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WO2025146160A1 - Composé hétérocyclique et composition pharmaceutique associée - Google Patents

Composé hétérocyclique et composition pharmaceutique associée Download PDF

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Publication number
WO2025146160A1
WO2025146160A1 PCT/CN2025/070537 CN2025070537W WO2025146160A1 WO 2025146160 A1 WO2025146160 A1 WO 2025146160A1 CN 2025070537 W CN2025070537 W CN 2025070537W WO 2025146160 A1 WO2025146160 A1 WO 2025146160A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
compound according
disease
independently selected
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
PCT/CN2025/070537
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English (en)
Chinese (zh)
Inventor
胡伟
祝力
戴丽光
杨艳青
张慧
杜云龙
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.)
Prime Gene Therapeutics Co Ltd
Original Assignee
Prime Gene Therapeutics Co Ltd
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 Prime Gene Therapeutics Co Ltd filed Critical Prime Gene Therapeutics Co Ltd
Publication of WO2025146160A1 publication Critical patent/WO2025146160A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/437—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 five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • inflammatory response is a common physiological and pathological activity in the body, and inflammasomes play an important regulatory role in this response.
  • inflammasomes There are currently five main types of inflammasomes discovered, namely NLRP1 inflammasome, NLRP3 inflammasome, NLRC4 inflammasome, IPAF inflammasome and AIM2 inflammasome.
  • NLRP3 inflammasome has been studied the most and most thoroughly.
  • NLRP3 The activation process of NLRP3 involves multiple signaling pathways. Generally speaking, the activation of NLRP3 requires two signals: the first signal induces the transcription and protein expression of NLRP3, such as through the activation of the Tol-like receptor (TLR) signaling pathway, and the second signal usually comes from intracellular damage signals or other stimuli, such as intracellular oxidative stress, potassium ion outflow, or mitochondrial dysfunction.
  • TLR Tol-like receptor
  • NLRP3 plays an important regulatory role in the inflammatory process. When the body is damaged, infected or otherwise stimulated, NLRP3 is activated and forms inflammasomes. NLRP3 inflammasomes participate in the development of diseases mainly by promoting the massive release of downstream inflammatory cytokines and inducing acute and chronic inflammatory responses. Its downstream related cytokines can participate in the development of immune diseases or parasitic diseases by regulating the function of the body's immune cells, such as IL-1 ⁇ can promote the aggregation of Th2 cells and the differentiation of Th17 cells, IL-18 can simultaneously enhance the immune response of Th1 and Th2 cells, and IL-33 can mediate the response of Th2 cells.
  • IL-1 ⁇ can promote the aggregation of Th2 cells and the differentiation of Th17 cells
  • IL-18 can simultaneously enhance the immune response of Th1 and Th2 cells
  • IL-33 can mediate the response of Th2 cells.
  • the present application relates to a compound as shown in formula I
  • the compound of formula I of the present invention is selected from:
  • Another aspect of the present invention is to provide a compound as shown in Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof for use in the preparation of a medicament for treating NLRP3-mediated diseases.
  • any concentration range, percentage range, ratio range or integer range should be understood to include the value of any integer within the range, and where appropriate, include its fraction (e.g., one tenth and one hundredth of an integer), unless otherwise stated.
  • the terms “about” and “approximately” mean ⁇ 20%, ⁇ 10%, ⁇ 5% or ⁇ 1% of the range, value or structure shown, unless otherwise stated.
  • the terms “one/a kind (a)” and “an” as used herein refer to “one/a kind or more/a variety” of the enumerated components.
  • alternatives e.g., "or” should be understood to mean one or both of the alternatives or any combination thereof.
  • R 1 is ethynyl, vinyl or propynyl (including, for example, prop-1-yn-1-yl, prop-1-yn-3-yl).
  • R4 and R5 are hydrogen.
  • X2 is -O-, -S-, -NH-, or -NC1-3alkyl- .
  • L is -NH-, -O-, -S-, or -CH2- .
  • L is -NH-.
  • W is a 4- to 8-membered heterocyclic group optionally substituted with 1 or 2 R W , the 4- to 8-membered heterocyclic group containing up to 3 heteroatoms independently selected from N and O, and the maximum number of O heteroatoms is 1, wherein R W is each independently selected from hydrogen, hydroxy, oxo, hydroxyC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 halocycloalkyl or NR w1 R w2 ; wherein R w1 and R w2 are each independently selected from hydrogen and C 1-6 alkyl.
  • the 4- to 8-membered heterocyclic group may be a monocyclic heterocyclic group, or a condensed heterocyclic group, for example, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, dioxane and the like.
  • W is a 6-membered heterocyclyl containing a single N heteroatom, such as piperidinyl, optionally substituted with 1 or 2 R W , wherein R W is each independently selected from C 1-6 alkyl, hydroxyC 1-6 alkyl or C 3-6 cycloalkyl.
  • W is one of the following structural formulas
  • R W are each independently selected from C 1-3 alkyl, hydroxy C 1-3 alkyl or C 3-6 cycloalkyl.
  • W is one of the following structural formulas
  • the compound is selected from the following compounds:
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ear, nasal, and topical administration.
  • parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.
  • the compounds described herein are administered in a local rather than systemic manner, for example, by injecting the compound directly into an organ, typically in the form of a depot preparation or a sustained release preparation.
  • the long-acting preparation is administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection.
  • the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to an organ and selectively absorbed by the organ.
  • the compounds as described herein are provided in the form of a rapid release preparation, a prolonged release preparation, or an intermediate release preparation. In other embodiments, the compounds described herein are administered locally.
