Cyclobutyl dihydroquinoline sulfonamide compounds

Abstract

To provide cyclobutyl dihydroquinoline sulfonamide compounds.SOLUTION: The present invention provides a cyclobutyl dihydroquinoline sulfonamide compound of formula (I) in the figure, an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof. The compounds are useful for the treatment of diseases associated with the activity of sodium channels such as pain disorders, cough, and itch.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention provides cyclobutyldihydroquinoline compounds that are inhibitors of voltage-gated sodium channels (Nav), particularly Nav 1.7, and that are useful in treating diseases treatable by inhibition of sodium channels, such as pain disorders. Pharmaceutical compositions containing the compounds of the invention are also provided. [Background technology]

[0002] A 2011 report from the Institute of Medicine estimated that 100 million adults in the United States, approximately 30% of the population, suffer from chronic pain (C & E News, Bethany Halford, "Changing the Channel," published 3-24). Chronic pain by definition involves abnormal electrical spike generation in neurons in the pain pathway: peripheral sensory neurons, spinal cord neurons, neurons in the pain matrix of the brain (e.g., somatosensory cortex, insular cortex, anterior cingulate cortex), and / or neurons in the brainstem. 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-gated sodium channels (Hille B, Ion Channels of Excitable Membranes. Sinauer Associates, Inc.: Sunderland MA, 3 rdThere are nine different isoforms of voltage-gated sodium channels (Nav 1.1 to Nav 1.9), which have distinct expression patterns in neurons and tissues, including cardiac and skeletal muscles (Goldin, A.L., "Resurgence of sodium channel research," Ann Rev Physiol 63:871-894, 2001; Wood, J., Nand, and Boorman, J. "Voltage-gated sodium channel blockers: target validation and therapeutic potential," Curr. Top Med. Chem. 5:529-537, 2005).

[0003] Nav1.1 and Nav1.2 are highly expressed in the brain (Raymond, CK, et al., J. Biol. Chem. (2004) 279(44):46234-41) and are essential for normal brain function. Some loss of function due to Nav1.1 mutations in humans is presumed to lead to epilepsy because these channels are expressed in inhibitory neurons (Yu, FH, et al., Nat. Neuroscience (2006), 9(9)1142-1149). Nav1.1 is also expressed in peripheral neuronal systems, and inhibition of Nav1.1 in the periphery can reduce pain. Therefore, while inhibition of Nav1.1 may be useful for treating pain, it may also cause anxiety and hyperexcitability, which may be undesirable. Nav1.3 is primarily expressed in the central nervous system during embryonic development, and its expression has been found to be upregulated after nerve injury in rats (Hains, B.D., et al., J. Neuroscience (2030) 23(26):8881-8892). Nav1.4 is primarily expressed in skeletal muscle. Mutations in its gene and its product have significant effects on muscle function, including 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. The 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-gated sodium channel expressed throughout the central and peripheral nervous systems. Nav1.8 is primarily expressed in sensory ganglia of the peripheral nervous system, such as the dorsal root ganglion. No Nav1.8 mutations have been identified that result in diverse pain responses 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 that is primarily 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 voltage-gated sodium ion channel Nav1.7 (SCN9A) is required for sensory pain. Rare genetic forms of primary erythromelalgia and paroxysmal excruciating pain, severe chronic pain, are caused by mutations that increase the activity of Nav1.7 (Fertleman CR, Baker MD, Parker KA, Moffatt S., et al., "SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlying distinct channel defects and phenotypes," Neuron 52:767-774, 2006; Yang Y., Wang Y., Li S., et al., "Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia," J. Med. Genet. 41:171-174, 2004; Drenth JPH, te Morsche RHM, Guillet G., Taieb A., et al., "SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage-gated sodium channels,”J Invest Dermatol 124:1333-1338).Conversely, two separate clinical studies have identified loss of function of Nav1.7 through mutations that truncate the protein and disrupt its function as the underlying cause of the genetic disorder congenital insensitivity to pain (CIP) (Cox JJ, Reimann F, Nicholas AK, et al. “An SCN9A channelopathy causes congenital inability to experience pain,” Nature 444:894-898, 2006; Goldberg YP, MacFarlane J., MacDonald ML, Thompson J., et al. “Loss-of-function mutations in the Nav1.7 gene underlying congenital indifference to pain in multiple human populations,” Clin Genet 71:311-319, 2007). This disorder is inherited in a Mendelian recessive manner with 100% penetrance. The phenotype associated with CIP is extreme: affected individuals have been reported to experience painless burns, childbirth, appendicitis, and fractures, and to be insensitive to clinical measures of pain, such as pinprick or tendon compression. However, sensory, motor, autonomic, and other measured functions are normal, with the only reported abnormality being anosmia (the inability to sense smell). These studies indicate that, among many possible targets in the pain pathway, Nav 1.7 controls one or more control points critical to pain perception.

[0005] Nonselective sodium channel inhibitors such as lidocaine, mexiletine, and carbamazepine have demonstrated clinical efficacy in chronic pain, including neuropathic pain. However, their potential to affect sodium channels other than those involved in pain pathways limits their dosage and application. Lidocaine is a local 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 systemic pain relief. Glenn F. King, a professor at the University of Queensland in Australia who studies ion channel-blocking venoms, has stated, "If you give a drug that blocks Nav1.7 but also blocks Nav1.5, the patient will die of heart failure." "It would be a completely painless death, but the patient will still die." Therefore, selectivity for Nav1.7 over Nav1.5 is particularly desirable. Researchers have striven to discover molecules that inhibit or block the activity of only Nav1.7. To complicate this problem, the identity, full location, full function and / or three-dimensional structure of each subtype of voltage-gated sodium channel protein is not known or is not fully understood.

[0006] As a result, some researchers have attempted to identify small molecule inhibitors of Nav1.7. For example, Chafeev et al., in U.S. Patent No. 8,101,647, disclose spiro-oxindole compounds for the treatment and / or prevention of sodium channel-mediated diseases, such as pain. WO 2013 / 134518 and WO 2014 / 201206 disclose sulfonamide derivatives different from those of the present invention. Therefore, there is a need to identify Nav1.7 inhibitors that are selective for at least Nav1.5 to treat pain. The present invention provides compounds that are selective inhibitors of Nav1.7 over at least Nav1.5. [Prior art documents] [Patent documents]

[0007]

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[0009] In embodiment 1, the present invention provides a compound of formula (I), its enantiomers, diastereoisomers, atropisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, R 1 is a saturated or partially saturated 4-membered monocyclic ring; or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring; said monocyclic or bicyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; and said monocyclic or bicyclic ring is selected from hydroxy, halo, C 1~8 alk, C 1~8 Helloalk, -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, or -N(C 1~4 alk)C 1~4 0, 1, 2 or 3 R selected from alk 1a substituted by a group; R 2 H, halo, C 1~6 alk or C 1~6 Helloalk; R 3 is C 1~6 alk, C 1~6 Helloalk, -OC 1~6 alk, or -CN; R 4 is a 5-6 membered heteroaryl; R 6 and R 7 each of is hydrogen; and R 5a ;R 5b ;R 5c ;R 5d ; and R 5e each of which is independently hydrogen or halo.

[0010] In a subembodiment 1a of embodiment 1, the compound of formula (I) has the subformula (Ia): [ka] (In the formula, R 1a is fluoro, chloro, methyl, —O—CF3, or CF3).

[0011] In a more preferred subembodiment 1a of embodiment 1, R 1a is CF3 or -O-CF3; R 2 is H, F, or methyl; and R 4 is isoxazolyl or pyridazinyl.

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

[0013] In a subembodiment 1b of embodiment 1, the compound of formula (I) has the subformula (Ib): [ka] (In the formula, each R 1ais fluoro or CF3).

[0014] In a more preferred subembodiment 1b of embodiment 1, each R 1a is F;R 2 is F or Cl; and R 4 is isoxazolyl.

[0015] In a most preferred subembodiment 1b of embodiment 1, each R 1a is F;R 2 is F; and R 4 is isoxazolyl.

[0016] In a subembodiment 1c of embodiment 1, the compound of formula (I) has the subformula (Ic): [ka] (In the formula, R 1a is CF3).

[0017] In a more preferred subembodiment 1c of embodiment 1, R 1a is CF3; R 2 is F; and R 4 is isoxazolyl or pyrimidyl.

[0018] In a most preferred subembodiment 1c of embodiment 1, R 1a is CF3; R 2 is F; and R 4 is isoxazolyl.

[0019] In embodiment 2, the present invention provides a compound of formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a The group is halo, C 1~8 alk, -OC 1~4 alk or C 1~8 wherein C is selected from haloalk 1~8 Helloalk is C1~8 It is a fluoroalkyl.

[0020] In embodiment 3, the present invention provides a compound of Formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a cyclobutyl ring; or a 5- or 6-membered bicyclic ring; said cyclobutyl ring or bicyclic ring contains zero N, O, and S atoms; and said cyclobutyl ring or bicyclic ring contains one, two, or three R selected from F, —CF3, —O—CF3, or —C(CH3)3. 1a The group is substituted.

[0021] In embodiment 4, the present invention provides a compound of Formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a cyclobutyl ring or a bicyclo[1.1.1]pentan-1-yl ring; each ring is substituted with one or two F or -CF3.

[0022] In embodiment 5, the present invention provides a compound of Formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a cyclobutyl ring substituted by one or two F or -CF3.

[0023] In a subembodiment 5a of embodiment 5, the compound of formula (I) has the above subformula of (Ia) and R 1a is F.

[0024] In a subembodiment 5b of embodiment 5, the compound of formula (I) has the above subformula of (Ib), and R 1a is -CF3.

[0025] In a subembodiment 5c of embodiment 5, R 1 is a cyclobutyl ring substituted with one -CF3.

[0026] In a subembodiment 5d of embodiment 5, R 1 is a cyclobutyl ring substituted by one or two F.

[0027] In a subembodiment 5c of embodiment 5, the compound of formula (I) has the above subformula of (Ic), and R 1a is -CF3.

[0028] In embodiment 6, the present invention provides a compound of Formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a bicyclo[1.1.1]pentan-1-yl ring substituted by one or two F or —CF 3 .

[0029] In embodiment 7, the present invention provides a compound of Formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is H, fluoro, chloro, methyl, CF3, CHF2, or CH2F. In a subembodiment 7a of embodiment 7, R 2 is fluoro.

[0030] In embodiment 8, the present invention provides a compound of Formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is H, fluoro, chloro, or methyl.

[0031] In embodiment 9, the present invention provides a compound of Formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is H or fluoro.

[0032] In embodiment 10, the present invention provides a compound of Formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is methoxy.

[0033] In embodiment 11, the present invention provides a compound of Formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5-membered heteroaryl.

[0034] In embodiment 12, the present invention provides a compound of Formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a six-membered heteroaryl.

[0035] In embodiment 13, the present invention provides a compound of Formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.

[0036] In a subembodiment of embodiment 13a of embodiment 13, R 4 is isoxazolyl, pyridazinyl, or pyrimidyl.

[0037] In another subembodiment 13b of embodiment 13, R 4 is isoxazolyl.

[0038] In embodiment 14a, the present invention provides a compound of Formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 5a ;R 5b ;R 5c ;R 5d ; and R 5e Each of is hydrogen.

[0039] In embodiment 14b, the present invention provides a compound of Formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 5a is F; and R 5b ;R 5c ;R 5d ; and R 5e Each of is hydrogen.

[0040] In embodiment 14c, the present invention provides a compound of Formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 5c is F; and R 5a ;R 5b ;R 5d ; and R 5e Each of is hydrogen.

[0041] In embodiment 15, the present invention provides a compound of formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is a compound of formula (Ia), (Ib), or (Ic): [ka] (wherein each R in the compound of formula (Ia), (Ib), or (Ic) 1a is independently selected from fluoro, chloro, methyl, —O—CF3, or CF3).

[0042] In embodiment 16, the present invention provides a compound of formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is a compound of formula (Ia); R 1a is CF; the cyclobutyl ring is a trans isomer; and R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, or oxazolyl.

[0043] In embodiment 16a, the compound of formula (I) is a compound of formula (Ia); R 1a is cisCF3; the cyclobutyl ring is a cis isomer; R 2 is F; and R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, or oxazolyl.

[0044] In embodiment 16b, the compound of Formula (I) is a compound of Formula (Ib); 1a is fluoro; R 2 is F; and R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.

[0045] In embodiment 16c, the compound of Formula (I) is a compound of Formula (Ib); 1a is fluoro; R 5a is F; and R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.

[0046] In embodiment 16d, the compound of Formula (I) is a compound of Formula (Ic); 1a is CF3.

[0047] In embodiment 17, the present invention provides a compound of formula (I), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is 1) (M)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 2) 1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 3) (P)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 4) (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 5) (P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 6) cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 7) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 8) trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 9) cis-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 10) cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 11) trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 12) cis-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 13) trans-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 14) (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 15) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; 16) cis-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; 17) trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; 18) (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; 19) trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; 20) trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 21) (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 22) (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 23) (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; 24) (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 25) (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 26) (P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; 27) (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; 28) (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; 29) (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 30) (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; 31) (P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; 32) (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 33) (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; 34) (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 35) trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 36) trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; 37) trans-(P)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; 38) trans-(P)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; 39) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; 40) (P)-7-Fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 41) (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 42) (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 43) (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 44) cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 45) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 46) trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 47) (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; 48) (P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or 49) trans-(P)-1-(5-chloro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0048] In embodiment 18, the present invention provides compounds of the sub-formula (Ia): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is 1) cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 2) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 3) cis-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 4) trans-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 5) trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; 6) trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; 7) trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 8) trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; 9) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; 10) (P)-7-Fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 11) (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 12) cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 13) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 14) trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or 15) trans-(P)-1-(5-chloro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl) phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0049] In a subembodiment 18a of embodiment 18, the present invention provides a compound of formula (I) having the above subformula of (Ia), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is 1) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 2) trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 3) trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; 4) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; 5) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or 6) trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0050] In a subembodiment 18b of embodiment 18, the present invention provides a compound of formula (I) having the above subformula of (Ia), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0051] In a subembodiment 18c of embodiment 18, the present invention provides a compound of formula (I) having the above subformula of (Ia), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is trans-(P)—N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0052] In a subembodiment 18d of embodiment 18, the present invention provides a compound of formula (I) having the above subformula of (Ia), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide.

[0053] In a subembodiment 18e of embodiment 18, the present invention provides a compound of formula (I) having the above subformula of (Ia), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide.

[0054] In a subembodiment 18f of embodiment 18, the present invention provides a compound of formula (I) having the above subformula of (Ia), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0055] In a subembodiment 18g of embodiment 18, the present invention provides a compound of formula (I) having the above subformula of (Ia), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0056] In embodiment 19, the present invention provides a compound of the sub-formula (Ib): [ka] or a pharmaceutically acceptable salt thereof, which is provided by a compound of formula (I) having the formula: 1) (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 2) (P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 3) trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 4) cis-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 5) cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 6) trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 7) (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or 8) (P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0057] In a subembodiment 19a of embodiment 19, the present invention provides a compound of formula (I) having the above subformula of (Ib), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is 1) (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 2) trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; 3) cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or 4) trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0058] In a subembodiment 19b of embodiment 19, the present invention provides a compound of formula (I) having the above subformula of (Ib), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0059] In a subembodiment 19c of embodiment 19, the present invention provides a compound of formula (I) having the above subformula of (Ib), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0060] In a subembodiment 19d of embodiment 19, the present invention provides a compound of formula (I) having the above subformula of (Ib), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0061] In a subembodiment 19e of embodiment 19, the present invention provides a compound of formula (I) having the above subformula of (Ib), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0062] In embodiment 20, the present invention provides a compound of the sub-formula (Ic): [ka] or a pharmaceutically acceptable salt thereof, which is provided by a compound of formula (I) having the formula: 1) (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or 2) (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide.

[0063] In a subembodiment 20a of embodiment 20, the present invention provides a compound of formula (I) having the above subformula of (Ic), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0064] In a subembodiment 20b of embodiment 20, the present invention provides a compound of formula (I) having the above subformula of (Ic), its enantiomer, diastereoisomer, atropisomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide.

[0065] In embodiment 21, the present invention provides the P atropisomer of each individual compound listed in embodiments 18, 19, and 20, or any subembodiments thereof, either individually or as mixtures thereof, or a pharmaceutically acceptable salt thereof.

[0066] In embodiment 22, the present invention provides the M atropisomer of each individual compound listed in embodiments 18, 19, and 20, or any subembodiment thereof, independently or mixtures thereof, or a pharmaceutically acceptable salt thereof.

[0067] In embodiment 23, the present invention provides a pharmaceutical composition comprising a compound according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or any subembodiment thereof, or an enantiomer, diastereoisomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0068] In embodiment 24, the invention provides a method of treating pain, cough, or itch, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or any sub-embodiment thereof, or an enantiomer, diastereoisomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

[0069] In embodiment 25, the invention provides the method of embodiment 24, 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.

[0070] In embodiment 26, the present invention provides the method of embodiment 24, wherein the cough is selected from post-infectious cough, viral cough, or acute viral cough. V 1.7 sodium channel: from molecule to man”, Nature Reviews Neuroscience (2013), 14, 49-62.

[0071] In embodiment 27, the present invention provides a compound of formula (A): [ka] wherein R is halo. 1. A process for the preparation of an intermediate compound used in the preparation of a compound of formula (I) having the formula: 1) Formula (B): [ka] wherein R is halo; and R 1 is a C1-C6 alkyl) reacting with UV or near UV light to form a cis-olefin compound (C); and 2) reacting said compound (C) with a chiral acid in an organic solvent to form said compound of formula (A).

[0072] In embodiment 28, the invention provides the method of embodiment 27, wherein the chiral acid is a phosphorus chiral acid.

[0073] In embodiment 29, the present invention relates to a compound having the formula: [ka] 28. The method of embodiment 27, wherein the (S)-TRIP has the formula:

[0074] In embodiment 30, the invention provides the method of embodiment 27, wherein the organic solvent is dichloromethane.

[0075] In embodiment 31, the invention provides the method of embodiment 27, wherein R is bromo.

[0076] In embodiment 32, the present invention provides a method for treating a steroid hormone comprising administering to a subject a subject, comprising administering to a subject ... 1 is ethyl; and the compound of formula (B) is of the formula: [ka] 28. The method of embodiment 27, comprising:

[0077] In embodiment 33, the invention provides the method of embodiment 27, wherein in reaction (2), the P atropisomer of the compound of formula (A) is selectively formed.

[0078] In embodiment 34, the present invention relates to a compound of formula (A) comprising a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1is a saturated or partially saturated 4-membered monocyclic ring; or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring; said monocyclic or bicyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; and said monocyclic or bicyclic ring is selected from hydroxy, halo, C 1~8 alk, C 1~8 Helloalk, -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, or -N(C 1~4 alk)C 1~4 0, 1, 2 or 3 R selected from alk 1a substituted by a group; R 2 H, halo, C 1~6 alk or C 1~6 Helloalk; R 3 is C 1~6 alk, C 1~6 Helloalk, -OC 1~6 alk, or -CN; R 4 is a 5-6 membered heteroaryl; R 6 and R 7 each of is hydrogen; and R 5a ;R 5b ;R 5c ;R 5d ; and R 5e each of which is independently hydrogen or halo, 28. The method of embodiment 27, wherein the P atropisomer of the compound of formula (I) is selectively formed. DETAILED DESCRIPTION OF THE INVENTION

[0079] The present invention provides a compound of formula (I), its enantiomer, diastereoisomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, as defined above. The present invention also provides a pharmaceutical composition comprising a compound of formula (I), its enantiomer, diastereoisomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a method of treating diseases and / or conditions, such as pain, using a compound of formula (I), its enantiomer, diastereoisomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

[0080] The term “C α~β "Alk" means an alkyl group containing a minimum of α carbon atoms and a maximum of β carbon atoms in a branched or linear arrangement or any combination of the two, where α and β represent integers. The designation COalk indicates a direct bond. 1~6 Examples of alk include: [ka] These include, but are not limited to:

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

[0082] The term “C α~β "Haloalk" means an alk group, as defined herein, in which at least one of the hydrogen atoms is replaced with a halo atom, as defined herein. α~β Haloalk groups are C 1~3 It is a fluoroalk. 1~3 An example of a fluoroalk group is -CF3.

[0083] As used herein, the term "heteroatom" means an oxygen, nitrogen, or sulfur atom.

[0084] As used herein, the term "monocyclic ring" refers to a group comprising one single ring. A monocyclic ring can be a carbocyclic ring (all of the ring atoms are carbon) or a heterocyclic ring (the ring atoms include, in addition to carbon atoms, at least one heteroatom, e.g., 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.

[0085] As used herein, the term "bicyclic ring" refers to a group comprising two connected rings. A bicyclic ring can be a carbocyclic ring (all of the ring atoms are carbon) or a heterocyclic ring (the ring atoms contain, in addition to carbon atoms, at least one heteroatom, e.g., 1, 2, or 3 heteroatoms such as N, O, or S). The two rings can both be aliphatic (e.g., decalin and norbornane), aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin). Bicyclic rings include (a) spirocyclic compounds (the two rings share only one atom, the spiroatom, which is usually a quaternary carbon). Examples of spirocyclic compounds include: [ka] including, but not limited to; or (b) Fused bicyclic compounds (two rings share two adjacent atoms; in other words, the rings share one covalent bond, i.e., the bridgehead atoms are directly connected (e.g., α-thujene and decalin). Examples of fused bicyclic rings include: [ka] including, but not limited to; and (c) Bridged Bicyclic Compounds (two rings share three or more atoms with a bridge containing at least one atom separating the two bridging atoms. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be thought of as a pair of cyclopentane rings each sharing three of their five carbon atoms. Examples of bridged bicyclic rings include: [ka] (including, but not limited to,

[0086] The term "aryl" refers to a cyclic aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Typical aryl groups are 6- to 13-membered rings.

[0087] The term "heteroaryl" refers to a cyclic aromatic hydrocarbon in which one or more carbon atoms of an aryl group are replaced with a heteroatom. 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, quinolizinyl, isoquinolyl, quinolyl, naphthyridinyl, quinoxalinyl, isothiazolyl, and benzo[b]thienyl. Common heteroaryl groups are 5- to 13-membered rings containing 1 to 4 heteroatoms. Five- and 6-membered heteroaryl groups containing 1 to 3 heteroatoms are particularly common.

[0088] The term "saturated, partially saturated, or unsaturated" includes substituents that are saturated with hydrogen, substituents that are not completely saturated with hydrogen, and substituents that are partially saturated with hydrogen.

[0089] The term "pharmaceutically acceptable salt" refers to salts prepared by conventional means and are well known to those skilled in the art. "Pharmacologically acceptable salts" include basic salts of inorganic and organic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid, and the like. For additional examples of "pharmacologically acceptable salts," see Berge et al., J. Pharm. Sci. 66:1 (1977).

[0090] The term "substituted" means that a hydrogen atom on a molecule or group is replaced with a group or atom other than hydrogen. Typical substituents include halogen, C 1~8 Alkyl, Hydroxyl, C 1~8 Alkoxy, -NR x R x , nitro, cyano, halo or perhalo C 1~8 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, -SR x , -S(=O)2R x , -C(=O)OR x , -C(=O)R x are listed, and each R x are independently hydrogen or C 1~8 The substituent is -NR x R x When R x It is recognized that the groups, together with the nitrogen atom attached, can form a ring.

[0091] The group or atom replacing the hydrogen atom is also called a substituent.

[0092] Any particular molecule or group may have one or more substituents depending on the number of hydrogen atoms that may be replaced.

[0093] The term "unsubstituted" refers to hydrogen atoms on a molecule or group.

[0094] The symbol "-" represents a covalent bond and may be used in a radical group to indicate the point of attachment to another group. In chemical structures, the symbol is commonly used to represent a methyl group in a molecule.

[0095] The term "leaving group" generally refers to a group that can be readily displaced 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, tosylates, and the like. Preferred leaving groups are indicated herein where appropriate.

[0096] The term "protecting group" generally refers to a group well known in the art that is used to prevent selected reactive groups, such as carboxy, amino, hydroxy, and mercapto, from undesired reactions, such as nucleophilic, electrophilic, oxidative, and reduced reactions. Preferred protecting groups are identified herein, where 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, silyl, and the like. Examples of aralkyls include, but are not limited to, benzyl, ortho-methylbenzyl, trityl, and benzhydryl, which may be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl, and the like, as well as salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl, and the like. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl groups preferably have 6 to 10 carbon atoms, including, but not limited to, cyclohexenylmethyl. Suitable acyl, alkoxycarbonyl, and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, and the like. Mixtures of protecting groups can be used to protect the same amino group; for example, a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group. Amino-protecting groups can also form heterocyclic rings together with the nitrogen to which they are attached, such as 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl, and the like; these heterocyclic groups can further include adjacent aryl and cycloalkyl rings. In addition, heterocyclic groups can be mono-, di-, or tri-substituted, such as nitrophthalimidyl. Amino groups can also be protected against undesired reactions, such as oxidation, through the formation of addition salts such as hydrochlorides, toluenesulfonic acid, trifluoroacetic acid, and the like.Many of the 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 groups for protecting hydroxy and mercapto groups.

[0097] Protecting groups are removed under conditions that do not affect the remainder of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis, and the like. A preferred method involves the removal of a protecting group, such as the removal of a benzyloxycarbonyl group by hydrogenolysis using palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, or the like, or a mixture thereof. A tert-butoxycarbonyl protecting group can be removed using an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can be readily neutralized to provide the free amine. Carboxy protecting groups, such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl, and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.

[0098] Prodrugs of the compounds of the present invention are also contemplated by the present invention. A prodrug is an active or inactive compound that is chemically modified by in vivo physiological action, such as hydrolysis or metabolism, to become a compound of the present invention after administration of the prodrug to a patient. The suitability and techniques involved in the production 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 in vivo, releasing the free drug and formaldehyde (Bundgaard J. Med. Chem. 2503 (1989)). Drugs containing acidic NH groups, such as imidazoles, imides, and indoles, have also been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy 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.

[0099] The term "therapeutically effective amount" refers to an amount of a compound that ameliorates, attenuates, or eliminates one or more symptoms of a particular disease or condition, or that prevents or delays the onset of one of the symptoms of a particular disease or condition.

[0100] The term "patient" refers to animals such as dogs, cats, cows, horses, sheep, and humans. Particular patients are mammals. The term patient includes males and females.

[0101] The term "pharmaceutically acceptable" means that the referenced substance (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.

[0102] The terms "treating", "treat", or "treatment" and the like include preventative (e.g., prophylactic) treatment and palliative treatment.

[0103] The term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient other than the active ingredient (API), which is typically included in the formulation and / or administration to a patient.

[0104] The compound of the present invention is administered to a patient in a therapeutically effective amount.The compound can be administered alone or as part of a pharmaceutically acceptable composition or formulation.In addition, the 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, by transdermal delivery.It should also be noted that the dose of the compound can be varied over time.

