Cyclobutyl dihydroquinoline sulfonamide compounds

Abstract

The invention relates to cyclobutyl dihydroquinoline sulfonamide compounds. The present invention provides a cyclobutyl dihydroquinoline sulfonamide compound of formula (I), enantiomers, diastereoisomers, atropisomers thereof, mixtures thereof, or pharmaceutically acceptable salts thereof, which inhibit voltage-gated sodium channels, in particular Nav1.7. These compounds are useful in the treatment of diseases associated with sodium channel activity, such as pain disorders, cough and pruritus. Also provided are pharmaceutical compositions containing the compounds of the invention. Also further provided are rotation-resistant selective formulations of the compounds of formula (I), and intermediates of the compounds. # imgabs0 #

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 037,001, filed on June 10, 2020. Technical Field

[0003] The present invention provides cyclobutyldihydroquinoline compounds which are inhibitors of voltage-gated sodium channels (Nav), particularly Nav1.7, and can be used to treat diseases treatable by inhibiting sodium channels, such as pain disorders. Also provided are pharmaceutical compositions containing the compounds of the present invention. Background Art

[0004] A 2011 report by the National Academy of Medicine estimated that approximately 30% of the 100 million adults in the United States suffer from chronic pain (C&E News, Bethany Halford, "Changing the Channel," published March 24). Chronic pain, by definition, involves abnormal electrical spikes in neurons in the pain pathway: peripheral sensory neurons, spinal cord neurons, neurons in the brain pain matrix (e.g., somatosensory cortex, insular cortex, anterior cingulate cortex), and / or neurons in the brainstem. Although the firing of these neurons is regulated and controlled by many different receptors, enzymes, and growth factors, in most neurons, the rapid upstroke of the electrical spike is generated by the entry of sodium ions through voltage-gated sodium channels (Hille B, Ion Channels of Excitable Membranes. Sinauer Associates, Inc.: Sunderland MA, 3rd ed. 2001). There are nine different isoforms of voltage-gated sodium channels (Nav1.1-Nav1.9), and they have different expression patterns in tissues including neurons and heart and skeletal muscle (Goldin, AL, "Resurgence of sodium channel research," Ann Rev Physiol 63:871-894, 2001; Wood, JN and Boorman, J. "Voltage-gated sodium channel blockers; target validation and therapeutic potential" Curr. Top Med. Chem. 5:529-537, 2005).

[0005] Nav1.1 and Nav1.2 are highly expressed in the brain (Raymond, CK, et al., J.Biol.Chem. [Journal of Biological Chemistry] (2004) 279 (44): 46234-41) and are essential for normal brain function. Due to the loss of some functions of Nav1.1 mutations in humans, epilepsy has been caused, probably because these channels are expressed in inhibitory neurons (Yu, FH, et al., Nat.Neuroscience [Natural Neuroscience] (2006), 9 (9) 1142-1149). Nav1.1 is also expressed in the peripheral nervous system, and the inhibition of Nav1.1 in the periphery can provide pain relief. Therefore, although the inhibition of Nav1.1 can provide for the treatment of pain, it may also be undesirable and may cause anxiety and overexcitement. Nav1.3 is mainly expressed in the fetal central nervous system and has been found to be upregulated after nerve injury in rats (Hains, BD, et al., J. Neuroscience [Journal of Neuroscience] (2030) 23 (26): 8881-8892). Nav1.4 is mainly expressed in skeletal muscle. Mutations in the gene and its product have significant effects on muscle function, including paralysis (Tamaoka A., Internal Medicine [Internal Medicine] (2003), (9): 769-770). Nav1.5 is mainly expressed in cardiomyocytes (including atria, ventricles, sinoatrial nodes, atrioventricular nodes, and cardiac Purkinje fibers). The rapid upstroke of the cardiac action potential and the rapid pulsation conduction through the cardiac tissue are due to the opening of the Nav1.5 channel. Mutations in the Nav1.5 channel lead to arrhythmic syndromes, including QTc prolongation, Brugada syndrome (BS), sudden unexplained 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 that is expressed throughout the central and peripheral nervous systems. Nav1.8 is primarily expressed in sensory ganglia (such as dorsal root ganglia) of the peripheral nervous system. There are unidentified Nav1.8 mutations that produce altered pain responses in humans. Nav1.8 differs from most neuronal Nav isoforms in that it is insensitive to inhibition by tetrodotoxin. Nav1.9, like Nav1.8, 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).

[0006] Recent evidence from several independent genetic studies shows that the tetrodotoxin-sensitive voltage-gated sodium channel Nav1.7 (SCN9A) is required for the perception of pain. Rare inherited forms of severe chronic pain, primary erythromelalgia and paroxysmal extreme pain disorder, are caused by mutations that increase Nav1.7 activity (Fertleman CR, Baker M.D., Parker KA, Moffatt S., et al., "SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes," Neuron 52:767-774, 2006; Yang Y., Wang Y., Li S, et al., "Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with (primary erythermalgia [SCN9A mutations encoding the alpha subunit of the sodium channel in patients with primary erythromelalgia]," J. Med. Genet. 41:171-174, 2004; Drenth JPH, te Morsche RHM, Guillet G., Taieb A., et al., "SCN9A mutations define primary erythermalgia as an aneuropathic disorder of voltage gated sodium channels," J Invest Dermatol 124:1333-1338).In contrast, two separate clinical studies have determined that the underlying cause of the genetic disorder congenital insensitivity to pain (CIP) is loss of function of Nav1.7 through mutations that truncate the protein and disrupt function (Cox JJ, Reimann F, Nicholas AK, et al. "An SCN9A channelopathy causes congenital inability to experience pain," Nature 444:894-898, 2006; Goldberg YP, MacFarlane J., MacDonald ML, Thompson J., et al. "Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations," Clin Genet 71:311-319, 2007). The disorder is inherited in a Mendelian recessive manner with 100% penetrance. The phenotype associated with CIP is extreme: affected individuals reportedly experience painless burns, childbirth, appendicitis, and fractures, and are insensitive to clinical pain measures such as pinprick or tendon compression. However, sensory, motor, autonomic, and other measured functions are normal, with the only reported abnormality being anosmia (inability to smell). These studies suggest that, among many possible targets in the pain pathway, Nav1.7 innervates one or more control points that are critical for pain perception.

[0007] Non-selective sodium channel inhibitors, such as lidocaine, mexiletine and carbamazepine, show clinical efficacy in chronic pain, including neuropathic pain, but they are limited in dosage and use, probably due to the effect on sodium channels outside the pain pathway. Lidocaine is a local anesthetic used by doctors for minor surgeries. Dentists use novocaine. However, these compounds do not distinguish between different sodium channel subtypes, making them unsuitable for use as systemic analgesics. Glenn F. King (a professor at the University of Queensland, Australia, who studies venom that blocks ion channels) said, "If you give a drug that blocks Nav1.7 but also blocks Nav1.5, the patient will die of heart failure [if you give a drug that blocks Nav1.7 and also blocks Nav1.5, the patient will die of heart failure]". "It will be a completely painless death, but the patient will die nonetheless [this will be a completely painless death, but the patient will still die]." Therefore, it is desirable to have selectivity for Nav1.7, especially compared to Nav1.5. The researchers have tailored their efforts to find a molecule that inhibits or blocks only the activity of Nav1.7. Complicating this problem is that the identity, location, function and / or tertiary structure of every subtype of the voltage-gated sodium channel protein is not known or fully understood.

[0008] Therefore, many researchers are trying to identify small molecule inhibitors of Nav1.7. For example, Chafeev et al. disclosed spiro-oxindole compounds for treating and / or preventing sodium channel-mediated diseases such as pain in U.S. Patent No. 8,101,647. International Publications WO 2013 / 134518 and WO 2014 / 201206 disclose sulfonamide derivatives that are different from the sulfonamide derivatives of the present invention. Therefore, it is necessary to identify inhibitors that are selective for Nav1.7 relative to at least Nav1.5 to treat pain. The present invention provides compounds that are selective inhibitors for Nav1.7 relative to at least Nav1.5. Summary of the invention

[0009] In Example 1, the present invention provides a compound having formula (I), its enantiomer, diastereomer, atropisomer, mixture thereof, or a pharmaceutically acceptable salt thereof,

[0010]

[0011] in:

[0012] R1 is a saturated or partially saturated 4-membered monocyclic ring; or a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered bicyclic ring; wherein the monocyclic ring or bicyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; and wherein the monocyclic ring or bicyclic ring is surrounded by 0, 1, 2, or 3 R selected from the following 1a Group substitution: hydroxyl, halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, -OC 1-4 Alkyl, -OC 1-8 Haloalkyl, -C(=O)C 1-4 Alkyl, -OC(=O)C 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, or -N(C 1-4 Alkyl)C 1-4 alkyl;

[0013] R 2 H, halogen, C 1-6 Alkyl, or C 1-6 Haloalkyl;

[0014] R 3 It is C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, or -CN;

[0015] R 4 is a 5- to 6-membered heteroaryl group;

[0016] R 6 and R 7 are each hydrogen; and

[0017] R 5a , R 5b , R 5c , R 5d , and R 5e are each independently hydrogen or halo.

[0018] In sub-embodiment 1a of embodiment 1, the compound having formula (I) has sub-formula (la):

[0019]

[0020] Where R 1a It is fluorine, chlorine, methyl, -O-CF3, or CF3.

[0021] In a more preferred sub-embodiment 1a of embodiment 1, R 1a is CF3 or -O-CF3; R 2is H, F or methyl; and R 4 isoxazolyl or pyridazinyl.

[0022] In the most preferred sub-embodiment 1a of embodiment 1, R 1a It is CF3; R 2 is F; and R 4 It is isoxazolyl.

[0023] In sub-embodiment 1b of embodiment 1, the compound having formula (I) has sub-formula (Ib):

[0024]

[0025] Each R 1a It is fluorine or CF3.

[0026] In a more preferred sub-embodiment 1b of embodiment 1, each R 1a It is F; R 2 is F or Cl; and R 4 It is isoxazolyl.

[0027] In the most preferred sub-embodiment 1b of embodiment 1, each R 1a It is F; R 2 is F; and R 4 It is isoxazolyl.

[0028] In sub-embodiment 1c of embodiment 1, the compound having formula (I) has sub-formula (Ic):

[0029]

[0030] Where R 1a It's CF3.

[0031] In a more preferred sub-embodiment 1c of embodiment 1, R 1a It is CF3; R 2 is F; and R 4 isoxazolyl or pyrimidinyl.

[0032] In the most preferred sub-embodiment 1c of embodiment 1, R 1a It is CF3; R 2 is F; and R 4 It is isoxazolyl.

[0033] In embodiment 2, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a The group is selected from halogen, C 1-8 Alkyl, -OC 1-4 Alkyl, or C1-8 haloalkyl, wherein the C 1-8 Haloalkyl is C 1-8 Fluoroalkyl.

[0034] In embodiment 3, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a cyclobutyl ring; or a 5-membered or 6-membered bicyclic ring; wherein the cyclobutyl ring or bicyclic ring contains 0 N, O and S atoms; and wherein the cyclobutyl ring or bicyclic ring is surrounded by 1, 2 or 3 R selected from the following 1a Group substitution: F, -CF3, -O-CF3 or -C(CH3)3.

[0035] In embodiment 4, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a cyclobutyl ring or a bicyclo[1.1.1]pentan-1-yl ring; wherein each ring is substituted by 1 or 2 F or -CF3.

[0036] In embodiment 5, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a cyclobutyl ring substituted with 1 or 2 F or -CF3.

[0037] In sub-embodiment 5a of embodiment 5, the compound of formula (I) has the above sub-formula (Ia) and R 1a It's F.

[0038] In sub-embodiment 5b of embodiment 5, the compound of formula (I) has the above sub-formula (Ib) and R 1a It is -CF3.

[0039] In sub-embodiment 5c of embodiment 5, R 1 It is a cyclobutyl ring substituted with one -CF3.

[0040] In sub-embodiment 5d of embodiment 5, R 1 is a cyclobutyl ring substituted with 1 or 2 F groups.

[0041] In sub-embodiment 5c of embodiment 5, the compound of formula (I) has the above sub-formula (Ic) and R 1a It is -CF3.

[0042] In embodiment 6, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a bicyclo[1.1.1]pentan-1-yl ring substituted by 1 or 2 F or -CF3.

[0043] In embodiment 7, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is H, fluorine, chlorine, methyl, CF3, CHF2, or CH2F. In sub-embodiment 7a of embodiment 7, R 2 It's fluorine.

[0044] In embodiment 8, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is H, fluorine, chlorine, or methyl.

[0045] In embodiment 9, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 It is H or fluorine.

[0046] In embodiment 10, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 It's a methoxy group.

[0047] In embodiment 11, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 It is a 5-membered heteroaryl.

[0048] In embodiment 12, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 It is a 6-membered heteroaryl.

[0049] In embodiment 13, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.

[0050] In a sub-embodiment of embodiment 13a of embodiment 13, R4 isoxazolyl, pyridazinyl, or pyrimidinyl.

[0051] In another sub-embodiment 13b of Embodiment 13, R 4 It is isoxazolyl.

[0052] In embodiment 14a, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5a , R 5b , R 5c , R 5d , and R 5e Each is hydrogen.

[0053] In embodiment 14b, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5a is F; and R 5b , R 5c , R 5d , and R 5e Each is hydrogen.

[0054] In embodiment 14c, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5c is F; and R 5a , R 5b , R 5d , and R 5e Each is hydrogen.

[0055] In embodiment 15, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound having formula (I) is selected from a compound having formula (Ia), (Ib) or (Ic):

[0056] or

[0057] wherein each R in the compound of formula (Ia), (Ib) or (Ic) 1a is independently fluorine, chlorine, methyl, -O-CF3, or CF3.

[0058] In Embodiment 16, the present invention provides a compound of formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia); wherein R 1a is CF3; the cyclobutyl ring is a trans isomer; and R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, or oxazolyl.

[0059] In embodiment 16a, the compound of formula (I) is a compound of formula (Ia); wherein R 1a is cis-CF3; the cyclobutyl ring is a cis isomer; R 2 is F; and R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, or oxazolyl.

[0060] In embodiment 16b, the compound of formula (I) is a compound of formula (Ib); wherein each R 1a is fluorine; R 2 is F; and R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.

[0061] In embodiment 16c, the compound of formula (I) is a compound of formula (Ib); wherein each R 1a is fluorine; R 5a is F; and R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.

[0062] In embodiment 16d, the compound of formula (I) is a compound of formula (Ic); wherein each R 1a It's CF3.

[0063] In embodiment 17, the present invention provides a compound having formula (I), an enantiomer, a diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0064] 1)(M)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0065] 2) 1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0066] 3)(P)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0067] 4) (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0068] 5)(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0069] 6) cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0070] 7) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0071] 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;

[0072] 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;

[0073] 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;

[0074] 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;

[0075] 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;

[0076] 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;

[0077] 14) (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0078] 15) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0079] 16) cis-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0080] 17) trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0081] 18) (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0082] 19) trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0083] 20) trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0084] 21)(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0085] 22)(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0086] 23) (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0087] 24) (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0088] 25)(P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0089] 26) (P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0090] 27)(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0091] 28) (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0092] 29) (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0093] 30)(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0094] 31)(P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0095] 32) (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0096] 33) (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0097] 34) (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0098] 35) trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0099] 36) trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0100] 37) trans-(P)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0101] 38) trans-(P)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0102] 39) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0103] 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;

[0104] 41)(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0105] 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;

[0106] 43)(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0107] 44) cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0108] 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;

[0109] 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;

[0110] 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;

[0111] 48)(P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or

[0112] 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.

[0113] In embodiment 18, the present invention provides a compound of formula (I) having sub-formula (Ia): Its enantiomers, diastereomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0114] 1) cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0115] 2) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0116] 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;

[0117] 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;

[0118] 5) trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0119] 6) trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0120] 7) trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0121] 8) trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0122] 9) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0123] 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;

[0124] 11)(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0125] 12) cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0126] 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;

[0127] 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

[0128] 15) trans-(P)-1-(5-chloro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)

[0129] 16) phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0130] In sub-embodiment 18a of embodiment 18, the present invention provides a compound of formula (I) (having sub-formula (Ia) above), its enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0131] 1) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0132] 2) trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0133] 3) trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0134] 4) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

[0135] 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

[0136] 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.

[0137] In sub-example 18b of Example 18, the present invention provides a compound of formula (I) (having the above sub-formula (Ia)), its enantiomers, diastereomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts 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.

[0138] In sub-example 18c of Example 18, the present invention provides a compound of formula (I) (having the above sub-formula (Ia)), its enantiomers, diastereomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which compound is trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0139] In sub-example 18d of Example 18, the present invention provides a compound of formula (I) (having the above sub-formula (Ia)), its enantiomers, diastereomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which compound is trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide.

[0140] In sub-example 18e of Example 18, the present invention provides a compound of formula (I) (having the above sub-formula (Ia)), its enantiomer, diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which compound is trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide.

[0141] In sub-example 18f of Example 18, the present invention provides a compound of formula (I) (having the above sub-formula (Ia)), its enantiomer, diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which compound 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.

[0142] In sub-example 18g of Example 18, the present invention provides a compound of formula (I) (having the above sub-formula (Ia)), its enantiomers, diastereomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which compound 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.

[0143] In embodiment 19, the present invention provides a compound of formula (I) having sub-formula (Ib): Its enantiomers, diastereomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the compound being selected from:

[0144] 1)(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0145] 2)(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0146] 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;

[0147] 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;

[0148] 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;

[0149] 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;

[0150] 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

[0151] 8)(P)-1-(5-Chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0152] In sub-embodiment 19a of embodiment 19, the present invention provides a compound of formula (I) (having sub-formula (Ib) above), its enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the compound being selected from:

[0153] 1)(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

[0154] 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;

[0155] 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

[0156] 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.

[0157] In sub-example 19b of Example 19, the present invention provides a compound of formula (I) (having the above sub-formula (Ib)), its enantiomers, diastereomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which compound is (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

[0158] In sub-example 19c of Example 19, the present invention provides a compound of formula (I) (having the above sub-formula (Ib)), its enantiomer, diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which compound 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.

[0159] In sub-example 19d of Example 19, the present invention provides a compound of formula (I) (having the above sub-formula (Ib)), its enantiomers, diastereomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which compound 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.

[0160] In sub-example 19e of Example 19, the present invention provides a compound of formula (I) (having the above sub-formula (Ib)), its enantiomer, diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which compound 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.

[0161] In embodiment 20, the present invention provides a compound of formula (I) having sub-formula (Ic): Its enantiomers, diastereomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the compound being selected from:

[0162] (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

[0163] (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.

[0164] In sub-example 20a of Example 20, the present invention provides a compound of formula (I) (having the above sub-formula (Ic)), its enantiomer, diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which compound 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.

[0165] In sub-example 20b of Example 20, the present invention provides a compound of formula (I) (having the above sub-formula (Ic)), its enantiomer, diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which compound 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.

[0166] In Example 21, the present invention provides a p-atropisomer of each individual compound described in Examples 18, 19 and 20, or any sub-examples thereof (independently or as a mixture thereof), or a pharmaceutically acceptable salt thereof.

[0167] In Example 22, the present invention provides the M atropisomer of each individual compound described in Examples 18, 19 and 20, or any sub-examples thereof, independently, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0168] 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 sub-embodiment thereof, an enantiomer, a diastereomer, a rotation isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0169] In Example 24, the present invention provides methods for treating pain, cough or pruritus, which methods comprise administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of Examples 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, an enantiomer, a diastereomer, a rotational isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0170] In embodiment 25, the present invention provides a method according to 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.

[0171] In embodiment 26, the present invention provides a method according to embodiment 24, wherein the cough is selected from post-viral cough, viral cough or acute viral cough. See Dib-Hajj. et al., "The Na V 1.7 sodium channel:from molecule to man[Na V 1.7 Sodium channels: from molecules to humans]”, Nature Reviews Neuroscience (2013), 14, 49-62.

[0172] In Example 27, the present invention provides a method for preparing an intermediate compound for preparing a compound of formula (I), wherein the intermediate compound has formula (A):

[0173] wherein R is a halogen group;

[0174] The method includes:

[0175] 1) making a trans-olefin compound having the formula (B):

[0176] wherein R is a halogen group; and R 1 is a C1-C6 alkyl group;

[0177] reacting with UV light or near-UV light; to form a cis-olefin compound (C); and

[0178] 2) reacting the compound (C) with a chiral acid in an organic solvent to form the compound having the formula (A).

[0179] In embodiment 28, the present invention provides the method according to embodiment 27, wherein the chiral acid is a phosphochiral acid.

[0180] In embodiment 29, the present invention provides the method according to embodiment 27, wherein the chiral acid is (S)-TRIP having the formula:

[0181]

[0182] In embodiment 30, the present invention provides the method according to embodiment 27, wherein the organic solvent is dichloromethane.

[0183] In embodiment 31, the present invention provides the method according to embodiment 27, wherein R is bromine.

[0184] In embodiment 32, the present invention provides the method according to embodiment 27, wherein said R 1 is ethyl; wherein the compound having formula (B) has the following formula:

[0185]

[0186] In embodiment 33, the present invention provides the method according to embodiment 27, wherein in reaction (2), the P-atropisomer of the compound having formula (A) is selectively formed.

