WO2023165551A1 - Dérivé à cycle aromatique à six chaînons pyrrolidone, composition pharmaceutique de celui-ci et son utilisation - Google Patents

Dérivé à cycle aromatique à six chaînons pyrrolidone, composition pharmaceutique de celui-ci et son utilisation Download PDF

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Publication number
WO2023165551A1
WO2023165551A1 PCT/CN2023/079240 CN2023079240W WO2023165551A1 WO 2023165551 A1 WO2023165551 A1 WO 2023165551A1 CN 2023079240 W CN2023079240 W CN 2023079240W WO 2023165551 A1 WO2023165551 A1 WO 2023165551A1
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Prior art keywords
ring
alkyl
compound
stereoisomer
pharmaceutically acceptable
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PCT/CN2023/079240
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English (en)
Chinese (zh)
Inventor
孙洪鹏
许峰
王海龙
席宝信
童忠安
马前
Original Assignee
上海海雁医药科技有限公司
扬子江药业集团有限公司
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Publication of WO2023165551A1 publication Critical patent/WO2023165551A1/fr

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles 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
    • A61K31/495—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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • R c is hydroxyl, halogen, C 1-3 alkyl, deuterated C 1-3 alkyl, C 3-6 cycloalkyl, halogenated C 1-3 alkyl or NR a1 R b1 ;
  • p1, p2, q1, q2 are each independently 1, 2 or 3;
  • R 1 and R 2 are each independently C 1-8 alkyl (in some embodiments, C 1-6 alkyl, in other embodiments C 1-3 alkyl), halogenated C 1-8 Alkyl (in some embodiments is halogenated C 1-6 alkyl, in other embodiments is halogenated C 1-3 alkane group) or C 3-6 cycloalkyl; said C 3-6 cycloalkyl is unsubstituted or substituted by 1 or 2 substituents independently selected from halogen and C 1-3 alkyl;
  • formula (Ia) is selected from one of the following structures:
  • a benzene ring or a 5- or 6-membered heteroaryl ring selected from the group consisting of thiophene ring, furan ring, thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, 1,2, 3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, 1,2,3 -Oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring , pyrimidine ring, pyrazine ring, triazine ring and tetrazine ring.
  • the structure shown in (Id) is selected from the following structures:
  • n is 2.
  • R is monochloromethyl , dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoro Methyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, monofluorosubstituted cyclopropyl Or a fluorine-substituted cyclobutyl;
  • R 2 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a fluoro-substituted cyclopropyl or a Fluorine-substit
  • Z is N or CH.
  • Alkyl refers to straight and branched chain saturated aliphatic hydrocarbon groups.
  • C 1-8 alkyl refers to an alkyl group having 1 to 8 carbon atoms, such as a C 1-6 alkyl group, and in some embodiments a C 1-3 alkyl group; non-limiting examples of alkyl groups Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2 -Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl Propyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3
  • C 3-8 cycloalkyl refers to a monocyclic cycloalkyl group with 3 to 8 carbon atoms
  • cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc.
  • Examples are C 3-6 cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 8-10 cycloalkyl refers to a fused bicyclic cyclic hydrocarbon group having 8 to 10 ring atoms, non-limiting examples of C 8-10 cycloalkyl include
  • Heteroarylheterocycloalkyl means a group in which a heteroaryl ring is fused with a heterocycloalkyl ring to form a bicyclic, tricyclic or polycyclic ring system, wherein the heterocycloalkyl ring is as defined above.
  • “Saturated or partially unsaturated monoheterocyclic ring” means that 1, 2 or 3 ring carbon atoms in a saturated or partially unsaturated monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t is an integer 0, 1 or 2), but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon.
  • the active substance of the present application or “the active compound of the present application” refers to the compound of formula (I) of the present application, or its pharmaceutically acceptable salt, or its solvate, or its stereoisomer, or its prodrug , which has PI3K ⁇ selective inhibitory activity.
  • the "pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • a pharmaceutically acceptable acid addition salt refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. These salts can be prepared by methods known in the art.
  • Step 3 Compound S-1-b (400 mg, 788.04 ⁇ mol) and Intermediate 1 (240.85 mg, 1.02 mmol) were dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (1 mL), argon Potassium carbonate (108.91 mg, 788.04 ⁇ mol), bis(2-diphenylphosphinocyclopentane-2,4-dien-1-yl)iron dichloropalladium (115.32 mg, 157.61 ⁇ mol) were added under gas protection, heat up Stir overnight at 80°C. The target product was found by LC-MS detection.
  • Step 4 Dissolve compound S-1-c (10 mg, 18.66 ⁇ mol) in methanol (5 mL), add ammonium fluoride (13.81 mg, 373.26 ⁇ mol) and dissolve in water (0.5 mL), and heat up to Stir overnight at 75 degrees.
  • Step 1 Intermediate 2 (300mg, 829.63 ⁇ mol) and 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (173.22mg , 1.08mmol) was dissolved in dioxane (6mL), then tris(dibenzylideneacetone)dipalladium (37.99mg, 41.48 ⁇ mol), 4,5-bisdiphenylphosphine-9,9-di Methylxanthene (48.00 mg, 82.96 ⁇ mol) and cesium carbonate (810.93 mg, 2.49 mmol) were added. The reaction was stirred in microwave at 150°C for 0.5 hours.
  • Step 2 Compound S-47-a (380 mg, 972.15 ⁇ mol) was dissolved in 1,4-dioxane (15 mL), cooled to -78 ° C under argon protection, and tetrakistriphenylphosphine palladium (101.99 mg, 97.21 ⁇ mol), stirred at -78°C for 2 hours, added dibutyl-(1-ethoxyvinyl)-propyltin (674.91mg, 1.94mmol) dropwise, and continued to stir at -78°C for 2 hours.
  • the target product was found by LC-MS detection.
  • Step 3 Dissolve compound S-53-b (100mg, 234.81 ⁇ mol) and intermediate 6 (186.87mg, 662.28 ⁇ mol) in water (0.5mL) and 1,4-dioxane (4mL), and then Sodium carbonate (116.99 mg, 1.10 mmol), Pd(dppf)Cl 2 (19.38 mg, 26.49 ⁇ mol) were added.
  • the reaction was stirred in the microwave at 120°C for 45 minutes. After the reaction of raw materials was completed, it was cooled to room temperature, diluted with dichloromethane, filtered, and the filtrate was concentrated under reduced pressure.
  • the crude product was prepared by alkaline method to obtain compound S-53 (22.46 mg, 17.76%).
  • Step 4 Dissolve compound S-47-c (300mg, 0.753mmol), 2-methylpropane-2-sulfonamide (547mg, 4.52mmol) in tetrahydrofuran (20mL), then add tetraethyl titanate (515mg , 2.26mmol), argon replacement, under the protection of argon, stirred and reacted at 70°C for 16 hours. LCMS detection, the reaction is complete. After the reaction solution was cooled, water (100 mL) and dichloromethane (200 mL) were added, stirred for 5 minutes, filtered, and the filter residue was washed with dichloromethane (100 mL ⁇ 3).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
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  • Engineering & Computer Science (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente demande concerne un dérivé à cycle aromatique à six chaînons pyrrolidone, et une composition pharmaceutique de celui-ci et son utilisation. Le dérivé à cycle aromatique à six chaînons pyrrolidone a la structure telle que représentée dans la formule (I).
PCT/CN2023/079240 2022-03-02 2023-03-02 Dérivé à cycle aromatique à six chaînons pyrrolidone, composition pharmaceutique de celui-ci et son utilisation WO2023165551A1 (fr)

