WO2022007924A1 - Dérivé oxa-azabicyclique, son procédé de préparation et son utilisation médicale - Google Patents

Dérivé oxa-azabicyclique, son procédé de préparation et son utilisation médicale Download PDF

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Publication number
WO2022007924A1
WO2022007924A1 PCT/CN2021/105396 CN2021105396W WO2022007924A1 WO 2022007924 A1 WO2022007924 A1 WO 2022007924A1 CN 2021105396 W CN2021105396 W CN 2021105396W WO 2022007924 A1 WO2022007924 A1 WO 2022007924A1
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alkyl
cancer
aryl
cycloalkyl
halogen
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PCT/CN2021/105396
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English (en)
Chinese (zh)
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陆标
沈晓冬
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 CN202180045864.3A priority Critical patent/CN115835863A/zh
Publication of WO2022007924A1 publication Critical patent/WO2022007924A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present disclosure belongs to the field of medicine, and relates to an oxazabicyclic derivative represented by the general formula (I), its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a PI3K ⁇ Use of inhibitors and use in the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of PI3K ⁇ .
  • Phosphoinositide 3-kinase is a key regulatory kinase in the PI3K/AKT/mTOR signaling pathway, which is involved in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis.
  • Abnormal activation of PI3K is closely related to the occurrence and development of various tumors, and different types of PI3K play different functions.
  • PI3K ⁇ is mainly expressed in immune cells and hematopoietic cells, participates in BCR signaling in B cells, and controls the development and maturation of B cells in the body.
  • the specific surface immunoglobulin Ig on the surface of BCR can bind to the antigen, resulting in the phosphorylation of ITAM in the intracellular segment of the CD79A/B complex.
  • the phosphorylated ITAM can recruit and activate SYK and further activate BTK and its downstream molecule PLC ⁇ 2.
  • Activated SYK can bind to the P85 subunit of PI3K ⁇ , activate PI3K ⁇ , and promote the generation of PIP3.
  • the generated PIP3 can recognize the N-terminal domain of BTK and interact with it to mediate the recruitment of BTK to the membrane, thereby activating BTK-mediated B cell signaling induces the expression of numerous related genes.
  • phosphorylated CD19 can also recruit PI3K ⁇ on the cell membrane, activate PI3K ⁇ , catalyze PIP2 to generate PIP3, activate AKT, and promote cell proliferation, migration, apoptosis and other processes (N Engl J Med, 379, 2052-2062).
  • PI3K ⁇ activation promotes Treg cell development, maturation, and recruitment (Cancer Immunol Res, 2, 1080-1089).
  • PI3K ⁇ Inhibition of PI3K ⁇ can promote the proliferation and survival of CD8+ memory T cells (Cancer Res, 77, 4135-4145). Therefore, PI3K ⁇ is an ideal target for the treatment of B-cell lymphoma, and the development of selective PI3K ⁇ inhibitors as a drug for the treatment of hematological tumors has attracted more and more attention.
  • Idelalisib the first selective inhibitor of PI3K ⁇ approved for marketing, was approved in 2014 for the treatment of chronic lymphocytic leukemia (CLL), follicular lymphoma (FL) and small lymphocytic lymphoma tumor (SLL).
  • Duvelisib (which acts on PI3K ⁇ and ⁇ ) was subsequently approved for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) in 2018.
  • CLL chronic lymphocytic leukemia
  • FL follicular lymphoma
  • PI3K ⁇ inhibitors have achieved very good results in the treatment of these hematological tumors, due to the poor selectivity of these early inhibitors for PI3K kinase, many drug-related hepatotoxicity and gastrointestinal toxicity have been seen in clinical practice.
  • IOA-24 is a second-generation PI3K ⁇ inhibitor developed by iOnctura (WO2011058149, WO2014121901). Compared with traditional PI3K ⁇ inhibitors, it is an ATP non-competitive inhibitor. inhibition is highly selective.
  • the purpose of the present disclosure is to provide a compound represented by the general formula (I) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or its tautomer, racemate, enantiomer, or mixture thereof.
  • Medicinal salt a compound represented by the general formula (I) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or its tautomer, racemate, enantiomer, or mixture thereof.
