WO2022089629A1 - Dérivé de 1,2,4-triazole, son procédé de préparation et son utilisation - Google Patents

Dérivé de 1,2,4-triazole, son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2022089629A1
WO2022089629A1 PCT/CN2021/127847 CN2021127847W WO2022089629A1 WO 2022089629 A1 WO2022089629 A1 WO 2022089629A1 CN 2021127847 W CN2021127847 W CN 2021127847W WO 2022089629 A1 WO2022089629 A1 WO 2022089629A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
mmol
hydroxyl
substituted
Prior art date
Application number
PCT/CN2021/127847
Other languages
English (en)
Chinese (zh)
Inventor
秦引林
苏梅
Original Assignee
江苏柯菲平医药股份有限公司
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 江苏柯菲平医药股份有限公司 filed Critical 江苏柯菲平医药股份有限公司
Publication of WO2022089629A1 publication Critical patent/WO2022089629A1/fr

Links

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
    • A61K31/41—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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the technical field of medicine, and particularly relates to novel compounds, pharmaceutical combinations comprising the compounds, methods for preparing the compounds, and the use of the compounds in the treatment of various diseases, disorders or conditions related to abnormal cellular responses triggered by inappropriate nuclear transport. use.
  • the nucleus of eukaryotes has a double-layered membrane structure, and macromolecules need to be transported across the nuclear membrane through the mediation of nucleocytoplasmic transport receptors.
  • Specific proteins and RNAs are transported into and out of the nucleus by specific transport molecules, wherein those that transport the molecules into the nucleus are classified as nuclear import proteins, and those that transport molecules out of the nucleus are classified as nuclear export proteins.
  • nuclear export protein 1 exportin 1, XPO1
  • CCM1 chromosomal region stabilizing protein 1
  • XPO1 can mediate the transport of more than 200 kinds of proteins, including tumor suppressor proteins (TSPs), P53, P73, etc., anti-apoptotic proteins (IAPs), nucleophsmim (NPM), survivin And growth regulatory proteins (GRPs) P21 and P27.
  • TSPs tumor suppressor proteins
  • IAPs anti-apoptotic proteins
  • NPM nucleophsmim
  • GFPs survivin And growth regulatory proteins
  • XPO1 inhibitors can induce apoptosis in cancer cells, even in the presence of oncogenic activating signals or growth stimulating signals, without affecting normal (untransformed) cells.
  • the expression level of XPO1 in cancer cells is 2-4 times higher than that in normal cells on average, which makes most of TSPs, IAPs, and GRPs transported out of the nucleus, which has an adverse effect on tumor suppressor protein recognition and induction of cancer cell apoptosis, which makes cancer cells proliferate. Differentiation is not limited.
  • the first-generation XPO1 inhibitor selinexor showed high blood-brain barrier penetration and greater toxicity in preclinical and clinical studies, and a new generation of XPO1 inhibitors is urgently needed to meet clinical needs.
  • the present invention provides a 1,2,4-triazole derivative and a preparation method and application thereof.
  • One of the objects of the present invention is to provide a compound, characterized in that the compound is the compound represented by formula I, or its optical isomer, enantiomer, diastereomer, racemate or racemate a mixture, or a solvate, prodrug, or a pharmaceutically acceptable salt thereof;
  • R 2 and R 3 are each independently selected from H or C 1 -C 3 alkyl groups
  • R 4 is selected from H or C 1 -C 3 alkyl
  • R 2 , R 3 are each independently selected from H, methyl or ethyl.
  • R4 is selected from H, methyl or ethyl.
  • R1 is selected from unsubstituted or optionally substituted by A 5-6-membered heteroaryl;
  • R1 is selected from unsubstituted or optionally substituted 8-15-membered fused heteroaryl; substituents are selected from halogen, hydroxyl, -CN, C 1 -C 3 alkyl, C 1 -C 3 Alkoxy, hydroxy C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl.
  • R1 is selected from unsubstituted or optionally substituted pyrrolyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl , thiadiazolyl or oxadiazolyl. Substituents may be as described above.
  • R1 is an optionally substituted 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • R1 is selected from unsubstituted or optionally substituted pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. Substituents may be as described above.
