WO2019223715A1 - Dérivé de benzopipéridine ou d'hétéroarylpipéridine, son procédé de préparation et son utilisation médicale - Google Patents

Dérivé de benzopipéridine ou d'hétéroarylpipéridine, son procédé de préparation et son utilisation médicale Download PDF

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WO2019223715A1
WO2019223715A1 PCT/CN2019/087944 CN2019087944W WO2019223715A1 WO 2019223715 A1 WO2019223715 A1 WO 2019223715A1 CN 2019087944 W CN2019087944 W CN 2019087944W WO 2019223715 A1 WO2019223715 A1 WO 2019223715A1
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group
general formula
cycloalkyl
alkyl
compound
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PCT/CN2019/087944
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English (en)
Chinese (zh)
Inventor
杨方龙
李晓东
王伟民
陈刚
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201980008818.9A priority Critical patent/CN111601797B/zh
Publication of WO2019223715A1 publication Critical patent/WO2019223715A1/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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • 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

Definitions

  • the invention belongs to the field of medicine, and relates to a benzopiperidine or a heteroaryl piperidine derivative, a preparation method thereof and application in medicine, and the invention discloses that it is used as an estrogen receptor modulator for prevention and / or Or use for the treatment of an estrogen receptor-mediated or dependent disease or condition, which is particularly preferably breast cancer.
  • ESR1 gene mutations were detected in 11 to 55% of patients with estrogen receptor-positive metastatic breast cancer who had been treated with aromatase inhibitors. Further research found that mutant receptors can occur independently of estrogen Phosphorylation, play a role in transcription, so that estrogen-dependent MCF7-vaccinated tumors can no longer rely on estrogen growth in the body, and mutant receptors will make the SERM tamoxifen and SERD fulvestrant Reduced activity. Therefore, ESR1 gene mutation may be one of the mechanisms of resistance in estrogen-positive breast cancer (Nat Rev Rev Clin Oncol. 2015 Oct; 12 (10): 573-83 and Nat Genet 2013; 45: 1439-45).
  • An object of the present invention is to provide a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or the In the form of a mixture, or a pharmaceutically acceptable salt thereof, the structure of the compound represented by the general formula (I) is as follows:
  • R 8 and R 9 are the same or different and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • n 0 or 1
  • R c and Rd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group
  • t is an integer from 1 to 6;
  • G, W, R a, R 1, R 3, R 4, n , and s are as formula (IV) as defined above.
  • R c and Rd are the same or different, and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl;
  • R a, R 1, R 3, R 4, n , and s are as formula (V) as defined above.
  • k is an integer from 1 to 6;
  • G, W, R a, R 1, R 3, R 4, n , and s are as in formula (I) as defined above.
  • X is halogen
  • Ring A, G, Z, R a , R 1, R 2, R 4 and s are as formula (IX) as defined above.
  • Another aspect of the present invention relates to a pharmaceutical composition containing a therapeutically effective dose of a compound represented by each of the above formulae or a tautomer, a racemate, a racemate, an enantiomer thereof. , Diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt as an active ingredient, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the prevention and / or treatment of an estrogen receptor-mediated or dependent disease or disorder.
  • the estrogen receptor-mediated or dependent disease or condition is cancer, preferably breast cancer, ovarian cancer, endometrial cancer, prostate cancer or uterine cancer; more preferably breast cancer.
  • the present invention further relates to a compound represented by the general formula (I) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a A mixture, or a pharmaceutically acceptable salt thereof, as a medicament for the treatment of an estrogen receptor-mediated or dependent disease or condition.
  • the estrogen receptor-mediated or dependent disease or disorder is as defined above.
  • the present invention further relates to a method for treating an estrogen receptor-mediated or dependent disease or condition, which method comprises administering to a patient in need thereof a therapeutically effective dose of a compound represented by the general formula (I) of the present invention or Tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof.
  • This method shows outstanding efficacy and fewer side effects.
  • the estrogen receptor-mediated or dependent disease or disorder is as defined above.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending, dispersing or wetting agents.
  • the active ingredient of the aqueous suspension may be a dispersible powder or granule. By adding water, the active ingredient is mixed with one or more dispersing, wetting or suspending agents.
  • the aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweetening agents.
  • the pharmaceutical composition of the present invention may be in the form of a sterile injectable water or oily suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • a sterile fixed oil can be conveniently used as a solvent or a suspension medium.
  • fatty acids can also be prepared for injection.
  • the compounds of the invention may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and therefore will dissolve in the rectum to release the drug.