[0105] In addition, the compounds of the present invention can be administered alone, in combination with other compounds of the present invention, or with other pharmaceutically active compounds. The other pharmaceutically active compounds may be intended to treat the same disease or condition as the compounds of the present invention, or may be intended to treat a different disease or condition. When a patient is or has been administered multiple pharmaceutically active compounds, these compounds can be administered simultaneously or sequentially. For example, in the case of tablets, the active compounds may be found in one tablet or in separate tablets, which may be administered at the same time or sequentially in any order. In addition, 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 are administered by injection or orally as a syrup. All combinations, delivery methods, and administration sequences are contemplated.

[0106] The compounds of the present invention may be used in the manufacture of a medicament for the treatment of diseases and / or conditions mediated by Nav 1.7, such as pain, chronic cough or itch.

[0107] Pain is usually divided into major types: chronic and acute pain based on the duration of pain. Chronic pain usually lasts for a period 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 origin, which is pain without an identified cause. An example of pain of unknown origin is fibromyalgia.

[0108] Another type of pain is nociceptive pain, which is caused by stimulation of peripheral nerve fibers that respond to highly noxious events such as thermal, mechanical, or chemical stimuli.

[0109] Yet 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 detects pain from a part of the body that is no longer present. For example, a person who has had a leg amputated may feel pain in the leg even though the leg is no longer present.

[0110] In one embodiment of the method of treatment provided by the present invention using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, the disease is chronic pain. In another aspect, the chronic pain is associated with, but is not limited to, postherpetic neuralgia (shingles), rheumatoid arthritis, osteoarthritis, diabetic neuropathy, complex regional pain syndrome (CRPS), cancer or chemotherapy-induced pain, chronic back pain, phantom limb pain, trigeminal neuralgia, HIV-induced neuropathy, cluster headache disorder, and migraine, erythromelalgia, and paroxysmal acute pain syndrome.Other indications for Nav 1.7 inhibitors include depression (Morinville et al., J Comp Neurol., 504:680-689 (2007)), bipolar and other CNS disorders (Ettinger and Argoff, Neurotherapeutics, 4:75-83 (2007)), epilepsy; ibid.; and Gonzalez, Termin, Wilson, Methods and Principles in Medicinal Chemistry, 29:168-192 (2006)), multiple sclerosis (Waxman, Nature Neurosci. 7:932-941 (2006)), Parkinson's disease (Do and Bean, Neuron 39:109-120 (2003); Puopolo et al. al., J. Neurosci. 27:645-656 (2007)), restless legs syndrome, ataxia, tremor, muscle weakness, dystonia, tetanus (Hamann M., et. al., Exp. Neurol. 184(2):830-838, 2003), anxiety, depression: McKinney 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 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)).

[0111] Further aspects of the invention include the treatment of acute and / or chronic inflammatory and neuropathic pain, toothache, general headache, migraine, cluster headache, mixed vascular and non-vascular syndrome, tension headache, general inflammation, arthritis, rheumatic diseases, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin diseases with an inflammatory component, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy. The present invention relates to a method for treating pain, causalgia, sympathetically maintained pain, deafferented pain syndrome, asthma, epithelial tissue damage or dysfunction, herpes simplex, visceral motility disorders in the respiratory, urogenital, gastrointestinal or vascular areas, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulcers, duodenal ulcers, diarrhea, gastric lesions induced by necrotizing agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, the method comprising 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.

[0112] In another aspect of the present invention, the compounds of the present invention can be used in combination with other compounds used to treat pain.Examples of such other compounds include, but are not limited to, aspirin, celecoxib, hydrocodone, oxycodone, codeine, fentanyl, ibuprofen, ketoprofen, naproxen, acetaminophen, gabapentin and pregabalin.Examples of classes of medicines containing compounds that can be used in combination with the compounds of the present invention include nonsteroidal anti-inflammatory compounds (NSAIDS), steroidal compounds, cyclooxygenase inhibitors and opioid analgesics.

[0113] The compounds of the present invention may also be used to treat diabetes, obesity, and / or promote weight loss.

[0114] The compounds of the present invention may be used in combination with other pharmaceutically active compounds. It is recognized that the term "pharmaceutically active compound" may include biologics such as proteins, antibodies, and peptibodies.

[0115] Because one aspect of the present invention contemplates treating a disease / condition with a combination of pharmaceutically active compounds that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions in kit form. The kit includes two separate pharmaceutical compositions: a compound of the present invention and a second pharmaceutical compound. The kit includes containers, such as divided bottles or divided foil packets, for containing the separate compositions. Further examples of containers include syringes, boxes, and bags. Typically, the kit includes instructions for use of the separate components. This kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dosage intervals, or when the prescribing physician or veterinarian desires to titrate the individual components of the combination.

[0116] One example of such a kit is a 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). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. The tablets or capsules are then placed in the recesses, and the plastic foil is sealed with a sheet of relatively stiff material on the side of the foil opposite to the side in which the recesses were formed. As a result, the tablets or capsules are sealed within the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure to the recesses, thereby forming openings in the sheet at the locations of the recesses. The tablets or capsules can then be removed through the openings.

[0117] It may be desirable to provide a memory aid on the kit (e.g., next to the tablets or capsules) in the form of numbers, the numbers corresponding to the days of the regimen in which the designated tablets or capsules should be taken. Another example of such a memory aid is a calendar printed on a card, e.g., "Week 1, Monday, Tuesday, ...etc... Week 2, Monday, Tuesday, ...", etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule, or multiple pills or capsules to be taken on a given day. Also, a daily dose of a compound of the invention can consist of one tablet or capsule, while a daily dose of a second compound can consist of multiple tablets or capsules, or vice versa. The memory aid should reflect this and aid in the correct administration of the active agents.

[0118] 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, the dispenser is equipped with a memory aid to further facilitate compliance with the regimen.An example of such a memory aid is a mechanical counter that indicates the number of daily doses dispensed.Another example of such a memory aid is, for example, a battery-powered microchip memory with a liquid crystal readout or an audible reminder signal that reads the date the last daily dose was taken and / or reminds the user of the date the next dose should be taken.

[0119] The compounds of the present invention and other pharmaceutically active compounds can be administered to a patient, as appropriate, either orally, rectally, parenterally (e.g., intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, topically (e.g., as a powder, ointment, or infusion), or via oral or nasal spray. All methods used by those skilled in the art to administer pharmaceutically active agents are contemplated.

[0120] Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (olive oil, etc.), and injectable organic esters (ethyl oleate, etc.). Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0121] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Microbial contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents (e.g., sugars, sodium chloride, etc.). Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption (e.g., aluminum monostearate and gelatin).

[0122] Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is dispersed in at least one inert conventional excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate), or in a carrier containing at least one of: (a) fillers or extenders (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 denaturant, etc.); starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate); (e) solution retarders (e.g., paraffin); (f) absorption accelerators (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. In the case of capsules and tablets, the dosage form may also contain buffering agents.

[0123] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0124] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, and other known in the art.They can also contain opacifying agents, and can be of a composition that releases active compound in a specific part of the intestinal tract in a delayed manner.Examples of embedding compositions that can be used include polymeric substances and waxes.The active compound can also be in microencapsulated form, optionally containing one or more of the above-mentioned excipients.

[0125] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms 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 of these substances.

[0126] In addition to such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents. In addition to the active compound, suspensions can include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, or mixtures of these substances.

[0127] Compositions for rectal administration are preferably suppositories which can be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax; the suppositories are solid at ordinary room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active ingredient.

[0128] The dosage form for topical administration of the compound of the present invention includes ointment, powder, spray and inhalant.The active compound or suitable compound is mixed with a physiologically acceptable carrier and any preservatives, buffers or propellants that may be required under sterile conditions.Ophthalmic preparations, eye ointments, powders and solutions are also considered to be within the scope of the present invention.

[0129] The compounds of the present invention may be administered to a patient at therapeutically effective dosage levels. The specific dosage and dosage range that can be used will depend on a number of factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered.

[0130] The compounds of the present invention can be administered as pharmaceutically acceptable salts, co-crystals, esters, amides, or prodrugs. The term "salt" refers to inorganic and organic salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base or acid form with an appropriate organic or inorganic acid and isolating the resulting salt. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. Salts may include cations based on alkali metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. See, e.g., S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66:1-19 (1977).

[0131] 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.

[0132] 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.

[0133] The term "prodrug" refers to a compound that is converted in vivo to yield a compound of the present invention. The conversion can occur by various mechanisms, such as by hydrolysis in blood. The use of prodrugs is provided in T. Higuchi and W. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0134] For example, if the compound of the invention contains a carboxylic acid functional group, the prodrug may be prepared by replacing the hydrogen atom of the acid group with (C1-C8 alkyl, (C2-C12))alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-methyl-1-(alkoxycarbonyloxy)ethyl having 3 to 9 carbon atoms, N-methyl-1-(alkoxycarbonyloxy)ethyl having 3 to 9 carbon atoms, N-methyl-1-(alkoxycarbonyloxy)ethyl having 3 to 6 carbon atoms, N-methyl-1-(alkoxycarbonyloxy)ethyl having 3 to 6 carbon atoms, N-methyl-1-(alkoxycarbonyloxy)ethyl having 3 to 7 carbon atoms, N-methyl-1-(alkoxycarbonyloxy)ethyl having 3 to 9 carbon atoms, N-methyl-1-(alkoxycarbonyloxy)ethyl having 3 to 6 ... These may include esters formed by substituting 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.

[0135] Similarly, when a compound of the invention contains an alcohol functional group, a prodrug may be formed by replacing the hydrogen atom of the alcohol group with a group such as (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 (the group resulting from removal of the hydroxyl group of the hemiacetal form of a carbohydrate).

[0136] Additionally, when a compound of the invention contains a sulfonamide moiety, a prodrug can be formed by replacing the sulfonamide N(H) with a group such as —CHP(O)(O(C1-C6)alkyl) or —CHOC(O)(C1-C6)alkyl.

[0137] The compounds of the invention also include tautomeric forms of the prodrugs.

[0138] The compounds of the present invention may have asymmetric or chiral centers, and therefore may exist in different stereoisomeric forms.All stereoisomeric forms of the compounds and their mixtures, including racemic mixtures, are contemplated as part of the present invention.In addition, the present invention contemplates 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 contemplated.In disubstituted cycloalkyl-containing compounds, cis and trans isomers refer to the relative positions of the substitutions.For example: [ka] (A) represents the trans cyclobutyl isomer because the -CF3 group points up while the -CH3 group points down, while (B) represents the cis cyclobutyl isomer because both the -CF3 and -CH3 groups point down.

[0139] Mixtures of stereoisomers, such as diastereomeric mixtures, can be separated into their individual stereochemical components on the basis of their physical chemical differences by known methods, such as chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., alcohol), separating the diastereomers, and converting the individual diastereomers into their corresponding pure enantiomers (e.g., by hydrolysis).

[0140] The compound of general formula (I) may also exist in the form of atropisomers. Atropisomers are compounds with the same structural formula, but with a specific spatial arrangement resulting from the rotation around a single bond being restricted by steric hindrance on both sides of this single bond. Atropisomers do not depend on the presence of asymmetric elements such as asymmetric carbons. The terms "P atropisomer" or "M atropisomer" are used herein to clearly name two atropisomers of the same pair. For example, the following intermediate compound with the following structure can be separated into a pair of atropisomers P and M through chiral column chromatography: [ka]

[0141] The compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrates), ethanol, etc. The present invention contemplates and encompasses both solvated and unsolvated forms.

[0142] Additionally, compounds of the present invention may exist in various tautomeric forms. All tautomers of the compounds of the present invention are contemplated. For example, all tautomeric forms of the tetrazole moiety are included in the present invention. 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]

[0143] Those skilled in the art will recognize that the compound names and structures contained herein may be based on a particular tautomer of the compound. Although the name or structure of only a particular tautomer may be used, it is intended that all tautomers are encompassed by the present invention unless otherwise stated.

[0144] The present disclosure is also intended to encompass compounds synthesized in vitro using laboratory techniques such as those familiar to synthetic chemists, or synthesized using in vivo techniques such as via metabolism, fermentation, digestion, etc. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.

[0145] The present invention also includes isotopically labeled compounds, which are identical to those enumerated herein except for the fact that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into 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. In another embodiment, the compounds of the present invention contain one or more deuterium atoms (2H) in place of one or more hydrogen atoms.

[0146] Compounds of the present invention that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, e.g., 3 H and 14 Those in which radioactive isotopes such as 3C are incorporated are useful in drug and / or substrate tissue distribution assays. Tritiated isotopes (i.e., 3 H isotopes, and carbon-14 isotopes (i.e. 14 C isotopes) are particularly preferred due to their ease of preparation and detectability. Additionally, deuterium, i.e. 2Substitution with heavier isotopes, such as H, can offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred. Isotopically labeled compounds of the invention can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0147] The compounds of the present invention may exist in various solid states, including crystalline and amorphous states. The different crystalline states (also called polymorphs) and amorphous states of the compounds of the present invention are contemplated as part of the present invention.

[0148] All patents and other publications cited herein are incorporated by reference in their entirety.

[0149] The following examples illustrate specific embodiments of the present invention, and are meant to be representative and are not intended to limit the scope of the claims in any way. [Example]

[0150] When percent (%) is used with respect to a liquid, it is recognized as a percent by volume relative to the solution. When used with a solid, it is a percentage relative to the solid composition. Materials obtained from commercial manufacturers are typically used without further purification. Reactions involving air- or moisture-sensitive reagents were typically performed under a nitrogen or argon atmosphere. Purity was determined using a high-performance liquid chromatography (HPLC) system (System A: HALO C8, 3.0 × 50 mm, 2.7 μm, 5–95% CH3CN in H2O containing 0.1% TFA at 2.0 mL / min for 2 min) (Agilent Technologies, Santa Clara, CA) with UV detection at 254 nm and 215 nm. Silica gel chromatography was typically performed on prepacked silica gel cartridges (BIOTAGE®, Uppsala, Sweden or Teledyne-Isco, Lincoln, NE). 1 H 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) downfield from tetramethylsilane (TMS) or other internal standard in the appropriate solvent specified. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant, and number of protons. Low-resolution mass spectral (MS) data were determined on an Agilent 1100 series (Agilent Technologies, Santa Clara, CA) LC / MS with UV detection at 254 nm and 215 nm and low-resonance electrospray mode (ESI).

[0151] The following abbreviations may be used herein:

[0152] 2-PrOH isopropanol AgOTf Silver(I) trifluoromethanesulfonate AIBN Azobisisobutyronitrile aq. water-based Bu butyl ca. approx. Cm centimeters CPhos 2-Dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl DAST Diethylaminosulfur trifluoride Dba Dibenzylideneacetone DCM dichloromethane Deoxy-Fluor Bis(2-methoxyethyl)aminosulfur trifluoride DIPEA N,N-Diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide ESI or ES electrospray ionization Et Ethyl Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol G Gram H time HPLC High Pressure Liquid Chromatography IPA 2-propanol Kg kilogram L liters LCMS Liquid Chromatography Mass Spectrometry LHMDS Lithium hexamethyldisilazide M molar concentration m / z mass divided by charge Me methyl MeOH Methanol Me-THF methyltetrahydrofuran Mg milligram MHz Megahertz Min mL or ml milliliter Mmol millimolar Mol MTBE Methyl tert-butyl ether N regulations NaOMe Sodium methoxide 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 racemic 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 percent XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XtalFluor-M Difluoro(morpholino)sulfonium tetrafluoroborate

[0153] The following compounds presented herein as examples of the present invention, and intermediates thereof as building blocks for preparing compounds provided by the present invention, can be made by various methods and synthetic strategies taught herein below. These compounds, and others provided by the present invention, can also be prepared using the methods described in International Publication No. WO 2014 / 201206, filed June 12, 2014, the specification of which is incorporated herein by reference in its entirety.

[0154] In addition, the present inventors have developed a photochemical atropisomeric ring closure to form N-aryl quinolinone compounds. Specifically, the P atropisomer compound 3 is selectively formed in the photochemical reaction of the present invention. A general representation of the photochemical process of the present invention is described below. [ka]

[0155] The reaction relies on UV or near UV light to excite olefin 1; R is halo; and R 1 is C1-C6 alkyl; and induces cis-trans isomerization to transiently form 2; R is halo; and R 1 is C1-C6 alkyl. Preferably, R 1 is ethyl. The cis olefin 2 can then be activated with the chiral acid (S)-TRIP to asymmetrically form the closed ring quinolinone 3, where R is as defined above. Preferably, R is Br. Screening of chiral phosphoric acids revealed that (S)-TRIP is the preferred chiral acid. The preferred organic solvent is dichloromethane. The photochemical reaction has been scaled up to 1 g in a batch reactor and demonstrated in a small photochemical flow reactor.

[0156] This photochemical process can work 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. The mild reaction conditions also allow compounds with low rotational barriers to be prepared in a stereoselective manner.

[0157] Intermediate A: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] [ka]

[0158] Step 1: 4-Bromo-2-iodoaniline To a solution of 4-bromoaniline (500 g, 2.90 mol) in cyclohexane (2.5 L) was added iodine (368 g, 1.45 mol), and the mixture was heated at 50 °C. After 30 min, the reaction mixture became homogeneous, and 30% aqueous hydrogen peroxide (250 mL) was added to the reaction mixture. The reaction was heated at 50 °C for 4 h. The reaction was cooled to room temperature, diluted with ethyl acetate (5.0 L), and washed with aqueous sodium sulfite (2.5 kg in 4.0 L). 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 give the initial product, which was purified by column chromatography (silica gel; mesh size 60-120, elution 0-20% ethyl acetate and hexane) to give 4-bromo-2-iodoaniline (650 g, 75%) as an off-white solid. TLC solvent system: 100% hexane. Product R f : 0.6. MS (ESI, positive ion) m / z: 297.0 (M+1). 1H 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).

[0159] Step 2: (E)-3-(2-amino-5-bromophenyl)acrylate ethyl To a solution of 4-bromo-2-iodoaniline (750 g, 2.51 mol) in DMF (5.0 L) was added ethyl acrylate (277 g, 2.76 mol) and sodium bicarbonate (680 g, 6.29 mol). The reaction mixture was degassed with nitrogen for 20 minutes, after which palladium acetate (28.8 g, 128.27 mol) 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 x 500 mL). The filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography (silica gel; mesh size 60-120, elution 0-20% ethyl acetate in hexane) to give (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g, 77%) as a yellow solid. TLC solvent system: 20% ethyl acetate in hexane. The R of the product was analyzed. f : 0.4. MS (ESI, positive ion) m / z: 270.2 (M+1). 1 H NMR (400 MHz, DMSO) δ 7.75 (d, J = 16.1 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 9.1, 2.4 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 6.43 (d, J = 8.6 Hz, 1H), 5.81 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H). Other acrylates can be used in place of ethyl acrylate to give different esters. For example, methyl acrylate, propyl acrylate, butyl acrylate, and others can be used in place of ethyl acrylate.

[0160] Step 3: (E)-3-(2-amino-5-(benzylthio)phenyl)acrylate ethyl To a solution of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g, 2.29 mol) in 1,4-dioxane (4.0 L) was added DIPEA (1.26 L, 8.88 mol, 3.9 equiv., GLR), and the mixture was degassed with 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 with nitrogen and heated to 80°C for 30 minutes. The reaction was cooled to room temperature, benzyl mercaptan (455.5 g, 3.67 mol) was added, and the reaction was heated at 80°C for an additional 4 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (4.0 L). The mixture was filtered through CELITE and the CELITE bed was washed with ethyl acetate (2 x 1.0 L). The filtrate was concentrated under reduced pressure to give the first product, which was purified by chromatography (silica gel; mesh size 60-120, elution 0-40% ethyl acetate and petroleum ether) to give (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (520 g, 72.0%) as a yellow solid. TLC solvent system: 30% ethyl acetate in hexane. The R of the product f : 0.4. MS (ESI, positive ion) m / z: 314.1 (M+1). 1 H NMR(400MHz,DMSO)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).

[0161] 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) was added silver trifluoromethanesulfonate (686.0 g, 2.68 mol) and the reaction mixture was stirred for 20 minutes. Iodine (678.0 g, 2.68 mol) was added to the reaction, 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 x 1.0 L), and the filtrate was washed with 20% aqueous sodium thiosulfate (3.0 L) and saturated aqueous sodium bicarbonate (3.0 L). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the first product, which was purified by chromatography (silica gel; mesh size 60-120, elution 0-5% ethyl acetate and petroleum ether) to give 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (720 g, 87%) as an off-white solid. TLC solvent system: 100% hexane. R of the product f : 0.6. MS (ESI, positive ion) 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).

[0162] Step 5: (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)ethyl acrylate To a solution of (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (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) was added CsCO (468 g, 1436.3 mmol). The resulting mixture was degassed with nitrogen for 20 minutes. Pd(dba) (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 allowed to cool to room temperature, diluted with dichloromethane (2.0 L), and filtered through CELITE. The filtrate was concentrated under reduced pressure to give the first product, which was purified by stirring with 5% ethyl acetate in hexanes (3.0 L) for 30 minutes and filtered to give (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (350 g, 71%) as a yellow solid. TLC solvent system: 30% ethyl acetate in hexanes. R of the product f : 0.5. MS (ESI, positive ion) m / z: 516.2 (M+1). 1 H NMR (400 MHz, DMSO) δ 7.73-7.61 (m, 3H), 7.34-7.15 (m, 6H), 7.02 (d, J = 11.4 Hz, 1H), 6.60 (d, J = 21.2 Hz, 1H), 6.33 (d, J = 14.1 Hz, 1H), 4.26 (s, 2H), 4.16-4.09 (m, 2H), 3.81 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H). Note: NH protons were not observed.

[0163] Step 6: 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one To a solution of (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (250.0 g, 484.0 mmol) in methanol (2.5 L) was added tri(n-butyl)phosphine (50% solution in ethyl acetate, 48.9 mL, 96.8 mmol) and the reaction mixture was heated at 70° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure to give the initial product, which was purified by stirring with 5% ethyl acetate in hexanes (1.0 mL) and filtering to give 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one (201.0 g, 88%) as an off-white solid. TLC solvent system: 30% ethyl acetate in hexanes. R of the product f : 0.3. MS (ESI, positive ion) m / z: 470.0 (M+1). 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).

[0164] Alternatively, the P atropisomer title compound of Step 6 can be selectively prepared by using a photochemical route from the ethyl (E)-3-[5-benzylsulfanyl-2-(4-bromo-5-fluoro-2-methoxy-anilino)phenyl]prop-2-enoate starting material as described in the following procedure.

[0165] Photochemical preparation method 1: [ka] A flask was charged with (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (4.0 g, 7.6 mmol), (S)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate ((S)-TRIP) (290 mg, 0.38 mmol), and DCM (40 mL). The resulting solution was continuously stirred and recirculated through a narrow diameter tube exposed to 467 nm LED light for 2.5 hours. The reaction solution was concentrated to approximately 8 mL and charged with MeOH (80 mL). The solution was concentrated to approximately 50 mL and heated to 60° C. The solution was filtered to remove precipitate and then allowed to cool to room temperature overnight. The resulting slurry was cooled to 0° C. for 2 hours and then filtered. The filter cake was rinsed with cold MeOH to give (P)-6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one as a tan solid (2.12 g, 89 wt%, 4.0 mmol). 1 H NMR(300MHz,DMSO-d6)δ 7.95(d,J=9.6Hz,1H),7.79(d,J=2.2Hz,1H),7.64(d,J=6.3Hz,1H),7.55(d,J=8.7Hz,1H), 7.42-7.16(m,6H),6.67(d,J=9.5Hz,1H),6.55(d,J=8.8Hz,1H),4.24(s,2H),3.68(s,3H). 19 F NMR (282 MHz, DMSO-d6) δ -117.08 (dd, 1F, J = 8.7, 6.3 Hz). ee was determined by chiral normal-phase chromatography (CHIRALPAK IC-3, 4.6 × 150 × 3) using a mobile phase of 60% heptane / 40% (0.2% ethanesulfonic acid in ethanol) v / v at a flow rate of 1.5 mL / min.

[0166] Photochemical preparation method 2: [ka] To a flask was added (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (50.0 g, 96.8 mmol), (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate ((S)-TRIP) (1.46 g, 1.94 mmol), toluene (750 mL), and DCM (750 mL). The reaction headspace was purged with N. The reaction solution was warmed to 30°C and stirred. The solution was recirculated at a flow rate of 50 g / min via a peristaltic pump through 1 / 8" FEP tubing (approximately 10 mL internal volume) exposed to 457 nm LED light for 10 hours. The reaction solution was concentrated to a tan solid, followed by filtration. i The mixture was slurried in PrOAc (250 mL) at 30° C. for 30 minutes. To the slurry, heptane (500 mL) was added over 30 minutes. The slurry was cooled to 0° C. for 2 hours and then placed in a −20° C. freezer for 36 hours. The slurry was filtered and the cake was diluted with 10% v / v i Rinsing with PrOAc / heptane (2 x 150 mL) gave the solid dried in a vacuum oven to give (P)-6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one (34.7 g, 98 wt%, 72.6 mmol, 89% ee) as a tan solid.

[0167] Steps 7 and 8: Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate To a solution of 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one (250.0 g, 531.5 mmol) in acetonitrile (2.5 L) was added acetic acid (200 mL) and water (130 mL). The resulting mixture was cooled to 0 °C, and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (188.5 g, 956.7 mmol) was added portionwise over 20 min, maintaining the internal temperature below 5 °C. The resulting suspension was stirred under nitrogen at 0–5 °C for 45 min. Next, a solution of pentafluorophenol (127.2 g, 690.95 mmol) in acetonitrile (200 mL) was added over 5 min, followed by NEt (307.7 mL, 2.12 mol) over 20 min, maintaining the internal temperature below 5 °C. The mixture was stirred at 0-5°C for 30 minutes. Water (4.0 L) was added and extracted with ethyl acetate (2 x 2.0 L). The organic layer was washed with brine (1.0 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the initial product, which was purified by stirring with isopropyl alcohol:hexane (1:1, 1.0 L) and filtered to give perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (190 g, 60%) as a white solid. TLC solvent system: 30% ethyl acetate in petroleum ether. f : 0.4. MS (ESI, positive ion) 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).

[0168] Step 9: (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid Racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenyl sulfonate (76.90 g) was separated via a Chiralcel OJ column (40% MeOH / 60% CO) to give (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate and (M)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate as pale yellow fluffy solids. Data for Peak 1: m / z (ESI) 594.0 (M+H). + Data for peak 2: m / z (ESI) 594.0 (M+H) + .

[0169] Step 10: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A solution of (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (6.00 g, 10.10 mmol) and 3-aminoisoxazole (0.821 mL, 11.11 mmol) in 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. After stirring the yellow solution at 0 °C for 15 min, it was quenched with 1 N HCl at 0 °C and extracted three times with EtOAc. The organic extracts were combined, dried over MgSO, filtered, and concentrated to give a light tan residue. EtO was added, and the slurry was triturated and sonicated. Filtration afforded an off-white solid, which was washed twice with EtO and dried in vacuo to give 3.88 g of product as an off-white solid. The filtrate was concentrated in vacuo and purified via column chromatography (12 g silica gel, 35% to 100% EtOAc / heptane gradient) to give an additional 1.36 g of product as a pale yellow fluffy solid. A total of 5.24 g of (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide was obtained. m / z (ESI) 494.1 (M+H). + .

