),2.5-2.6(m,1H),1.4-1.6(m,2H),m / z(ESI,cation)542.2(M+H)+ .

[0298] Examples 47 and 48: (P)-7-fluoro-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-7-fluoro-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] [ka]

[0299] Step 1: (E)-3-(2-amino-5-bromo-4-fluorophenyl) ethyl acrylate A 100 mL round-bottom flask was packed with 4-bromo-5-fluoro-2-iodoaniline (15 g, 47.5 mmol), ethyl acrylate (4.99 g, 5.43 mL, 49.9 mmol), sodium bicarbonate (9.97 g, 119 mmol), palladium(II) acetate (0.533 g, 2.374 mmol), and N,N-dimethylformamide (31.7 mL). The reaction mixture was stirred under nitrogen at 100 °C for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered through a CELITE filter. The filtrate was concentrated and purified by column chromatography (Biotage Snapultra 340 g, 0-60% ethyl acetate in heptane with 10% dichloromethane additive) to obtain (E)-3-(2-amino-5-bromo-4-fluorophenyl)acrylate (11.3 g, 39.2 mmol, yield 83%). m / z (ESI, cation) 288.0 (M+H) + .

[0300] Step 2: (E)-3-(2-amino-5-(benzylthio)-4-fluorophenyl)ethyl acrylate A 250 mL round-bottom flask was packed with ethyl (E)-3-(2-amino-5-bromo-4-fluorophenyl)acrylate (10 g, 34.7 mmol), 1,4-dioxane (87 mL), and n,n-diisopropylethylamine (13.46 g, 18.19 mL, 104 mmol). The mixture was aerated with nitrogen for 20 minutes, followed by the addition of bis[tris(dibenzylideneacetone)palladium(0)] (1.589 g, 1.735 mmol), (5-diphenylphosphanyl-9,9-dimethylxanthene-4-yl)-diphenylphosphan (2.008 g, 3.47 mmol), and benzyl mercaptan (5.17 g, 4.88 mL, 41.6 mmol). The reaction mixture was heated to 80°C overnight. The reaction mixture was cooled and filtered on CELITE. CELITE was washed with dichloromethane, and the solvent was removed under vacuum. The crude product was purified by column chromatography (Biotage SNAP ultra 100 g, gradient elution in heptane, 0-80% ethyl acetate) to obtain (E)-3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate ethyl (9.9 g, 29.9 mmol, yield 86%). m / z (ESI, cation) 332.0 (M+H) + .

[0301] Step 3: (E)-3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)-4-fluorophenyl)ethyl acrylate A 100 mL round-bottom flask was filled with cesium carbonate (14.35 g, 44.1 mmol), ethyl (E)-3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate (3.65 g, 11.01 mmol), 4-bromo-1-iodo-2-methoxybenzene (3.45 g, 11.01 mmol), and toluene (36.7 mL). The mixture was aerated with nitrogen for 20 minutes, followed by the addition of tris(dibenzylideneacetone)dipalladium (0.555 g, 0.606 mmol) and (5-diphenylphosphanyl-9,9-dimethylxanthene-4-yl)-diphenylphosphan (0.701 g, 1.212 mmol). The reaction mixture was stirred overnight at 110 °C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through CELITE. The filtrate was concentrated under reduced pressure to obtain the initial product, which was purified by column chromatography (Biotage Snapultra 50g, 0-70% ethyl acetate with 10% dichloromethane as an additive) to obtain (E)-3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)-4-fluorophenyl) ethyl acrylate (1.95g, 3.78 mmol, yield 34%). m / z (ESI, cation) 517.8 (M+H) + .

