WO2023205463A1 - Heteroaryl compounds for the treatment of pain - Google Patents

Heteroaryl compounds for the treatment of pain Download PDF

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Publication number
WO2023205463A1
WO2023205463A1 PCT/US2023/019469 US2023019469W WO2023205463A1 WO 2023205463 A1 WO2023205463 A1 WO 2023205463A1 US 2023019469 W US2023019469 W US 2023019469W WO 2023205463 A1 WO2023205463 A1 WO 2023205463A1
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Prior art keywords
compound
pharmaceutically acceptable
pain
acceptable salt
alkyl
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PCT/US2023/019469
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English (en)
French (fr)
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WO2023205463A8 (en
Inventor
Mark Thomas Miller
Dennis James Hurley
Timothy Donald Neubert
Vijayalaksmi Arumugam
Sara Sabina HADIDA RUAH
Jason Mccartney
Jinglan Zhou
Jaclyn CHAU
Robert Martin DEMORET
Senait G. GHIRMAI
Roman Askatovich VALIULIN
Alexander Frederik KINTZER
David Robert SLOCHOWER
Kathleen Aertgeerts
Elizabeth Mary BECK
James Jun Bon MUI
Miranda Adele WRIGHT
Ronald Marcellus Alphonsus Knegtel
Ewa Iwona CHUDYK
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Priority to PE2024002287A priority Critical patent/PE20251179A1/es
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Priority to AU2023256603A priority patent/AU2023256603A1/en
Priority to CN202380047901.3A priority patent/CN119677737A/zh
Priority to IL316462A priority patent/IL316462A/en
Priority to CR20240513A priority patent/CR20240513A/es
Priority to KR1020247039041A priority patent/KR20250005373A/ko
Priority to JP2024562079A priority patent/JP2025513455A/ja
Priority to EP23724521.2A priority patent/EP4511116A1/en
Publication of WO2023205463A1 publication Critical patent/WO2023205463A1/en
Publication of WO2023205463A8 publication Critical patent/WO2023205463A8/en
Priority to DO2024000209A priority patent/DOP2024000209A/es
Priority to JOJO/P/2024/0235A priority patent/JOP20240235A1/ar
Priority to MX2024013020A priority patent/MX2024013020A/es
Anticipated expiration legal-status Critical
Priority to CONC2024/0015820A priority patent/CO2024015820A2/es
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • a “C 1 -C 6 alkoxy” group is a radical of the formula -OR a where R a is an alkyl group having the between one and six carbon atoms.
  • the term “haloalkoxy” refers to an alkoxy group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the of the alkyl group are replaced by halo groups.
  • the term “alkylene” refers to a divalent, straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having the specified number of carbon atoms, which is attached to the rest of the molecule by two single bonds.
  • stereochemical designators associated with the stereocenters of known absolute configuration are marked with an asterisk (*), e.g., (R*)- and (S*)-, while the stereochemical designators associated with stereocenters of unknown absolute configuration are not so marked.
  • the unmarked stereochemical designators associated with the stereocenters of unknown absolute configuration reflect the relative stereochemistry of those stereocenters with respect to other stereocenters of unknown absolute configuration, but do not necessarily reflect the relative stereochemistry with respect to the stereocenters of known absolute configuration.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of abdominoplasty pain.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of visceral pain.
  • the visceral pain comprises visceral pain from abdominoplasty.
  • the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity of acute pain, sub-acute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociplastic pain, arthritis, migraine, cluster headaches, tension headaches, and all other forms of headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecific chronic back pain, head pain
  • doxazosin tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-l, 2,3,4- tetrahydroisoquinolin-2-yl)-5-(2-pyridyl) quinazoline;
  • a tricyclic antidepressant e.g. desipramine, imipramine, amitriptyline or nortriptyline
  • an anticonvulsant e.g.
  • the invention in another aspect, includes a composition for coating an implantable device comprising a compound or salt of the invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
  • the invention includes an implantable device coated with a composition comprising a compound or salt of the invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121.
  • Step 2 8-benzyloxy-6-chloro-1,5-naphthyridine-2-carbonitrile
  • 8-Benzyloxy-6-chloro-1,5-naphthyridine-2-carbonitrile was prepared from 8-benzyloxy- 6-chloro-1-oxido-1,5-naphthyridin-1-ium using a procedure analogous to that found in Intermediate A - 4, step 3.
  • the reaction mixture was cooled to room temperature and partitioned between water (100 mL) and MTBE (500 mL).
  • the biphasic mixture was filtered through Celite® and the layers were separated.
  • the organic layer was washed with water (4x) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the residue was adsorbed on silica gel under vacuum and purified by silica chromatography (120 g silica, 0-10% ethyl acetate/heptane) to provide 1.4 g of material.
  • Step 7 2-[4-tert-butyl-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-phenyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane [00415] n-BuLi (1.2 mL of 2.5 M, 3.0 mmol) was slowly added to a solution of 2-bromo-5-tert- butyl-1-(4-fluoro-2-methoxy-phenoxy)-3-methyl-benzene (1.0 g, 2.7 mmol) in THF (20 mL) at -78 °C.
