WO2024046454A1 - Dérivé de pyridopyrrolidone substituté par hétéroaryle, ainsi que composition pharmaceutique et son utilisation - Google Patents

Dérivé de pyridopyrrolidone substituté par hétéroaryle, ainsi que composition pharmaceutique et son utilisation Download PDF

Info

Publication number
WO2024046454A1
WO2024046454A1 PCT/CN2023/116425 CN2023116425W WO2024046454A1 WO 2024046454 A1 WO2024046454 A1 WO 2024046454A1 CN 2023116425 W CN2023116425 W CN 2023116425W WO 2024046454 A1 WO2024046454 A1 WO 2024046454A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
ring
group
compound
substituted
Prior art date
Application number
PCT/CN2023/116425
Other languages
English (en)
Chinese (zh)
Inventor
孙洪鹏
许峰
王海龙
席宝信
童忠安
马前
李鑫
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
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 上海海雁医药科技有限公司, 扬子江药业集团有限公司 filed Critical 上海海雁医药科技有限公司
Publication of WO2024046454A1 publication Critical patent/WO2024046454A1/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
    • A61K31/425—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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

  • the present application relates to the field of medical technology, and in particular to a heteroaryl-substituted pyridopyrrolone derivative, its pharmaceutical composition and application.
  • Phosphoinositide 3-kinase is a type of phosphatidyl kinase with the function of phosphorylating the phosphoinositide ring. It is divided into three categories: type I, type II and type III. Among them, type I PI3K is the most widely studied. This type is further divided into two subgroups (IA and IB). Class IA PI3K consists of three closely related kinases, PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ , now present as a heterodimer composed of a catalytic subunit (p110 ⁇ , p110 ⁇ , or p110 ⁇ ) and one of several regulatory subunits.
  • PI3K ⁇ and PI3K ⁇ are widely expressed and play roles in cell growth, division and survival (Thomas M, et al., Curr. Opin. Pharmacol., 2008; 8:267-274).
  • the roles of these two kinases in many biological functions are enhanced by the embryonic lethality observed in mice lacking PI3K ⁇ or PI3K ⁇ . Due to their role in homeostasis, clinical evaluation of PI3K ⁇ and PI3K ⁇ has been limited to the field of oncology, and some compounds are also in various stages of clinical development.
  • the single class 1B isoform of PI3K ⁇ mainly responds to G-protein coupled receptors (GPCR) and is composed of the p110 ⁇ catalytic subunit and one of two different regulatory subunits.
  • GPCR G-protein coupled receptors
  • PI3K ⁇ isoforms are expressed in immune cells and have limited expression in normal or malignant epithelial and connective tissue cells.
  • Research results on PI3K ⁇ knockout mice indicate that PI3K ⁇ is important for cell activation and the migration of some chemokines (Sasaki T., et al., Science, 2000; 287:1040-1046; Hirsch E., et al. ,Science,2000;287:1049-1053).
  • PI3K ⁇ signaling is particularly important for myeloid cell function, and Camps et al. described that treatment with the selective PI3K ⁇ inhibitor AS-60485023 inhibited the progression of joint inflammation and damage in two different mouse models of rheumatoid arthritis (Camps M, et al., Nat. Med. 2005, 11, 936-943). Based on studies at the cellular level and efficacy observed in various disease models, PI3K ⁇ inhibitors can potentially be used to treat various diseases, such as inflammation, metabolism, and cancer (Cushing, T.D., et al., J. Med.
  • the purpose of this application is to provide a heteroaryl-substituted pyridopyrrolone derivative with good selectivity and good pharmacokinetic properties.
  • the first aspect of this application provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
  • Ring A is a 5- or 6-membered heteroaryl ring
  • (R 3 ) n means that the hydrogen on ring A is replaced by n R 3s , n is 0, 1, 2, 3 or 4; each R 3 is the same or different, and each R 3 is independently deuterium, halogen, cyano, or hydroxyl , carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-3 alkyl, halo C 1-3 alkoxy , NR a1 R b1 , -N(R a3 )-C(O)C 1-3 alkyl, -N(R a3 )-C(O)-deuterated C 1-3 alkyl, -N(R a3 )-C(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 C 3-6 cycloalkyl, -C(O)NR a1 R b1 , -C(O)OC
  • R Z , RT , and RU are each independently hydrogen, halogen, NR a1 R b1 or C 1-8 alkyl; wherein, the C 1-8 alkyl is preferably C 1-6 alkyl, and more preferably C 1-3 alkyl;
  • R W and R Y are each independently hydrogen, halogen, C 1-8 alkyl, halogenated C 1-8 alkyl, halogenated C 1-8 alkoxy, NR a1 R b1 or C 3-6 cycloalkyl base; wherein, the C 1-8 alkyl group is preferably a C 1-6 alkyl group, and more preferably a C 1-3 alkyl group;
  • R W and R Y are connected to form a 9- or 10-membered heteroaryl ring, a 9- or 10-membered phenyl heterocycloalkyl ring, or a 9- or 10-membered heteroaryl heterocycloalkyl ring with the adjacent 6-membered ring.
  • the 9- or 10-membered heteroaryl ring, the 9- or 10-membered phenyl heterocycloalkyl ring, and the 9- or 10-membered heteroaryl heterocycloalkyl ring are each independently unsubstituted or substituted by 1 or 2 Or substituted by 3 substituents each independently selected from the substituent group Q;
  • R 1 and R 2 are each independently C 1-8 alkyl, halogenated C 1-8 alkyl or C 3-6 cycloalkyl; wherein, the C 3-6 cycloalkyl is unsubstituted or substituted 1 or 2 substituents each independently selected from halogen and C 1-3 alkyl are substituted; the C 1-8 alkyl is preferably C 1-6 alkyl, more preferably C 1-3 alkyl; so The halogenated C 1-8 alkyl group is preferably a halogenated C 1-6 alkyl group, and more preferably a halogenated C 1-3 alkyl group;
  • the substituent group Q is selected from halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl group, halogenated C 1-3 alkoxy group, NR a1 R b1 , -SO 2 C 1-3 alkyl group, -S(O)C 1-3 alkyl group, -C(O)NR a1 R b1 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3 to 6-membered heterocycloalkyl , phenyl or 5 to 6-membered heteroaryl;
  • R a1 and R b1 are each independently hydrogen, C 1-3 alkyl or acetyl, or R a1 , R b1 and the connected nitrogen atom together form a 4- to 6-membered saturated monoheterocyclic ring; the 4- to 6-membered saturated
  • the monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the following: deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkyl Oxygen group, C 2-4 alkenyl group, C 2-4 alkynyl group, halogenated C 1-3 alkyl group, halogenated C 1-3 alkoxy group, -SO 2 C 1-3 alkyl group, -S(O )C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2
  • R a3 is hydrogen or C 1-8 alkyl; wherein the C 1-8 alkyl is preferably C 1-6 alkyl, more preferably C 1-3 alkyl.
  • one of T, W, Y, and U is N.
  • T is CRT ; U is CRU ; W is N or CRW ; Y is N or CRY ; and W and Y are not N at the same time.
  • two of T, W, Y, and U are N.
  • the structure is selected from the group consisting of formula (A), formula (B) and formula (C):
  • the 9- or 10-membered heteroaryl ring is selected from: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothiophene base, benzofuryl, benzisofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzene Thiadiazolyl, indanazinyl, purinyl, pyrido[3,2-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyridine And[4,3-d]pyrimidinyl, 1,8-naphthyridinyl, 1,7-naphthyridinyl, 1,6-naphthy
  • the heterocycloalkyl groups in the 9- or 10-membered phenylheterocycloalkyl ring and the 9- or 10-membered heteroarylheterocycloalkyl ring are each independently selected from tetrahydrofuranyl.