[0302] Step 4: 6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)-7-fluoroquinoline-2(1H)-one Ethyl (E)-3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)-4-fluorophenyl)acrylate (1.9 g, 3.68 mmol) was dissolved in methanol (9.68 mL). Tributylphosphine (0.223 g, 0.276 mL, 1.104 mmol) was added to the reaction mixture. The reaction mixture was then stirred at 70°C for 5 hours. The solvent was then removed under vacuum. The crude product was purified by column chromatography (Biotage Snapultra 25 g, 0-80% ethyl acetate in heptane) to obtain 6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)-7-fluoroquinoline-2(1H)-one (1.32 g, 2.81 mmol, yield 76%). m / z (ESI, cation) 472.0(M+H)+.

[0303] Steps 5 and 6: 1-(4-bromo-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl A 100 mL round-bottom flask was filled with 6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)-7-fluoroquinoline-2(1H)-one (1.3 g, 2.76 mmol), acetonitrile (14 mL), acetic acid (0.800 mL), and water (0.500 mL). The resulting mixture was cooled to 0°C, and 1,3-dichloro-5,5-dimethyl-2,4-imidazolidinedione (0.871 g, 4.42 mmol) was added in small amounts. The resulting suspension was stirred at 0°C for 15 minutes. Next, a solution of pentafluorophenol (1.017 g, 5.53 mmol) in acetonitrile (14 mL) was added over 10 minutes, followed by the addition of triethylamine, anhydrous (1.398 g, 1.942 mL, 13.82 mmol) over 20 minutes. The mixture was continued to stir for 30 minutes. Ice water was added, the precipitated solid was filtered, and washed with water. The initial product was purified by stirring with methanol (150 mL), filtered, washed with MeOH (50 mL), and dried to obtain 1-(4-bromo-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl (1300 mg, 2.188 mmol, yield 79%) as a grayish-white solid. m / z (ESI, cation) 593.8(M+H)+.

[0304] Step 7: 1-(4-bromo-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl was first purified by SFC using a Chiralcel OJ-H column (3 × 15 cm, 5 micron) with a mobile phase of 15% isopropanol at a flow rate of 160 mL / min. Next, the obtained product was purified by SFC using a Whilk-O s,s column (2 × 15 cm, 5 micron) with a mobile phase of 50% 3:1 isopropanol:dichloromethane at a flow rate of 80 mL / min. This yielded 1-(4-bromo-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-perfluorophenyl (380 mg, 0.639 mmol, yield 29%).

[0305] Step 8: (P)-1-(4-bromo-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide 1-(4-bromo-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid (P)-perfluorophenyl (380 mg, 0.639 mmol) and N-(4-methoxybenzyl)isoxazole-3-amine (157 mg, 0.767 mmol) were dissolved in tetrahydrofuran (3.20 mL). The solution was cooled to -78°C. A 30% solution of sodium tert-pentoxide in THF (384 μl, 0.959 mmol) was slowly added to the solution. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction was quenched with 5 M aqueous ammonium chloride solution and extracted with siRNA (2×). The organic layer was separated and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage Snapultra 100g, 0-80% ethyl acetate in heptane with 10% dichloromethane additive) to obtain (P)-1-(4-bromo-2-methoxyphenyl)-7-fluoro-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (316 mg, 0.514 mmol, yield 80%) as a white solid. m / z(ESI, cation)613.8(M+H)+.

[0306] Step 9: trans-(P)-7-fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 40 mL vial was filled with (P)-1-(4-bromo-2-methoxyphenyl)-7-fluoro-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (316 mg, 0.514 mmol), trans-6-methyl-2-(2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazabolocan-4,8-dione (164 mg, 0.617 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ii) (67.0 mg, 0.103 mmol), and tripotassium phosphate (437 mg, 2.057 mmol). The vial was capped and aerated with nitrogen for 5 minutes, after which toluene (2.57 mL) and water (0.643 mL) were added. The resulting mixture was aerated with nitrogen for 10 minutes, followed by stirring at 50°C for 4 hours. The crude mixture was extracted with ethyl acetate. The organic layer was separated and concentrated. The crude product was purified by column chromatography (Biotage snapultra 10 g, 0-60% ethyl acetate in heptane with 10% dichloromethane as an additive) to obtain trans-(P)-7-fluoro-N-(isoxazole-3-yl)-1-(2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (340 mg, 0.528 mmol, yield 103%). m / z(ESI, cation) 644.0(M+H)+.