[0187] In embodiment 34, the invention provides the method according to embodiment 27, wherein the compound having formula (A) is in the compound having formula (I):

[0188] or a pharmaceutically acceptable salt thereof for use as an intermediate compound,

[0189] in:

[0190] R 1 is a saturated or partially saturated 4-membered monocyclic ring; or a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered bicyclic ring; wherein the monocyclic ring or bicyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; and wherein the monocyclic ring or bicyclic ring is surrounded by 0, 1, 2, or 3 R selected from the following 1a Group substitution: hydroxyl, halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, -OC 1-4 Alkyl, -OC 1-8 Haloalkyl, -C(=O)C 1-4 Alkyl, -OC(=O)C 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, or -N(C 1-4 Alkyl)C 1-4 alkyl;

[0191] R 2 H, halogen, C 1-6 Alkyl, or C 1-6 Haloalkyl;

[0192] R 3 It is C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, or -CN;

[0193] R 4 is a 5- to 6-membered heteroaryl group;

[0194] R 6 and R 7 are each hydrogen; and

[0195] R 5a , R 5b , R 5c , R 5d , and R 5e are each independently hydrogen or halo; and

[0196] wherein the P-atropisomer of the compound of formula (I) is selectively formed. DETAILED DESCRIPTION

[0197] The present invention provides a compound of formula (I) as defined above, its enantiomer, diastereomer, atropisomer, mixture thereof, or a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition comprising a compound of formula (I), its enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a method of using a compound of formula (I), its enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof to treat a disease and / or condition such as pain.

[0198] The term "C α-β "Alkyl" means an alkyl group containing a minimum of α and a maximum of β carbon atoms in a branched or linear relationship or any combination of the two, wherein α and β represent integers. The designation C0 alkyl indicates a direct bond. C 1-6 Examples of alkyl groups include, but are not limited to, the following:

[0199]

[0200] The term "halo" or "halogen" means a halogen atom selected from F, Cl, Br or I.

[0201] The term "C α-β "Haloalkyl" means an alkyl group as defined herein in which at least one of the hydrogen atoms has been replaced by a halogen atom as defined herein. Common C α-β Haloalkyl is C 1-3 Fluoroalkyl. Common C 1-3 An example of a fluoroalkyl group is -CF3.

[0202] The term "heteroatom" as used herein means an oxygen, nitrogen or sulfur atom.

[0203] As used herein, the term "monocyclic" means a group characterized by a single ring. The monocyclic ring can be a carbocyclic ring (all ring atoms are carbon) or a heterocyclic ring (in addition to carbon atoms, the ring atoms also include at least 1 heteroatom, such as 1, 2 or 3 heteroatoms, such as N, O or S). Examples of monocyclic rings include, but are not limited to, cyclobutyl, cyclopentyl or cyclohexyl.

[0204] As used herein, the term "bicyclic" means a group characterized by two connected rings. Bicyclic can be a carbocyclic ring (all ring atoms are carbon) or a heterocyclic ring (in addition to carbon atoms, the ring atoms also include at least one heteroatom, such as 1, 2 or 3 heteroatoms, such as N, O or S). The two rings can be aliphatic (e.g., decalin and norbornane), or can be aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin). Bicyclic includes (a) spirocyclic compounds, in which the two rings share only one single atom (spiro atom, which is usually a quaternary carbon). Examples of spirocyclic compounds include, but are not limited to:

[0205]

[0206] or

[0207] (b) Fused bicyclic compounds, where the 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, but are not limited to:

[0208] as well as

[0209] (c) Bridged bicyclic compounds, in which two rings share three or more atoms, with the two bridgehead atoms separated by a bridge comprising at least one atom. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be considered a pair of cyclopentane rings, each ring sharing three of their five carbon atoms. Examples of bridged bicyclic rings include, but are not limited to:

[0210]

[0211] The term "aryl" means a cyclic aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Common aryl groups are six- to thirteen-membered rings.

[0212] The term "heteroaryl" means a cyclic aromatic hydrocarbon in which one or more carbon atoms of the aryl group have been replaced by a heteroatom. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, indolyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, naphthyridinyl, quinoxalinyl, isothiazolyl and benzo[b]thienyl. Common heteroaryl groups are five- to thirteen-membered rings containing from 1 to 4 heteroatoms. Heteroaryl groups that are five- and six-membered rings containing from 1 to 3 heteroatoms are particularly common.

[0213] The term "saturated, partially saturated or unsaturated" includes substituents saturated with hydrogen, substituents fully unsaturated with hydrogen and substituents partially saturated with hydrogen.

[0214] The term "pharmaceutically acceptable salt" means a salt prepared by conventional means and is well known to those skilled in the art. "Pharmaceutically acceptable salts" include alkaline salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid, and the like. For additional examples of "pharmaceutically acceptable salts", Berge et al., J. Pharm. Sci. [Journal of Pharmaceutical Sciences] 66: 1 (1977).

[0215] The term "substituted" means that a hydrogen atom on a molecule or group is replaced by a group or atom other than hydrogen. Typical substituents include: halogen, C 1-8 Alkyl, hydroxyl, C 1-8 Alkoxy, -NR x R x , nitro, cyano, halogenated or perhalogenated C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, -SR x 、-S(=O)2R x 、-C(=O)OR x 、-C(=O)R x , where each R x is independently hydrogen or C1-C8 alkyl. It should be noted that when the substituent is -NR x R x When R x The groups may be linked together with the nitrogen atom to form a ring.

[0216] The group or atom replacing a hydrogen atom is also called a substituent.

[0217] Any particular molecule or group may have one or more substituents, depending on the number of hydrogen atoms that may be replaced.

[0218] The term "unsubstituted" refers to hydrogen atoms on a molecule or group.

[0219] The symbol "-" represents a covalent bond and can also be used in a group to indicate the point of attachment to another group. In chemical structures, this symbol is often used to represent a methyl group in a molecule.

[0220] The term "leaving group" generally refers to a group that is easily displaced by a nucleophile (such as an amine, thiol or alcohol nucleophile) or by a metal reagent (such as boric acid or borate) under transition metal catalyzed coupling conditions. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflate, tosylate, etc. Preferred leaving groups are indicated herein where appropriate.

[0221] The term "protecting group" generally refers to a group well known in the art, which is used to prevent selected reactive groups such as carboxyl, amino, hydroxyl, sulfhydryl, etc. from undesirable reactions, such as nucleophilic, electrophilic, oxidative, reduction, etc. Preferred protecting groups are indicated in this article when appropriate. Examples of amino protecting groups include but are not limited to aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkyloxycarbonyl, silyl, etc. Examples of aralkyl include but are not limited to benzyl, o-methylbenzyl, trityl and diphenylmethyl, which can be optionally substituted by halogen, alkyl, alkoxy, hydroxyl, nitro, acylamino, acyl, etc. and salts (such as phosphonium salts and ammonium salts). Examples of aryl include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl, etc. Examples of cycloalkenylalkyl or substituted cycloalkenylalkyl groups preferably have 6 to 10 carbon atoms, including but not limited to cyclohexenylmethyl, etc. Suitable acyl, alkoxycarbonyl and aralkyloxycarbonyl include benzyloxycarbonyl, tert-butoxycarbonyl, isobutyloxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, etc. A mixture of protecting groups can be used to protect the same amino group, such as primary amino groups can be protected by both aralkyl and aralkyloxycarbonyl. Amino protecting groups can also form heterocycles with the nitrogen to which they are attached, for example, 1,2-bis(methylene)benzene, phthalimide, succinimidyl, maleimido, etc., and wherein these heterocyclic groups can further include adjacent aryl and cycloalkyl rings. In addition, heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimide. Amino groups can also be protected from undesirable reactions, such as oxidation, by forming addition salts (such as hydrochloride, p-toluenesulfonic acid, trifluoroacetic acid, etc.). Many amino protecting groups are also suitable for protecting carboxyl, hydroxyl and sulfhydryl groups. For example, aralkyl. Alkyl groups are also suitable for protecting hydroxyl and sulfhydryl groups, such as tert-butyl.

[0222] The protecting group is removed under conditions that will not affect the remainder of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis, etc. A preferred method involves removing the protecting group, for example by utilizing palladium carbon hydrogenolysis in a suitable solvent system (such as alcohol, acetic acid, etc. or a mixture thereof) to remove the benzyloxycarbonyl group. The 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 dichloromethane). The resulting amino salt can be easily neutralized to obtain free amine. The carboxyl protecting group (such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl, etc.) can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.

[0223] The present invention also contemplates prodrugs of the compounds of the present invention. Prodrugs are active or inactive compounds that are chemically modified to compounds of the present invention by physiological effects in vivo such as hydrolysis, metabolism, etc. after the prodrug is administered to a patient. The suitability and techniques for preparing and using prodrugs are well known to those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson and Tunek, Drug Metabolism Reviews [Drug Metabolism Review] 165 (1988) and Bundgaard, Design of Prodrugs [Prodrug Design], Elsevier (1985). Examples of masked carboxylate anions include a variety of 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 which are cleaved in vivo by esterases, releasing the free drug and formaldehyde (Bundgaard J. Med. Chem. 2503 (1989)). Similarly, drugs containing acidic NH groups (e.g., imidazoles, imides, indoles, etc.) have been masked as N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4 / 11 / 81) discloses Mannich base hydroxamic acid prodrugs, their preparation and use.

[0224] The term "therapeutically effective amount" means an amount of a compound that improves, reduces or eliminates one or more symptoms of a particular disease or condition or prevents or delays the onset of one or more symptoms of a particular disease or condition.

[0225] 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.

[0226] The term "pharmaceutically acceptable" means that the substance in question, such as a compound of formula (I), or a salt of a compound of formula (I), or a formulation containing a compound of formula (I), or a specific excipient, is suitable for administration to a patient.

[0227] The terms "treating," "treat," or "treatment" and such include preventative (eg, prophylactic) and palliative treatment.

[0228] The term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient other than the active pharmaceutical ingredient (API) that is typically incorporated for formulation and / or administration to a patient.

[0229] The compounds of the present invention are administered to the patient in a therapeutically effective amount. These compounds may be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, these compounds or compositions may be administered simultaneously, for example, by multiple bolus injections (e.g., by a series of tablets), or delivered substantially uniformly over a period of time using, for example, transdermal delivery. It should also be noted that the dosage of the compound may vary over time.

[0230] In addition, the compounds of the present invention can be administered alone, with other compounds of the present invention, or in combination with other pharmaceutically active compounds. Other pharmaceutically active compounds may be intended to treat the same disease or condition as the compounds of the present invention or different diseases or conditions. If the patient will receive or is receiving a variety of pharmaceutically active compounds, these compounds can be administered simultaneously or sequentially. For example, in the case of tablets, the active compound can be found in one tablet or in a plurality of tablets separated, and the tablet can be administered once or sequentially in any order. In addition, it should be appreciated that the composition can be in different forms. For example, one or more compounds can be delivered by tablets, while another compound is administered as a syrup by injection or oral administration. All combinations, delivery methods, and administration sequences are encompassed.

[0231] The compounds of the present invention can be used in the manufacture of a medicament for treating diseases and / or conditions mediated by Nav1.7, such as pain, chronic cough or pruritus.

[0232] Pain is typically divided into the following major types: chronic pain and acute pain based on the duration of pain. Typically, chronic pain lasts longer than 3 months. Examples of chronic pain include pain associated with rheumatoid arthritis, osteoarthritis, lumbosacral radiculopathy, or cancer. Chronic pain also includes primary pain, which is pain without an identified cause. An example of primary pain is fibromyalgia.

[0233] Another type of pain is nociceptive pain. Nociceptive pain is caused by the stimulation of peripheral nerve fibers in response to highly noxious events, such as thermal, mechanical, or chemical stimuli.

[0234] Yet another type of pain is neuropathic pain. Neuropathic pain is pain caused by an injury or disease that affects part of the nervous system. Phantom limb pain is a type of neuropathic pain. In phantom limb pain, the body perceives pain coming from a part of the body that is no longer there. For example, a person who has had a leg amputated may feel pain in the leg even though the leg is no longer there.

[0235] In one embodiment of the methods of treatment provided by the present invention using a compound of formula (I) or a pharmaceutically acceptable salt thereof, the disease is chronic pain. On the other hand, chronic pain is associated with, but is not limited to, post-herpetic neuralgia (shingles), rheumatoid arthritis, osteoarthritis, diabetic neuropathy, complex regional pain syndrome (CRPS), pain caused by cancer or chemotherapy, chronic back pain, phantom limb pain, trigeminal neuralgia, HIV-induced neuropathy, cluster headache disorder and migraine, primary erythromelalgia, and paroxysmal extreme pain disorder.Other indications for Nav1.7 inhibitors include, but are not limited to, depression (Morinville et al., J Comp Neurol., 504:680-689 (2007)), bipolar disorder and other CNS disorders (Ettinger and Argoff, Neurotherapeutics, 4:75-83 (2007)), epilepsy: supra and Gonzalez, Termin, Wilson, Methods and Principles in Medicinal Chemistry, 29:168-192 (2006)), multiple sclerosis (Waxman, Nature Neurosci. [Nature Neuroscience] 7:932-941 (2006)), Parkinson's disease (Do and Bean, Neuron [Neuron] 39:109-120 (2003); Puopolo et al., J. Neurosci. [Journal of Neuroscience] 27:645-656 (2007)), restless legs syndrome, ataxia, tremor, muscle weakness, dystonia, tetanus (Hamann M., et al., Exp. Neurol. [Experimental Neurology] 184 (2): 830-838, 2003), anxiety, depression: McKinney BC, et al., Genes Brain Behav. [Genes, Brain and Behavior] 7 (6): 629-638, 2008), learning and memory, cognition (Woodruff-Pak DS, et al., Behav. Neurosci. 120(2):229-240, 2006), arrhythmias and fibrillation, contractions, congestive heart failure, sick sinus syndrome (Haufe V., et al., J Mol. Cell Cardiol. 42(3):469-477, 2007), schizophrenia, post-stroke neuroprotection, 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)).

[0236] Another aspect of the invention relates to a method of treating acute and / or chronic inflammatory and neuropathic pain, dental pain, orthostatic headache, migraine, cluster headache, mixed vascular and non-vascular syndrome, tension headache, systemic 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 Pain, diabetic neuropathy pain, causalgia, sympathetic maintenance pain, deafferentation pain syndrome, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbance of visceral activity at the respiratory tract, urogenital tract, gastrointestinal tract or vascular area, trauma, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulcers, duodenal ulcers, diarrhea, gastric lesions induced by necrotic agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, the method comprising the step of administering a compound of the invention. A preferred type of pain to be treated is chronic neuropathic pain. Another preferred type of pain to be treated is chronic inflammatory pain.

[0237] In another aspect of the present invention, the compounds of this invention can be used in combination with other compounds for the treatment of pain. Examples of such other compounds include but are not limited to aspirin, celecoxib, hydrocodone, oxycodone, codeine, fentanyl, ibuprofen, ketoprofen, naproxen, acetaminophen, gabapentin and pregabalin. Examples of drug classes containing compounds that can be used in combination with the compounds of the present invention include non-steroidal anti-inflammatory compounds (NSAIDS), steroidal compounds, cyclooxygenase inhibitors and opioid analgesics.

[0238] The compounds of the invention may also be used to treat diabetes, obesity and / or promote weight loss.

[0239] The compounds of the present invention may be used in combination with other pharmaceutically active compounds. It should be noted that the term "pharmaceutically active compound" may include biologics such as proteins, antibodies and peptibodies.

[0240] Since one aspect of the present invention contemplates treating diseases / disorders with combinations of pharmaceutically active compounds that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of the present invention and a second pharmaceutical compound. The kit comprises a container for holding the separate compositions, such as a separate bottle or a separate foil bag. Other examples of containers include syringes, boxes, and bags. Typically, the kit comprises instructions for use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), when administered at different dosage intervals, or when the prescribing physician or veterinarian requires titration of the individual components in the combination.

[0241] The example of such a test kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used in the packaging of drug unit dosage forms (tablets, capsules, etc.). Blister packs are usually composed of a sheet of relatively hard material, and the sheet of this material is covered with a foil of a preferably transparent plastic material. In the packaging process, a groove is formed in the plastic foil. The groove has the size and shape of the tablet or capsule to be packaged. Then, the tablet or capsule is placed in the groove, and the sheet of relatively hard material is sealed on the plastic foil on the face of the foil opposite to the groove formation direction. As a result, the tablet or capsule is sealed in the groove between the plastic foil and the sheet. Preferably, the strength of the sheet makes it possible to form an opening at the groove in the sheet by manually applying pressure on the groove, so that the tablet or capsule can be taken out from the blister pack. Then the tablet or capsule can be taken out through the opening.

[0242] It may be desirable to provide a memory aid on the kit, for example in the form of numbers next to the tablets or capsules, where the numbers correspond to the days of the regimen on which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on a card, for example, as follows: "First week, Monday, Tuesday, ... and so on ... Second week, Monday, Tuesday ..." and so on. Other variations of memory aids will be readily understood. A "daily dose" can be a single tablet or capsule or several pills or capsules taken on a given day. Moreover, 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 several tablets or capsules, and vice versa. The memory aid should reflect this and help to correctly administer the active agent.

[0243] 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 promote compliance with the regimen. An example of such a memory aid is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of such a memory aid is a battery-powered microchip memory that is coupled to a liquid crystal readout or an audible reminder signal, for example, the readout or signal reads out the date of the last daily dose taken and / or reminds the date of the next dose.

[0244] If desired, the compounds of the present invention and other pharmaceutically active compounds can be administered to the patient orally, rectally, parenterally (e.g., intravenously, intramuscularly or subcutaneously), intracisternal, intravaginal, intraperitoneal, intravesical, topically (e.g., powders, ointments or drops), or as buccal or nasal sprays. All methods used by those skilled in the art to administer pharmaceutically active agents are contemplated.

[0245] Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Suitable fluidity can be maintained, for example, by using a coating such as lecithin, in the case of dispersions, by maintaining the desired particle size and by using a surfactant.

[0246] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Microbial contamination may be prevented by adding various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, etc.). It may also be desirable to include isotonic agents, such as sugar, sodium chloride, etc. The extended absorption of injectable pharmaceutical compositions may be achieved by using agents that delay absorption (e.g., aluminum monostearate and gelatin).

[0247] Solid dosage forms for oral administration include capsules, tablets, powders and granules. In such solid dosage forms, the active compound is mixed with: at least one inert conventional excipient (or carrier) (such as sodium citrate or dicalcium phosphate) or (a) fillers or extenders, such as starch, lactose, sucrose, mannitol and silicic acid; (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (a) solution retarders, such as paraffin; (f) absorption promoters, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin and bentonite; and (i) lubricants, such as 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 comprise buffering agents.

[0248] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose (lactose or milk sugar) and high molecular weight polyethylene glycols.

[0249] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other forms well known in the art. They can also contain opacifiers and can also have such compositions that they release one or more active compounds in certain parts of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. If appropriate, the active compound can also be in the form of microencapsulation with one or more of the above-mentioned excipients.

[0250] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, or mixtures of these substances, etc.

[0251] In addition to such inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or mixtures of these substances, etc.

[0252] Compositions for rectal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which 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 ingredients.

[0253] The dosage form for topical application of the compound of the present invention includes ointments, powders, sprays and inhalants. The active compound or multiple suitable compounds are mixed with a physiologically acceptable carrier and any preservative, buffer or propellant that may be needed under sterile conditions. Ophthalmic preparations, eye ointments, powders and solutions are also considered to be within the scope of the present invention.

[0254] The compounds of the present invention may be administered to a patient at a therapeutically effective dosage level. The specific dosage and dosage range that may be used depends on a number of factors, including the needs of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered.

[0255] The compounds of the present invention can be used as pharmaceutically acceptable salts, co-crystals, esters, amides or prodrugs. The term "salt" refers to inorganic and organic salts of the compounds of the present invention. These salts can be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound with its free alkali or acid form with a suitable organic or inorganic base or acid alone and separating the salt formed thereby. Representative salts include hydrobromate, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate and lauryl sulfonate etc. Salts can include alkali and alkaline earth metal based cations, such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. See, e.g., SM Berge, et al., "Pharmaceutical Salts," J Pharm Sci, 66: 1-19 (1977).

[0256] 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 aralkyl esters, such as benzyl esters. C1-C4 alkyl esters are generally used. Esters of the compounds of the present invention can be prepared according to methods well known in the art.

[0257] Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, C1-C8 alkyl primary amines and C1-C8 dialkyl secondary amines. In the case of secondary amines, the amine may also be in the form of a 5 or 6-membered heterocycloalkyl containing at least one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines 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 to those skilled in the art.

[0258] The term "prodrug" means a compound that is converted in vivo to produce a compound of the invention. The conversion can occur by a variety of mechanisms, such as by hydrolysis in the blood. A discussion of the use of prodrugs is provided in T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Volume 14 of the ACS Symposium Series and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987.

[0259] For illustration, if the compound of the invention contains a carboxylic acid functional group, the prodrug may comprise an ester formed by replacing the hydrogen atom of the acid group with a group such as (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, alkylamino) alkyl, N-(C1-C2) ... 2-3 ) alkyl, pyrrolidino (C 2-3 )alkyl or morpholinyl (C 2-3 )alkyl.