  • the compound of the present invention is the compound represented by formula I-1, or its optical isomer, enantiomer, diastereomer, racemate or a racemic mixture, or a solvate, prodrug, or a pharmaceutically acceptable salt thereof;
  • R1 is as described above.
  • the compound is selected from the group consisting of:
  • the present invention also provides a compound, which is characterized in that it is a compound represented by formula II, or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a solvate thereof drug, prodrug or a pharmaceutically acceptable salt thereof;
  • ring C is selected from 5-6 membered heteroaryl, 5-6 membered heterocyclyl, wherein said heteroaryl or heterocyclyl is optionally further substituted by one or more R 7 ; preferably, ring C is selected from from 5-6 membered heterocyclyl, wherein said heterocyclyl is optionally further substituted with one or two R7 ;
  • R 7 is selected from hydrogen atom, halogen, cyano, hydroxyl, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 haloalkyl, C 3 ⁇ C 10 halogenated cycloalkyl, C 1 -C 8 halogenated alkoxy; preferably, R 7 is selected from hydrogen atom, halogen, cyano, hydroxyl, C 1 -C 3 alkyl, C 3 -C 6 cycloalkane base, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 3 haloalkoxy;
  • R 9 is selected from the following groups unsubstituted or optionally substituted by one or more E: hydroxyl, amino;
  • Substituent E is selected from: halogen, hydroxyl, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl , C 2 -C 10 heterocyclyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 10 halocycloalkyl, Or form a 4-8 membered heterocycle with the substituted atom;
  • R 9 is selected from: hydrogen atom, hydroxyl, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 10 halocycloalkyl, C 6 -C 10 aryl, C 2 -C 10 heteroaryl or C 2 -C 10 heterocyclic.
  • R 9 is selected from the following groups unsubstituted or optionally substituted by one or more E: hydroxyl, amino;
  • Substituent E is selected from: halogen, hydroxyl, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl , C 2 -C 8 heterocyclyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 3 -C 8 halocycloalkyl, Or form a 4-6 membered heterocycle with the substituted atom;
  • R 9 is selected from: hydrogen atom, hydroxyl, C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkane
  • the present invention also provides compounds represented by formula II-1 or formula II-2, or optical isomers, enantiomers, diastereomers, racemates or exoisomers thereof A racemic mixture, or a solvate, prodrug or a pharmaceutically acceptable salt thereof:
  • R 8 and R 9 are as previously described; in some more specific embodiments, R 8 is H or pyrimidine.
  • the present invention also provides compounds shown below, or optical isomers, enantiomers, diastereomers, racemates or racemic mixtures thereof, or solvates thereof , a prodrug or a pharmaceutically acceptable salt thereof:
  • the second object of the present invention is to provide a preparation method of the compound.
  • the third purpose of this paper is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the compounds represented by formula I and formula II, or optical isomers, enantiomers, diastereomers, racemates or racemic mixtures thereof, or a solvate, prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the fourth purpose of this paper is to provide compounds represented by formula I and formula II, or optical isomers, enantiomers, diastereomers, racemates or racemic mixtures thereof, or solvates and prodrugs thereof , or a pharmaceutically acceptable salt thereof, or the application of the composition of the present invention as an XPO1 inhibitor.
  • the fifth purpose of this paper is to provide compounds represented by formula I and formula II, or optical isomers, enantiomers, diastereomers, racemates or racemic mixtures thereof, or solvates and prodrugs thereof , or a pharmaceutically acceptable salt thereof, or the composition of the present invention as a use in the manufacture of a medicament for the treatment of various diseases, disorders or conditions associated with abnormal cellular responses triggered by inappropriate nuclear transport.
  • the compounds represented by formula I and formula II of the present invention are also useful for the treatment of various diseases, disorders or conditions associated with abnormal cellular responses triggered by inappropriate nuclear transport.