[0307] Step 10: trans-(P)-7-fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)-7-fluoro-N-(isoxazole-3-yl)-1-(2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (340 mg, 0.528 mmol) was dissolved in trifluoroacetic acid (26.4 mL). The reaction mixture was stirred at 40°C for 4 hours. The solvent was removed by a stream of nitrogen. The initial product was purified by column chromatography (Biotage Snapultra 10 g, 0-60% ethyl acetate in heptane with 10% dichloromethane as an additive) to obtain trans-(P)-7-fluoro-N-(isoxazole-3-yl)-1-(2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0308] Step 11: (P)-7-fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-7-fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide trans-(P)-7-fluoro-N-(isoxazole-3-yl)-1-(2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, two Chiralpak Purification by SFC via a 25% ethanol mobile phase using an AS-H, 5 μm column (3 × 25 cm + 3 × 25 cm) at a flow rate of 80 mL / min yielded (P)-7-fluoro-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (44 mg, 0.085 mmol, yield 16%) and (P)-7-fluoro-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (36 mg, 0.068 mmol, yield 13%). 1 H NMR(500MHz,DMSO-d6)δ ppm 11.95(br s,1H),8.60(s,1H),8.38(d,J=7.7Hz,1H),8.18(d,J=9.6Hz,1H),7.21(d,J=8.0Hz,1H),7.10(d,J=1. 7Hz,1H),6.99(dd,J=8.1,1.8Hz,1H),6.70(d,J=9.6Hz,1H),6.29-6.36(m,2H),3.69(s,3H),2.93(br s,1H),2.52-2.56(m,1H),1.38-1.47(m,2H);m / z(ESI,cation)524.0(M+H)+ and 1H NMR(500MHz,DMSO-d6)δ ppm 11.96(br s,1H),8.60(s,1H),8.38(d,J=7.5Hz,1H),8.18(d,J=9.6Hz,1H),7.21(d,J=7.9Hz,1H),7.12(d,J=1. 7Hz,1H),6.98(dd,J=8.1,1.8Hz,1H),6.70(d,J=9.6Hz,1H),6.29-6.36(m,2H),3.69(s,3H),2.93(br s,1H),2.52-2.56(m,1H),1.34-1.46(m,2H);m / z(ESI,cation)524.0(M+H)+.

[0309] Biological examples The following assays were used to test exemplary compounds of the present invention. Data relating to those examples, tested according to the procedures described below, are presented in Table 1.

[0310] IONWORKS BARRACUDA (IWB) Automated Patch Clamp Assay (Same protocol for both human and mouse) The current of human NaV1.7 was 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 used in the IonWorks Quattro trial. 1The cells were cultured and prepared according to the previously described records. The external solution consisted of 140 NaCl, 5 KCl, 2 CaCl, 2 MgCl, 1 HEPES, and 11 glucose, with 320 mOsmol N-methyl-D-glucamine (in mM). The internal solution consisted of 70 KCl, 70 KF, 2 MgCl, 5 HEDTA, and 1 HEPES, with 300 mOsmol N-methyl-D-glucamine (in mM). The internal solution consisted of 7.25 KCl, 70 KF, 2 MgCl, 5 HEDTA, and 10 HEPES, with 300 mOsmol N-methyl-D-glucamine (in mM). From a holding potential of -110 mV, the current was induced by a series of 26 depolarizations with durations of 150 ms each, down to -20 mV, at a frequency of 5 Hz. 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, cells were clamped to -110mV for 3 seconds to collect unbound channels and subjected to the same 26-pulse voltage protocol as above. The inhibition percentage 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. Concentration-response curves of the inhibition percentage depending on the concentration were generated and IC was performed 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.

