US20230234948A1 - Cyclopropyl dihydroquinoline sulfonamide compounds - Google Patents

Cyclopropyl dihydroquinoline sulfonamide compounds Download PDF

Info

Publication number
US20230234948A1
US20230234948A1 US18/009,682 US202118009682A US2023234948A1 US 20230234948 A1 US20230234948 A1 US 20230234948A1 US 202118009682 A US202118009682 A US 202118009682A US 2023234948 A1 US2023234948 A1 US 2023234948A1
Authority
US
United States
Prior art keywords
cyclopropyl
dihydroquinoline
oxo
phenyl
methoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
US18/009,682
Other languages
English (en)
Inventor
Benjamin C. MILGRAM
Issac E. MARX
John Stellwagen
Wei Zhao
Alan H. CHERNEY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amgen Inc
Original Assignee
Amgen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amgen Inc filed Critical Amgen Inc
Priority to US18/009,682 priority Critical patent/US20230234948A1/en
Publication of US20230234948A1 publication Critical patent/US20230234948A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention provides compounds that are inhibitors of voltage-gated sodium channels (NaV), in particular NaV 1.7, and are useful for the treatment of diseases treatable by inhibition of sodium channels such as pain disorders. Also provided are pharmaceutical compositions containing compounds of the present invention.
  • NaV voltage-gated sodium channels
  • Chronic pain by definition involves abnormal electrical spiking of neurons in the pain pathways: peripheral sensory neurons, spinal cord neurons, neurons in the pain matrix of the brain (e.g., somatosensory cortex, insular cortex, anterior cingular cortex), and/or neurons in brainstem.
  • somatosensory cortex e.g., insular cortex, anterior cingular cortex
  • neurons in brainstem e.g., somatosensory cortex, insular cortex, anterior cingular cortex
  • firing of these neurons is modulated and governed by many different receptors, enzymes, and growth factors, in most neurons the fast upstroke of the electrical spike is produced by entry of sodium ions through voltage-gated sodium channels (Hille B, Ion Channels of Excitable Membranes.
  • NaV1.1 and NaV1.2 are highly expressed in the brain (Raymond, C. K., et al., J. Biol. Chem . (2004) 279 (44):46234-41) and are vital to normal brain function. Some loss of function due to NaV 1.1 mutations in humans, have resulted in epilepsy, presumably as these channels are expressed in inhibitory neurons (Yu, F. H., et al., Nat. Neuroscience (2006), 9 (9) 1142-1149). NaV1.1 is also expressed in the peripheral nervous system and inhibition of NaV1.1 in the periphery may provide relief of pain. Hence, while inhibiting NaV1.1 may provide use fro treating pain, it may also be undesirable possibly leading to anxiety and over excitability.
  • NaV1.3 is expressed primarily in the fetal central nervous system, and expression was found to be upregulated after nerve injury in rats (Hains, B. D., et al., J. Neuroscience (2030) 23(26):8881-8892).
  • NaV1.4 is expressed primarily in skeletal muscle. Mutations of the gene and its' product have significant impact on muscle function, including paralysis (Tamaoka A., Internal Medicine (2003), (9):769-770).
  • NaV1.5 is expressed mainly in cardiac myocytes, including atria, ventricles, the sino-atrial node, atrioventricular node and cardiac Purkinje fibers. The rapid upstroke of the cardiac action potential and the rapid impulse conduction through cardiac tissue is due to the opening of the NaV1.5 channel.
  • NaV1.5 is widely distributed voltage-gated sodium channel expressed throughout the central and peripheral nervous system.
  • NaV1.8 is expressed primarily in sensory ganglia of the peripheral nervous system, such as the dorsal root ganglia. There are no identified NaV1.8 mutations that produce varied pain responses in humans.
  • NaV1.8 differs from most neuronal NaV isotypes in that it is insensitive to inhibition by tetrodotoxin.
  • NaV1.9 similar to NaV1.8, is also a tetrodotoxin insensitive sodium channels expressed primarily in dorsal root ganglia neurons (Dib-Hajj, S. D., et al., Proc. Natl. Acad. Sci. USA (1998), 95(15):8963-8968).
  • Nonselective sodium channel inhibitors such as lidocaine, mexiletine, and carbamazepine show clinical efficacy in chronic pain, including neuropathic pain, but they are limited in dose and in use, likely due to effects on sodium channels outside the pain pathway.
  • Lidocaine is a local anesthetic that doctors use for minor surgery. Dentists use novocaine. However, these compounds do not distinguish between the various sodium channel subtypes, making them unsuitable for use as systemic pain killers. “If you give a drug that blocks NaV1.7 but also blocks NaV1.5, the patient will die of heart failure,” says Glenn F. King, a professor at Australia's University of Queensland who studies venoms that block ion channels.
  • the present invention provides a compound of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 1 is a cyclopropyl ring; or a 4-, 5-, 6-, 7-, or 8-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S; and wherein said cyclopropyl ring or bicyclic ring is substituted by 0, 1, 2 or 3 R 1a groups selected from hydroxy, halo, C 1-8 alk, C 1-8 haloalk, —O—C 1-4 alk, —O—C 1-8 haloalk, —C( ⁇ O)C 1-4 alk, —O—C( ⁇ O)C 1-4 alk, —NH 2 , —NHC 1-4 alk, —N(C 1-4 alk)C 1-4 alk, 3-, 4-, or 5-membered cycloalkyl, or 6-membered aryl;
  • R 2 is H, halo, CN, C 1-6 alk, or C 1-6 haloalk
  • R 3 is C 1-6 alk, C 1-6 haloalk, —O—C 1-6 alk, —O-cyclopropyl, or —O-cyclobutyl;
  • R 4 is a 5- to 6-membered heteroaryl
  • R 6 and R 7 are hydrogen;
  • Each of R 5a ; R 5b ; R 5c ; R 5d ; and R 5e is independently hydrogen or halo.
  • the compound of Formula (I) has a sub-formula of (Ia):
  • R 1a is fluoro, methyl, —O—CF 3 , —CH 2 —O—CF 3 , CF 3 , cyclopropyl, or phenyl.
  • R 1a is methyl, CF 3 , or phenyl; and R 4 is isoxazolyl or pyridazinyl.
  • R 1a is CF 3 ; R 2 is F; and R 4 is isoxazolyl.
  • the compound of formula (I) has a sub-formula of (Ib):
  • R 1a is fluoro, methyl, or CF 3 .
  • R 1a is fluoro or methyl.
  • the compound of Formula (I) has a sub-formula of (Ic):
  • R 1a is fluoro, methyl, or CF 3 .
  • R 1a is CF 3 .
  • the compound of formula (I) has a sub-formula of (Id):
  • R 1a is fluoro, methyl, or CF 3 .
  • R 1a is CF 3 .
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a group is selected from halo, C 1-8 alk, —O—C 1-4 alk, C 1-8 haloalk, cyclopropyl, or phenyl; wherein said C 1-8 haloalk is C 1-8 fluoroalkyl.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a cyclopropyl ring; or a 4-, 5-, or 6-membered bicyclic ring; wherein said bicyclic ring contains 0 N, O, and S atoms; and wherein said cyclopropyl ring or bicyclic ring is substituted by 1, 2 or 3 R 1a groups selected from F, —CF 3 , —O—CF 3 , —C(CH 3 ) 3 , cyclopropyl, or phenyl.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a cyclopropyl ring or bicyclo[1.1.0]butan-1-yl ring; wherein each ring is substituted by 1 or 2 F or —CF 3 .
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a cyclopropyl ring substituted by 1 or 2 F or —CF 3 ; wherein said cyclopropyl ring is a trans isomer.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a bicyclo[1.1.0]butan-1-yl ring substituted by 1 or 2 F or —CF 3 .
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is H, fluoro, chloro, CN, methyl, CF 3 , CHF 2 , or CH 2 F. In sub embodiment 7a of embodiment 7, R 2 is fluoro.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is H, fluoro, chloro, CN, or methyl.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is H or fluoro.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is methoxy.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5-membered heteroaryl.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 6-membered heteroaryl.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.
  • R 4 is isoxazolyl, pyridazinyl, or pyrimidyl.
  • R 4 is isoxazolyl.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein a) each of R 5a ; R 5b ; R 5c ; R 5d ; and R 5e is hydrogen; b) R 5a is F; and each of R 5a ; R 5b ; R 5c ; R 5d ; and R 5e is hydrogen; or c) R 5d is F; and each of R 5a ; R 5b ; R 5c ; and R 5e is hydrogen.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each of R 5a ; R 5b ; R 5c ; R 5d ; and R 5e is hydrogen.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5a is F; and each of R 5b ; R 5c ; R 5d ; and R 5c is hydrogen.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5d ; is F; and each of R 5a ; R 5b ; R 5c ; and R 5e is hydrogen.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (I) is of formula (Ia):
  • each R 1a is independently fluoro, methyl, —O—CF 3 , CF 3 , cyclopropyl, or phenyl.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a is CF 3 or methyl; the cyclopropyl ring is a trans isomer; R 2 is H or F; R 4 is isoxazolyl, pyridazinyl, thiazolyl, or thiadiazolyl; and R 5a is H or F.
  • R 1a is CF 3 or methyl
  • the cyclopropyl ring is a trans isomer
  • R 2 is H or F
  • R 4 is isoxazolyl, pyridazinyl, thiazolyl, or thiadiazolyl
  • R 5a is H or F.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a is CF 3 or methyl; the cyclopropyl ring is a cis isomer; R 2 is H or F; R 4 is isoxazolyl, pyridazinyl, thiazolyl, or thiadiazolyl; and R 5a is H or F.
  • R 1a is CF 3 or methyl
  • the cyclopropyl ring is a cis isomer
  • R 2 is H or F
  • R 4 is isoxazolyl, pyridazinyl, thiazolyl, or thiadiazolyl
  • R 5a is H or F.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a is CF 3 ; the cyclopropyl ring is a trans isomer; R 2 is H; R 4 is isoxazolyl, pyridazinyl, thiazolyl, or thiadiazolyl; and R 5a is F. In sub embodiment of embodiment 15c, preferably, R 4 is isoxazolyl.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a is CF 3 ; the cyclopropyl ring is a trans isomer; R 2 is F; R 4 is isoxazolyl, pyridazinyl, thiazolyl, or thiadiazolyl; and R 5a is H. In sub embodiment of embodiment 15d, preferably, R 4 is isoxazolyl.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, a tropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound is an atropisomer and is a P atropisomer.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-methylcyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-phenylcyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-phenylcyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-1-(5-cyano-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl) cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl) cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl) cyclopropyl)phenyl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-6-(benzylthio)-1-(5-fluoro-2-hydroxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2(1H)-one.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-4-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (P)-7-fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • the present invention provides a P atropisomer of each individual compound, independently, or a mixture thereof, or pharmaceutically acceptable salts thereof, recited in embodiment 18a to 18p.
  • the present invention provides an M atropisomer of each individual compound, independently, or a mixture thereof, or pharmaceutically acceptable salts thereof, recited in embodiments 18a to 18p.
  • the present invention provides compounds of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (I) is of formula (Ia):
  • the present invention provides pharmaceutical compositions comprising a compound, an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or pharmaceutically acceptable salts thereof, in accordance with 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, or any sub embodiments thereof, and a pharmaceutically acceptable excipient.
  • the present invention provides methods of treating pain, cough, or itch, the methods comprising administering to a patient in need thereof a therapeutically effective amount of a compound, an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or pharmaceutically acceptable salts thereof, in accordance with 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, or any sub embodiments thereof.
  • the present invention provides methods of embodiment 23 wherein the pain is selected from chronic pain, acute pain, neuropathic pain, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, pain associated with cancer, peripheral diabetic neuropathy, and neuropathic low back pain.
  • the present invention provides methods of embodiment 23 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”, Nature Reviews Neuroscience (2013), 14, 49-62.