[0170] Intermediate A: (3-(tert-butyl)cyclobutyl)zinc(II) iodide, 0.2M in THF [ka] A three-neck, oven-dried round-bottom flask equipped with a magnetic stir bar and rubber septum was charged with lithium chloride (96 mg, 2.3 mmol). The vessel was heated under vacuum with a heat gun for 10 minutes, cooled to room temperature, and backfilled with nitrogen. Zinc (148 mg, 2.27 mmol) was added. The vessel was again heated under vacuum with a heat gun for 10 minutes, cooled to room temperature, and backfilled with nitrogen. THF (3.4 mL) and 1,2-dibromoethane (4.9 μL, 0.057 mmol) were added via syringe, and the reaction mixture was heated at 60 °C until bubbles appeared. After cooling to room temperature, a solution of chlorotrimethylsilane (4.4 μL, 0.034 mmol) and iodine (2.9 mg, 0.011 mmol) in THF (0.1 mL) was added via syringe. The reaction mixture was heated at 60 °C for 20 minutes and then cooled to room temperature. 1-(tert-Butyl)-3-iodocyclobutane (270 mg, 1.13 mmol) was added and the reaction was stirred at 50° C. for 18 hours. The reaction mixture was allowed to stand at room temperature for 1 hour. The solution was titrated by dropwise addition to a cooled (0° C.) solution of iodine (3 mg, 0.012 mmol) in lithium chloride (0.5 M in THF, 2.3 mL, 1.1 mmol) until the orange color disappeared. 0.06 mL of solution was used, corresponding to a concentration of 0.2 M.

[0171] Intermediate B: 5,8-dioxaspiro[3.4]octan-2-ylzinc(II) bromide, 0.1M in THF [ka] An oven-dried round-bottom flask equipped with a magnetic stir bar and rubber septum was charged with lithium chloride (0.878 g, 20.72 mmol). The vessel was heated under vacuum with a heat gun for 10 minutes, cooled to room temperature, and backfilled with nitrogen. Zinc (1.355 g, 20.72 mmol) was added. The vessel was again heated under vacuum with a heat gun for 10 minutes, cooled to room temperature, and backfilled with nitrogen. THF (13.8 mL) and 1,2-dibromoethane (0.045 mL, 0.518 mmol) were added via syringe, and the reaction mixture was heated at 60 °C until bubbles appeared. After cooling to room temperature, a solution of chlorotrimethylsilane (0.040 mL, 0.311 mmol) and iodine (0.026 g, 0.104 mmol) in THF (0.2 mL) was added via syringe. The reaction mixture was heated at 60° C. for 20 minutes and then cooled to room temperature. 2-Bromo-5,8-dioxaspiro[3.4]octane (1.3 mL, 10 mmol) was added and the reaction was stirred at 50° C. for 16 hours. The resulting solution was used as is.

[0172] Intermediate C: (3-(trifluoromethyl)cyclobutyl)zinc(II) bromide, 0.15 M in THF [ka] This intermediate was synthesized in the same manner and stoichiometry as Intermediate B using 1-bromo-3-(trifluoromethyl)cyclobutane (2.00 g, 9.85 mmol).

[0173] Intermediate D: (P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester [ka]

[0174] Step 1: (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl)acrylate A round-bottom flask was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (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), 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 heating bath. After 2 h, an additional portion of cesium carbonate (1.4 g) was added, and the bath temperature was increased to 120 °C. The mixture was heated for an additional 2 h, then cooled to room temperature, diluted with EtOAc, and filtered through CELITE with EtOAc. The filtrate was concentrated. The oily residue was dissolved in 2-PrOH. The mixture was concentrated to give a yellow solid with some oily solid present. The mixture was dissolved in 2-PrOH to give a suspension, and the suspension was stirred for 16 hours. The mixture was filtered, and the filtered solid was washed with 2-PrOH (3x). The collected solid was dried on the filter under a stream of N2 for 15 minutes to give 3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl) as a golden yellow solid. (E)-Ethyl acrylate (3.136 g, 6.29 mmol, 83% yield) was obtained. 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) + .

[0175] Step 2: 6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)quinolin-2(1H)-one A round-bottom flask was charged with (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl)acrylate (3.13 g, 6.28 mmol) and MeOH (31.4 mL) to give a yellow suspension. Sodium methoxide (25 wt% in MeOH, 0.271 mL, 1.256 mmol) was added. A reflux condenser was attached and the flask was lowered into a 75 °C heating bath. The bath was ramped to approximately 80-85 °C but returned to 70-75 °C after 30 min. The reaction was stirred for 16 h, and the mixture was 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% EtOAc / heptane) to give 6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)quinolin-2(1H)-one (1.95 g, 4.31 mmol, 69% yield) 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) + .

[0176] Step 3: Perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate A round-bottom flask was charged with 6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)quinolin-2(1H)-one (1.777 g, 3.93 mmol), acetonitrile (18.49 mL), acetic acid (0.693 mL), and water (0.462 mL) to give a solution. The flask was cooled in an ice-water bath for 10 minutes, after which 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.813 g, 4.12 mmol) was added in one portion. After 20 minutes, an additional portion of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.813 g, 4.12 mmol) was added in one portion. After an additional 20 min, 2,3,4,5,6-pentafluorophenol (1.085 g, 5.89 mmol) was added, and the mixture was stirred for 5 min. Triethylamine (2.190 mL, 15.71 mmol) was added dropwise over 30 min, followed by stirring for 20 min. The reaction mixture was diluted with water and extracted with DCM (3x). The combined organic extracts were 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% EtOAc / heptane). 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate perfluorophenyl ester (1.644 g, 2.85 mmol, 72.6% yield) 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) + .

[0177] Step 4: (P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester and (M)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester Racemic 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenyl sulfonate (3000 g) was separated into five 600-g batches using a Regis Whelk-O(S,S) 3 x 15 cm column. The mobile phase was run under isocratic conditions: 60% supercritical CO2 in 2:3 isopropanol:dichloromethane; flow rate: 150 mL / min. The first eluting peak was assigned to (P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenyl sulfonate (1459.2 g). The second eluting peak was assigned to (M)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenyl sulfonate (1492.9 g).

[0178] Step 5: (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide Racemic 1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (400 mg) was purified using a (S,S) Whelk-O, 2 x 15 cm column. The mobile phase was run under isocratic conditions: 60% isopropanol in supercritical CO2; flow rate: 80 mL / min. The first eluting peak was assigned to (M)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (150 mg). The second eluting peak was assigned to (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-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) + Peak 2 data: 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) + .

[0179] Intermediate E: N-(4-methoxybenzyl)isoxazol-3-amine [ka] A 20 L round-bottom flask was charged with isoxazol-3-amine (150 g, 1784 mmol) and 4-methoxybenzaldehyde (274 g, 2016 mmol) in methanol (9000 mL), water (150 mL), and acetic acid (101 mL) and stirred at room temperature for 15 minutes. Molybdenum dichloride dioxide (17.74 g, 89 mmol) and phenylsilane (193 g, 1784 mmol) were then added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mass was concentrated, diluted with dichloromethane (5000 mL), and washed with saturated aqueous NaHCO3 (2000 mL). The organic layer was washed with water (2000 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the initial product as an orange solid. The initial product was adsorbed onto a plug of silica gel and purified by column chromatography (silica gel, 60–120 mesh) eluting with a gradient of 0%–30% EtOAc in hexanes to give N-(4-methoxybenzyl)isoxazol-3-amine (272 g, 1332 mmol, 75% yield) as an off-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) + .

[0180] Intermediate F: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0181] Step 1: 4-Bromo-2-iodoaniline To a solution of 4-bromo-aniline (500 g, 2.90 mol, 2.0 equiv, Saibain Chem) in cyclohexane (2.5 L) was added iodine (368 g, 1.45 mol, 1.0 equiv, Qualigens) and the mixture was heated at 50° C. After 30 minutes, the reaction mixture became homogeneous. 30% aqueous hydrogen peroxide (250 mL, Spectrochem) 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 (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 give the initial product, which was purified by column chromatography (silica gel; mesh size 60-120, elution 0-20% ethyl acetate and hexane) to give 4-bromo-2-iodoaniline (650 g, 75.0%) as an off-white solid. TLC solvent system: 100% hexane. The R of the product f : 0.6. MS (ESI, positive ion) 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).

[0182] Step 2: (E)-3-(2-amino-5-bromophenyl)acrylate ethyl To a solution of 4-bromo-2-iodoaniline (750 g, 2.51 mol, 1.0 equiv) in DMF (5.0 L) was added ethyl acrylate (277 g, 2.76 mol, 1.1 equiv, Avra) and sodium bicarbonate (680 g, 6.29 mol, 2.5 equiv). The reaction mixture was degassed with nitrogen for 20 minutes, after which palladium acetate (28.8 g, 128.27 mol, 0.05 equiv, Hindustan Platinum) was added. The reaction mixture was heated at 70° C. for 3 hours. The reaction was filtered through CELITE®, and the CELITE® bed was washed with ethyl acetate (2×500 mL). The filtrate was concentrated under reduced pressure to give the first product, which was purified by column chromatography (silica gel; mesh size 60-120, elution 0-20% ethyl acetate in hexane) to give (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g, 77.0%) as a yellow solid. TLC solvent system: 20% ethyl acetate in hexane. The R f : 0.4. MS (ESI, positive ion) m / z: 270.2 (M+1). 1 H NMR(400MHz,DMSO)δ 7.75(d,J=16.1Hz,1H),7.57(d,J=2.0Hz,1H),7.16(dd,J=9.1,2.4Hz,1H),6.66(d,J=8.6 Hz,1H),6.43(d,J=8.6Hz,1H),5.81(s,2H),4.20(q,J=7.2Hz,2H),1.27(t,J=7.2Hz,3H). [ka]

[0183] Step 3: (E)-3-(2-amino-5-(benzylthio)phenyl)acrylate ethyl To a solution of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g, 2.29 mol, 1.0 equiv.) in 1,4-dioxane (4.0 L), DIPEA (1.26 L, 8.88 mol, 3.9 equiv., GLR) was added and the mixture was degassed with nitrogen for 20 minutes. XantPhos (92.9 g, 106 mmol, 0.05 equiv., GLR) and tris(dibenzylideneacetone)dipalladium (84 g, 91.0 mmol, 0.04 equiv., Hindustan Platinum) were added to the reaction mixture. The mixture was purged with nitrogen and heated to 80 °C for 30 minutes. The reaction was cooled to room temperature, and benzyl mercaptan (455.5 g, 3.67 mol, 1.6 equiv., Alfa Aesar) was added, and the reaction was heated at 80 °C for an additional 4 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (4.0 L). The mixture was filtered through CELITE® and the CELITE® bed was washed with ethyl acetate (2 x 1.0 L). The filtrate was concentrated under reduced pressure to give the initial product, which was purified by chromatography (silica gel; mesh size 60-120, elution 0-40% ethyl acetate and petroleum ether) to give (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (520 g, 72.0%) as a yellow solid. TLC solvent system: 30% ethyl acetate in hexane. The R of the product f : 0.4. MS (ESI, positive ion) m / z: 314.1 (M+1). 1 H NMR(400MHz,DMSO)δ 7.79(d,J=16.1Hz,1H),7.37(d,J=2.0Hz,1H),7.25-7.17(m,5H)7.10(dd,J=8.4,2.1Hz,1H),6.61(d,J=8 .3Hz,1H),6.32(d,J=15.2Hz,1H),5.75(s,2H),4.20(q,J=7.2Hz,2H),4.01(s,2H),1.27(t,J=7.2Hz,3H). [ka]

[0184] 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 equiv.) in DCM (5.0 L) was added silver trifluoromethanesulfonate (686.0 g, 2.68 mol, 1.1 equiv., Angene), and the reaction mixture was stirred for 20 minutes. Iodine (678.0 g, 2.68 mol, 1.1 equiv.) was added to the reaction, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM (3.0 L) and filtered through CELITE®. The CELITE bed was washed with DCM (2 x 1.0 L), and the filtrate was washed with 20% aqueous sodium thiosulfate (3.0 L) and saturated aqueous sodium bicarbonate (3.0 L). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the first product, which was purified by chromatography (silica gel; mesh size 60-120, elution 0-5% ethyl acetate and petroleum ether) to give 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (720 g, 87%) as an off-white solid. TLC solvent system: 100% hexane. R of the product f : 0.6. MS (ESI, positive ion) 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).

[0185] Step 5: (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)ethyl acrylate To a solution of (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (300 g, 958.1 mmol, 1.0 equiv.) and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (348.0 g, 1051.6 mmol, 1.1 equiv.) in toluene (2.5 L) was added CsCO (468 g, 1436.3 mmol, 1.5 equiv., Spectrochem), and the mixture was degassed with nitrogen for 20 min. Pd(dba) (35 g, 38.2 mmol, 0.04 equiv., Hindustan Platinum) and XantPhos (44.6 g, 76.4 mmol, 0.08 equiv., GLR) were added to the reaction mixture, and the mixture was heated at 110 °C for 5 h. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane (2.0 L), and filtered through CELITE®. The filtrate was concentrated under reduced pressure to give the first product, which was purified by stirring with 5% ethyl acetate in hexanes (3.0 L) for 30 minutes and filtered to give (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (350 g, 71%) as a yellow solid. TLC solvent system: 30% ethyl acetate in hexanes. The R of the product f : 0.5. MS (ESI, positive ion) m / z: 516.2 (M+1). 1 H NMR (400 MHz, DMSO) δ 7.73-7.61 (m, 3H), 7.34-7.15 (m, 6H), 7.02 (d, J = 11.4 Hz, 1H), 6.60 (d, J = 21.2 Hz, 1H), 6.33 (d, J = 14.1 Hz, 1H), 4.26 (s, 2H), 4.16-4.09 (m, 2H), 3.81 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H). Note: NH protons were not observed. [ka]

[0186] Step 6: 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one To a solution of (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (250.0 g, 484.0 mmol, 1.0 equiv.) in methanol (2.5 L) was added tri(n-butyl)phosphine (50% solution in ethyl acetate, 48.9 mL, 96.8 mmol, 0.2 equiv., Spectrochem) and the reaction mixture was heated at 70° C. for 5 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to give the first product, which was purified by stirring with 5% ethyl acetate in hexanes (1.0 mL) and filtering to give 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one (201.0 g, 88%) as an off-white solid. TLC solvent system: 30% ethyl acetate in hexanes. R of the product f : 0.3. MS (ESI, positive ion) m / z: 470.0 (M+1). 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).

[0187] Steps 7+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)quinolin-2(1H)-one (250.0 g, 531.5 mmol, 1.0 equiv) in acetonitrile (2.5 L) was added acetic acid (200 mL) and water (130 mL). The resulting mixture was cooled to 0°C, and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (188.5 g, 956.7 mmol, 1.8 equiv, Aldrich) was added in small portions over 20 minutes, 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 equiv., Apollo) in acetonitrile (200 mL) was added over 5 min, followed by NEt (307.7 mL, 2.12 mol, 4.0 equiv.) over 20 min, maintaining the internal temperature below 5 °C. The mixture was stirred at 0–5 °C for 30 min. 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 give the starting material, which was purified by stirring with isopropyl alcohol:hexane (1:1, 1.0 L) and filtered to give racemic perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (190 g, 60%) as a white solid. TLC solvent system: 30% ethyl acetate in petroleum ether, product R f : 0.4. MS (ESI, positive ion) 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). [ka]

[0188] Step 9: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide Racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenyl sulfonate was separated via a Chiralcel OJ column (40% MeOH / 60% CO) to give (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate and (M)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate as pale yellow fluffy solids. Data for Peak 1: m / z (ESI) 594.0 (M+H). + Data for peak 2: m / z (ESI) 594.0 (M+H) + . [ka]

[0189] Step 10: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 250 mL round-bottom flask was charged with (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (11.34 g, 19.08 mmol) and N-(4-methoxybenzyl)isoxazol-3-amine (4.09 g, 20.04 mmol) and subsequently 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 via syringe to the stirred reaction mixture over 10 minutes. After 15 minutes, 1.0 N HCl (100 mL) was introduced, and the resulting reaction mixture was allowed to warm to room temperature. The mixture was diluted with EtOAc (100 mL), the layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 100 mL). The combined organic layers were then washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by flash column chromatography (100-g BIOTAGE® column, eluent: gradient, 0 to 100% EtOAc in heptane with 10% CHCl) to afford (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (9.54 g, 15.53 mmol, 81% yield) as a white amorphous solid. 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) + .

[0190] 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) was added silver(I) trifluoromethanesulfonate (638 g, 2483 mmol) at ambient temperature under a nitrogen atmosphere. 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. The mixture was then diluted with DCM (4500 mL) and filtered through Celite. The Celite bed was washed with DCM (2 x 1.0 L). The filtrate was washed with 20% aqueous sodium thiosulfate (5.0 L) and saturated aqueous sodium bicarbonate (5.0 L). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the initial product, which was purified by chromatography (silica gel; mesh size 60–120, elution with 0–5% ethyl acetate and petroleum ether) to give 1-bromo-2-chloro-4-iodo-5-methoxybenzene (610 g, 1756 mmol, 78% yield) as an off-white solid. 1 H NMR(400MHz,CDCl3)δ ppm 7.83(s,1H),7.03(s,1H),3.89(s,3H).

[0191] Intermediate H: N-(4-methoxybenzyl)pyrimidin-2-amine [ka] In a 50-mL microwave vial, EtOH (20 mL), 2-chloropyrimidine (1.5 g, 13.10 mmol), (4-methoxyphenyl)methenamine (2.15 g, 15.72 mmol, 1.2 equiv.), and triethylamine (2.65 g, 26.2 mmol, 2.0 equiv.) were dissolved sequentially. The reaction tube was sealed and irradiated in a microwave reactor cavity at a ceiling temperature of 120 °C and a maximum power of 80 W for 1 h. After the reaction mixture was cooled by airflow for 15 min, it was diluted with water (100 mL), extracted with CHCl (2 × 150 mL), and dried over NaSO. 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 NaCl (1 × 50 mL) and dried over NaSO. The solution was filtered and concentrated in vacuo to give the initial product as a yellow oil. The initial product was adsorbed onto a plug of silica gel and purified by chromatography on a Redi-Sep pre-packed silica gel column (12 g) eluting with a gradient of 20% to 30% EtOAc in hexanes to give N-(4-methoxybenzyl)pyrimidin-2-amine (1.5 g, 6.97 mmol, 53% yield) as an off-white solid. m / z (ESI) 216.2 (M+H). + .

[0192] Intermediate I: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka]

[0193] Step 1: (E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl) acrylate To a solution of (E)-3-(2-amino-5-(benzylthio)phenyl)ethyl 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) was added cesium carbonate (357.5 g, 1100 mmol), and the mixture was degassed with nitrogen for 20 minutes. Tris(dibenzylideneacetone)dipalladium(0) (12.5 g, 13.0 mmol) and XantPhos (15.8 g, 27.2 mmol, 0.05 equiv.) were added to the reaction mixture, and the mixture was heated at 110 °C for 5 hours. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane (1.0 L), and filtered through Celite. The filtrate was concentrated under reduced pressure to give the first product, which was purified by stirring with 5% ethyl acetate in hexanes (1.5 L) for 30 minutes and filtered to give ethyl (E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate (290 g, 85% yield) as a yellow solid. m / z (ESI) 532.2 (M+H). + .

[0194] Step 2: 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)-one To a solution of ethyl (E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate (300.0 g, 5630.0 mmol) in methanol (3.0 L) was added tri(n-butyl)phosphine (50% solution in ethyl acetate, 56.2 mL, 1126 mmol), and the reaction mixture was heated at 70° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to give the first product, which was purified by stirring with 5% ethyl acetate in hexanes (1.0 mL) and filtering to give 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)-one (210.0 g, 76.6%) as an off-white solid. m / z (ESI) 486.0 (M+H). + .

[0195] Step 3: Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate To a solution of 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)-one (400.0 g, 824.9 mmol) in acetonitrile (2.5 L) and THF (2.5 L) was added acetic acid (1.0 L) and water (700 mL). The resulting mixture was cooled to 0° C., and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (292 g, 1484.8 mmol) was added in small portions over 30 minutes, 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 triethylamine (477 mL, 3299 mmol) over 30 minutes, maintaining the internal temperature below 5°C. The mixture was continued stirring at 0°C for 50 minutes. Water (4.0 L) was added and extracted with ethyl acetate (3 x 2.0 L). The organic layer was washed with brine (2.0 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the initial product, which was purified by stirring with isopropyl alcohol / hexane (1:1, 2.0 L) and filtered to give perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (360 g, 72%) as a white solid. m / z (ESI) 610.6 (M+H). + .

[0196] Step 4: (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid and (M)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (156 g, 255 mmol) was purified via chiral SFC chromatography ((S,S)Whelk-O, 45% isopropanol) to give (P)-perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (72.66 g, 93% yield) and (M)-perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (76.13 g, 98% yield) as white solids. m / z (ESI) 610.6 (M+H). + .

[0197] Step 5: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide N-(4-Methoxybenzyl)pyrimidin-2-amine (9.72 g, 45.1 mmol) and (P)-perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (25.06 g, 41.0 mmol) were added to a 500-mL flask. The flask was flushed with a stream of N, followed by the addition of tetrahydrofuran (136 mL), and the reaction was cooled to 2 °C under N. Sodium tert-pentoxide (30% solution in THF, 197 mL, 492 mmol) was added via addition funnel over 30 minutes, maintaining an internal temperature of approximately 5 °C; the pale yellow solution turned orange upon addition. The reaction was stirred in an ice bath for 30 minutes. The reaction was then quenched with saturated aqueous NH4Cl and diluted with EtOAc. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organics were dried over Na2SO4, filtered, and evaporated. IPA was added and a white precipitate precipitated. The solvent was evaporated to approximately 100 mL, followed by the addition of additional IPA and the reaction was stirred for 18 hours. The slurry was filtered and the solid was washed with IPA.

[0198] The solid was dissolved in 150 mL of MTBE and heated at 40° C. for 2 hours. The slurry was cooled to ambient temperature and filtered to give a white solid. The impure material was dissolved in 500 mL of 10% MeOH / DCM and stirred with 500 mL of saturated aqueous NaHCO3 for 30 minutes. The layers were separated and the aqueous layer was extracted twice with 10% MeOH / DCM. The combined organic layers were dried and evaporated. The filtrates from the IPA and MTBE titrations were combined, loaded onto a 25 g silica cartridge, and purified by column chromatography (RediSep Rf Gold 120 g column, gradient elution 10% to 50% 3:1 EtOAc:EtOH in heptane with 10% dichloromethane additive). The pure product from the column and the product from the NaHCO extraction were combined to give (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (16.94 g, 26.4 mmol, 64% yield) as a pale yellow foam. 1 H 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) + .

[0199] Intermediate J: N-(4-methoxybenzyl)pyridazin-3-amine [ka] To a 25 mL round-bottom flask was added 4-methoxybenzaldehyde (1.00 g, 7.34 mmol) and pyridazin-3-amine (0.838 g, 8.81 mmol) in tetrahydrofuran (10 mL). Titanium(IV) isopropoxide (6.46 mL, 22.03 mmol) was then added, and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was then cooled to 0 °C, and sodium borohydride (0.556 g, 14.69 mmol) was added in small portions. The reaction mixture was then stirred at 0 °C for 2 h. The reaction mixture was diluted with water (20 mL) and filtered. The filtrate was then extracted with EtOAc (3 × 50 mL). The organic extract was washed with saturated aqueous NaCl (30 mL) and dried over Na SO . The solution was filtered and concentrated in vacuo to give the first product as an orange oil. The initial product was adsorbed onto a plug of silica gel and purified by chromatography on a Redi-Sep pre-packed silica gel column (40 g) eluting with 0% to 15% MeOH in CHCl to give N-(4-methoxybenzyl)pyridazin-3-amine (0.680 g, 3.16 mmol, 43.0% yield) as a yellow solid. m / z (ESI, positive ion) 216.2 (M+H). + .

[0200] Intermediate K: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-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-perfluorophenylsulfonate (5.00 g, 8.41 mmol) and N-(4-methoxybenzyl)pyridazin-3-amine (1.902 g, 8.83 mmol) was flushed with nitrogen and subsequently charged 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, after which the volatiles were removed in vacuo. Water was added, resulting in the formation of a white precipitate. This precipitate was isolated, dissolved in dichloromethane, and treated with heptane, resulting in the formation 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, 80% yield) as a white precipitate. m / z (ESI, positive ion) 625.0 (M+H). + .

[0201] Intermediate L: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester [ka]

[0202] Step 1: (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxy-5-methylphenyl)amino)phenyl)acrylate A round-bottom flask was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (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 h, an additional portion of tris(dibenzylideneacetone)dipalladium(0) (172 mg) and XantPhos (213 mg) was added. After 2 h, an additional portion of cesium carbonate (approximately 2 g) and 1-bromo-4-iodo-5-methoxy-2-methylbenzene (600 mg) were added. After an additional 30 min of refluxing, the mixture was cooled and filtered through CELITE. The filter pad was washed with EtOAc (3x). The filtrate was concentrated. The residue was concentrated from MeOH and dissolved in MeOH. The resulting suspension was heated to boiling, followed by sonication and cooling to room temperature. The mixture was filtered, and the collected solid was washed with MeOH (3x) and dried under a stream of N2 for 48 h to give (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxy-5-methylphenyl)amino)phenyl)acrylate (5.21 g, 10.17 mmol, 67.4% yield) as a golden 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) + .

[0203] Step 2: 6-(benzylthio)-1-(4-bromo-2-methoxy-5-methylphenyl)quinolin-2(1H)-one A round-bottom flask was charged with (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxy-5-methylphenyl)amino)phenyl)acrylate (5.12 g, 9.99 mmol) and MeOH (50.0 mL) to give a yellow suspension. Sodium methoxide (25 wt% in MeOH, 0.432 mL, 1.998 mmol) was added. A reflux condenser was attached, and the flask was lowered into a 70 °C heat bath. After 1 h, additional portions of MeOH (25 mL) and sodium methoxide solution (ca. 0.85 mL) were added sequentially. After 7 h, the mixture was cooled and concentrated in vacuo. 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% EtOAc / heptane containing 10% DCM). The product-containing fractions were combined and concentrated to give 6-(benzylthio)-1-(4-bromo-2-methoxy-5-methylphenyl)quinolin-2(1H)-one (4.233 g, 9.08 mmol, 91% yield) as a tan solid. m / z (ESI) 466.1 (M+H)+.