[0260] Similarly, if the compound of the invention contains an alcohol functional group, the prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as: (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanoyl, arylacyl and α-aminoacyl or α-aminoacyl-α-aminoacyl, wherein each α-aminoacyl group is independently selected from a natural L-amino acid, -P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2 or a glycosidic group (a group resulting from the removal of a hydroxyl group in the hemiacetal form of a carbohydrate).

[0261] Additionally, if a compound of the invention contains a sulfonamide moiety, a prodrug may be formed by replacing the sulfonamide N(H) with a group such as -CH2P(O)(O(C1-C6)alkyl)2 or -CH2OC(O)(C1-C6)alkyl.

[0262] The compounds of the present invention also include tautomeric forms of the prodrugs.

[0263] The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of these compounds and mixtures thereof (including racemic mixtures) are expected to form part of the present invention. In addition, the present invention encompasses all geometric and positional isomers. For example, if the compound contains a double bond or a disubstituted cycloalkyl, both cis and trans isomers (unless specific isomers are specified) and mixtures are considered. In compounds containing disubstituted cycloalkyls, cis and trans isomers refer to the relative positions of the substitutions. For example: (A) represents the trans-cyclobutyl isomer, since the -CF3 group is facing upward and the -CH3 group is facing downward, while (B) represents the cis-cyclobutyl isomer, since both the -CF3 group and the -CH3 group are facing downward.

[0264] Mixtures of stereoisomers, such as diastereomeric mixtures, can be separated into their individual stereochemical components on the basis of their physical chemical differences by known methods, such as chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound, such as an alcohol, separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.

[0265] Compounds of formula (I) may also exist as atropisomers. Atropisomers are compounds with the same structural formula, but they have a specific spatial configuration due to limited rotation around a single bond (due to steric hindrance on either side of the single bond). Atropisomerism is independent of the presence of stereo elements (such as asymmetric carbons). The terms "P atropisomer" or "M atropisomer" are used herein so that two atropisomers of the same pair can be clearly named. For example, the following intermediate compound having the following structure can be separated into a pair of atropisomers P and M by chiral column chromatography:

[0266]

[0267] The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrate), ethanol, etc. Both solvated and unsolvated forms are contemplated and encompassed by the present invention.

[0268] The compounds of the present invention may also exist in different tautomeric forms. All tautomers of the compounds of the present invention are contemplated. For example, all tautomeric forms of the tetrazole moiety are included in the present invention. Also, for example, all keto-enol or imine-enamine forms of the compound are included in the present invention. Other examples of tautomerism are as follows:

[0269]

[0270] Those skilled in the art will recognize that the compound names and structures contained herein may be based on specific tautomers of the compounds. Although names or structures for only specific tautomers may be used, the present invention is intended to encompass all tautomers unless otherwise specified.

[0271] The invention is also intended to encompass compounds synthesized in vitro using laboratory techniques such as those well known to synthetic chemists; or compounds synthesized using in vivo techniques such as via metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the invention may be synthesized using a combination of in vitro and in vivo techniques.

[0272] The present invention also includes isotopically labeled compounds, which are identical to those described herein, but which are due to the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H. 3 H. 13 C. 14 C. 15 N. 16 O. 17 O.31 P. 32 P. 35 S. 18 F and 36 Cl. In another aspect, the compounds of the invention contain one or more deuterium atoms (2H) in place of one or more hydrogen atoms.

[0273] Compounds of the invention containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled compounds of the invention (e.g., compounds into which radioactive isotopes such as 3 H and 14 C) can be used for drug and / or substrate tissue distribution assays. 3 H and carbon-14 14 C isotopes are particularly preferred. Further, heavier isotopes (such as deuterium, i.e. 2 H) substitution may provide certain therapeutic advantages derived from greater metabolic stability (e.g., extended in vivo half-life or reduced dosage requirements) and is therefore preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0274] The compounds of the present invention may exist in a variety of solid states, including crystalline states, and as an amorphous state. Different crystalline states (also referred to as polymorphs) and amorphous states of the compounds of the present invention are contemplated as part of the present invention.

[0275] All patents and other publications cited herein are incorporated by reference in their entirety.

[0276] The examples presented below illustrate specific embodiments of the present invention. These examples are representative and are not intended to limit the scope of the claims in any way.

[0277] It should be noted that when percentages (%) are used with respect to liquids, this is the volume percentage relative to the solution. When used with solids, this is the percentage relative to the solid composition. Materials obtained from commercial suppliers are generally used without further purification. Reactions involving air or moisture sensitive reagents are generally carried out under a nitrogen or argon atmosphere. Purity is measured using a high performance liquid chromatography (HPLC) system with UV detection at 254 nm and 215 nm (System A: HALO C8, 3.0x50 mm, 2.7 μm, 5% to 95% CH3CN in H2O (with 0.1% TFA) at 2.0 mL / min for 2.0 min) (Agilent Technologies, Santa Clara, CA). Silica gel chromatography generally uses pre-packed silica gel cartridges ( The results were obtained from a 3D scanning microscope at the ELISA facility in 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 in parts per million (ppm) downfield from tetramethylsilane (TMS) or other internal reference in the appropriate solvent as 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 spectrometry (MS) data were determined on an Agilent 1100 series (Agilent Technologies, Santa Clara, CA) LC / MS using UV detection at 254 nm and 215 nm and low-resonance electrospray mode (ESI).

[0278] The following abbreviations may be used in this article:

[0279] 2-PrOH Isopropyl alcohol

[0280] AgOTf Silver(I) trifluoromethanesulfonate

[0281] AIBN Azobisisobutyronitrile

[0282] aq. water-based

[0283] Bu Butyl

[0284] ca. about

[0285] Cm centimeters

[0286] CPhos 2-Dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl

[0287] DAST Diethylaminosulfur trifluoride

[0288] Dba Dibenzylideneacetone

[0289] DCM Dichloromethane

[0290] Deoxy-Fluor Bis(2-methoxyethyl)aminosulfur trifluoride

[0291] DIPEA N,N-Diisopropylethylamine

[0292] DMF N,N-Dimethylformamide

[0293] DMSO Dimethyl sulfoxide

[0294] ESI or ES Electrospray ionization

[0295] Et Ethyl

[0296] Et2O Diethyl ether

[0297] EtOAc Ethyl acetate

[0298] EtOH

[0299] G grams

[0300] H Hour

[0301] HPLC High Pressure Liquid Chromatography

[0302] IPA 2-Propanol

[0303] Kg kilogram

[0304] L Liter

[0305] LCMS Liquid chromatography mass spectrometry

[0306] LHMDS Lithium Hexamethyldisilazide

[0307] M Moore

[0308] m / z mass-to-charge ratio

[0309] Me Methyl

[0310] MeOH Methanol

[0311] Me-THF Methyltetrahydrofuran

[0312] Mg mg

[0313] MHz Megahertz

[0314] Min Minutes

[0315] mL or ml milliliters

[0316] Mmol millimole

[0317] Mol

[0318] MTBE Methyl tert-butyl ether

[0319] N Normal

[0320] NaOMe Sodium Methanol

[0321] n-Bu n-butyl

[0322] NEt3 Triethylamine

[0323] NMR Nuclear Magnetic Resonance

[0324] OAc Acetate

[0325] OTf trifluoromethanesulfonate

[0326] PFP-OH Pentafluorophenol

[0327] Ph Phenyl

[0328] PhMe Toluene

[0329] PMB 4-methoxybenzyl

[0330] Ppm parts per million

[0331] Pr Propyl

[0332] rac racemic

[0333] rt room temperature

[0334] sat. saturated

[0335] SFC Supercritical Fluid Chromatography

[0336] TBAF Tetra-n-butylammonium fluoride

[0337] TFA Trifluoroacetic acid

[0338] THF Tetrahydrofuran

[0339] Ti(OiPr)4 Titanium(IV) Isopropoxide

[0340] TLC Thin layer chromatography

[0341] TMS-CF3 (trifluoromethyl)trimethylsilane

[0342] wt% weight percentage

[0343] XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0344] XtalFluor-M Difluoro(morpholine)sulfonium tetrafluoroborate

[0345] The following compounds presented herein (as examples of the present invention) and intermediates thereof as the structural unit for preparing the compound provided by the invention can be manufactured by the various methods and synthetic strategies taught below. These compounds and other compounds provided by the invention can also be prepared using the method described in the International Publication No. WO 2014 / 201206 submitted on June 12, 2014, the specification of which is incorporated herein by reference in its entirety.

[0346] In addition, the inventors have developed a photochemical atropisomer selective ring closure to form N-arylquinolinone compounds. Specifically, the P-atropisomer compound 3 is selectively formed in the photochemical reaction of the present invention. The general representation of the photochemical steps of the present invention is as follows:

[0347]

[0348] The reaction relies on UV or near-UV light to excite the olefin 1; where R is a halide; and R 1 is a C1-C6 alkyl group; and induces cis-trans isomerization to instantaneously form 2; wherein R is a halide; and R 1 is a C1-C6 alkyl group. Preferably, R 1 is ethyl. The cis-olefin 2 can then be activated by the chiral acid (S)-TRIP to asymmetrically form the closed-ring quinolinone 3, wherein R is as defined above. Preferably, R is Br. Screening of chiral phosphoric acids shows 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 has also been demonstrated in a small photochemical flow reactor.

[0349] The photochemical procedure of the present invention works well without the presence of bulky rotation barrier substituents, such as tert-butyl, in the starting materials. In contrast, the novel photochemical procedure of the present invention has been demonstrated in the presence of much smaller methoxy groups in the starting materials. The mild reaction conditions further allow the preparation of compounds with low rotation barriers in a stereoselective manner.

[0350] Intermediate A: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dimethoxyphenyl Hydroquinoline-6-sulfonamide.

[0351]

[0352]

[0353] Step 1: 4-Bromo-2-iodoaniline

[0354] Iodine (368g, 1.45mol) was added to a solution of 4-bromo-aniline (500g, 2.90mol) in cyclohexane (2.5L), and the mixture was heated at 50°C. After 30min, the reaction mixture became uniform, and 30% aqueous hydrogen peroxide solution (250mL) was added to the reaction mixture. The reaction was heated at 50°C for 4h. The reaction was cooled to room temperature, diluted with ethyl acetate (5.0L) and washed with an aqueous sodium sulfite solution (2.5kg in 4.0L). The organic layer was washed with water (3.0L) and brine (3.0L), dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the initial product, which was purified by column chromatography (silica gel; mesh size 60-120, eluting 0-20% ethyl acetate and hexane) to obtain 4-bromo-2-iodoaniline (650g, 75%) as an off-white solid. TLC solvent system: 100% hexane. R of the product f : 0.6. MS (ESI, positive ion) m / z: 297.0 (M+1). 1 H NMR (400MHz, CDCl3) δ7.72 (d, J = 2.5 Hz, 1H), 7.23 (dd, J = 8.4, 2.1 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 4.09 (s, 2H).

[0355] Step 2: (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate

[0356] 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 min, followed by the addition of palladium acetate (28.8 g, 128.27 mmol). The reaction mixture was heated at 70 °C for 3 h. The reaction was stirred for 1 h. The CELITE bed was filtered and washed with ethyl acetate (2×500 mL). The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (silica gel; mesh size 60-120, eluting in hexanes 0-20% ethyl acetate) to obtain (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g, 77%) as a yellow solid. TLC solvent system: 20% ethyl acetate in hexanes. The R of the productf : 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 instead of ethyl acrylate to provide different esters. For example, methyl acrylate, propyl acrylate, butyl acrylate, etc. can be used instead of ethyl acrylate.

[0357] Step 3: (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate

[0358] 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 mins. 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 min. The reaction was cooled to RT, benzyl mercaptan (455.5 g, 3.67 mol) was added, and the reaction was heated at 80 °C for another 4 h. The reaction was cooled to room temperature and diluted with ethyl acetate (4.0 L). The mixture was filtered through diatomaceous earth, and the diatomaceous earth bed was washed with ethyl acetate (2×1.0 L). The filtrate was concentrated under reduced pressure to obtain the initial product, which was purified by chromatography (silica gel; mesh size 60-120, elution 0-40% ethyl acetate and petroleum ether) to obtain (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). 1H NMR (400MHz, DMSO) δ7.79 (d, J = 16.1Hz, 1H), 7.37 (d, J = 2.0Hz, 1H), 7.25-7.17 (m, 5H) 7.10 (dd, J = 8.4, 2.1Hz, 1H), 6. 61(d,J=8.3Hz,1H), 6.32(d,J=15.2Hz,1H), 5.75(s,2H), 4.20(q,J=7.2Hz,2H), 4.01(s,2H), 1.27(t,J=7.2Hz,3H).

[0359] Step 4: 1-Bromo-2-fluoro-4-iodo-5-methoxybenzene

[0360] Silver trifluoromethanesulfonate (686.0g, 2.68mol) was added to a solution of 2-bromo-1-fluoro-4-methoxybenzene (500.0g, 2.44mol) in DCM (5.0L), and the reaction mixture was stirred for 20min. Iodine (678.0g, 2.68mol) was added to the reaction and the mixture was stirred at room temperature for 16h. The mixture was diluted with DCM (3.0L) and filtered through diatomite. The diatomite bed was washed with DCM (2×1.0L), and the filtrate was washed with 20% aqueous sodium thiosulfate (3.0L) and saturated sodium bicarbonate aqueous solution (3.0L). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the initial product, which was purified by chromatography (silica gel; mesh size 60-120, eluting 0-5% ethyl acetate and petroleum ether) to obtain 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (720g, 87%) as an off-white solid. TLC solvent system: 100% hexane. f : 0.6. MS (ESI, positive ion) m / z: 331.0 (M+1). 1 H NMR (400MHz, CDCl3) δ7.55 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 5.6 Hz, 1H), 3.89 (s, 3H).

[0361] Step 5: (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate

[0362] 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 mins. 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 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (2.0 L) and filtered through celite. The filtrate was concentrated under reduced pressure to obtain the initial product, which was purified by stirring with 5% ethyl acetate (3.0 L) in hexanes for 30 min and filtered to obtain (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (350 g, 71%) as a yellow solid. TLC solvent system: 30% ethyl acetate in 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: No NH protons were observed.

[0363] Step 6: 6-(Benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one

[0364] 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 h. The reaction mixture was cooled to rt and then concentrated under reduced pressure to obtain the initial product, which was purified by stirring with 5% ethyl acetate (1.0 mL) in hexanes and filtered to obtain 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 productf : 0.3. MS (ESI, positive ion) m / z; 470.0 (M+1). 1 H NMR (400MHz, DMSO) δ7.92(d,J=9.1Hz,1H),7.79(d,J=1.7Hz,1H),7.65(d,J=6.1Hz,1H),7.57(d,J=8 .8Hz,1H),7.40-7.22(m,6H),6.68(d,J=9.6Hz,1H),6.56(d,J=8.8Hz,1H),4.24(s,2H),3.69(s,3H).

[0365] Alternatively, the P-atropisomer title compound of step 6 can be selectively prepared from (E)-3-[5-benzylsulfanyl-2-(4-bromo-5-fluoro-2-methoxy-anilino)phenyl]prop-2-enoic acid ethyl ester starting material by using a photochemical route as described in the following procedure:

[0366] Photochemical preparation method 1:

[0367]

[0368] To a flask was added (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 h. 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 any precipitate and then allowed to cool to room temperature overnight. The resulting slurry was cooled to 0° C. for 2 h 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 (2.12 g, 89 wt%, 4.0 mmol) as a tan solid. 1 H NMR (300MHz, DMSO-d6) δ7.95(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). The ee was determined by chiral normal phase chromatography (CHIRALPAKIC-3, 4.6 x 150 x 3) with a mobile phase of 60% heptane / 40% (0.2% ethanesulfonic acid in ethanol) v / v at a flow rate of 1.5 mL / min.

[0369] Photochemical preparation method 2:

[0370]

[0371] To a flask was added ethyl (E)-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 N2. The reaction solution was warmed to 30°C and stirred. The solution was recirculated via a peristaltic pump at a flow rate of 50 g / min through a 1 / 8" FEP tube (approximately 10 mL internal volume) exposed to 457 nm LED light for 10 h. The reaction solution was concentrated to a yellow-brown solid and then heated to 40°C. i The slurry was slurried in PrOAc (250 mL) at 30 °C for 30 min. Heptane (500 mL) was added to the slurry over 30 min. The slurry was cooled to 0 °C over 2 h and then placed in a -20 °C freezer for 36 h. The slurry was filtered and washed with 10% v / v i The filter cake was rinsed with PrOAc / heptane (2 x 150 mL). The solid was dried in a vacuum oven to afford (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.

[0372] Steps 7 and 8: Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate

[0373] 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, keeping the internal temperature below 5°C. The resulting suspension was stirred at 0-5°C under nitrogen for 45 min. A solution of pentafluorophenol (127.2 g, 690.95 mmol) in acetonitrile (200 mL) was then added over 5 min, followed by NEt3 (307.7 mL, 2.12 mol) over 20 min, keeping 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 obtain the initial product, which was purified by stirring with isopropanol: hexane (1:1, 1.0 L) and filtered to obtain 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (190 g, 60%) as a white solid. TLC solvent system: 30% ethyl acetate in petroleum ether, R of the product f : 0.4. MS (ESI, positive ion) m / z; 594.2 (M+1). 1 H-NMR(400MHz,DMSO)δppm 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).

[0374] Step 9: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0375] Racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (76.90 g) was separated by Chiralcel OJ column (40% MeOH / 60% CO2) to give (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester and (M)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester as pale yellow flocculent solids. Peak 1 data: m / z (ESI) 594.0 (M+H)+ Peak 2 data: m / z (ESI) 594.0 (M+H) + .

[0376] Step 10: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0377] A solution of (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (6.00 g, 10.10 mmol) and 3-aminoisoxazole (0.821 mL, 11.11 mmol) in THF (200 mL) was cooled to 0 ° C in a 250-mL round-bottom flask, and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 21.20 mL, 21.20 mmol) was added dropwise. After the yellow solution was stirred at 0 ° C for 15 min, it was quenched with 1N HCl at 0 ° C and extracted three times with EtOAc. The organic extracts were combined, dried over MgSO4, filtered and concentrated to a light tan residue. Et2O was added, and the slurry was triturated and sonicated. Filtration gave an off-white solid, which was washed twice with Et2O and dried in vacuo to give 3.88 g of the product as an off-white solid. The filtrate was concentrated in vacuo and purified by column chromatography (12 g silica gel, 35% to 100% EtOAc / heptane gradient) to give another 1.36 g of the product as a light yellow flocculent solid. A total of 5.24 g of (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide was obtained. m / z(ESI)494.1(M+H) + .

[0378] Intermediate A: (3-(tert-butyl)cyclobutyl)zinc(II) iodide, 0.2 M in THF

[0379]

[0380] Lithium chloride (96 mg, 2.3 mmol) was loaded into a three-necked oven-dried round-bottom flask equipped with a magnetic stirring bar and a rubber septum. The container was heated with a heat gun under vacuum for 10 min and backfilled with nitrogen after cooling to room temperature. Zinc (148 mg, 2.27 mmol) was added. The container was heated with a heat gun under vacuum for 10 min again and backfilled with nitrogen after cooling to room temperature. THF (3.4 mL) and 1,2-dibromoethane (4.9 μL, 0.057 mmol) were added by syringe, and the reaction mixture was heated at 60 ° C until bubbling occurred. 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 by syringe. The reaction mixture was heated at 60 ° C for 20 min, 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 h. The reaction mixture was allowed to stand at room temperature for 1 h. 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 THF, 2.3 mL, 1.1 mmol) until the orange color disappeared. 0.06 mL of the solution was used, corresponding to a concentration of 0.2 M.

[0381] Intermediate B: 5,8-Dioxaspiro[3.4]octan-2-ylzinc(II) bromide, 0.1 M in THF

[0382]

[0383] Lithium chloride (0.878 g, 20.72 mmol) was loaded into an oven-dried round-bottom flask equipped with a magnetic stirring bar and a rubber septum. The container was heated with a heat gun under vacuum for 10 min and backfilled with nitrogen after cooling to room temperature. Zinc (1.355 g, 20.72 mmol) was added. The container was heated with a heat gun under vacuum for 10 min again and backfilled with nitrogen after cooling to room temperature. THF (13.8 mL) and 1,2-dibromoethane (0.045 mL, 0.518 mmol) were added by syringe, and the reaction mixture was heated at 60 ° C until bubbling occurred. 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 by syringe. The reaction mixture was heated at 60 ° C for 20 min, 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 for 16 h at 50° C. The resulting solution was used as is.

[0384] Intermediate C: (3-(Trifluoromethyl)cyclobutyl)zinc(II) bromide, 0.15 M in THF

[0385]

[0386] 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).