  • the present invention provides a method of preparation of a compound of Formula (A):
  • R is halo or the group
  • R is halo or the group
  • R 1 is C 1 -C 6 alkyl; with a UV light or near UV light; to form a cis olefin compound (C);
  • the present invention provides a method of embodiment 26, wherein said chiral acid is a phosphorus chiral acid.
  • the present invention provides a method of embodiment 26, wherein said chiral acid is (S)-TRIP having the Formula:
  • the present invention provides a method of embodiment 26, wherein said organic solvent is dichloromethane.
  • the present invention provides a method of embodiment 26, wherein said R is bromo.
  • the present invention provides a method of embodiment 26, wherein said R is the group
  • the present invention provides a method of embodiment 26, wherein said R 1 is ethyl; wherein the compound of Formula (B) has the formula:
  • the present invention provides a method of embodiment 26, wherein in reaction (2), a P atropisomer of said compound of Formula (A) is selectively formed.
  • the present invention provides a method of embodiment 26, wherein said compound of Formula (A) is used as an intermediate compound in preparation of a compound of Formula (I):
  • R 1 is a cyclopropyl ring; or a 4-, 5-, 6-, 7-, or 8-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S; and wherein said cyclopropyl ring or bicyclic ring is substituted by 0, 1, 2 or 3 R 1a groups selected from hydroxy, halo, C 1-8 alk, C 1-8 haloalk, —O—C 1-4 alk, —O—C 1-8 haloalk, —C( ⁇ O)C 1-4 alk, —O—C( ⁇ O)C 1-4 alk, —NH 2 , —NHC 1-4 alk, —N(C 1-4 alk)C 1-4 alk, 3-, 4-, or 5-membered cycloalkyl, or 6-membered aryl;
  • R 2 is H, halo, CN, C 1-6 alk, or C 1-6 haloalk
  • R 3 is C 1-6 alk, C 1-6 haloalk, —O—C 1-6 alk, —O-cyclopropyl, or —O-cyclobutyl;
  • R 4 is a 5- to 6-membered heteroaryl
  • R 6 and R 7 are hydrogen;
  • R 5a ; R 5b ; R 5c ; R 5d and R 5e is independently hydrogen or halo;
  • the present invention provides compounds of Formula (I), as defined above, an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or pharmaceutically acceptable salts thereof.
  • the present invention also provides pharmaceutical compositions comprising a compound of Formula (I), compound, an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or pharmaceutically acceptable salts thereof, and methods of treating diseases and/or conditions, such as pain, using compounds of Formula (I), compound, an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or pharmaceutically acceptable salts thereof.
  • C ⁇ - ⁇ alk as used herein means an alkyl group comprising a minimum of ⁇ and a maximum of ⁇ carbon atoms in a branched or linear relationship or any combination of the two, wherein ⁇ and ⁇ represent integers.
  • a designation of C 0 alk indicates a direct bond.
  • Examples of C 1-6 alk include, but are not limited to the following:
  • halo or halogen means a halogen atoms selected from F, Cl, Br or I.
  • C ⁇ - ⁇ haloalk as used herein means an alk group, as defined herein, in which at least one of the hydrogen atoms has been replaced with a halo atom, as defined herein.
  • Common C ⁇ - ⁇ haloalk groups are C 1-3 fluoroalk.
  • An example of a common C 1-3 fluoroalk group is —CF 3 .
  • cycloalkyl as used herein means a cyclic, nonaromatic hydrocarbon.
  • examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a cycloalkyl group can contain one or more double bond.
  • Examples of cycloalkyl groups that contain double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl and cyclobutadienyl.
  • Common cycloalkyl groups are C 3-8 cycloalkyl groups.
  • aryl as used herein means a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Common aryl groups are six to thirteen membered rings.
  • embodiment includes any and all sub-embodiments, including those labelled as ‘a’, ‘b’, ‘c’, etc.
  • embodiment 18 includes any and all sub-embodiments 18a to 18p.
  • heteroaryl as used herein means a cyclic, aromatic hydrocarbon in which one or more carbon atoms of an aryl group have been replaced with a heteroatom. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different.
  • heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, indolyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, naphthyridinyl, quinoxalinyl, isothiazolyl and benzo[b]thienyl.
  • Common heteroaryl groups are five to thirteen membered rings that contain from 1 to 4 heteroatoms. Heteroaryl groups that are five and six membered rings that contain 1 to 3 heteroatoms are particularly common.
  • heteroatom as used herein means an oxygen, nitrogen or sulfur atom.
  • monocyclic ring as used herein means a group that features one single ring.
  • a monocyclic ring can be carbocyclic (all of the ring atoms are carbons), or heterocyclic (the rings atoms include at least 1 heteroatom, for example, 1, 2 or 3 heteroatoms, such as N, O, or S, in addition to carbon atoms).
  • Examples of monocyclic rings include, but are not limited to: cyclobutyl, cyclopentyl, or cyclohexyl.
  • bicyclic ring as used herein means a group that features two joined rings.
  • a bicyclic ring can be carbocyclic (all of the ring atoms are carbons), or heterocyclic (the rings atoms include at least 1 heteroatom, for example, 1, 2 or 3 heteroatoms, such as N, O, or S, in addition to carbon atoms).
  • the two rings can both 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 rings include:
  • spirocyclic compounds wherein the two rings share only one single atom, the spiro atom, which is usually a quaternary carbon.
  • spirocyclic compound include, but are not limited to:
  • fused bicyclic compounds wherein two rings share two adjacent atoms.
  • the rings share one covalent bond, i.e. the bridgehead atoms are directly connected (e.g. ⁇ -thujene and decalin).
  • fused bicyclic rings include, but are not limited to:
  • bridged bicyclic compounds wherein the two rings share three or more atoms, separating; the two bridgehead atoms by a bridge containing at least one atom.
  • norbornane also known as bicyclo[2.2.1]heptane
  • bridged bicyclic rings include, but are not limited to:
  • saturated, partially-saturated or unsaturated includes substituents saturated with hydrogens, substituents completely unsaturated with hydrogens and substituents partially saturated with hydrogens.
  • pharmaceutically acceptable salt means a salt prepared by conventional means, and are well known by those skilled in the art.
  • pharmaceutically acceptable salts include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like.
  • pharmaceutically acceptable salts and Berge et al., J. Pharm. Sci. 66:1 (1977).
  • substituted means that a hydrogen atom on a molecule or group is replaced with a group or atom other than hydrogen.
  • substituents include: halogen, C 1-8 alkyl, hydroxyl, C 1-8 alkoxy, —NR x R x , nitro, cyano, halo or perhaloC 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, —SR x , —S( ⁇ O) 2 R x , —C( ⁇ O)OR x , —C( ⁇ O)R x , wherein each R x is independently hydrogen or C 1 -C 8 alkyl. It is noted that when the substituent is —NR x R x , the R x groups may be joined together with the nitrogen atom to form a ring. A group or atom that replaces a hydrogen atom is also called a substituent.
  • Any particular molecule or group can have one or more substituent depending on the number of hydrogen atoms that can be replaced.
  • unsubstituted means a hydrogen atom on a molecule or group.
  • the symbol “-” represents a covalent bond and can also be used in a radical group to indicate the point of attachment to another group. In chemical structures, the symbol is commonly used to represent a methyl group in a molecule.
  • leaving group generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile, or by metallic agent such as boronic acids or boronates under transition metal catalyzed coupling conditions.
  • a nucleophile such as an amine, a thiol or an alcohol nucleophile
  • metallic agent such as boronic acids or boronates under transition metal catalyzed coupling conditions.
  • leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
  • protecting group generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like.
  • aralkyl examples include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts.
  • aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like.
  • cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like.
  • Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl, phthaloyl and the like.
  • a mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group.
  • Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings.
  • the heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl.
  • Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
  • an addition salt such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
  • Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups.
  • aralkyl groups are also suitable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
  • Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like.
  • a preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof.
  • a tert-butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine.
  • Carboxy protecting group such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.
  • Prodrugs of the compounds of this invention are also contemplated by this invention.
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985).
  • Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • esters such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard J. Med. Chem. 2503 (19
  • drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy 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.
  • terapéuticaally effective amount means an amount of a compound that ameliorates, attenuates or eliminates one or more symptom of a particular disease or condition, or prevents or delays the onset of one of more symptom of a particular disease or condition.
  • patient means animals, such as dogs, cats, cows, horses, sheep and humans. Particular patients are mammals.
  • patient includes males and females.
  • pharmaceutically acceptable means that the referenced substance, 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 particular excipient, are suitable for administration to a patient.
  • treating include preventative (e.g., prophylactic) and palliative treatment.
  • excipient means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration to a patient.
  • API active pharmaceutical ingredient
  • the compounds of the present invention are administered to a patient in a therapeutically effective amount.
  • the compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation.
  • the compounds or compositions can be administered all at once, as for example, by a bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. It is also noted that the dose of the compound can be varied overtime.
  • the compounds of the present invention can be administered alone, in combination with other compounds of the present invention, or with other pharmaceutically active compounds.
  • the other pharmaceutically active compounds can be intended to treat the same disease or condition as the compounds of the present invention or a different disease or condition. If the patient is to receive or is receiving multiple pharmaceutically active compounds, the compounds can be administered simultaneously, or sequentially.
  • the active compounds may be found in one tablet or in separate tablets, which can be administered at once or sequentially in any order.
  • the compositions may be different forms. For example, one or more compound may be delivered by a tablet, while another is administered by injection or orally as syrup. All combinations, delivery methods and administration sequences are contemplated.
  • the compounds of the present invention may be used in the manufacture of a medicament for the treatment of a disease and/or condition mediated by NaV 1.7, such as pain, chronic cough or itch.
  • Pain is typically divided into primary types: chronic and acute pain based on the duration of the pain. Typically, chronic pain lasts for longer than 3 months. Examples of chronic pain include pain associated with rheumatoid arthritis, osteoarthritis, lumbosacral radiculopathy or cancer. Chronic pain also includes idiopathic pain, which is pain that has no identified cause. An example of idiopathic pain is fibromyalgia.
  • Nociceptive pain is caused by stimulation of peripheral nerve fibers that respond to highly noxious events such as thermal, mechanical or chemical stimuli.