[0204] Step 3: Perfluorophenyl 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate A round-bottom flask was charged with 6-(benzylthio)-1-(4-bromo-2-methoxy-5-methylphenyl)quinolin-2(1H)-one (4.23 g, 9.07 mmol), DCM (71.1 mL), acetic acid (2.67 mL), and water (1.778 mL) to give a clear, light brown solution. The flask was cooled in an ice-water bath for 10 minutes, followed by the addition of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (3.66 g, 18.59 mmol) in one portion. After 40 minutes, an additional portion of the oxidized product (850 mg) was added. The mixture was stirred for an additional 20 minutes, followed by the sequential addition of 2,3,4,5,6-pentafluorophenol (2.504 g, 13.60 mmol) and triethylamine (5.06 mL, 36.3 mmol). After 20 min, the mixture was diluted with water. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic extracts were 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, 10–60% EtOAc / heptane with 10% DCM) to give perfluorophenyl 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (3.37 g, 5.71 mmol, 63% yield). m / z (ESI) 590.0 (M+H). + .

[0205] Step 4: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl Perfluorophenyl 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (22.896 g, 38.79 mmol) was purified using a (S,S) Whelk-O, 5 x 25 cm column. The mobile phase was run under isocratic conditions: 50% dichloromethane in supercritical CO2; flow rate: 350 mL / min. The first eluting peak was assigned to (P)-perfluorophenyl 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (10.425 g). The second eluting peak was assigned to (M)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenylsulfonate (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) + .

[0206] Intermediate M: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] A 250 mL round-bottom flask was sequentially charged with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenylsulfonate (2.00 g, 3.37 mmol), tetrahydrofuran (17 mL), and N-(4-methoxybenzyl)pyrimidin-2-amine (0.724 g, 3.37 mmol), and the resulting solution was cooled to 0 °C. Lithium bis(trimethylsilyl)amide (3.70 mL, 3.70 mmol, 1.0 M in THF) was then added dropwise to the stirred reaction mixture. After 15 min, aqueous HCl (1.0 M, 100 mL) and EtOAc (100 mL) were added to the reaction mixture, which was subsequently allowed to warm to ambient temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were then washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by flash column chromatography (100 g BIOTAGE® column, gradient elution 0-100% EtOAc:heptane with 10% dichloromethane as co-eluent) to afford (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (1.10 g, 1.76 mmol, 52% yield) as a white solid. m / z (ESI, positive ion) 625.8 (M+H). + .

[0207] Intermediate N: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] To a solution of N-(4-methoxybenzyl)isoxazol-3-amine (83 mg, 0.407 mmol) and (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenyl sulfonate (200 mg, 0.339 mmol) in tetrahydrofuran (1.7 mL) at 0° C., sodium tert-pentoxide (30 wt % in THF, 176 μL, 0.440 mmol) was added slowly. The reaction was stirred at 0° C. for 30 minutes. After 30 minutes, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was concentrated, and the residue was triturated with MTBE (2 mL) to give (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (191 mg, 0.313 mmol, 92% yield) as a white powder. m / z (ESI, positive ion) 609.8 (M+H). + .

[0208] Intermediate O: N-(4-methoxybenzyl)oxazol-2-amine [ka] In a 250-mL flask, 1,3-oxazol-2-amine (5.00 g, 59.5 mmol) and 4-anisaldehyde (10.53 g, 8.85 mL, 77 mmol) in toluene (119 mL) were heated at 90° C. for 2 hours. The reaction was cooled to ambient temperature, and sodium triacetoxyhydroborate (18.91 g, 89 mmol) was added in small portions. The yellow reaction was stirred for 18 hours. The reaction was then quenched with water, the layers were separated, and the aqueous layer was extracted twice with dichloromethane. The combined organics were dried over NaSO, filtered, and concentrated. The residue was loaded onto a 25 g silica cartridge and purified by column chromatography (RediSep Rf Gold 120 g column, gradient elution 10-50% EtOAc:heptane) to give N-(4-methoxybenzyl)oxazol-2-amine (1.588 g, 7.78 mmol, 13% yield) as a white solid.1 H NMR(500MHz,DMSO-d6)δ ppm 7.55(br t,J=6.1Hz,1H),7.39(d,J=1.0Hz,1H),7.24(d,J=8.6Hz,2H),6.87(d,J=8.6Hz,2H), 6.73(d,J=1.0Hz,1H),4.26(d,J=6.2Hz,2H),3.72(s,3H).m / z(ESI,cation)205.2(M+H) + .

[0209] Intermediate P: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] To a solution of N-(4-methoxybenzyl)oxazol-2-amine (82 mg, 0.404 mmol) and (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenyl sulfonate (200 mg, 0.337 mmol) in tetrahydrofuran (1.6 mL) at 0° C., sodium tert-pentoxide (30% wt in THF, 175 μL, 0.438 mmol) was added slowly. The reaction was stirred at 0° C. for 30 minutes. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was concentrated. The residue was purified by silica gel column chromatography (gradient elution 20-80% [3:1 ethyl acetate / ethanol]:heptane with 10% dichloromethane as co-eluent) to give (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (180 mg, 0.293 mmol, 87% yield) as a white powder. m / z (ESI, positive ion) 613.8 (M+H) + .

[0210] Intermediate Q: (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] To a solution of N-(4-methoxybenzyl)isoxazol-3-amine (128 mg, 0.625 mmol) and (P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenyl sulfonate (300 mg, 0.521 mmol) in tetrahydrofuran (2.6 mL) at 0° C., sodium tert-pentoxide (30 wt % in THF, 271 μL, 0.677 mmol) was added slowly. The reaction was stirred at 0° C. for 30 minutes. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was concentrated. The residue was triturated with MTBE to give 1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (350 mg, 0.587 mmol, >99% yield) as an off-white solid. m / z (ESI, positive ion) 595.8 (M+H). + .

[0211] Intermediate R: (P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared following the method and purification protocol for Intermediate R using N-(4-methoxybenzyl)pyrimidin-2-amine (134 mg, 0.625 mmol). This gave 1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (140 mg, 0.230 mmol, 44% yield) as an off-white solid. m / z (ESI, positive ion) 606.8 (M+H). + .

[0212] Intermediate S: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared following the method and purification protocol for Intermediate R using (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenyl sulfonate (200 mg, 0.339 mmol). This gave (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (130 mg, 0.209 mmol, 62% yield) as a white solid. m / z (ESI, positive ion) 620.8 (M+H). + .

[0213] Intermediate T: N-(2,4-dimethoxybenzyl)oxazol-2-amine [ka] In a 250 mL flask, a mixture of 1,3-oxazol-2-amine (5.00 g, 59.5 mmol) and 2,4-dimethoxybenzaldehyde (10.87 g, 65.4 mmol) in toluene (100 mL) was heated at 90° C. for 1 hour. The reaction was cooled to room temperature and then treated with sodium triacetoxyborohydride (18.91 g, 89 mmol). The mixture was stirred at 100° C. for 1 hour, followed by room temperature for 60 hours. Additional sodium triacetoxyborohydride (18.91 g, 89 mmol) was added, and the reaction was stirred at 100° C. for 2 hours. The reaction was then cooled and diluted with ethyl acetate (500 mL) and water (100 mL). The organic layer was washed with saturated sodium bicarbonate solution (3×200 mL) and brine (2×100 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure to give a sticky brown oil, which was flushed through a plug of silica gel and washed with 50% [3:1 ethyl acetate:ethanol]:heptane. The filtrate was concentrated and subsequently purified by flash chromatography (HP silica 220 g column, gradient elution 0-70% ethyl acetate:[9:1 heptane:DCM]) to give N-(2,4-dimethoxybenzyl)oxazol-2-amine (1.18 g, 5.04 mmol, 8% yield) as a pale yellow solid. m / z (ESI, positive ion) 235.2 (M+H). + .

[0214] Intermediate U: (P)-1-(4-bromo-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] To a solution of N-(2,4-dimethoxybenzyl)oxazol-2-amine (146 mg, 0.625 mmol) and (P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenyl sulfonate (300 mg, 0.521 mmol) in tetrahydrofuran (2.6 mL) at 0° C., sodium tert-pentoxide (30 wt % in THF, 0.271 mL, 0.677 mmol) was added slowly. The reaction was stirred at 0° C. for 30 minutes. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was concentrated. The residue was purified by silica gel column chromatography (gradient elution 40-100% ethyl acetate:heptane with 10% dichloromethane as co-eluent) to give (P)-1-(4-bromo-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.200 g, 0.319 mmol, 61.3% yield) as a colorless oil. m / z (ESI, positive ion) 625.8 (M+H). + .

[0215] Intermediate V: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] To a solution of N-(4-methoxybenzyl)pyridazin-3-amine (0.219 g, 1.02 mmol) and (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenyl sulfonate (0.5 g, 0.847 mmol) in tetrahydrofuran (4.2 mL) at 0° C., sodium tert-pentoxide (30% wt in THF, 0.41 mL, 1.0 mmol) was added slowly. The reaction was stirred at 0° C. for 30 minutes. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was concentrated. The residue was purified by silica gel column chromatography (gradient elution 40-100% ethyl acetate:heptane with 10% dichloromethane as co-eluent) to give (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (367 mg, 0.591 mmol, 70% yield) as a white solid. m / z (ESI, positive ion) 620.8 (M+H). + .

[0216] Intermediate W: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] N-(2,4-Dimethoxybenzyl)oxazol-2-amine (0.211 g, 0.901 mmol) and (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenyl sulfonate (0.500 g, 0.819 mmol, Syngene) were added to a 40-mL vial. The vial was flushed with nitrogen, and tetrahydrofuran (2.7 mL) was added. The reaction was then cooled to 0 °C. Sodium tert-pentoxide (3.2 M in PhMe, 0.33 mL, 1.1 mmol) was added slowly. After stirring at 0 °C for 30 min, saturated aqueous ammonium chloride and EtOAc were added to the cold reaction. The phases were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were dried and evaporated. The residue was purified by column chromatography (two consecutive RediSep Rf Gold 40 g columns, gradient elution 0-40% [3:1 EtOAc:EtOH]:[10:1 heptane:dichloromethane]) to give (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.347 g, 0.525 mmol, 64% yield) as a yellow solid. m / z (ESI, positive ion) 681.8 (M+H). + .

[0217] Intermediate X: (P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] In a 250-mL flask, (P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenylsulfonate (7.00 g, 12.15 mmol) and N-(4-methoxybenzyl)pyridazin-3-amine (3.14 g, 14.58 mmol) were suspended in tetrahydrofuran (100 mL). The light brown suspension was cooled in an ice bath and treated dropwise with sodium tert-pentoxide (40 wt% in toluene, 7.77 mL, 19.43 mmol). The reaction was stirred at 0°C for 30 minutes and allowed to warm to room temperature. After 2 hours, additional base, sodium tert-pentoxide (40 wt% in toluene, 1 mL), was added, and the reaction was stirred at room temperature for an additional 15 hours. Additional tert-pentoxide (40 wt% in toluene, 1 mL) was added, and the reaction was stirred at room temperature for an additional 2 h. The reaction was cooled in an ice bath and quenched with saturated ammonium chloride solution (50 mL), and the reaction was stirred vigorously for 15 min. The phases were separated, and the aqueous phase was extracted with ethyl acetate (3 × 50 mL). The residue was purified via silica gel column chromatography (gradient elution 0–100% [3:1 EtOAc:EtOH]:[9:1 heptane:dichloromethane]). The product was further purified by trituration with ethyl acetate:heptane (1:1) to give (P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (1.56 g, 2.57 mmol, 21% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.04(dd,J=4.5,1.7Hz,1H),8.26(d,J=2.3Hz,1H),8.16(d,J=9.3Hz,1H),7.6 7-7.77(m,2H),7.64(dd,J=9.1,2.3Hz,1H),7.53(d,J=1.8Hz,1H),7.35-7.40( m,1H),7.30-7.34(m,1H),7.15(d,J=8.8Hz,2H),6.76-6.85(m,3H),6.72(d,J= 9.1Hz,1H),5.03(s,2H),3.72(s,3H),3.66(s,3H).m / z(ESI,cation)607.0(M+H) + .

[0218] Intermediate Y: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared following the method and purification protocol for Intermediate V using (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-perfluorophenyl sulfonate (5.00 g, 8.19 mmol). This gave (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, 54% yield). m / z (ESI, positive ion) 641.0 (M+H). + .

[0219] Intermediate Z: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared using N-(2,4-dimethoxybenzyl)oxazol-2-amine (0.236 g, 1.01 mmol) following the method for Intermediate N. The product was purified by column chromatography (two consecutive RediSep Rf Gold 40 g columns, gradient elution 0–40% [3:1 EtOAc:EtOH]:[9:1 heptane:dichloromethane]) to give (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.38 g, 0.59 mmol, 65% yield). 1 H NMR(500MHz,chloroform-d)δ ppm 7.92(d,J=2.1Hz,1H),7.86(dd,J=9.0,2.2Hz,1H),7.69(d,J=9.6Hz,1H),7.46(d, J=0.8Hz,1H),7.33(s,1H),7.16(d,J=8.3Hz,1H),7.08(s,1H),7.01(d,J=0.8Hz,1 H),6.82(d,J=9.6Hz,1H),6.68(d,J=9.1Hz,1H),6.37(dd,J=8.3,2.3Hz,1H),6.17 (d,J=2.3Hz,1H),4.94(s,2H),3.74(s,3H),3.73(s,3H),3.44(s,3H),2.40(s,3H).

[0220] Intermediate AB: (3-(trifluoromethyl)bicyclo[1.1.1] Pentan-1-yl)zinc(II) iodide [ka] An oven-dried vial was charged with 1-iodo-3-(trifluoromethyl)bicyclo[1.1.1]pentane (100 mg, 0.382 mmol), purged with nitrogen, and Rieke zinc 5% in tetrahydrofuran (27 mg, 0.549 mL, 0.420 mmol) was added. The mixture was stirred at room temperature for 3 hours. The resulting suspension was allowed to settle. The product was used without further purification.

[0221] Intermediate AC: (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid [ka]

[0222] Step 1: 4-Bromo-5-fluoro-2-iodoaniline N-Iodosuccinimide (710 g, 3158 mmol) was added portionwise to a solution of 4-bromo-3-fluoroaniline (500 g, 2631 mmol) in acetic acid (4000 mL) at 10-15 °C. The reaction was stirred at room temperature for 1 hour. The reaction was then quenched with ice water (7 L), and the precipitated solid was filtered. The solid was washed with 5% sodium thiosulfate solution (6 L) and water (4 L) and dried to give 4-bromo-5-fluoro-2-iodoaniline (750 g, 2374 mmol, 90% yield). 1 H NMR (400MHz, DMSO-d6): δ ppm 7.76(d,J=7.8Hz,1H),6.68(d,J=11.5Hz,1H),5.68(s,2H).

[0223] Step 2: (E)-3-(2-amino-5-bromo-4-fluorophenyl)acrylate ethyl To a stirred solution of 4-bromo-5-fluoro-2-iodoaniline (500 g, 1583 mmol) in isopropanol (2550 mL) was added triethylamine (331 mL, 2374 mmol) at room temperature. The reaction mixture was degassed with nitrogen for 20 minutes. Tris(dibenzylideneacetone)dipalladium(0) (36.2 g, 39.6 mmol) was added, followed by the slow addition of ethyl acrylate (162 g, 1614 mmol) under a nitrogen atmosphere. The reaction mixture was then heated to 70°C and stirred for 6 hours. Upon completion, the reaction mixture was filtered through Celite and washed with dichloromethane (2 L). The filtrate was concentrated under reduced pressure to give the first product. The first product was slurried in 3% ethyl acetate in petroleum ether (6 L) and filtered. The resulting solid was washed with 3% EtOAc in petroleum ether (2 L) and dried to give ethyl (E)-3-(2-amino-5-bromo-4-fluorophenyl)acrylate (433 g, 1505 mmol, 95% yield) as a yellow solid. MS (ESI, positive ion) m / z: 288.0 (M+1). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.69-7.98(m,2H),6.61(d,J=11.4Hz,1H),6.45(d,J=15.6Hz,1H),6.12(s,2H),4.17(q,J=7.1Hz,2H),1.26(t,J=7.1Hz,3H).

[0224] Step 3: (E)-3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate ethyl To a solution of (E)-ethyl 3-(2-amino-5-bromo-4-fluorophenyl)acrylate (500.0 g, 1735 mmol) in 1,4-dioxane (2500 mL) was added N-ethyl-N-isopropylpropan-2-amine (449 g, 3471 mmol) and the mixture was degassed with nitrogen for 20 minutes. (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (50.2 g, 87 mmol) and tris(dibenzylideneacetone)dipalladium(0) (39.7 g, 43.4 mmol) were added to the reaction mixture. The mixture was purged with nitrogen and heated to 80°C for 10 minutes. The reaction was cooled to room temperature and phenylmethanethiol (237 g, 1909 mmol) was added. The reaction was heated at 90°C for 12 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (1000 mL). The mixture was filtered through Celite, and the Celite bed was washed with ethyl acetate (2500 mL). The filtrate was concentrated under reduced pressure to give the initial product. The initial product was purified by column chromatography (silica gel; mesh size 60-120, gradient elution 0-15% ethyl acetate and petroleum ether) to give ethyl (E)-3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate (300.0 g, 905 mmol, 52% yield) as a yellow solid. MS (ESI, positive ion) m / z: 332.1 (M+1). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.72(d,J=15.7Hz,1H),7.41(d,J=8.5Hz,1H),7.01-7.32(m,5H),6.38-6.55(m,1H),6.24(d, J=15.7Hz,1H),6.11(s,2H),4.17(q,J=7.1Hz,2H),3.89-4.07(m,2H),1.26(t,J=7.1Hz,3H).

[0225] Step 4: (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-4-fluorophenyl)acrylate ethyl To a 250 mL three-necked round-bottom flask charged with (E)-3-(2-amino-5-(benzylthio)-4-fluorophenyl)ethyl acrylate (10 g, 30.2 mmol) and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (10.48 g, 31.7 mmol) in toluene (100 mL) was added cesium carbonate (39.3 g, 121 mmol). The mixture was degassed with nitrogen for 15 minutes. Tris(dibenzylideneacetone)dipalladium(0) (1.105 g, 1.207 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (1.397 g, 2.414 mmol) were added to the reaction mixture, and the mixture was heated at 110 °C for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane (200 mL), and filtered through Celite. The filtrate was concentrated under reduced pressure to give the first product, which was purified by stirring with methanol (250 mL) for 1 hour and filtered. The cake was washed with methanol (100 mL) and dried to give ethyl (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-4-fluorophenyl)acrylate (13.5 g, 25.3 mmol, 84% yield) as a yellow solid. MS (ESI, positive ion) m / z: 534.0 (M+1). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.97(s,1H),7.75(d,J=8.4Hz,1H),7.66(d,J=15.9Hz,1H),7.05-7.43(m,6H),6.77(d,J=11.1Hz,1H),6.63(d, J=10.2Hz,1H),6.52(d,J=15.9Hz,1H),4.25(s,2H),4.16(q,J=7.1Hz,2H),3.82(s,3H),1.23(t,J=7.1Hz,3H).

[0226] Step 5: 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoroquinolin-2(1H)-one A 500 mL three-neck round-bottom flask was charged with (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-4-fluorophenyl)ethyl acrylate (13.5 g, 25.3 mmol) in methanol (140 mL), and tributylphosphane (50% solution in ethyl acetate) (3.74 mL, 7.58 mmol) was added. The reaction mixture was heated at 70° C. for 5 hours. The reaction mixture was allowed to cool to 15° C., filtered, washed with cold methanol (100 mL), and dried to give 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoroquinolin-2(1H)-one (9.5 g, 19.45 mmol, 77% yield) as a yellow solid. MS (ESI, positive ion) m / z: 488.0 (M+1). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.88-8.02(m,2H),7.64(d,J=6.3Hz,1H),7.56(d,J=8.6Hz,1H),7.20-7.38(m ,5H),6.64(d,J=9.6Hz,1H),6.48(d,J=11.3Hz,1H),4.23(s,2H),3.71(s,3H).

[0227] Steps 6 and 7: Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate To a 250 mL three-neck round-bottom flask charged with 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoroquinolin-2(1H)-one (9.5 g, 19.45 mmol) in acetonitrile (95 mL) was added acetic acid (6.4 mL) and water (4.13 mL). The resulting mixture was cooled to 0-5°C, and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (6.13 g, 31.1 mmol) was added in small portions over 10-20 minutes, maintaining the internal temperature below 5-10°C. The resulting suspension was stirred under nitrogen at 5-10°C for 45 minutes. Next, a solution of 2,3,4,5,6-pentafluorophenol (7.16 g, 38.9 mmol) in acetonitrile (10 mL) was added over 10–15 min, followed by triethylamine (13.54 mL, 97 mmol) over 20 min, maintaining the internal temperature below 5–10 °C. The mixture was continued stirring at 5–10 °C for 30 min. Ice water (200 mL) was added, and the precipitated solid was filtered and washed with water (100 mL). The initial product was purified by stirring with methanol (50 mL), filtering, washing with MeOH (50 mL), and drying to give perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate (9.5 g, 15.52 mmol, 80% yield) as an off-white solid. MS (ESI, positive ion) m / z: 612.0 (M+1). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.53(d,J=7.4Hz,1H),8.20(d,J=9.8Hz,1H),7.67(dd,J=16.2,7.4Hz,2H),6.99(d,J=12.1Hz,1H),6.83(d,J=9.8Hz,1H),3.74(s,3H).

[0228] Step 8: (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate (135 g, 220 mmol) was purified by SFC using a Regis Whelk-O s,s 5 × 15 cm, 5 μm column with a mobile phase of 50% dichloromethane at a flow rate of 350 mL / min to give (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate (49.2 g, 80.4 mmol, 36% yield). MS (ESI, positive ion) m / z: 612.7 (M+1).

[0229] Chemical Examples Examples 1 and 2: (M)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and 1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, respectively [ka]

[0230] Step 1: (M)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A vial was charged with palladium(II) acetate (2.7 mg, 0.012 mmol), 2'-(dicyclohexylphosphino)-N 2 ,N 2 ,N 6 ,N 6A solution of 1,1'-tetramethyl-[1,1'-biphenyl]-2,6-diamine (10.6 mg, 0.024 mmol) and (M)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.100 g, 0.202 mmol) was charged. (3-(tert-butyl)cyclobutyl)zinc(II) iodide (0.2 M in THF, 2.0 mL, 0.41 mmol) was added, and the reaction was stirred at 50 °C for 2 hours. The reaction was then diluted with ethyl acetate and washed twice with 1 N HCl. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g column, gradient elution 0-50% [3:1 EtOAc:EtOH]:heptane) to afford (M)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (50 mg, 0.095 mmol, 47% yield) as a mixture of cis and trans isomers. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.65(s,1H),8.73(d,J=1.9Hz,1H),8.30-8.41(m,1H),8.20(d,J=10. 0Hz,1H),7.72-8.00(m,1H),7.04-7.29(m,2H),6.73-6.85(m,2H),6.4 4(d,J=1.5Hz,1H),3.64-3.75(m,3H),3.45-3.63(m,1H),2.18-2.38(m,4H),1.89-2.04(m,1H),0.83-0.97(m,9H).m / z(ESI, cation)526.2(M+H) + .

[0231] Step 2: 1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (M)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (44 mg) was epimerized in DMSO by heating at 130° C. for 3 hours, which was then concentrated and dried to give 1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.66(s,1H),8.74(d,J=1.7Hz,1H),8.31-8.41(m,1H),8.14-8.30(m, 1H),7.75-7.93(m,1H),7.03-7.32(m,2H),6.74-6.84(m,2H),6.45(d, J=1.5Hz,1H),3.70(d,J=10.0Hz,3H),3.57-3.64(m,1H),2.19-2.41(m,4H),1.91-2.06(m,1H),0.86-0.96(m,9H).m / z(ESI,cation)526.2(M+H) + .

[0232] Example 3: (P)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] A vial was charged with palladium(II) acetate (7.3 mg, 0.032 mmol), 2'-(dicyclohexylphosphino)-N 2 ,N 2 ,N 6 ,N 6A solution of 1,1'-tetramethyl-[1,1'-biphenyl]-2,6-diamine (28 mg, 0.065 mmol) and (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (160 mg, 0.324 mmol) was charged. (3-(tert-butyl)cyclobutyl)zinc(II) iodide (0.2 M in THF, 3.2 mL, 0.65 mmol) was added, and the reaction was stirred at 50 °C for 2 hours. The reaction was then diluted with ethyl acetate and washed twice with 1 N HCl. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g column, gradient elution 0–50% [3:1 EtOAc:EtOH]:heptane) to afford (P)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (90 mg, 0.17 mmol, 53% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm 11.65(s,1H),8.72(d,J=1.9Hz,1H),8.29-8.38(m,1H),8.20(d,J=10.0Hz ,1H),7.84(dt,J=9.0,1.9Hz,1H),7.03-7.33(m,2H),6.71-6.85(m,2H),6 .44(d,J=1.7Hz,1H),3.69(d,J=10.2Hz,3H),3.53-3.63(m,1H),2.16-2.3 7(m,4H),1.91-2.07(m,1H),0.80-0.95(m,9H).m / z(ESI,cation)526.2(M+H) + .

[0233] Example 4: (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0234] Step 1: (P)-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A vial was charged with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (Intermediate F) (0.500 g, 0.814 mmol), palladium(II) acetate (10.96 mg, 0.049 mmol), and 2'-(dicyclohexylphosphino)-N 2 ,N 2 ,N 6 ,N 6 The reaction mixture was charged with 1,1'-tetramethyl-[1,1'-biphenyl]-2,6-diamine (0.043 g, 0.098 mmol). 5,8-Dioxaspiro[3.4]octan-2-ylzinc(II) bromide (0.1 M in THF, 14 mL, 0.70 mmol) was added, and the reaction was stirred at 50 °C for 16 hours. The reaction was then diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g column, gradient elution 0-100% EtOAc:heptane) to give (P)-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.258 g, 0.398 mmol, 49% yield) as a pale yellow solid. m / z (ESI, positive ion) 648.2 (M+H). + .

[0235] Step 2: (P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)-1-(5-Fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.258 g, 0.398 mmol) was dissolved in tetrahydrofuran (4 mL). Hydrochloric acid (1 N in water, 2.0 mL, 2.0 mmol) was added and the reaction was stirred at 50° C. for 3 days. The reaction was then diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g column, gradient elution 0-100% EtOAc:heptane) to give (P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.179 g, 0.297 mmol, 74% yield) as a pale yellow solid. m / z (ESI, positive ion) 604.2 (M+H) + .

[0236] Step 3: (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A vial was charged with (P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.169 g, 0.280 mmol) and diethylaminosulfur trifluoride (1.85 mL, 14.0 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was then poured into a 250-mL round-bottom flask, diluted with ethyl acetate, and saturated aqueous sodium bicarbonate was carefully added until bubbling ceased. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g column, gradient elution 0-100% EtOAc:heptane) to give (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.142 g, 0.227 mmol, 81% yield) as a white solid. m / z (ESI, positive ion) 626.2 (M+H) + .