  • one embodiment of the present invention is the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the treatment of various diseases, disorders or conditions associated with abnormal cellular responses triggered by inappropriate nuclear transport.
  • the compounds provided by the present invention are also useful for the study of nuclear transport regulation in biological and pathological phenomena, such as the study of kinase-mediated intracellular signal transduction pathways and the comparative evaluation of novel nuclear transport modulators.
  • various diseases, disorders or conditions described herein that are associated with abnormal cellular responses triggered by inappropriate nuclear transport include, but are not limited to, proliferative disorders, cancers, inflammatory disorders, autoimmune disorders, viruses Infections, neurodegenerative disorders, ophthalmic disorders, disorders of abnormal tissue growth, disorders related to food intake, allergies, and respiratory disorders.
  • Also provided herein is a method for treating a patient having a disease, disorder or condition associated with various inappropriate nuclear transport-triggered abnormal cellular responses, comprising administering to the patient a therapeutically effective amount of formula I as defined herein
  • the patient is a human.
  • halogen means -F (sometimes referred to herein as “fluoro"), -Cl, -Br and -I.
  • C1-C3 alkyl refers to groups having one to three, one to six, two to six, respectively A saturated linear or branched monovalent hydrocarbon radical of one or three to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl base, neopentyl and hexyl.
  • C1-C6 alkoxy refers to a saturated straight or branched monovalent alkoxy group having one to six carbon atoms, wherein the bond is on an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.
  • hydroxy C1-C6 alkyl- refers to a saturated straight or branched chain monovalent alkyl group having one to six carbon atoms, wherein at least one carbon atom is substituted with a hydroxyl group.
  • haloC1-C6alkyl- refers to a saturated straight or branched monovalent alkyl group having one to six carbon atoms, wherein at least one carbon atom is substituted with a halogen.
  • cyano C1-C6 alkyl- refers to a saturated straight or branched monovalent alkyl group having one to six carbon atoms, one of which is replaced by a cyano group.
  • C3-C6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • heterocycle refers to a monocyclic or bicyclic non-aromatic heterocycle containing, in addition to carbon atoms, 1-4 heteroatoms selected from the group consisting of oxygen atoms, sulfur atoms and nitrogen atoms, as Specific examples include azetidine, pyrrolidine, pyrazolidine, piperidine, oxetane, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, dihydroimidazole, imidazolidine ( imidazolidine), tetrahydropyrazine, piperazine, morpholine, etc.
  • the 5-15 membered heterocycloalkyl is a 5-15 membered heterocycloalkyl having 1-2 heteroatoms independently optionally selected from N, S, or O.
  • the 5-10 membered heterocycloalkyl is a 5-10 membered heterocycloalkyl having 1-2 heteroatoms independently optionally selected from N, S, or O.
  • heteroaryl represents a stable monocyclic ring of up to 3-15 atoms in the ring or a bicyclic carbocyclic ring of up to 3-15 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 A heteroatom selected from O, N and S.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxolinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, benzene thienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl.
  • the 5-15 membered heteroaryl group is a 5-15 membered heteroaryl group having 1-2 heteroatoms independently arbitrarily selected from N, S, or O.
  • the 5-10 membered heteroaryl group is a 5-10 membered heteroaryl group having 1-2 heteroatoms independently arbitrarily selected from N, S, or O.
  • fused heterocycle refers to a cyclic hydrocarbon in which 2-3 rings share two adjacent (ortho) atoms; at least one ring is an aromatic ring containing 1 to 3 heteroatoms selected from O, N and S , in some instances, is a cyclic hydrocarbon in which 2 rings share two adjacent (ortho) atoms; one ring is an aromatic ring containing 1 to 3 heteroatoms selected from O, N, and S, and the other ring is a saturated heterocycle.