  • neuropathic pain is pain that is caused by damage or disease affecting a part of the nervous system.
  • Phantom limb pain is a type of neuropathic pain.
  • the body detects pain from a part of a body that no longer exists. For example, a person who has had a leg amputated may feel leg pain even though the leg no longer exists.
  • the disease is chronic pain.
  • the chronic pain is associated with, but are not limited to, post-herpetic neuralgia (shingles), rheumatoid arthritis, osteoarthritis, diabetic neuropathy, complex regional pain syndrome (CRPS), cancer or chemotherapy-induced pain, chronic back pain, phantom limb pain, trigeminal neuralgia, HIV-induced neuropathy, cluster headache disorders, and migraine, primary erythromelalgia, and paroxysmal extreme pain disorder.
  • NaV 1.7 inhibitors include, but are not limited to, depression (Morinville et al., J Comp Neurol., 504:680-689 (2007)), bipolar and other CNS disorders (Ettinger and Argoff, Neurotherapeutics, 4:75-83 (2007)), epilepsy: ibid., and Gonzalez, Termin, Wilson, Methods and Principles in Medicinal Chemistry, 29:168-192 (2006)), multiple sclerosis (Waxman, Nature Neurosci. 7:932-941 (2006)), Parkinson's (Do and Bean, Neuron 39:109-120 (2003); Puopolo et al., J. Neurosci.
  • Another aspect of the invention relates to a method of treating acute and/or chronic inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation pain syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal
  • the compounds of the present invention can be used in combination with other compounds that are used to treat pain.
  • other compounds include, but are not limited to aspirin, celecoxib, hydrocodone, oxycodone, codeine, fentanyl, ibuprofen, ketoprofen, naproxen, acetaminophen, gabapentin and pregabalin.
  • classes of medicines that contain 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 opiod analgesics.
  • the compounds of the present invention may also be used to treat diabetes, obesity and/or to facilitate weight loss.
  • the compounds of the present invention may be used in combination with other pharmaceutically active compounds.
  • pharmaceutically active compounds can include biologics, such as proteins, antibodies and peptibodies.
  • kits comprises two separate pharmaceutical compositions: a compound of the present invention, and a second pharmaceutical compound.
  • the kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes and bags.
  • the kit comprises directions for the 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), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician or veterinarian.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed by said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . . Second Week, Monday, Tuesday, . . . ” etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a compound of the present invention can consist of one tablet or capsule, while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this and aid in correct administration of the active agents.
  • a dispenser designed to dispense the daily doses one at a time in the order of their intended use.
  • the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
  • a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed.
  • a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
  • the compounds of the present invention and other pharmaceutically active compounds can be administered to a patient either orally, rectally, parenterally, (for example, intravenously, intramuscularly, or subcutaneously) intracisternally, intravaginally, intraperitoneally, intravesically, locally (for example, powders, ointments or drops), or as a buccal or nasal spray. All methods that are used by those skilled in the art to administer a pharmaceutically active agent are contemplated.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
  • Microorganism contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example, sugars, sodium chloride, and the like.
  • Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, mannitol, and silicic acid;
  • binders as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia;
  • humectants as for example, glycerol;
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
  • solution retarders as for example, paraffin;
  • absorption accelerators as for example, quaternary ammonium compounds; wetting agents, as for example,
  • compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
  • Solid dosage forms such as tablets, dragées, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizing
  • the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administration are preferable suppositories, which can be prepared by mixing the compounds of the present 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, melt in the rectum or vaginal cavity and release the active component.
  • 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, melt in the rectum or vaginal cavity and release the active component.
  • Dosage forms for topical administration of a compound of the present invention include ointments, powders, sprays and inhalants.
  • the active compound or fit compounds are admixed under sterile condition with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • the compounds of the present invention can be administered to a patient at therapeutically effective dosage levels.
  • the specific dosage and dosage range that can be used depends on a number of factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered.
  • the compounds of the present invention can be administered as pharmaceutically acceptable salts, co-crystals, esters, amides or prodrugs.
  • salts refers to inorganic and organic salts of compounds of the present invention.
  • the salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
  • the salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J Pharm Sci, 66: 1-19 (1977).
  • esters of the compounds of the present invention examples include C 1 -C 8 alkyl esters. Acceptable esters also include C 5 -C 7 cycloalkyl esters, as well as arylalkyl esters such as benzyl. C 1 -C 4 alkyl esters are commonly used. Esters of compounds of the present invention may be prepared according to methods that are well known in the art.
  • Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, primary C 1 -C 8 alkyl amines, and secondary C 1 -C 8 dialkyl amines.
  • the amine may also be in the form of a 5 or 6 membered heterocycloalkyl group containing at least one nitrogen atom.
  • Amides derived from ammonia, C 1 -C 3 primary alkyl amines and C 1 -C 2 dialkyl secondary amines are commonly used. Amides of the compounds of the present invention may be prepared according to methods well known to those skilled in the art.
  • prodrug means compounds that are transformed in vivo to yield a compound of the present invention. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C 1 -C 8 alkyl, (C 2 -C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)aminomethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crot
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 -C 6 )alkoxycarbonyloxymethyl, N—(C 1 -C 6 )alkoxycarbonylaminomethyl, succinoyl, (C 1 -C 6 )alkanoyl, ⁇ -amino(C 1 -C 4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, —P(O)(
  • a prodrug can be formed by replacement of the sulfonamide N(H) with a group such as —CH 2 P(O)(O(C 1 -C 6 )alkyl) 2 or —CH 2 OC(O)(C 1 -C 6 )alkyl.
  • the compounds of the present invention also include tautomeric forms of prodrugs.
  • the compounds of the present invention may contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention contemplates all geometric and positional isomers. For example, if the compound contains a double bond or disubstituted cycloalkyl group, both the cis and trans isomers, unless the specific isomer is specified, as well as mixtures, are contemplated. In disubstituted cycloalkyl containing compounds, the cis and trans isomers refer to the relative positions of the substitutions.
  • (A) represents trans cyclobutyl isomer because the —CF 3 group is pointing up while the —CH 3 group is pointing down
  • (B) represents cis cyclobutyl isomer because both the —CF 3 group and the —CH 3 groups are pointing down.
  • stereoisomers such as diastereomeric mixtures
  • Enantiomers can also be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., an alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., an alcohol
  • the compounds of general Formula (I) may also exist in the form of atropisomers.
  • Atropisomers are compounds with identical structural formulae, but which have a particular spatial configuration resulting from a restricted rotation around a single bond, due to a major steric hindrance on either side of this single bond. Atropisomerism is independent of the presence of stereogenic elements, such as an asymmetric carbon.
  • the terms “P atropisomer” or “M atropisomer” are used herein in order to be able to clearly name two atropisomers of the same pair.
  • the following compound of Intermediate B1, Step 1, having the structure below can be separated into the pair of atropisomers P and M via a chiral column:
  • the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrate), ethanol, and the like.
  • pharmaceutically acceptable solvents such as water (hydrate), ethanol, and the like.
  • the present invention contemplates and encompasses both the solvated and unsolvated forms.
  • compounds of the present invention may exist in different tautomeric forms. All tautomers of compounds of the present invention are contemplated. For example, all of the tautomeric forms of the tetrazole moiety are included in this invention. Also, for example, all keto-enol or imine-enamine forms of the compounds are included in this invention. Other examples of tautomerism are as follows:
  • the present invention encompass compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.
  • the present invention also includes isotopically-labelled compounds, which are identical to those recited herein, but for 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.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, 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.
  • the compounds of the present invention contain one or more deuterium atoms (2H) in place of one or more hydrogen atoms.
  • isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detection.
  • Isotopically labelled compounds of this invention can generally be prepared by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the compounds of the present invention may exist in various solid states including crystalline states and as an amorphous state.
  • crystalline states also called polymorphs, and the amorphous states of the present compounds are contemplated as part of this invention.
  • Silica gel chromatography was generally performed with prepacked silica gel cartridges (Biotage, Uppsala, Sweden or Teledyne-Isco, Lincoln, Nebr.). 1 H NMR spectra were recorded on a Bruker AV-400 (400 MHz) spectrometer (Bruker Corporation, Madison, Wis.) or a Varian (Agilent Technologies, Santa Clara, Calif.) 400 MHz spectrometer at ambient temperature. All observed protons are reported as parts per million (ppm) downfield from tetramethylsilane (TMS) or other internal reference in the appropriate solvent indicated.
  • TMS tetramethylsilane
  • MS mass spectral
  • the present inventors have developed a photochemical atrop-selective ring-closure to form N-aryl quinolinones compounds. Specifically, the P atropisomer compound 3 is selectively formed in the photochemical reaction of the invention.
  • a general representation of the photochemistry step of the present invention is described below:
  • reaction relies on UV or near-UV light to excite the olefin 1; wherein R is halo or the group
  • R 1 is C 1 -C 6 alkyl; and induce a cis-trans isomerization to transiently form 2; wherein each R and R 1 is as defined above.
  • R 1 is ethyl.
  • Cis olefin 2 can then be activated by chiral acid (S)-TRIP to asymmetrically form ring-closed quinolinone 3, wherein R is as defined above.
  • R is Br or
  • the present photochemical step can operate well without the present of a bulky barrier substituent to rotation, such as tert-butyl group in the starting material. Rather, the present novel photochemical step has been demonstrated in the presence of a much smaller methoxy group in the starting material.
  • the mild reaction conditions further allow for compounds with low barriers to rotation to be prepared in a stereoselective fashion.