[0237] Step 4: (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.142 g, 0.227 mmol) was dissolved in TFA (1 mL). The solution was heated to 50° C. and stirred for 2 hours. The reaction was concentrated and purified via column chromatography (RediSep Gold 40 g column, gradient elution 0–75% [3:1 EtOAc:EtOH]:heptane) to afford (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.109 g, 0.216 mmol, 95% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.66(s,1H),8.74(d,J=1.9Hz,1H),8.37(d,J=2.3Hz,1H),8.22(d,J=9.5Hz,1H),7.84(dd,J=8.9,2.3Hz,1H),7.36(d,J=10.2Hz,1H),7.2 7(d,J=6.8Hz,1H),6.76-6.84(m,2H),6.45(d,J=1.7Hz,1H),3.71(s,3H),3.57-3.68(m,1H),2.91-3.13(m,4H).m / z(ESI,cation)506.0(M+H) + .

[0238] Example 5: (P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0239] Step 1: (P)-1-(5-fluoro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A round-bottom flask was charged with (P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.500 g, 0.828 mmol) and THF (4.1 mL). Trifluoromethyltrimethylsilane (0.21 mL, 1.4 mmol) and tetra-n-butylammonium fluoride (1.0 M in THF, 0.083 mL, 0.083 mmol) were added sequentially, and the reaction was stirred at room temperature for 1 hour. Additional (trifluoromethyl)trimethylsilane (0.208 mL, 1.408 mmol) and tetra-n-butylammonium fluoride (1.0 M in THF, 0.5 mL, 0.5 mmol) were added, and the reaction was stirred for 16 hours. HCl (1N in water, 5.8 mL, 5.8 mmol) was added and the reaction was stirred for 1 hour. The reaction was then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (BIOTAGE® SNAP 25 g column, gradient elution 0-100% EtOAc:heptane) to afford (P)-1-(5-fluoro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.433 g, 0.643 mmol, 78% yield) as a tan solid. m / z (ESI, positive ion) 674.0 (M+H) + .

[0240] Step 2: (P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A vial was charged with (P)-1-(5-fluoro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.131 g, 0.194 mmol) and bis(2-methoxyethyl)aminosulfur trifluoride (1.0 mL, 5.4 mmol) was added. The reaction was heated to 50° C. and stirred for 16 hours. The reaction was diluted with ethyl acetate and carefully quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g column, gradient elution 0-100% EtOAc:heptane) followed by reverse-phase HPLC using an XBridge Prep Shield RP18 19 x 100 mm column. The mobile phase was run under gradient elution; 50-95% acetonitrile:water with 0.1% formic acid; flow rate: 40 mL / min. This gave (P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.027 g, 0.040 mmol, 21% yield) as a white solid. m / z (ESI, positive ion) 676.0 (M+H). + .

[0241] Step 3: (P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A vial was charged with (P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.027 g, 0.040 mmol) and TFA (0.2 mL) and stirred at room temperature overnight. The reaction was then concentrated and purified via column chromatography (BIOTAGE® SNAP 10 g column, gradient elution 0-75% [3:1 EtOAc:EtOH]:heptane) to afford (P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.018 g, 0.032 mmol, 81% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.67(s,1H),8.73(d,J=1.7Hz,1H),8.38(d,J=2.1Hz,1H),8.23(d,J=9.5Hz,1 H),7.85(dd,J=8.9,2.3Hz,1H),7.41-7.53(m,2H),6.81(d,J=9.7Hz,1H),6.76 (d,J=9.1Hz,1H),6.45(d,J=1.9Hz,1H),5.95-6.22(m,2H),5.86(s,1H),3.64- 3.80(m,3H),3.07-3.21(m,1H),2.81-2.98(m,1H).m / z(ESI, cation)556.0(M+H) + .

[0242] Examples 6 and 7: cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, respectively [ka]

[0243] Step 1: (P)—O-(3-(2-fluoro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)O-phenyl carbonothioate (P)-1-(5-fluoro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.200 g, 0.297 mmol), prepared according to the procedure described in Steps 1-2 of Example 4 followed by Step 1 of Example 5, was dissolved in THF (1.5 mL) and cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 0.018 g, 0.45 mmol) was added and the reaction was allowed to warm to room temperature over 30 minutes. Phenyl chlorothionoformate (0.103 mL, 0.742 mmol) was added and the reaction was stirred for 3 hours. The reaction was then cooled to 0° C. and an additional portion of sodium hydride (60% dispersion in mineral oil, 0.018 g, 0.445 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 30 minutes, followed by the addition of additional phenyl chlorothionoformate (0.103 mL, 0.742 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (BIOTAGE® SNAP 25 g column, gradient elution 0-100% EtOAc:heptane) to afford (P)—O-(3-(2-fluoro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)O-phenyl carbonothioate (0.215 g, 0.265 mmol, 89% yield) as a pale yellow solid.

[0244] Step 2: (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)—O-(3-(2-fluoro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)-O-phenyl carbonothioate (0.119 g, 0.147 mmol) was dissolved in toluene (1.5 mL). Tri-n-butyltin hydride (0.39 mL, 1.5 mmol) and azobisisobutyronitrile (0.024 g, 0.15 mmol) were added, and the reaction was degassed with nitrogen for 20 minutes, then heated to 50° C. and stirred for 2 hours. The reaction was also carried out twice under the same conditions and reagent stoichiometry using O-(3-(2-fluoro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)-O-phenyl carbonothioate (0.025 g, 0.031 mmol). All three reactions were then combined, loaded onto a silica cartridge, and purified via column chromatography (BIOTAGE® SNAP 25 g column, gradient elution 0-100 g EtOAc:heptane) to afford (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.101 g, 0.154 mmol, 74% yield) as a pale yellow solid. m / z (ESI, positive ion) 658.0 (M+H). + .

[0245] Step 3: cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A vial was charged with (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.101 g, 0.154 mmol) and TFA (1.0 mL) and stirred overnight at room temperature. The reaction was then concentrated and purified via column chromatography (BIOTAGE® SNAP 10 g column, gradient elution 0-75% [3:1 EtOAc:EtOH]:heptane) to afford 81 mg of material as an off-white solid. This material was further purified using two consecutive Chiralcel OJ-H, 2 x 25 cm columns. The mobile phase was run under isocratic conditions: 15% methanol in supercritical CO2; flow rate: 80 mL / min. The first eluting peak was assigned to cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (39 mg). The second eluting peak was assigned to trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (11 mg). Data for Peak 1: 1H NMR (500 MHz, DMSO-d6) δ ppm 11.65(s,1H),8.60-8.83(m,1H),8.35(d,J=2.1Hz,1H),8.20(d,J=9.6Hz,1H) ,7.83(dd,J=9.0,2.2Hz,1H),7.31(d,J=10.1Hz,1H),7.14(d,J=6.7Hz,1H),6. 71-6.89(m,2H),6.44(d,J=1.8Hz,1H),3.71-3.83(m,1H),3.69(s,3H),3.24- 3.31(m,1H),2.56-2.65(m,2H),2.31-2.44(m,2H).m / z(ESI, cation)538.0(M+H) + Peak 2 data: 1 H NMR(500MHz,DMSO-d6)δ ppm 11.65(s,1H),8.73(d,J=1.8Hz,1H),8.36(d,J=2.3Hz,1H),8.21(d,J=9.6Hz,1H),7.84(dd,J=9.0,2.2Hz,1H),7.24-7.40(m,2H),6.79(d,J =9.6Hz,2H),6.44(d,J=1.6Hz,1H),3.94(quin,J=8.9Hz,1H),3.71(s,3H),3.25-3.31(m,1H),2.56-2.75(m,4H).m / z(ESI,cation)538.0(M+H) + .

[0246] Example 7A: trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0247] Step 1: (P)-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 2 L three-neck round-bottom flask equipped with an overhead stirrer, distillation head, thermocouple, addition funnel, and nitrogen inlet was charged with zinc powder (112 g, 1.72 mol), lithium chloride (16.0 g, 389 mmol), and anhydrous tetrahydrofuran (750 mL). Half of the tetrahydrofuran was removed via distillation at atmospheric pressure. The resulting mixture was cooled to 30 °C, and chlorotrimethylsilane (3.0 mL, 23.5 mmol) was added. The mixture was warmed to 50 °C for 30 min, the temperature was increased, and the reaction volume was reduced by approximately 50 mL via distillation. After cooling the resulting mixture to 30 °C, trans-1-bromo-3-(trifluoromethyl)cyclobutane (75.0 g, 369 mmol, Enamine, LLC) was introduced. The mixture was then warmed to 40 °C. A significant exotherm was observed, and the heating mantle was replaced with an ambient temperature water bath. After the exotherm subsided, the water bath was removed and the reaction mixture was stirred at 50°C for 1 hour. The mixture was allowed to stand overnight and cool to ambient temperature. The supernatant was used without further manipulation. A separate 2 L three-neck round-bottom flask equipped with an overhead stirrer, thermocouple, reflux condenser, and nitrogen inlet was charged with 1,2,3,4,5-pentaphenyl-1'-(di-t-butylphosphino)ferrocene (0.90 g, 1.27 mmol, Strem Chemicals, Inc.), tris(dibenzylideneacetone)dipalladium (0.60 g, 0.66 mmol, Strem Chemicals, Inc.), and anhydrous tetrahydrofuran (50 mL). The resulting mixture was warmed to 45°C. After 15 minutes, the reaction mixture was allowed to cool to room temperature, after which anhydrous tetrahydrofuran (250 mL) and (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (Intermediate F) (187 g, 304 mmol) were introduced, and the mixture was stirred until all solids dissolved. The resulting reaction mixture was warmed to 40° C., after which the supernatant from the previous reaction containing trans-3-(trifluoromethyl)cyclobutyl)zinc(II) bromide in THF was added dropwise via cannula.The reaction was mildly exothermic, and the rate of addition was adjusted to maintain an internal temperature of 40-45°C. After the addition was complete, the mixture was warmed to 50°C. After 3 h, an aqueous solution of citric acid (1 M, 400 mL) and water (500 mL) were introduced, and the resulting mixture was extracted with ethyl acetate (1500 mL). The organic layer was washed with brine (500 mL) and concentrated under reduced pressure. The resulting solid was suspended in isopropanol (1 L) and stirred at 40°C for 20 min. The mixture was cooled to ambient temperature and filtered through a sintered glass frit filter. The solid was washed with isopropanol (40 mL) and transferred to a 2 L round-bottom flask. Isopropyl acetate (1 L) was added, and the mixture was stirred at 40°C for 20 min. The suspension was filtered through a sintered glass frit filter, and the solid was washed with additional isopropyl acetate (50 mL). The filtrate was transferred to a 2 L round-bottom flask, and SiliaMetS Thiol metal scavenger (20 g, Silicycle) and activated carbon (20 g) were added. The mixture was stirred at ambient temperature for 20 minutes. The supernatant was filtered through a pad of Celite, and the solid was washed with isopropyl acetate (500 mL). The filtrate was concentrated under reduced pressure. A mixture of dichloromethane and methyl tert-butyl ether (1:1 mixture, 1 L) was added to the solid, and the resulting mixture was stirred at 40 °C for 20 minutes. The mixture was filtered through a sintered glass frit filter, and the trace solid was washed with methyl tert-butyl ether (30 mL). The combined filtrate was concentrated under reduced pressure to give (P)-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (150 g, 228 mmol, 75% yield) as a reddish solid, which was used in the next step without further purification. m / z (ESI) 658.0 (M+H). + .

[0248] Step 2: (P)-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 2 L three-neck round-bottom flask equipped with an overhead stirrer, Claisen adapter, addition funnel, thermocouple, reflux condenser, and nitrogen inlet was charged with (P)-1-(5-fluoro-2-methoxy-4-(1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (150 g, 228 mmol) and triethylsilane (85 mL, 532 mmol). Trifluoroacetic acid (500 mL) was added dropwise over 60 min at a rate that prevented the internal temperature of the reaction from exceeding 40-50 °C. The reaction mixture was warmed to 50 °C for 30 min, after which it was allowed to cool to room temperature. Heptane (800 mL) was introduced, and the mixture was concentrated under reduced pressure. The resulting solid was azeotroped with heptane (2 x 800 mL) and then suspended in heptane (800 mL). The mixture was stirred at ambient temperature for 10 minutes, after which the heptane was decanted and discarded. The remaining material was dissolved in dichloromethane (1.5 L) and washed with an aqueous solution of trisodium phosphate (0.2 N, 2 x 300 mL). The organic layer was separated and concentrated under reduced pressure. The residue was suspended in methyl tert-butyl ether (2 L) and stirred at 40 °C for 20 minutes. The suspension was filtered through a sintered glass frit filter, and the solid was washed with methyl tert-butyl ether (100 mL). The filtrate was evaporated to dryness under reduced pressure, and the product was suspended in methanol (500 mL). The resulting suspension was concentrated under reduced pressure and the residue was purified via two-step SFC (Step 1: Waters Torus 2-PIC, 5 μM, 3 × 15 cm column using 25% methanol as eluent at a flow rate of 180 mL / min; Step 2: Chiralcel OJ-H, 5 μm, 5 × 40 cm column using 20% ​​methanol as eluent at a flow rate of 240 mL / min) to give (P)-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (63.3 g, 118 mmol, 52% yield). 1H NMR(500MHz,CDCl3)δ:8.58(s,1H),8.26(s,1H),8.16(d,J=1.8Hz,1H),7.78(t,J=9.9Hz,2H),6.92-6.98(m,2H),6.86(d,J=9.6Hz,1H),6 .77(d,J=9.0Hz,1H),6.59(s,1H),3.98(quin,J=9.0Hz,1H),3.72-3.80(m,3H),2.99-3.11(m,1H),2.69-2.74(m,2H),2.60-2.65(m,2H). 13 C NMR(126MHz,CDCl3)δ:161.57,159.89,156.85,154.94(d,J=241.6Hz),151.41(d,J =2.7Hz),143.79,139.41,133.89(d,J=15.4Hz),132.62,128.19,128.30(q,J=276.1 Hz),124.00,123.34,120.04,117.16(d,J=25.4Hz),116.42,111.73(d,J=5.5Hz),9 8.59,56.39,34.01(q,J=30.0Hz),31.80,27.76,27.50,27.31.m / z(ESI)538.0(M+H) + .

[0249] Examples 8 and 9: trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and cis-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, respectively [ka] A vial was charged with (P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.212 g, 0.314 mmol) and TFA (1 mL) and stirred at 50 °C for 2 h. The reaction was then concentrated and purified using two consecutive Chiralpak IC, 2 × 15 cm columns. The mobile phase was run under isocratic conditions: supercritical CO2 in 25% methanol; flow rate: 80 mL / min. The first eluting peak was assigned to trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (62 mg). The second eluting peak was assigned to cis-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (42 mg). Data for Peak 1: 1 H NMR(400MHz,DMSO-d6)δ ppm 11.65(s,1H),8.73(d,J=1.7Hz,1H),8.37(d,J=2.3Hz,1H),8.22(d,J=9.5Hz,1H), 7.84(dd,J=8.9,2.3Hz,1H),7.49(d,J=10.2Hz,1H),7.44(d,J=6.2Hz,1H),6.79(d d,J=9.2,5.7Hz,2H),6.44(d,J=1.9Hz,1H),5.95-6.14(m,2H),5.85(s,1H),3.71( s,3H),3.15(td,J=15.3,9.8Hz,1H),2.79-2.99(m,1H).m / z(ESI,cation)555.2(M+H) + Peak 2 data: 1H NMR(400MHz,DMSO-d6)δ ppm 11.65(s,1H),8.73(d,J=1.7Hz,1H),8.37(d,J=2.3Hz,1H),8.23(d,J=9.7Hz,1H),7.8 4(dd,J=8.9,2.3Hz,1H),7.49(d,J=10.0Hz,1H),7.44(d,J=6.2Hz,1H),6.80(d,J=9.7H z,1H),6.76(d,J=9.1Hz,1H),6.45(d,J=1.7Hz,1H),5.96-6.17(m,2H),5.85(s,1H),3. 70(s,3H),3.14(td,J=15.5,9.6Hz,1H),2.79-2.99(m,1H).m / z(ESI,cation)555.4(M+H) + .

[0250] Examples 10 and 11: cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, respectively [ka]

[0251] Step 1: (P)-1-(5-chloro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide In a 250 mL three-necked round-bottom flask equipped with a reflux adapter and an internal temperature probe was placed (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (5 g, 7.93 mmol), palladium(II) acetate (0.107 g, 0.476 mmol), and 2'-(dicyclohexylphosphino)-N 2 ,N 2 ,N 6 ,N 6 The mixture was charged with 1,1'-tetramethyl-[1,1'-biphenyl]-2,6-diamine (0.415 g, 0.951 mmol), followed by evaporation and backfilling with nitrogen. 5,8-Dioxaspiro[3.4]octan-2-ylzinc(II) bromide (0.4 M in THF, 30 mL, 12 mmol) was added, and the reaction was stirred at 50°C for 20 hours. The mixture was then quenched with 2N aqueous HCl (80 mL). The temperature was raised to 50°C, and the mixture was stirred for 4 hours. The mixture was then partitioned between water and EtOAc. The layers were separated. The aqueous extract was extracted with EtOAc (2 x 100 mL). The combined extracts were washed with brine and then concentrated to give a black residue. The product was purified by column chromatography (200 g silica column, gradient elution 0-100% EtOAc:heptane) to give (P)-1-(5-chloro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide as a tan solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.80(d,J=1.6Hz,1H),8.36(d,J=2.1Hz,1H),8.15(d,J=9.9Hz,1H),7.78(dd,J =9.1,2.1Hz,1H),7.56(s,1H),7.47(s,1H),7.25(d,J=8.8Hz,2H),6.86(d,J=8 .6Hz,2H),6.82(d,J=9.6Hz,1H),6.69-6.76(m,2H),4.91(s,2H),3.97-4.07(m ,2H),3.75(s,3H),3.71(s,3H),3.47-3.52(m,3H).m / z(ESI,cation)620.0(M+H) + .

[0252] Step 2: (P)-1-(5-chloro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 25-mL round-bottom flask was charged with (P)-1-(5-chloro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.806 g, 1.30 mmol) and THF (6.5 mL) and equipped with an internal temperature probe. (Trifluoromethyl)trimethylsilane (0.38 mL, 2.6 mmol) was introduced, and a 1.0 m solution of tetrabutylammonium fluoride in tetrahydrofuran (1.300 mL, 1.300 mmol) was added dropwise to the reaction mixture, ensuring that the internal temperature did not exceed 35 °C. An exotherm and bubbling were observed. The reaction was stirred for 3 h, then diluted with saturated aqueous NH4Cl and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (BIOTAGE® SNAP 100 g column, gradient elution 0-100% EtOAc:heptane) to afford (P)-1-(5-chloro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide as an off-white solid. m / z (ESI, positive ion) 690.0 (M+H) + .

[0253] Step 3: (P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 50-mL two-neck round-bottom flask equipped with a reflux adapter was purged with nitrogen and then charged with triethylamine trihydrofluoride (1.4 mL, 8.7 mmol), triethylamine (0.61 mL, 4.4 mmol), and dichloromethane (9.7 mL) and cooled to 0° C. A solution of difluoro(morpholino)sulfonium tetrafluoroborate (1.58 g, 6.52 mmol) and (P)-1-(5-chloro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.00 g, 1.45 mmol) in dichloromethane (4.8 mL) was added sequentially, and the reaction was warmed to 50° C. and stirred for 16 h. The reaction was then cooled to 0°C and carefully quenched with saturated aqueous sodium bicarbonate, followed by extraction three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The material was purified via column chromatography (BIOTAGE® SNAP 50 g column, gradient elution 0 to 100% EtOAc:heptane) to afford (P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (599 mg, 0.866 mmol, 60% yield) as a tan solid. 1H NMR(500MHz,DMSO-d6)δ ppm 8.81(d,J=1.0Hz,1H),8.32-8.44(m,1H),8.16(d,J=9.6Hz,1H),7.78(dd,J=9.1,2.1Hz,1 H),7.67(d,J=4.2Hz,1H),7.47(d,J=6.2Hz,1H),7.26(d,J=8.6Hz,2H),6.80-6.90(m,3H) ,6.69-6.77(m,2H),5.97-6.16(m,2H),5.88(s,1H),4.92(s,2H),3.76(d,J=4.7Hz,3H),3 .71(s,3H),3.06(tt,J=15.8,10.8Hz,1H),2.78-2.96(m,1H).m / z(ESI,cation)692.2(M+H) + .

[0254] Step 4: cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 40-mL vial was charged with (P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (599 mg, 0.866 mmol), dichloromethane (1.3 mL), and TFA (1.3 mL). The vial was sealed, warmed to 50 °C, and stirred for 16 h. The reaction was then concentrated under reduced pressure and purified by silica gel column chromatography (50 g column, gradient elution 0–75% [3:1 EtOAc / EtOH]:heptane). Further purification was performed using a Chiralpak IC, 2 × 25 cm column. The mobile phase was isocratic: 30% methanol in supercritical CO2; flow rate: 80 mL / min. The first eluting peak was assigned to cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. The second eluting peak was assigned to trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. Data for Peak 1: 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.66(s,1H),8.73(d,J=1.8Hz,1H),8.37(d,J=1.8Hz,1H),8.22(d,J=9.9Hz, 1H),7.84(dd,J=8.8,2.1Hz,1H),7.66(s,1H),7.46(s,1H),6.80(dd,J=9.2,4 .3Hz,2H),6.44(d,J=1.6Hz,1H),5.97-6.14(m,2H),5.88(s,1H),3.75(s,3H) ,3.06(td,J=15.8,9.9Hz,1H),2.78-2.94(m,1H).m / z(ESI,cation)572.0(M+H) + Peak 2 data: 1H NMR(500MHz,DMSO-d6)δ ppm 11.66(s,1H),8.73(d,J=1.6Hz,1H),8.38(d,J=2.1Hz,1H),8.23(d,J=9.6Hz,1H) ,7.84(dd,J=8.8,2.1Hz,1H),7.66(s,1H),7.45(s,1H),6.80(d,J=9.9Hz,1H),6.7 7(d,J=8.8Hz,1H),6.45(d,J=1.6Hz,1H),6.00-6.18(m,2H),5.89(s,1H),3.74(s ,3H),3.05(td,J=16.2,9.5Hz,1H),2.79-2.94(m,1H).m / z(ESI,cation)572.0(M+H) + .

[0255] Examples 12 and 13: cis-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, respectively [ka]

[0256] Step 1: (P)—O-(3-(2-chloro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)O-phenyl carbonothioate (P)-1-(5-chloro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.00 g, 1.45 mmol) was dissolved in THF (7.25 mL) and cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 0.087 g, 2.2 mmol) was added and the reaction was allowed to warm to room temperature over 30 minutes. Phenyl chlorothionoformate (0.50 mL, 3.6 mmol) was added and the reaction was stirred for 2 hours. Saturated aqueous sodium bicarbonate solution was then introduced. The mixture was extracted three times with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The material was purified via column chromatography (BIOTAGE® SNAP 50 g column, gradient elution 0-100% EtOAc:heptane) to afford (P)—O-(3-(2-chloro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)O-phenyl carbonothioate (896 mg, 1.08 mmol, 75% yield) as a pale yellow solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 8.71-8.87(m,1H),8.37(d,J=1.8Hz,1H),8.15(d,J=9.6Hz,1H),7.73-7.82(m,1H),7.56(s,1H),7.44-7.55(m,2H),7.29-7.42(m,3H),7. 25(d,J=8.3Hz,3H),6.86(d,J=8.8Hz,2H),6.82(d,J=9.9Hz,1H),6.65-6.77(m,2H),4.91(s,2H),3.75-3.80(m,3H),3.71(s,3H),3.67(br d,J=9.1Hz,1H),3.53-3.62(m,1H),3.33-3.42(m,2H),3.04-3.18(m,1H).m / z(ESI,cation)826.1(M+H) + .

[0257] Step 2: (P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 40-mL vial was charged with (P)—O-(3-(2-chloro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)O-phenyl carbonothioate (896 mg, 1.08 mmol), toluene (11 mL), tri-n-butyltin hydride (2.87 mL, 10.8 mmol), and azobisisobutyronitrile (178 mg, 1.08 mmol). The reaction mixture was degassed with nitrogen for 20 minutes, then sealed and heated to 50° C. for 1 hour. The reaction was then stirred at room temperature for 16 hours. During this time, a white solid formed, which was isolated and washed with heptane to give (P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (596 mg, 0.884 mmol, 82% yield) as an off-white solid. m / z (ESI, positive ion) 674.2 (M+H). + .

[0258] Step 3: cis-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 20 mL vial was charged with (P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (596 mg, 0.884 mmol), dichloromethane (1.4 mL), and TFA (1.4 mL). The vial was sealed and warmed to 50 °C for 16 h. The reaction was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (50 g silica gel column, gradient elution 0–75% [3:1 EtOAc / EtOH]:heptane). Further purification was performed using two consecutive Chiralcel OJ-H, 2 × 25 cm columns. The mobile phase was run under isocratic conditions: 15% methanol in supercritical CO2; flow rate: 80 mL / min. The first eluting peak was assigned to cis-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (305 mg). The second eluting peak was assigned to trans-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (72 mg). Data for Peak 1: 1 H NMR(500MHz,DMSO-d6)δ ppm 11.65(s,1H),8.73(d,J=1.8Hz,1H),8.36(d,J=2.1Hz,1H),8.21(d,J=9.6Hz,1H),7.83(dd,J=9 .0,2.2Hz,1H),7.50(s,1H),7.18(s,1H),6.79(d,J=9.6Hz,2H),6.44(d,J=1.8Hz,1H),3.79(br t,J=9.2Hz,1H),3.73(s,3H),3.27-3.34(m,1H),2.61-2.71(m,2H),2.26-2.43(m,2H).m / z(ESI,cation)554.0(M+H) + Peak 2 data: 1H NMR(500MHz,DMSO-d6)δ ppm 11.65(br s,1H),8.72(d,J=1.6Hz,1H),8.35(d,J=1.8Hz,1H),8.21(d,J=9.6Hz,1H),7.84(dd,J=9.1,2.1Hz,1H),7.51(s,1H),7.37(s ,1H),6.78(dd,J=9.3,6.0Hz,2H),6.44(d,J=1.6Hz,1H),4.00(quin,J=8.9Hz,1H),3.76(s,3H),3.22-3.28(m,1H),2.93(br d,J=3.6Hz,1H),2.66-2.75(m,1H),2.59-2.63(m,2H).m / z(ESI,cation)554.0(M+H) + .