  • an effective amount of at least one compound of structure (I) is administered to an individual suffering from or diagnosed as suffering from such a disease, disorder or medical condition.
  • the effective amount or dosage can be determined by methods such as modeling, dose escalation studies or clinical trials, such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and progression of the disease, disorder or condition, the individual's previous or ongoing therapy, the individual's health status and response to the drug, and the judgment of the treating physician.
  • the compounds according to the present disclosure are effective in a wide dosage range.
  • dosages of 10 to 5000 mg/day, 100 to 5000 mg/day, 1000 to 4000 mg/day, and 1000 to 3000 mg/day are examples of dosages used in some embodiments.
  • the exact dosage depends on the route of administration, the compound form administered, the object to be treated, the weight of the object to be treated, the preference and experience of the attending physician.
  • the compounds of the present disclosure are administered in a single dose.
  • such administration will be by injection, such as intravenous injection, so as to quickly introduce the agent.
  • other routes are used as appropriate.
  • a single dose of a compound of the present disclosure can also be used to treat acute conditions.
  • the compounds described herein are formulated into pharmaceutical compositions.
  • pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate processing of the disclosed compounds into pharmaceutically acceptable formulations. Appropriate formulations depend on the selected route of administration.
  • compositions comprising one or more compounds of structure (I) and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising one or more compounds selected from the compounds of structure (I) and a pharmaceutically acceptable diluent, excipient and carrier.
  • the compound is administered as a pharmaceutical composition, wherein one or more compounds selected from the compounds of structure (I) are mixed with other active ingredients, such as in combination therapy. All combinations of active substances described in the combination therapy section below and all combinations of active substances described throughout the disclosure are contemplated herein.
  • the pharmaceutical composition includes one or more compounds of structure (I).
  • pharmaceutical composition refers to a mixture of one or more compounds selected from the compound of structure (I) and other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and/or excipients.
  • the pharmaceutical composition promotes the administration of the compound to an organism.
  • a therapeutically effective amount of one or more compounds selected from the compound of structure (I) provided herein is applied to a mammal suffering from a disease to be treated, a disorder or a medical condition in a pharmaceutical composition.
  • the mammal is a human.
  • the therapeutically effective amount varies according to the severity of the disease, the age and relative health of the individual, the efficacy of the compound used, and other factors.
  • the compounds described herein are used as components of a mixture alone or in combination with one or more therapeutic agents.
  • the compounds described herein are formulated for oral administration.
  • the compounds described herein are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient.
  • the compounds described herein are formulated into oral dosage forms including, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.
  • pharmaceutical preparations for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable auxiliaries (if necessary) to obtain tablets or dragee cores.
  • suitable excipients are in particular fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as: corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other substances, such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • PVP polyvinylpyrrolidone
  • povidone calcium phosphate
  • a disintegrant is optionally added.
  • disintegrants include cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.
  • the present disclosure also relates to methods of treating NLRP3-mediated disorders, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition of the present disclosure.
  • the compounds disclosed herein have NEK7 enzymatic inhibitory activity and thus can be used to treat or prevent NLRP3-mediated disorders, and to prepare drugs for treating or preventing NLRP3-mediated disorders.
  • the host or patient may be of any mammalian species, such as primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental research, providing models for treating human diseases.
  • the NLRP3-mediated disorder can be selected from autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, transplant rejection, lung injury, respiratory diseases and ischemic conditions.
  • the NLRP3-mediated disorder can be selected from type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage caused by infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced skin sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis and Muller-Weiss syndrome.
  • the NLRP3-mediated disorder can be selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndromes, cryptopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL-1 receptor antagonist), Alzheimer's disease, Parkinson's disease and cancer.
  • the compound of formula 1 and the compound of formula 2 undergo coupling reaction in the presence of pinacol diboron under palladium catalysis to generate the compound of formula 3, and the compound of formula 3 is deprotected to generate the compound of formula I of the present application.
  • the reaction liquid was filtered with diatomaceous earth while hot, and the diatomaceous earth layer was washed with ethyl acetate (50mL).
  • the filtrate was extracted with water (25mL), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (25mL), the organic phase was separated and combined, and the brown oily crude product was obtained by concentration under reduced pressure.
  • Step C 2-Methoxy-6-methyl-4-((trimethylsilyl)ethynyl)phenyl trifluoromethanesulfonate
  • Step C (R)-5-Bromo-N-(1-methylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine

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

Abstract

L'invention concerne un composé hétérocyclique et une composition pharmaceutique associée. Le composé a une structure telle que représentée dans la formule I, est un inhibiteur de NLRP3 efficace, et peut être utilisé pour traiter diverses maladies médiées par NLRP3.
PCT/CN2025/070537 2024-01-05 2025-01-03 Composé hétérocyclique et composition pharmaceutique associée Pending WO2025146160A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202410019637.9 2024-01-05
CN202410019637 2024-01-05

Publications (1)

Publication Number Publication Date
WO2025146160A1 true WO2025146160A1 (fr) 2025-07-10

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022253326A1 (fr) * 2021-06-05 2022-12-08 药捷安康(南京)科技股份有限公司 Inhibiteur de l'inflammasome nlrp3 et son utilisation
WO2023028534A1 (fr) * 2021-08-25 2023-03-02 Ptc Therapeutics, Inc. Inhibiteurs de nlrp3
WO2023051761A1 (fr) * 2021-09-30 2023-04-06 成都奥睿药业有限公司 Utilisation pharmaceutique et procédé de préparation d'un dérivé d'hétéroaryl-phtalazine substitué
WO2023066377A1 (fr) * 2021-10-22 2023-04-27 索智生物科技（浙江）有限公司 Composé contenant de l'azote, son procédé de préparation et son application
WO2023066825A1 (fr) * 2021-10-19 2023-04-27 F. Hoffmann-La Roche Ag Composés hétéroaryle bicycliques fusionnés utiles en tant qu'inhibiteurs de nlrp3
CN116410140A (zh) * 2022-01-07 2023-07-11 药捷安康(南京)科技股份有限公司 Nlrp3炎症小体抑制剂及其应用
CN118852153A (zh) * 2023-04-27 2024-10-29 药捷安康(南京)科技股份有限公司 Nlrp3炎症小体抑制剂及其应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022253326A1 (fr) * 2021-06-05 2022-12-08 药捷安康(南京)科技股份有限公司 Inhibiteur de l'inflammasome nlrp3 et son utilisation
WO2023028534A1 (fr) * 2021-08-25 2023-03-02 Ptc Therapeutics, Inc. Inhibiteurs de nlrp3
WO2023051761A1 (fr) * 2021-09-30 2023-04-06 成都奥睿药业有限公司 Utilisation pharmaceutique et procédé de préparation d'un dérivé d'hétéroaryl-phtalazine substitué
WO2023066825A1 (fr) * 2021-10-19 2023-04-27 F. Hoffmann-La Roche Ag Composés hétéroaryle bicycliques fusionnés utiles en tant qu'inhibiteurs de nlrp3
WO2023066377A1 (fr) * 2021-10-22 2023-04-27 索智生物科技（浙江）有限公司 Composé contenant de l'azote, son procédé de préparation et son application
CN116410140A (zh) * 2022-01-07 2023-07-11 药捷安康(南京)科技股份有限公司 Nlrp3炎症小体抑制剂及其应用
CN118852153A (zh) * 2023-04-27 2024-10-29 药捷安康(南京)科技股份有限公司 Nlrp3炎症小体抑制剂及其应用

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