  • Step 1 3-bromo-2-(3,4-difluoro-2-methyl-phenoxy)-4-methyl-5- (trifluoromethyl)pyridine
  • Step 2 A mixture of 3-bromo-2-chloro-4-methyl-5-(trifluoromethyl)pyridine (2.63 g, 9.58 mmol) and 3,4-difluoro-2-methyl-phenol (2.6 g, 18 mmol) was dissolved in DMSO (26 mL). To this solution was added cesium carbonate (7.73 g, 23.7 mmol) and the mixture stirred at 90 °C for 2.5 h. The mixture was allowed to cool to room temperature then diluted with ethyl acetate.
  • the material was purified by reverse phase chromatography (C18, 5-95% acetonitrile/water containing 0.1 % formic acid) and the product-containing fractions concentrated to remove the acetonitrile.
  • the resulting aqueous solution was extracted with ethyl acetate (3 x 100 mL).
  • the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide [2-(3,4-difluoro-2-methyl-phenoxy)-4- methyl-5-(trifluoromethyl)-3-pyridyl]boronic acid (1.64 g, 90%) as a white solid.
  • Step 3 3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-ol
  • 3-Bromo-6-methyl-5-(trifluoromethyl)pyridin-2-ol was prepared from 6-methyl-5- (trifluoromethyl)pyridin-2-ol using a procedure analogous to that found in Intermediate B - 7, step 2.
  • ESI- MS m/z calc.254.95, found 255.79 (M+1) + .
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 12.66 (s, 1H), 7.99 (s, 1H), 2.33-2.25 (m, 3H).
  • Step 4 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridine-3- carboxylic acid
  • methyl 2-(3,4-difluoro-2-methyl-phenoxy)-5-methyl-6- (trifluoromethyl)pyridine-3-carboxylate (30 g, 78.5 mmol) in methanol (60 mL), THF (120 mL), and water (60 mL) was added lithium hydroxide monohydrate (6.5 g, 155 mmol). The mixture was stirred at room temperature for 2 h and then the volatiles were removed under reduced pressure. The residue was acidified ( ⁇ pH 6) using 2 M HCl.
  • Step 7 5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridin-3-amine
  • 5-Chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridin-3-amine was prepared from tert-butyl N-[5-chloro-2-(3,4-difluoro-2-methyl-phenoxy)-6-(trifluoromethyl)-3- pyridyl]carbamate using a procedure analogous to that found in Intermediate B - 11, step 6.
  • Step 1 methyl 2-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridine-3- carboxylate
  • Methyl 2-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate was prepared from methyl 2-chloro-5-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (Intermediate B - 11, step 2) and 4,4-difluoroazepane using a procedure analogous to that found in Intermediate B - 20, step 1 using cesium carbonate as the base and DMF as solvent.
  • Step 2 1-(5-chloro-3-iodo-4,6-dimethyl-2-pyridyl)-4,4-difluoro-azepane
  • Step 3 [2-(4,4-difluoroazepan-1-yl)-5,6,7,8-tetrahydroquinolin-3-yl]boronic acid
  • [2-(4,4-difluoroazepan-1-yl)-5,6,7,8-tetrahydroquinolin-3-yl]boronic acid was prepared from 3-Bromo-2-(4,4-difluoroazepan-1-yl)-5,6,7,8-tetrahydroquinoline using a procedure analogous to that found in Intermediate B - 20, step 2.
  • ESI-MS m/z calc.310.17, found 311.2 (M+1) + .
  • Step 2 2-bromo-6-tert-butyl-5-chloro-pyridine-3-carbonitrile
  • Step 3 5-bromo-2-(3,3-difluorocyclobutyl)-4-(4,4-difluorocyclohexyl)pyrimidine
  • 5-Bromo-2-(3,3-difluorocyclobutyl)-4-(4,4-difluorocyclohexyl)pyrimidine was prepared from 5-Bromo-2-(3,3-difluorocyclobutyl)-6-(4,4-difluorocyclohexyl)pyrimidine-4-carboxylic acid using a procedure analogous to that found in Intermediate B - 40, step 3 with heating at 60 oC for 90 min.
  • Step 3 [6-[[3-bromo-4-methyl-5-(trifluoromethyl)-2-pyridyl]oxy]-2,3-difluoro- phenyl]methoxy-tert-butyl-dimethyl-silane [00949] [6-[[3-Bromo-4-methyl-5-(trifluoromethyl)-2-pyridyl]oxy]-2,3-difluoro-phenyl]methoxy- tert-butyl-dimethyl-silane was prepared from 2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,4-difluoro- phenol using a procedure analogous to that found in Intermediate B - 64, step 2.
  • Step 2 [6-(3,3-difluorocyclobutyl)-4-(3,4-difluoro-2-methyl-phenoxy)-3-pyridyl]boronic acid
  • Step 2 A mixture of the protected intermediate I and Pd/C is stirred in the appropriate solvent (e.g. methanol, ethanol, or ethyl acetate) under an atmosphere of hydrogen. The reaction mixture is filtered, concentrated, and purified via silica gel column chromatography or reverse phase column chromatography to provide the desired product I.
  • the appropriate solvent e.g. methanol, ethanol, or ethyl acetate
  • the reaction mixture is filtered, concentrated, and purified via silica gel column chromatography or reverse phase column chromatography to provide the desired product I.
  • a solution of protected intermediate I in the appropriate solvent DCM, dioxane or toluene
  • acid e.g. HCl or TFA
  • Step 2 4-benzyloxy-5-chloro-2-[2-(3,4-difluoro-2-methyl-phenoxy)-3-quinolyl]-1,6- naphthyridine
  • Step 3 4-Benzyloxy-2-[2-(3,4-difluoro-2-methyl-phenoxy)-3-quinolyl]-6-oxido-1,6- naphthyridin-6-ium (100 mg, 0.192 mmol) was treated with POCl 3 (400 ⁇ L, 4.29 mmol) and stirred at 50 °C for 2 h and then concentrated in vacuo.
  • Step 2 tert-butyl 2-(3,4-difluoro-2-methoxy-phenoxy)-5-fluoro-4- (trifluoromethyl)benzoate
  • tert-Butyl 2,5-difluoro-4-(trifluoromethyl)benzoate (69.8 g, 247 mmol)
  • 3,4-difluoro-2- methoxy-phenol 55 g, 344 mmol
  • cesium carbonate 140 g, 430 mmol
  • reaction mixture was quenched in an aqueous sodium bisulfite solution (10% w/w, 100 mL). The mixture was then filtered and the solid recovered in MTBE (50 mL), filtered on silica (10 g) and washed with MTBE (50 mL). Evaporation afforded 2-[2-(3,4-difluoro-2-methoxy-phenoxy)-5-fluoro-4- (trifluoromethyl)phenyl]-4-oxo-1H-1,6-naphthyridine-5-carboxamide (142, 2.05 g, 60%) as a beige solid.