  • R 5 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally is selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH 2) s NR 7 R 8, -OR 9, -COR 9, -COOR 9, -OS (O) t R 9 , -S(O) t R 9 , -NR 6 COR 9 , -NR 6 SO 2 R 9 and one or more substituents in R, wherein R is selected from cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, wherein each R is independently optionally selected from halogen, alkyl, haloalkyl ,
  • R 1 are the same or different, each independently selected from hydrogen, alkyl, halogen, alkoxy, haloalkoxy, cyano, hydroxy, hydroxyalkyl, -(CH 2 ) s NR 7 R 8 , cycloalkyl, Cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted selected from halogen, alkyl, haloalkyl, cyano, nitro, - (CH 2) s NR 7 R 8 and a substituted or more of -OR 9 is substituted by a group; when m is greater than or equal to 2, two R 1 can form a spiro or bridged ring system on the heterocyclic ring to which it is connected;
  • R 2 and R 4 are the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, cycloalkylalkyl, aryl alkyl, heterocyclylalkyl, and heteroarylalkyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, alkyl halide group, halogen, cyano, nitro, -(CH 2 ) s NR 7 R 8 , -OR 9 , -COR 9 , -COOR 9 , -OS(O) t R 9 , -S(O) t R 9 , -NR 6 COR 9 and -NR 6 SO 2 R 9 are substituted with one or more substituents;
  • R 3 is the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, -(CH 2 ) s NR 7 R 8 , -OR 9 , -COR 9 , -COOR 9 , -OS (O) t R 9, -S (O) t R 9, -NR 6 COR 9, -NR 6 SO 2 R 9, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted group selected from alkyl, haloalkyl, halo, cyano, nitro, - (CH 2) s NR 7 R 8, -OR 9, -COR 9, -COOR 9,,, a -OS (O) t R 9 -S (O) t R 9 -NR 6 COR 9 , and -NR 6 SO 2 R 9 or
  • cycloalkyl, heterocyclyl, aryl or heteroaryl group each of which is independently is optionally selected from the group consisting of alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl
  • substituents in the base are substituted;
  • R 6 are each independently selected from hydrogen atoms, alkyl groups, cycloalkyl groups and aryl groups, wherein said alkyl groups, cycloalkyl groups and aryl groups are each independently optionally selected from alkyl groups, alkoxy groups, oxo groups substituted with one or more of the substituents in group, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 7 and R 8 are the same or different, and are each 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;
  • R 7 and R 8 form together with the nitrogen atom a heterocyclic group, a heterocyclic group optionally substituted selected from alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy , substituted with one or more substituents in hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 9 is each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, -(CH 2 ) s NR 7 R 8 , cycloalkyl, heterocyclyl, aryl wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxy Substituted with one or more substituents of alkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • n 0, 1, 2, 3, 4 or 5;
  • n 1 or 2;
  • q 0, 1, 2, 3 or 4;
  • s 0, 1, 2, 3, 4, or 5;
  • t 0, 1 or 2.
  • R 1 -R 5 , n, q and m are as defined in general formula (I).
  • R 6 -R 9 , s and t are as defined in general formulae (I), (I-1) and (I-2).
  • R 5 is an aryl group, the aryl group is optionally substituted by a heterocyclylalkyl group, and the heterocyclylalkyl group is optionally selected from one or more selected from the group consisting of halogen, alkyl and haloalkyl substituted by a substituent;
  • R 5 is phenyl substituted with morpholinylmethyl, even more preferably, R 5 is
  • a compound represented by general formula (I), (I-1) and (I-2) or its tautomer, racemate, enantiomer Constructs, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof wherein R 5 is a 6-10-membered aryl group, and the 6-10-membered aryl group is optionally surrounded by a 3-6-membered heterocycle substituted by C 1-6 alkyl group, the 3-6 membered heterocyclic C 1-6 alkyl group is optionally selected from one or more of halogen, C 1-6 alkyl and C 1-6 haloalkyl substituted by a substituent.
  • R 10 are the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) s NR 7 R 8 , -OR 9 , cycloalkyl, Heterocyclyl, aryl, and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy substituted with one or more substituents in -(CH 2 ) s NR 7 R 8;
  • R 11 are the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, nitro, -(CH 2 ) s NR 7 R 8. Cycloalkyl, cycloalkyloxy and cycloalkylalkyl;
  • R 12 are the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) s NR 7 R 8 , -OR 9 , cycloalkyl, Cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; when u is greater than or equal to 2, two R 12 can form a spiro or bridged ring system on the morpholine ring;
  • w 0, 1, 2, 3, or 4;
  • u 0, 1, 2, 3, 4, 5 or 6;
  • R 1 -R 4 , R 7 -R 9 , s, m and q are as defined in general formula (I).