[0387] Intermediate D: (P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0388]

[0389] Step 1: (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl)acrylate

[0390] 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). A reflux condenser was connected and the flask was moved down to a heating bath at 110° C. After 2 h, an additional portion of cesium carbonate (1.4 g) was added and the bath temperature was raised 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 the aid of EtOAc. The filtrate was concentrated. The oily residue was taken up in 2-PrOH. The mixture is concentrated to obtain a yellow solid in which there are some oily solids. The mixture is absorbed in 2-PrOH to obtain a suspension, and the suspension is stirred for 16h. The mixture is filtered, and the filtered solid is washed with 2-PrOH (3x). The collected solid is dried for 15min under N2 flow on the filter, and (E) -3- (5- (benzylthio) -2- ((4- bromo-2-methoxyphenyl) amino) phenyl) ethyl acrylate (3.136g, 6.29mmol, 83% yield) is obtained as a bright yellow solid. 1H NMR (400MHz, DMSO-d6) δppm7.72(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) + .

[0391] Step 2: 6-(Benzylthio)-1-(4-bromo-2-methoxyphenyl)quinolin-2(1H)-one

[0392] 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 %, 0.271 mL, 1.256 mmol in MeOH) was added. A reflux condenser was attached and the flask was moved down to a 75°C heating bath. The bath quickly surged to about 80°C-85°C but returned to 70°C-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 silica gel chromatography (50-g SNAP Ultra column, 25-g silica loaded 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)δppm 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) + .

[0393] Step 3: 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0394] 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 min, and then 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.813 g, 4.12 mmol) was added in one portion. After 20 min, another portion of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.813 g, 4.12 mmol) was added in one portion. After another 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 (2.190mL, 15.71mmol) was added dropwise in 30s, and the mixture was then stirred for 20min. 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 silica gel chromatography (50-g SNAP Ultra columns, 25-g silica gel loaded columns, 10%-60% EtOAc / heptanes). 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (1.644g, 2.85mmol, 72.6% yield) was isolated as white foam. 1 H NMR(400MHz,DMSO-d6)δppm 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=1.9Hz, 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) + .

[0395] 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

[0396] Racemic 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (3000 g) was separated using a Regis Whelk-O(S,S), 3x15 cm column in a 5600-g batch. The mobile phase was run under isocratic conditions; supercritical CO2 with 60% [2:3 isopropanol: dichloromethane]; flow rate: 150 mL / min. The first eluting peak was designated as (P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (1459.2 g). The second eluting peak was designated as (M)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (1492.9 g).

[0397] Step 5: (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0398] 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, 2x15 cm column. The mobile phase was run under isocratic conditions; supercritical CO2 with 60% isopropanol; flow rate: 80 mL / min. The first eluting peak was designated as (M)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (150 mg). The second eluting peak was designated as (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (154 mg). Data for Peak 1: 1 HNMR (400MHz, acetonitrile-d3) δppm 8.65-8.94 (m, 1H), 8.37 (d, J = 1.9 Hz, 1H), 8.23 ​​(d, J = 2.3 Hz, 1H), 7.97 (d, J = 9.3 Hz, 1H), 7.78 (dd, J = 8.9, 2.3 Hz, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 8.3, 2.1 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 6.70-6.80 (m, 2H), 6.45 (d, J = 1.9 Hz, 1H), 3.69 (s, 3H). m / z (ESI, positive ion) 476.0 (M+H) + . Data for Peak 2: 1H NMR (400 MHz, acetonitrile-d3) δ ppm 8.72-8.87 (m, 1H), 8.37 (d, J = 1.7 Hz, 1H), 8.23 ​​(d, J = 2.1 Hz, 1H), 7.97 (d, J = 9.5 Hz, 1H), 7.78 (dd, J = 9.0, 2.2 Hz, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 8.3, 1.9 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 6.69-6.80 (m, 2H), 6.45 (d, J = 1.9 Hz, 1H), 3.69 (s, 3H). m / z (ESI, positive ion) 476.0 (M+H) + .

[0399] Intermediate E: N-(4-methoxybenzyl)isoxazol-3-amine

[0400]

[0401] In 20-L round-bottom flask, add isoxazole-3-amine (150g, 1784mmol) and 4-methoxybenzaldehyde (274g, 2016mmol) in methanol (9000mL), water (150mL) and acetic acid (101mL) and stir at room temperature for 15min.Then add dichloro platinum dioxide (17.74g, 89mmol) and phenylsilane (193g, 1784mmol).The reaction mixture is stirred at room temperature for 16h.After the reaction is completed, the reaction mass is concentrated, diluted with dichloromethane (5000mL) and washed with saturated NaHCO solution (2000mL).The organic layer is washed with water (2000mL), and dried over NaSO.The solution is filtered and concentrated in a vacuum to obtain the initial product in the form of an orange solid. The initial product was adsorbed onto a silica gel plug and purified by column chromatography (silica gel, 60-120 mesh) eluting with a gradient of 0% to 30% EtOAc in hexanes to afford N-(4-methoxybenzyl)isoxazol-3-amine (272 g, 1332 mmol, 75% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δppm 8.36 (d, J = 1.8 Hz, 1H), 7.16-7.37 (m, 2H), 6.71-6.97 (m, 2H), 6.56 (t, J = 6.0 Hz, 1H), 5.97 (d, J = 1.8 Hz, 1H), 4.18 (d, J = 6.0 Hz, 2H), 3.73 (s, 3H). m / z (ESI, positive ion) 205.1 (M+H) + .

[0402] Intermediate F: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0403]

[0404] Step 1: 4-Bromo-2-iodoaniline

[0405] 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 min, the reaction mixture became homogeneous. A 30% aqueous solution of hydrogen peroxide (250 mL, Spectrochem) 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 an aqueous sodium sulfite solution (2.5 Kg in 4.0 L). The organic layer was washed with water (3.0 L) and brine (3.0 L), dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 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. R of the product f : 0.6. MS (ESI, positive ion) m / z: 297.0 (M+1). 1 H NMR (400MHz, CDCl3) δ7.72 (d, J = 2.5 Hz, 1H), 7.23 (dd, J = 8.4, 2.1 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 4.09 (s, 2H).

[0406] Step 2: (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate

[0407] To a solution of 4-bromo-2-iodoaniline (750 g, 2.51 mol, 1.0 eq.) in DMF (5.0 L) was added ethyl acrylate (277 g, 2.76 mol, 1.1 eq., Avra) and sodium bicarbonate (680 g, 6.29 mol, 2.5 eq.). The reaction mixture was degassed with nitrogen for 20 min, followed by addition of palladium acetate (28.8 g, 128.27 mmol, 0.05 eq., Hindustan Platinum). The reaction mixture was heated at 70 °C for 3 h. The reaction was stirred for 1 h. Filter and The bed was washed with ethyl acetate (2×500 mL). The filtrate was concentrated under reduced pressure to obtain the initial product, which was purified by column chromatography (silica gel; mesh size 60-120, eluting in hexanes 0-20% ethyl acetate) to obtain (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g, 77.0%) as a yellow solid. TLC solvent system: 20% ethyl acetate in hexanes. The R of the product f : 0.4. MS (ESI, positive ion) m / z: 270.2 (M+1). 1 H NMR (400MHz, DMSO) δ7.75(d,J=16.1Hz,1H),7.57(d,J=2.0Hz,1H),7.16(dd,J=9.1,2.4Hz,1H),6.6 6(d,J=8.6Hz,1H), 6.43(d,J=8.6Hz,1H), 5.81(s,2H), 4.20(q,J=7.2Hz,2H), 1.27(t,J=7.2Hz,3H).

[0408]

[0409] Step 3: (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate

[0410] To a solution of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g, 2.29 mol, 1.0 eq) in 1,4-dioxane (4.0 L) was added DIPEA (1.26 L, 8.88 mol, 3.9 eq, GLR) and it was degassed with nitrogen for 20 mins. XantPhos (92.9 g, 106 mmol, 0.05 eq, GLR) and tris(dibenzylideneacetone)dipalladium (84 g, 91.0 mmol, 0.04 eq, Hindustan Platinum) were added to the reaction mixture. The mixture was purged with nitrogen and heated to 80 °C for 30 mins. The reaction was cooled to RT and benzyl mercaptan (455.5 g, 3.67 mol, 1.6 eq, Alfa Aesar) was added and the reaction was heated at 80 °C for another 4 h. The reaction was cooled to room temperature and diluted with ethyl acetate (4.0 L). The mixture was washed with Filter and The bed was washed with ethyl acetate (2 x 1.0 L). The filtrate was concentrated under reduced pressure to obtain the initial product, which was purified by chromatography (silica gel; mesh size 60-120, elution 0-40% ethyl acetate and petroleum ether) to obtain (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 productf : 0.4. MS (ESI, positive ion) m / z: 314.1 (M+1). 1 H NMR (400MHz, DMSO) δ7.79 (d, J = 16.1Hz, 1H), 7.37 (d, J = 2.0Hz, 1H), 7.25-7.17 (m, 5H) 7.10 (dd, J = 8.4, 2.1Hz, 1H), 6. 61(d,J=8.3Hz,1H), 6.32(d,J=15.2Hz,1H), 5.75(s,2H), 4.20(q,J=7.2Hz,2H), 4.01(s,2H), 1.27(t,J=7.2Hz,3H).

[0411]

[0412] Step 4: 1-Bromo-2-fluoro-4-iodo-5-methoxybenzene

[0413] To a solution of 2-bromo-1-fluoro-4-methoxybenzene (500.0 g, 2.44 mol, 1.0 eq.) in DCM (5.0 L) was added silver trifluoromethanesulfonate (686.0 g, 2.68 mol, 1.1 eq., Angene) and the reaction mixture was stirred for 20 mins. Iodine (678.0 g, 2.68 mol, 1.1 eq.) was added to the reaction and the mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM (3.0 L) and filtered. Filter. The celite bed was washed with DCM (2×1.0 L), and the filtrate was washed with 20% aqueous sodium thiosulfate (3.0 L) and saturated aqueous sodium bicarbonate solution (3.0 L). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the initial 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) δ7.55 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 5.6 Hz, 1H), 3.89 (s, 3H).

[0414] Step 5: (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate

[0415] To a solution of ethyl (E)-3-(2-amino-5-(benzylthio)phenyl)acrylate (300 g, 958.1 mmol, 1.0 eq.) and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (348.0 g, 1051.6 mmol, 1.1 eq.) in toluene (2.5 L) was added Cs2CO3 (468 g, 1436.3 mmol, 1.5 eq., Spectrochem) and the mixture was degassed with nitrogen for 20 mins. Pd2(dba)3 (35 g, 38.2 mmol, 0.04 eq., Hindustan Platinum) and XantPhos (44.6 g, 76.4 mmol, 0.08 eq., GLR) were added to the reaction mixture and the mixture was heated at 110°C for 5 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (2.0 L) and filtered through The filtrate was concentrated under reduced pressure to obtain the initial product, which was purified by stirring with 5% ethyl acetate (3.0 L) in hexanes for 30 min and filtered to obtain (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (350 g, 71%) as a yellow solid. TLC solvent system: 30% ethyl acetate in 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: No NH protons were observed.

[0416]

[0417] Step 6: 6-(Benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one

[0418] 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 eq) in methanol (2.5 L) was added tri(n-butyl)phosphine (50% solution in ethyl acetate, 48.9 mL, 96.8 mmol, 0.2 eq, Spectrochem) and the reaction mixture was heated at 70 °C for 5 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to obtain the initial product, which was purified by stirring with 5% ethyl acetate (1.0 mL) in hexanes and filtered to obtain 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) δ7.92(d,J=9.1Hz,1H),7.79(d,J=1.7Hz,1H),7.65(d,J=6.1Hz,1H),7.57(d,J=8 .8Hz,1H),7.40-7.22(m,6H),6.68(d,J=9.6Hz,1H),6.56(d,J=8.8Hz,1H),4.24(s,2H),3.69(s,3H).

[0419] Step 7+8: 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0420] To a solution of 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one (250.0 g, 531.5 mmol, 1.0 eq) in acetonitrile (2.5 L) was added acetic acid (200 mL) and water (130 mL). The resulting mixture was cooled to 0°C and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (188.5 g, 956.7 mmol, 1.8 eq, Aldrich) was added portionwise over 20 min, keeping the internal temperature below 5°C. The resulting suspension was stirred at 0-5°C under nitrogen for 45 min. Then add pentafluorophenol (127.2g, 690.95mmol, 1.3 equivalents, Apollo) in acetonitrile (200mL) solution within 5min, then add NEt3 (307.7mL, 2.12mol, 4.0 equivalents) within 20min, keep the internal temperature below 5°C. The mixture is stirred for 30min at 0-5°C. Add water (4.0L) and extract with ethyl acetate (2×2.0L). The organic layer is washed with brine (1.0L), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the initial material, which is purified by stirring with isopropanol: hexane (1:1, 1.0L) and filtered to obtain racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (190g, 60%) as a white solid. TLC solvent system: 30% ethyl acetate in petroleum ether, R f : 0.4. MS (ESI, positive ion) m / z; 594.2 (M+1). 1 H-NMR (400MHz, DMSO) δ8.60(d,J=2.0Hz,1H),8.26(d,J=9.8Hz,1H),7.95(dd,J=2.2,9.1Hz,1H),7.70(t,J=8.6Hz,2H),6.95-6.88(m,2H),3.72(s,3H).

[0421]

[0422] Step 9: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0423] Racemic 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester was separated by Chiralcel OJ column (40% MeOH / 60% CO2) to give (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester and (M)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester as pale yellow flocculent solids. Peak 1 data: m / z (ESI) 594.0 (M+H) + Peak 2 data: m / z (ESI) 594.0 (M+H) + .

[0424]

[0425] Step 10: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0426] A 250-mL round-bottom flask was charged with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (11.34 g, 19.08 mmol) and N-(4-methoxybenzyl)isoxazol-3-amine (4.09 g, 20.04 mmol) and then purged with nitrogen. Tetrahydrofuran (191 mL) was introduced and the resulting brown solution was cooled to 0°C. A solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 21.0 mL, 21.0 mmol) was added dropwise to the stirred reaction mixture via a syringe over 10 min. After 15 min, 1.0 N HCl (100 mL) was introduced and the resulting reaction mixture was allowed to warm to rt. 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 Column, eluent: gradient, 0 to 100% EtOAc in heptane with 10% CH2Cl2 as additive) was purified to give (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (9.54 g, 15.53 mmol, 81% yield) as a white amorphous solid. 1H NMR(400MHz,DMSO-d6)δppm 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) + .

[0427] Intermediate G: 1-bromo-2-chloro-4-iodo-5-methoxybenzene

[0428]

[0429] 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 nitrogen. The reaction mixture was stirred for 20 mins at ambient temperature and iodine (630 g, 2483 mmol) was added. The reaction mixture was stirred for 16 h at ambient temperature. The mixture was then diluted with DCM (4500 mL) and filtered through diatomaceous earth. The diatomaceous earth bed was washed with DCM (2×1.0 L). The filtrate was washed with 20% aqueous sodium thiosulfate solution (5.0 L) and saturated aqueous sodium bicarbonate solution (5.0 L). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the starting product, which was purified by column chromatography (silica gel; mesh size 60-120, elution 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) δppm 7.83 (s, 1H), 7.03 (s, 1H), 3.89 (s, 3H).

[0430] Intermediate H: N-(4-methoxybenzyl)pyrimidin-2-amine

[0431]

[0432] 2-Chloropyrimidine (1.5 g, 13.10 mmol), (4-methoxyphenyl)methylamine (2.15 g, 15.72 mmol, 1.2 equivalents) and triethylamine (2.65 g, 26.2 mmol, 2.0 equivalents) were dissolved in EtOH (20 mL) in a 50-mL microwave vial. The reaction tube was sealed and irradiated with a maximum power of 80 W at an upper limit temperature of 120 ° C for 1 h in the cavity of a microwave reactor. After the reaction mixture was cooled with an air stream for 15 min, it was diluted with water (100 mL), extracted with CH2Cl2 (2 × 150 mL) and dried over Na2SO4. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic extract was washed with a saturated NaCl aqueous solution (1 × 50 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to obtain the initial product as a yellow oil. The initial product was adsorbed onto a silica gel plug and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g) (with a 20% to 30% EtOAc gradient in hexanes) to afford 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) + .

[0433] Intermediate I: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide

[0434]

[0435]

[0436] Step 1: (E)-3-(5-(Benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate

[0437] To a solution of (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (175 g, 555.0 mmol) and 1-bromo-2-chloro-4-iodo-5-methoxybenzene (231.3 g, 666.2, mmol) in toluene (1.5 L) was added cesium carbonate (357.5 g, 1100 mmol), and the mixture was degassed with nitrogen for 20 mins. 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 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (1.0 L) and filtered through celite. The filtrate was concentrated under reduced pressure to obtain the starting product, which was purified by stirring with 5% ethyl acetate (1.5 L) in hexane for 30 min and filtered to obtain (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate (290 g, 85%) as a yellow solid. m / z (ESI) 532.2 (M+H) + .

[0438] Step 2: 6-(Benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)-one

[0439] To a solution of (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate (300.0 g, 5630.0 mmol) 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 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to afford the starting product, which was purified by stirring with 5% ethyl acetate in hexanes (1.0 mL) and filtered to afford 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)-one (210.0 g, 76.6%) as an off-white solid, m / z (ESI) 486.0 (M+H) + .

[0440] Step 3: l-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0441] 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 portionwise over 30 min, keeping the internal temperature below 5°C. The resulting suspension was stirred at 0°C under nitrogen for 45 min. A solution of pentafluorophenol (197.4 g, 1072.3 mmol) in acetonitrile (500 mL) was then added over 5 min, followed by triethylamine (477 mL, 3299 mmol) over 30 min, keeping the internal temperature below 5°C. The mixture was stirred at 0°C for a further 50 min. Water (4.0 L) was added and extracted with ethyl acetate (3×2.0 L). The organic layer was washed with brine (2.0 L), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the initial product, which was purified by stirring with isopropanol / hexane (1:1, 2.0 L) and filtered to obtain 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (360 g, 72%) as a white solid. m / z (ESI) 610.6 (M+H) + .

[0442] Step 4: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester and (M)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0443] Perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (156 g, 255 mmol) was purified by chiral SFC chromatography ((S,S) Whelk-O, 45% isopropanol) to give (P)-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) + .

[0444] Step 5: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide

[0445] N-(4-methoxybenzyl)pyrimidin-2-amine (9.72 g, 45.1 mmol) and (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (25.06 g, 41.0 mmol) were added to a 500-mL flask. The flask was flushed with a stream of N2, then tetrahydrofuran (136 mL) was added and the reaction was cooled to 2 °C under N2. Sodium tert-amyl alcohol (30% solution in THF, 197 mL, 492 mmol) was added via an addition funnel over 30 min, keeping the internal temperature at about 5 °C, and the light yellow solution turned orange after addition. The reaction was stirred in an ice bath for 30 min. The reaction was then quenched with saturated NH4Cl solution 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 out. The solvent was evaporated to approximately 100 mL, then additional IPA was added and the reaction was stirred for 18 h. The slurry was filtered and the solids were washed with IPA.

[0446] Solid is absorbed in 150mL MTBE and heated at 40 ℃ for 2 hours.Slurries are cooled to environment temperature and filtered to obtain white solid.Impure material is dissolved in 500mL 10%MeOH / DCM, and with 500mL saturated NaHCO solution is stirred 30 minutes.The layers are separated, and water layer is extracted twice with 10%MeOH / DCM.Dry and evaporate the organic layer merged.The filtrate from IPA and MTBE titration is merged and loaded on 25g silica column and by column chromatography (RediSep RfGold 120g posts, gradient elution in heptane with 10% dichloromethane additive 10% to 50%3:1EtOAc:EtOH) purifying. The pure product from the column and the product from the NaHCO3 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 light yellow foam. 1H NMR(500MHz,DMSO-d6)δppm 8.58(d,J=4.9Hz,2H),8.39(d,J=2.1Hz,1H),8.13(d,J=9.6Hz,1H),7.96(dd,J=9.1,2.3Hz,1H),7.76(s,1H),7.73(s,1H),7.29(d,J=8.8 Hz,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, positive ion) 642.8 (M+H) + .

[0447] Intermediate J: N-(4-methoxybenzyl)pyridazin-3-amine

[0448]

[0449] 4-methoxybenzaldehyde (1.00 g, 7.34 mmol) and pyridazine-3-amine (0.838 g, 8.81 mmol) in tetrahydrofuran (10 mL) were added to a 25-mL round-bottom flask. Then, titanium (IV) isopropoxide (6.46 mL, 22.03 mmol) was 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 batches. 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 a saturated NaCl aqueous solution (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to obtain the initial product as an orange oil. The initial product was adsorbed onto a silica gel plug and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with 0% to 15% MeOH in CH2Cl2 to afford 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) + .

[0450] Intermediate K: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0451]

[0452] A 100-mL recovery flask containing (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (5.00 g, 8.41 mmol) and N-(4-methoxybenzyl)pyridazine-3-amine (1.902 g, 8.83 mmol) was flushed with nitrogen and then charged with THF (34 mL). The solution was cooled to 0 ° C, and sodium tert-amyl alcohol (8.4 mL, 11.78 mmol, 1.4 M in THF) was slowly added. The light yellow solution was stirred at 0 ° C for 15 min, and then volatiles were removed in vacuo. Water was added to form a white precipitate. The precipitate was isolated, dissolved in dichloromethane, and treated with heptane to form (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) + .