[0259] Example 14: (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] A vial was charged with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (146 mg, 0.238 mmol), palladium(II) acetate (2.7 mg, 0.012 mmol), 2'-(dicyclohexylphosphino)-N 2 ,N 2 ,N 6 ,N 6To the reaction mixture were added 1,4-tetramethyl-[1,1'-biphenyl]-2,6-diamine (8.3 mg, 0.019 mmol) and cyclobutylzinc bromide (0.5 M in THF, 0.95 mL, 0.47 mmol). The reaction mixture was flushed with nitrogen and stirred at 50 °C for 1 h. The mixture was then directly purified via column chromatography (gradient elution: 0–30% [3:1 EtOAc / EtOH]:heptane). The isolated product was then dissolved in TFA (0.5 mL) and heated to 50 °C for 16 h. The reaction mixture was then concentrated in vacuo and purified using a Torus 2-PIC, 30 × 150 cm column. The mobile phase was run under gradient elution conditions: 20–50% methanol in supercritical CO2; flow rate: 100 mL / min. This gave (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (101 mg, 0.215 mmol, 90% yield). 1 H NMR(600MHz,DMSO-d6)δ ppm 11.23-12.01(m,1H),8.70(d,J=1.5Hz,1H),8.34(d,J=2.2Hz,1H),8.19(d,J=9.4Hz,1 H),7.83(dd,J=9.1,2.2Hz,1H),7.24(d,J=9.8Hz,1H),7.19(d,J=6.9Hz,1H),6.77(d, J=9.4Hz,2H),6.43(d,J=1.8Hz,1H),3.74-3.83(m,1H),3.69(s,3H),2.32-2.40(m,3H) ),2.22-2.31(m,1H),2.01-2.13(m,1H),1.84-1.94(m,1H).m / z(ESI, cation)470.0(M+H) + .

[0260] Example 15: trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] A vial was charged with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (359 mg, 0.573 mmol), palladium(II) acetate (6.4 mg, 0.029 mmol), 2'-(dicyclohexylphosphino)-N 2 ,N 2 ,N 6 ,N 6 To the reaction mixture was added 25 mg (0.057 mmol) of tetramethyl-[1,1'-biphenyl]-2,6-diamine (3-(trifluoromethyl)cyclobutyl)zinc(II) bromide (0.15 M in THF, 5.7 mL, 0.86 mmol). The reaction mixture was flushed with nitrogen and stirred at 50 °C for 1 h. The mixture was then directly purified via column chromatography (gradient elution: 0-30% [3:1 EtOAc / EtOH]:heptane). The isolated product was then dissolved in TFA (0.5 mL) and heated to 50 °C for 16 h. The reaction mixture was then concentrated in vacuo and purified using sequential Chiralcel OJ-H, 2 x 15 and 2 x 25 cm columns. The mobile phase was isocratic: 20% methanol in supercritical CO2; flow rate: 80 mL / min. This gave trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (63 mg). 1H NMR(500MHz,chloroform-d)δ ppm 9.60-9.88(m,1H),8.51-8.63(m,2H),8.44(d,J=2.1Hz,1H),8.06(dd,J=9.0,2.2Hz,1 H),7.85(d,J=9.9Hz,1H),6.99(t,J=4.9Hz,1H),6.91-6.96(m,2H),6.85(d,J=9.6Hz, 1H),6.77(d,J=8.8Hz,1H),3.98(quin,J=8.8Hz,1H),3.73(s,3H),3.04(dtd,J=14.9, 9.8,9.8,4.9Hz,1H),2.67-2.79(m,2H),2.54-2.66(m,2H).m / z(ESI, cation)549.2(M+H) + .

[0261] Examples 16 and 17: cis-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide and trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared according to the method of Example 15 using (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (368 mg, 0.573 mmol). The sample was purified using a Chiralcel OJ-H, 2 x 15 cm column. The mobile phase was run under isocratic conditions: supercritical CO2 with 30% methanol; flow rate: 80 mL / min. The sample was further purified using a Chiralcel OJ-H, 3 x 25 cm column. The mobile phase was run under isocratic conditions: supercritical CO2 with 20% methanol; flow rate: 100 mL / min. The first eluting peak was assigned to cis-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (21.8 mg). The second eluting peak was assigned to trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (142.8 mg). Data for Peak 1: 1 H NMR(500MHz,chloroform-d)δ ppm 9.99-10.35(m,1H),8.59(d,J=4.7Hz,2H),8.43(d,J=2.1Hz,1H),8.07(dd,J=9.0,2.2 Hz,1H),7.85(d,J=9.6Hz,1H),7.19(s,1H),7.02(s,1H),6.99(t,J=4.9Hz,1H),6.85( d,J=9.6Hz,1H),6.76(d,J=9.1Hz,1H),3.82(quin,J=9.3Hz,1H),3.76(s,3H),2.99-3 .11(m,1H),2.66-2.77(m,2H),2.37(quin,J=10.8Hz,2H).m / z(ESI, cation)564.8(M+H) + Peak 2 data: 1H NMR(500MHz,chloroform-d)δ ppm 9.09-9.31(m,1H),8.54(d,J=4.9Hz,2H),8.44(d,J=2.1Hz,1H),8.07(dd,J=9.0, 2.2Hz,1H),7.85(d,J=9.6Hz,1H),7.21(s,1H),7.05(s,1H),6.98(t,J=4.9Hz,1H) ,6.85(d,J=9.6Hz,1H),6.76(d,J=8.8Hz,1H),4.04-4.13(m,1H),3.77(s,3H),2. 92-3.05(m,1H),2.71-2.84(m,2H),2.47-2.66(m,2H).m / z(ESI, cation)564.8(M+H) + .

[0262] Example 18: (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared according to the method of Example 14 using (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (153 mg, 0.238 mmol). The sample was purified via reverse-phase HPLC using an XBridge Prep Shield RP18 19 x 100 mm column. The mobile phase was run under gradient elution: 25-70% acetonitrile:water with 0.1% formic acid; flow rate: 40 mL / min. This afforded (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (18 mg, 0.036 mmol, 15% yield). 1H NMR(500MHz,chloroform-d)δ ppm 11.20-11.51(m,1H),8.65(d,J=4.9Hz,2H),8.41(d,J=2.1Hz,1H),8.04(dd,J=9.1,2.1H z,1H),7.84(d,J=9.6Hz,1H),7.15(s,1H),7.06(s,1H),7.01(t,J=5.1Hz,1H),6.85(d,J= 9.9Hz,1H),6.77(d,J=8.8Hz,1H),3.87(quin,J=8.8Hz,1H),3.75(s,3H),2.44-2.53(m, 2H),2.15-2.30(m,2H),2.03-2.15(m,1H),1.85-1.97(m,1H).m / z(ESI, cation)497.0(M+H) + .

[0263] Example 19: trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared according to the method of Example 15 using (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (368 mg, 0.573 mmol). The sample was purified using a Zorbax Eclipse Plus C18, 2.1 x 10 cm column. The mobile phase was run under gradient elution conditions: 41.3-61.3% water: acetonitrile with 0.1% formic acid as a co-eluent; flow rate: 40 mL / min. The material was further purified using a Chiralcel OJ-H, 2 x 15 cm column. The mobile phase was run under isocratic conditions: 25% methanol in supercritical CO2; flow rate: 80 mL / min. This gave trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (38.4 mg). 1 H NMR (500 MHz, chloroform-d) δ ppm 12.38-12.76 (m, 1H), 8.24 (d, J = 2.1 Hz, 1H), 8.10 (dd, J = 3.9, 1.6 Hz, 1H), 7.91 (dd, J = 9.1, 2.1 Hz, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.33-7.37 (m, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.21 (s, 1H), 7.0 .05(s,1H),6.84(d,J=9.6Hz,1H),6.75(d,J=8.8Hz,1H),4.08(quin,J=8.9Hz,1H),3.77(s ,3H),2.91-3.06(m,1H),2.69-2.83(m,2H),2.48-2.62(m,2H).m / z(ESI,cation)565.2(M+H) + .

[0264] Example 20: trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared according to the method of Example 15 using (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (350 mg, 0.573 mmol). The sample was purified using a Zorbax Eclipse Plus C18, 2.1 x 10 cm column. The mobile phase was run under gradient elution conditions: 46.4-66.4% acetonitrile:water with 0.1% formic acid as a co-eluent; flow rate: 40 mL / min. The material was further purified using a Chiralcel OJ-H, 2 x 15 cm column. The mobile phase was run under isocratic conditions: 20% methanol in supercritical CO2; flow rate: 80 mL / min. This gave trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (65.8 mg). 1 H NMR (500 MHz, chloroform-d) δ ppm 8.25 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.83-8.04 (m, 1H), 7.76 (d, J = 9.6 Hz, 1H), 7.72 (dd, J = 9.0, 2.2 Hz, 1H), 7.01 (s, 1H), 6.95 (s, 1H), 6.86 (d, J = 9.6 Hz, 1H), 6.76 (d, J = 9.1 Hz ,1H),6.60(d,J=1.8Hz,1H),3.94(quin,J=8.8Hz,1H),3.75(s,3H),2.89-3.07(m,1H),2.7 0(ddd,J=12.8,8.8,4.0Hz,2H),2.46-2.60(m,2H),2.19(s,3H).m / z(ESI,cation)534.2(M+H) + .

[0265] Example 21: (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared according to the method of Example 14 using (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (150 mg, 0.238 mmol). The sample was purified via reverse-phase HPLC using an XBridge Prep Shield RP18 19 x 100 mm column. The mobile phase was run under gradient elution: 25-70% acetonitrile:water with 0.1% formic acid; flow rate: 40 mL / min. This afforded (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (92 mg, 80% yield). 1 H NMR (500 MHz, chloroform-d) δ ppm 8.40 (br s, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.75 (dd, J = 9.0, 2.2 Hz, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 6.87 (d, J = 9.6 Hz, 1H), 6.77 (d, J = 9.1 Hz,1H),6.59(d,J=1.8Hz,1H),3.80-3.91(m,1H),3.75(s,3H),2.42-2.56(m,2H),2 .16-2.27(m,2H),2.04-2.16(m,1H),1.84-1.96(m,1H).m / z(ESI, cation)486.0(M+H) + .

[0266] Example 22: (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0267] Step 1: (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide To a solution of (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (191 mg, 0.313 mmol) in THF (1 mL) was added 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (27.3 mg, 0.063 mmol) and palladium(II) acetate (14.05 mg, 0.063 mmol). The reaction mixture was aerated with argon, followed by the addition of cyclobutylzinc bromide (0.5 M in THF, 1.9 mL, 0.94 mmol). The reaction was stirred at 50 °C. After 2 h, an additional portion of 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (27.3 mg, 0.063 mmol), palladium(II) acetate (14.1 mg, 0.063 mmol), and cyclobutylzinc bromide (0.5 M in THF, 1.9 mL, 0.94 mmol) was added. After stirring at 50 °C for 1 h, the reaction was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate, and partitioned between water and ethyl acetate. The organic extract was concentrated and purified by silica gel column chromatography (gradient elution, 40-100% EtOAc:heptane with 10% dichloromethane coeluent) to give (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (123 mg, 0.210 mmol, 67% yield) as a brown solid. m / z (ESI, positive ion) 586.0 (M+H). + .

[0268] Step 2: (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (123 mg, 0.210 mmol) was dissolved in TFA (2 mL) and stirred at 40° C. After 2 h, the reaction was concentrated, and the residue was purified by silica gel column chromatography (gradient elution 20–80% [3:1 EtOAc / EtOH]:heptane with 10% dichloromethane coeluent) to afford (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (73 mg, 0.157 mmol, 75% yield) as a pale purple solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 11.60(br s,1H),8.71(d,J=1.8Hz,1H),8.33(d,J=2.1Hz,1H),8.18(d,J=9.6Hz,1H),7.82(dd,J=9. 0,2.2Hz,1H),7.09(s,1H),7.00(s,1H),6.77(d,J=9.6Hz,1H),6.72(d,J=8.8Hz,1H),6.43 (d,J=1.8Hz,1H),3.69-3.74(m,1H),3.68(s,3H),2.33-2.43(m,2H),2.26(quin,J=9.6Hz ,1H),2.11-2.19(m,4H),1.98-2.09(m,1H),1.79-1.90(m,1H).m / z(ESI, cation)465.8(M+H) + .

[0269] Example 23: (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide [ka]

[0270] Step 1: (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide To a solution of (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (150 mg, 0.240 mmol) in THF (0.8 mL) was added 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (20.9 mg, 0.048 mmol) and palladium(II) acetate (10.8 mg, 0.048 mmol). The reaction mixture was aerated with argon, followed by the addition of cyclobutylzinc bromide (0.5 M in THF, 1.4 mL, 0.72 mmol). The reaction was stirred at 50 °C. After 90 min, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and partitioned between water and ethyl acetate. The organic layer was concentrated. The residue was purified by silica gel column chromatography (gradient elution 40-100% EtOAc:heptane with 10% dichloromethane coeluent) to give (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (156 mg, 0.260 mmol, >99% yield) as a brown solid. m / z (ESI, positive ion) 601.0 (M+H). + .

[0271] Step 2: (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (P)-1-(4-Cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (156 mg, 0.260 mmol) was dissolved in TFA (3.0 mL) and stirred at 40° C. After 2 h, the reaction was concentrated, and the residue was purified by silica gel chromatography (20–80% [3:1 EtOAc / EtOH]:heptane with 10% dichloromethane coeluent) to afford 1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (86 mg, 0.179 mmol, 69% yield) as an off-white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 14.28-14.68(m,1H),8.23-8.39(m,2H),8.17(d,J=9.6Hz,1H),7.89-8.00(m,1H),7.79-7. 86(m,1H),7.68(dd,J=9.5,4.0Hz,1H),7.22(d,J=9.9Hz,1H),7.19(d,J=6.7Hz,1H),6.75( d,J=9.6Hz,1H),6.70(d,J=8.8Hz,1H),3.78(quin,J=8.9Hz,1H),3.69(s,3H),2.32-2.38( m,3H),2.23-2.32(m,1H),2.02-2.14(m,1H),1.84-1.95(m,1H).m / z(ESI,cation)480.8(M+H) + .

[0272] Example 24: (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared following the method and purification protocol of Example 23 using (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (180 mg, 0.293 mmol). This gave (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (54 mg, 0.115 mmol, 39% yield over two steps) as a pale purple solid. 1 H NMR(500MHz,chloroform-d)δ ppm 9.65-10.09(m,1H),8.19(d,J=2.1Hz,1H),7.87(dd,J=9.0,2.2Hz,1H),7.81(d,J=9.6Hz,1H) ,7.08(d,J=1.8Hz,1H),6.98(d,J=6.2Hz,1H),6.88(d,J=9.3Hz,1H),6.86(d,J=1.8Hz,1H),6 .84(d,J=9.6Hz,1H),6.76(d,J=9.1Hz,1H),3.82(quin,J=8.8Hz,1H),3.72(s,3H),2.39-2.4 9(m,2H),2.21-2.34(m,2H),2.08-2.18(m,1H),1.88-1.99(m,1H).m / z(ESI, cation)469.8(M+H) + .

[0273] Example 25: (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared following the method and purification protocol of Example 23 using (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (140 mg, 0.235 mmol). This gave (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (89 mg, 0.197 mmol, 84% yield over two steps) as an off-white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 11.60(s,1H),8.72(d,J=1.8Hz,1H),8.34(d,J=2.3Hz,1H),8.19(d,J=9.9Hz,1H),7.83(dd,J=9. 0,2.2Hz,1H),7.18(d,J=8.0Hz,1H),7.12(d,J=1.6Hz,1H),7.02(dd,J=7.9,1.7Hz,1H),6.77(d,J =9.6Hz,1H),6.72(d,J=8.8Hz,1H),6.44(d,J=1.8Hz,1H),3.67(s,3H),3.58-3.67(m,1H),2.32- 2.42(m,2H),2.16-2.27(m,2H),1.99-2.08(m,1H),1.82-1.92(m,1H).m / z(ESI,cation)452.0(M+H) + .

[0274] Example 26: (P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared following the method and purification protocol of Example 23 using (P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (140 mg, 0.230 mmol). This gave (P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (50 mg, 0.108 mmol, 47% yield over two steps) as a white solid. 1 H NMR (500MHz, chloroform-d) δ ppm 8.57(d,J=4.9Hz,2H),8.42(d,J=2.1Hz,1H),8.02(dd,J=9.1,2.1Hz,1H),7.84( d,J=9.6Hz,1H),7.07-7.10(m,1H),6.93-7.03(m,3H),6.87(d,J=9.6Hz,1H),6.7 8(d,J=9.1Hz,1H),3.72(s,3H),3.65(quin,J=9.0Hz,1H),2.34-2.46(m,2H),2.1 8-2.31(m,2H),2.06-2.14(m,1H),1.85-1.96(m,1H).m / z(ESI, cation)463.0(M+H) + .

[0275] Example 27: (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared following the method and purification protocol of Example 22 using (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (130 mg, 0.209 mmol). This gave (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (60 mg, 0.126 mmol, 60% yield over two steps) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 11.43-12.18(m,1H),8.50(d,J=4.9Hz,2H),8.44(d,J=2.1Hz,1H),8.21(d,J=9.6Hz,1H),7.95(dd,J=9.0,2.2Hz,1H),7.09(s,1H),7.05(br t,J=4.8Hz,1H),6.99(s,1H),6.75(d,J=9.9Hz,1H),6.69(d,J=9.1Hz,1H),3.68-3.75(m,1H),3.67(s,3H),2.32-2.44 (m,2H),2.26(quin,J=9.7Hz,1H),2.11-2.20(m,4H),1.99-2.07(m,1H),1.80-1.90(m,1H).m / z(ESI,cation)477.0(M+H) + .

[0276] Example 28: (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared following the method and purification protocol of Example 23 using (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (120 mg, 0.192 mmol). This gave (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (20 mg, 0.042 mmol, 22% yield). 1 H NMR (500MHz, chloroform-d) δ ppm 8.59(d,J=4.9Hz,2H),8.43(d,J=2.1Hz,1H),8.06(dd,J=9.0,2.2Hz,1H),7.84(d ,J=9.6Hz,1H),6.96-7.02(m,2H),6.87(d,J=3.6Hz,1H),6.85(d,J=4.4Hz,1H),6. 78(d,J=9.1Hz,1H),3.82(quin,J=9.1Hz,1H),3.72(s,3H),2.37-2.48(m,2H),2. 23-2.35(m,2H),2.07-2.18(m,1H),1.88-2.00(m,1H).m / z(ESI, cation)481.0(M+H) + .

[0277] Example 29: (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0278] Step 1: (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide To a solution of (P)-1-(4-bromo-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (200 mg, 0.319 mmol) in THF (1.2 mL) was added 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (41.8 mg, 0.096 mmol) and palladium(II) acetate (21.50 mg, 0.096 mmol). The reaction mixture was aerated with argon, followed by the addition of cyclobutylzinc bromide (0.5 M in THF, 2.55 mL, 1.28 mmol). The reaction was stirred at 50 °C. After 3 h, the reaction was quenched with saturated aqueous sodium bicarbonate and partitioned between water and ethyl acetate. The organic layer was concentrated. The residue was purified by silica gel column chromatography (gradient elution 40-100% ethyl acetate:heptane with 10% dichloromethane as co-eluent) to give (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (73 mg, 0.12 mmol, 38% yield) as a yellow oil. m / z (ESI, positive ion) 602.0 (M+H) + .

[0279] Step 2: (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (73 mg, 0.12 mmol) was dissolved in TFA (3.0 mL). The reaction mixture was stirred at 40 °C. After 1 h, the reaction was concentrated, and the residue was purified by silica gel column chromatography (gradient elution 20-80% [3:1 EtOAc / EtOH]:heptane with 10% dichloromethane coeluent) to give (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (46 mg, 0.10 mmol, 85% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 12.12(br s,1H),8.29(d,J=2.1Hz,1H),8.15(d,J=9.6Hz,1H),7.83(dd,J=9.0,2.2Hz,1H),7.59(d,J=1.8 Hz,1H),7.26(d,J=1.6Hz,1H),7.17(d,J=7.8Hz,1H),7.12(d,J=1.6Hz,1H),7.02(dd,J=8.0,1. 6Hz,1H),6.74(d,J=9.6Hz,1H),6.64(d,J=8.8Hz,1H),3.68(s,3H),3.58-3.67(m,1H),2.31-2. 39(m,2H),2.17-2.28(m,2H),1.96-2.10(m,1H),1.82-1.92(m,1H).m / z(ESI, cation)451.8(M+H) + .

[0280] Example 30: (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared following the method and purification protocol of Example 23 using (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (367 mg, 0.591 mmol). This gave (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (144 mg, 0.302 mmol, 51% yield over two steps) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 14.35-14.59(m,1H),8.23-8.34(m,2H),8.16(d,J=9.5Hz,1H),7.88-7.98(m,1H),7.82(br d,J=8.3Hz,1H),7.59-7.73(m,1H),7.08(s,1H),6.99(s,1H),6.74(d,J=9.5Hz,1H),6.65(d,J=8.9Hz,1H),3.63-3.76(m,4H) ),2.31-2.44(m,2H),2.21-2.30(m,1H),2.13-2.20(m,4H),2.00-2.09(m,1H),1.81-1.92(m,1H).m / z(ESI,Cation)477.0(M+H) + .

[0281] Example 31: (P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared according to the method of Example 23 using (P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (300 mg, 0.494 mmol). The sample was purified via reverse-phase HPLC using an XBridge Prep Shield RP18 19 x 100 mm column. The mobile phase was run under gradient elution: 15-70% acetonitrile:water with 0.1% formic acid; flow rate: 40 mL / min. This afforded (P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (130 mg, 0.281 mmol, 57% yield over two steps) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 14.39(br s,1H),8.31(d,J=2.1Hz,2H),8.16(d,J=9.6Hz,1H),7.85-7.93(m,1H),7.82(dd,J=9.0,2.2Hz, 1H),7.66(dd,J=9.6,4.2Hz,1H),7.16(d,J=8.0Hz,1H),7.11(d,J=1.6Hz,1H),7.02(dd,J=8.0,1 .3Hz,1H),6.74(d,J=9.6Hz,1H),6.64(d,J=8.8Hz,1H),3.67(s,3H),3.59-3.66(m,1H),2.30-2 .41(m,2H),2.16-2.29(m,2H),1.96-2.10(m,1H),1.81-1.93(m,1H).m / z(ESI, cation)463.0(M+H) + .

[0282] Example 32: (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared according to the method of Example 23 using (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (347 mg, 0.525 mmol). The sample was purified via reverse-phase HPLC using an XBridge Prep Shield RP18 19 x 100 mm column. The mobile phase was run under gradient elution: 15-60% acetonitrile:water with 0.1% formic acid; flow rate: 40 mL / min. The material was further purified using a Whelk-O, 2 x 15 cm column. The mobile phase was run under isocratic conditions: supercritical CO2 with 60% isopropanol; flow rate: 70 mL / min. This gave (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (74 mg, 0.15 mmol, 29% yield over two steps) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 12.15(br s,1H),8.30(d,J=2.1Hz,1H),8.16(d,J=9.6Hz,1H),7.84(dd,J=9.0,2.2Hz,1H),7.59( d,J=1.6Hz,1H),7.43(s,1H),7.23-7.30(m,2H),6.75(d,J=9.6Hz,1H),6.69(d,J=8.8Hz ,1H),3.82(quin,J=8.8Hz,1H),3.74(s,3H),2.39-2.44(m,2H),2.29-2.35(m,1H),2.2 3(quin,J=9.5Hz,1H),2.00-2.12(m,1H),1.81-1.92(m,1H).m / z(ESI,cation)486.0(M+H) + .

[0283] Example 33: (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide [ka]

[0284] Step 1: (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide To a 20-mL scintillation vial were added 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (20.4 mg, 0.047 mmol), palladium(II) acetate (5.3 mg, 0.023 mmol), and (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (300 mg, 0.467 mmol). The reaction mixture was purged with nitrogen, followed by the addition of cyclobutylzinc bromide (0.5 M in THF, 1.87 mL, 0.935 mmol). After stirring at 50 °C for 1 h, an additional portion of cyclobutylzinc bromide (0.5 M in THF, 1.87 mL, 0.935 mmol) was added. After stirring at 50 °C for an additional 2 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and partitioned between water and ethyl acetate. The organic layer was concentrated. The initial product was purified by silica gel column chromatography (gradient elution 0-60% [3:1 EtOAc:EtOH]:heptane with 10% dichloromethane coeluent) to give (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (216 mg, 0.350 mmol, 75% yield) as a yellow solid. m / z (ESI, positive ion) 616.8 (M+H). + .

[0285] Step 2: (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (216 mg, 0.350 mmol) was dissolved in trifluoroacetic acid (2.6 mL) and the reaction was heated to 40 °C. After 2 h, the reaction was concentrated and purified via reverse-phase HPLC using an XBridge Prep Shield RP18 19 x 100 mm column. The mobile phase was gradient elution: 15-70% acetonitrile:water with 0.1% formic acid; flow rate: 40 mL / min. This gave (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (83 mg, 0.167 mmol, 48% yield) as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 14.46(br s,1H),8.33(d,J=2.1Hz,2H),8.17(d,J=9.6Hz,1H),7.88(br d,J=3.9Hz,1H),7.83(dd,J=9.0,2.2Hz,1H),7.67(dd,J=9.6,4.2Hz,1H),7.42 (s,1H),7.24(s,1H),6.75(d,J=9.6Hz,1H),6.69(d,J=8.8Hz,1H),3.82(quin, J=8.8Hz,1H),3.73(s,3H),2.35-2.47(m,2H),2.28-2.34(m,1H),2.22(quin,J =9.9Hz,1H),1.97-2.11(m,1H),1.80-1.91(m,1H).m / z(ESI, cation)497.0(M+H) + .

[0286] Example 34: (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0287] Step 1: (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide To a 20-mL scintillation vial were added 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (26 mg, 0.060 mmol), palladium(II) acetate (6.7 mg, 0.030 mmol), and (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (384 mg, 0.600 mmol). The reaction mixture was purged with nitrogen, followed by the addition of cyclobutylzinc bromide (0.5 M in tetrahydrofuran, 3.60 mL, 1.80 mmol). The reaction was stirred at 50 °C. After 1 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (gradient elution 0-30% [3:1 EtOAc:EtOH]:heptane with 10% dichloromethane coeluent) to give (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (255 mg, 0.414 mmol, 69% yield) as a white solid. m / z (ESI, positive ion) 616.2 (M+H). + .

[0288] Step 2: (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (255 mg, 0.414 mmol) was dissolved in TFA (3 mL) and heated to 50 °C. After stirring for 1 h, the reaction mixture was concentrated and purified using a Torus 2-PIC, 3 x 15 cm column. The mobile phase was run under gradient elution conditions: 10–40% methanol in supercritical CO2; flow rate: 100 mL / min. This afforded (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (71 mg, 0.15 mmol, 25% yield over two steps). 1 H NMR(600MHz,DMSO-d6)δ ppm 12.12(br s,1H),8.29(d,J=1.8Hz,1H),8.15(d,J=9.4Hz,1H),7.83(dd,J=8.9,2.0Hz,1H),7.59 (d,J=1.5Hz,1H),7.26(d,J=1.5Hz,1H),7.09(s,1H),6.99(s,1H),6.74(d,J=9.4Hz,1H ),6.65(d,J=8.7Hz,1H),3.63-3.75(m,4H),2.33-2.44(m,2H),2.27(quin,J=9.7Hz,1H ),2.12-2.21(m,4H),1.97-2.10(m,1H),1.80-1.92(m,1H).m / z(ESI, cation)466.0(M+H) + .