  • a compound represented by general formula (I) or (II) or its tautomer, racemate, enantiomer, diastereomer isomer, or a mixture thereof or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (II-1) or (II-2) or its tautomer, racemate, enantiomer , diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 1 -R 4 , R 10 -R 12 , q, u, w and m are as defined in general formula (II).
  • R 1 are the same or different, each independently selected from hydrogen, alkyl, halogen, alkoxy and haloalkoxy, wherein said alkyl is optionally selected from halogen, cyano and -OR 9 with one or more substituents; R 9 wherein general formula (I), (I-1 ), (I-2), (II), (II-1) and (II-2) as defined in .
  • R 1 are the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; further preferably hydrogen.
  • R 2 and R 4 are the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; more preferably, both R 2 and R 4 are hydrogen.
  • a compound of formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or a tautomer, racemate, to, diastereomers thereof, or a mixture of enantiomers, or a pharmaceutically acceptable salt thereof wherein R 3 are the same or different, are each independently selected from hydrogen , halogen, alkyl, haloalkyl, cyano, nitro, -(CH 2 ) s NR 7 R 8 and -OR 9 ; wherein R 7 -R 9 and s are as in general formula (I), (I-1) , (I-2), (II), (II-1) and (II-2).
  • R 3 is the same or different, each independently selected from hydrogen, halogen, halogenated C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkyl;
  • R 3 is the same or different, and each is independently selected from hydrogen, halogen and C 1-6 alkyl;
  • R 3 is the same or different, and each is independently selected from fluorine, chlorine, methyl, methoxy and trifluoromethyl;
  • R 3 is fluoro
  • a compound of formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or a tautomer, racemate, to, diastereomers thereof, or a mixture of enantiomers, or a pharmaceutically acceptable salt thereof wherein R 6 is selected from hydrogen, alkyl and cycloalkyl wherein the alkyl and cycloalkyl groups are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, hydroxy and hydroxyalkyl;
  • R 6 is a hydrogen atom or a C 1-6 alkyl group.
  • a compound of formula (I), (I-1), (I-2), (II), (II-1) and (II-2) tautomers, racemates, enantiomers, diastereomers, or mixtures thereof in the form of a pharmaceutically acceptable salt thereof wherein the same or R 7 and R 8 or different and are each independently is selected from hydrogen atoms, alkyl groups, haloalkyl groups and cycloalkyl groups; or R 7 and R 8 together with the attached nitrogen atom form a heterocyclic group optionally selected from alkyl, alkoxy , substituted with one or more substituents in halogen, hydroxyalkyl and cycloalkyl;
  • R 7 and R 8 are the same or different, and are each independently selected from hydrogen atoms, C 1-6 alkyl and C 1-6 haloalkyl; or R 7 and R 8 together with the attached nitrogen atom form a heterocycle
  • the heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and halogen.
  • a compound of formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or a tautomer, racemate, to, diastereomers thereof, or a mixture of enantiomers, or a pharmaceutically acceptable salt thereof wherein R 9 is independently selected from a hydrogen atom, an alkyl group, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected Substituted from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, cyano and amino;
  • R 9 is independently selected from hydrogen atoms, alkyl, haloalkyl and cycloalkyl; wherein said alkyl and cycloalkyl are each independently optionally selected from halogen, alkyl, alkoxy and haloalkane substituted with one or more substituents in the group.
  • R 9 is independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl and 3-6 membered cycloalkyl; wherein said C 1-6 alkyl and 3-6 membered cycloalkyl
  • the cycloalkyl groups are each independently optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkyl.
  • R 10 is the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; more preferably hydrogen.
  • a compound represented by general formula (II), (II-1) and (II-2) or its tautomer, racemate, enantiomer isomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof wherein R 11 are the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy , hydroxy, hydroxyalkyl, cyano and -(CH 2 ) s NR 7 R 8 ; wherein R 7 -R 8 and s are as defined in general formulae (II), (II-1) and (II-2) .
  • R 11 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 alkyl; more preferably hydrogen.
  • a compound represented by general formula (II), (II-1) and (II-2) or its tautomer, racemate, enantiomer isomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof wherein R 12 are the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxy alkyl, - (CH 2) s NR 7 R 8 and -OR 9; wherein R 7 -R 9 and s are as formula (II), (II-1 ) and (II-2) as defined above.
  • R 12 are the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; more preferably hydrogen or methyl; further preferably hydrogen.