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PCT/US2023/019469 2022-04-22 2023-04-21 Heteroaryl compounds for the treatment of pain Ceased WO2023205463A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
EP23724521.2A EP4511116A1 (en) 2022-04-22 2023-04-21 Heteroaryl compounds for the treatment of pain
AU2023256603A AU2023256603A1 (en) 2022-04-22 2023-04-21 Heteroaryl compounds for the treatment of pain
CN202380047901.3A CN119677737A (zh) 2022-04-22 2023-04-21 用于治疗疼痛的杂芳基化合物
IL316462A IL316462A (en) 2022-04-22 2023-04-21 Heteroaryl compounds for the treatment of pain
CR20240513A CR20240513A (es) 2022-04-22 2023-04-21 Compuestos de heteroarilo para el tratamiento del dolor
KR1020247039041A KR20250005373A (ko) 2022-04-22 2023-04-21 통증 치료를 위한 헤테로아릴 화합물
JP2024562079A JP2025513455A (ja) 2022-04-22 2023-04-21 疼痛の治療のためのヘテロアリール化合物
PE2024002287A PE20251179A1 (es) 2022-04-22 2023-04-21 Compuestos de heteroarilo para el tratamiento del dolor
DO2024000209A DOP2024000209A (es) 2022-04-22 2024-10-21 Compuestos de heteroarilo para el tratamiento del dolor
MX2024013020A MX2024013020A (es) 2022-04-22 2024-10-22 Compuestos de heteroarilo para el tratamiento del dolor
JOJO/P/2024/0235A JOP20240235A1 (ar) 2022-04-22 2024-10-22 مركبات أريل غير متجانسة لمعالجة الألم
CONC2024/0015820A CO2024015820A2 (es) 2022-04-22 2024-11-21 Compuestos de heteroarilo para el tratamiento del dolor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263333875P 2022-04-22 2022-04-22
US63/333,875 2022-04-22

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WO2023205463A1 true WO2023205463A1 (en) 2023-10-26
WO2023205463A8 WO2023205463A8 (en) 2024-03-28

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