  • 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 an additional 4 h.
  • the reaction was cooled to room temperature and diluted with ethyl acetate (4.0 L).
  • the mixture was filtered through CELITE and the CELITE bed was washed with ethyl acetate (2 ⁇ 1.0 L).
  • Step 5 Ethyl (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl) acrylate
  • Step 6 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one
  • Steps 7 & 8 Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydro quinoline-6-sulfonate
  • Step 9 (P)-Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • Racemic perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (76.90 g) was separated via Chiralcel OJ column (40% MeOH/60% CO 2 ) to give (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate and (M)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate as pale yellow flocculent solids.
  • Step 10 (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Step 1 (E)-Ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl)acrylate
  • Step 3 Perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • Step 4 1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Step 5 (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Racemic 1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide 400 mg was purified using a (S,S) Whelk-O, 2 ⁇ 15 cm column. The mobile phase was run under isocratic conditions; supercritical CO 2 with 60% isopropanol; flow rate: 80 mL/min. The first eluting peak was assigned (M)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (150 mg).
  • the second eluting peak was assigned (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (154 mg).
  • the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 ⁇ 50 mL). The organic extract was washed with sat. aq. NaCl (1 ⁇ 50 mL) and dried over Na 2 SO 4 . The solution was filtered and concentrated in vacuo to give the Initial product as a yellow oil.
  • the Initial product was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 20% to 30% EtOAc in hexane, to provide N-(4-methoxybenzyl)pyrimidin-2-amine (1.5 g, 6.97 mmol, 53% yield) as an off white solid.
  • Step 1 (E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate
  • Step 3 Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • Step 4 (P)-Perfluorophenyl 1-(4-Bromo-5-Fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydro quinoline-6-sulfonate & (M)-Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydro quinoline-6-sulfonate
  • Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydro quinoline-6-sulfonate (156 g, 255 mmol) was purified via chiral SFC chromatography ((S,S) Whelk-O, 45% isopropanol) to afford (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) + .
  • Step 5 (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide
  • N-(4-Methoxybenzyl)pyrimidin-2-amine (9.72 g, 45.1 mmol) and (P)-perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (25.06 g, 41.0 mmol) were added to a 500-mL flask. The flask was flushed with N 2 stream then tetrahydrofuran (136 mL) was added and the reaction was cooled to 2° C. under N 2 .
  • the slurry was filtered and the solid was washed with IPA.
  • the solid was taken up in 150 mL of MTBE and heated at 40° C. for 2 hours.
  • the slurry was cooled to ambient temperature and filtered to obtain a white solid.
  • the impure material was dissolved in 500 mL of 10% MeOH/DCM and stirred with 500 mL of sat. aq. NaHCO 3 for 30 minutes.
  • the layers were separated and the water layer was extracted twice with 10% MeOH/DCM.
  • the combined organics layers were dried and evaporated.
  • Step 1 (E)-Ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxy-5-methylphenyl)amino)phenyl)acrylate
  • Step 3 Perfluorophenyl 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • Step 4 Perfluorophenyl(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • Perfluorophenyl 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (22.896 g, 38.79 mmol) was purified using a (S,S) Whelk-O, 5 ⁇ 25 cm column. The mobile phase was run under isocratic conditions; supercritical CO 2 with 50% dichloromethane; flow rate: 350 mL/min. The first eluting peak was assigned perfluorophenyl (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (10.425 g).
  • the second eluting peak was assigned perfluorophenyl (M)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (10.76 g).
  • Data for peak 1 m/z (ESI) 590.0 (M+H) + .
  • Data for peak 2 m/z (ESI) 590.0 (M+H) + .
  • aqueous HCl solution 1.0 M, 100 mL
  • EtOAc 100 mL
  • 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 reaction was cooled to RT and benzyl mercaptan (455.5 g, 3.67 mol, 1.6 equiv, Alfa Aesar) was added and the reaction was heated at 80° C. for an additional 4 h.
  • the reaction was cooled to room temperature and diluted with ethyl acetate (4.0 L).
  • the mixture was filtered through CELITE® and the CELITE® bed was washed with ethyl acetate (2 ⁇ 1.0 L).
  • Step-5 Ethyl (E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl) acrylate
  • Step-6 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one
  • Steps 7 & 8 Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydro quinoline-6-sulfonate
  • Step 1 (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • Racemic perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate See Steps 7&8 of Intermediate O above, 76.90 g was separated via Chiralcel OJ column (40% MeOH/60% CO 2 ) to give (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate and (M)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate as pale yellow flocculent solids.
  • Step 2 (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-Sulfonamide
  • the reaction vessel was then sequentially charged with 1,4-dioxane (3 mL) and an aqueous solution of sodium carbonate (1 mL, 1.9 M) via syringe.
  • the vial was sealed with a PTFE-lined cap, and the resultant red mixture was sparged with nitrogen for 10 min.
  • the reaction mixture was the heated to 50° C. After 16 h, the mixture was allowed to cool to ambient temperature, and 1 M HCl was added carefully followed by EtOAc. The layers separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were concentrated to dryness.
  • the brown residue was purified by reverse phase HPLC using a XBridge Prep Shield RP18 19 ⁇ 100 mm column.
  • the reaction vessel was then sequentially charged with 1,4-dioxane (3 mL) and an aqueous solution of sodium carbonate (1 mL, 1.9 M) via syringe.
  • the vial was sealed with a PTFE-lined cap, and the resultant red mixture was sparged with nitrogen for 10 min.
  • the reaction mixture was the heated to 50° C. After 16 h, the mixture was allowed to cool to ambient temperature, and 1 M HCl was added carefully followed by EtOAc. The layers separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were concentrated to dryness.
  • the brown residue was purified by reverse phase HPLC using a XBridge Prep Shield RP18 19 ⁇ 100 mm column.
  • 1,4-Dioxane (1.5 mL) and water (0.5 mL) were added, the vial was flushed with argon, and the reaction was heated at 130° C. for six hours. The reaction was then diluted with ethyl acetate and washed twice with 1 N HCl solution. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated.
  • Diastereomers and atropisomers were separated from trans-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (63 mg) using two successive chiral SFC chromatography steps.
  • a (S,S) Whelk-O, 2 ⁇ 15 cm column was used.
  • the mobile phase was run under isocratic conditions; supercritical CO 2 with 30% methanol; flow rate: 80 mL/min.
  • the first eluting peak from this separation was then separated further using a Chiralcel OJ 2 ⁇ 25 cm column.
  • the mobile phase was run under isocratic conditions; supercritical CO 2 with 20% ethanol; flow rate: 65 mL/min.
  • the first eluting peak was assigned (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (16 mg)
  • the second eluting peak was assigned (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (12 mg).
  • the vial was sparged with nitrogen for 30 seconds and then heated to 65° C. After stirring for 6 h, the reaction was filtered through a phase separator, washing with dichloromethane. The filtrate was concentrated in vacuo, and the residue was retaken in dichloromethane (1 mL) and treated with trifluoromethanesulfonic acid (0.13 mL, 1.5 mmol). After stirring for 2 h, volatiles were removed in vacuo, and the residue was purified using a Chiralcel OJ-H, 2 ⁇ 25 cm column. The mobile phase was run under isocratic conditions; supercritical CO 2 with 25% methanol; flow rate: 80 mL/min.
  • the first eluting peak was assigned (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-methylcyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (20 mg).
  • the second eluting peak was assigned (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-methylcyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (16 mg).
  • trans-2-phenylcyclopropylboronic acid pinacol ester 155 mg, 0.635 mmol
  • the purification was accomplished using a Chiralcel OJ-H, 2 ⁇ 25 cm column. The mobile phase was run under isocratic conditions; supercritical CO 2 with 45% methanol; flow rate: 70 mL/min.
  • the first eluting peak was assigned (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-phenylcyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (6 mg).
  • the second eluting peak was assigned (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-phenylcyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (4 mg).
  • the first eluting peak was assigned (P)-(R)-1-(4-(2,2-difluorocyclopropyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • the second eluting peak was assigned (P)-(S)-1-(4-(2,2-difluorocyclopropyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • Examples 12 & 13 (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamine and (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamine, respectively
  • Step 1 Trans-(P)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamine
  • the vial was capped and backfilled with nitrogen. 1,4-Dioxane (4.5 mL) and water (1.5 mL) were added, and the reaction mixture was sparged with nitrogen for 15 min. The vial was then heated to 100° C. for 4 h and then at 80° C. for 16 h. The reaction was cooled to rt, diluted with EtOAc, and quenched with water. The layers were separated and the aqueous extract was extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na 2 SO 4 , and concentrated.
  • Step 2 (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamine and (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamine
  • the first eluting peak was assigned (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (43 mg).
  • the second eluting peak was assigned (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (37 mg).
  • Examples 14 & 15 (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamine and (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamine, respectively
  • Step 1 (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-SULFONAMIDE
  • reaction mixture was cooled to 0° C., and sodium tert-pentoxide (6.7 mL, 9.4 mmol, 1.4 M in THF) was added dropwise over 5-10 minutes. After 1.5 h, the reaction was quenched by addition of sat. aq. ammonium chloride. The heterogeneous mixture was diluted with water and extracted thrice with EtOAc. The combined organic extracts were washed with brine, dried over Na 2 SO 4 and concentrated.
  • Step 2 Trans-(P)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamine
  • the vial was capped and backfilled with nitrogen. 1,4-Dioxane (5.8 mL) and water (1.9 mL) were added, and the reaction mixture was sparged with nitrogen for 15 min. The vial was then heated to 80° C. for 16 h. The reaction was cooled to rt, and then additional portions of trans-6-methyl-2-(2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazaborocane-4,8-dione (0.200 g, 0.744 mmol) and RuPhos Pd 4 th generation precatalyst (0.100 g, 0.118 mmol) were added.
  • Step 3 (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamine and (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamine
  • the mobile phase was run under isocratic conditions; supercritical CO 2 with 25% methanol; flow rate: 80 mL/min.
  • the first eluting peak was assigned (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (51 mg).
  • the second eluting peak was assigned (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (50 mg).
  • Examples 16 & 17 (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamine and (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamine, respectively