  • a compound represented by general formula (II), (II-1) or (II-2) or its tautomer, racemate, enantiomer isomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof wherein R 1 are the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; m is 0, 1 or 2; R 2 and R 4 are the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; R 3 is the same or different, each independently selected from hydrogen, halogen, halogenated C 1-6 alkyl , C 1-6 alkoxy and C 1-6 alkyl; q is 0, 1, 2 or 3; R 10 is the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; w is 0, 1 or 2; R 11 is the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; R 12 is the same or different, each independently selected from each independently selected from
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (I) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or
  • the method of its pharmaceutically acceptable salt comprises the following steps:
  • R 1 -R 5 , n, q and m are as defined in general formula (I).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or
  • the method of its pharmaceutically acceptable salt comprises the following steps:
  • R 1 -R 4 , R 10 -R 12 , q, u, w and m are as defined in general formula (II).
  • compositions comprising a therapeutically effective amount of the general formulae (I), (I-1), (I-2), (II), (II- 1), (II-2) and the compounds shown in Table A or their tautomers, racemates, enantiomers, diastereomers or their mixtures, or their pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to compounds of general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or their tautomers Use of isomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting PI3K ⁇ .
  • the present disclosure further relates to compounds of general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or their tautomers Forms of isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in preparation for the treatment and/or prevention of PI3K ⁇ -mediated Use in medicine for induced diseases.
  • the present disclosure further relates to compounds of general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or their tautomers Forms of isomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in preparation for the treatment and/or prevention of inflammatory diseases , use in medicines for autoimmune diseases, cancer and related diseases; in particular, the cancer and related diseases are preferably selected from the group consisting of melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, Colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer, prostate cancer, sperm Primary cell
  • the present disclosure also relates to a method of inhibiting PI3K ⁇ , comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), (I-1), (I-2), (II), (II-1), ( II-2) and Table A or the compounds shown or tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or Pharmaceutical compositions comprising the same.
  • the present disclosure also relates to a method of treating and/or preventing PI3K ⁇ -mediated diseases, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), (I-1), (I-2), (II) , (II-1), (II-2) and the compounds shown in Table A or their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure also relates to a method of treating and/or preventing inflammatory diseases, autoimmune diseases, cancer, and related diseases, comprising administering to a patient in need thereof a therapeutically effective amount of general formula (I), (I-1), ( I-2), (II), (II-1), (II-2) and the compounds shown in Table A or their tautomers, racemates, enantiomers, diastereomers Construct or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same;
  • the cancer and related diseases are preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer , gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureter
  • the present disclosure further relates to a compound represented by general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or its tautomerism
  • the present disclosure also relates to compounds of general formulae (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or their tautomers Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as PI3K ⁇ inhibitors.
  • the present disclosure also relates to compounds of general formulae (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or their tautomers Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for the treatment and/or prevention of PI3K ⁇ -mediated diseases .
  • the present disclosure also relates to compounds of general formulae (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or their tautomers Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of inflammatory diseases , autoimmune diseases, cancer and related diseases; the diseases are preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric oncology, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck Tumor, End
  • the PI3K ⁇ -mediated disease in the present disclosure is selected from inflammatory diseases, autoimmune diseases, cancer and related diseases; preferably, the cancer and related diseases are preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasal Pharyngeal cancer, stomach cancer, esophagus cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer , ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, neuroendocrine cancer, Brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma; the leukemia
  • the active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation.
  • the compounds of the present disclosure may also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compounds of the present disclosure are preferably presented in unit dosage form or in a form that the patient can self-administer in a single dose.
  • a unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.
  • Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils.
  • the oily suspensions may contain thickening agents.
  • the aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase can be vegetable oil, or mineral oil or a mixture thereof.
  • Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • a sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase.
  • the injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure.
  • a continuous intravenous drug delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions 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 in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used.
  • fatty acids are also available in the preparation of injectables.
  • the compounds of the present disclosure can 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 which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension.
  • These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
  • the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, the health of the patient condition, patient's behavior, patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, optimal treatment mode such as mode of treatment, daily dose of compound or type of pharmaceutically acceptable salt It can be verified according to the traditional treatment plan.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms (eg 1, 2, 3, 4, 5 or 6).
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, 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-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from the group consisting of D atoms, halogen, alkoxy, haloalkanes one of the group consisting of: group, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple substituents.