[0453] Intermediate L: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0454]

[0455] Step 1: (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxy-5-methylphenyl)amino)phenyl)acrylate

[0456] 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), cesium carbonate (9.83 g, 30.2 mmol) and toluene (30 mL). A reflux condenser was attached and the mixture was heated to reflux. After 4 h, additional portions of tris(dibenzylideneacetone)dipalladium(0) (172 mg) and XantPhos (213 mg) were added. After 2 h, additional portions of cesium carbonate (about 2 g) and 1-bromo-4-iodo-5-methoxy-2-methylbenzene (600 mg) were added. After refluxing for 30min, the mixture is cooled and filtered through diatomite.The filter pad is washed with EtOAc (3x).The filtrate is concentrated.Residue is concentrated from MeOH, and absorbed in MeOH.The gained suspension is heated to boiling, then ultrasonicated and cooled to RT.The mixture is filtered, and the collected solid is washed with MeOH (3x) and dried under N2 stream for 48h, to obtain (E) -3- (5- (benzylthio) -2- ((4- bromo-2-methoxy-5-methylphenyl) amino) phenyl) ethyl acrylate (5.21g, 10.17mmol, 67.4% yield) as bright yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 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),6.6 2(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) + .

[0457] Step 2: 6-(Benzylthio)-1-(4-bromo-2-methoxy-5-methylphenyl)quinolin-2(1H)-one

[0458] 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 %, 0.432 mL, 1.998 mmol in MeOH) was added. A reflux condenser was connected and the flask was moved down to a 70° C. heating bath. After 1 h, additional portions of MeOH (25 mL) and sodium methoxide solution (about 0.85 mL) were added sequentially. After 7 h, the mixture was cooled and concentrated under vacuum. The residue was purified by silica gel chromatography (80-g Redi-Sep column, 25-g silica loaded column, loaded as a solution in MeOH-DCM, then eluted with 25%-75% EtOAc / heptane containing 10% DCM). Fractions containing product 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)+.

[0459] Step 3: 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0460] A round-bottom flask was charged with 6-(benzylthio)-1-(4-bromo-2-methoxy-5-methylphenyl)quinoline-2(1H)-one (4.23 g, 9.07 mmol), DCM (71.1 mL), acetic acid (2.67 mL), and water (1.778 mL) to obtain a clear light brown solution. The flask was cooled in an ice-water bath for 10 min, and then 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (3.66 g, 18.59 mmol) was added in one go. After 40 min, an additional portion of the oxidant (850 mg) was added. The mixture was stirred for another 20 min, and then 2,3,4,5,6-pentafluorophenol (2.504 g, 13.60 mmol) and triethylamine (5.06 mL, 36.3 mmol) were added in sequence. 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 silica gel chromatography (80-g Redi-Sep Gold column, 25-g silica gel loaded column, 10%-60% EtOAc / heptane (with 10% DCM)) to give 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (3.37 g, 5.71 mmol, 63% yield). m / z (ESI) 590.0 (M+H) + .

[0461] Step 4: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0462] 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (22.896 g, 38.79 mmol) was purified using a (S,S) Whelk-O, 5x25 cm column. The mobile phase was run under isocratic conditions; supercritical CO2 with 50% dichloromethane; flow rate: 350 mL / min. The first eluting peak was designated as (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (10.425 g). The second eluting peak was designated as (M)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (10.76 g). Peak 1 data: m / z (ESI) 590.0 (M+H) + Peak 2 data: m / z (ESI) 590.0 (M+H) + .

[0463] Intermediate M: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide

[0464]

[0465] A 250-mL round-bottom flask was charged with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (2.00 g, 3.37 mmol), tetrahydrofuran (17 mL) and N-(4-methoxybenzyl)pyrimidin-2-amine (0.724 g, 3.37 mmol) in sequence 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 then 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 Column, gradient elution 0-100% EtOAc:heptane (with 10% dichloromethane as co-eluent)) to give (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) + .

[0466] Intermediate N: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0467]

[0468] To a 0°C 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-sulfonic acid perfluorophenyl ester (200 mg, 0.339 mmol) in tetrahydrofuran (1.7 mL) was slowly added sodium tert-amyl oxide (30 wt% in THF, 176 μL, 0.440 mmol). The reaction was stirred at 0°C for 30 minutes. After 30 min, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was concentrated, and the residue was triturated with MTBE (2 mL) to afford (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) + .

[0469] Intermediate O: N-(4-methoxybenzyl)oxazol-2-amine

[0470]

[0471] In a 250-mL flask, 1,3-oxazole-2-amine (5.00 g, 59.5 mmol) and 4-anisaldehyde (10.53 g, 8.85 mL, 77 mmol) were heated in toluene (119 mL) at 90 ° C for 2 hours. The reaction was cooled to ambient temperature and sodium triacetoxyborohydride (18.91 g, 89 mmol) was added in batches. 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 with Na2SO4, filtered and concentrated. The residue was loaded onto a 25 g silica column and purified by column chromatography (RediSep RfGold 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 (500 MHz, DMSO-d6) δ ppm 7.55 (br t, J = 6.1 Hz, 1H), 7.39 (d, J = 1.0 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 1.0 Hz, 1H), 4.26 (d, J = 6.2 Hz, 2H), 3.72 (s, 3H). m / z (ESI, positive ion) 205.2 (M+H) + .

[0472] Intermediate P: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0473]

[0474] 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-sulfonic acid perfluorophenyl ester (200 mg, 0.337 mmol) in tetrahydrofuran (1.6 mL) at 0°C was slowly added sodium tert-amyl alcohol (30 wt % in THF, 175 μL, 0.438 mmol). The reaction was stirred at 0°C for 30 minutes. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. 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 provide (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) + .

[0475] Intermediate Q: (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0476]

[0477] To a solution of N-(4-methoxybenzyl)isoxazole-3-amine (128 mg, 0.625 mmol) and (P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (300 mg, 0.521 mmol) in tetrahydrofuran (2.6 mL) at 0°C was slowly added sodium tert-amyl alcohol (30 wt% in THF, 271 μL, 0.677 mmol). The reaction was stirred at 0°C for 30 minutes. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was concentrated. The residue was triturated with MTBE to afford 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) + .

[0478] Intermediate R: (P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide

[0479]

[0480] The title compound was prepared according to the method and purification scheme of 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) + .

[0481] Intermediate S: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide

[0482]

[0483] The title compound was prepared according to the method and purification scheme of Intermediate R using (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (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) + .

[0484] Intermediate T: N-(2,4-dimethoxybenzyl)oxazol-2-amine

[0485]

[0486] 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) was heated in toluene (100 mL) at 90 ° C for 1 h. The reaction was cooled to rt and then treated with sodium triacetoxyborohydride (18.91 g, 89 mmol). The mixture was stirred at 100 ° C for 1 h and then at rt for 60 h. Additional sodium triacetoxyborohydride (18.91 g, 89 mmol) was added and the reaction was stirred at 100 ° C for 2 h. 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 viscous brown oil, which was purged through a plug of silica gel and washed with 50% [3:1 ethyl acetate:ethanol]:heptane. The filtrate was concentrated and then 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 light yellow solid. m / z (ESI, positive ion) 235.2 (M+H) + .

[0487] Intermediate U: (P)-1-(4-bromo-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0488]

[0489] 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-sulfonic acid perfluorophenyl ester (300 mg, 0.521 mmol) in tetrahydrofuran (2.6 mL) at 0°C was slowly added sodium tert-amyl alcohol (30 wt% in THF, 0.271 mL, 0.677 mmol). 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 afford (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) + .

[0490] Intermediate V: (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0491]

[0492] To a solution of N-(4-methoxybenzyl)pyridazine-3-amine (0.219 g, 1.02 mmol) and (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (0.5 g, 0.847 mmol) in tetrahydrofuran (4.2 mL) at 0°C was slowly added sodium tert-amyl alcohol (30 wt% solution in THF, 0.41 mL, 1.0 mmol). The reaction was stirred at 0°C for 30 minutes. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. 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 afford (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) + .

[0493] 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

[0494]

[0495] 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-sulfonic acid perfluorophenyl ester (0.500 g, 0.819 mmol, Syngene) were added to a 40-mL vial. The vial was flushed with nitrogen, tetrahydrofuran (2.7 mL) was added, and the reaction was then cooled to 0 ° C. Sodium tert-amyl alcohol (3.2 M in PhMe, 0.33 mL, 1.1 mmol) was slowly added. After stirring at ° C for 30 min, saturated aqueous ammonium chloride solution 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 afford (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+Na) + .

[0496] Intermediate X: (P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0497]

[0498] In a 250-mL flask, (P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (7.00 g, 12.15 mmol) and N-(4-methoxybenzyl)pyridazine-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-amyl alcohol (40 wt %, 7.77 mL, 19.43 mmol in toluene). The reaction was stirred at 0 ° C for 30 min and allowed to warm to rt. After 2 h, additional base sodium tert-amyl alcohol (40 wt %, 1 mL in toluene) was added, and the reaction was stirred for another 15 h at rt. Additional tert-amyl oxide (40 wt %, 1 mL in toluene) was added, and the reaction was stirred for another 2 h at rt. The reaction was cooled in an ice bath and quenched with a 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 by silica gel column chromatography (gradient elution 0-100% [3: 1 EtOAc: EtOH]: [9: 1 heptane: dichloromethane]). The product was further purified by grinding with ethyl acetate: heptane (1: 1) to obtain (P) -1- (4- bromo-2-methoxyphenyl) -N- (4- methoxybenzyl) -2- oxo -N- (pyridazine -3- bases) -1,2- dihydroquinoline -6- sulfonamide (1.56 g, 2.57 mmol, 21% yield) as an off-white solid. 1 H NMR(500MHz,DMSO-d6)δppm 9.04(dd,J=4.5,1.7Hz,1H),8.26(d,J=2.3Hz,1H),8.16(d,J=9.3Hz,1H),7.67-7.77(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),6.76-6.8 5(m,3H),6.72(d,J=9.1Hz,1H),5.03(s,2H),3.72(s,3H),3.66(s,3H). m / z (ESI, positive ion) 607.0 (M+H) + .

[0499] Intermediate Y: (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0500]

[0501] The title compound was prepared according to the method and purification scheme of Intermediate V using (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (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) + .

[0502] 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

[0503]

[0504] The title compound was prepared according to the method of Intermediate N using N-(2,4-dimethoxybenzyl)oxazol-2-amine (0.236 g, 1.01 mmol). 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 (500 MHz, chloroform-d) δ ppm 7.92 (d, J = 2.1 Hz, 1H), 7.86 (dd, J = 9.0, 2.2 Hz, 1H), 7.69 (d, J = 9.6 Hz, 1H), 7.46 (d, J = 0.8 Hz, 1H), 7.33 (s, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.08 (s, 1H), 7.01 (d, J = 0.8 Hz, 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).

[0505] Intermediate AB: (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)zinc(II) iodide

[0506]

[0507] 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 5% Rieke's zinc 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.

[0508] Intermediate AC: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester.

[0509]

[0510] Step 1: 4-Bromo-5-fluoro-2-iodoaniline

[0511] At 10 ℃-15 ℃, N-iodosuccinimide (710g, 3158mmol) is added to the solution of 4-bromo-3-fluoroaniline (500g, 2631mmol) in acetic acid (4000mL) in batches.The reaction is stirred at room temperature for 1 hour.Then the reaction is quenched with ice water (7L), and the precipitated solid is filtered.Solid is washed and dried with 5% sodium thiosulfate solution (6L) and water (4L), and 4-bromo-5-fluoro-2-iodoaniline (750g, 2374mmol, 90% yield) is obtained as a brown solid. 1 H NMR (400MHz, DMSO-d6): δppm 7.76 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 11.5 Hz, 1H), 5.68 (s, 2H).

[0512] Step 2: (E)-ethyl 3-(2-amino-5-bromo-4-fluorophenyl)acrylate

[0513] At room temperature, triethylamine (331mL, 2374mmol) is added to the stirring solution of 4-bromo-5-fluoro-2-iodoaniline (500g, 1583mmol) in isopropanol (2550mL).Reaction mixture is degassed with nitrogen for 20 minutes.Add tris(dibenzylideneacetone)dipalladium (0) (36.2g, 39.6mmol), then slowly add ethyl acrylate (162g, 1614mmol) under nitrogen atmosphere.Then reaction mixture is heated to 70 ℃ and stirred for 6 hours.After completion, reaction mixture is filtered through diatomite and washed with dichloromethane (2L).Filtrate is concentrated under reduced pressure to obtain initial product.Initial product is stirred and filtered in 3% ethyl acetate (6L) in petroleum ether. The obtained solid was washed with 3% EtOAc in petroleum ether (2 L) and dried to give (E)-ethyl 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): δppm 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).

[0514] Step 3: (E)-ethyl 3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate

[0515] To a solution of (E)-3-(2-amino-5-bromo-4-fluorophenyl)ethyl acrylate (500.0g, 1735mmol) in 1,4-dioxane (2500mL) was added N-ethyl-N-isopropylpropane-2-amine (449g, 3471mmol) and degassed with nitrogen for 20 minutes. (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (50.2g, 87mmol) and tris(dibenzylideneacetone)dipalladium(0) (39.7g, 43.4mmol) 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 phenylmethyl mercaptan (237g, 1909mmol) was added. The reaction was heated at 90°C for 12 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (1000mL). The mixture is filtered through diatomite, and the diatomite bed is washed with ethyl acetate (2500mL). The filtrate is concentrated under reduced pressure to obtain the initial product. The initial product is purified by column chromatography (silica gel; mesh size 60-120, gradient elution 0-15% ethyl acetate and petroleum ether) to obtain (E) -3- (2- amino -5- (benzylthio) -4- fluorophenyl) ethyl acrylate (300.0g, 905mmol, 52% yield) as a yellow solid. MS (ESI, positive ion) m / z: 332.1 (M+1). 1 H NMR (400MHz, DMSO-d6): δppm 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).

[0516] Step 4: (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-4-fluorophenyl)acrylate

[0517] To a 250 mL 3-neck round bottom flask containing (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(diphenylphosphine) (1.397 g, 2.414 mmol) were added to the reaction mixture and the mixture was heated at 110 ° C for 16 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (200 mL) and filtered through celite. The filtrate was concentrated under reduced pressure to obtain the initial product, which was stirred with methanol (250 mL) for 1 hour for purification and filtered. The cake was washed with methanol (100 mL) and dried to obtain (E)-ethyl 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): δppm 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).

[0518] Step 5: 6-(Benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoroquinolin-2(1H)-one

[0519] To a 500 mL 3-neck round bottom flask charged with ethyl (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-4-fluorophenyl)acrylate (13.5 g, 25.3 mmol) in methanol (140 mL) was added tributylphosphane (50% solution in ethyl acetate) (3.74 mL, 7.58 mmol). The reaction mixture was heated at 70 ° C for 5 hours. The reaction mixture was cooled to 15 ° C, filtered and 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 HNMR (400MHz, DMSO-d6): δppm 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).

[0520] Steps 6 and 7: Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate.

[0521] To a 250 mL 3-necked 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 portionwise over 10-20 min, keeping the internal temperature below 5-10°C. The resulting suspension was stirred at 5-10°C under nitrogen for 45 minutes. Then add 2,3,4,5,6-pentafluorophenol (7.16g, 38.9mmol) in acetonitrile (10mL) solution in 10-15min, then add triethylamine (13.54mL, 97mmol) in 20min, keep the internal temperature below 5℃-10℃. The mixture is stirred for 30min at 5℃-10℃. Add ice water (200mL), and the precipitated solid is filtered and washed with water (100mL). The initial product is purified by stirring with methanol (50mL), filtered, washed with MeOH (50mL) and dried to obtain 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (9.5g, 15.52mmol, 80% yield) as off-white solid. MS (ESI, positive ion) m / z; 612.0 (M+1). 1 H NMR (400MHz, DMSO-d6): δppm 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).

[0522] Step 8: (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate.

[0523] 1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (135 g, 220 mmol) was purified by SFC via a Regis Whelk-O s,s 5x15 cm, 5 μm column; a mobile phase of 50% dichloromethane was used at a flow rate of 350 mL / min to produce (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (49.2 g, 80.4 mmol, 36% yield). MS (ESI, positive ion) m / z: 612.7 (M+1).

[0524] Chemical Examples

[0525] 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

[0526]

[0527] Step 1: (M)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0528] A vial was charged with palladium(II) acetate (2.7 mg, 0.012 mmol), 2'-(dicyclohexylphosphino)-N 2 ,N 2 ,N 6 ,N 6-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). (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 two 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 by 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 (400 MHz, DMSO-d6) δppm 11.65 (s, 1H), 8.73 (d, J = 1.9 Hz, 1H), 8.30-8.41 (m, 1H), 8.20 (d, J = 10.0 Hz, 1H), 7.72-8.00 (m, 1H), 7.04-7.29 (m, 2H), 6.73-6.85 (m, 2H), 6.44 (d, J = 1.5 Hz, 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, positive ion) 526.2 (M+H) + .

[0529] Step 2: 1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0530] (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 by heating in DMSO at 130° C. for 3 h. It 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. 1H NMR (400 MHz, DMSO-d6) δppm 11.66 (s, 1H), 8.74 (d, J = 1.7 Hz, 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 = 1.5 Hz, 1H), 3.70 (d, J = 10.0 Hz, 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, positive ion) 526.2 (M+H) + .

[0531] Example 3: (P)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0532]

[0533] A vial was charged with palladium(II) acetate (7.3 mg, 0.032 mmol), 2'-(dicyclohexylphosphino)-N 2 ,N 2 ,N 6 ,N 6 -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). (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 two hours. The reaction was then diluted with ethyl acetate and washed twice with 1N HCl. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (RediSep Gold 40 g column, gradient elution 0-50% [3:1 EtOAc:EtOH]:heptane) to give (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). 1H NMR(400MHz,DMSO-d6)δppm 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),2.16-2.37(m,4H),1.91-2.07(m,1H),0.80-0.95(m,9H). m / z (ESI, positive ion) 526.2 (M+H) + .

[0534] Example 4: (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0535]

[0536] 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

[0537] 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-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (Intermediate F). 2 ,N 2 ,N 6 ,N 6-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 h. 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 by column chromatography (RediSep Gold 40 g column, gradient elution 0-100% EtOAc:heptane) to afford (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 bright yellow solid. m / z (ESI, positive ion) 648.2 (M+H) + .

[0538] 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

[0539] (P)-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]oct-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 three 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 by column chromatography (RediSep Gold 40g 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 bright yellow solid. m / z (ESI, positive ion) 604.2 (M+H) + .

[0540] 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

[0541] 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 one hour. The reaction was then poured into a 250-mL round-bottom flask, diluted with ethyl acetate, and saturated aqueous sodium bicarbonate solution was carefully added until bubbling stopped. 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 by 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) + .

[0542] Step 4: (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0543] (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 two hours. The reaction was concentrated and purified by column chromatography (RediSep Gold 40 g column, gradient elution 0-75% [3:1 EtOAc / EtOH]:heptane) to give (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. 1H NMR (400 MHz, DMSO-d6) δppm 11.66 (s, 1H), 8.74 (d, J = 1.9 Hz, 1H), 8.37 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 9.5 Hz, 1H), 7.84 (dd, J = 8.9, 2.3 Hz, 1H), 7.36 (d, J = 10.2 Hz, 1H), 7.27 (d, J = 6.8 Hz, 1H), 6.76-6.84 (m, 2H), 6.45 (d, J = 1.7 Hz, 1H), 3.71 (s, 3H), 3.57-3.68 (m, 1H), 2.91-3.13 (m, 4H). m / z (ESI, positive ion) 506.0 (M+H) + .

[0544] 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

[0545]

[0546]

[0547] 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

[0548] 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 one 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 h. HCl (1 N in water, 5.8 mL, 5.8 mmol) was added and the reaction was stirred for one 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 by column chromatography ( SNAP 25g 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) + .

[0549] 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

[0550] To a vial containing (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) was added bis(2-methoxyethyl)aminosulfur trifluoride (1.0 mL, 5.4 mmol). The reaction was heated to 50 °C and stirred for 16 h. 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 by column chromatography (RediSep Gold 12 g column, gradient elution 0-100% EtOAc:heptane) and then by reverse phase HPLC using an XBridgePrep Shield RP18 19x100 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 afforded (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) + .

[0551] 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

[0552] 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 by column chromatography ( The product was purified by SNAP10 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(400MHz,DMSO-d6)δppm 11.67(s,1H),8.73(d,J=1.7Hz,1H),8.38(d,J=2.1Hz,1H),8.23(d,J=9.5Hz,1H),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, positive ion) 556.0 (M+H) + .

[0553] 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

[0554]

[0555] 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-phenylcarbonothioate

[0556] (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 chlorothiocarbonylformate (0.103 mL, 0.742 mmol) was added and the reaction was stirred for three 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 warmed to room temperature and stirred for 30 minutes, then additional chlorothiocarbonyl formic acid phenyl ester (0.103mL, 0.742mmol) was added. The reactant was stirred at room temperature for 16h. The reaction was then diluted with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography ( 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-phenylcarbonothioate (0.215 g, 0.265 mmol, 89% yield) as a light yellow solid.

[0557] 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

[0558] (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-phenylcarbonothioate (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. This reaction was also performed twice 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-phenylcarbonothioate (0.025 g, 0.031 mmol) under the same conditions and reagent stoichiometry. All three reactions were then combined, loaded onto a silica column, and purified by column chromatography ( SNAP 25g column, gradient elution 0-100% 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 light yellow solid. m / z (ESI, positive ion) 658.0 (M+H) + .