[0311] Microsome-specific clearance assay The objective of this assay was to determine the intrinsic clearance of the test compound in microsomes from pre-symptomatic species and humans by monitoring the time-dependent disappearance of the test article in liver microsomes. Microsomes of 20 mg / mL stock stored at -80°C were used. The list of chemicals used was: (1) test article, 10 mM stock (DMSO), or powder from the 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 microsomal protein and 0.5 μM test article, and incubation was performed in triplicates. Typical time points for the assay were 1, 5, 10, 20, 30, and 40. The assay was performed in a 96-well format, with samples continuously drawn from 400 μL of incubation. At the appropriate time, 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 calculations were performed using Galileo.

[0312] procedure: Microsomes were removed from a -80°C freezer and thawed at room temperature or in a 37°C water bath. After thawing, they were stored on ice. Microsomes were added to 0.1 M phosphate buffer (0.53 mg / L), and a constant volume of 250 μL was taken per reaction. A 10 mM stock of the test material was prepared in DMSO. 1 / 100 of the stock was diluted with acetonitrile:water 50:50 to prepare a 100 μM stock. Approximately 2.5 μL of the 100 μM test material stock was added to each reaction to achieve a final substrate concentration of 1.05 μM. (NB: At this stage, the concentration was approximately twice as high as the final incubation concentration, considering that it would be diluted approximately 1:1 with NADPH).

[0313] A 1.9 mM NADPH solution was prepared in 0.1 mM phosphate buffer. Four × 250 μL replication wells containing the substrate and microsomes with 1.05 μM substrate and 0.53 mg / mL protein were prepared. Three replication wells containing 210 μL of 1.90 mM NADPH and one well containing buffer (-NADPH) were also prepared. The microsomes, 0.1 M phosphate buffer, and test material were pre-incubated at 37°C for 5 minutes. To initiate the reaction, 190 μL of substrate was added to the NADPH-containing well to obtain final concentrations of 0.25 mg / mL microsomes, 0.5 μM test material, and 1 mM NADPH. Fixed amounts of 35 μL were taken at 1, 5, 10, 20, 30, and 40 minutes. The reaction was then quenched with acetonitrile containing an internal standard in a 1:1 ratio, placed in a vortex mixer, and centrifuged. Next, the solution was transferred for bioanalysis by LC-MS / MS.

[0314] 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 volume of 10 ml / kg. The solvents used were 1% Tween 80 pH10 with 2% HPMC / NaOH; DI water at pH10 w / NaOH; or 2% HPMC / 1% Tween 80 pH2.2.

[0315] Two to three hours after treatment with the test material, animals were placed in open-field chambers 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, 16" x 16" open-field chambers, KINDER SCIENTIFIC®, San Diego, CA were used. For the experiments at Cambridge Massachusetts, 16" x 16" open-field chambers, SAN DIEGO INSTRUMENTS®, San Diego, CA were used. Spontaneous motor activity (horizontal movement and standing behavior) parameters were measured by an automated method involving the blocking of an infrared light beam.

[0316] 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 allow the hepatocytes to form a confluent layer. 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 carried out 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 replaced daily until the sample was treated. After 72 hours of incubation, the samples were 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 obtained as percentage of control (POC) and, where appropriate, according to guidance from 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 presented as such.

[0317] 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 allow the hepatocytes to form a confluent layer. 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 culture medium containing the appropriate concentration of the test compound was replaced daily until the sample was treated. After 72 hours of incubation, the samples were 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). The data were analyzed, and the percentage of control (POC) and, where appropriate, the 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 presented as such.

[0318] The compounds of the present invention can also be tested in the following in vivo assays.