  • tetrahydrothienyl tetrahydropyrrolyl, oxazolidinyl, dioxolanyl, piperidyl, piperazinyl, morpholinyl, dioxane, thiomorpholinyl, thiomorpholine -1,1-dioxide, tetrahydropyranyl, azetidine-2-one, oxetane-2-one, dihydrofuran-2(3H)-one, pyrrole Alk-2-one group, pyrrolidine-2,5-dione group, dihydrofuran-2,5-dione group, piperidin-2-one group, tetrahydro-2H-pyran-2-one group , piperazine-2-one group, morpholin-3-one group.
  • the heteroaryl group in the 9- or 10-membered heteroaryl heterocycloalkyl ring is selected from the group consisting of pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • R T is hydrogen; R U is hydrogen; R W is hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl or halo C 1-6 alkoxy.
  • R T is hydrogen;
  • R U is hydrogen;
  • R W is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, Trifluoromethyl or trifluoromethoxy.
  • R T is hydrogen;
  • R U is hydrogen;
  • R Y is hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy or C 3-6 cycloalkyl.
  • R T is hydrogen;
  • R U is hydrogen;
  • R Y is fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, trifluoro Methyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the structure Choose one of the following structures:
  • Ring A is a 5- or 6-membered heteroaryl ring selected from the following group: 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 or tetrazine ring.
  • Ring A is a thiazole ring.
  • n is 2.
  • each R 3 is the same or different, and each is independently C 1-3 alkyl, -NH-C(O)C 1-3 alkyl, -NH-C(O)- Deuterated C 1-3 alkyl or -NH-C(O)OC 1-3 alkyl.
  • R 01 and R 02 are each independently deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogen Substituted C 1-3 alkyl, halogenated C 1-3 alkoxy, NR a1 R b1 , -N(R a3 )-C(O)C 1-3 alkyl, -N(R a3 )-C( O)- Deuterated C 1-3 alkyl, -N(R a3 )-C(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 C 3-6 cycloalkyl, -C (O)NR a1 R b1 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy,
  • R 01 is halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl or halo C 1- 3 alkoxy;
  • R 02 is -NH-C(O)C 1-3 alkyl, -NH-C(O)-deuterated C 1-3 alkyl or -NH-C(O)OC 1-3 alkyl.
  • R 01 is methyl, ethyl, n-propyl or isopropyl. Further preferably, R 01 is methyl.
  • R 02 is -NH-C(O)C 1-3 alkyl, -NH-C(O)-deuterated C 1-3 alkyl or -NH-C(O)OC 1-3 alkyl . Further preferably, R 02 is -NH-C(O)CH 3 , -NH-C(O)-CD 3 or -NH-C(O)OCH 3 .
  • R 1 is monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl , monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, monofluoro-substituted Cyclopropyl or monofluoro-substituted cyclobutyl;
  • R 2 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, monofluoro-substituted cyclopropyl group or a fluorine-substi
  • R1 is cyclopropyl, cyclobutyl or trifluoromethyl.
  • R2 is methyl, ethyl, cyclopropyl or cyclobutyl.
  • Z is N or CH.
  • the 5- or 6-membered heteroaryl (ring) described in the group R 3 and substituent group Q in each of the above structural formulas are each independently selected from: thienyl, furyl, thiazole base, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5- Triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or tetrazinyl.
  • the 5- or 6-membered heteroaryl (ring) is each independently selected from the following structures:
  • the 3- to 6-membered heterocycloalkyl groups described in the above structural formulas, the group R 3 and the substituent group Q are 4 to 6-membered heterocycloalkyl groups, each independently selected from : Azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl , dioxanyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, pyrrolidin-2-one, dihydrofuran-2(3H)-one base, morpholin-3-one group, piperazin-2-one group and piperidin-2-one group.
  • the compound of formula (I) is selected from any one of the following structures:
  • the second aspect of the present application provides a pharmaceutical composition, which includes the compound described in the first aspect of the present application, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • the third aspect of this application provides the compounds described in the first aspect of this application, or pharmaceutically acceptable salts thereof, or their stereoisomers, and the pharmaceutical compositions described in the second aspect of this application in the preparation of treatments and/or Use in drugs to prevent diseases associated with or mediated by PI3K ⁇ activity.
  • the disease related to or mediated by PI3K ⁇ activity is inflammation, metabolic disease or cancer.
  • Figure 1 shows the tumor growth curve of the mixed inoculation model of MC38 and macrophages in C57BL/6 mice
  • Figure 2 shows the tumor weight on day 27 of C57BL/6 mouse MC38 and macrophage mixed inoculation model.
  • 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, preferably C 1-6 alkyl, more preferably C 1-3 alkyl; non-limiting examples of alkyl include : Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-di Methylpropyl, 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-dimethyl But
  • Alkynyl refers to straight-chain and branched unsaturated aliphatic hydrocarbon groups with one or more carbon-carbon triple bonds
  • C 2-8 alkynyl refers to alkynyl groups with 2 to 8 carbon atoms, preferably C 2-6 alkynyl, more preferably C 2-4 alkynyl, is similarly defined; non-limiting examples of alkynyl include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl Alkynyl etc.
  • Cycloalkyl and “cycloalkyl ring” are used interchangeably and both refer to a saturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon group which may be fused to an aryl or heteroaryl group. Cycloalkyl rings may be optionally substituted. In certain embodiments, cycloalkyl rings contain one or more carbonyl groups, such as oxo groups. “C 3-8 cycloalkyl” refers to a monocyclic cycloalkyl group having 3 to 8 carbon atoms.
  • Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc.
  • Preferred is 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
  • Heterocycloalkyl and “heterocycloalkyl ring” are used interchangeably and both refer to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, which group may be associated with an aryl or heteroaryl group. Condensation. Heterocycloalkyl rings may be optionally substituted. In certain embodiments, heterocycloalkyl rings contain one or more carbonyl or thiocarbonyl groups, such as groups containing oxo and thio.
  • 3- to 8-membered heterocycloalkyl refers to a monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, preferably 4 to 8-membered heterocycloalkyl. More preferred is a 3- to 6-membered heterocycloalkyl group, which has 3 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Further preferred is a 4- to 6-membered heterocycloalkyl group having 4 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples include aziridyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, oxazolidinyl, di Oxopentyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, aza cyclobutane-2-one group, oxetan-2-one group, dihydrofuran-2(3H)-one group, pyrrolidine-2-one group, pyrrolidine-2,5-dione group , dihydrofuran-2,5-dione group, piperidin-2-one group, tetrahydro-2H-pyran-2-one group, piperazine-2-one group, morpholin-3-one group, etc
  • 6- to 12-membered heterocycloalkyl and “6- to 12-membered fused heterocycloalkyl” are used interchangeably and refer to having 6 to 12 ring atoms, of which 1, 2 or 3 ring atoms are selected from A fused bicyclic cyclic hydrocarbon radical of heteroatoms of nitrogen, oxygen and sulfur.
  • 8 to 10 membered heterocycloalkyl and “8 to 10 membered fused heterocycloalkyl” can Used interchangeably, it refers to a fused bicyclic cyclic hydrocarbon group having 8 to 10 ring atoms, of which 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples include hexahydro-1H-furan[3,4-c]pyrrole, octahydro-1H-cyclopenta[c]pyridine, hexahydro-1H-pyrrolo[2,1-c][1, 4]oxazine, octahydropyrrolo[1,2-a]pyrazine, hexahydropyrro[1,2-a]pyrazin-4(1H)-one, octahydrocyclopenta[c]pyrrole, etc.
  • the point of attachment may be a carbon or nitrogen atom as long as the valency permits.
  • Bicyclic heterocycloalkyl systems may include one or more heteroatoms in one or both rings.
  • Heteroaryl and “heteroaryl ring” are used interchangeably and both refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system having ring carbon atoms and ring heteroatoms (e.g., having a Arrange shared 6 or 10 ⁇ electrons) groups in which each heteroatom is independently selected from nitrogen, oxygen and sulfur. Heteroaryl rings may be optionally substituted.
  • "5- to 10-membered heteroaryl” refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms.
  • 5- to 6-membered heteroaryl refers to a monocyclic heteroaryl group with 5 to 6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms.
  • Non-limiting examples include thienyl, furan base, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2 ,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl Azolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl
  • 9- or 10-membered heteroaryl refers to a bicyclic heteroaryl group with 9 or 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms.
  • Non-limiting examples include indolyl, iso- Indolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzoiso Oxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanazinyl, purinyl, pyrido[3,2-d]pyrimidinyl, pyrido [2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-naph
  • Heteroatom means nitrogen, oxygen or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valency permits. Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings.
  • “Fused” refers to a structure in which two or more rings share one or more bonds.
  • Phenylheterocycloalkyl refers to a group in which a benzene ring is fused with a heterocycloalkyl ring to form a bicyclic, tricyclic or polycyclic system, wherein the heterocycloalkyl ring is as defined above.
  • "9- or 10-membered phenylheterocycloalkyl” refers to a bicyclic cyclic group having 9 or 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. .
  • Non-limiting examples include indoline, benzo[d][1,3]dioxazole, 1,2,3,4-tetrahydroisoquinoline, 3,4-dihydro-2H-benzo[ b][1,4]oxazine, indole-2-one, isoindolin-1-one, 1,4-dihydroisoquinolin-3(2H)-one, etc.
  • Heteroarylheterocycloalkyl refers to a group in which a heteroaryl ring is fused with a heterocycloalkyl ring to form a bicyclic, tricyclic or polycyclic system, wherein the heterocycloalkyl ring is as defined above.
  • “9- or 10-membered heteroarylheterocycloalkyl” refers to a bicyclic cyclic group having 9 or 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. group.
  • Non-limiting examples include 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, [1,3]dioxola[4,5-b]pyridine, 2,3-dihydro -1H-pyrido[3,4-b][1,4]oxazine, 2,3,4,6-tetrahydropyrrolo[3,4-b][1,4]oxazine, 2,4 ,5,6-tetrahydropyrano[2,3-c]pyrazole, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, etc.
  • Alkoxy refers to -O-alkyl, where alkyl is as defined above. It is preferably a C 1-8 alkoxy group, more preferably a C 1-6 alkoxy group, and most preferably a C 1-3 alkoxy group. Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentyloxy, and the like.
  • Cycloalkyloxy refers to -O-cycloalkyl, where cycloalkyl is as defined above. A C 3-8 cycloalkyloxy group is preferred, and a C 3-6 cycloalkyloxy group is more preferred. Non-limiting examples of cycloalkyloxy include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • a bond means that the two groups connected thereto are connected by a covalent bond.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Halo means that one or more (eg, 1, 2, 3, 4 or 5) hydrogens in a group are replaced by halogen.
  • haloalkyl refers to an alkyl group in which the hydrogens are replaced by one or more (eg, 1, 2, 3, 4 or 5) halogens, where alkyl is as defined above.
  • a halogenated C 1-8 alkyl group is preferred, a halogenated C 1-6 alkyl group is more preferred, and a halogenated C 1-3 alkyl group is even more preferred.
  • haloalkyl groups include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl base, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.
  • haloalkoxy means that the hydrogen on the alkoxy group is substituted by one or more (such as 1, 2, 3, 4 or 5) halogens, where the alkoxy group is as defined above.
  • a halogenated C 1-8 alkoxy group is preferred, a halogenated C 1-6 alkoxy group is more preferred, and a halogenated C 1-3 alkoxy group is even more preferred.
  • Haloalkoxy groups include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
  • halogenated cycloalkyl means that the hydrogen on the cycloalkyl group is substituted by one or more (such as 1, 2, 3, 4 or 5) halogens, wherein the cycloalkyl group is as defined above.
  • a halogenated C 3-8 cycloalkyl group is preferred, and a halogenated C 3-6 cycloalkyl group is more preferred.
  • Halogenated cycloalkyl groups include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, etc.
  • Deuterated alkyl means that the hydrogen on the alkyl group is replaced by one or more (eg, 1, 2, 3, 4 or 5) deuterium atoms, where alkyl is as defined above. It is preferably a deuterated C 1-8 alkyl group, more preferably a deuterated C 1-6 alkyl group, and even more preferably a deuterated C 1-3 alkyl group. Examples of deuterated alkyl groups include, but are not limited to, monodeuterated methyl, monodeuterated ethyl, dideuterated methyl, dideuterated ethyl, trideuterated methyl, trideuterated ethyl, and the like.
  • Amino refers to NH 2
  • cyano refers to CN
  • nitro refers to NO 2
  • benzyl refers to -CH 2 -phenyl
  • oxo O
  • carboxyl refers to -C (O)OH
  • acetyl refers to -C(O)CH 3
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CHOHCH 3
  • hydroxyl refers to -OH
  • mercapto refers to SH
  • the structure of "cyclopropylene” is:
  • Substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are each independently substituted by a corresponding number of substituents, and more preferably 1 to 3 hydrogen atoms are each independently substituted by a corresponding number of substituents. Substituted with substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • L is (CR 01 R 02 ) s .
  • L is (CR 01 R 02 )-(CR 01 R 02 ).
  • the two R 01 can be the same or different, and the two R 02 can be Identical or different, they are independent species.
  • L can be C(CH 3 )(CN)-C(CH 2 CH 3 )(OH), C(CH 3 )(CN)-C(CH 3 )(OH ) or C(CN)(CH 2 CH 3 )-C(OH)(CH 2 CH 3 ).
  • any group in this application may be substituted or unsubstituted.
  • the substituents are preferably 1 to 5 or less groups, independently selected from cyano, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl) , more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amino, halogenated C 1-8 alkyl substituted Amino, acetyl, hydroxyl, hydroxymethyl, hydroxyethyl
  • any two “preferences” may be independent of each other.
  • any two substituents may be the same or different.
  • it can be substituted by two identical or different halogens, or it can be substituted by one halogen and one hydroxyl group.
  • Sub represents various substituents described in this application; Represents the connection position to other atoms.
  • the compounds of the present application or their pharmaceutically acceptable salts or their stereoisomers can be combined with one or more pharmaceutical carriers to form a suitable dosage form for administration.
  • dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and and syrup, etc.
  • the compounds of the present application contained in these preparations can be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, etc.
  • the above dosage forms can be prepared from the active compound and one or more carriers or excipients through common pharmaceutical methods.
  • the above carriers need to be compatible with the active compound or other excipients.
  • the active compounds can form solutions or suspensions with carriers.
  • “Pharmaceutically acceptable carrier” means a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary preparation or excipient of any type that is compatible with the patient, preferably a mammal , more preferably human, which is suitable for delivering the active agent to the intended target site without terminating the activity of the agent.
  • Compounds of the present application refer to compounds of formula (I) of the present application, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, which have PI3K ⁇ selective inhibitory activity, and preparation of compounds of formula (I), or pharmaceutically acceptable salts thereof. Acceptable salts, or intermediate compounds of its stereoisomers.
  • compositions of the present application are formulated, dosed, and administered in a manner consistent with good medical practice.
  • the "therapeutically effective amount" of a compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • “Therapeutically effective amount” refers to the amount of a compound of the present application that will induce a biological or medical response in an individual, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating disease, slowing or delaying disease progression, or preventing disease, etc.
  • the pharmaceutical composition of the present application or the therapeutically effective amount of the compound of the present application or its pharmaceutically acceptable salt or its stereoisomer contained in the pharmaceutical composition is preferably 0.1 mg/kg-5g/kg ( weight).
  • Patient means an animal, preferably a mammal, more preferably a human being.
  • mammal refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
  • Treatment means to alleviate, delay the progression, attenuate, prevent, or maintain an existing disease or condition (eg, cancer). Treatment also includes curing, preventing the progression of, or alleviating to some degree one or more symptoms of a disease or condition.
  • compositions include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • Pharmaceutically acceptable acid addition salts refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. These salts can be prepared by methods known in the art.
  • “Pharmaceutically acceptable base addition salts” include, but are not limited to, salts of inorganic bases such as sodium salts, potassium salts, calcium salts and magnesium salts. Including but not limited to salts of organic bases, such as ammonium salts, triethylamine salts, lysine salts, arginine salts, etc. These salts can be prepared by methods known in the art.
  • the compound represented by formula (I) of the present application may exist in different optically active forms.
  • a compound of formula (I) contains a chiral center, the compound contains a pair of enantiomers.
  • Two enantiomers of the compound as well as mixtures of the pair of enantiomers, such as racemic mixtures, are also within the scope of the present application.
  • Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography.
  • the compound contains more than one chiral center, the compound contains enantiomers and diastereomers.
  • Enantiomers and diastereomers of this compound can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • the compounds described in this application can be synthesized using methods similar to those described below or the exemplary methods described in the Examples, or relevant publications used by those skilled in the art, by using appropriate alternative starting materials.
  • Starting materials for the compounds described herein may be synthesized or may be obtained from commercial sources.
  • the compounds described herein and other related compounds having various substituents can be synthesized using techniques and starting materials known to those skilled in the art.
  • General methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties in the molecules provided herein.
  • the IC 50 value of the inhibitory activity against PI3K ⁇ kinase is less than 100 nM. , in some embodiments having an IC 50 value of less than 50 nM, in some embodiments having an IC 50 value of less than 10 nM, and therefore can be used as a therapeutic agent for the treatment and/or prevention of diseases associated with or mediated by PI3K ⁇ activity. drug.
  • Known starting materials can be synthesized by methods known in the art, or can be purchased from ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc) and Dari Chemicals, etc. company.
  • DCM dichloromethane
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphorus)ferrocene]palladium dichloride
  • dppf 1 ,1'-bis(diphenylphosphine)ferrocene
  • Pin 2 B 2 pinacol diboronate
  • SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride
  • ACN acetonitrile
  • TFA trifluoroacetic acid
  • DCM dichloromethane
  • MeOH methanol
  • n-BuLi n-butyllithium
  • KOAc potassium acetate
  • 1,4-Dioxane 1,4-dioxane
  • CombiFlash fast liquid phase Preparative chromatograph
  • EA ethyl acetate
  • PE petroleum ether
  • DMSO dimethyl sulfoxide
  • the percentage content involved in this application refers to mass percentage for solid-liquid mixing and solid-solid phase mixing, and refers to volume percentage for liquid-liquid phase mixing.
  • the final product of the present application can be obtained through preparation and purification, and the purification and separation conditions can be obtained by those skilled in the art based on the characteristics of the compound through tests with common knowledge in the art.
  • room temperature refers to about 20-30°C.
  • Step 1 Dissolve 2,6-dichloro-4-methylnicotinic acid (40.00g, 194.15mmol) and potassium carbonate (67.08g, 485.38mmol) in DMF (200mL), add methyl iodide (41.34g) dropwise at room temperature ,291.23mmol), then react at 24°C for 1 hour, Pour the reaction solution into water, extract with ethyl acetate, wash the organic phase twice with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a brown crude product, 2,6-dichloro-4-methylnicotinic acid methyl. Ester (39.00g, yield: 92.86%). MS(ESI)220.0[M+H] + .
  • Step 2 Combine the crude product 2,6-dichloro-4-methylnicotinic acid methyl ester (39.00g, 177.23mmol) and N-bromosuccinimide (47.32g, 265.85mmol) and benzyl peroxide
  • the acyl 64.40 g, 265.85 mmol
  • Step 3 Combine the crude product 2,6-dichloro-4-methylnicotinic acid-4-(bromomethyl)-2,6-dichloronicotinic acid methyl ester (25.00g, 84.20mmol) and 2,6- Dichloro-4-(dibromomethyl)nicotinic acid methyl ester (25.00g, 66.17mmol) was dissolved in ACN (300mL), and the temperature was lowered to 5°C under N 2 protection. At this temperature, N, N-dioic acid was added dropwise.
  • Step 4 Combine 2,6-dichloro-4-methylnicotinic acid-4-(bromomethyl)-2,6-dichloronicotinic acid methyl ester (28.00g, 93.66mmol) and (S)-1- Cyclopropylethylamine hydrochloride (11.39g, 93.66mmol) was dissolved in acetonitrile (200mL), and then boric acid (5.79g, 93.66mmol) and potassium carbonate (25.89g, 187.32mmol) were added. The reaction was stirred at 24°C for 12 hours. The suspension was filtered, and the filtrate was spun to dryness to obtain crude product.