  • the 8-15 membered fused heteroaryl group of the present invention has an 8-15 membered fused heterocycle with 1-2 heteroatoms selected from N or O.
  • compositions of the present invention refer to salts of the compounds of the present invention, such salts are safe and effective when used in mammals, and have due biological activity.
  • the compounds of the present invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers.
  • the R and S configurations for each asymmetric center the Z and E double bond isomers and the Z and E conformers. Accordingly, single stereoisomers as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the compounds of the present invention are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • treating or “treatment” as referred to throughout this document is conventional, eg, to manage or care for an individual for the purpose of counteracting, alleviating, reducing, alleviating, ameliorating the condition of a disease or disorder .
  • the term "individual” or “patient” includes organisms, such as humans and non-human animals, capable of suffering from a variety of diseases, disorders or conditions associated with abnormal cellular responses triggered by inappropriate nuclear transport, or that would benefit from administration of the compounds of the present invention .
  • Preferred humans include human patients suffering from or susceptible to suffering from various diseases, disorders or conditions or related states associated with inappropriate nuclear transport-triggered abnormal cellular responses as described herein.
  • non-human animal includes vertebrates, such as mammals, such as non-human primates, sheep, cows, dogs, cats, and rodents (eg, mice), as well as non-mammals, such as chickens, amphibians , reptiles, etc.
  • the compounds of the present invention can be used to treat various diseases, disorders or conditions related to abnormal cellular responses triggered by inappropriate nuclear transport.
  • the study of nuclear transport regulation in biological and pathological phenomena such as the study of kinase-mediated intracellular signal transduction pathways, and the comparative evaluation of new nuclear transport regulators are also valuable.
  • the compounds of the present invention have better cellular activity and selectivity, better water solubility, reduced blood-brain barrier penetration ability to reduce central nervous system toxicity, and reduced hERG activity to reduce cardiotoxicity. More specifically, the compounds of the present invention have the characteristics of high activity, good selectivity and low toxicity, so the compounds of the present invention have better druggability.
  • the synthetic route is as follows:
  • reaction mixture was stirred at 85°C for 10 h under nitrogen protection, then filtered and concentrated under reduced pressure. Separation and purification were carried out by prep-TLC (eluent: ethyl acetate) and prep-HPLC to obtain compound P-11 (22.4 mg, purity 97.67%, yield 17.12%) as a white solid.
  • the synthetic route is as follows:
  • 3-Bromo-1,2,4-triazole (SM1, 4.44 g, 30.0 mmol) was dissolved in 30 ml of DMF and triethylenediamine (6.73 g, 60.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then (2Z)-isopropyl-3-iodoprop-2-enoate (7.92 g, 33.0 mmol) was added and the final mixture was stirred at room temperature for 1 h. The mixture was poured into 100ml ice water and the aqueous phase was extracted with ethyl acetate (3x50ml).
  • the crude product was purified by preparative TLC, and purified by preparative HPLC (mobile phase: ACN/H2O: 60/40 ⁇ 40/60) to obtain the target product P-25 (12 mg, yield 18.3%) as a white solid.
  • the crude product was purified by preparative TLC, and purified by preparative HPLC (mobile phase: ACN/H2O: 60/40 ⁇ 20/80) to obtain the target product P-26 (16.3 mg, yield: 32.8%) in white solid.
  • Test compounds against different cell lines MM1S (myeloma cells), SKM-1 (human myelodysplastic syndrome cells), LNcap (prostate cancer cells), MOLT-4 (acute lymphoblastic leukemia cells), COLO205 (human colon cancer cells) Cells), RPMI 8226 (human multiple myeloma peripheral blood B lymphocytes) and other proliferation inhibitory activities.
  • MM1S myeloma cells
  • SKM-1 human myelodysplastic syndrome cells
  • LNcap prostate cancer cells
  • MOLT-4 acute lymphoblastic leukemia cells
  • COLO205 human colon cancer cells
  • RPMI 8226 human multiple myeloma peripheral blood B lymphocytes
  • KPT-8602 is compound 124 in the patent (CN105339358A), and its structural formula is as follows:
  • U2OS-Rev(1.4)-NES-mGEP C#52 cell line human osteosarcoma cells labeled with HIV Rev response element with green fluorescent protein
  • U2OS-Rev(1.4)-NES-mGEP C#52 cell line human osteosarcoma cells labeled with HIV Rev response element with green fluorescent protein
  • cells were resuspended in inoculation medium and incubated overnight at 37°C with 5% CO2.
  • Compounds were serially diluted 3-fold to 0.51 nM in DMSO, added to cell culture plates at a 100-fold dilution with medium McCoy'5A, and incubated for 4 hr.
  • PFA paraformaldehyde solution
  • HEK293 cells expressing hERG channels Using HEK293 cells expressing hERG channels, the effect of compounds of the present invention on hERG ion channels was investigated. Compounds were perfused using a perfusion system utilizing its own gravity. Five concentrations of each compound were tested, 0.3, 1, 3, 10, 30 ⁇ M, and at least two cells were tested for each concentration. After the current was stable (or 5 minutes), the current magnitude changes before and after the compound was used were compared to calculate the blocking effect of the compound. The cells were transferred to a perfusion tank and perfused with extracellular fluid. Electrodes were drawn with PC-10 (Narishige, Japan). Whole-cell patch-clamp recordings, with noise filtered at one-fifth of the sampling frequency.
  • hERG tail currents are pure hERG currents.
  • the maximum current induced by the second square wave was detected.
  • the test compound was perfused.
  • the blocking intensity was calculated. The value of the current before the compound was used was denoted as a, and the value when the compound was perfused until the current was stable was denoted as b.
  • the average blocking rate was the average value of the parallel detection data, and the compound concentration and the average blocking rate were fitted with origin software to obtain the IC 50 value.
  • Both the test substance and KPT8602 were orally administered to rats at 10 mg/kg, and the administration volume was 10 mL/kg.
  • test substance solution accurately weigh 10 mg of test substance, add 1 mL DMSO solution, vortex for 5 min, add 0.8 mL Solutol solution, vortex for 5 min, add 1.5 mL PEG400 solution, and mix well , add water to a certain volume of 10mL.
  • Example 46 In vivo efficacy test of the compound in animals
  • MM.1S cells were routinely cultured in RPMI1640 medium containing 10% fetal bovine serum under the culture condition of 5% CO 2 at 37°C; according to cell growth conditions, passage 1 to 2 times a week, and the passage ratio was 1:2 ⁇ 3.
  • the patients were randomly divided into groups according to the tumor volume.
  • control group was given KPT-8602 at a dose of 5 mg/kg, and the experimental group was administered at a dose of 2.5, 5, 7.5, and 10, once a day, and the administration period was 4 weeks.
  • the tumor inhibitory efficacy of the compounds was evaluated by tumor volume tumor inhibition rate (GI) or relative tumor proliferation rate T/C (%).
  • T/C (%) (T RTV /C RTV ) ⁇ 100%, where T RTV represents the relative tumor volume of the treatment group, and C RTV represents the solvent control group relative tumor volume.
  • Example 47 Subacute toxicity test of the compounds of the present invention
  • Oral gavage was administered to SD rats at 3, 9, and 18 mg/kg, with an administration volume of 5 mL/kg, 5 days a week for 2 consecutive weeks.
  • Solvent Weigh an appropriate amount of Solutol and MC to prepare 20% Solutol+0.5% MC.
  • the preparation method is as follows: Weigh an appropriate amount of the sample powder of the test substance, grind, add an appropriate amount of solvent, vortex to completely dissolve the sample and mix well, ultrasonically , prepared into the desired suspension, now with the current use.
  • the observation by the cage includes the appearance of the animal, coat, physical signs, behavioral activities, respiratory status, gland secretion, animal posture, feces, death, etc.
  • Body weight Measure body weight once a week
  • Animal anesthesia and dissection After the administration, the animals were euthanized, and the tissues and organs were visually inspected for abnormalities, such as heart, liver, spleen, lung, kidney, brain, adrenal gland, thymus, testis, epididymis, uterus, and ovary. Calculate the organ coefficient.
  • Organ coefficient [Organ weight (g) / Body weight (g)] * 100