  • the vial was sparged with nitrogen and then heated to 95° C. After stirring for 6 h, the mixture was filtered through a phase separator, washing with dichloromethane. Volatiles were removed in vacuo. The residue was taken up in dichloromethane (1 mL) and treated with trifluoromethanesulfonic acid (0.2 mL, 2.4 mmol). After heating at 50° C. for 1 h, volatiles were removed, and the product was purified using a (S,S) Whelk-O, 2 ⁇ 25 cm column. The mobile phase was run under isocratic conditions; supercritical CO 2 with 40% methanol; flow rate: 80 mL/min.
  • the first peak was further purified using a Chiralcel OJ-H, 3 ⁇ 25 cm column.
  • the mobile phase was run under isocratic conditions; supercritical CO 2 with 25% methanol; flow rate: 80 mL/min.
  • the first eluting peak was assigned (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (31 mg).
  • the second eluting peak was assigned (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (37 mg).
  • Examples 18 & 19 (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine, respectively
  • Step 1 6-(benzylthio)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2(1H)-one
  • the vial was capped and backfilled with nitrogen before 1,4-dioxane (15.4 mL) and water (5.1 mL) were added.
  • the reaction mixture was stirred vigorously and sparged with nitrogen.
  • additional RuPhos Pd 4 th generation precatalyst 150 mg, 0.176 mmol was added, and the reaction was heated to 100° C. for 8 h.
  • the reaction was poured onto a mixture of EtOAc and water and extracted thrice with EtOAc. The combined organic extracts were washed with brine, dried over Na 2 SO 4 and concentrated.
  • Step 2 Perfluorophenyl trans-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • Step 3 (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • the first peak was further purified using two in-line Chiralcel OJ-H, 3 ⁇ 25 cm and Chiralcel OJ-H, 3 ⁇ 15 cm columns.
  • the mobile phase was run under isocratic conditions; supercritical CO 2 with 30% methanol; flow rate: 80 mL/min.
  • the first eluting peak was assigned (P)-1-(5-chloro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (70 mg).
  • the second eluting peak was assigned (P)-1-(5-chloro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (70 mg).
  • Examples 20 & 21 (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamine and (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamine, respectively
  • the vial was sparged with nitrogen and then heated to 95° C. After stirring for 6 h, the mixture was filtered through a phase separator, washing with dichloromethane. Volatiles were removed in vacuo. The residue was taken up in dichloromethane (1 mL) and treated with trifluoromethanesulfonic acid (0.2 mL, 2.4 mmol). After heating at 50° C. for 1 h, volatiles were removed, and the product was purified using a (S,S) Whelk-O, 2 ⁇ 25 cm column. The mobile phase was run under isocratic conditions; supercritical CO 2 with 40% methanol; flow rate: 80 mL/min.
  • the first peak was further purified using a Chiralcel OJ-H, 3 ⁇ 25 cm column.
  • the mobile phase was run under isocratic conditions; supercritical CO 2 with 25% methanol; flow rate: 80 mL/min.
  • the second and third eluting peaks were isolated, and each was taken up in PhMe (1 mL) and heated to 100° C. for 1 h. Solvent was then removed.
  • the second peak was further purified using a (S,S) Whelk-01, 2.1 ⁇ 25 cm column.
  • the mobile phase was run under isocratic conditions; supercritical CO 2 with 35% methanol; flow rate: 80 mL/min.
  • the first eluting peak was assigned (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (14.3 mg).
  • the third peak from above was further purified using a (S,S) Whelk-01, 2.1 ⁇ 25 cm column.
  • the mobile phase was run under isocratic conditions; supercritical CO 2 with 40% methanol; flow rate: 80 mL/min.
  • the first eluting peak was assigned (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (13.7 mg).
  • Step 1 (P)-6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)quinolin-2(1H)-one
  • the vial was flushed with nitrogen before 1,4-dioxane (18 mL), water (6.1 mL), and 1-(trifluoromethyl)vinylboronic acid hexylene glycol ester (1.1 mL, 5.3 mmol) were added.
  • the vessel was warmed to 50° C. and stirred at this temperature for 16 h.
  • the reaction was cooled to room temperature, diluted with EtOAc and water, and extracted thrice with EtOAc.
  • the combined organic extracts were washed with brine, dried over Na 2 SO 4 , and concentrated.
  • Step 2 (P)-6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2(1H)-one
  • the mixture was sparged with nitrogen, irradiated with blue LEDs in a Penn OC Photoreactor ml at 5% intensity, 1000 rpm stirring, and 4500 rpm fan speed for 6 h, and then at 50% intensity, 1000 rpm stirring, and 4500 rpm fan speed for 2.5 h.
  • the reaction was diluted with EtOAc and washed thrice with 2 N NaOH.
  • the organic extract was washed with water then brine, dried over Na 2 SO 4 , and concentrated.
  • Step 3 Perfluorophenyl(P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • Step 4 (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • a 2-dram vial was charged with isoxazol-3-amine (0.019 mL, 0.28 mmol), perfluorophenyl (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (150 mg, 0.241 mmol), and THF (1.6 mL).
  • the vial was cooled to 0° C., and sodium tert-pentoxide (0.34 mL, 0.48 mmol, 1.4 M in THF) was added. The resulting yellow solution was stirred at 0° C. for 1 h.
  • a 2-dram vial was charged with 2-pyrimidinamine (26 mg, 0.28 mmol), perfluorophenyl (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (150 mg, 0.241 mmol), and THF (1.6 mL).
  • the vial was cooled to 0° C., and sodium tert-pentoxide (0.34 mL, 0.48 mmol, 1.4 M in THF) was added. The resulting yellow solution was stirred at 0° C. for 1 h.
  • Step 1 (P)-6-(benzylthio)-1-(5-chloro-2-methoxy-4-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)quinolin-2(1H)-one
  • the vial was flushed with nitrogen before 1,4-dioxane (27 mL), water (9 mL), and 1-(trifluoromethyl)vinylboronic acid hexylene glycol ester (1.9 mL, 9.4 mmol) were added.
  • the vessel was warmed to 50° C. and stirred at this temperature for 1 h and then stirred at 45° C. for 15.5 h.
  • the reaction was cooled to room temperature, diluted with EtOAc and water, and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over Na 2 SO 4 , and concentrated.
  • Step 2 (P)-6-(benzylthio)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2(1H)-one
  • Step 3 Perfluorophenyl(P)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • Step 4 (P)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • a 2-dram vial was charged with isoxazol-3-amine (0.025 mL, 0.37 mmol), perfluorophenyl (P)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (203 mg, 0.317 mmol), and THF (2 mL).
  • the vial was cooled to 0° C., and sodium tert-pentoxide (0.40 mL, 0.56 mmol, 1.4 M in THF) was added. The resulting yellow solution was stirred at 0° C.
  • a 2-dram vial was charged with 2-pyrimidinamine (35 mg, 0.37 mmol), perfluorophenyl (P)-1-(5-chloro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (203 mg, 0.317 mmol), and THF (2 mL).
  • the vial was cooled to 0° C., and sodium tert-pentoxide (0.40 mL, 0.56 mmol, 1.4 M in THF) was added.
  • the resulting yellow solution was stirred at 0° C. for 20 min, and then quenched through the addition of 1 N HCl and water.
  • Step 1 (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
  • Step 2 Trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Step 3 (P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl) phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • a 40-mL vial containing trans-(P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (404 mg, 0.632 mmol) was charged with trifluoroacetic acid (4 mL). The reaction was stirred at rt for 16.75 h. The reaction was then poured onto stirring sat. aq. NaHCO 3 . After gas evolution had ceased, the mixture was extracted thrice with dichloromethane.
  • the second eluting peak was assigned (P)-N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (123.2 mg).
  • Examples 28 & 29 (P)-1-(2-methoxy-5-methyl-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamine and (P)-1-(2-methoxy-5-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamine, respectively
  • Step 1 (P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide
  • Step 2 Trans-(P)-1-(2-methoxy-5-methyl-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamine
  • Step 3 (P)-1-(2-methoxy-5-methyl-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamine and (P)-1-(2-methoxy-5-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamine
  • a 40-mL vial containing trans-(P)-1-(2-methoxy-5-methyl-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (307 mg, 0.472 mmol) was charged with trifluoroacetic acid (2.4 mL). The reaction was stirred at rt for 17.5 h. The reaction was then poured onto stirring sat. aq. NaHCO 3 . After gas evolution had ceased, the mixture was extracted thrice with dichloromethane.
  • the second eluting peak was assigned (P)-1-(2-methoxy-5-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (70.1 mg).
  • Step 1 Trans-(P)-1-(4-([1,1′-bi(cyclopropan)]-2-yl)-5-fluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Step 2 (P)-1-(4-((1S,2S)-[1,1′-bi(cyclopropan)]-2-yl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(4-((1R,2S)-[1,1′-bi(cyclopropan)]-2-yl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
  • the mobile phase was run under a gradient elution; 25-70% water/acetonitrile with 0.1% formic acid; flow rate: 40 mL/min.
  • the material was further purified using a Chiralcel OJ-H, 2 ⁇ 25 cm column.
  • the mobile phase was run under isocratic conditions; supercritical CO 2 with 30% methanol; flow rate: 60 mL/min.
  • the first eluting peak was assigned (P)-1-(4-((1S,2S)-[1,1′-bi(cyclopropan)]-2-yl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (101.5 mg).
  • the second eluting peak was assigned (P)-1-(4-((1R,2S)-[1,1′-bi(cyclopropan)]-2-yl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (136.7 mg).
  • Examples 32 & 33 (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-((trifluoromethoxy) methyl)cyclopropyl) phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine, respectively
  • Step 1 (P)-1-(4-(2-(((tert-butyldiphenylsilyl)oxy)methyl) cyclopropyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • the vial was purged with nitrogen, and then toluene (3.9 mL) and water (0.98 mL) were added. The reaction was stirred at 50° C. for 16 hours. The reaction mixture was filtered through a plug of Celite and concentrated under reduced pressure. The crude mixture was purified on column to give the desired product as a mixture of trans cyclopropyl isomers (0.96 g).
  • Step 2 (P)-1-(5-fluoro-4-(2-(hydroxymethyl)cyclopropyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Step 3 (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-((trifluoromethoxy) methyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl) phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine, respectively
  • a vial was charged with potassium fluoride (200 mg, 3.45 mmol), silver trifluoromethanesulfonate (670 mg, 2.6 mmol), Selectfluor® (460 mg, 1.3 mmol), and (P)-1-(5-fluoro-4-(2-(hydroxymethyl)cyclopropyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (526 mg, 0.87 mmol) under a stream of nitrogen.
  • the vial was purged with nitrogen, and ethyl acetate (2.18 mL), 2-fluoropyridine (253 mg, 225 ⁇ L, 2.61 mmol), and trimethyl(trifluoromethyl)silane (371 mg, 386 ⁇ L, 2.61 mmol) were added.
  • the reaction mixture was stirred at room temperature for 48 hours.
  • the reaction mixture was filtered through a plug of Celite, which was washed with ethyl acetate.
  • the filtrate was concentrated, and the product was purified by column chromatography (silica gel: elution 0-40% (3:1 EtOAc/ethanol with 10% DCM) in heptanes).
  • the second eluting peak was assigned (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (50.4 mg).
  • Step 4 (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-((trifluoromethoxy) methyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl) phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, respectively
  • Step 1 Perfluorophenyl(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • the vial was flushed with nitrogen, and then toluene (450 ⁇ L) and water (112 ⁇ L) were added.