[0319] Rat formalin model of persistent pain On the day of the test, animals (untreated, male Sprague Dolly rats) weighing between 260 and 300 g at the start of the test may be obtained from Harlan (Indianapolis, IN). All animals may be housed under a 12 / 12 light / dark cycle with light at 0600. Rodents may be housed two per cage in cages with a sturdy floor laid on corn cobs, with free access to food and water. Animals should be acclimatized to their enclosures for at least 5 days before the start of the test and should be placed in the laboratory at least 30 minutes before administration. Animals are pre-treated with the appropriate test compound by either forced oral administration or intraperitoneal injection at a desired pre-treatment time (typically 2 hours before the start of the test), and then returned to their home cages. After administration and at least 30 minutes before the start of the test, animals may be acclimatized to their individual test chambers. At the time of the test, each animal may be lightly wrapped in a towel with its left hind limb 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 a volume of up to 50 μL using a 30 g needle. Immediately after injection, a small metal band can be attached to the plantar side of the left hind limb with a drop of LOCTITE (adhesive). The animal may then be placed in a test chamber, and the number of flinches can be recorded between 10 and 40 minutes after formalin injection. A flinch is defined as a rapid, spontaneous movement of the injected hind limb that is not associated with walking movement. Flinches can be quantified with the help of an automated pain analyzer developed by the Anesthesiology Department of the University of California, San Diego. Individual data can be expressed as % Maximum Potential Effect (%MPE), calculated by the following formula: (-(Individual score - Solvent mean score) / Solvent mean score)) * 100 = %MPE

[0320] Statistical analysis may be performed by analysis of variance (ANOVA) along with a post-hoc analysis using Bonferroni, comparing the solvent group with the solvent group for significant main effects. Data may be expressed as mean %MPE + / - standard error for each group.

[0321] Rat open-field assay On the day of the test, animals (untreated, male Sprague Dolly rats) weighing between 260 and 300 g at the start of the test may be obtained from Harlan (Indianapolis, IN). All animals may be housed under a 12 / 12 light / dark cycle with light at 0600. Rodents may be housed two per cage in cages with a sturdy floor laid with corn cobs, and food and water may be freely available. Animals should be acclimatized to their enclosures for at least 5 days before the start of the test and should be placed in the laboratory at least 30 minutes before administration. In a room separate from the laboratory, animals may be pre-treated with the appropriate test compound by either forced oral administration or intraperitoneal injection for a 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 may be moved to an open-field laboratory in their home cages. Each animal may be placed in a separate test chamber and a motion tracking system is initiated. The laboratory house lights should be turned off, and the animals may be allowed to explore a new open field for 30 minutes. An automated motion tracking device, manufactured by San Diego Instruments, San Diego, CA, can be used to capture the animals' exploration with the help of an infrared light beam to detect their movements. These movements include basic movements and vertical standing, which may be used as the primary endpoint of this assay. At the end of the test, the house lights may be turned on, and the animals should be removed from the apparatus. Data may be expressed as a percentage change from the solvent control using the following formula: (1 - (Test average / Solvent average)) * 100 = % change

[0322] Statistical analysis may be performed by analysis of variance (ANOVA) along with post-hoc analysis using Dunnett to track significant main effects.

[0323] Mouse formalin model of persistent pain Mice (untreated, male C57Bl / 6) weighing between 22 and 30 g at the start of the study were obtained from Harlan (Indianapolis, IN). All animals were housed under a 12 / 12 light / dark cycle with light at 06:30. Rodents were housed individually in cages with a sturdy floor laid on corn cobs, and had free access to food and water. Animals were acclimatized to their enclosures for at least 5 days before the start of the study and placed in the laboratory at least 30 minutes before administration. Animals were pre-treated with the appropriate test compound by either forced oral administration or intraperitoneal injection at a desired pre-treatment time (typically 2 hours before the start of the study) and subsequently returned to their home cages. After administration and at least 5 minutes before the start of the study, animals were acclimatized to their individual test chambers. At the time of 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 in volumes up to 20 μL using a 30 g needle. 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 movement.