  • the dosage of a drug depends on many factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the patient's health, and the patient's behavior , The patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc .;
  • the best treatment methods such as the mode of treatment, the daily dosage of the general compound (I) or the pharmaceutically acceptable salt
  • the type can be verified according to the traditional treatment plan.
  • the invention introduces a covalent binding group into a small molecule inhibitor, so that the molecule can covalently bind with a thiol group in the ER protein, thereby forming an irreversible covalent compound with the ER protein.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 2,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpent
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Methyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl and the like.
  • the alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy Is substituted with one or more substituents of the group, cycloalkylthio, heterocycloalkylthio and oxo.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl groups, and the like; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl.
  • spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group that shares one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings have complete conjugation. ⁇ electronic system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. Spirocycloalkyl is divided into monospirocycloalkyl, bisspirocycloalkyl or polyspirocycloalkyl according to the number of common spiro atoms between the rings, preferably monospirocycloalkyl and bisspirocycloalkyl.
  • spirocycloalkyl More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, or 5 yuan / 6 yuan monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to a 5- to 20-membered, full-cyclic polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system.
  • One or more of the rings may contain one or Multiple double bonds, but none of the rings have a completely conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of constituent rings, preferably bicyclic or tricyclic, and more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl.
  • fused cycloalkyl include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a complete Conjugate ⁇ electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • groups which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthi
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that contains 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) A heteroatom of m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, piperidinyl and pyrrolidinyl are preferred.
  • Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group that shares one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O ) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a completely conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • Spiro heterocyclyl is divided into monospiroheterocyclyl, bispiroheterocyclyl or polyspiroheterocyclyl according to the number of common spiro atoms between the rings, preferably monospiroheterocyclyl and bispiroheterocyclyl. More preferred are 4-membered / 4-membered, 4-membered-5-membered, 4-membered-6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl.
  • Non-limiting examples of spiroheterocyclyl include:
  • Aryl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate, preferably phenyl.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, Pyrimidinyl, thiadiazole, pyrazinyl and the like are preferably imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl or thiazolyl.
  • the heteroaryl ring includes the above heteroaryl group fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples
  • haloalkyl refers to an alkyl group substituted with halogen, wherein alkyl is as defined above.
  • aldehyde group refers to -CHO.
  • carboxylate refers to -C (O) O (alkyl) or -C (O) O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, or C
  • X is A, B, or C
  • the above reaction is preferably performed in a solvent.
  • the solvents used include, but are not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethylsulfoxide, 1,4-dioxane, water, N, N- Dimethylformamide or a mixed solvent thereof.
  • Ring A, G, Z, Y, R a, R 1, R 2, R 4 and s are as formula (II) as defined above.
  • the above reaction is preferably performed in a solvent.
  • the solvents used include, but are not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethylsulfoxide, 1,4-dioxane, water, N, N- Dimethylformamide or a mixed solvent thereof.
  • a method for preparing an isomer or a mixture thereof, or a pharmaceutically acceptable salt thereof includes the following steps:
  • n 1;
  • the reagents for providing basic conditions include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, Sodium tert-butoxide or potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate, sodium hydroxide and lithium hydroxide; preferably diisopropylethyl amine.
  • the reagents for providing basic conditions include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, Sodium tert-butoxide or potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate, sodium hydroxide and lithium hydroxide; preferably diisopropylethyl amine.
  • the starting material 8c (0.12 g, 225.73 mmol) was dissolved in a dioxane solution (4N, 3 mL) of hydrogen chloride, and the reaction was stirred at room temperature for 2 hours to stop the reaction.
  • the reaction solution was concentrated, a saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with dichloromethane (50 mL ⁇ 2). The organic phases were combined. It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 8d (83 mg).