  • the reaction mixture was sparged with nitrogen, capped, and stirred at 50° C. for 14 hours.
  • the reaction mixture was then partitioned between half-saturated aqueous sodium chloride and ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate.
  • the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the Initial product was adsorbed onto a plug of silica gel and eluted with 60% ethyl acetate/heptane.
  • Step 2 (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl) cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-1,2-dihydroquinoline-6-sulfonamine
  • a vial was charged with N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (121 mg, 0.546 mmol) and perfluorophenyl (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl) phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (309.4 mg, 0.496 mmol).
  • the vial was flushed with nitrogen, and then tetrahydrofuran (5.0 mL) was added and the reaction was cooled to 0° C.
  • Step 3 (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl) cyclopropyl)phenyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-1,2-dihydroquinoline-6-sulfonamine
  • Examples 35 & 36 (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl) phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine, respectively
  • Step 1 (P)-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl))—N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Step 2 (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl) cyclopropyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine, respectively
  • the first eluting peak was assigned: (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (144 mg, 0.28 mmol, 23% yield).
  • the second eluting peak was assigned (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl) cyclopropyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (205 mg, 0.39 mmol, 32% yield).
  • Step 1 (P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
  • Step 2 (P)-1-(5-chloro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl) phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Step 3 (P)-1-(5-cyano-2-methoxy-4-((1S,2S)-2-(trifluoromethyl) cyclopropyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • the isomers were separated by chiral chromatography using a ASH 21 ⁇ 250 cm, 5 ⁇ m column.
  • the mobile phase was run under isocratic conditions; supercritical CO 2 with 20% ethanol; flow rate: 40 mL/min.
  • the first eluting peak was assigned: (P)-1-(5-cyano-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (44 mg, 0.068 mmol, 18% yield).
  • the second eluting peak was assigned (P)-1-(5-cyano-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (38 mg, 0.058 mmol, 15% yield).
  • Data for Peak 2 m/z (ESI, positive ion) 650.8 (M+H) + .
  • Step 4 (P)-1-(5-cyano-2-methoxy-4-((1S,2S)-2-(trifluoromethyl) cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Examples 38 & 39 (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine, respectively
  • Step 1 (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl) cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine, respectively
  • the mixture of isomers was separated by chiral chromatography using a ASH 21 ⁇ 250 cm, 5 ⁇ m column.
  • the mobile phase was run under isocratic conditions; supercritical CO 2 with 15% ethanol; flow rate: 50 mL/min.
  • the first eluting peak was assigned: (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (133 mg, 0.213 mmol, 14% yield).
  • the second eluting peak was assigned (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl) phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (147 mg, 0.235 mmol, 16% yield).
  • Step 2 (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine, respectively
  • Step 1 (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl) cyclopropyl)phenyl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-6-sulfonamine
  • the crude product was purified by column chromatography (silica gel: elution 0-100% (3:1 ethyl acetate/ethanol) in (9:1 heptane/DCM)) to provide (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl) cyclopropyl)phenyl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-6-sulfonamide (322 mg, 0.60 mmol, 74% yield) as a white powder.
  • Step 1 (P)-6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl) cyclopropyl)phenyl)quinolin-2(1H)-one
  • Step 2 (P)-6-(benzylthio)-1-(5-fluoro-2-hydroxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2(1H)-one
  • the first eluting peak was assigned: (P)-6-(benzylthio)-1-(5-fluoro-2-hydroxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2(1H)-one (1.60 g, 1.73 mmol, 17% yield). m/z (ESI, positive ion) 486.0 (M+H) + .
  • Step 3 (P)-6-(benzylthio)-1-(2-cyclopropoxy-5-fluoro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2(1H)-one
  • a microwave vial was charged with (P)-6-(benzylthio)-1-(5-fluoro-2-hydroxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2(1H)-one (0.84 g, 1.73 mmol), N,N-dimethylacetamide (5.8 mL), cesium carbonate (1.7 g, 5.2 mmol), potassium iodide (0.14 g, 0.87 mmol), and bromocyclopropane (0.209 g, 1.73 mmol).
  • the vial was capped and irradiated for 24 hours at 150° C.
  • the vial was cooled to ambient temperature, and the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 ⁇ 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the crude product was purified by column chromatography (silica gel: elution 0-100% ethyl acetate in heptane with 10% DCM) to provide 6-(benzylthio)-1-(2-cyclopropoxy-5-fluoro-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2(1H)-one (0.65 g, 1.24 mmol, 71% yield) as an off-white solid.
  • Step 4 Perfluorophenyl 1-(2-cyclopropoxy-5-fluoro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • Step 5 (P)-1-(2-cyclopropoxy-5-fluoro-4-((1S,2S)-2-(trifluoromethyl) cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • the atropisomers were separated by chiral chromatography using a Whelk-O (S,S) 2 ⁇ 15 cm, 5 m column.
  • the mobile phase was run under isocratic conditions; supercritical CO 2 with 30% methanol; flow rate: 80 mL/min.
  • the first eluting peak was assigned: (P)-6-(benzylthio)-1-(5-fluoro-2-hydroxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2(1H)-one (192 mg, 0.35 mmol, 37% yield).
  • Examples 42 & 43 (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (M)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine, respectively
  • Step 1 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)quinolin-2(1H)-one
  • reaction vessel was then sequentially charged with dioxane (3.8 mL) and water (1.3 mL) via syringe.
  • the vial was sealed and heated to 50° C. After 16 h, the reaction mixture was allowed to cool to ambient temperature and an aqueous solution of 1.0 N HCL (5 mL) was added and the mixture diluted with EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 ⁇ 5 mL).
  • Step 2 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)-4,5-dihydro-3H-pyrazol-3-yl)phenyl)quinolin-2(1H)-one
  • Step 3 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl) cyclopropyl)phenyl)quinolin-2(1H)-one
  • a 140-mL pressure vessel equipped with a pressure relief valve was charged with 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)-4,5-dihydro-3H-pyrazol-3-yl)phenyl)quinolin-2(1H)-one (1.13 g, 2.14 mmol) and 1,2-dichlorobenzene (10.7 mL). The reaction was stirred at 208° C. for 6 hours, and then at 230° C. for an additional 9 hours.
  • Step 4 Perfluorophenyl 1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • Step 5 (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl) phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (M)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl) phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine, respectively
  • the first eluting peak was assigned: (P)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl)cyclopropyl) phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (11.9 mg, 0.023 mmol, 9% yield), and the second peak was assigned: (M)-1-(5-fluoro-2-methoxy-4-(1-(trifluoromethyl) cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (12.3 mg, 0.024 mmol, 10% yield).
  • Step 1 1-(5-(benzylthio)-2-((5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl) amino)phenyl)ethan-1-one
  • Step 2 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-4-hydroxyquinolin-2(1H)-one
  • Step 3 6-(benzylthio)-4-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2(1H)-one
  • the PhenoFluor Mix was dried by heating to 140° C. under high vac for 2 hours. After cooling to ambient temperature under vacuum, 6-(benzylthio)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-4-hydroxyquinolin-2(1H)-one (500 mg, 0.970 mmol) slurried in dry toluene (9.7 mL) was added to the vial. The reaction was stirred at room temperature for half hour and then at 100° C. for 1.5 hours under nitrogen.
  • Step 4 & 5 Perfluorophenyl 4-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • Step 6 4-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Step 7 (P)-4-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Example 45 & 46 (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl) phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
  • Step 1 (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Step 2 Trans-(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • This flask was capped and purged with nitrogen for 5 minutes before addition of toluene (30.9 mL) and water (7.74 mL). The resulting mixture was sparged with nitrogen for 15 minutes, then stirred at 50° C. After 16 hours, the reaction was cooled to room temperature and extracted with ethyl acetate. The organic layer was separated and solvents were removed under reduced pressure.
  • Step 3 (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Step 4 (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Examples 47 & 48 (P)-7-fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-7-fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • Step 4 6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)-7-fluoroquinolin-2(1H)-one
  • E Ethyl (E)-3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)-4-fluorophenyl)acrylate (1.9 g, 3.68 mmol) was dissolved in methanol (9.68 mL). Tributylphosphine (0.223 g, 0.276 mL, 1.104 mmol) was added to the reaction. The reaction was then stirred at 70° C. for 5 hours. Solvent was then removed in vacuo.
  • Step 5 & 6 Perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • Step 7 (P)-perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate
  • Perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate was first purified by SFC using a Chiralcel OJ-H column (3 ⁇ 15 cm, 5 micron), with a mobile phase of 15% isopropanol using a flowrate of 160 mL/min. The resulting product was then purified by SFC using a Whelk-O s,s column (2 ⁇ 15 cm, 5 micron), with a mobile phase of 50% 3:1 isopropanol:dichloromethane using a flowrate of 80 mL/min.
  • Step 8 (P)-1-(4-bromo-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
  • Step 9 Trans-(P)-7-fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • This vial was capped and purged with nitrogen for 5 minutes before addition of toluene (2.57 mL) and water (0.643 mL). The resulting mixture was sparged with nitrogen for 10 minutes and then stirred at 50° C. for 4 hours. The crude mixture was extracted with ethyl acetate. The organic layer was separated and concentrated.
  • Step 10 Trans-(P)-7-fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • the Initial product was purified by column chromatography (Biotage Snapultra 10 g, 0-60% ethyl acetate in heptane with 10% dichloromethane as addivtive) to yield trans-(P)-7-fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
  • Step 11 (P)-7-fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine and (P)-7-fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamine
  • trans-(P)-7-Fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-(2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide was purified by SFC via two Chiralpak AS-H, 5 ⁇ m columns (3 ⁇ 25 cm+3 ⁇ 25 cm); a mobile phase of 25% ethanol using a flowrate of 80 mL/min to generate (P)-7-fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (44 mg, 0.085 mmol, 16% yield) and (P)-7-fluoro-N-(isoxazol-3-yl)-1-(2-methoxy-4-(
  • IWB Ionworks Barracuda
  • the internal solution consisted of the following (in mM): KCl 70, KF 70, MgCl 2 0.25, HEDTA 5, and HEPES 10, pH 7.25, with Nmethyl-D-glucamine, 300 mOsmol. From a holding potential of ⁇ 110 mV, currents were elicited by a train of 26 depolarizations of 150 ms duration to ⁇ 20 mV at a frequency of 5 Hz. Cells were then clamped to ⁇ 20 mV for a period of 4 minutes in the presence of a single concentration of test compound. Following this compound incubation period, cells were clamped to ⁇ 110 mV for three seconds to recover unbound channels and put through the same 26 pulse voltage protocol as above.