[0289] Example 35: trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0290] Step 1: (P)—N-(isoxazol-3-yl)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.47 g, 0.788 mmol), palladium(II) acetate (0.023 g, 0.10 mmol), and 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (0.076 g, 0.173 mmol) were placed in a vial, and the resulting mixture was aerated with nitrogen before the addition of tetrahydrofuran (3.1 mL). Next, (3-(trifluoromethyl)cyclobutyl)zinc(II) bromide (0.125 M in THF, 9.46 mL, 1.182 mmol) was added dropwise. The reaction mixture was then warmed to 50 °C and stirred at this temperature for 1.25 h. After cooling to ambient temperature, the reaction mixture was quenched with 5 M aqueous ammonium chloride solution, and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (gradient elution 0–50% [3:1 EtOAc:EtOH]:heptane with 10% dichloromethane coeluent) to give (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.489 g, 0.764 mmol, 97% yield). m / z (ESI, positive ion) 640.2 (M+H). + .

[0291] Step 2: trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)—N-(isoxazol-3-yl)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.489 g, 0.764 mmol) was dissolved in TFA (1.3 mL) and stirred at 40° C. for 2.5 hours. After cooling to ambient temperature, the volatiles were removed under vacuum and the residue was purified using a ChromegaChiral CC4, 2×25 cm column. The mobile phase was run under isocratic conditions: supercritical CO2 with 40% methanol; flow rate: 80 mL / min. This gave trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (296 mg, 0.570 mmol, 72% yield over two steps). 1 H NMR(500MHz,DMSO-d6)δ ppm 11.60(s,1H),8.71(d,J=1.6Hz,1H),8.34(d,J=2.1Hz,1H),8.19(d,J=9.6Hz,1H), 7.83(dd,J=9.1,2.3Hz,1H),7.20-7.28(m,2H),7.11(dd,J=7.9,1.4Hz,1H),6.78(d ,J=9.6Hz,1H),6.71(d,J=9.1Hz,1H),6.43(d,J=1.8Hz,1H),3.80(quin,J=8.6Hz, 1H),3.69(s,3H),3.22-3.28(m,1H),2.54-2.61(m,4H).m / z(ESI, cation)520.0(M+H) + .

[0292] Example 36: trans-(P)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared according to the method of Example 23 by substituting (P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (479 mg, 0.788 mmol) for (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide. The sample was purified using a Chiralpak IC, 2 x 15 cm column. The mobile phase was run under isocratic conditions: supercritical CO2 with 60% [1:1 methanol:dichloromethane]; flow rate: 80 mL / min. This gave trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (204 mg, 0.384 mmol, 49% yield over two steps). 1 H NMR(500MHz,DMSO-d6)δ ppm 11.57-12.03(m,1H),8.50(br d,J=4.9Hz,2H),8.45(d,J=1.8Hz,1H),8.22(d,J=9.6Hz,1H),7.82-8.03(m,1H),7.18-7.25(m,2H),7.11(dd,J=8.0,1.6Hz,1H),7.05(br s,1H),6.76(d,J=9.6Hz,1H),6.69(d,J=8.8Hz,1H),3.80(quin,J=9.0Hz,1H), 3.68(s,3H),3.21-3.28(m,1H),2.53-2.63(m,4H).m / z(ESI,cation)531.0(M+H) + .

[0293] Example 37: trans-(P)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared according to the method of Example 35 by substituting (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (470 mg, 0.756 mmol) for (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide. The sample was purified using two consecutive Chiralpak OJ-H, 3 × 15 cm columns. The mobile phase was run under isocratic conditions: supercritical CO2 with 20% methanol; flow rate: 80 mL / min. The sample was further purified by silica gel column chromatography (gradient elution 0–100% EtOAc:heptane with 10% dichloromethane coeluent) to afford trans-(P)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (103 mg, 0.189 mmol, 25% yield over two steps) as a pale pink solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 14.17-14.75(m,1H),8.25-8.35(m,2H),8.16(d,J=9.9Hz,1H),7.86-7.99(m,1H),7.83(dd,J=8.7,1.7Hz,1H),7.67(br dd,J=8.6,3.9Hz,1H),7.22(s,1H),7.04(s,1H),6.74(d,J=9.6Hz,1H),6.65(d,J=9.1Hz,1H),3.88(quin, J=8.9Hz,1H),3.71(s,3H),3.18-3.28(m,1H),2.54-2.66(m,4H),2.16(s,3H).m / z(ESI,cation)545.0(M+H) + .

[0294] Example 38: trans-(P)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared according to the method of Example 35 by substituting (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (459 mg, 0.756 mmol) for (P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide. The sample was purified using a Chiralpak AS-H, 2 x 25 cm column. The mobile phase was run under isocratic conditions: supercritical CO2 with 35% methanol; flow rate: 50 mL / min. The sample was further purified by silica gel column chromatography (gradient elution 0–100% EtOAc:heptane with 10% dichloromethane coeluent) to afford trans-(P)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (247 mg, 466 mmol, 62% yield over two steps) as a pale pink solid. 1H NMR(500MHz,DMSO-d6)δ ppm 14.26-14.69(m,1H),8.23-8.35(m,2H),8.16(d,J=9.6Hz,1H),7.89-7.98(m,1H),7.82(br d,J=8.0Hz,1H),7.68(br dd,J=9.7,4.0Hz,1H),7.18-7.25(m,2H),7.11(dd,J=8.0,1.6Hz,1H),6.75(d,J=9.6Hz,1H),6.65(d,J=9.1Hz ,1H),3.80(quin,J=8.8Hz,1H),3.69(s,3H),3.24-3.28(m,1H),2.54-2.62(m,4H).m / z(ESI,cation)531.0(M+H) + .

[0295] Example 39: trans-(P)-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide [ka] The title compound was prepared according to the method of Example 35 by substituting (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (382 mg, 0.756 mmol) for (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide. The sample was purified using two consecutive Chiralcel 3 × 15 cm columns. The mobile phase was run under isocratic conditions: supercritical CO2 with 20% methanol; flow rate: 80 mL / min. The sample was further purified by silica gel column chromatography (gradient elution 0–100% EtOAc:heptane with 10% dichloromethane coeluent) to afford trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (59.5 mg, 0.108 mmol, 14% yield over two steps) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 14.23-14.74(m,1H),8.24-8.37(m,2H),8.18(d,J=9.6Hz,1H),7.88-7.98(m,1H),7.80-7.86(m,1H),7.68(br dd,J=9.5,3.8Hz,1H),7.32(d,J=7.0Hz,1H),7.29(d,J=9.9Hz,1H),6.75(d,J=9.6Hz,1H),6.70(d,J=9.1Hz, 1H),3.95(quin,J=9.0Hz,1H),3.71(s,3H),3.24-3.28(m,1H),2.56-2.70(m,4H).m / z(ESI,cation)549.0(M+H) + .

[0296] Example 40: (P)-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0297] Step 1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 250 mL round-bottom flask was charged with (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate (5.0 g, 8.17 mmol) and N-(2,4-dimethoxybenzyl)isoxazol-3-amine (2.37 g, 10.1 mmol). The flask was purged with nitrogen for 5 minutes, and then tetrahydrofuran (20 mL) was introduced. The resulting mixture was cooled to −78° C. in a dry ice-acetone bath, and sodium tert-pentoxide (30% solution in THF, 5.0 mL, 12.5 mmol) was added dropwise. The reaction mixture was then stirred for 15 minutes. An aqueous solution of ammonium chloride (5 M) was introduced, and the resulting mixture was allowed to warm to ambient temperature and subsequently extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (BIOTAGE®, 100 g silica cartridge, eluent: 0 to 80% ethyl acetate in heptane with 10% dichloromethane additive) to give (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.92 g, 2.90 mmol, 35.5% yield) as a white solid. m / z (ESI) 662.0 and 664.0 (M+H). +.

[0298] Step 2: (P)—N-(2,4-dimethoxybenzyl)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 100 mL round-bottom flask equipped with a reflux condenser was charged with magnesium turnings (796 mg, 32.8 mmol) and purged with nitrogen for 15 minutes. Iodine (151 mg, 0.596 mmol) was introduced, and the flask was heated with a heat gun until iodine sublimed visibly. After cooling to ambient temperature, a slight vacuum was applied to remove excess iodine. Tetrahydrofuran (12.5 mL) was then introduced. trans-1-bromo-3-(trifluoromethyl)cyclobutane (5.00 g, 24.6 mmol, Enamine, LLC) was then slowly added via syringe to the stirred reaction mixture, resulting in a slight exotherm and disappearance of the iodine color. The reaction vessel was immersed in an ice / water bath as needed to prevent excessive exotherm. After stirring for 1 hour, tetrahydrofuran (12.5 mL) was added. After an additional hour, zinc chloride solution (1.9 M in 2-methyltetrahydrofuran, 14.0 mL, 26.6 mmol, Sigma-Aldrich Corporation) was added, resulting in the formation of a white precipitate. The resulting mixture was stirred overnight at ambient temperature and used without further manipulation. The organozinc solution was titrated with iodine to give an estimated concentration of 0.33 M. A separate 100 mL round-bottom flask was charged with 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (0.501 g, 1.15 mmol), (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.90 g, 2.87 mmol), palladium(II) acetate (129 mg, 0.57 mmol), and tetrahydrofuran (14.0 mL). The reaction mixture was aerated with nitrogen for 10 minutes. A portion of the (3-(trifluoromethyl)cyclobutyl)zinc(II) bromide solution prepared above (10 mL, 3.30 mmol) was added dropwise to the reaction mixture via syringe. After the addition, the resulting mixture was warmed to 50° C. After 1.5 hours, water was introduced and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography (BIOTAGE®, 100 g silica cartridge, eluent: 0 to 50% ethyl acetate in heptane with 10% DCM additive) to give (P)-N-(2,4-dimethoxybenzyl)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (2.0 g, 2.83 mmol, 99% yield). m / z (ESI) 705.8 (M+H). + .

[0299] Step 3: (P)-7-Fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 50 mL round-bottom flask was charged with (P)-N-(2,4-dimethoxybenzyl)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (2.0 g, 2.83 mmol), dichloromethane (12 mL), and trifluoroacetic acid (2.8 mL). The reaction mixture was stirred at room temperature for 2 h, after which the solvent was removed under a stream of nitrogen. The residue was purified by flash column chromatography (BIOTAGE®, 25 g silica cartridge, eluent: 0-70% ethyl acetate in heptane with 10% DCM additive). Fractions containing the desired product were combined, the solvent removed under reduced pressure, and the residue (1.5 g) was further purified by SFC using a Chiralpak AD-H column (3 × 25 cm, 5 microns) with a mobile phase of 20% ethanol using a flow rate of 160 mL / min to give (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (844 mg, 1.52 mmol, 54% yield). 1 H NMR(500MHz,DMSO-d6,)δ:11.97(br s,1H),8.72(d,J=1.8Hz,1H),8.46(d,J=7.8Hz,1H),8.22(d,J=9.7Hz,1H),7.23-7.40(m,2H),6.75(d,J=9.7Hz,1H),6.53(d,J= 11.9Hz,1H),6.39(d,J=1.8Hz,1H),3.86-4.02(m,1H),3.73(s,3H),3.17-3.30(m,1H),2.53-2.75(m,4H).m / z(ESI)556.0(M+H) + .

[0300] Example 41: (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0301] Step 1: (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid and (M)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid rac-Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate (see Intermediate AB) (257 g, 420 mmol) was purified using a Regis Whelk-O s,s, 5 x 15 cm, 5 μm column using a flow rate of 350 mL / min; Purification by SFC using a mobile phase of isopropanol / dichloromethane (1:1 mixture) gave (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate (123 g, 201 mmol) as the first eluting peak and (M)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate (137 g, 224 mmol) as the second eluting peak.

[0302] Step 2: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 3 L three-neck round-bottom flask equipped with a thermocouple, overhead stirrer, addition funnel, and nitrogen inlet was charged with (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate (175 g, 286 mmol), N-(4-methoxybenzyl)isoxazol-3-amine (64.2 g, 314 mmol), and 2-methyltetrahydrofuran (953 mL). The reaction vessel was then purged with nitrogen. The reaction mixture was cooled to 0 °C. The addition funnel was charged with a 30% solution of sodium tert-pentoxide in THF (149 mL, 372 mmol) and added dropwise to the stirred reaction mixture over 15 minutes. After 10 minutes, an aqueous solution of HCl (2 N, 200 mL) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by SFC using a Regis Whelk-O s,s, 5 x 15 cm, 5 µm column at a flow rate of 350 mL / min; a mobile phase of 40% methanol / dichloromethane (1:1 mixture) to give (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (148 g, 234 mmol, 82% yield). m / z (ESI) 632.0 / 634.0 (M+H)+.

[0303] Step 3: (P)-7-Fluoro-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 100 mL, oven-dried, three-necked round-bottom flask was charged with zinc powder (10.3 g, 158 mmol) and a solution of lithium chloride in THF (0.5 M, 45.0 mL, Sigma-Aldrich). The mixture was stirred at 50 °C under a nitrogen stream until the reaction volume was reduced by half. 1,2-Dibromoethane (0.74 g, 0.34 mL, 3.95 mmol) was introduced, and the reaction mixture was warmed to 50 °C. Once the internal temperature reached 50 °C, the reaction mixture was held at that temperature for 20 minutes and then cooled to room temperature. Chlorotrimethylsilane (0.43 g, 0.50 mL, 3.95 mmol) was added, and the reaction mixture was warmed to 50 °C, held for 20 minutes, and then cooled to room temperature. Next, a solution of iodine (0.40 g, 1.58 mmol) in THF (1.0 mL) was added, and the reaction mixture was warmed to 50 °C and held for 20 minutes. 2-Bromo-5,8-dioxaspiro[3.4]octane (15.3 g, 15.3 mL, 79.0 mmol, Enamine, LLC) was added, and the reaction mixture was stirred at 50 °C for 48 h. The reaction mixture was then cooled to room temperature, and after the remaining zinc powder had settled, the supernatant solution was removed via syringe and used without further purification. A separate oven-dried 100 mL round-bottom flask was charged with palladium(II) acetate (0.36 g, 1.58 mmol), CPhos (1.38 g, 3.16 mmol), and THF (10 mL). Next, a solution of (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (10.0 g, 15.8 mmol) in THF (10 mL) was introduced, and the resulting mixture was aerated with nitrogen for 10 minutes. Next, the previously prepared solution of the organozinc complex was added to the reaction mixture via syringe, and the resulting mixture was stirred at 50 °C. After 2 h, methanol (5 mL) and silica gel (approximately 25 g) were added to the reaction mixture, and the volatiles were removed under reduced pressure.The silica-adsorbed material was purified by flash column chromatography (ISCO CombiFlash®, 330 g silica cartridge, eluent: 0 to 70% ethyl acetate / ethanol (3:1 mixture) gradient in heptane / DCM (9:1 mixture)) to give (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (9.56 g, 14.4 mmol, 91% yield). m / z (ESI) 666.2 (M+H).

[0304] Step 4: (P)-7-Fluoro-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 100 mL round-bottom flask was charged with (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (9.56 g, 14.4 mmol) and THF (20 mL). An aqueous solution of HCl (6 M, 10 mL) was introduced, and the resulting reaction mixture was warmed to 40 °C. After 2 h, the reaction mixture was cooled to room temperature, and then saturated sodium bicarbonate solution (100 mL) and DCM (100 mL) were introduced. The layers were separated, and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (ISCO CombiFlash, 330 g, silica cartridge, eluent: 0 to 70% ethyl acetate / ethanol (3:1 mixture) gradient in heptane / DCM (9:1 mixture)) to give (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (8.56 g, 13.8 mmol, 87% yield). m / z (ESI) 622.0 (M+H).

[0305] Step 5: (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 250 mL round-bottom flask was charged with (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (5.00 g, 8.04 mmol) and DCM (40.2 mL). The reaction mixture was cooled to 0° C. in an ice-water bath, and then DAST (25.9 g, 21.3 mL, 161 mmol) was added slowly via syringe. The ice-water bath was removed, and the reaction mixture was allowed to warm to room temperature. After 2 hours, the reaction mixture was carefully transferred to a mixture of saturated aqueous sodium bicarbonate and ice (approximately 300 mL, 1:1). The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (ISCO CombiFlash, 100 g silica cartridge, eluent: 0 to 70% ethyl acetate / ethanol (3:1 mixture) gradient in heptane / DCM (9:1 mixture)) to give (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (4.32 g, 6.71 mmol, 83% yield). m / z (ESI) 644.0 (M+H).

[0306] Step 6: (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 250 mL round-bottom flask was charged with (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (9.90 g, 15.4 mmol), triethylsilane (8.94 g, 8.94 mL, 77.0 mmol), and 1,1,1-trifluoroacetic acid (52.3 g, 35.1 mL, 459 mmol). The reaction mixture was warmed to 40 °C. After 6 h, the reaction mixture was concentrated under reduced pressure and carefully poured into a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with EtOAc (3x), and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The product was azeotroped with heptane (3 × 70 mL) and purified by flash column chromatography (BIOTAGE®, 100 g silica cartridge, eluent: 0–50% EtOAc / heptane) to give (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (6.85 g, 13.1 mmol, 85% yield). 1 H NMR(DMSO-d6,500MHz)δ:11.8-12.1(m,1H),8.70(d,1H,J=1.7Hz),8.44(d,1H,J=7.7Hz),8.22(d,1H,J=9.6Hz),7.33(d,1H,J =10.0Hz),7.24(d,1H,J=6.9Hz),6.74(d,1H,J=9.7Hz),6.51(s,1H),6.54(s,1H),6.37(d,1H,J=1.7Hz),3.72(s,3H),3.62(br t,1H,J=8.8Hz),2.9-3.1(m,4H).m / z(ESI)524.0(M+H)+.

[0307] Example 42: (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0308] Step 1: (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide In an oven-dried 40-mL vial, 2'-(dicyclohexylphosphino)-N 2 ,N 2 ,N 6 ,N 6 A mixture of 1,1'-tetramethyl-[1,1'-biphenyl]-2,6-diamine (32.9 mg, 0.075 mmol), palladium(II) acetate (8.47 mg, 0.038 mmol), and 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (464 mg, 0.755 mmol) was charged to the reaction mixture. The reaction mixture was aerated with nitrogen for 15 minutes and then filtered through a 0.45 micron PTFE filter before the addition of (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)zinc(II) iodide solution (272 mg, 0.83 mmol). The reaction mixture was stirred at 50°C. After 2 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and partitioned between water and ethyl acetate; the organic layer was dried over sodium sulfate and concentrated. The initial product was purified via column chromatography (elution with 0–40% ethyl acetate in heptane with 10% dichloromethane) to give (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (128 mg, 0.191 mmol, 25% yield) as a brown foam. m / z (ESI, positive ion) 670.0 (M+H). + .

[0309] Step 2: (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)-1-(5-Fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (190 mg, 0.284 mmol) was dissolved in TFA (1.2 mL) and stirred at 40° C. Upon completion, the reaction was concentrated and subjected to reverse-phase purification eluting with 35% to 80% acetonitrile in water (containing 0.1% formic acid) to afford (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (112 mg, 0.204 mmol, 72% yield) as a white solid after lyophilization. 1 H NMR(500MHz,chloroform-d,)δ ppm 8.28(d,J=1.7Hz,1H),8.13(d,J=2.1Hz,1H),7.80(d,J=9.6Hz,1H),7.76(dd,J=2.2,9.0Hz,1H),7.72(s,1H),6.94(d,J=9.1Hz,1H),6.8 7(d,J=9.7Hz,1H),6.8-6.8(m,1H),6.77(d,J=9.0Hz,1H),6.62(d,J=1.8Hz,1H),3.73(s,3H),2.43(s,6H).m / z(ESI, cation)550.0(M+H)+.

[0310] Example 43: trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0311] Step 1: trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A vial was charged with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.494 g, 0.804 mmol), palladium(II) acetate (0.023 g, 0.102 mmol), and 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (0.076 g, 0.173 mmol). The resulting mixture was sealed with a septum cap and aerated with nitrogen for 10 minutes, after which tetrahydrofuran (3.09 mL) was added. Next, trans-(3-(trifluoromethyl)cyclobutyl)zinc(II) bromide (9.46 mL, 1.182 mmol) solution was added dropwise via syringe. After the addition was complete, the reaction was warmed to 50 °C and stirred at this temperature for 1.25 h. After cooling to ambient temperature, the reaction was quenched with 5 M aqueous ammonium chloride. The mixture was extracted with ethyl acetate (2x). After removal of the solvent, the residue was purified by flash column chromatography (eluent: 0 to 50% 3:1 ethyl acetate:ethanol in heptane with 10% dichloromethane additive) to give trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.384 g, 0.584 mmol, 73% yield). m / z (ESI, positive ion) 658.0 (M+H)+.

[0312] Step 2: trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)-1-(5-Fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.384 g, 0.584 mmol) was dissolved in 1,1,1-trifluoroacetic acid (1.348 g, 1.348 mL, 11.82 mmol) and stirred at 40° C. under a nitrogen atmosphere for 2.5 hours. After cooling to ambient temperature, excess TFA was removed under vacuum and the resulting solid was triturated with diethyl ether and filtered. The initial product was purified by column chromatography (gradient elution of 0 to 100% EtOAc in heptane with 10% dichloromethane as additive) to give (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (70.8 mg, 0.132 mmol, 23% yield). 1 H NMR(500MHz,DMSO-d6)δ ppm 12.13(br s,1H),8.31(d,J=2.21Hz,1H),8.17(d,J=9.60Hz,1H),7.84(dd,J=8.89Hz,2.14Hz,1H),7.59(d,J=1.56Hz,1H),7.34-7.25(m,3H),6.75(d,J=9 .32Hz,1H),6.70(d,J=8.76Hz,1H),3.95(quin,J=8.99Hz,1H),3.72(s,3H),3.29-3.21(m,1H),2.75-2.56(m,4H).m / z(ESI,cation)538.0(M+H)+.

[0313] Examples 44 and 45: 1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and 1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0314] Step 1: (P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A vial was charged with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.850 g, 1.383 mmol), diacetoxypalladium (0.040 g, 0.180 mmol), and 2'-(dicyclohexylphosphanyl)-N 2 ,N 2 ,N 6 ,N 6The resulting mixture was charged with 1,1'-tetramethyl-[1,1'-biphenyl]-2,6-diamine (0.133 g, 0.304 mmol). The resulting mixture was sealed via a septum cap and purged with nitrogen for 10 minutes, after which tetrahydrofuran (6.92 mL) was added. Next, (5,8-dioxaspiro[3.4]octan-2-yl)zinc(II) bromide solution (1.660 mmol) was added dropwise via syringe. After the addition was complete, the reaction was warmed to 50 °C and stirred for 1.25 hours. After cooling to ambient temperature, the reaction was quenched with 5 M aqueous ammonium chloride solution, and the product was extracted with ethyl acetate (2x). The combined organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (0–50% 3:1 ethyl acetate:ethanol in heptane with 10% dichloromethane as eluent) to give (P)-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.896 g, 1.383 mmol, 100% yield). m / z (ESI, positive ion) 648.0 (M+H)+.

[0315] (P)-1-(5-Fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.896 g, 1.383 mmol) was dissolved in THF (13.8 mL). Hydrochloric acid (1 N in water) (6.92 mL, 6.92 mmol) was added and the reaction was stirred at 50° C. overnight. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The so obtained (P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.835 g, 1.383 mmol, 100% yield) was used directly in the next step. m / z (ESI, positive ion) 604.0 (M+H)+.

[0316] Step 2: (P)-1-(5-fluoro-4-(3-hydroxycyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A vial was charged with (P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.835 g, 1.383 mmol) in methanol (6.92 mL) and THF (6.92 mL) at 0° C., and sodium tetrahydroborate (0.052 g, 1.383 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 15 minutes, then at room temperature for 30 minutes. The reaction mixture was quenched with water and extracted with DCM (3×). The combined organic phases were concentrated in vacuo. The initial product was purified by column chromatography (gradient elution: 0–40% EtOAc / EtOH in heptane with 10% dichloromethane as additive) to give (P)-1-(5-fluoro-4-(3-hydroxycyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.454 g, 0.749 mmol, 54% yield). m / z (ESI, positive ion) 606.0 (M+H)+.

[0317] Step 3: cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide The vial was charged with silver trifluoromethanesulfonate (0.513 g, 1.996 mmol), selectfluor (0.354 g, 0.998 mmol), potassium fluoride (0.155 g, 2.66 mmol), and (P)-1-(5-fluoro-4-(3-hydroxycyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.4029 g, 0.665 mmol) in a nitrogen-filled glove box. Next, anhydrous ethyl acetate (3.33 mL), 2-fluoropyridine (0.194 g, 0.172 mL, 1.996 mmol), and trimethyl(trifluoromethyl)silane (0.284 g, 0.295 mL, 1.996 mmol) were added sequentially under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered through a plug of silica (eluted with ethyl acetate). The filtrate was concentrated, and the product was purified by column chromatography (gradient elution: 0 to 40% EtOAc / EtOH (3 / 1) in heptane with 10% dichloromethane as additive) to give (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (358 mg, 0.531 mmol, 80% yield). m / z (ESI, positive ion) 674.0 (M+H)+.

[0318] The two isomers were separated by SFC on two Chiralpak AD-H, 5 μm columns (3 × 25 cm + 3 × 15 cm) with a mobile phase of 25% ethanol using a flow rate of 80 mL / min. Peak 1 was assigned to cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (28.8 mg), and peak 2 was assigned to trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (228.4 mg).

[0319] Step 4: 1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and 1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide Cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.0288 g, 0.043 mmol), triethylsilane (0.044 g, 0.061 mL, 0.375 mmol), and trifluoroacetic acid (0.370 g, 0.242 mL, 3.25 mmol) were combined under nitrogen. The reaction mixture was stirred at 50° C. for 5 hours. The mixture was cooled, diluted with heptane, and evaporated to dryness under reduced pressure. The product was then purified by flash chromatography (gradient elution: 0 to 40% ethyl acetate / EtOH (3:1) in heptane with 10% dichloromethane as additive) to give cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (13.3 mg, 0.024 mmol, 56% yield). 1 H NMR(500MHz,DMSO-d6)δ ppm 11.62(s,1H),8.71(s,1H),8.34(d,J=2.08Hz,1H),8.20(d,J=9.60Hz,1H) ,7.83(dd,J=8.95,2.21Hz,1H),7.32-7.27(m,2H),6.78(d,J=9.38Hz,2H) ,6.43(d,J=1.43Hz,1H),5.11(t,J=5.77Hz,1H),4.00-3.92(m,1H),3.71( s,3H),2.83-2.71(m,4H),2.55-2.52(m,1H).m / z(ESI, cation)554.0(M+H)+.