  • alkylene refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is a residue containing 1 straight or branched chain groups of up to 20 carbon atoms, preferably containing 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, More preferred are alkylene groups containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1- ethylene (-CH (CH 3) -) , 1,2- ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from alkenyl, alkynyl, alkoxy , haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents of cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkenyl refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy
  • the substituents of yl, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl are preferably one or more of the substituents of yl, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy One or more of the substituents of yl, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms Carbon atoms (eg 3, 4, 5, 6, 7 and 8), more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered polycyclic group having one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • spirocycloalkyl More preferably, it is 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicycloalkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include etc.; preferably
  • Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from halogen, alkyl, alkoxy, one of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple substituents.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy alkyl, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur,
  • the sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), but does not include ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • It preferably contains 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1-4 (eg 1, 2, 3 and 4) are heterocyclic atoms; more preferably contain 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8) of which 1-3 (eg 1, 2 and 3) are heteroatoms; more preferably contain 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1-3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur.
  • the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably 3-membered/5-membered, 3-membered/6-membered, 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:
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g. 7, 8, 9 or 10 yuan).
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the
  • the rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from halogen, alkyl, alkoxy, one of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple substituents.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :
  • Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from halo, alkyl, alkoxy, haloalkane one of the group consisting of: group, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple substituents.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms (e.g. 1, 2, 3 or 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
  • the heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from halogen, alkyl, alkoxy, one of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple substituents.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or by removing two hydrogen atoms from the same or two different ring atoms of the parent. Derived residues, ie "divalent cycloalkyl”, “divalent heterocyclyl”, “arylene”, “heteroarylene”.
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • cycloalkylalkyl refers to cycloalkyl-alkyl-, wherein cycloalkyl, alkyl are as defined above.
  • heterocyclylalkyl refers to heterocyclyl-alkyl-, wherein heterocyclyl, alkyl are as defined above.
  • arylalkyl refers to aryl-alkyl-, wherein aryl, alkyl are as defined above.
  • heteroarylalkyl refers to heteroaryl-alkyl-, wherein heteroaryl, alkyl are as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • thiol refers to -SH.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2.
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl, cycloalkyl are as defined above.
  • the compounds of the present disclosure may also include isotopic derivatives thereof.
  • isotopic derivatives refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms.
  • the present disclosure having the structure, except that "deuterium” or “tritium” in place of a hydrogen, fluorine or instead of fluorine-labeled with 18 F- (18 F isotope), or with 11 C- 13 C-, 14 C- or rich, Compounds in which a set of carbon ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) in place of carbon atoms are within the scope of this disclosure.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.
  • the present disclosure also includes compounds in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compounds.
  • deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in a group are independently of each other substituted by the corresponding number of substituents.
  • a person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, together with other components such as a physiological/pharmaceutically acceptable carrier and excipient.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient and thereby exert biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of compounds of the present disclosure that are safe and effective when used in mammals, and that possess the desired biological activity.
  • the salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia.
  • Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the term "therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • solvate refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. This physical bond includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated in the crystal lattice of the crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • Prodrug means a compound that can be transformed in vivo under physiological conditions, such as by hydrolysis in blood, to yield the active prodrug compound.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.
  • the compound represented by the general formula (I) of the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable salt preparation method including the following steps:
  • R 1 -R 5 , n, q and m are as defined in general formula (I).
  • R 1 -R 4 , R 10 -R 12 , q, u, w and m are as defined in general formula (II).
  • the general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable salt is subjected to chiral resolution to obtain the general formula Compounds of (I-1) and general formula (I-2) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable Salt;
  • R 1 -R 5 , n, q and m are as defined in general formula (I).
  • the general formula (II) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof are subjected to chiral resolution to obtain the general formula Compounds of (II-1) and general formula (II-2) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable Salt;
  • R 1 -R 4 , R 10 -R 12 , q, u, w and m are as defined in general formula (II).
  • the reagents that provide alkaline conditions in the above reaction include organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamine Lithium amide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, Sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine.
  • the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamine Lithium amide, potassium
  • the condensing agent described in the above reaction includes but is not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N , N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-Hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azabenzotriazole azole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 2-(7-benzotriazole)-N,N,N',N'-tetrazolium Methylurea hexa
  • the above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide , 1,4-dioxane, ethylene glycol dimethyl ether, water, toluene, xylene, pyridine, dioxane, N,N-dimethylacetamide or N,N-dimethylformamide and its mixture.
  • the solvent used includes but is not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sul
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS The determination of MS was performed with Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector) or THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.