[0559] 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

[0560] 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 allowed to stir at room temperature overnight. The reaction was then concentrated and purified by column chromatography ( SNAP10g column, gradient elution 0-75% [3:1 EtOAc / EtOH]:heptane) was purified to give 81 mg of the substance as an off-white solid. The substance was further purified using two consecutive Chiralcel OJ-H, 2x25 cm columns. The mobile phase was run under isocratic conditions; supercritical CO2 with 15% methanol; flow rate: 80 mL / min. The first eluting peak was designated as 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 designated as 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: 1 H NMR(500MHz,DMSO-d6)δppm 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, positive ion) 538.0 (M+H) + . Data for Peak 2: 1 HNMR(500MHz,DMSO-d6)δppm 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,2 H), 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, positive ion) 538.0 (M+H) + .

[0561] 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

[0562]

[0563] 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

[0564] Zinc powder (112g, 1.72mol), lithium chloride (16.0g, 389mmol) and anhydrous tetrahydrofuran (750mL) were loaded into a 2L three-necked round-bottom flask equipped with an overhead stirrer, distillation head, thermocouple, addition funnel and nitrogen inlet. Half of the tetrahydrofuran was removed by distillation at atmospheric pressure. The resulting mixture was cooled to 30°C and chlorotrimethylsilane (3.0mL, 23.5mmol) was added. The mixture was warmed to 50°C for 30 minutes, the temperature was raised, and the reaction volume was reduced by about 50mL by distillation. Before introducing trans-1-bromo-3-(trifluoromethyl)cyclobutane (75.0g, 369mmol, Enamine Co., Ltd.), the resulting mixture was cooled to 30°C. The mixture was then warmed to 40°C. Significant exothermicity was observed and the heating mantle was replaced with an ambient temperature water bath. Once the exothermicity stopped, 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 cooled to ambient temperature. The supernatant was used without further manipulation. 1,2,3,4,5-pentaphenyl-1'-(di-tert-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) were loaded into a separate 2L three-necked round-bottom flask equipped with an overhead stirrer, a thermocouple, a reflux condenser, and a nitrogen inlet. The resulting mixture was warmed to 45 °C. After 15 minutes, the reaction mixture was cooled to room temperature before 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 before the supernatant from the previous reaction of 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 the internal temperature between 40°C and 45°C. Once the addition was complete, the mixture was warmed to 50°C. After 3 hours, aqueous 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 obtained solid was suspended in isopropanol (1 L) and stirred at 40 ° C for 20 minutes. The mixture was cooled to ambient temperature and filtered through a sintered glass porous filter. The solid was washed with isopropanol (40 mL) and transferred to a 2L round-bottom flask. Isopropyl acetate (1 L) was added and the mixture was stirred at 40 ° C for 20 minutes.The suspension is filtered through a sintered glass porous filter, and the solid is washed with additional isopropyl acetate (50 mL). The filtrate is transferred to a 2L round-bottom flask, and SiliaMetS Thiol metal scavenger (20 g, Silicycle) and activated carbon (20 g) are added. The mixture is stirred at ambient temperature for 20 minutes. The suspension is filtered through a diatomaceous earth pad, and the solid is washed with isopropyl acetate (500 mL). The filtrate is concentrated under reduced pressure. A mixture of dichloromethane and methyl tert-butyl ether (1: 1 mixture, 1 L) is added to the solid, and the resulting mixture is stirred at 40 ° C for 20 minutes. The mixture is filtered through a sintered glass porous filter, and trace solids are washed with methyl tert-butyl ether (30 mL). The combined filtrates were 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). + .

[0565] 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

[0566] A 2L three-necked 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°C-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 (2×800 mL) and then suspended in heptane (800 mL). Before decanting off heptane, the mixture was stirred at ambient temperature for 10 minutes. The remaining material was dissolved in dichloromethane (1.5L) and washed with tribasic sodium phosphate aqueous solution (0.2N, 2×300mL). The organic layer was separated and concentrated under reduced pressure. The residue was suspended in methyl tert-butyl ether (2L) and stirred at 40°C for 20 minutes. The suspension was filtered through a sintered glass porous filter, and the solid was washed with methyl tert-butyl ether (100mL). The filtrate was evaporated to dryness under reduced pressure and the product was suspended in methanol (500mL). The resulting suspension was concentrated under reduced pressure, and the residue was purified by SFC in two steps (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). 1 H 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). 13C 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=276.1Hz),124.00,123.34,120.04,117.16(d,J=25.4Hz),116.42,111.73 (d, J = 5.5Hz), 98.59, 56.39, 34.01 (q, J = 30.0Hz), 31.80, 27.76, 27.50, 27.31. m / z(ESI)538.0(M+H) + .

[0567] 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

[0568]

[0569] 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 two hours. The reaction was then concentrated and purified using two consecutive Chiralpak IC, 2x15 cm columns. The mobile phase was run under isocratic conditions; supercritical CO2 with 25% methanol; flow rate: 80 mL / min. The first eluting peak was designated as 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 designated as 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: 1H NMR (400 MHz, 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=9.5H z,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(dd,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, positive ion) 555.2 (M+H) + . Data for Peak 2: 1 H NMR (400 MHz, 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 ),7.84(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=9.7Hz,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, positive ion) 555.4 (M+H) + .

[0570] 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

[0571]

[0572] 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

[0573] A 3-neck 250-mL round-bottom flask equipped with a reflux adapter and an internal temperature probe 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 (5 g, 7.93 mmol), palladium(II) acetate (0.107 g, 0.476 mmol), and 2′-(dicyclohexylphosphino)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. 2 ,N 2 ,N 6 ,N 6 -tetramethyl-[1,1'-biphenyl]-2,6-diamine (0.415 g, 0.951 mmol), then evacuate and backfill with nitrogen. Add 5,8-dioxaspiro[3.4]octan-2-ylzinc bromide (II) (0.4M in THF, 30 mL, 12 mmol) and stir the reaction at 50 ° C for 20 h. The mixture is then quenched with 2N HCl aqueous solution (80 mL). The temperature is raised to 50 ° C, and the mixture is stirred for 4 h. The mixture is then distributed between water and EtOAc. Separate the layers. The aqueous extract is extracted with EtAOc (2×100 mL). The combined extracts are washed with brine and then concentrated to a black residue. The product was purified by column chromatography (200 g silica column, gradient elution 0-100% EtOAc:heptane) to afford (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. 1 H NMR(500MHz,DMSO-d6)δppm 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, positive ion) 620.0 (M+H) + .

[0574] 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

[0575] 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 tetrabutylammonium fluoride, a 1.0 M solution 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. Exotherm and bubbling were observed. The reaction was stirred for 3 h and 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 by column chromatography ( SNAP 100g 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) + .

[0576] 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

[0577] A 2-neck 50-mL 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. Difluoro(morpholine)sulfonium tetrafluoroborate (1.58 g, 6.52 mmol) and a solution of (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) were 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 solution and then extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The material was purified by column chromatography ( SNAP 50 g column, gradient elution 0-100% 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. 1 H NMR(500MHz,DMSO-d6)δppm 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,1H),7.67(d,J=4.2Hz,1H),7.47(d,J=6.2Hz,1H),7.26(d,J=8.6Hz,2H),6.8 0-6.90 (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 = 4.7 Hz, 3H), 3.71 (s, 3H), 3.06 (tt, J = 15.8, 10.8 Hz, 1H), 2.78-2.96 (m, 1H). m / z (ESI, positive ion) 692.2 (M+H) + .

[0578] 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

[0579] 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 and 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 accomplished using a Chiralpak IC, 2x25 cm column. The mobile phase was run under isocratic conditions; supercritical CO2 with 30% methanol; flow rate: 80 mL / min. The first eluting peak was designated as 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 designated as 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(500MHz,DMSO-d6)δppm 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),6.8 0(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, positive ion) 572.0 (M+H) + . Data for Peak 2: 1H NMR(500MHz,DMSO-d6)δppm 11.66(s,1H),8.73(d,J=1.6Hz,1H),8.38(d,J=2.1Hz,1H),8.23(d,J=9.6 Hz,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),6.77(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, positive ion) 572.0 (M+H) + .

[0580] 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

[0581]

[0582] 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-phenylcarbonothioate

[0583] (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 chlorothiocarbonylformate (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 by column chromatography ( 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-phenylcarbonothioate (896 mg, 1.08 mmol, 75% yield) as a light yellow solid. 1 H NMR(500MHz,DMSO-d6)δppm 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 = 9.1 Hz, 1H), 3.53-3.62 (m, 1H), 3.33-3.42 (m, 2H), 3.04-3.18 (m, 1H). m / z (ESI, positive ion) 826.1 (M+H) + .

[0584] 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

[0585] 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-phenylcarbonothioate (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 rt for 16 h. 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) + .

[0586] 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

[0587] 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 RT and concentrated under reduced pressure. The residue was purified by column chromatography (50 g silica column, gradient elution 0-75% [3:1 EtOAc / EtOH]:heptane). Further purification was accomplished using two consecutive Chiralcel OJ-H, 2x25 cm columns. The mobile phase was run under isocratic conditions; supercritical CO2 with 15% methanol; flow rate: 80 mL / min. The first eluting peak was designated as 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 designated as 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)δppm 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, positive ion) 554.0 (M+H) + . Data for Peak 2: 1H NMR(500MHz,DMSO-d6)δppm 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 = 3.6 Hz, 1H), 2.66-2.75 (m, 1H), 2.59-2.63 (m, 2H). m / z (ESI, positive ion) 554.0 (M+H) + .

[0588] Example 14: (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0589]

[0590] To the vial was added (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 6-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 purged with nitrogen and stirred at 50 ° C for 1 h. The mixture was then directly purified by column chromatography (gradient elution 0-30% [3:1 EtOAc / EtOH]: heptane). The isolated product was then taken up in TFA (0.5 mL) and heated to 50 ° C for 16 h. The reaction was then concentrated in vacuo and purified using a Torus 2-PIC, 30x150 cm column. The mobile phase was run under gradient elution conditions; supercritical CO2 with 20%-50% methanol; flow rate: 100 mL / min. This afforded (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 (600 MHz, 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,1H),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,3 H),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, positive ion) 470.0 (M+H) + .

[0591] 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

[0592]

[0593] To the vial was added (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 ,N2 ,N 6 ,N 6 -Tetramethyl-[1,1'-biphenyl]-2,6-diamine (25 mg, 0.057 mmol), (3-(trifluoromethyl)cyclobutyl)zinc(II) bromide (0.15 M in THF, 5.7 mL, 0.86 mmol). The reaction mixture was purged with nitrogen and stirred at 50 °C for 1 h. The mixture was then directly purified by column chromatography (gradient elution 0-30% [3:1 EtOAc / EtOH]:heptane). The isolated product was then taken up in TFA (0.5 mL) and heated to 50 °C for 16 h. The reaction was then concentrated under vacuum and purified using consecutive Chiralcel OJ-H, 2x15 and 2x25 cm columns. The mobile phase was run under isocratic conditions; supercritical CO2 with 20% methanol; 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). 1 H NMR (500 MHz, 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,1H),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, positive ion) 549.2 (M+H) + .

[0594] 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, respectively

[0595]

[0596] 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, 2x15 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, 3x25 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 designated as 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 designated as 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 (500 MHz, 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 .0,2.2Hz,1H),7.85(d,J=9.6Hz,1H),7.19(s,1H),7.02(s,1H),6.99(t,J=4.9 Hz,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, positive ion) 564.8 (M+H) + . Data for Peak 2: 1H NMR (500MHz, chloroform-d) δppm 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, positive ion) 564.8 (M+H) + .

[0597] Example 18: (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide

[0598]

[0599] 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 by reverse phase HPLC using an XBridge Prep Shield RP18 19x100 mm column. The mobile phase was run at a gradient elution; 25%-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-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (18 mg, 0.036 mmol, 15% yield). 1H NMR (500MHz, chloroform-d) δppm 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. 1,2.1Hz,1H),7.84(d,J=9.6Hz,1H),7.15(s,1H),7.06(s,1H),7.01(t,J=5.1Hz,1 H), 6.85 (d, J = 9.9 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 3.87 (quin, J = 8.8 Hz, 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, positive ion) 497.0 (M+H) + .

[0600] 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

[0601]

[0602] 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, 2.1x10 cm column. The mobile phase was run under gradient elution conditions; 41.3%-61.3% water:acetonitrile (with 0.1% formic acid as co-eluent); flow rate: 40 mL / min. The material was further purified using a Chiralcel OJ-H, 2x15 cm column. The mobile phase was run under isocratic conditions; supercritical CO2 with 25% methanol; 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). 1H NMR (500MHz, chloroform-d) δppm 12.38-12.76(m,1H),8.24(d,J=2.1Hz,1H),8.10(dd,J=3.9,1.6Hz,1H),7.91(dd,J =9.1,2.1Hz,1H),7.83(d,J=9.6Hz,1H),7.33-7.37(m,1H),7.29(d,J=1.6Hz,1H),7 .21 (s, 1H), 7.05 (s, 1H), 6.84 (d, J = 9.6 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.08 (quin, J = 8.9 Hz, 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, positive ion) 565.2 (M+H) + .

[0603] 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

[0604]

[0605] 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, 2.1x10 cm column. The mobile phase was run under gradient elution conditions; 46.4%-66.4% acetonitrile:water (with 0.1% formic acid as co-eluent); flow rate: 40 mL / min. The material was further purified using a Chiralcel OJ-H, 2x15 cm column. The mobile phase was run under isocratic conditions; supercritical CO2 with 20% methanol; 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). 1H 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), 6.7 6 (d, J = 9.1 Hz, 1H), 6.60 (d, J = 1.8 Hz, 1H), 3.94 (quin, J = 8.8 Hz, 1H), 3.75 (s, 3H), 2.89-3.07 (m, 1H), 2.70 (ddd, J = 12.8, 8.8, 4.0 Hz, 2H), 2.46-2.60 (m, 2H), 2.19 (s, 3H). m / z (ESI, positive ion) 534.2 (M+H) + .

[0606] Example 21: (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0607]

[0608] 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 by reverse phase HPLC using an XBridge Prep Shield RP18 19x100 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 gave (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (92 mg, 80% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 8.40 (br s,1H),8.25(d,J=1.6Hz,1H),8.13(d,J=2.1Hz,1H),7.78(d,J=9.6Hz,1H),7 .75(dd,J=9.0,2.2Hz,1H),7.15(s,1H),7.05(s,1H),6.87(d,J=9.6Hz,1H), 6.77(d,J=9.1Hz,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, positive ion) 486.0 (M+H) + .

[0609] Example 22: (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0610]

[0611] Step 1: (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0612] 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 bubbled with argon, and then cyclobutylzinc bromide (0.5 M in THF, 1.9 mL, 0.94 mmol) was added. The reaction was stirred at 50 °C. After 2 h, additional portions 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) were added. After stirring at 50 °C for 1 h, the reaction was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, and partitioned between water and ethyl acetate. The organic extracts were concentrated and purified by silica gel column chromatography (gradient elution, 40%-100% EtOAc:heptane (with 10% dichloromethane co-eluent)) 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) + .

[0613] Step 2: (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0614] (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 co-eluent) to give (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 light purple solid. 1H NMR(500MHz,DMSO-d6)δppm 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(d d,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, positive ion) 465.8 (M+H) + .

[0615] Example 23: (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0616]

[0617] Step 1: (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0618] 2-Dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (20.9mg, 0.048mmol) and palladium (II) acetate (10.8mg, 0.048mmol) were added to a THF (0.8mL) solution of (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazine-3-yl)-1,2-dihydroquinoline-6-sulfonamide (150mg, 0.240mmol). The reaction mixture was bubbled with argon, and then cyclobutylzinc bromide (0.5m in THF, 1.4mL, 0.72mmol) was added. The reaction was stirred at 50°C. After 90min, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution and distributed 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 co-elutant) 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, posit) 601.0 (M+H) + .

[0619] Step 2: (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0620] (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 co-eluent) to give 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. 1H NMR(500MHz,DMSO-d6)δppm 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=6.7H z, 1H), 6.75 (d, J = 9.6 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 3.78 (quin, J = 8.9 Hz, 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, positive ion) 480.8 (M+H) + .

[0621] Example 24: (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0622]

[0623] The title compound was prepared according to the method and purification scheme 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 afforded (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 2 steps) as a light purple solid. 1H NMR (500 MHz, chloroform-d) δ ppm 9.65-10.09 (m, 1H), 8.19 (d, J = 2.1 Hz, 1H), 7.87 (dd, J = 9.0, 2.2 Hz, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 6.98 (d, J = 6.2 Hz, 1H), 6.88 (d, J = 9.3 Hz, 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),2.39-2.49(m,2H),2.21-2.34(m,2H),2.08-2.18(m,1H),1.88-1.99(m,1H). m / z(ESI,positive ion)469.8(M+H) + .

[0624] Example 25: (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0625]

[0626] The title compound was prepared 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) according to the method and purification scheme of Example 23. This afforded (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 2 steps) as an off-white solid. 1HNMR(500MHz,DMSO-d6)δppm 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(d d,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 = 9.6 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 1.8 Hz, 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, positive ion) 452.0 (M+H) + .

[0627] Example 26: (P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide

[0628]

[0629] The title compound was prepared 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) according to the method and purification scheme of Example 23. This afforded (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 2 steps) as a white solid. 1H NMR (500MHz, chloroform-d) δppm 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),6.78(d,J=9.1Hz,1H),3.72(s,3H),3.65(quin,J=9.0Hz,1H),2. 34-2.46(m,2H),2.18-2.31(m,2H),2.06-2.14(m,1H),1.85-1.96(m,1H). m / z (ESI, positive ion) 463.0 (M+H) + .

[0630] Example 27: (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide

[0631]

[0632] The title compound was prepared 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) according to the method and purification scheme of Example 22. This afforded (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 2 steps) as a white solid. 1H NMR(500MHz,DMSO-d6)δppm 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 = 4.8 Hz, 1H), 6.99 (s, 1H), 6.75 (d, J = 9.9 Hz, 1H), 6.69 (d, J = 9.1 Hz, 1H), 3.68-3.75 (m, 1H), 3.67 (s, 3H), 2.32-2.44 (m, 2H), 2.26 (quin, J = 9.7 Hz, 1H), 2.11-2.20 (m, 4H), 1.99-2.07 (m, 1H), 1.80-1.90 (m, 1H). m / z (ESI, positive ion) 477.0 (M+H) + .

[0633] Example 28: (P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide

[0634]

[0635] The title compound was prepared 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) according to the method and purification scheme of Example 23. This afforded (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). 1H NMR (500MHz, chloroform-d) δppm8.59(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, positive ion) 481.0 (M+H) + .

[0636] Example 29: (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0637]

[0638] Step 1: (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0639] 2-Dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (41.8mg, 0.096mmol) and palladium (II) acetate (21.50mg, 0.096mmol) were added 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 (200mg, 0.319mmol) in THF (1.2mL). The reaction mixture was bubbled with argon, and then cyclobutylzinc bromide (0.5M in THF, 2.55mL, 1.28mmol) was added. The reaction was stirred at 50°C. After 3h, the reaction was quenched with saturated sodium bicarbonate aqueous solution and distributed 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 afford (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)+ .

[0640] Step 2: (P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0641] (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 co-eluent)) 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)δppm 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=1.8Hz,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, 1.6 Hz, 1H), 6.74 (d, J = 9.6 Hz, 1H), 6.64 (d, J = 8.8 Hz, 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, positive ion) 451.8 (M+H) + .

[0642] Example 30: (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0643]

[0644] The title compound was prepared 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) according to the method and purification scheme of Example 23. This afforded (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 2 steps) as a white solid. 1 H NMR (400MHz, DMSO-d6) δppm 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 = 8.3 Hz, 1H), 7.59-7.73 (m, 1H), 7.08 (s, 1H), 6.99 (s, 1H), 6.74 (d, J = 9.5 Hz, 1H), 6.65 (d, J = 8.9 Hz, 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, positive ion) 477.0 (M+H) + .

[0645] Example 31: (P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0646]

[0647] The title compound is prepared according to the method of Example 23 using (P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazine-3-yl)-1,2-dihydroquinoline-6-sulfonamide (300 mg, 0.494 mmol). The sample is purified by reverse phase HPLC using an XBridge Prep Shield RP18 19x100 mm column. The mobile phase is run under gradient elution; 15%-70% acetonitrile: water (with 0.1% formic acid); flow rate: 40 mL / min. This gives (P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazine-3-yl)-1,2-dihydroquinoline-6-sulfonamide (130 mg, 0.281 mmol, 57% yield over 2 steps) as a white solid. 1H NMR(500MHz,DMSO-d6)δppm 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),7.0 2 (dd, J = 8.0, 1.3 Hz, 1H), 6.74 (d, J = 9.6 Hz, 1H), 6.64 (d, J = 8.8 Hz, 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, positive ion) 463.0 (M+H) + .

[0648] Example 32: (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0649]

[0650] 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 by reverse phase HPLC using an XBridge Prep Shield RP18 19x100 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, 2x15 cm column. The mobile phase was run under isocratic conditions; supercritical CO2 with 60% isopropanol; flow rate: 70 mL / min. This afforded (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 2 steps) as a white solid. 1H NMR(500MHz,DMSO-d6)δppm 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),2.23(quin,J=9.5Hz,1H),2.00-2.12(m,1H),1.81-1.92(m,1H). m / z (ESI, positive ion) 486.0 (M+H) + .