[0320] trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.2284 g, 0.339 mmol), triethylsilane (0.346 g, 0.481 mL, 2.98 mmol), and trifluoroacetic acid (2.94 g, 1.920 mL, 25.8 mmol) were combined under nitrogen. The reaction mixture was stirred at 50° C. for 5 hours. The mixture was cooled, diluted with heptane, and evaporated to dryness under reduced pressure. The product was then purified by flash chromatography (gradient elution: 0 to 40% ethyl acetate / EtOH (3:1) in heptane with 10% dichloromethane as additive) to give trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.1623 g, 0.293 mmol, 86% yield). 1 H NMR(500MHz,DMSO-d6)δ ppm 11.62(s,1H),8.72(d,J=1.82Hz,1H),8.35(d,J=2.21Hz,1H),8.20(d,J=9.60Hz,1H),7.83(dd,J=9.02 ,2.27Hz,1H),7.30(d,J=9.99Hz,1H),7.23(d,J=6.62Hz,1H),6.78(d,J=9.47Hz,2H),6.44(d,J=1.82Hz ,1H),4.92(quin,J=7.40Hz,1H),3.38(tt,J=10.46,7.51Hz,1H),3.32-3.25(m,3H),2.84(dquin,J=12 .05,6.07,6.07,6.07,6.07Hz,2H),2.55-2.52(m,1H),2.47-2.41(m,1H).m / z(ESI,Cation)554.0(M+H)+.

[0321] Example 46: trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0322] Step 1: 4-Bromo-3-fluoro-2-iodoaniline To a solution of 2-iodo-3-fluoroaniline hydrochloride (6.45 g, 23.59 mmol) and N,N'-diisopropylethylamine (3.05 g, 4.11 mL, 23.59 mmol) in N,N-dimethylformamide (59.0 mL) was added N-bromosuccinimide (4.20 g, 23.59 mmol). After 20 minutes, the reaction was quenched with water. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the initial product, which was purified by column chromatography (BIOTAGE® ISOLERA ONE, BIOTAGE SFAER SILICA 50 g, 0-30% ethyl acetate in heptane) to give 4-bromo-3-fluoro-2-iodoaniline (6.8 g, 21.52 mmol, 91% yield) as a tan, almost copper-colored solid. m / z (ESI, positive ion) 315.8 (M+H)+.

[0323] Step 2: (E)-3-(6-amino-3-bromo-2-fluorophenyl)acrylate ethyl A 100 mL flask was charged with sodium bicarbonate (4.19 g, 49.9 mmol), ethyl acrylate (2.096 g, 2.355 mL, 20.94 mmol), and palladium(II) acetate (0.090 g, 0.399 mmol). A solution of 4-bromo-3-fluoro-2-iodoaniline (6.3 g, 19.94 mmol) in N,N-dimethylformamide (13.29 mL) was added to the reaction mixture. The reaction was stirred at 100° C. under nitrogen for 3 hours. The reaction was diluted with ethyl acetate and filtered through CELITE. The filtrate was concentrated under reduced pressure to give the initial product, which was purified by column chromatography to give (E)-3-(6-amino-3-bromo-2-fluorophenyl)ethyl acrylate (5.92 g, 20.55 mmol, 103% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm 7.50-7.68(m,1H),7.29(t,J=8.3Hz,1H),6.34-6.60(m,2H),6.07(s,1H),3.98-4.24(m,2H),3.35(br s,1H),1.08-1.36(m,3H).

[0324] Step 3: (E)-3-(6-amino-3-(benzylthio)-2-fluorophenyl)acrylate ethyl ester A 250 mL round-bottom flask was charged with (E)-ethyl 3-(6-amino-3-bromo-2-fluorophenyl)acrylate (4.0 g, 13.88 mmol), 1,4-dioxane (34.7 mL), and 1,1'-dimethyltriethylamine (3.59 g, 4.85 mL, 27.8 mmol). The flask was sealed and aerated with nitrogen for 20 minutes. In a separate 20 mL vial, bis[tris(dibenzylideneacetone)palladium(0)] (0.890 g, 0.972 mmol) and (5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)-diphenylphosphane (1.125 g, 1.944 mmol) were added. The vial was aerated with nitrogen for 5 minutes, after which 1,4-dioxane (5 mL) was added. This catalyst solution was transferred via syringe to the flask containing the acrylate salt. Next, 1-toluenethiol (1.379 g, 1.379 mL, 11.11 mmol) was added in one portion. The mixture was stirred at 80 °C for 16 h. The reaction was cooled and filtered over CELITE. The CELITE was washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (BIOTAGE® Isolera One, BIOTAGE® SNAP Ultra 100 g, 0-30% ethyl acetate in heptane) to give ethyl (E)-3-(6-amino-3-(benzylthio)-2-fluorophenyl)acrylate (2.78 g, 8.39 mmol, 60% yield) as a yellow-orange solid. m / z (ESI, positive ion) 332.2 (M+H)+.

[0325] Step 4: (E)-3-(3-(benzylthio)-6-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-2-fluorophenyl)acrylate ethyl A 40 mL vial was charged with (E)-3-(6-amino-3-(benzylthio)-2-fluorophenyl)ethyl acrylate (0.876 g, 2.64 mmol), 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (1.07 g, 3.23 mmol), and cesium carbonate (2.58 g, 7.93 mmol). Toluene (8.81 mL) was added to the vial. The mixture was purged with nitrogen for 20 minutes, after which tris(dibenzylideneacetone)-dipalladium(0) (0.194 g, 0.194 mL, 0.211 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.245 g, 0.423 mmol) were added rapidly. After purging with nitrogen for an additional 5 minutes, the reaction was warmed to 110 °C. After stirring for 16 hours, the reaction was cooled to ambient temperature, diluted with dichloromethane, and filtered over Celite. The solvent was removed under reduced pressure. The residue was purified by column chromatography (BIOTAGE® ISOLERA ONE, BIOTAGE SFAER SILICAHC 25 g, 0-40% ethyl acetate in heptane) to give ethyl (E)-3-(3-(benzylthio)-6-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-2-fluorophenyl)acrylate (0.600 g, 1.123 mmol, 43% yield) as a yellow solid. m / z (ESI, positive ion) 535.8 (M+H)+.

[0326] Step 5: 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoroquinolin-2(1H)-one Ethyl (E)-3-(3-(benzylthio)-6-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-2-fluorophenyl)acrylate (1.44 g, 2.69 mmol) was dissolved in methanol (33 mL). Sodium methoxide, 25 wt % solution in methanol (0.582 g, 0.616 mL, 2.69 mmol) was added at ambient temperature. The reaction was warmed to 60° C. and stirred at this temperature for 2 hours. The reaction was cooled to ambient temperature and quenched by the addition of water. The product was extracted with ethyl acetate (2×). The organic layer was separated and the solvent removed in vacuo. The residue was purified by column chromatography (BIOTAGE® Isolera One, BIOTAGE® Sfar Silica HC1 D 50 g, 0-40% ethyl acetate in heptane with 10% dichloromethane as additive) to give 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoroquinolin-2(1H)-one (0.717 g, 1.468 mmol, 55% yield) as an off-white solid. m / z (ESI, positive ion) 490.0 (M+H)+.

[0327] Steps 6 and 7: Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate A 40 mL vial was charged with 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoroquinolin-2(1H)-one (0.710 g, 1.454 mmol), acetonitrile (7.04 mL), acetic acid (0.134 mL), and water (0.095 mL). The reaction was cooled to 0 °C in an ice bath, and then 1,3-dichloro-5,5-dimethyl-2,4-imidazolidinedione (0.430 g, 2.181 mmol) was added in one portion. After 10 min, pentafluorophenol (0.321 g, 1.745 mmol) was added, followed by anhydrous triethylamine (0.588 g, 0.817 mL, 5.82 mmol). After 1 h, the reaction was quenched with 2 M aqueous HCl and extracted with ethyl acetate. The organic layer was separated and the solvent removed in vacuo. The residue was purified by column chromatography (BIOTAGE® Isolera One, BIOTAGE® Sfar 25 g silica HCl D, 0 to 40% ethyl acetate in heptane with 10% dichloromethane as additive) to give perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.676 g, 1.104 mmol, 76% yield) as a white solid. m / z (ESI, positive ion) 614.0 (M+H)+.

[0328] Step 8: 1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 40 mL vial was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-6-perfluorophenylsulfonate (0.676 g, 1.104 mmol) and N-(4-methoxybenzyl)isoxazol-3-amine (0.271 g, 1.325 mmol). The vial was purged with nitrogen for 5 minutes, after which tetrahydrofuran (2.208 mL) was added. The reaction was then cooled to -78 °C, and sodium tert-pentoxide, a 30% solution in THF (0.574 mL, 1.435 mmol) was slowly added. After 10 minutes, the reaction was allowed to warm to 0 °C and then quenched with 5 M aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate. The organic layer was separated, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (BIOTAGE® ISOLERA ONE, BIOTAGE SFAER SILICA 25 g, 0-50% ethyl acetate in heptane with 10% dichloromethane as additive) to give 1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.302 g, 0.478 mmol, 43% yield) as a white solid. m / z (ESI, positive ion) 634.0 (M+H)+.

[0329] Step 9: 5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide In a 40 mL vial, 1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.320 g, 0.506 mmol), palladium(II) acetate (0.011 g, 0.051 mmol), and 2'-(dicyclohexylphosphino)-N 2 ,N 2 ,N6 ,N 6 The reaction mixture was charged with 1,1'-tetramethyl-[1,1'-biphenyl]-2,6-diamine (0.044 g, 0.101 mmol). The vial was sealed and purged with nitrogen for 5 minutes. Tetrahydrofuran (2.53 mL) was then added, followed by (3-(trifluoromethyl)cyclobutyl)zinc(II) bromide (1.381 mmol). The reaction was then stirred at 50°C for 1.5 hours. The reaction was cooled to ambient temperature, quenched with 5 M aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was separated, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (BIOTAGE® ISOLERA ONE, BIOTAGE SFAER SILICAHC D 10 g, 0-40% ethyl acetate in heptane with 10% dichloromethane as additive) to give 5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.208 g, 0.308 mmol, 61% yield) as a pale pink solid. m / z (ESI, positive ion) 676.2 (M+H)+.

[0330] Step 10: 5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A 40 mL vial was charged with 5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.208 g, 0.308 mmol), triethylsilane (0.179 g, 0.249 mL, 1.539 mmol), and 1,1,1-trifluoroacetic acid (2.282 g, 2.282 mL, 20.01 mmol). The mixture was stirred at 40° C. for 2 hours. The solvent was removed in vacuo. The mixture was purified by column chromatography (BIOTAGE® ISOLERA ONE, BIOTAGE SFAER SILICAHC D 10 g, 0-100% ethyl acetate in heptane with 10% dichloromethane as additive) to give 5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.153 g, 0.275 mmol, 89% yield) as an off-white solid. m / z (ESI, positive ion) 556.2 (M+H)+.

[0331] Step 11: trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide 5-Fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.153 g, 0.275 mmol) was purified by SFC in two steps: Step 1: Regis Whelk-O s,s 2×15 cm, 5 μm column; 35% methanol mobile phase using a flow rate of 60 mL / min; Step 2: (separation of peak 1 and peak 2): two Chiralpak AD-H, 5 μm columns (3×15 cm + 3×25 cm); 30% ethanol mobile phase using a flow rate of 80 mL / min. Peak 1 was lyophilized to give trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.0305 g, 0.055 mmol, 18% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 12.01(br s,1H),8.72(d,J=1.8Hz,1H),8.18(d,J=9.9Hz,1H),7.87(t,J=8.1Hz,1H),7.34(s,1H),7.33(d,J=3.4Hz,1H),6.83(d,J=9.9Hz,1H),6.59(d ,J=9.2Hz,1H),6.37(d,J=1.8Hz,1H),3.95(t,J=9.0Hz,1H),3.73(s,3H),3.22-3.28(m,1H),2.55-2.72(m,4H).m / z(ESI,cation)556.2(M+H)+.

[0332] Example 47: (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0333] Step 1: (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide In an oven-dried 40-mL vial, 2'-(dicyclohexylphosphanyl)-N 2 ,N 2 ,N 6 ,N 6 A mixture of 1,1'-tetramethyl-[1,1'-biphenyl]-2,6-diamine (0.046 g, 0.106 mmol), palladium(II) acetate (0.012 g, 0.053 mmol), and (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (0.663 g, 1.060 mmol) was charged to the reaction mixture. The reaction mixture was purged with nitrogen for 15 minutes and then filtered through a 0.45 micron PTFE filter. After this, (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)zinc(II) iodide solution (1.59 mmol) was added. The reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The initial product was purified by column chromatography (gradient elution: 0 to 60% ethyl acetate in heptane with 10% dichloromethane as additive) to give (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (0.241 g, 0.354 mmol, 33% yield) as a pale gray foam. m / z (ESI, positive ion) 681.1 (M+H). + .

[0334] Step 2: (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (P)-1-(5-Fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (241 mg, 0.354 mmol) was dissolved in trifluoroacetic acid (3.63 g, 2.44 mL, 31.9 mmol) in a 20 mL vial and the reaction was heated to 40° C. and stirred for 2 hours. The reaction was cooled to room temperature. The reaction was made basic using saturated NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated. The initial product was subjected to reverse-phase purification (gradient elution 25–70% acetonitrile in water with 0.1% formic acid) to give (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (103 mg, 0.184 mmol, 52% yield) as a white solid after lyophilization. 1 H NMR(chloroform-d,500MHz)δ ppm 10.27(br s,1H),8.60(d,J=4.9Hz,2H),8.43(d,J=2.1Hz,1H),8.07(dd,J=2.1,9.0Hz,1H),7.85(d,J=9.6Hz,1H),7.00(t,J=4.9Hz,1H),6.93(d,J =9.2Hz,1H),6.85(d,J=9.6Hz,1H),6.83(d,J=6.4Hz,1H),6.77(d,J=9.0Hz,1H),3.72(s,3H),2.42(s,6H).m / z(ESI,cation)561.0(M+H)+.

[0335] Example 48: (P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0336] Step 1: (P)-1-(5-chloro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A vial was charged with (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.500 g, 0.793 mmol), tetrahydrofuran (1.585 mL), palladium(II) acetate (0.018 g, 0.079 mmol), and 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (0.069 g, 0.159 mmol). After purging the vial with nitrogen, dioxaspiro[3.4]octan-2-ylzinc(II) bromide (0.1 M in THF, 1.110 mmol) was added, and the reaction was stirred at 50 °C for 1 hour. The reaction was then diluted with ethyl acetate and acidified with 1 N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (gradient elution 0-100% EtOAc:heptane) to give (P)-1-(5-chloro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.420 g, 0.632 mmol, 80% yield). m / z (ESI, positive ion) 664.0 (M+H). + .

[0337] Step 2: (P)-1-(5-chloro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)-1-(5-chloro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.420 g, 0.632 mmol) was dissolved in dichloromethane (2 mL). Hydrochloric acid (2 N in water, 2.0 mL, 4.0 mmol) was added and the reaction was stirred at 50° C. for 3 days. The reaction was then diluted with dichloromethane and washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting (P)-1-(5-chloro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.330 g, 0.532 mmol, 67% yield) was used in the next step without further purification. m / z (ESI, positive ion) 620.0 (M+H). + .

[0338] Step 3: (P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A vial was charged with (P)-1-(5-chloro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.330 g, 0.532 mmol), dichloromethane (1.064 mL), and diethylaminosulfur trifluoride (2.145 g, 1.758 mL, 13.30 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was then poured into a round-bottom flask, diluted with dichloromethane, and saturated aqueous sodium bicarbonate was carefully added until bubbling ceased. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (gradient elution 0–50% EtOAc:heptane) to give (P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.350 g, 0.545 mmol, 102% yield).

[0339] Step 4: (P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.350 g, 0.545 mmol) was dissolved in TFA (1 mL) and dichloromethane (1 mL). The solution was heated to 40 °C and stirred overnight. The solvent was removed in vacuo, and the residue was washed with an aqueous solution of NaHCO3. The mixture was extracted with dichloromethane, dried over MgSO4, and filtered. The initial product was purified via flash column chromatography (gradient elution 0 to 50% EtOAc in heptane). The sample was purified again by SFC through a Regis Whelk-O s,s, 2 × 15 cm, 5 μm column with a mobile phase of 40% methanol using a flow rate of 70 mL / min to give (P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.173 g, 0.331 mmol, 62% yield). 1 H NMR(600MHz,DMSO-d6)δ ppm 11.63(br s,1H),8.71(d,J=1.63Hz,1H),8.35(d,J=2.18Hz,1H),8.20(d,J=9.63Hz,1H),7.8 3(dd,J=8.99,2.27Hz,1H),7.54(s,1H),7.30(s,1H),6.78(dd,J=9.35,5.36Hz,2H ),6.44(d,J=1.82Hz,1H),3.74(s,3H),3.67(quin,J=8.67Hz,1H),3.09(dtt,J=18 .20,9.04,9.04,4.38,4.38Hz,2H),3.02-2.89(m,2H).m / z(ESI,cation)521.8(M+H) + .

[0340] Example 49: trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide [ka]

[0341] Step 1: trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide A vial was charged with (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.508 g, 0.804 mmol), palladium(II) acetate (0.023 g, 0.102 mmol), and 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (0.076 g, 0.173 mmol). The resulting mixture was sealed via a septum cap and purged with nitrogen for 10 minutes, after which tetrahydrofuran (3.09 mL) was added. (3-(trifluoromethyl)cyclobutyl)zinc(II) bromide (1.182 mmol) solution was added. After the addition was complete, the reaction was warmed to 50 °C and stirred at this temperature for 1.25 hours. After cooling to ambient temperature, the reaction was quenched with 5 M aqueous ammonium chloride. The mixture was extracted with ethyl acetate (2×). The organic layer was separated. After removal of the solvent, the residue was purified by flash column chromatography (gradient elution: 0 to 50% 3:1 ethyl acetate:ethanol in heptane with 10% dichloromethane as additive) to give trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.368 g, 0.546 mmol, 68% yield). m / z (ESI, positive ion) 673.6 (M+H)+.

[0342] Step 2: trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.368 g, 0.546 mmol) was dissolved in 1,1,1-trifluoroacetic acid (1.348 g, 1.348 mL, 11.82 mmol). The reaction was stirred at 40° C. under a nitrogen atmosphere for 2.5 hours. After cooling to ambient temperature, excess TFA was removed in vacuo and the resulting solid was triturated with diethyl ether and filtered. The initial product was purified by column chromatography (gradient elution 0–100% in heptane with 10% dichloromethane as additive) to give trans-(P)-1-(5-chloro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (49.6 mg, 0.092 mmol, 17% yield). 1 H NMR(500MHz,DMSO-d6)δ ppm 12.13(br s,1H),8.31(d,J=2.08Hz,1H),8.17(d,J=9.60Hz,1H),7.84(dd,J=8.95,2.21H z,1H),7.59(d,J=1.56Hz,1H),7.49(s,1H),7.38(s,1H),7.25(d,J=1.43Hz,1H ),6.75(d,J=9.60Hz,1H),6.69(d,J=8.95Hz,1H),4.00(quin,J=8.99Hz,1H),3 .77(s,3H),3.27-3.20(m,1H),2.75-2.60(m,4H).m / z(ESI, cation)554.0(M+H)+.

[0343] Biological Examples The following assays were used in testing exemplary compounds of the invention. Data for those examples tested according to the procedures below are presented in Table 1 below.

[0344] IONWORKS BARRACUDA (IWB) Automated Patch Clamp Assay (same protocol for both human and mouse) Human Nav1.7 currents were recorded in population patch clamp mode with an IWB automated electrophysiology system (Molecular Devices, LLC, Sunnyvale, CA). Spiking HEK cells (without Kir2.1 transfection) were recorded in the IonWorks Quattro assay. 1Cells were cultured and prepared for recording as previously described. The external solution consisted of (in mM): NaCl 140, KCl 5, CaCl 2, MgCl 1, HEPES 10, and glucose 11, with 320 mOsmol N-methyl-D-glucamine. The internal solution consisted of (in mM): KCl 70, KF 70, MgCl 0.25, HEDTA 5, and HEPES 10, with 300 mOsmol N-methyl-D-glucamine, pH 7.25. From a holding potential of -110 mV, currents were elicited by a train of 26 depolarizations of 150 ms duration to -20 mV at a frequency of 5 Hz. Cells were then clamped at -20 mV for 4 minutes in the presence of a single concentration of test compound. After this compound incubation period, cells were clamped at -110 mV for 3 seconds to recover unbound channels, and then subjected to the same 26-pulse voltage protocol as above. The peak inward current during the 26th pulse to -20 mV in the presence of compound was divided by the peak inward current induced by the 26th pulse to -20 mV in the absence of compound to determine percent inhibition. Concentration-response curves of percent inhibition as a function of concentration were generated to obtain the IC 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 values ​​were calculated.

[0345] Microsome-specific clearance assay The purpose of this assay is to determine the intrinsic clearance of test compounds in microsomes from pre-symptomatic species and humans by monitoring the disappearance of the test article in liver microsomes over time. Microsomes from a 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). Final incubation concentrations were 0.25 mg / mL microsomal protein and 0.5 μM test article, with incubations performed in triplicate. Typical time points for the assay were 1, 5, 10, 20, 30, and 40. The assay was performed in a 96-well format, with serial withdrawals from 400 μL incubations. At the appropriate time points, the incubation was quenched with acetonitrile containing an internal standard (tolbutamide). Tolbutamide was the default internal standard because it has a signal by positive or negative ion mass spectrometry. The positive control for the microsomal intrinsic clearance assay was verapamil. Samples were subjected to LC-MS / MS analysis, and the relative amounts of compounds were calculated by the compound peak area normalized to the peak area of ​​the internal standard (A / IS). Intrinsic clearance calculations were performed on a Galileo.

[0346] procedure: Microsomes were removed from a -80°C freezer and thawed at room temperature or in a 37°C water bath. Once thawed, they were stored on ice. Microsomes were added to 0.1 M phosphate buffer (0.53 mg / L) and 250 μL aliquots were taken per reaction. 10 mM stocks of test articles were prepared in DMSO. A 1 / 100 aliquot was diluted in 50:50 acetonitrile:water to create a 100 μM stock. Approximately 2.5 μL of the 100 μM test article stock was added to each reaction to give a final concentration of 1.05 μM substrate. (NB: at this stage, the concentration was approximately 2-fold higher than the final incubation concentration to account for the approximately 1:1 dilution with NADPH.)

[0347] A 1.9 mM NADPH solution was prepared in 0.1 mM phosphate buffer. Four 250 μL replicate wells of substrate and microsomes containing 1.05 μM substrate and 0.53 mg / mL protein were prepared. Three replicate wells containing 210 μL of 1.90 mM NADPH and one well of buffer (-NADPH) were also prepared. Microsomes, 0.1 M phosphate buffer, and test article were pre-incubated at 37°C for 5 minutes. To initiate the reaction, 190 μL of substrate was added to the well containing NADPH, resulting in final concentrations of 0.25 mg / mL microsomes, 0.5 μM test article, and 1 mM NADPH. 35 μL aliquots were removed 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. The solution was then transferred for bioanalysis by LC-MS / MS.

[0348] Open-field locomotor activity in mice. On the day of testing, C57B1 / 6 male mice were orally administered either the Nav1.7 compound or a vehicle control formulation at a dose volume of 10 ml / kg. The vehicles used were 1% Tween 80 pH 10 with 2% HPMC / NaOH; DI water at pH 10 w / NaOH; or 2% HPMC / 1% Tween 80 pH 2.2.

[0349] Two to three hours after treatment with the test article, animals were placed in an open field chamber according to the cmax of each Nav1.7 test compound of the present invention, and their behavior was monitored for 30 minutes. For the experiments at Thousand Oaks, a 16" x 16" open field chamber was used, KINDER SCIENTIFIC®, San Diego, CA. For the experiments at Cambridge Massachusetts, a 16" x 16" open field chamber was used, SAN DIEGO INSTRUMENTS®, San Diego, CA. Locomotor activity (horizontal movement and rearing) parameters were measured automatically via interruption of an infrared light beam.

[0350] Human CYP 3A4 induction assay Cryopreserved human hepatocytes were seeded at 70,000 cells per well onto 96-well collagen-coated plates in hepatocyte plating medium (HPM, final concentrations: 1x Dulbecco's Modified Eagle's Medium, 0.1 μM dexamethasone, 10% fetal bovine serum, 1x ITS, 1x PSG) and incubated at 37°C under 5% CO2 and 90% relative humidity for 2 days to allow hepatocytes to form a confluent layer. On day 3, hepatocytes were treated with either test compounds or rifampin (20 μM, a positive control for CYP3A induction) prepared in hepatocyte incubation medium (HIM, final concentrations: 1x Williams' Medium E, 0.1 μM dexamethasone, 1x ITS, 1x PSG). Treatment was performed for 72 hours with either two concentrations (2 μM or 10 μM) or a range of concentrations (0.001 μM to 100 μM) of test compound to obtain a full dose-response curve. Fresh medium containing the appropriate concentration of test compound was replaced daily until samples were processed. After 72 hours of incubation, samples were processed for mRNA analysis using bDNA technology according to the manufacturer's instructions (Affymetrix, Fremont, CA). Cell viability was tested at the end of the experiment using an MTT assay kit (Roche Diagnostics, Basel, Switzerland). Data were analyzed and reported as percent of control (POC) and Efficacy (EF) values ​​obtained 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, as appropriate. max and EC...

Claims

1. Compounds of formula (Ia): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (In the formula, R 1a is fluoro, chloro, methyl, —O—CF 3 , or CF 3 ; R ２ is H, halo, C １～６ Alkyl, or C １～６ haloalkyl; R ３ is C １～６ Alkyl, C １～６ Haloalkyl, —O—C １～６ alkyl, or —CN; R ４ is a 5-6 membered heteroaryl containing 1-3 heteroatoms; R ６ and R ７ each is hydrogen; and R ５ａ ;R ５ｂ ;R ５ｃ ;R ５ｄ and R ５ｅ each is independently hydrogen or halo.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is H, fluoro, chloro, methyl, CF 3 , CHF 2 , or CH 2 F.

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

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is H or fluoro.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 is methoxy.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is isoxazolyl.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyridazinyl.

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

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

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

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

12. (a) Each of R 5a ; R 5b ; R 5c ; R 5d ; and R 5e is hydrogen; (b) R 5a is F; and each of R 5b ; R 5c ; R 5d ; and R 5e is hydrogen; or (c) R 5c is F; and each of R 5a ; R 5b ; R 5d ; and R 5e is hydrogen; 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 5a is F.

14. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein each of R 5a ; R 5b ; R 5c ; R 5d ; and R 5e is hydrogen.

15. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R 5a is F; and each of R 5b ; R 5c ; R 5d ; and R 5e is hydrogen.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for treating pain, cough, or itching.

18. The pharmaceutical composition of claim 17, 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 lower back pain.

19. The pharmaceutical composition described in claim 17, wherein the cough is selected from post-viral cough, viral cough, or acute viral cough.

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