  • HPLC preparations used Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.2mm, and the size of the TLC separation and purification products is 0.4mm -0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C-30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • compound 2b 51 g, 165.91 mmol was dissolved in 80 mL of methanol, and a solution of hydrogen chloride in 1,4-dioxane (350 mL, 4.0 M, from Yanfeng Technology) was added dropwise, and the temperature was naturally warmed to room temperature and stirred. The reaction was carried out for 17 hours. Concentration under reduced pressure gave the crude title compound 2c as the hydrochloride salt (45.4 g), which was used in the next reaction without purification.
  • 1,4-dioxane 350 mL, 4.0 M, from Yanfeng Technology
  • the reaction solution was concentrated under reduced pressure, 400 mL of water was added to the residue, extracted with dichloromethane (200 mL ⁇ 2), the pH of the aqueous phase was adjusted to about 2 with 5M hydrochloric acid solution, extracted with ethyl acetate (200 mL ⁇ 3), and the organic phases were combined with brine (200 mL ⁇ 2), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 3b (13.2 g). The product was directly carried out to the next step without purification.
  • the compound sodium ethoxide (19.267g, 56.62mmol, 20% content) was added to a 500mL single-neck flask, 300mL of a toluene solution of diethyl oxalate (6.207g, 42.47mmol) was added at 0°C, and 7-methoxythio was added Chroman-4-one 4a (5.5 g, 28.31 mmol, prepared by the method disclosed in "Organic Letters, 2020, 22(3), 1155-1159"), stirred at room temperature for 17 hours.
  • reaction solution was concentrated under reduced pressure, 400 mL of water was added to the residue, extracted with dichloromethane (200 mL ⁇ 2), the pH of the aqueous phase was adjusted to about 2 with 5M hydrochloric acid solution, extracted with ethyl acetate (200 mL ⁇ 3), and the organic phases were combined for Washed with brine (200 mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 4b (8.3 g).
  • reaction solution was concentrated under reduced pressure, 400 ml of water was added to the residue, and extracted with dichloromethane (200 mL ⁇ 2); the aqueous phase was adjusted to pH 2 with 5M hydrochloric acid solution, extracted with ethyl acetate (200 mL ⁇ 3), the organic phases were combined, and the Washed with saturated brine (200 mL ⁇ 2), dried over anhydrous sodium sulfate for 15 min, filtered, and the filtrate was spin-dried to obtain the title product 5d (24 g), yield: 99.0%.
  • reaction solution was concentrated, 200 mL of water was added to the reaction solution, the pH was adjusted to neutral with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (100 mL ⁇ 3), the organic phases were combined, washed with saturated brine (50 mL ⁇ 2), no Dry over aqueous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 6f (1.388 g, yield: 73.3%).
  • reaction solution was concentrated under reduced pressure, 80 mL of water was added to the residue, extracted with dichloromethane (80 mL ⁇ 2); the pH of the aqueous phase was adjusted to about 2 with 5M hydrochloric acid solution, extracted with ethyl acetate (70 mL ⁇ 3), the organic phases were combined, Washed with saturated brine (60 mL ⁇ 2), dried over anhydrous sodium sulfate for 15 min, filtered, and the filtrate was spin-dried to obtain the title product 7d (2.6 g), yield: 98.6%.
  • 2-(Trifluoromethyl)thiophenol 8a (10.4g, 58.3mmol, TCI) was dissolved in N,N-dimethylformamide (60mL), potassium carbonate (16.1g, 116.5mmol) was added, 60 °C was stirred for 30 minutes. After cooling, bromopropionic acid (9.8 g, 64.3 mmol) was added, and stirring was continued at 60° C. for 3 hours.
  • reaction solution was concentrated under reduced pressure, 300 mL of water was added to the residue, extracted with dichloromethane (100 mL ⁇ 2), the pH of the aqueous phase was adjusted to about 2 with 5M hydrochloric acid solution, extracted with ethyl acetate (100 mL ⁇ 3), and the organic phases were combined with brine (200 mL ⁇ 2), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 8d (9.1 g), which was directly put into the next step.
  • reaction solution was concentrated under reduced pressure, 400 mL of water was added to the residue, extracted with dichloromethane (200 mL ⁇ 2), the pH of the aqueous phase was adjusted to about 2 with 5M hydrochloric acid solution, extracted with ethyl acetate (200 mL ⁇ 3), and the organic phases were combined with brine (200 mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 9b (13.7 g), which was directly put into the next step without purification.
  • the crude compound 10b (8.94 g, 45.5 mmol) was dissolved in 100 mL of concentrated sulfuric acid and stirred at room temperature for 3 hours. The reaction solution was carefully poured into 500 g of ice water to quench, and the layers were separated. The aqueous phase was extracted with ethyl acetate (80 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by developing solvent system B to obtain the title compound 10c (5.17 g, yield: 63.7%).
  • the reaction solution was concentrated, 200 ml of water was added to quench the reaction, the pH was adjusted to neutrality with 3M saline solution, the aqueous phase was extracted with ethyl acetate (100 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed. Concentration gave the crude title compound 10e (7.87 g, yield: 97.5%), which was directly used in the next step without purification.
  • 3-Chloro-2-fluorothiophenol 11a (8g, 49.20mmol, Wuxi Kehua) was dissolved in 100mL of N,N-dimethylformamide, potassium carbonate (8.840g, 63.96mmol) was added, 60°C After stirring for 30 minutes, 3-bromopropionic acid (8.279 g, 54.12 mmol, Adamas) was added, and the reaction was stirred at 60° C. for 2 hours.
  • the crude compound 11b (11.116 g, 47.37 mmol) was dissolved in 100 mL of concentrated sulfuric acid and stirred at room temperature for 3 hours.
  • the reaction solution was carefully poured into 500 mL of ice water to quench, the aqueous phase was extracted with ethyl acetate (200 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 11c (8.731 g, yield : 85.1%), the product was directly used in the next reaction without purification.
  • the reaction solution was concentrated, 600 mL of water was added to quench the reaction, the pH was adjusted to about 3 with concentrated hydrochloric acid, the aqueous phase was extracted with ethyl acetate (250 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The crude title compound 11d was obtained (11.919 g, yield: 93.4%).
  • the crude compound 11f (16 g, 30.77 mmol) was dissolved in 250 mL of tetrahydrofuran, an aqueous sodium hydroxide solution (2.5 M, 62 mL) was added, and the mixture was stirred at room temperature for 4 hours.
  • the pH of the reaction solution was adjusted to about 3 with 3M hydrochloric acid, and concentrated under reduced pressure to obtain 11 g of the crude title product (15 g, yield: 99.1%).
  • the product was directly subjected to the next reaction without purification.
  • reaction was quenched by adding 50 mL of saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3), the organic phases were combined, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title product 11 ( 77.2 mg, yield: 23.3%).
  • the reaction solution was concentrated, 200 ml of water was added to quench the reaction, the pH was adjusted to neutrality with 3M saline solution, the aqueous phase was extracted with ethyl acetate (100 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed. Concentration gave the crude title compound 12a (3.66 g, yield: 69.56%), which was directly used in the next reaction without purification.
  • the crude compound 12c (1.35 g, 1.54 mmol) was dissolved in 15 mL of tetrahydrofuran, sodium hydroxide aqueous solution (2.5 M, 3 mL) was added, and the mixture was heated and stirred at 60° C. for 1 hour. After the reaction was cooled to room temperature, the pH was adjusted to neutrality with 3M hydrochloric acid, the organic solution was concentrated, and the remaining aqueous phase was lyophilized to obtain the crude title product 12d (2.2 g). The product was directly subjected to the next reaction without purification.
  • Test Example 1 Inhibitory activity and selectivity test of compounds of the present disclosure on PI3K ⁇ enzyme
  • the purpose of this experiment is to test the inhibitory effect and selectivity of the compound on the enzymatic activity of PI3K ⁇ , and to evaluate the in vitro activity of the compound according to the IC 50 size.
  • the ADP-Glo TM Kinase Assay Kit was used. Under the action of the enzyme, the substrate was phosphorylated and ADP was produced at the same time. ADP-Glo Reagent was added to remove the unreacted substances in the reaction system. ATP, Kinase detection reagent (Kinase detection reagent) detects the ADP produced by the reaction. The inhibition rate of the compound is calculated by measuring the signal value in the presence of the compound.
  • the test concentration of the test compound is 10000nM initial, 3-fold dilution, 11 concentrations, repeated well test. 11 different concentration solutions were serially diluted to 100-fold final concentration in 384-well plates. 50nL was transferred to compound wells of 384-well plate with Echo; 50nL of DMSO was added to negative and positive control wells, respectively. Kinase solution at 2x final concentration was prepared with 1x Kinase buffer. Add 2.5 ⁇ L of 2x final concentration of kinase solution to compound wells and positive control wells respectively; add 2.5 ⁇ L of 1 ⁇ kinase buffer to negative control wells. Centrifuge at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for 10 minutes.