[0651] Example 33: (P)-1-(5-Chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0652]

[0653] Step 1: (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0654] To a 20-mL scintillation vial was 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 bubbled with nitrogen, and then cyclobutylzinc bromide (0.5 M in THF, 1.87 mL, 0.935 mmol) was added. 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 for another 2h at 50°C, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and distributed 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 co-eluent)) to provide (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazine-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) + .

[0655] Step 2: (P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0656] (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 taken up in trifluoroacetic acid (2.6 mL) and the reaction was heated to 40°C. After 2 h, the reaction was then concentrated and purified by reverse phase HPLC using an XBridge Prep Shield RP18 19x100 mm column. The mobile phase was run at a gradient elution; 15%-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-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (83 mg, 0.167 mmol, 48% yield) as a yellow solid. 1H NMR (500MHz, DMSO-d6) δppm 14.46 (br s, 1H), 8.33 (d, J = 2.1Hz, 2H), 8.17 (d, J = 9.6Hz, 1H), 7.88 (br d, J = 3.9 Hz, 1H), 7.83 (dd, J = 9.0, 2.2 Hz, 1H), 7.67 (dd, J = 9.6, 4.2 Hz, 1H), 7.42 (s, 1H), 7.24 (s, 1H), 6.75 (d, J = 9.6 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 3.82 (quin, J = 8.8 Hz, 1H), 3.73 (s, 3H), 2.35-2.47 (m, 2H), 2.28-2.34 (m, 1H), 2.22 (quin, J = 9.9 Hz, 1H), 1.97-2.11 (m, 1H), 1.80-1.91 (m, 1H). m / z (ESI, positive ion) 497.0 (M+H) + .

[0657] 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

[0658]

[0659] 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

[0660] 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) were added to a 20-mL scintillation vial. The reaction mixture was bubbled with nitrogen, and then cyclobutylzinc bromide (0.5 M in tetrahydrofuran, 3.60 mL, 1.80 mmol) was added. The reactants were stirred at 50 °C. After 1 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and distributed 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 co-eluent) to afford (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) + .

[0661] Step 2: (P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0662] (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 taken up in TFA (3 mL) and heated to 50 °C. After stirring for 1 h, the reaction was concentrated and purified using a Torus 2-PIC, 3x15 cm column. The mobile phase was run under gradient elution conditions; supercritical CO2 with 10%-40% methanol; flow rate: 100 mL / min. This gave (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 2 steps). 1H NMR(600MHz,DMSO-d6)δppm 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),2.2 7(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, positive ion) 466.0 (M+H) + .

[0663] Example 35: trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0664]

[0665] 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

[0666] (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 bubbled with nitrogen, followed by the addition of tetrahydrofuran (3.1 mL). (3-(trifluoromethyl)cyclobutyl)zinc(II) bromide (0.125 M in THF, 9.46 mL, 1.182 mmol) was then 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 5M 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 under vacuum. The resulting residue was purified by flash column chromatography (gradient elution 0-50% [3:1 EtOAc / EtOH]: heptane (with 10% dichloromethane co-eluent)) 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) + .

[0667] Step 2: trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0668] (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 h. After cooling to ambient temperature, the volatiles were removed under vacuum and the residue was purified using a ChromegaChiral CC4, 2x25 cm column. The mobile phase was run under isocratic conditions; supercritical CO2 with 40% methanol; flow rate: 80 mL / min. This afforded 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 2 steps). 1H NMR(500MHz,DMSO-d6)δppm 11.60(s,1H),8.71(d,J=1.6Hz,1H),8.34(d,J=2.1Hz,1H),8.19(d,J=9.6H z,1H),7.83(dd,J=9.1,2.3Hz,1H),7.20-7.28(m,2H),7.11(dd,J=7.9,1.4H z,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, positive ion) 520.0 (M+H) + .

[0669] Example 36: trans-(P)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide

[0670]

[0671] The title compound was prepared according to the method of Example 23 by using (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) instead of (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide. The sample was purified using a Chiralpak IC, 2x15 cm column. The mobile phase was run under isocratic conditions; supercritical CO2 with 60% [1:1 methanol: dichloromethane]; flow rate: 80 mL / min. This afforded 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 2 steps). 1H NMR(500MHz,DMSO-d6)δppm 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, positive ion) 531.0 (M+H) + .

[0672] 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

[0673]

[0674] The title compound was prepared according to the method of Example 35 by using (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) instead of (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. The sample was purified using two consecutive Chiralpak OJ-H, 3x15 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 co-elutant) 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 2 steps) as a light pink solid. 1H NMR (500MHz, DMSO-d6) δppm 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, 3.9 Hz, 1H), 7.22 (s, 1H), 7.04 (s, 1H), 6.74 (d, J = 9.6 Hz, 1H), 6.65 (d, J = 9.1 Hz, 1H), 3.88 (quin, J = 8.9 Hz, 1H), 3.71 (s, 3H), 3.18-3.28 (m, 1H), 2.54-2.66 (m, 4H), 2.16 (s, 3H). m / z (ESI, positive ion) 545.0 (M+H) + .

[0675] Example 38: trans-(P)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide

[0676]

[0677] The title compound was prepared according to the method of Example 35 using (P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (459 mg, 0.756 mmol) instead of (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. The sample was purified using a Chiralpak AS-H, 2x25 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 co-elutant) 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 2 steps) as a light pink solid. 1H NMR (500MHz, DMSO-d6) δppm 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, 4.0 Hz, 1H), 7.18-7.25 (m, 2H), 7.11 (dd, J = 8.0, 1.6 Hz, 1H), 6.75 (d, J = 9.6 Hz, 1H), 6.65 (d, J = 9.1 Hz, 1H), 3.80 (quin, J = 8.8 Hz, 1H), 3.69 (s, 3H), 3.24-3.28 (m, 1H), 2.54-2.62 (m, 4H). m / z (ESI, positive ion) 531.0 (M+H) + .

[0678] 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

[0679]

[0680] The title compound was prepared according to the method of Example 35 by using (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) instead of (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. The sample was purified using two consecutive Chiralcel, 3x15 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 co-elutant) 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 2 steps) as a white solid. 1H NMR (500MHz, DMSO-d6) δppm 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, positive ion) 549.0 (M+H) + .

[0681] 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

[0682]

[0683] 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

[0684] A 250mL round-bottom flask was charged with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (5.0 g, 8.17 mmol) and N-(2,4-dimethoxybenzyl)isoxazole-3-amine (2.37 g, 10.1 mmol). The flask was purged with nitrogen for 5 minutes, after which tetrahydrofuran (20 mL) was introduced. The resulting mixture was cooled to -78 ° C in a dry ice-acetone bath and sodium tert-amyl alcohol (30% solution in THF, 5.0 mL, 12.5 mmol) was added dropwise. The reaction mixture was then stirred for 15 min. An aqueous ammonium chloride solution (5 M) was introduced, the resulting mixture was warmed to ambient temperature, and then 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 ( 100 g silica column, eluent: 0-80% ethyl acetate in heptane (with 10% dichloromethane co-elutant) 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) + .

[0685] 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

[0686] In a 100mL round-bottom flask equipped with a reflux condenser, magnesium chips (796mg, 32.8mmol) are loaded and purged with nitrogen for 15 minutes. Iodine (151mg, 0.596mmol) is introduced and the flask is heated with a heat gun until iodine is obviously sublimed. After being cooled to ambient temperature, a slight vacuum is applied to remove excess iodine. Tetrahydrofuran (12.5mL) is introduced. Then trans-1-bromo-3-(trifluoromethyl) cyclobutane (5.00g, 24.6mmol, Enamine Co., Ltd.) is slowly added to the stirred reaction mixture by a syringe, thereby producing a slight heat release and the disappearance of iodine color. As required, the reaction vessel is immersed in an ice / water bath to prevent excessive heat release. After stirring for 1h, tetrahydrofuran (12.5mL) is added. After an additional 1 h, 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 provide 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 bubbled 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 a syringe. After addition, the resulting mixture was warmed to 50 ° C. After 1.5 h, 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 ( 100 g silica column, eluent: 0-50% 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) + .

[0687] 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

[0688] 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 hours, after which the solvent was removed under a stream of nitrogen. The residue was purified by flash column chromatography ( The product was purified by HPLC-MS / MS (HPLC-MS / MS) using a 25 g silica column, eluent: 0-70% ethyl acetate in heptane (with 10% DCM additive). The fractions containing the desired product were combined, the solvent was removed under reduced pressure, and the residue (1.5 g) was further purified by SFC using a Chiralpak AD-H column (3 x 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(brs,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) + .

[0689] 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

[0690]

[0691]

[0692] Step 1: (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester and (M)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester

[0693] Racemic-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (see Intermediate AB) (257 g, 420 mmol) was purified by SFC via a Regis Whelk-O s,s,5x15cm,5μm column; 40% isopropanol / dichloromethane (1:1 mixture) mobile phase was purified using a flow rate of 350mL / min; to produce (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (123g, 201mmol) as the first elution peak and (M)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (137g, 224mmol) as the second elution peak.

[0694] 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

[0695] A 3L three-necked round bottom flask equipped with a thermocouple, an overhead stirrer, an addition funnel, and a nitrogen inlet was charged with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (175 g, 286 mmol), N-(4-methoxybenzyl)isoxazole-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. A 30% solution of sodium tert-amyl alcohol in THF (149 mL, 372 mmol) was charged to the addition funnel and added dropwise to the stirred reaction mixture over 15 mins. After 10 min, an aqueous solution of HCl (2N, 200 mL) was added to the reaction mixture at 0°C. The resulting mixture was allowed to warm to room temperature and the layers were separated. The aqueous layer was extracted with EtOAc (2x100mL). 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 via a Regis Whelk-O s,s 5x15cm, 5μm column; a mobile phase of 40% methanol / dichloromethane (1:1 mixed) was used at a flow rate of 350mL / min to obtain (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (148g, 234mmol, 82% yield). m / z(ESI)632.0 / 634.0(M+H)+.

[0696] 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

[0697] Zinc powder (10.3 g, 158 mmol) and lithium chloride solution (0.5 M, 45.0 mL, Sigma Aldrich) in THF were placed in an oven-dried 100 mL three-necked round-bottom flask. 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 kept at this temperature for 20 min 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 and kept for 20 min and then cooled to room temperature. A solution of iodine (0.40 g, 1.58 mmol) in THF (1.0 mL) was then added, and the reaction mixture was warmed to 50 ° C and kept for 20 min. 2-Bromo-5,8-dioxaspiro[3.4]octane (15.3 g, 15.3 mL, 79.0 mmol, Enamine Co., Ltd.) was added and the reaction mixture was stirred at 50°C for 48 hours. The reaction mixture was then cooled to room temperature and the residual zinc dust was allowed to settle, after which the supernatant 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). Then 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 bubbled with nitrogen for 10 min. The previously prepared organozinc complex solution was then added to the reaction mixture via a syringe, and the resulting mixture was stirred at 50° C. After 2 h, methanol (5 mL) and silica gel (about 25 g) were added to the reaction mixture, and the volatiles were removed under reduced pressure. The silica gel adsorbed material was purified by flash column chromatography (ISCO CombiFlash, 330 g silica column, eluent: 0-70% ethyl acetate / ethanol (3:1 mixed) gradient in heptane / DCM (9:1 mixed)) 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)+.

[0698] 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

[0699] 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). Aqueous 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, followed by the introduction of saturated sodium bicarbonate solution (100 mL) and DCM (100 mL). 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 column, eluent: 0-70% ethyl acetate / ethanol (3:1 mixed) gradient in heptane / DCM (9:1 mixed)) 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)+.

[0700] 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

[0701] 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, after which DAST (25.9 g, 21.3 mL, 161 mmol) was slowly added via syringe. The ice-water bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was carefully transferred to a mixture of saturated aqueous sodium bicarbonate solution 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 column, eluent: 0-70% ethyl acetate / ethanol (3:1 mixed) gradient in heptane / DCM (9:1 mixed)) 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)+.

[0702] 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

[0703] 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 hours, the reaction mixture was concentrated under reduced pressure and carefully poured into saturated aqueous sodium bicarbonate solution. 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 (3x70 mL) and purified by flash column chromatography ( 100 g silica column, 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)+.

[0704] 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

[0705]

[0706] 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

[0707] An oven-dried 40-mL vial was charged with 2'-(dicyclohexylphosphino)-N 2 ,N 2 ,N 6 ,N 6-tetramethyl-[1,1'-biphenyl]-2,6-diamine (32.9 mg, 0.075 mmol) and 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). The reaction mixture was bubbled with nitrogen for 15 min, and then (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)zinc(II) iodide solution (272 mg, 0.83 mmol) was added after filtering through a 0.45 micron PTFE filter. The reactants were stirred at 50°C. After 2 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution 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 (eluting with 0-40% ethyl acetate in heptane with 10% dichloromethane) to afford (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) + .

[0708] 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

[0709] (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 (with 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. 1H NMR (500 MHz, CHLOROFORM-d,) δ ppm 8.28 (d, J = 1.7 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.76 (dd, J = 2.2, 9.0 Hz, 1H), 7.72 (s, 1H), 6.94 (d, J = 9.1 Hz, 1H), 6.87 (d, J = 9.7 Hz, 1H), 6.8-6.8 (m, 1H), 6.77 (d, J = 9.0 Hz, 1H), 6.62 (d, J = 1.8 Hz, 1H), 3.73 (s, 3H), 2.43 (s, 6H). m / z (ESI, positive ion) 550.0 (M+H)+.

[0710] 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

[0711]

[0712] 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

[0713] 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 bubbled with nitrogen for 10 minutes before tetrahydrofuran (3.09 mL) was added. A solution of trans-(3-(trifluoromethyl)cyclobutyl)zinc(II) bromide (9.46 mL, 1.182 mmol) was then added dropwise via syringe. After the addition was complete, the reaction was warmed to 50 °C and stirred at that temperature for 1.25 hours. After cooling to ambient temperature, the reaction was quenched with 5M aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (2X). After removing the solvent, the residue was purified by flash column chromatography (eluted in heptane (with 10% dichloromethane additive) 0-50% 3: 1 ethyl acetate: ethanol) to obtain 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)+.

[0714] 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

[0715] (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. for 2.5 hours under a nitrogen atmosphere. After cooling to ambient temperature, excess TFA was removed under vacuum and the resulting solid was triturated with diethyl ether and filtered. The crude product was purified by column chromatography (gradient elution: 0-100% 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). 1H NMR(500MHz,DMSO-d6)δppm 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, positive ion) 538.0 (M+H)+.

[0716] Examples 44 and 45: 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

[0717]

[0718] 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

[0719] 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)-N2,N2,N6,N6-tetramethyl-[1,1'-biphenyl]-2,6-diamine (0.133 g, 0.304 mmol). The resulting mixture was sealed with a septum cap and bubbled with nitrogen for 10 minutes before tetrahydrofuran (6.92 mL) was added. A solution of (5,8-dioxaspiro[3.4]octan-2-yl)zinc(II) bromide (1.660 mmol) was then added dropwise via syringe. After addition, the reaction was warmed to 50 ° C and stirred for 1.25 hours. After cooling to ambient temperature, the reaction was quenched with 5M 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 (eluted in heptane (with 10% dichloromethane as an additive) 0-50% 3: 1 ethyl acetate: ethanol) to obtain (P)-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]oct-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)+.

[0720] (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). Hydrogen chloride (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 (P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide thus obtained (0.835 g, 1.383 mmol, 100% yield) was used as such in the next step. m / z (ESI, positive ion) 604.0 (M+H)+.

[0721] 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

[0722] (P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazole-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) was loaded in a vial at 0 ° C, sodium tetrahydroborate (0.052 g, 1.383 mmol) was added in batches. The reaction mixture was stirred at 0 ° C for 15 minutes, and then stirred at RT for 30 minutes. The reaction mixture was quenched with water and extracted with DCM (3x). The combined organic phase was concentrated in vacuo. The crude product was purified by column chromatography (gradient elution 0-40% EtOAc / EtOH (3 / 1) 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)+.

[0723] 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

[0724] Silver trifluoromethanesulfonate (0.513 g, 1.996 mmol), fluorine reagent (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) were placed in a vial in a nitrogen-filled glove box. 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 then added in sequence 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 gel (eluting with ethyl acetate). The filtrate was concentrated and the product was purified by column chromatography (gradient elution 0-40% 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)+.

[0725] The two isomers were separated by SFC via two Chiralpak AD-H, 5 μm columns (3×25 cm+3×15 cm) using a flow rate of 80 mL / min under a mobile phase of 25% ethanol. Peak 1 was assigned as 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 as 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).

[0726] Step 4: 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

[0727] 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 0-40% 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 (500 MHz, DMSO-d6) δ ppm 11.62 (s, 1H), 8.71 (s, 1H), 8.34 (d, J = 2.08 Hz, 1H), 8.20 (d, J = 9.60 Hz, 1H), 7.83 (dd, J = 8.95, 2.21 Hz, 1H), 7.32-7.27 (m, 2H), 6.78 (d, J = 9.38 Hz, 2H), 6.43 (d, J = 1.43 Hz, 1H), 5.11 (t, J = 5.77 Hz, 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, positive ion) 554.0 (M+H)+.

[0728] 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 0-40% ethyl acetate / EtOH (3:1) in heptane with 10% dichloromethane as an 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)δppm 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 = 1.82 Hz, 1H), 4.92 (quin, J = 7.40 Hz, 1H), 3.38 (tt, J = 10.46, 7.51 Hz, 1H), 3.32-3.25 (m, 3H), 2.84 (dquin, J = 12.05, 6.07, 6.07, 6.07, 6.07 Hz, 2H), 2.55-2.52 (m, 1H), 2.47-2.41 (m, 1H). m / z (ESI, positive ion) 554.0 (M+H)+.

[0729] 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

[0730]

[0731] Step 1: 4-Bromo-3-fluoro-2-iodoaniline

[0732] 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 obtain the initial product, which was purified by column chromatography ( ISOLERA ONE,BIOTAGE 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, nearly copper solid. m / z (ESI, posit) 315.8 (M+H)+.

[0733] Step 2: (E)-ethyl 3-(6-amino-3-bromo-2-fluorophenyl)acrylate

[0734] Sodium bicarbonate (4.19g, 49.9mmol), ethyl acrylate (2.096g, 2.355mL, 20.94mmol) and palladium acetate (ii) (0.090g, 0.399mmol) were loaded into a 100mL flask. A solution of 4-bromo-3-fluoro-2-iodoaniline (6.3g, 19.94mmol) in N,N-dimethylformamide (13.29mL) was added to the reaction mixture. The reaction was stirred for 3 hours at 100°C under nitrogen. The reaction was diluted with ethyl acetate and filtered through diatomite. The filtrate was concentrated under reduced pressure to obtain the initial product, which was purified by column chromatography to obtain (E)-3-(6-amino-3-bromo-2-fluorophenyl)ethyl acrylate (5.92g, 20.55mmol, 103% yield). 1 H NMR (400MHz, DMSO-d6) δppm 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).

[0735] Step 3: (E)-ethyl 3-(6-amino-3-(benzylthio)-2-fluorophenyl)acrylate

[0736] 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 bubbled with nitrogen for 20 minutes. In a separate 20 mL vial, bis[tri(dibenzylideneacetone)palladium(0)] (0.890 g, 0.972 mmol) and (5-diphenylphosphane-9,9-dimethylxanthen-4-yl)-diphenylphosphane (1.125 g, 1.944 mmol) were added. The vial was bubbled with nitrogen for 5 minutes before adding 1,4-dioxane (5 mL). The catalyst solution was transferred to the flask containing the acrylate via a syringe. 1-Toluenethiol (1.379 g, 1.379 mL, 11.11 mmol) was then added in one portion. The mixture was stirred at 80 °C for 16 hours. The reaction was cooled and filtered through celite. The celite was washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was purified by column chromatography ( Isolera One, SNAP Ultra 100 g, 0-30% ethyl acetate in heptane) to give (E)-ethyl 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)+.

[0737] Step 4: (E)-ethyl 3-(3-(benzylthio)-6-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-2-fluorophenyl)acrylate

[0738] A 40 mL vial was charged with (E)-ethyl 3-(6-amino-3-(benzylthio)-2-fluorophenyl)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 bubbled 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 quickly added. After bubbling with nitrogen for another 5 minutes, the reaction was heated to 110°C. After stirring for 16 hours, the reaction was cooled to ambient temperature, diluted with dichloromethane, and filtered through celite. The solvent was removed under reduced pressure. The residue was purified by column chromatography ( ISOLERA ONE,BIOTAGE SILICA H C D25g, 0-40% ethyl acetate in heptane) to give (E)-ethyl 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, posit) 535.8 (M+H)+.

[0739] Step 5: 6-(Benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoroquinolin-2(1H)-one

[0740] (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, a 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 adding water. The product was extracted with ethyl acetate (2X). The organic layer was separated and the solvent was removed in vacuo. The residue was purified by column chromatography ( Isolera One, Sfar Silica HC D 50 g, 0-40% ethyl acetate in heptane with 10% dichloromethane as additive) was purified to provide 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)+.