[0324] Statistical analysis was performed by analysis of variance (ANOVA) along with a post-hoc analysis using Dunnett's post-hoc analysis for significant main effects compared to the solvent group. Data were expressed as mean + / - standard error for each group.

[0325] Table 1 provides data and priority documents relating to the compounds exemplified in this application as representative compounds of the present invention, as follows: compound names (named using ChemDraw Ultra version 15.1; with specific stereochemical designations such as P, M, cis, and trans added, where available); and in vitro human Nav 1.7 IWQ data (IC in uM units). 50 Biological data including human CYP3A4 mRNA induction at 10 μM of control and percentage (POC) (%). Ex.# refers to the example number. ND means data is not available.

[0326] The efficacy of the compound of the present invention is Na V Using the IonWorks Barracuda automated electrophysiology platform described above, we evaluated the ability of compounds to block sodium permeability through the 1.7 channel, human Na V 1.7 channels were evaluated. Voltage protocols that perform both state-dependent and use-dependent inhibition were found to be related to the innate state of Na in pain-sensing neurons in vivo. V It was used because it was considered more appropriate for 1.7 channels.

[0327] Cytochrome P450 (CYP) is a well-known superfamily of enzymes involved in the oxidative and reductive metabolic transformations of drugs used in clinical practice. In addition, CYP enzymes are generally associated with the causes of many clinically relevant drug interactions. Among CYP enzymes, CYP3A4 is not only the most dominant CYP enzyme in the liver and intestines, but is also involved in the metabolism and excretion of approximately 50% of commercially available drugs. Furthermore, CYP3A4 activity can be induced (increased) or inhibited (decreased) in response to the administration of certain drugs, thereby affecting the concentrations of those drugs themselves or certain concomitant drugs in the body. Typically, CYP3A4 induction is an undesirable characteristic of drug molecules because it can lead to decreased concentrations of the parent drug, potentially resulting in an increased risk of ineffectiveness for the patient, or increased formation of metabolites, potentially leading to safety risks. The characteristics of CYP3A4 induction were evaluated in in vitro induction assays in which human hepatocytes were exposed to test compounds at physiologically appropriate concentrations. Changes in CYP3A4 levels were evaluated at the end of the experiment and compared to the elevation in levels observed after treatment with rifampin, a well-established CYP3A4 inducer.

[0328] A representative compound of the present invention exhibits either preferred activity for hNav1.7 IWQ or preferred human CYP3A4 induction data compared to compound X named 1-(4-cyclopropyl-5-fluoro-2-methoxyphenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide), which has the structure shown below: [ka]

[0329] Compound X is illustrated in International Publication No. 2014201206A1, Example No. 1145. The preferred compounds of the present invention have both preferred activity against human Nav1.7 IWQ and preferred human CYP3A4 induction data compared to compound X.

[0330] [Table 8]

[0331] [Table 9]

[0332] [Table 10]

[0333] [Table 11]

[0334] The invention described above has been described in some detail with illustrations and examples for clarity and understanding. Those skilled in the art will understand that variations and modifications may be made within the scope of the appended claims. Therefore, it should be understood that the above description is intended to be illustrative and not limiting. Accordingly, the scope of the invention should be determined not in light of the above description, but rather in light of the appended claims below, along with the full scope of equivalents to which such claims are granted.

[0335] All patents, patent applications, and publications referenced herein are incorporated herein by reference in whole for all purposes to the same extent that each individual patent, patent application, or publication is thus indicated individually.