Landscapes

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

Abstract

La présente invention concerne un dérivé de 1,2,4-triazole, son procédé de préparation et son utilisation. Le dérivé de 1,2,4-triazole est un composé représenté par la formule I, ou un isomère optique, un énantiomère, un diastéréoisomère, un racémate, ou un mélange racémique de celui-ci, ou un solvate et un promédicament de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci. Le composé peut être utilisé pour traiter diverses maladies, troubles ou états liés à des réponses cellulaires anormales déclenchées par un transport nucléaire inapproprié.
PCT/CN2021/127847 2020-11-02 2021-11-01 Dérivé de 1,2,4-triazole, son procédé de préparation et son utilisation WO2022089629A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202011206697 2020-11-02
CN202011206697.X 2020-11-02
CN202011637273 2020-12-31
CN202011637273.9 2020-12-31
CN202110436190 2021-04-22
CN202110436190.1 2021-04-22

Publications (1)

Publication Number Publication Date
WO2022089629A1 true WO2022089629A1 (fr) 2022-05-05

Family

ID=81381892

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/127847 WO2022089629A1 (fr) 2020-11-02 2021-11-01 Dérivé de 1,2,4-triazole, son procédé de préparation et son utilisation

Country Status (1)

Country Link
WO (1) WO2022089629A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023134629A1 (fr) * 2022-01-12 2023-07-20 上海海雁医药科技有限公司 Régulateur de transport nucléaire et son utilisation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103002742A (zh) * 2010-03-05 2013-03-27 卡尔约药物治疗公司 核转运调节剂及其应用
WO2014144772A1 (fr) * 2013-03-15 2014-09-18 Karyopharm Therapeutics Inc. Procédés de promotion de la cicatrisation d'une plaie à l'aide d'inhibiteurs de crm1
CN105339358A (zh) * 2013-06-21 2016-02-17 卡尔约药物治疗公司 核转运调节剂及其用途
WO2017117529A1 (fr) * 2015-12-31 2017-07-06 Karyopharm Therapeutics Inc. Modulateurs de transport nucléaire et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103002742A (zh) * 2010-03-05 2013-03-27 卡尔约药物治疗公司 核转运调节剂及其应用
WO2014144772A1 (fr) * 2013-03-15 2014-09-18 Karyopharm Therapeutics Inc. Procédés de promotion de la cicatrisation d'une plaie à l'aide d'inhibiteurs de crm1
CN105339358A (zh) * 2013-06-21 2016-02-17 卡尔约药物治疗公司 核转运调节剂及其用途
WO2017117529A1 (fr) * 2015-12-31 2017-07-06 Karyopharm Therapeutics Inc. Modulateurs de transport nucléaire et leurs utilisations

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023134629A1 (fr) * 2022-01-12 2023-07-20 上海海雁医药科技有限公司 Régulateur de transport nucléaire et son utilisation

Similar Documents

Publication Publication Date Title
CN105636953B (zh) 1,4‑二取代的哒嗪衍生物及其用于治疗与smn缺乏相关的病症的用途
WO2021104431A1 (fr) Composé inhibiteur de kras g12c et son utilisation
WO2020177653A1 (fr) Dérivé de pyrazine et son application dans l'inhibition de shp2
CN104936955B (zh) 噻二唑类似物以及治疗与smn缺乏相关的病症的方法
WO2021143701A1 (fr) Composé hétérocyclique de pyrimidine-4(3h)-cétone, son procédé de préparation et son utilisation en médecine et en pharmacologie
CN108430998A (zh) 氮杂双环衍生物及其制备方法和用途
WO2022100623A1 (fr) Composés thiophène hétérocycliques substitués par azote et leur utilisation
WO2023174175A1 (fr) Inhibiteur de kif18a
WO2016169504A1 (fr) Dérivé pyrimidylamino à cycle condensé, son procédé de préparation, et intermédiaire, composition pharmaceutique et applications associées
CN108558889A (zh) 布罗莫结构域抑制剂
JP2001139550A (ja) アミド化合物の新規用途
WO2022100625A1 (fr) Composé aminocarbonate thiophène substitué par azote et son utilisation
WO2022127923A1 (fr) Composé cyclique benzénique et son utilisation
JP4933428B2 (ja) ピロロベンズイミダゾロン及びその抗増殖薬としての使用
WO2020182018A1 (fr) Composé hétérocyclique azoté, son procédé de préparation et son utilisation
CN114206861A (zh) 用作ripk1抑制剂的稠环杂芳基化合物
WO2020108661A1 (fr) Composé hétérocyclique utilisé en tant qu'inhibiteur de cdk-hdac à double canal
WO2021079962A1 (fr) Composition destinée à la prévention, et/ou au traitement d'une perte d'audition
WO2022089629A1 (fr) Dérivé de 1,2,4-triazole, son procédé de préparation et son utilisation
WO2022166469A1 (fr) Inhibiteur de kinase fgfr et son utilisation
CN110418790A (zh) 作为p53-MDM2抑制剂的咪唑并吡咯酮化合物
WO2021078227A1 (fr) Dérivé d'hétéroaryle fusionné, son procédé de préparation et son utilisation en médecine
WO2020200284A1 (fr) Procédé de préparation de composé tricyclique et son utilisation dans le domaine de la médecine
WO2022257960A1 (fr) Composé bicyclique pour traiter des maladies médiées par le récepteur ep2 et ep4
WO2023274280A1 (fr) Forme cristalline d'un inhibiteur de dérivé de biphényle et son procédé de préparation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21885355

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21885355

Country of ref document: EP

Kind code of ref document: A1