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Abstract

La présente invention concerne un dérivé de benzopipéridine ou d'hétéroarylpipéridine, son procédé de préparation et son utilisation médicale. En particulier, la présente invention concerne un dérivé de benzopipéridine ou un dérivé d'hétéroarylpipéridine représenté par la formule générale (I), un procédé de préparation correspondant, une composition pharmaceutique comprenant le dérivé, et l'utilisation de celui-ci en tant que modulateur du récepteur des œstrogènes dans la prévention et/ou le traitement de maladies ou d'affections induites ou dépendantes du récepteur des œstrogènes, les maladies étant en particulier et de préférence des cancers du sein. La définition de chaque substituant dans la formule générale (I) est identique à celle donnée dans la description.
PCT/CN2019/087944 2018-05-23 2019-05-22 Dérivé de benzopipéridine ou d'hétéroarylpipéridine, son procédé de préparation et son utilisation médicale WO2019223715A1 (fr)

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CN201980008818.9A CN111601797B (zh) 2018-05-23 2019-05-22 苯并哌啶或杂芳基并哌啶类衍生物、其制备方法及其在医药上的应用

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CN113024460A (zh) * 2021-03-10 2021-06-25 中国药科大学 作为雌激素受体与组蛋白去乙酰化酶双靶点化合物的四氢异喹啉类化合物、合成方法及用途
WO2021143822A1 (fr) * 2020-01-16 2021-07-22 江苏恒瑞医药股份有限公司 Dérivé imide bicyclique, son procédé de préparation et son application en médecine
WO2021143816A1 (fr) * 2020-01-16 2021-07-22 江苏恒瑞医药股份有限公司 Dérivé imide fusionné, son procédé de préparation et son utilisation médicale
WO2021228210A1 (fr) * 2020-05-15 2021-11-18 江苏先声药业有限公司 Composé pyrrolidine et son utilisation
CN114105977A (zh) * 2020-08-28 2022-03-01 江苏先声药业有限公司 雌激素受体调节剂化合物及其用途
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WO2022194096A1 (fr) * 2021-03-15 2022-09-22 深圳福沃药业有限公司 Antagoniste du récepteur des oestrogènes
WO2023083292A1 (fr) * 2021-11-12 2023-05-19 先声药业有限公司 Sel de composé de pyrrolidine, forme cristalline de celui-ci et son procédé de préparation
WO2024017131A1 (fr) * 2022-07-21 2024-01-25 贝达药业股份有限公司 Dérivé d'hétéroarylopipéridine, et composition pharmaceutique et utilisation s'y rapportant

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WO2015092634A1 (fr) * 2013-12-16 2015-06-25 Novartis Ag Composés et compositions de 1,2,3,4-tétrahydroisoquinoléine en tant qu'antagonistes et agents de dégradation sélectifs des récepteurs des œstrogènes
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Cited By (13)

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Publication number Priority date Publication date Assignee Title
WO2021143822A1 (fr) * 2020-01-16 2021-07-22 江苏恒瑞医药股份有限公司 Dérivé imide bicyclique, son procédé de préparation et son application en médecine
WO2021143816A1 (fr) * 2020-01-16 2021-07-22 江苏恒瑞医药股份有限公司 Dérivé imide fusionné, son procédé de préparation et son utilisation médicale
CN115836068A (zh) * 2020-05-15 2023-03-21 先声药业有限公司 吡咯烷类化合物及其应用
WO2021228210A1 (fr) * 2020-05-15 2021-11-18 江苏先声药业有限公司 Composé pyrrolidine et son utilisation
EP4151636A4 (fr) * 2020-05-15 2024-02-28 Simcere Pharmaceutical Co. Ltd. Composé pyrrolidine et son utilisation
CN114105977B (zh) * 2020-08-28 2023-09-01 先声再明医药有限公司 雌激素受体调节剂化合物及其用途
CN114105977A (zh) * 2020-08-28 2022-03-01 江苏先声药业有限公司 雌激素受体调节剂化合物及其用途
US11339162B1 (en) 2020-12-23 2022-05-24 Recurium Ip Holdings, Llc Estrogen receptor modulators
US11999728B2 (en) 2020-12-23 2024-06-04 Recurium Ip Holdings, Llc Estrogen receptor modulators
CN113024460A (zh) * 2021-03-10 2021-06-25 中国药科大学 作为雌激素受体与组蛋白去乙酰化酶双靶点化合物的四氢异喹啉类化合物、合成方法及用途
WO2022194096A1 (fr) * 2021-03-15 2022-09-22 深圳福沃药业有限公司 Antagoniste du récepteur des oestrogènes
WO2023083292A1 (fr) * 2021-11-12 2023-05-19 先声药业有限公司 Sel de composé de pyrrolidine, forme cristalline de celui-ci et son procédé de préparation
WO2024017131A1 (fr) * 2022-07-21 2024-01-25 贝达药业股份有限公司 Dérivé d'hétéroarylopipéridine, et composition pharmaceutique et utilisation s'y rapportant

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