Claims

1. Equation (Ia): 【Chemistry 1】 (In the formula, R １ａ is methyl, -O-CF ３ CF ３ , cyclopropyl, or phenyl; R ２ H, Halo, CN, C １～６ Alkyl, or C １～６ It is a haloalkyl; R ３ is, -O-C １～６ It is alkyl, -O-cyclopropyl, or -O-cyclobutyl; R ４ is isoxazolyl, pyridazinyl, thiadiazolyl, oxazolyl, or pyrimidinyl; R ６ and R ７ Each of them is H; and R ５ａ ;R ５ｂ ;R ５ｃ ;R ５ｄ ; and R ５ｅ Each of these is independently either H or halo. A compound thereof, or a pharmaceutically acceptable salt thereof, The compound is a P-atrop isomer. A compound, or a pharmaceutically acceptable salt thereof.

2. R ２ However, H, fluoro, chloro, CN, methyl, CF ３ CHF ２ , or CH ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is F.

3. R ２ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is H, fluoro, chloro, CN, or methyl.

4. R ２ A compound according to any one of claims 1 to 3, wherein the compound is H or fluoro, or a pharmaceutically acceptable salt thereof.

5. R ３ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound is methoxy.

6. R ４ The compound according to any one of claims 1 to 5, wherein the compound is isoxazolyl, or a pharmaceutically acceptable salt thereof.

7. R ４ The compound according to any one of claims 1 to 5, wherein the compound is pyridazinyl, or a pharmaceutically acceptable salt thereof.

8. R ４ The compound according to any one of claims 1 to 5, wherein the compound is thiadiazolyl, or a pharmaceutically acceptable salt thereof.

9. a) R ５ａ ;R ５ｂ ;R ５ｃ ;R ５ｄ ; and R ５ｅ Is each of them hydrogen? b) R ５ａ is F; and R ５ｂ ;R ５ｃ ;R ５ｄ ; and R ５ｅ Each of them is hydrogen; or c) R ５ｄ is F; and R ５ａ ;R ５ｂ ;R ５ｃ ; and R ５ｅ Each of them is hydrogen. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

10. R １ａ However, CF ３ or methyl; R １ａ The cyclopropyl ring bonded to the R by a single bond is a trans isomer; ２ However, it is H or F; R ４ However, it is isoxazolyl, pyridazinyl, or thiadiazolyl; and R ５ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is H or F.

11. R １ａ However, CF ３ or methyl; R １ａ The cyclopropyl ring bonded to the cyclopropyl ring by a single bond is a cis isomer; R ２ However, it is H or F; R ４ However, it is isoxazolyl, pyridazinyl, or thiadiazolyl; and R ５ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is H or F.

12. R １ａ However, CF ３ And; R １ａ The cyclopropyl ring bonded to the R by a single bond is a trans isomer; ２ However, it is H; R ４ However, it is isoxazolyl, pyridazinyl, or thiadiazolyl; and R ５ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein F is present.

13. R １ａ However, CF ３ And; R １ａ The cyclopropyl ring bonded to the R by a single bond is a trans isomer; ２ However, F is; R ４ However, it is isoxazolyl, pyridazinyl, or thiadiazolyl; and R ５ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein H is present.

14. R ４ The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein the compound is isoxazolyl.

15. R ４ The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein the compound is isoxazolyl.

16. The aforementioned compound, a) (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; b) (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; c) (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-methylcyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; d) (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-phenylcyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; e) (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-phenylcyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; f) (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; g) (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; h)(P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(1,2,4-thiadiazole-5-yl)-1,2-dihydroquinoline-6-sulfonamide; i) (P)-1-(5-cyano-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; j)(P)-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; k)(P)-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; l)(P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(1,3,4-thiadiazole-2-yl)-1,2-dihydroquinoline-6-sulfonamide; m)(P)-1-(2-cyclopropoxy-5-fluoro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; n)(P)-4-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; o)(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazole-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or p)(P)-7-fluoro-N-(isoxazole-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

18. A pharmaceutical composition for treating pain, cough, or itching, comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition according to claim 18, 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.

20. The pharmaceutical composition according to claim 18, wherein the cough is selected from post-viral infection cough, viral cough, or acute viral cough.

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