[0741] Steps 6 and 7: Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate

[0742] 6-(Benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoroquinoline-2(1H)-one (0.710 g, 1.454 mmol), acetonitrile (7.04 mL), acetic acid (0.134 mL) and water (0.095 mL) were loaded into a 40 mL vial. The reaction was cooled to 0 ° C by an ice bath, after which 1,3-dichloro-5,5-dimethyl-2,4-imidazole dione (0.430 g, 2.181 mmol) was added at once. After 10 minutes, pentafluorophenol (0.321 g, 1.745 mmol) and then anhydrous triethylamine (0.588 g, 0.817 mL, 5.82 mmol) were added. After 1 hour, the reaction was quenched with 2M HCl aqueous solution and extracted with ethyl acetate. The organic layer was separated and the solvent was removed in vacuo. The residue was purified by column chromatography ( Isolera One, Sfar 25g silica HC D, 0-40% ethyl acetate in heptane with 10% dichloromethane as additive) was purified to provide 1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (0.676 g, 1.104 mmol, 76% yield) as a white solid. m / z (ESI, positive ion) 614.0 (M+H)+.

[0743] 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

[0744] 1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonic acid perfluorophenyl ester (0.676 g, 1.104 mmol) and N-(4-methoxybenzyl)isoxazole-3-amine (0.271 g, 1.325 mmol) were placed in a 40 mL vial. The vial was purged with nitrogen for 5 minutes before tetrahydrofuran (2.208 mL) was added. The reaction was then cooled to -78 ° C and sodium tert-amyl alcohol, a 30% solution in thf (0.574 mL, 1.435 mmol) was slowly added. After 10 minutes, the reaction was warmed to 0 ° C, after which the reaction was quenched with 5M 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 ( ISOLERA ONE,BIOTAGE SILICA 25g, 0-50% ethyl acetate in heptane with 10% dichloromethane as additive) was purified to provide 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)+.

[0745] 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

[0746] A 40 mL vial was charged with 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-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. 2 ,N 2 ,N 6 ,N 6 -Tetramethyl-[1,1'-biphenyl]-2,6-diamine (0.044 g, 0.101 mmol). The vial was sealed and bubbled 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 5M aqueous ammonium chloride solution, 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 ( ISOLERA ONE,BIOTAGE SILICA HCD 10g, 0-40% ethyl acetate in heptane with 10% dichloromethane as additive) was purified 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 light pink solid. m / z (ESI, positive ion) 676.2 (M+H)+.

[0747] 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

[0748] 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 ( ISOLERA ONE,BIOTAGE SILICA HC D 10g, 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)+.

[0749] 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

[0750] 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 via 2 steps. Step 1: Regis Whelk-O s,s 2x15cm, 5μm column; 35% methanol mobile phase, using a flow rate of 60mL / min; Step 2: (separation of peak 1 and peak 2): two Chiralpak AD-H, 5μm columns (3x15cm+3x25cm); 30% ethanol mobile phase, using a flow rate of 80mL / min. Peak 1 was lyophilized to yield 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)δppm 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=9.9H z, 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, positive ion) 556.2 (M+H)+.

[0751] Example 47: (P)-1-(5-Fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(pyrimidin-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0752]

[0753] 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

[0754] An oven-dried 40 mL vial was charged with 2'-(dicyclohexylphosphanyl)-N 2 ,N 2 ,N 6 ,N6 -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). The reaction mixture was bubbled with nitrogen for 15 minutes, and then (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)zinc(II) iodide solution (1.59 mmol) was added after filtering through a 0.45 micron PTFE filter. The reaction was stirred at 50° C. for 3 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution 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 0-60% 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 light grey foam. m / z (ESI, positive ion) 681.1 (M+H) + .

[0755] 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

[0756] (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 RT. The reaction was made basic with 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% to 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, 500 MHz) δ ppm 10.27 (br s, 1H), 8.60 (d, J = 4.9 Hz, 2H), 8.43 (d, J = 2.1 Hz, 1H), 8.07 (dd, J = 2.1, 9.0 Hz, 1H), 7.85 (d, J = 9.6 Hz, 1H), 7.00 (t, J = 4.9 Hz, 1H), 6.93 (d, J = 9.2 Hz, 1H), 6.85 (d, J = 9.6 Hz, 1H), 6.83 (d, J = 6.4 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 3.72 (s, 3H), 2.42 (s, 6H). m / z (ESI, positive ion) 561.0 (M+H)+.

[0757] Example 48: (P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0758]

[0759] 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

[0760] (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazole-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.500 g, 0.793 mmol), tetrahydrofuran (1.585 mL), palladium acetate (II) (0.018 g, 0.079 mmol), and 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (0.069 g, 0.159 mmol) were loaded into a vial. The vial was purged with nitrogen, followed by addition of 5,8-dioxaspiro[3.4]octan-2-ylzinc bromide (II) (0.1 M in THF, 1.110 mmol) and the reaction was stirred at 50 ° C for 1 hour. The reaction was then diluted with ethyl acetate and acidified with 1N 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) + .

[0761] 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

[0762] (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 (2N in water, 2.0 mL, 4.0 mmol) was added and the reaction was stirred at 50 °C for three 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 obtained (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) + .

[0763] 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

[0764] 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 solution was carefully added until bubbling stopped. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was 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).

[0765] Step 4: (P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

[0766] (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 aqueous NaHCO3. The mixture was extracted with dichloromethane, dried over MgSO4 and filtered. The initial product was purified by flash column chromatography (gradient elution 0-50% EtOAc in heptane). The sample was purified by SFC via a Regis Whelk-O s,s 2x15 cm, 5 μm column under 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)δppm 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,1 H),7.83(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, positive ion) 521.8 (M+H) + .

[0767] 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

[0768]

[0769] 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

[0770] 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 with a septum cap and bubbled with nitrogen for 10 minutes before tetrahydrofuran (3.09 mL) was added. A solution of (3-(trifluoromethyl)cyclobutyl)zinc(II)bromide (1.182 mmol) was added. After the addition was complete, the reaction was warmed to 50 °C and stirred at that temperature for 1.25 hours. After cooling to ambient temperature, the reaction was quenched with 5M aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (2X). The organic layer was separated. After removal of the solvent, the residue was purified by flash column chromatography (gradient elution 0-50% 3:1 ethyl acetate:ethanol in heptane (with 10% dichloromethane as an 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)+.

[0771] 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

[0772] (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 for 2.5 hours under a nitrogen atmosphere. 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). 1H NMR(500MHz,DMSO-d6)δppm12.13(br s,1H),8.31(d,J=2.08Hz,1H),8.17(d,J=9.60Hz,1H),7.84(dd,J=8.95,2.21Hz,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, positive ion) 554.0 (M+H)+.

[0773] Biological Examples

[0774] The following assays were used to test exemplary compounds of the invention. The data for those examples tested according to the following procedure are shown in Table 1 below.

[0775] IONWORKS BARRACUDA (IWB) automated patch clamp assay (same protocol for both human and mouse)

[0776] Human Nav1.7 currents were recorded in population patch clamp mode using an IWB automated electrophysiology system (Molecular Devices, LLC, Sunnyvale, CA). Spiking HEK cells (in the absence of Kir2.1 transfection) were cultured and prepared for recordings as previously tested for the IonWorks Quattro 1The external solution is composed of the following items (in mM): NaCl 140, KCl 5, CaCl22, MgCl21, HEPES10 and glucose 11, pH 7.4, with N-methyl-D-glucosamine, at 320mOsmol. The internal solution is composed of the following items (in mM): KCl70, KF 70, MgCl20.25, HEDTA 5 and HEPES10, pH 7.25, with N-methyl-D-glucosamine, 300mOsmol. From the holding potential of -110mV, 26 depolarization sequences with a duration of 150ms at a frequency of 5Hz are used to stimulate current to -20mV. Then in the presence of a single concentration of the test compound, the cell is clamped at -20mV for a period of 4 minutes. Following this compound incubation period, cells were clamped at -110 mV for three seconds to recover unbound channels and 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 evoked 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 calculate IC 50 Values, 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.

[0777] Microsomal intrinsic clearance assay

[0778] The purpose of this assay is to determine the intrinsic clearance of test compounds in microsomes from preclinical species and humans by monitoring the disappearance of the test compound in liver microsomes over time. Microsomes stored at -80°C were used at 20 mg / mL stock solution. List of chemicals used: (1) test compound, 10 mM stock solution (DMSO) or powder from a sample bank; (2) verapamil, 10 mM stock solution; (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 compound, and incubations were 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 and samples were taken continuously from 400 μL incubations. At the appropriate time point, the incubation was quenched with acetonitrile containing an internal standard (tolbutamide). Tolbutamide is the default internal standard because it obtains signals by positive or negative ion mass spectrometry. The positive control for the microsomal intrinsic clearance assay is verapamil. The samples were analyzed by LC-MS / MS, and the relative amount of the compound was calculated by the compound peak area (A / IS) normalized to the internal standard peak area. The calculation of intrinsic clearance was performed using the Galileo system.

[0779] program:

[0780] Remove the microsomes from the -80°C freezer and thaw at room temperature or in a 37°C water bath. Once thawed, they are stored on ice. Add the microsomes (0.53 mg / ) to 0.1 M phosphate buffer and take 250 μL aliquots for each reaction. Prepare a 10 mM stock solution of the test substance in DMSO. Dilute a 1 / 100 portion in acetonitrile: water 50:50 to prepare a 100 μM stock solution. Add approximately 2.5 μL of the 100 μM test substance stock solution to each reaction to give a final substrate concentration of 1.05 μM. (Note: At this stage, the concentration is approximately 2 times higher than the final incubation conditions to account for the approximately 1:1 dilution with NADPH).

[0781] 1.9mM NADPH solution was prepared in 0.1mM phosphate buffer. 4x250μL substrate and microsome replicate wells containing 1.05μM substrate and 0.53mg / mL protein were prepared. Three replicate wells containing 210μL 1.90mM NADPH + 1 well of buffer (-NADPH) were also prepared. Microsomes, 0.1M phosphate buffer and test substance were pre-incubated at 37°C for 5 minutes. To start the reaction, 190μL substrate was added to the well containing NADPH to produce a final concentration of 0.25mg / mL microsomes, 0.5μM test substance and 1mM NADPH. 35μL aliquots were removed at 1, 5, 10, 20, 30 and 40 minutes. The reaction was then quenched with acetonitrile containing internal standard at a 1:1 ratio, placed in a vortex mixer and centrifuged. The solution was then transferred for bioanalysis by LC-MS / MS.

[0782] Open-field locomotor activity in mice.

[0783] On the test day, C57B1 / 6 male mice were orally administered Nav1.7 compound or vehicle control formulation at a dose volume of 10 ml / kg. The vehicles used were 2% HPMC / 1% Tween 80 pH 10 (with NaOH); deionized water w / NaOH at pH 10; or 2% HPMC / 1% Tween 80 pH 2.2.

[0784] Two to three hours after test article treatment, depending on the cmax of each Nav1.7 test compound of the invention, the animals were placed in an open field chamber and animal behavior was monitored over a 30 minute period. For the Thousand Oaks experiments, a 16"x16" open field chamber was used, KINDER San Diego, CA. For the Cambridge, MA field experiments, a 16"x16" open field chamber was used. San Diego, CA. Locomotor activity (horizontal locomotion and rearing activity) parameters were measured in an automated fashion by infrared beam interruption.

[0785] Human CYP 3A4 Induction Assay

[0786] Cryopreserved human hepatocytes were seeded at 70,000 cells per well in a 96-well collagen-coated plate in hepatocyte seeding medium (HPM, final concentration: 1x Dubeck's modified Eagle's medium, 0.1 μM dexamethasone, 10% fetal bovine serum, 1x ITS, 1x PSG), followed by incubation at 37°C, 5% CO2 and 90% relative humidity for 2 days to allow the hepatocytes to form a confluent layer. On day 3, hepatocytes were treated with test compounds prepared in hepatocyte culture medium (HIM, final concentration: 1X Williams' medium E, 0.1 μM dexamethasone, 1x ITS, 1x PSG) or rifampicin (20 μM, positive control for CYP3A induction). Treatment was continued for 72 hours with 2 concentrations (2 μM or 10 μM) or a series of concentrations (0.001 μM to 100 μM) of the test compound to obtain a complete dose-response curve. The fresh culture medium containing the test compound of relevant concentration is replaced every day until the sample is processed. After incubation for 72 hours, the sample is subjected to mRNA analysis using the instructions of the manufacturer (Affymetrix, Fremont, CA) using bDNA technology. Cell viability is tested using MTT assay kit (Roche Diagnostics, Basel, Switzerland) at the end of the experiment. According to the guidelines of Center for Drug Evaluation and Research [Drug Evaluation and Research Center] (CDER), 2006, Guidance for Industry [Industry Guide], Drug Interaction Studies-Study Design, Data Analysis, and Implications for Dosing and Labeling [Drug Interaction Studies-Study Design, Data Analysis and the Effect on Dosing and Labeling], the data are analyzed and the E obtained when the control percentage (POC) and when appropriate are used. max and EC 50 presented in the form of.

[0787] Cryopreserved human hepatocytes were seeded at 70,000 cells per well in a 96-well collagen-coated plate in hepatocyte seeding medium (HPM, final concentration: 1x Dubeck's modified Eagle's medium, 0.1 μM dexamethasone, 10% fetal bovine serum, 1x ITS, 1x PSG), followed by incubation at 37°C, 5% CO2 and 90% relative humidity for 2 days to allow the hepatocytes to form a confluent layer. On day 3, hepatocytes were treated with test compounds prepared in hepatocyte culture medium (HIM, final concentration: 1X Williams' medium E, 0.1 μM dexamethasone, 1x ITS, 1x PSG) or rifampicin (20 μM, positive control for CYP3A induction). Treatment was continued for 72 hours with 2 concentrations (2 μM or 10 μM) or a series of concentrations (0.001 μM to 100 μM) of the test compound to obtain a complete dose-response curve. Fresh medium containing the test compound of relevant concentration was replaced every day until the sample was processed. After 72 hours of incubation, samples were processed for mRNA analysis using bDNA technology using the manufac...

Claims

1. A compound having formula (I): enantiomers, diastereomers, atropisomers, mixtures thereof, or pharmaceutically acceptable salts thereof; in: R 1 is a saturated or partially saturated 4-membered monocyclic ring; or a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered bicyclic ring; wherein the monocyclic ring or bicyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; and wherein the monocyclic ring or bicyclic ring is surrounded by 0, 1, 2, or 3 R selected from the following 1a Group substitution: hydroxyl, halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, -OC 1-4 Alkyl, -OC 1-8 Haloalkyl, -C(=O)C 1-4 Alkyl, -OC(=O)C 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, or -N(C 1-4 Alkyl)C 1-4 alkyl; R 2 H, halogen, C 1-6 Alkyl, or C 1-6 Haloalkyl; R 3 It is C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, or -CN; R 4 is a 5- to 6-membered heteroaryl group; R 6 and R 7 are each hydrogen; and R 5a , R 5b , R 5c , R 5d , and R 5e are each independently hydrogen or halo.

2. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 1a The group is selected from halogen, C 1-8 Alkyl, -OC 1-4 Alkyl, or C 1-8 haloalkyl, wherein the C 1-8 Haloalkyl is C 1-8 Fluoroalkyl.

3. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 1 is a cyclobutyl ring; or a 5-membered or 6-membered bicyclic ring; wherein the cyclobutyl ring or bicyclic ring contains 0 N, O and S atoms; and wherein the cyclobutyl ring or bicyclic ring is surrounded by 1, 2 or 3 R selected from the following 1a Group substitution: F, -CF3, -O-CF3 or -C(CH3)3.

4. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 1 is a cyclobutyl ring or a bicyclo[1.1.1]pentan-1-yl ring; wherein each ring is substituted by 1 or 2 F or -CF3.

5. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 1 It is a cyclobutyl ring substituted with 1 or 2 F or -CF3.

6. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 1 It is a cyclobutyl ring substituted with 1 or 2 -CF3 groups.

7. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 1 is a cyclobutyl ring substituted with 1 or 2 F groups.

8. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 1 It is a bicyclo[1.1.1]pentan-1-yl ring substituted by 1 or 2 F or -CF3.

9. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 2 is H, fluorine, chlorine, methyl, CF3, CHF2, or CH2F.

10. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 2 is H, fluorine, chlorine, or methyl.

11. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 2 It is H or fluorine.

12. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 3 It's a methoxy group.

13. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 4 It is a 5-membered heteroaryl.

14. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 4 It is a 6-membered heteroaryl.

15. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.

16. The compound according to claim 15, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 4 It is isoxazolyl.

17. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: (a)R 5a , R 5b , R 5c , R 5d , and R 5e each is hydrogen; (b) R 5a is F; and R 5b , R 5c , R 5d , and R 5e are each hydrogen; or (c) R 5c is F; and R 5a , R 5b , R 5d , and R 5e Each is hydrogen.

18. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The R 5a It's F.

19. The compound according to claim 15, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R 5a , R 5b , R 5c , R 5d , and R 5e Each is hydrogen.

20. The compound according to claim 15, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R 5a is F; and R 5b , R 5c , R 5d , and R 5e Each is hydrogen.

21. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The compound of formula (I) is selected from compounds of formula (Ia), (Ib) or (Ic): or wherein each R in the compound of formula (Ia), (Ib) or (Ic) 1a is independently fluorine, chlorine, methyl, -O-CF3, or CF3.

22. The compound according to claim 21, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The compound of formula (I) is a compound of formula (Ia); wherein R 1a is CF3; the cyclobutyl ring is a trans isomer; and R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, or oxazolyl.

23. The compound according to claim 21, its enantiomer, diastereomer, atropisomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein: The compound of formula (I) is a compound of formula (Ia); wherein R 1a is cis-CF3; the cyclobutyl ring is a cis isomer; R 2 is F; and R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, or oxazolyl.

24. The compound according to claim 21, its enantiomer, diastereomer, atropisomer, mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound of formula (I) is a compound of formula (Ib); wherein each R 1a is fluorine; R 2 is F; and R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.

25. The compound of claim 21, its enantiomer, diastereomer, atropisomer, mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound of formula (I) is a compound of formula (Ib); wherein each R 1a is fluorine; R 5a is F; and R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.

26. The compound of claim 21, its enantiomer, diastereomer, atropisomer, mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound of formula (I) is a compound of formula (Ic); wherein each R 1a It's CF3.

27. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from: a) cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; b) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; c) 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; d) 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; e) trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; f) trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; g) trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; h) trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; i) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; j) (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; k) (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; l) cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; m) 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; n) 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 o) 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.

28. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from: a) (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; b) (P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; c) trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; d) cis-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; e) cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; f) trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; g) (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or h) (P)-1-(5-Chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

29. The compound according to claim 1, its enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from: a) (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 b) (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.

30. The compound of claim 1, its enantiomer, diastereomer, atropisomer, mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: The atropisomer is the P atropisomer.

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

32. A method for treating pain, cough or pruritus, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1, an enantiomer, a diastereomer, an atropisomer, a mixture thereof, or a pharmaceutically acceptable salt thereof.

33. The method according to claim 32; wherein: The pain is selected from the group consisting of 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.

34. The method according to claim 32; wherein: The cough is selected from a post-viral cough, a viral cough or an acute viral cough.

35. A method for preparing a compound having formula (A): wherein R is a halogen group; The method includes: (1) a trans-olefin compound having the formula (B): wherein R is a halogen group; and R 1 is a C1-C6 alkyl group; reacting with UV light or near-UV light to form a cis-olefin compound (C); as well as (2) reacting the compound (C) with a chiral acid in an organic solvent to form the compound having the formula (A).

36. The method of claim 35, wherein: The chiral acid is a phosphorus chiral acid.

37. The method of claim 35, wherein: The chiral acid is (S)-TRIP having the formula:

38. The method of claim 35, wherein: The organic solvent is dichloromethane.

39. The method of claim 35, wherein: Said R is bromine.

40. The method of claim 35, wherein: The R 1 It is ethyl.

41. The method of claim 35, wherein: In reaction (2), the P-atropisomer of the compound of formula (A) is selectively formed.

42. The method of claim 35, wherein: The compound having formula (A) is a compound having formula (I): or a pharmaceutically acceptable salt thereof for use as an intermediate compound, in: R 1 is a saturated or partially saturated 4-membered monocyclic ring; or a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered bicyclic ring; wherein the monocyclic ring or bicyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; and wherein the monocyclic ring or bicyclic ring is surrounded by 0, 1, 2, or 3 R selected from the following 1a Group substitution: hydroxyl, halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, -OC 1-4 Alkyl, -OC 1-8 Haloalkyl, -C(=O)C 1-4 Alkyl, -OC(=O)C 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, or -N(C 1-4 Alkyl)C 1-4 alkyl; R 2 H, halogen, C 1-6 Alkyl, or C 1-6 Haloalkyl; R 3 It is C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, or -CN; R 4 is a 5- to 6-membered heteroaryl group; R 6 and R 7 are each hydrogen; and R 5a , R 5b , R 5c , R 5d , and R 5e are each independently hydrogen or halo; and wherein the P-atropisomer of the compound of formula (I) is selectively formed.

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