  • Step 1 Dissolve 6-chloropyrazolopyridine (1g, 6.51mmol, 1eq) in DMF (10mL), protect it with argon, add NaH (188mg, 7.81mmol, 1.2eq, 60wt%) at -5°C, React for 10 minutes, add SEM-Cl (1.3g, 7.81mmol, 1.2eq) dropwise at -5°C, remove the ice bath after adding, return to room temperature (rt), and react for 3 hours and 10 minutes. Send LCMS to detect the success of the reaction. Pour the reaction solution into an appropriate amount of ice water, extract three times with ethyl acetate (30 mL ⁇ 3), and wash once with saturated aqueous sodium chloride solution (30 mL).
  • Step 2 Combine 6-chloro-1-(2-trimethylsilylethoxy)methylpyrazolopyridine (1.3g, 4.58mmol, 1eq), Pin 2 B 2 (1.4g, 5.50mmol, 1.2 eq), KOAc (899mg, 9.16mmol, 2eq) were dissolved in DMF (20mL), replaced with argon, added Pd(dppf)Cl 2 (335mg, 0.4mmol, 0.1eq), replaced with argon, under argon protection. , stirring reaction at 100°C for 5 hours. Sent LCMS for testing and the reaction was successful. After the reaction solution was cooled, it was diluted with water (20 mL), and extracted three times with dichloromethane (30 mL ⁇ 3). The organic phase was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and spin-dried to obtain intermediate 5 (1.9 g, purity: 77%, yield: 99%, black-gray solid).
  • Step 1 Dissolve 6-chloropyrrole (4.5g, 29.49mmol, 1eq) in DMF (40mL), replace with argon, protect with argon, and add NaH (60wt%) (849mg, 35.39mmol, 1.2) at -5°C. eq), react for 10 minutes, add SEM-Cl (5.9g, 35.39mmol, 1.2eq) dropwise at -5°C, remove the ice bath after adding, return to room temperature (RT), and react for 3 hours. Send LCMS to detect the success of the reaction.
  • reaction solution was poured into ice water, extracted three times with ethyl acetate, washed once with sodium chloride, dried over anhydrous sodium sulfate, spin-dried and purified through column to obtain the product 6-chloro-1-(2-trimethylsilylethane) Oxy)methylpyrrolidine (8g, purity: 80.08%, yield: 76.80%, light yellow liquid).
  • Step 2 Combine 6-chloro-1-(2-trimethylsilylethoxy)methylpyrrolidine (3g, 10.61mmol, 1eq), Pin 2 B 2 (3.2g, 12.73mmol, 1.2eq), KOAc (2.1g, 21.22mmol, 2eq) was dissolved in 1,4-dioxane (30mL), replaced with argon, added Pd(dppf)Cl 2 (776mg, 1.06mmol, 0.1eq), replaced with argon, Under argon protection, the reaction was stirred at 90°C for 5 hours. Sent LCMS for testing and the reaction solution was successful.
  • Step 1 Dissolve 6-bromo-1H-pyrazolopyridine (4.5g, 22.73mmol, 1eq) in DMF (40mL), replace with argon, protect with argon, and add NaH (60wt%) at -5°C ( 654mg, 27.27mmol, 1.2eq), react for 10 minutes, add SEM-Cl (4.5g, 27.27mmol, 1.2eq) dropwise at -5°C, remove the ice bath after adding, return to room temperature, and react for 3 hours. Send LCMS to detect the success of the reaction.
  • reaction solution was poured into ice water, extracted three times with ethyl acetate, washed once with sodium chloride, dried over anhydrous sodium sulfate, spin-dried and purified through column to obtain the product 6-bromo-1-(2-trimethylsilylethane) Oxy)methyl-1H-pyrazolo[4,3-b]pyridine (4.3g, purity: 97.50%, yield: 56.20%, light yellow liquid).
  • Step 2 Combine 6-bromo-1-(2-trimethylsilylethoxy)methyl-1H-pyrazolo[4,3-b]pyridine (4.3g, 13.098mmol, 1eq), Pin 2 B 2 (3.991g, 15.718mmol, 1.2eq) and KOAc (2.571g, 26.196mmol, 2eq) were dissolved in 1,4-dioxane (100mL), replaced with argon, and Pd(dppf)Cl 2 ( 479 mg, 0.655 mmol, 0.05 eq), replaced with argon, stirred and reacted at 120°C for 12 hours under argon protection. Sent LCMS for testing and the reaction solution was successful.
  • Step 1 Dissolve 6-chloro-1H-pyrazole[3,4-b]pyrazine (2g, 13mmol, 1eq) in DMF (50mL), put it in an ice-salt bath (-5°C), and add NaH ( 0.67g, 16.9mmol, 1.3eq, 60wt%), stir for 30 minutes, add SEM-Cl (2.6g, 15.6mmol, 1.2eq) dropwise, protect with argon, return to room temperature, react for 3 hours, add ice water (30mL ), quenched, extracted three times with ethyl acetate (50mL )Methyl)-1h-pyrazoline[3,4-b]pyrazine (2.3g, crude product), brown oily product. The product was directly used in the next reaction.
  • Step 2 Add 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1h-pyrazoline[3,4-b]pyrazine (1.5g, 5.3mmol, 1eq) was dissolved in 1,4-dioxane (50mL), add Pin 2 B 2 (1.74g, 6.84mmol, 1.3eq), Pd(dppf)Cl 2 ) (384mg, 0.53mmol, 0.1eq), KOAc (1.56g, 15.9mmol, 3eq), replaced with argon three times, heated the oil bath to 120°C and reacted for 12 hours.
  • Step 1 Place the raw material 4-bromopyridine (2g, 12.6mmol, 1eq) in a 250mL single-mouth bottle, add 100mL THF to dissolve, protect with argon, cool to -78°C, and start adding cyclopropylmagnesium bromide ( 40mL, 25.2mmol, 2eq), keep the temperature at -78°C, stir for 5 minutes after the dropwise addition, start to dropwise add phenyl chloroformate (2.4mL, 12.6mmol, 1eq), complete the dropwise addition, react for 10 minutes, return to room temperature, react The solution was diluted with ethyl acetate (150 mL), washed with water (30 mL), 0.1 M (mol/L) hydrochloric acid (30 mL), and brine (30 mL) respectively, and the organic phase was dried and spin-dried to obtain 2.1 g of crude product.
  • cyclopropylmagnesium bromide 40mL, 25.2mmol, 2
  • Step 2 Combine the raw materials 2-cyclopropyl-4-bromopyridine (1.5g, 7.5mmol, 1eq), Pin 2 B 2 (2.3g, 9mmol, 1.2eq), potassium acetate (1.5g, 15mmol, 2eq) ), place it in a 250mL three-necked flask, add 75mL of 1,4-dioxane, replace with argon, add Pd(dppf)Cl 2 (280mg, 0.39mmol, 0.05eq), replace with argon, stir and heat to 120°C. After 12 hours of reaction, LCMS sampling was performed. LCMS showed that the raw material was completely reacted, but LCMS of the product did not show it.
  • Step 1 Dissolve intermediate 1 (400mg, 1.02mmol, 1eq), intermediate 5 (900mg, 3.07mmol, 3eq), K 2 CO 3 (283mg, 2.05mmol, 2eq) in 1,4-dioxane (20 mL) and water (4 mL), replace with argon, add Pd(dppf)Cl 2 (75 mg, 0.10 mmol, 0.1 eq), replace with argon, stir and react at 100°C for 2 hours under argon protection. LCMS detection showed that the reaction was successful. After the reaction solution was cooled, it was diluted with water (20 mL) and extracted with dichloromethane (20 mL ⁇ 3). The combined organic phases were washed once with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. Spin to dryness to obtain 1.2g of crude compound S6-1 (1.2g, purity: 73%).
  • Step 2 Dissolve compound S6-1 (1.2g, 1.45mmol, 1eq) in dichloromethane (50mL), add trifluoroacetic acid (9.4g, 82.7mmol, 57eq), protect with argon, and react at room temperature for 12 hours. Add K 2 CO 3 (1.0g, 7.25mmol, 5eq), methanol (50mL), water (10mL), and stir for 12 hours. Extract with dichloromethane (80mL ⁇ 3). The combined organic phases were washed once with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. Spin to dryness and send to preparation and purification to obtain compound S6 (16.31 mg, 0.034 mmol, yield: 2.37%).
  • Step 1 Dissolve intermediate 1 (300mg, 0.77mmol, 1eq), intermediate 6 (673mg, 2.30mmol, 3eq), K 2 CO 3 (212mg, 1.53mmol, 2eq) in 1,4-dioxane (20 mL), add Troubles distilled water (4 mL), replace with argon, add Pd(dppf)Cl 2 (56 mg, 0.077 mmol, 0.1 eq), replace with argon, stir the reaction at 100°C under argon protection 2 Hour. Sent LCMS for testing and the reaction solution was successful.
  • Step 2 Dissolve compound S7-1 (453mg, purity: 76.59%, 0.58mmol, 1eq) in dichloromethane (50mL), add trifluoroacetic acid (3.7g, 32.81mmol, 57eq), protect with argon, room temperature Reaction takes 10 hours. At the end of the reaction, adjust the pH to neutral, spin to dryness, add K 2 CO 3 (398 mg, 2.88 mmol, 5 eq), 50 mL of methanol, and 10 mL of Treconite distilled water, and react for 2 hours.
  • Step 1 Dissolve intermediate 1 (300mg, 0.77mmol, 1eq), intermediate 7 (432mg, 1.15mmol, 1.5eq), K 2 CO 3 (212mg, 1.53mmol, 2eq) in 1,4-dioxane ring (20 mL), add Tribune distilled water (4 mL), replace with argon, add Pd(dppf)Cl 2 (56 mg, 0.077 mmol, 0.1 eq), replace with argon, and stir the reaction at 100°C under argon protection. 2 hours. Sent LCMS for testing and the reaction solution was successful.
  • Step 2 Dissolve compound S8-1 (500mg, purity: 74.49%, 0.617mmol, 1eq) in dichloromethane (50mL), add trifluoroacetic acid (4.0g, 35.16mmol, 57eq), protect with argon, room temperature Reaction takes 10 hours. After the reaction is completed, adjust the pH to neutral, spin to dryness, add K 2 CO 3 (426 mg, 3.08 mmol, 5 eq), 50 mL of methanol, and 10 mL of Trecroft distilled water, and react for 2 hours.
  • Step 1 Dissolve intermediate 1 (500mg, 1.28mmol, 1eq) in 1,4-dioxane (25mL), water (5mL), add intermediate 8 (1.5g, 5.1mmol, 4eq), Pd (dppf)Cl 2 (94.2mg, 0.13mmol, 0.1eq), sodium carbonate (1.25g, 0.77mmol, 3eq), protected by argon, stirred and reacted at 100°C for 2 hours.
  • LCMS monitored product formation. After cooling, the reaction solution was diluted with water (30 mL), extracted with dichloromethane three times (30 mL ⁇ 3), and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound S9-1 (1 g).
  • Step 2 Dissolve compound S9-1 (1g, crude product) in DCM (35mL), add trifluoroacetic acid (5mL), and react at room temperature for 10 hours.
  • the reaction solution was concentrated to dryness, the crude product was dissolved in 25 mL of methanol and 5 mL of water, potassium carbonate (1.37 g, 10 mmol, 5 eq) was added, stirred at room temperature for 2 hours, filtered, the filter cake was washed with a small amount of methanol, and the solvent was concentrated under reduced pressure.
  • Step 1 Dissolve compound 1 (100mg, 0.256mmol) in N,N-dimethylformamide (3mL), add zinc cyanide (150mg, 1.28mmol) and 1,1'-bis(diphenyl) respectively.
  • Phosphine) ferrocene (56.7 mg, 0.1 mmol)
  • activated zinc powder (16.6 mg, 0.256 mmol)
  • blow argon gas into the reaction solution for 30 seconds
  • tris(dibenzylideneacetone) dipalladium 46.6 mg, 0.05 mmol
  • Microwave at 125°C for one hour.
  • the reaction solution was brought to room temperature, filtered, and the filter cake was washed twice with dichloromethane.
  • Step 2 Dissolve compound S-34-a (30 mg, 0.079 mmol) and azidotributylstannane (261 mg, 0.79 mmol) in toluene (2 mL), replace the argon gas three times, and react in an oil bath at 120°C for 36 hours.
  • the reaction solution was brought to room temperature, filtered, and the filter cake was washed twice with dichloromethane.
  • the filter cake was dissolved in dimethyl sulfoxide (5 mL) and prepared using alkaline method [NH 4 HCO 3 ] conditions to obtain compound S-34 (1.21 mg, white solid, purity 99%).
  • Test Example 1 Inhibition of Akt S473 phosphorylation level in Raw264.7 cells
  • This experiment uses ELISA method for detection.
  • Raw264.7 cells were purchased from ATCC; mC5a protein was purchased from R&D; DMEM serum-free medium was purchased from Gibco; fetal calf serum (BSA) was purchased from Gibco; RIPA buffer was purchased from CST; protease phosphatase inhibitor was purchased from CST; phosphate
  • the ELISA detection kit for Akt S473 was purchased from R&D; the 96-well plate was purchased from Falcon; the high binding 96-well plate was purchased from Costar; the Infinite M1000 fluorescence microplate reader was purchased from Tecan.
  • Capture Prepare the capture antibody (Capture) solution according to the instructions of the ELISA detection kit for phosphorylated Akt S473 (R&D DYC887BE). Add 100 ⁇ L of the Capture solution per well into a high binding 96-well plate (Costar 42592) and incubate at room temperature overnight. . Wash three times with 300 ⁇ L PBST, add blocking solution (PBS solution containing 1% (w/v) BSA) (Genview FA016-100G), incubate at room temperature for 2 hours, then wash three times with 300 ⁇ L PBST; add 90 ⁇ L control group and blank group respectively.
  • PBS solution containing 1% (w/v) BSA Block FA016-100G
  • Adding DMSO without mC5a protein was the blank group, and adding DMSO and mC5a protein was the control group.
  • Inhibition% [1-(Total mean(experimental group)-total mean(blank group))/(Total mean(control group)-total mean(blank group))] ⁇ 100%; among them, Inhibition%: compound’s effect on Raw264 .7% inhibition of Akt S473 phosphorylation level in cells; total mean: total mean.
  • Test Example 2 Inhibition of Akt S473 phosphorylation levels in T47D and PC3 cells
  • T47D cells were purchased from ATCC; PC3 cells were purchased from SIBS; RPMI 1640 and F12K culture media were purchased from Gibco; phosphorylated Akt S473 (Ser473-p-Akt) antibody was purchased from CST; 96-well plates were purchased from Falcon; Infinite M1000 fluorescent enzyme label The instrument was purchased from Tecan; YZJ-0673 is compound S-37 in patent WO2016095833.
  • T47D (PI3K ⁇ ) (culture conditions: RPMI 1640+10% FBS (v/v)) and PC3 (PI3K ⁇ ) (culture conditions: F12K + 10% FBS (v/v)) cells in the logarithmic growth phase and incubate them at 2.2 ⁇ 90 ⁇ L of a concentration of 10 5 cells/mL (PC3) or 4.4 ⁇ 10 5 cells/mL (T47D) was plated in a 96-well plate (Falcon 353072), cultured at 37°C, 5% CO 2 , and left overnight until the cells were attached.
  • PC3 10 5 cells/mL
  • the control group, background group and experimental group respectively took out the Triton X-100 solution, washed it twice with 200 ⁇ L PBS (300 rpm, 1 minute each time), and added blocking solution (PBS solution containing 1% (w/v) BSA) (Genview FA016-100G), incubate at room temperature for 2 hours, take it out, wash once with 200 ⁇ L PBS (300 rpm, 1 minute), add 30 ⁇ L Ser473-p-Akt antibody 0.1% (w/v) BSA dilution (cell signaling 4060L), 4°C Incubate overnight.
  • PBS solution containing 1% (w/v) BSA Genview FA016-100G
  • the compound of the present application has high inhibitory activity on the phosphorylation level of Akt S473 in Raw264.7 cells and low inhibitory activity on T47D and PC3 cells, indicating that the compound of the present application has high inhibitory activity on PI3K ⁇ . Select inhibitory activity.
  • Test Example 3 Determination of PI3K kinase inhibitory activity
  • Human PI3K ⁇ and PI3K ⁇ kinase were purchased from Millipore, human PI3K ⁇ kinase was purchased from Invitrogen, human PI3K ⁇ kinase was purchased from Eurofins, ADP-Glo kinase detection kit was purchased from Promega, and PIP2 lipid substrate was purchased from Life Technologies, 384-well plate Purchased from PE.
  • This experiment uses the ADP-Glo method to detect the inhibition of the activities of PI3K ⁇ , PI3K ⁇ , PI3K ⁇ and PI3K ⁇ by compounds.
  • the reagents used are PI3K ⁇ (Millipore 14-558), PI3K ⁇ (Invitrogen PV4788), PI3K ⁇ (Eurofins 14-603M), PI3K ⁇ (Millipore 14-604M), PIP2 (Life Technologies PR8982B), ADP-Glo (Promega V9102/3).
  • the inhibitory effect of the test compounds on PI3K kinase activity in Table 3 was determined by the following method.
  • the test compounds were prepared with 100% DMSO into a 100 ⁇ DMSO solution with the maximum concentration required for the experiment, and then 3-fold gradient dilution was performed with 100% DMSO. There are 10 concentration points in total. Add 50nL of the prepared test compound solution to the 384-well plate (PE 6008289), and add DMSO to the blank wells and control wells.
  • Inhibition rate % [1-(average value (experimental group)-average value (blank group))/(average value (control group)-average value (blank group))] ⁇ 100%
  • Table 3 IC 50 value of compounds inhibiting PI3K ⁇ kinase activity
  • Table 4 IC 50 values of compounds inhibiting PI3K ⁇ , PI3K ⁇ and PI3K ⁇ kinase activity
  • the LC/MS/MS method was used to determine the drug concentration in the plasma of mice at different times after intravenous injection and oral gavage administration of the compound of the present application.
  • the known compound D1 and the compounds of the present application S11, S5 and S18 were For example, study the pharmacokinetic behavior of the compound of the present application in mice and evaluate its pharmacokinetic characteristics.
  • compound D1 (CAS No. 2504036-13-7) is as follows, which can be prepared by referring to existing literature or purchased commercially.
  • mice in the intravenous injection group can drink water and eat freely; mice in the intragastric administration group are fasted overnight, and can drink water and eat freely 4 hours after administration) ;
  • Dosing method and dosage Select the drug that meets the experimental requirements before administration (qualifies for quarantine, passes the laboratory adaptation period, and has a weight that meets the requirements of the experiment) Animals that meet the requirements are weighed and marked. ICR mice were administered via tail vein, the dosage was 2 mg/kg, the solvent was 5% DMSO + 30% (10% Solutol HS15) + 65% (20% Captisol, pH 7.4), v/v/v; administered by gavage The dosage is 10 mg/kg, the solvent is 5% DMSO + 30% (10% Solutol HS15) + 65% (20% Captisol, pH 7.4), v/v/v.
  • Blood sample collection Before collecting blood samples, bind the mice, and each administered mouse will collect blood at predetermined blood collection time points (intravenous administration: respectively at 0.083, 0.25, 0.5, 1, 2, 4, Collect blood at 7 and 24 hours, a total of 8 time points; intragastric administration: Collect blood at 0.083, 0.25, 0.5, 1, 2, 4, 7, and 24 hours after administration, a total of 8 time points), through the canthus vein Collect approximately 100 ⁇ L of blood. Transfer the whole blood to a 1.5 mL test tube pre-added with the anticoagulant EDTA-K 2 , centrifuge for 6 minutes (8000 rpm, 4°C), and separate the plasma. The entire process is completed within 15 minutes after blood collection. All samples need to be stored in a -20°C refrigerator until sample analysis.
  • the chromatographic column is: Waters XBridge-C18 (2.1 ⁇ 50mm, 3.5 ⁇ m), mobile phase A: containing Aqueous solution of 0.05% formic acid and 5mmol/L ammonium acetate (v/v), mobile phase B: methanol solution (v/v) containing 0.05% formic acid and 5mmol/L ammonium acetate, the flow rate is 0.6mL/min, and the column temperature is 40°C, the injection volume is 2 ⁇ L, and the liquid phase gradient is:
  • Mass spectrometry conditions are: scan mode: multiple reaction ion monitoring (positive ion mode);
  • Ion source turbine spray
  • ionization mode electrospray ionization.
  • C max in Table 5 is the peak concentration
  • AUC 0-t is the area under the plasma concentration-time curve from time 0 to the final quantifiable time point
  • F is the oral bioavailability
  • Test Example 5 Pharmacodynamic test in a tumor model in which mouse colon cancer cells MC38 and in vitro differentiated M2 macrophages were mixed subcutaneously and transplanted
  • the anti-tumor effect of the compound of the present application was evaluated in a tumor model in which mouse colon cancer cell MC38 cells and macrophages cultured in vitro were mixed subcutaneously and transplanted.
  • mice C57BL/6 mice, female, 8-9 weeks old (the age of mice when tumor cells were inoculated), weight 18.0-20.0g, 8 mice in each group. Purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd.
  • Mouse colon cancer cell MC38 (purchased from Shanghai Jiao Tong University) was cultured in a medium containing 10% (v/v) fetal calf serum (Gibco; 10099-141C), 100 U/mL penicillin and 100 pg/mL streptomycin (Gibco; 15140122). in RPMI-1640 culture medium (Gibco; 61870-036). MC38 cells in the exponential growth phase were collected and resuspended in PBS to a suitable concentration for subcutaneous tumor inoculation in mice.
  • Bone marrow cells were isolated from the leg bones of C57BL/6 mice, prepared into single cell suspension, and added with 50ng/mL M-CSF (Peprotech; 315-02) to induce bone marrow-derived M0 macrophages; in M0 macrophage induction During the process, 20ng/mL interleukin 4 (IL4) (Peprotech; 214-14) was added and cultured for 48 hours to obtain polarized M2 macrophages; M0 macrophages and M2 macrophages cultured in vitro were closely related to mouse colon cancer.
  • the cell line MC38 was mixed at a ratio of 1:1 (number) and inoculated subcutaneously, with a total of 10 6 cells/mouse.
  • mice in the control group were administered with vehicle as the vehicle group, and the administration volume was 10 ⁇ L/g; the mice in the M0 group were administered with vehicle as the vehicle group mixed with M0 macrophages.
  • the drug volume is 10 ⁇ L/g; 8 mice in the M2 group are randomly selected to be gavaged with the vehicle as the vehicle group mixed with M2 macrophages, and the dosage volume is 10 ⁇ L/g; 8 mice in the M2 group are randomly selected to be gavaged with 1 mg/mL of the drug.
  • the compound S11 administration preparation was used as the compound S11 group mixed with M2 macrophages, and the dosage was 10 mg/kg; the mice in the remaining M2 group were administered 1 mg/mL compound D1 administration preparation as the compound D1 mixed with M2 macrophages.
  • the dosage was 10 mg/kg.
  • Routine monitoring includes observing the impact of tumor growth and treatment on the normal behavior of animals, including the activity of experimental animals, food and water intake, weight gain or loss, eyes, coat and other abnormalities. Weigh and measure the tumor volume twice a week. The dosing period is 27 days. On the 27th day, the body weight is measured and the tumor volume is measured. The mice are then killed and the tumor block is taken out and weighed (TW). The tumor volume (TV) and relative tumor weight are calculated. Growth rate (T/C) and tumor growth inhibition rate (tumor weight) (TGI) were analyzed statistically.
  • T/C (%) T/C ⁇ 100%
  • TGI (%) (1-T/C) ⁇ 100%
  • T and C are the treatment groups respectively (compound S11 group mixed with M2 macrophages or The relative tumor volume or weight at a specific time point between the compound D1 group mixed with M2 macrophages) and the control group (vehicle group).
  • the mouse tumor growth curve is shown in Figure 1.
  • vehicle vehicle group
  • M0+ vehicle vehicle group mixed with M0 macrophages
  • M2+ vehicle vehicle group mixed with M2 macrophages
  • M2+ compound D1 compound mixed with M2 macrophages D1 group, 10 mg/kg (mpk), administered by gavage, once a day
  • M2+ compound S11 compound S11 group mixed with M2 macrophages, 10 mg/kg, administered by gavage, once a day.
  • **, P ⁇ 0.01; ***, P ⁇ 0.001; ns, P>0.05. (n 8, mean ⁇ standard error).
  • mice The tumor weight analysis of mice in each group of the model on the 27th day after administration is shown in Figure 2.
  • vehicle vehicle group
  • M0+ vehicle vehicle group mixed with M0 macrophages
  • M2+ vehicle vehicle group mixed with M2 macrophages
  • M2+ compound D1 compound mixed with M2 macrophages D1 group, 10 mg/kg, administered by gavage, once a day
  • M2+ compound S11 compound S11 group mixed with M2 macrophages, 10 mg/kg, administered by gavage, once a day.
  • **, P ⁇ 0.01; ns, P>0.05. (n 8, mean ⁇ standard error).
  • T/C in Table 6 indicates relative tumor weight growth rate
  • TGI tumor growth inhibition rate (tumor weight)
  • ⁇ indicates no corresponding parameter

Landscapes

  • 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)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé de pyridopyrrolidone substitué par hétéroaryle, ainsi qu'une composition pharmaceutique et son utilisation. Le dérivé de pyridopyrrolidone substitué par hétéroaryle a une structure telle que représentée dans la formule (I). Le composé de la présente invention a une activité inhibitrice sélective relativement élevée sur la PI3Kγ et une activité pharmacocinétique in vivo améliorée, et a une valeur pratique.
PCT/CN2023/116425 2022-09-01 2023-09-01 Dérivé de pyridopyrrolidone substituté par hétéroaryle, ainsi que composition pharmaceutique et son utilisation WO2024046454A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211062585.0 2022-09-01
CN202211062585 2022-09-01

Publications (1)

Publication Number Publication Date
WO2024046454A1 true WO2024046454A1 (fr) 2024-03-07

Family

ID=90100444

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/116425 WO2024046454A1 (fr) 2022-09-01 2023-09-01 Dérivé de pyridopyrrolidone substituté par hétéroaryle, ainsi que composition pharmaceutique et son utilisation

Country Status (1)

Country Link
WO (1) WO2024046454A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107001348A (zh) * 2014-12-17 2017-08-01 上海海雁医药科技有限公司 2‑吗啉‑4,6‑二取代的嘧啶衍生物、其制法与医药上的用途
CN108779110A (zh) * 2016-03-10 2018-11-09 阿斯利康(瑞典)有限公司 磷脂酰肌醇3-激酶γ的新颖抑制剂
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
CN114206332A (zh) * 2019-06-04 2022-03-18 艾库斯生物科学有限公司 2,3,5-三取代吡唑并[1,5-a]嘧啶化合物
CN114258393A (zh) * 2020-07-21 2022-03-29 中国医药研究开发中心有限公司 具有磷脂酰肌醇3-激酶δ和γ的双重抑制剂活性的杂环化合物及其医药用途
WO2023165551A1 (fr) * 2022-03-02 2023-09-07 上海海雁医药科技有限公司 Dérivé à cycle aromatique à six chaînons pyrrolidone, composition pharmaceutique de celui-ci et son utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107001348A (zh) * 2014-12-17 2017-08-01 上海海雁医药科技有限公司 2‑吗啉‑4,6‑二取代的嘧啶衍生物、其制法与医药上的用途
CN108779110A (zh) * 2016-03-10 2018-11-09 阿斯利康(瑞典)有限公司 磷脂酰肌醇3-激酶γ的新颖抑制剂
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
CN114206332A (zh) * 2019-06-04 2022-03-18 艾库斯生物科学有限公司 2,3,5-三取代吡唑并[1,5-a]嘧啶化合物
CN114258393A (zh) * 2020-07-21 2022-03-29 中国医药研究开发中心有限公司 具有磷脂酰肌醇3-激酶δ和γ的双重抑制剂活性的杂环化合物及其医药用途
WO2023165551A1 (fr) * 2022-03-02 2023-09-07 上海海雁医药科技有限公司 Dérivé à cycle aromatique à six chaînons pyrrolidone, composition pharmaceutique de celui-ci et son utilisation

Similar Documents

Publication Publication Date Title
CA2660899C (fr) Derives de compose tricyclique utiles pour le traitement de troubles neoplastiques, de troubles inflammatoires et de troubles immunomodulatoires
TWI751163B (zh) Ｆｇｆｒ４抑制劑、其製備方法和應用
CN110117284B (zh) 含氮杂环类化合物及其制备方法和用途
TW202214605A (zh) 免疫調節劑、組合物及其方法
CN113474338A (zh) 吡嗪类衍生物及其在抑制shp2中的应用
JP7442652B2 (ja) アザビシクロ置換オキサスピロ環誘導体、その調製方法及び医学的使用
CN113646050A (zh) 噻吩并[3,2-b]吡咯[3,2-d]哒嗪酮衍生物和其作为用于治疗癌症、肥胖和糖尿病相关病症的pkm2衍生物的用途
WO2021143803A1 (fr) Dérivé de pyrrolopyrazole oxaspiro-substitué optiquement pur, son procédé de préparation et son utilisation pharmaceutique
CN110267954B (zh) 苯胺取代的1,2-二氢吡咯并[3,4-c]吡啶/嘧啶-3-酮衍生物及用途
JP2023501799A (ja) Ｒｏｃｋ阻害剤及びその製造方法と用途
WO2020143763A1 (fr) Composés d'halogénoallylamine et leur utilisation
WO2020233669A1 (fr) Inhibiteur contenant un dérivé d'indole, son procédé de préparation et son utilisation
CN113454081A (zh) 咪唑并吡啶基化合物及其用于治疗增生性疾病的用途
TW202317564A (zh) Cdk2抑制劑及其製備方法和用途
WO2023165551A1 (fr) Dérivé à cycle aromatique à six chaînons pyrrolidone, composition pharmaceutique de celui-ci et son utilisation
CN110256446B (zh) 苯并杂环取代的环戊二烯并[4,5]吡咯并吡嗪-1-酮衍生物及其应用
WO2024046454A1 (fr) Dérivé de pyridopyrrolidone substituté par hétéroaryle, ainsi que composition pharmaceutique et son utilisation
CN115232144B (zh) 含氮稠环类衍生物、药物组合物及其制备方法和应用
CN111727186A (zh) 双杂环取代的吡啶-2(1h)-酮衍生物、其制法与医药上的用途
CN114085220B (zh) 取代的吗啉-4-羧酸酯衍生物、其组合物及医药上的用途
JP2024509243A (ja) 複素環置換ケトン類誘導体、その組成物および医薬における使用
WO2022033455A1 (fr) Dérivé de triazine ayant une activité inhibitrice d'egfr, son procédé de préparation et son utilisation
KR20230107271A (ko) 이환식 유도체를 포함하는 억제제 유리염기의 결정형, 이의 제조방법 및 용도
CN113880833A (zh) 联苯多环类衍生物抑制剂、其制备方法和应用
TW202214634A (zh) 雜環化合物及其衍生物

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: 23859482

Country of ref document: EP

Kind code of ref document: A1