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CN202210202749.9 2022-03-02
CN202210202749 2022-03-02
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CN202211144337 2022-09-20

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116813608A (zh) * 2023-06-08 2023-09-29 英矽智能科技(上海)有限公司 噻唑类化合物及其应用
WO2024046454A1 (fr) * 2022-09-01 2024-03-07 上海海雁医药科技有限公司 Dérivé de pyridopyrrolidone substituté par hétéroaryle, ainsi que composition pharmaceutique et son utilisation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020102216A1 (fr) * 2018-11-13 2020-05-22 Incyte Corporation Dérivés hétécycliques substitués utiles en tant qu'inhibiteurs de pi3k
WO2020247496A1 (fr) * 2019-06-04 2020-12-10 Arcus Biosciences, Inc. Composés de pyrazolo[1,5-a]pyrimidine 2,3,5-trisubstitués
WO2022017371A1 (fr) * 2020-07-21 2022-01-27 中国医药研究开发中心有限公司 Composé hétérocylique présentant une double activité inhibitrice de phosphatidylinositol 3-kinase δ et γ et son utilisation médicale
CN114025756A (zh) * 2019-04-10 2022-02-08 南京征祥医药有限公司 磷脂酰肌醇3-激酶抑制剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020102216A1 (fr) * 2018-11-13 2020-05-22 Incyte Corporation Dérivés hétécycliques substitués utiles en tant qu'inhibiteurs de pi3k
CN114025756A (zh) * 2019-04-10 2022-02-08 南京征祥医药有限公司 磷脂酰肌醇3-激酶抑制剂
WO2020247496A1 (fr) * 2019-06-04 2020-12-10 Arcus Biosciences, Inc. Composés de pyrazolo[1,5-a]pyrimidine 2,3,5-trisubstitués
WO2022017371A1 (fr) * 2020-07-21 2022-01-27 中国医药研究开发中心有限公司 Composé hétérocylique présentant une double activité inhibitrice de phosphatidylinositol 3-kinase δ et γ et son utilisation médicale

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MILES DILLON H., YAN XUELEI, THOMAS-TRAN RHIANNON, FOURNIER JEREMY, SHARIF EHESAN U., DREW SAMUEL L., MATA GUILLAUME, LAWSON KENNE: "Discovery of Potent and Selective 7-Azaindole Isoindolinone-Based PI3Kγ Inhibitors", ACS MEDICINAL CHEMISTRY LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 11, no. 11, 12 November 2020 (2020-11-12), US , pages 2244 - 2252, XP055954608, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.0c00387 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024046454A1 (fr) * 2022-09-01 2024-03-07 上海海雁医药科技有限公司 Dérivé de pyridopyrrolidone substituté par hétéroaryle, ainsi que composition pharmaceutique et son utilisation
CN116813608A (zh) * 2023-06-08 2023-09-29 英矽智能科技(上海)有限公司 噻唑类化合物及其应用
CN116813608B (zh) * 2023-06-08 2024-03-22 英矽智能科技(上海)有限公司 噻唑类化合物及其应用

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