  • This assay is to determine the intrinsic clearance of test compound in microsomes from preclinical species and human by monitoring the disappearance of test article over time in hepatic microsomes. 20 mg/mL stock, stored at ⁇ 80° C. microsome was used. List of chemical used: (1) Test article, 10 mM stock (DMSO) or powder from sample bank; (2) Verapamil, 10 mM stock; (3) NADPH, powder (Sigma); (4) Potassium phosphate buffer, 100 mM, pH 7.4; and (5) Tolbutamide (or equivalent). Final incubation concentrations were 0.25 mg/mL microsomal protein and 0.5 ⁇ M test article, and incubations are performed in triplicate.
  • the typical time points for the assay were 1, 5, 10, 20, 30, and 40.
  • the assay was carried out in 96-well format, and serially sampled from 400 ⁇ L incubation. At the appropriate timepoints, the incubations were quenched with acetonitrile containing internal standard (tolbutamide). Tolbutamide was the default internal standard because it has a signal by positive or negative ion mass spectrometry.
  • the positive control for microsomal intrinsic clearance assay was verapamil. Samples were subjected to LC-MS/MS analysis, and relative amount of compound was calculated by peak area of compound normalized to peak area of internal standard (A/IS). Calculations of intrinsic clearance were performed with Galileo.
  • Microsomes were removed from ⁇ 80° C. freezer and thawed at room temperature or in 37° C. water bath. Once thawed, they were stored on ice. Microsomes were added (0.53 mg/) to 0.1 M phosphate buffer and 250 ⁇ L aliquot was taken per reaction. 10 mM stock of test article was prepared in DMSO. A 1/100 portion was diluted into acetonitrile:water 50:50 to make 100 ⁇ M stock. About 2.5 ⁇ L of the 100 ⁇ M test article stock was added to each reaction to a final concentration of 1.05 ⁇ M substrate. (NB: At this stage, concentrations were about 2 ⁇ higher than the final incubation conditions, to account for about 1:1 dilution with NADPH).
  • 1.9 mM NADPH solution was prepared in 0.1 mM phosphate buffer. 4 ⁇ 250 ⁇ L replicate wells of substrate and the microsomes containing 1.05 ⁇ M substrate and 0.53 mg/mL protein were the prepared. 3 replicate wells containing 210 ⁇ L 1.90 mM NADPH+1 well of buffer (—NADPH) were also prepared. The microsomes, 0.1 M phosphate buffer, and the test article were preincubated for 5 minutes at 37° C. To initiate the reaction, 190 ⁇ L of the substrate was added to the wells containing NADPH, to yield a final concentration of 0.25 mg/mL microsomes, 0.5 ⁇ M test article, and 1 mM NADPH.
  • mice were orally administered either NaV1.7 compound or a vehicle control formulation at a dose volume of 10 ml/kg.
  • the vehicle used was 2% HPMC/1% Tween 80 pH 10 with NaOH; DI water at pH 10 w/NaOH; or 2% HPMC/1% Tween 80 pH 2.2.
  • Cryopreserved human hepatocytes were seeded in 96-well collagen coated plates at 70,000 cells per well in hepatocyte plating media (HPM, final concentrations: 1 ⁇ Dulbecco's Modified Eagle's Medium, 0.1 ⁇ M dexamethasone, 10% fetal bovine serum, 1 ⁇ ITS, 1 ⁇ PSG) followed by incubation at 37° C. under 5% CO2 and 90% relative humidity for 2 days to allow hepatocytes to form a confluent layer.
  • HPM hepatocyte plating media
  • hepatocytes were treated with either test compound or rifampin (20 ⁇ M, positive control for CYP3A induction) prepared in hepatocyte incubation media ((HIM, final concentrations: 1 ⁇ William's Medium E, 0.1 ⁇ M dexamethasone, 1 ⁇ ITS, 1 ⁇ PSG). Treatment was performed for 72 hours with either 2 concentrations (2 ⁇ M or 10 ⁇ M) or a range of concentrations (0.001 ⁇ M to 100 ⁇ M) of the test compound to obtain full dose-response curve. Fresh media containing the relevant concentrations of the test compound was replaced every day until the samples were processed.
  • Cryopreserved human hepatocytes were seeded in 96-well collagen coated plates at 70,000 cells per well in hepatocyte plating media (HPM, final concentrations: 1 ⁇ Dulbecco's Modified Eagle's Medium, 0.1 ⁇ M dexamethasone, 10% fetal bovine serum, 1 ⁇ ITS, 1 ⁇ PSG) followed by incubation at 37° C. under 5% CO2 and 90% relative humidity for 2 days to allow hepatocytes to form a confluent layer.
  • HPM hepatocyte plating media
  • hepatocytes were treated with either test compound or rifampin (20 ⁇ M, positive control for CYP3A induction) prepared in hepatocyte incubation media ((HIM, final concentrations: 1 ⁇ William's Medium E, 0.1 ⁇ M dexamethasone, 1 ⁇ ITS, 1 ⁇ PSG). Treatment was performed for 72 hours with either 2 concentrations (2 ⁇ M or 10 ⁇ M) or a range of concentrations (0.001 ⁇ M to 100 ⁇ M) of the test compound to obtain full dose-response curve. Fresh media containing the relevant concentrations of the test compound was replaced every day until the samples were processed.
  • the compounds of the present invention may also be tested in the following in vivo assays.
  • animals Na ⁇ ve, male Sprague Dawley rats weighing between 260-300 g at the start of testing can be obtained from Harlan (Indianapolis, Ind.). All animals may be housed under a 12/12 h light/dark cycle with lights on at 0600. Rodents can be housed two to a cage on solid bottom cages with corn cob bedding and can have access to food and water ad libitum. Animals should be allowed to habituate to the vivarium for at least five days before testing is begun and should be brought into the testing room at least 30 minutes prior to dosing.
  • Animals are pretreated with the appropriate test compound either by oral gavage or intraperitoneal injection at the desired pretreatment time (typically two hours before test onset) and then returned to their home cages. After dosing and at least 30 minutes prior to test onset, animals can be acclimated to the individual testing chambers. At test time, each animal can be gently wrapped in a towel with the left hind paw exposed. A dilute solution of formalin (2.5%) in phosphate buffered saline can be injected subcutaneously into the dorsal surface of the left hind paw in a volume to 50 ⁇ L with a 30 g needle.
  • Statistical analysis can be performed by analysis of variance (ANOVA), with post-hoc analysis using Bonferroni compared to the vehicle group for a significant main effect. Data can be represented as mean % MPE+/ ⁇ standard error for each group.
  • animals Na ⁇ ve, male Sprague Dawley rats weighing between 260-300 g at the start of testing may be obtained from Harlan (Indianapolis, Ind.). All animals can be housed under a 12/12 h light/dark cycle with lights on at 0600. Rodents can be housed two to a cage on solid bottom cages with corn cob bedding and can have access to food and water ad libitum. Animals should be allowed to habituate to the vivarium for at least five days before testing is begun and should be brought into the testing room at least 30 minutes prior to dosing.
  • animals can be pretreated with the appropriate test compound either by oral gavage or intraperitoneal injection at the desired pretreatment time (typically two hours before test onset) and then can be returned to their home cages until the pretreatment has elapsed.
  • desired pretreatment time typically two hours before test onset
  • animal can be transferred to the open field testing room in their home cages.
  • Each animal may be placed in a separate testing chamber and the motion tracking system is started.
  • the house lights in the testing room should be turned off and the animals can be allowed to explore the novel open field for 30 minutes.
  • An automated motion tracker made by San Diego Instruments, San Diego, Calif., can be used to capture animal exploration with the aid of infrared photo beams to detect animal movement.
  • mice (Na ⁇ ve, male C57Bl/6) weighing between 22-30 g at the start of testing were obtained from Harlan (Indianapolis, Ind.). All animals were housed under a 12/12 h light/dark cycle with lights on at 0630. Rodents were singly housed on solid bottom cages with corn cob bedding and had access to food and water ad libitum. Animals were allowed to habituate to the vivarium for at least five days before testing was begun and were brought into the testing room at least 30 minutes prior to dosing. Animals were pretreated with the appropriate test compound either by oral gavage or intraperitoneal injection at the desired pretreatment time (typically two hours before test onset) and then returned to their home cages.
  • mice were acclimated to the individual testing chambers. At test time, each animal was gently wrapped in a cloth glove with the left hind paw exposed. A dilute solution of formalin (2%) in phosphate buffered saline was injected subcutaneously into the dorsal surface of the left hind paw in a volume to 20 ⁇ L with a 30 g needle. Animals were then placed into the observation chambers and the behaviors were recorded for 60 minutes following the formalin injection. A pain-like behavior was defined as licking and/or non-weight bearing of the injected hind paw not associated with ambulation.
  • Table 1 provides data for compounds exemplified in the present application and priority document thereof, as representative compounds of the present invention, as follows: compound name (as named using ChemDraw Ultra version 15.1; specific stereochemical designations such as P, M, cis, and trans were added); and biological data including in-vitro human Nav 1.7 IWQ data (IC 50 in uM) and Human CYP3A4 mRNA Induction at 10 uM percent of control (POC) (%), where available.
  • Ex. # refer to Example No. ND means no data was available.
  • the potency of the compounds of the present invention were evaluated on human Na V 1.7 channels using the above described IonWorks Barracuda automated electrophysiology platform that evaluates the ability of compounds to block sodium conductance through Na V 1.7 channels.
  • a voltage-protocol that prosecutes both state-dependent as well as use-dependent inhibition was used as these modes of action are thought to be more relevant for the native state of Na V 1.7 channels in pain sensing neurons in vivo.
  • cytochrome P450 The cytochrome P450 (CYP) is a well-known superfamily of enzymes that are responsible for the oxidative and reductive metabolic transformation of medications used in clinical practice. In addition, the CYP enzymes are commonly associated with causing many clinically relevant drug-drug interactions. Of the CYP enzymes, CYP3A4 is not only the most prevalent CYP enzyme in the liver and intestine, but is responsible for metabolism and elimination of approximately 50% of marketed drugs. In addition, CYP3A4 activity can be induced (or increased) or inhibited (decreased) in response to administration of certain drugs, thereby affecting concentrations of their own or certain concomitant drugs present in the body.
  • the induction of CYP3A4 is an undesired property of the drug molecule as it can result in the reduction of parent drug concentrations that may put patients at increased risk for lack of efficacy or increased metabolite formation that can lead to safety risk.
  • the CYP3A4 induction property was evaluated in an in vitro induction assay where human hepatocytes were exposed to the test compounds at physiologically relevant concentrations. Changes in the levels of CYP3A4 were evaluated at the end of the experiment and compared against the increased levels upon treatment with rifampin, a well-established CYP3A4 inducer.
  • Representative compounds of the present invention show either favorable activities against hNav1.7 IWQ or favorable human CYP3A4 induction data as compared to Compound X, which is named 1-(4-cyclopropyl-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide, having the structure below:
  • Compound X was exemplified in International Patent Publication No. WO2014201206A1, Example No. 1145.
  • Preferred compounds of the present invention have both favorable activities against human Nav1.7 IWQ and favorable human CYP3A4 induction data as compared to Compound X.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US18/009,682 2020-06-10 2021-06-10 Cyclopropyl dihydroquinoline sulfonamide compounds Pending US20230234948A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US18/009,682 US20230234948A1 (en) 2020-06-10 2021-06-10 Cyclopropyl dihydroquinoline sulfonamide compounds