  • a mixed solution of 2x final concentration of ATP and substrate P1P2 was prepared in 1x kinase buffer. The reaction was initiated by adding 2.5 ⁇ L of a mixed solution of 2x final concentration of ATP and substrate. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake and mix well, and react at room temperature for 120 minutes. Add 5 ⁇ L ADP-Glo reagent, centrifuge at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for 40 minutes. Add 10 ⁇ L of kinase detection reagent, centrifuge at 1000 rpm for 30 seconds, and incubate at room temperature for 30 minutes after shaking and mixing. The luminescence value RLU was read with an Envision microplate reader.
  • Compound B was prepared by the method disclosed in the patent "Example 339 on page 339 of the specification in CN102695710B".
  • the disclosed compounds have strong inhibitory activity and selectivity to PI3K ⁇ enzyme.
  • Test Example 2 Proliferation inhibition test of the compounds of the present disclosure on TMD-8 cells
  • the purpose of this experiment is to test the inhibitory effect of the compound on the proliferation activity of TMD-8 cells, and to evaluate the in vitro activity of the compound according to the IC 50 size.
  • ATP is an indicator of the metabolism of living cells.
  • the Luminescent Cell Viability Assay is a homogeneous assay for detecting the number of viable cells by quantifying ATP.
  • Fetal bovine serum (Gibco, 10099-141)
  • TMD-8 cell suspension to a 96-well cell culture plate, the number is 2000 cells/well, the medium is RPMI1640 with 10% FBS, and only 200 ⁇ L of RPMI1640 with 10% FBS is added to the periphery of the 96-well plate.
  • the plates were incubated in an incubator (37°C, 5% CO 2 ) for 24 hours.
  • the next day 20 ⁇ L of the formulated compounds at different concentrations (20 ⁇ M for the initial concentration, 3-fold dilution, 9 concentrations in total) were added to the culture plate.
  • the plates were incubated in an incubator for 6 d (37°C, 5% CO 2 ).
  • the inhibitory activity of the compounds of the present disclosure on the proliferation of TMD-8 cells can be determined by the above test, and the measured IC 50 values are shown in Table 2.
  • Table 2 discloses compounds TMD-8 cell proliferation inhibition IC 50

Abstract

La présente invention concerne un dérivé oxa-azabicyclique, son procédé de préparation et son utilisation médicale. En particulier, la présente invention concerne un dérivé oxa-azabicyclique représenté par la formule générale (I), un procédé de préparation de celui-ci, une composition pharmaceutique contenant le dérivé, et son utilisation en tant qu'agent thérapeutique, en particulier son utilisation en tant qu'inhibiteur de PI3Kδ et son utilisation dans la préparation d'un médicament pour le traitement d'états ou de symptômes améliorés par l'inhibition de PI3Kδ.
PCT/CN2021/105396 2020-07-09 2021-07-09 Dérivé oxa-azabicyclique, son procédé de préparation et son utilisation médicale WO2022007924A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102695710A (zh) * 2009-11-13 2012-09-26 默克雪兰诺有限公司 三环吡唑胺衍生物
WO2014121901A1 (fr) * 2013-02-07 2014-08-14 Merck Patent Gmbh Formes polymorphes
CN105473596A (zh) * 2013-06-24 2016-04-06 默克专利有限公司 用作卵泡刺激素受体调节剂的吡唑化合物及其用途
CN106573937A (zh) * 2014-06-23 2017-04-19 托口福药业 作为fshr调节剂的吡唑化合物及其用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102695710A (zh) * 2009-11-13 2012-09-26 默克雪兰诺有限公司 三环吡唑胺衍生物
WO2014121901A1 (fr) * 2013-02-07 2014-08-14 Merck Patent Gmbh Formes polymorphes
CN105473596A (zh) * 2013-06-24 2016-04-06 默克专利有限公司 用作卵泡刺激素受体调节剂的吡唑化合物及其用途
CN106573937A (zh) * 2014-06-23 2017-04-19 托口福药业 作为fshr调节剂的吡唑化合物及其用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HASELMAYER, P. ET AL.: "Characterization of Novel PI3KS Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies", FRONTIERS IN IMMUNOLOGY, vol. 5, 22 May 2014 (2014-05-22), XP055712279, ISSN: 1664-3224, DOI: 10.3389/fimmu.2014.00233 *

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