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US202063036999P 2020-06-10 2020-06-10
PCT/US2021/036894 WO2021252818A1 (fr) 2020-06-10 2021-06-10 Composés de cyclopropyl-dihydroquinoléine sulfonamide
US18/009,682 US20230234948A1 (en) 2020-06-10 2021-06-10 Cyclopropyl dihydroquinoline sulfonamide compounds

Publications (1)

Publication Number Publication Date
US20230234948A1 true US20230234948A1 (en) 2023-07-27

Family

ID=76845312

Family Applications (2)

Application Number Title Priority Date Filing Date
US17/344,939 Active 2041-07-13 US11807634B2 (en) 2020-06-10 2021-06-10 Cyclopropyl dihydroquinoline sulfonamide compounds
US18/009,682 Pending US20230234948A1 (en) 2020-06-10 2021-06-10 Cyclopropyl dihydroquinoline sulfonamide compounds

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US17/344,939 Active 2041-07-13 US11807634B2 (en) 2020-06-10 2021-06-10 Cyclopropyl dihydroquinoline sulfonamide compounds

Country Status (10)

Country Link
US (2) US11807634B2 (fr)
EP (1) EP4164748A1 (fr)
JP (1) JP2021195367A (fr)
AR (1) AR122593A1 (fr)
AU (1) AU2021289741A1 (fr)
CA (1) CA3183814A1 (fr)
MX (1) MX2022015622A (fr)
TW (1) TW202214587A (fr)
UY (1) UY39264A (fr)
WO (1) WO2021252818A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117813302A (zh) 2021-06-04 2024-04-02 沃泰克斯药物股份有限公司 经取代的四氢呋喃-2-甲酰胺作为钠通道调节剂
EP4347031A1 (fr) 2021-06-04 2024-04-10 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hétéro)aryl) tétrahydrofuran carboxamides utilisés en tant que modulateurs de canaux sodiques
AU2022285758A1 (en) 2021-06-04 2023-11-30 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofuran analogs as modulators of sodium channels
WO2022256708A1 (fr) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Formes galéniques solides et schémas posologiques comprenant du (2r,3s,4s,5r)-4-[[3-(3,4-difluoro-2-méthoxy-phényl)-4,5-diméthyl-5-(trifluorométhyl)tétrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide
JP2024520643A (ja) 2021-06-04 2024-05-24 バーテックス ファーマシューティカルズ インコーポレイテッド ナトリウムチャネルの調節因子としてのヒドロキシ及び（ハロ）アルコキシ置換テトラヒドロフラン
EP4347584A1 (fr) 2021-06-04 2024-04-10 Vertex Pharmaceuticals Incorporated Analogues de n-(hydroxyalkyl(hétéro)aryl)tétrahydrofurane carboxamide en tant que modulateurs de canaux sodiques
WO2023205465A1 (fr) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Composés hétéroaryles pour le traitement de la douleur
US20230382910A1 (en) 2022-04-22 2023-11-30 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2023205468A1 (fr) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Composés hétéroaryle pour le traitement de la douleur
US20230373925A1 (en) 2022-04-22 2023-11-23 Vertex Pharma Heteroaryl compounds for the treatment of pain

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT72878B (en) 1980-04-24 1983-03-29 Merck & Co Inc Process for preparing mannich-base hydroxamic acid pro-drugs for the improved delivery of non-steroidal anti-inflammatory agents
US4412994A (en) 1980-04-24 1983-11-01 Interx Research Corporation Mannich-base hydroxamic acid prodrugs, compositions and use
GT200600381A (es) 2005-08-25 2007-03-28 Compuestos organicos
US8101647B2 (en) 2008-10-17 2012-01-24 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their use as therapeutic agents
WO2013134518A1 (fr) 2012-03-09 2013-09-12 Amgen Inc. Inhibiteurs sulfamides des canaux de sodium
US9212182B2 (en) 2013-06-12 2015-12-15 Amgen Inc. Bicyclic sulfonamide compounds as sodium channel inhibitors
MY188700A (en) * 2015-03-02 2021-12-23 Amgen Inc Bicyclic ketone sulfonamide compounds
US10729684B2 (en) * 2015-12-18 2020-08-04 Amgen Inc. Alkynyl dihydroquinoline sulfonamide compounds
JP6903663B2 (ja) * 2015-12-18 2021-07-14 アムジエン・インコーポレーテツド アルキルジヒドロキノリンスルホンアミド化合物

Also Published As

Publication number Publication date
CA3183814A1 (fr) 2021-12-16
US20210387977A1 (en) 2021-12-16
WO2021252818A1 (fr) 2021-12-16
JP2021195367A (ja) 2021-12-27
TW202214587A (zh) 2022-04-16
EP4164748A1 (fr) 2023-04-19
AU2021289741A1 (en) 2022-12-22
US11807634B2 (en) 2023-11-07
AR122593A1 (es) 2022-09-21
UY39264A (es) 2021-12-31
MX2022015622A (es) 2023-01-11

Similar Documents

Publication Publication Date Title
US11807634B2 (en) Cyclopropyl dihydroquinoline sulfonamide compounds
US20220306604A1 (en) Cyclobutyl dihydroquinoline sulfonamide compounds
US20230227442A1 (en) Heteroalkyl dihydroquinoline sulfonamide compounds
US10472356B2 (en) Bicyclic ketone sulfonamide compounds
US20230322732A1 (en) RIP1 Inhibitory Compounds and Methods for Making and Using the Same
US20200009129A1 (en) Alkyl dihydroquinoline sulfonamide compounds
US10729684B2 (en) Alkynyl dihydroquinoline sulfonamide compounds
EP3828174A1 (fr) Dérivé de pyridazinone
CN102372701A (zh) 氮杂双环己烷类衍生物、其制备方法及其在医药上的应用

Legal Events

Date Code Title Description
STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION