WO2022022630A1 - 氧杂氮杂螺环类衍生物、其制备方法及其在医药上的应用 - Google Patents

氧杂氮杂螺环类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2022022630A1
WO2022022630A1 PCT/CN2021/109205 CN2021109205W WO2022022630A1 WO 2022022630 A1 WO2022022630 A1 WO 2022022630A1 CN 2021109205 W CN2021109205 W CN 2021109205W WO 2022022630 A1 WO2022022630 A1 WO 2022022630A1
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alkyl
group
cancer
aryl
cycloalkyl
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PCT/CN2021/109205
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English (en)
French (fr)
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陆标
张蔡华
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 US18/007,166 priority Critical patent/US20230234962A1/en
Priority to CA3186193A priority patent/CA3186193A1/en
Priority to EP21851201.0A priority patent/EP4190789A1/en
Priority to CN202180046644.2A priority patent/CN115836077A/zh
Priority to JP2023505442A priority patent/JP2023536442A/ja
Publication of WO2022022630A1 publication Critical patent/WO2022022630A1/zh

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    • 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
    • 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 oxazaspirocyclic derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a Use of PI3K ⁇ inhibitors and in the manufacture of a medicament for the treatment of diseases or conditions 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-244 is a second-generation PI3K ⁇ inhibitor developed by iOnctura (WO2011058149, WO2014121901). Compared with traditional PI3K ⁇ inhibitors, it is an ATP non-competitive inhibitor, which makes this drug highly selective for the inhibition of PI3K ⁇ isoforms.
  • 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 Medicinal salts:
  • R 0 , R 1 , Ra , R b , R c , R d , Re and R f are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a halogen, an alkoxy group, a haloalkoxy group, a cyano radical, 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 selected from halogen, alkyl, haloalkyl, cyano, nitro substituted with one or more substituents in radical, -(CH 2 ) y NR g Rh and -OR 9 ; wherein, R
  • R' is the same or different, and is each independently selected from a hydrogen atom, an alkyl group, a halogen, an alkoxy group, a haloalkoxy group, a cyano group, a hydroxy group, a hydroxyalkyl group, -(CH 2 ) s NR 7 R 8 and a nitro group ;
  • R 5 is selected from hydrogen atom, alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group; said alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently optional is selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) y NR g Rh , -OR 9 , -COR 9 , -COOR 9 , -OS(O) t substituted by one or more substituents among R 9 , -S(O) t R 9 , -NR 6 COR 9 , -NR 6 SO 2 R 9 and R;
  • R is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, and said R is each independently optionally selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - ( CH2 ) yNRgRh , -OR9 , cycloalkyl, cycloalkylalkyl, hetero substituted with one or more substituents of cyclyl, heterocyclylalkyl, aryl and heteroaryl;
  • R 2 and R 4 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, cycloalkylalkyl , arylalkyl, heterocyclylalkyl and heteroarylalkyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl , haloalkyl, halogen, cyano, nitro, -(CH 2 ) y NR g Rh , -OR 9 , -COR 9 , -COOR 9 , -OS(O) t R 9 , -S(O) t substituted with one or more substituents in R 9 , -NR 6 COR 9 and -NR 6 SO 2 R 9 ;
  • R 3 is the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, haloalkyl, cyano, nitro, -(CH 2 ) s NR 7 R 8 , -OR i , -COR i , -COOR i , -OS (O) xRi , -S(O ) xRi , -NR6CORi , -NR6SO2Ri , cycloalkyl, heterocyclyl, aryl and heteroaryl ; wherein The alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, haloalkyl, halogen, cyano, nitro, -( CH2 ) yNR One of g Rh , -OR 9 , -COR 9 , -COOR 9 , -OS(O) t R 9 , -S(O
  • each of said cycloalkyl, heterocyclyl, aryl or heteroaryl groups independently optionally selected from the group consisting of hydrogen atom, alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and one or more substituents in heteroaryl;
  • R is selected from hydrogen atom, alkyl, cycloalkyl and aryl, wherein said alkyl, cycloalkyl and aryl are each independently optionally selected from alkyl, alkoxy, oxo, halogen , amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;
  • R 7 , R 8 , R g and Rh 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 heterocyclyl group, an aryl group, and a heteroaryl group;
  • R 7 and R 8 , R g and R h together with the attached nitrogen atom form a heterocyclyl group optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano substituted with one or more substituents in the group consisting of radical, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 9 and R i are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, -(CH 2 ) s NR 7 R 8 , ring Alkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy substituted with one or more of the substituents in group, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • n 1 or 2;
  • q 0, 1, 2, 3 or 4;
  • s and y are the same or different, each independently selected from 0, 1, 2, 3, 4 or 5;
  • t and x are the same or different and are each independently selected from 0, 1 or 2.
  • the present disclosure also aims to provide a compound represented by the general formula (I) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salts:
  • R a , R b , R c , R d , Re and R f are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a halogen, an alkoxy group, a haloalkoxy group, a cyano group, a hydroxyl group, a hydroxyalkane group radical, - ( CH2 ) sNR7R8 , cycloalkyl , cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl and heteroaryl wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, cyano, nitro, -(CH 2 ) substituted by one or more substituents in y NR g R h and -OR 9 ;
  • R 0 , R 1 together with the carbon atoms to which they are attached together form a spiro ring on the attached heterocycle, and the spiro ring is optionally substituted by one or more R';
  • R' is the same or different, and is each independently selected from a hydrogen atom, an alkyl group, a halogen, an alkoxy group, a haloalkoxy group, a cyano group, a hydroxy group, a hydroxyalkyl group, -(CH 2 ) s NR 7 R 8 and a nitro group ;
  • R 5 is selected from hydrogen atom, alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group; said alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently optional is selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) y NR g Rh , -OR 9 , -COR 9 , -COOR 9 , -OS(O) t substituted by one or more substituents among R 9 , -S(O) t R 9 , -NR 6 COR 9 , -NR 6 SO 2 R 9 and R;
  • R is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, and said R is each independently optionally selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - ( CH2 ) yNRgRh , -OR9 , cycloalkyl, cycloalkylalkyl, hetero substituted with one or more substituents of cyclyl, heterocyclylalkyl, aryl and heteroaryl;
  • R 2 and R 4 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, cycloalkylalkyl , arylalkyl, heterocyclylalkyl and heteroarylalkyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl , haloalkyl, halogen, cyano, nitro, -(CH 2 ) y NR g Rh , -OR 9 , -COR 9 , -COOR 9 , -OS(O) t R 9 , -S(O) t substituted with one or more substituents in R 9 , -NR 6 COR 9 and -NR 6 SO 2 R 9 ;
  • R 3 is the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, haloalkyl, cyano, nitro, -(CH 2 ) s NR 7 R 8 , -OR i , -COR i , -COOR i , -OS (O) xRi , -S(O ) xRi , -NR6CORi , -NR6SO2Ri , cycloalkyl, heterocyclyl, aryl and heteroaryl ; wherein The alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, haloalkyl, halogen, cyano, nitro, -( CH2 ) yNR One of g Rh , -OR 9 , -COR 9 , -COOR 9 , -OS(O) t R 9 , -S(O
  • each of said cycloalkyl, heterocyclyl, aryl or heteroaryl groups independently optionally selected from the group consisting of hydrogen atom, alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and one or more substituents in heteroaryl;
  • R is selected from hydrogen atom, alkyl, cycloalkyl and aryl, wherein said alkyl, cycloalkyl and aryl are each independently optionally selected from alkyl, alkoxy, oxo, halogen , amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;
  • R 7 , R 8 , R g and Rh 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 heterocyclyl group, an aryl group, and a heteroaryl group;
  • R 7 and R 8 , R g and R h together with the attached nitrogen atom form a heterocyclyl group optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano substituted with one or more substituents in the group consisting of radical, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 9 and R i are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, -(CH 2 ) s NR 7 R 8 , ring Alkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy substituted with one or more of the substituents in group, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • n 1 or 2;
  • q 0, 1, 2, 3 or 4;
  • s and y are the same or different, and are each independently selected from 0, 1, 2, 3, 4, or 5;
  • t and x are the same or different and are each independently selected from 0, 1 or 2.
  • a compound represented by general formula (I) or a tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof the compound represented by the general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof:
  • m 0, 1, 2 or 3;
  • R', Ra - Rf , R2 - R5 and q are as defined in general formula (I).
  • a compound represented by general formula (I) or (II) or its tautomer, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 5 is aryl or heteroaryl, and said aryl and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl , nitro, cyano, hydroxyalkyl, -(CH 2 ) y NR g Rh , -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;
  • R is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, and said R is each independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl and -OR ;
  • R 6 , R 9 , R g , Rh , y and t are as defined in general formula (I) or (II).
  • a compound represented by general formula (I) or (II) or its tautomer, racemate, enantiomer, diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 5 is an aryl group or a heteroaryl group, the aryl group and the heteroaryl group are each independently optionally substituted by R, and the R is selected from From cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, said Rs are each independently optionally substituted with one or more selected from halogen, alkyl and haloalkyl base substituted;
  • 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 a 6-10-membered aryl group, and the 6-10-membered aryl group is optionally substituted by a 3-8-membered heterocyclic C 1-6 alkyl group, and the 3-8-membered heterocyclic ring
  • the base C 1-6 alkyl is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 5 is phenyl substituted with morpholinylmethyl, even more preferably, R 5 is
  • 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 (III) or its tautomer, racemate, enantiomer, and diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • R 10 is the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) s NR 7 R 8 , -OR 9 , cycloalkane cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of alkyl, haloalkyl, alkoxy, substituted with one or more substituents of haloalkoxy, halogen, cyano, nitro and -(CH 2 ) y NR g R h ;
  • R 11 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, nitro, -(CH 2 ) y NR g R h , cycloalkyl, cycloalkyloxy and cycloalkylalkyl;
  • Each R 12 is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) y NR g Rh , -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 on the morpholine ring system;
  • w 0, 1, 2, 3, or 4;
  • u 0, 1, 2, 3, 4, 5 or 6;
  • R', Ra - Rh , R2 - R4, R7 - R9 , s, m, y and q are as defined in general formula (I) or (II).
  • a compound represented by general formula (I), (II) or (III) or its tautomer, racemate, enantiomer, Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof wherein R' is the same or different, and each is independently selected from a hydrogen atom, an alkyl group and a halogen; preferably, R' is the same or different, each independently selected from hydrogen atoms, C 1-6 alkyl groups and halogens; more preferably hydrogen atoms.
  • R 2 and R 4 are the same or different, and are each independently selected from hydrogen atoms, halogens, and C 1-6 alkyl groups; more preferably, both R 2 and R 4 are hydrogen atoms.
  • R 3 is the same or different, and each is independently selected from hydrogen atom, 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 a hydrogen atom, a halogen and a C 1-6 alkyl group; further preferably, it is fluorine.
  • a compound represented by general formula (I), (II) or (III) or its tautomer, racemate, enantiomer, An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R is selected from a hydrogen atom, an alkyl group, and a cycloalkyl group, wherein said alkyl group and cycloalkyl group are each independently optionally substituted by one or more substituents selected from alkyl, alkoxy, halogen, hydroxy and hydroxyalkyl; preferably, R 6 is a hydrogen atom or a C 1-6 alkyl group.
  • a compound represented by general formula (I), (II) or (III), or its tautomer, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R7 and R8 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, and a cycloalkyl group; or R 7 and R 8 together with the attached nitrogen atom form a heterocyclyl group optionally substituted with one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxyalkyl and cycloalkyl base substituted;
  • 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 represented by general formula (I), (II) or (III), or its tautomer, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 9 and R i are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a ring Alkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy substituted with one or more of the substituents in group, haloalkyl, cyano and amino;
  • R 9 and R i are the same or different, and are each independently selected from hydrogen atoms, alkyl groups, haloalkyl groups and cycloalkyl groups; wherein said alkyl groups and cycloalkyl groups are each independently optionally selected from halogen , substituted with one or more substituents in alkyl, alkoxy and haloalkyl;
  • R 9 and R i are the same or different, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group and a C 1-6 haloalkyl group.
  • R 10 are the same or different, and are each independently a hydrogen atom, a halogen and a C 1-6 alkyl group; more preferably a hydrogen atom.
  • R 11 is the same or different, and is each independently a hydrogen atom, a halogen and a C 1-6 alkyl group; more preferably a hydrogen atom.
  • R 12 are the same or different, and are each independently a hydrogen atom, a halogen and a C 1-6 alkyl group; more preferably a hydrogen atom.
  • R a to R f are the same or different, and each is independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl group; more preferably, both R a to R f are a hydrogen atom.
  • a compound represented by general formula (II) or (III) or its tautomer, racemate, enantiomer, diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein m is 0, 1 or 2, preferably 0 or 1, more preferably 0.
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising the steps of:
  • R 0 -R 5 , R a -R f , n and q are as defined in general formula (I).
  • Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising the steps of:
  • R', R2 - R5, Ra - Rf , m and q are as defined in general formula (II).
  • Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising the steps of:
  • R', R 2 -R 4 , Ra -R f , R 10 -R 12 , q, u, w and m are as defined in general formula (III).
  • compositions comprising a compound represented by the general formula (I), (II), (III) or Table A of the present disclosure, or a tautomer, exo A racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the present disclosure further relates to compounds represented by general formula (I), (II), (III) or Table A or tautomers, racemates, enantiomers, diastereomers, Use of the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same in the preparation of a medicament for inhibiting PI3K ⁇ .
  • the present disclosure further relates to compounds represented by general formula (I), (II), (III) or Table A or tautomers, racemates, enantiomers, diastereomers, or the use of a mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same in the preparation of a medicament for the treatment and/or prevention of inflammatory diseases, autoimmune diseases, cancer and related diseases; the described
  • the cancer is 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, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial
  • the present disclosure also relates to a method of inhibiting PI3K ⁇ , comprising administering to a patient in need thereof an inhibitory effective amount of a compound of general formula (I), (II), (III) or Table A or shown, or a tautomer thereof, A racemate, an enantiomer, a diastereomer, or a mixture 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 a PI3K ⁇ -mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I), (II), (III) or Table A or Its 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 inflammatory diseases, autoimmune diseases, cancer, and related diseases, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of formulas (I), (II), ( III) or a compound shown in Table A or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or containing
  • the pharmaceutical composition thereof; the cancer is preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric 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 cancer, prostate cancer, seminoma, testicular tumor,
  • the present disclosure further relates to a compound represented by general formula (I), (II), (III) or expression A or a tautomer, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
  • the present disclosure also relates to compounds of general formula (I), (II), (III) or Table A or tautomers, racemates, enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a PI3K ⁇ inhibitor.
  • the present disclosure also relates to compounds of general formula (I), (II), (III) or Table A or tautomers, racemates, enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the treatment and/or prevention of PI3K ⁇ -mediated diseases.
  • the present disclosure also relates to compounds of general formula (I), (II), (III) or Table A or tautomers, racemates, enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the treatment and/or prevention of inflammatory diseases, autoimmune diseases, cancer and related diseases;
  • the cancer is 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 oncology, 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, sarcom
  • 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 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, behavior of the patient, diet of the patient, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the optimal mode of treatment such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.
  • 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 and 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 groups include, but are not limited to, methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene ( -CH2) 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 (eg 3, 4, 5, 6, 7 and 8) carbon atoms, 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 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan or 6-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 to 4 (eg 1, 2, 3 and 4) are heterocyclic atom; more preferably contains 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8) of which 1-3 are heteroatoms (eg 1, 2 and 3); more preferably contains 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.
  • spiroheterocyclyl More preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan or 6-membered/6-membered mono-spiroheterocyclyl.
  • 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 (eg 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 groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 (eg 1, 2, 3 and 4) heteroatoms, 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”.
  • amino protecting group is used to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when the other part of the molecule is reacted.
  • Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • hydroxyl protecting group is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts) for hydroxyl protecting groups.
  • the hydroxyl protecting group can be a (C 1-10 alkyl or aryl) 3 silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl Silyl, tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 alkoxy substituted C 1-6 alkyl or phenyl substituted C 1-6 alkyl, most preferably C 1-4 alkoxy substituted C 1-4 alkyl, for example: methyl, tert-butyl, allyl, benzyl
  • arylalkyl refers to aryl-alkylene-, wherein aryl and alkylene are as defined above.
  • heteroarylalkyl refers to a heteroaryl-alkylene-, wherein heteroaryl and alkylene are as defined above.
  • cycloalkylalkyl refers to cycloalkyl-alkylene-, wherein cycloalkyl and alkylene are as defined above.
  • heterocyclylalkyl refers to heterocyclyl-alkylene-, wherein heterocyclyl and alkylene are as defined above.
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is 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 refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or or both and Two configurations.
  • 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. For example, having the structures of the present disclosure, except replacing hydrogen with “deuterium” or “tritium”, or replacing fluorine with an18F -fluorine label ( 18F isotope), or using11C- , 13C- , or14C -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 of Formula (I), (II), (III) or Table A in various deuterated forms.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • a person skilled in the art can refer to the relevant literature to synthesize a compound of formula (I), (II), (III) or Table A in deuterated form.
  • deuterated starting materials can be used in preparing deuterated forms of compounds of formula (I), (II), (III) or Table A, or they can be synthesized using conventional techniques using deuterated reagents including deuterated reagents But not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, 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 in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are 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, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salts” refers to salts of the 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.
  • 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.
  • R 0 -R 5 , R a -R f , n and q are as defined in general formula (I).
  • R', R2 - R5, Ra - Rf , m and q are as defined in general formula (II).
  • R', R 2 -R 4 , Ra -R f , R 10 -R 12 , q, u, w and m are as defined in general formula (III).
  • the reagents that the above-mentioned reaction provides alkaline conditions include organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, n-butyl base lithium, lithium diisopropylamide, 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 and/or 4- Dimethylaminopyridine; more preferably a combination of N,N-diisopropylethylamine and 4-dimethylaminopyridine.
  • 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, also known as N,N,N',N'-tetramethyl-O-(7-azabenzoyl) Triazol-1-yl
  • 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 used 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), 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 to 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: In the dichloromethane/methanol 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
  • reaction solution was concentrated under reduced pressure, 400 mL of water was added to the residue, extracted with dichloromethane (200 mL x 2), the pH of the aqueous phase was adjusted to about 2 with 5M HCl solution, extracted with ethyl acetate (250 mL x 3), the organic phases were combined, Washed with saturated saline solution (200 mL x 2), dried over anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain 1 g (22 g) of the crude title compound, which was used in the next reaction without purification.
  • 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 saturated 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 crude title compound 4b (8.3 g). The product was directly subjected to the next reaction without purification.
  • 2-Methoxythiophenol 5a (25.0g, 178.31mmol, Shaoyuan) and potassium carbonate (36.9g, 267.50mmol, Chinese medicine) were dissolved in 200mL N,N-dimethylformamide, under nitrogen atmosphere, Stir at 60°C for 30 minutes, cool to room temperature, add 3-bromopropionic acid (28.6 g, 187.28 mmol, Admass), and continue stirring at 60°C for 3 hours under nitrogen atmosphere.
  • 3-bromopropionic acid 28.6 g, 187.28 mmol, Admass
  • 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 and used Washed with saturated brine (60 mL ⁇ 2), dried over anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 5d (2.6 g), yield: 98.6%.
  • 2-Methylthiophenol 6a (25.0g, 201.2mmol, Shaoyuan) and potassium carbonate (41.7g, 301.9mmol) were dissolved in 200mL of N,N-dimethylformamide, and stirred at 60°C for 30 minutes under nitrogen atmosphere. minute. After cooling to room temperature, 3-bromopropionic acid (32.3 g, 211.4 mmol, Admass) was added, and stirring was continued at 60° C. for 3 hours under nitrogen atmosphere.
  • 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), the organic phases were combined and used Washed with saturated brine (200 mL ⁇ 2), dried over anhydrous sodium sulfate for 15 min, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 6d (24 g), yield: 99.0%.
  • 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 saturated 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 7b (13.7 g). The product was directly subjected to the next step without purification.
  • 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 saturated 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 crude title compound 8d (9.1 g), which was used in the next step without purification.
  • the crude compound 9b (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, the aqueous phase was extracted with ethyl acetate (80 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography.
  • the resulting residue was purified by developing solvent system B to obtain the title compound 9c (5.17 g, yield: 63.7%).
  • the reaction solution was concentrated under reduced pressure, 200 mL of water was added to quench the reaction, the pH was adjusted to neutrality with 3M aqueous hydrochloric acid, 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 Concentration under reduced pressure gave the crude title compound 9e (7.87 g, yield: 97.5%).
  • the crude compound 9 g (5 g, 10.38 mmol) was dissolved in 60 mL of tetrahydrofuran, sodium hydroxide aqueous solution (2.5 M, 10 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 solvent was removed under reduced pressure, and the remaining aqueous phase was lyophilized to obtain the crude title product 9h (9g). The product was directly subjected to 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, and stirred at 60°C After 30 minutes, 3-bromopropionic acid (8.279 g, 54.12 mmol) 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 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 (72.6 mg, yield: 23.6%).
  • the crude compound 9b (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, 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, the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography The resulting residue was purified by chromatography with developing solvent system B to give the title compound 12a (5.17 g, yield: 41.6%).
  • reaction solution was concentrated under reduced pressure, 200 ml of water was added to quench the reaction, the pH was adjusted to neutrality with 3M aqueous hydrochloric acid, 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 Concentration under reduced pressure gave the crude title compound 12b (3.66 g, yield: 69.56%), which was directly subjected to the next reaction without purification.
  • the crude compound 12d (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 solvent was removed under reduced pressure, and the remaining aqueous phase was lyophilized to obtain the crude title product 12e (2.2 g), which 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.
  • ADP-Glo TM Kinase Assay Kit was used in this experiment. 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 was 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. Transfer 50 nL of Echo to compound wells of a 384-well plate; add 50 nL of DMSO to negative control wells. 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; add 2.5 ⁇ L of 1 ⁇ kinase buffer (Kinase buffer) to negative control wells. Centrifuge at 1000 rpm for 30 seconds, and incubate at room temperature for 10 minutes after shaking and mixing.
  • a mixed solution of 2x final concentration of ATP and substrate P1P2 was prepared in 1 ⁇ 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 of ADP-Glo reagent, centrifuge at 1000 rpm for 30 seconds, and incubate at room temperature for 40 minutes after shaking and mixing. Add 10 ⁇ L of Kinase Detection Reagent (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.
  • IC50 values of compound inhibitory activity were calculated using Graphpad Prism software, and the results are shown in Table 1 below.

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Abstract

公开了一种氧杂氮杂螺环类衍生物、其制备方法及其在医药上的应用。具体而言，公开了一种通式(I)所示的氧杂氮杂螺环类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂的用途，特别是作为PI3Kδ抑制剂的用途和在制备用于治疗通过对PI3Kδ的抑制而改善的疾病或病症的药物中的用途。

Description

氧杂氮杂螺环类衍生物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种通式(I)所示的氧杂氮杂螺环类衍生物、其制备方法、含有该衍生物的药物组合物以及其作为治疗剂的用途，特别是作为PI3Kδ抑制剂的用途和在制备用于治疗通过对PI3Kδ的抑制而改善的疾病或病症的药物中的用途。
背景技术
磷脂酰肌醇3-激酶(phosphoinositide 3-kinase，PI3K)是PI3K/AKT/mTOR信号通路中的关键调节激酶，参与调控细胞的增殖、分化、凋亡以及血管生成等过程。PI3K异常激活与多种肿瘤的发生发展密切相关，不同类型的PI3K发挥着不同的功能。PI3K有四种亚型，分别是α、β、γ和δ，其中PI3Kδ主要存在于免疫细胞和血液细胞中，与免疫、血液肿瘤以及炎症的发生密切有关(Cell,170(4),605-635)。
PI3Kδ主要表达于免疫细胞和造血细胞中，参与B细胞中BCR的信号传导，控制机体内B细胞的发育和成熟过程。当有抗原刺激机体时，BCR表面的特异性表面免疫球蛋白Ig能与抗原结合，导致CD79A/B复合物胞内段的ITAM磷酸化，磷酸化的ITAM能够募集并激活SYK，并进一步激活BTK及其下游分子PLCγ2。活化的SYK能与PI3Kδ的P85亚基结合，激活PI3Kδ，促使生成PIP3，生成的PIP3能够与BTK的N端结构域识别，并与之相互作用介导BTK向膜上募集，从而激活BTK介导的B细胞信号传导，诱导众多相关基因的表达。另外，磷酸化的CD19也能募集细胞膜上PI3Kδ，激活PI3Kδ,催化PIP2生成PIP3，活化AKT，促进细胞增殖、迁移、凋亡等过程(N Engl J Med,379,2052-2062)。除了调节B细胞功能外，近期研究报道PI3Kδ激活能促进Treg细胞的发育、成熟以及募集(Cancer Immunol Res,2,1080-1089)。抑制PI3Kδ能促进CD8+记忆T细胞的增殖和存活(Cancer Res,77,4135-4145)。因此PI3Kδ是治疗B细胞淋巴瘤的一个理想靶点，开发选择性PI3Kδ抑制剂作为治疗血液肿瘤的药物越来越受重视。
艾代拉里斯(Idelalisib)是第一个获批上市的PI3Kδ选择性抑制剂，2014年被批准用于治疗慢性淋巴细胞白血病(CLL)、滤泡性淋巴瘤(FL)和小淋巴细胞性淋巴瘤(SLL)。随后2018年Duvelisib(作用于PI3Kδ和γ)被批准治疗慢性淋巴性白血病(CLL)和滤泡性淋巴瘤(FL)。尽管PI3Kδ抑制剂在治疗这些血液肿瘤上取得了非常不错的效果，但由于早期的这些抑制剂通常对于PI3K激酶的选择性比较差，因此在临床上看到了很多与药物相关的肝毒性及胃肠道毒副作用。为了进一步减低PI3Kδ抑制剂潜在的副作用，最近几年很多公司在积极开发了第二代高选择性PI3Kδ抑制剂，比较有代表性的有Parsaclisib、ME-401和IOA-244等，这些药物目前分别处于不同的临床阶段。
IOA-244是由iOnctura公司开发的第二代PI3Kδ抑制剂(WO2011058149，WO2014121901)。与传统的PI3Kδ抑制剂相比，它是一个ATP非竞争性的抑制剂，这个特点导致这个药物对于PI3Kδ亚型的抑制具有高度的选择性。
考虑到目前已上市的第一代PI3Kδ抑制剂的副作用都比较明显，限制了该类型药物在更多患者人群中的使用，所以开发第二代高选择性的PI3Kδ抑制剂在相关病患人群中存在重大未满足的医学需求。
目前相关专利申请包括WO2011058149A1、WO2015196759A1、WO2015196335A1、WO2014209980A1、WO2004069824A1等。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
Figure PCTCN2021109205-appb-000001
其中：
R 0、R 1、R a、R b、R c、R d、R e和R f相同或不同，且各自独立地选自氢原子、烷基、卤素、烷氧基、卤代烷氧基、氰基、羟基、羟烷基、-(CH 2) sNR 7R 8、环烷基、环烷基烷基、环烷基氧基、杂环基、杂环基烷基、杂环基氧基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、卤代烷基、氰基、硝基、-(CH 2) yNR gR h和-OR 9中的一个或多个取代基所取代；其中，R 0、R 1、R a、R b、R c、R d、R e和R f中至少有两个与共同连接的碳原子一起在所连杂环上形成螺环，所述螺环任选被一个或多个R’取代；
R’相同或不同，且各自独立地选自氢原子、烷基、卤素、烷氧基、卤代烷氧基、氰基、羟基、羟烷基、-(CH 2) sNR 7R 8和硝基；
R 5选自氢原子、烷基、环烷基、杂环基、芳基和杂芳基；所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、硝基、氰基、羟烷基、-(CH 2) yNR gR h、-OR 9、-COR 9、-COOR 9、-OS(O) tR 9、-S(O) tR 9、-NR 6COR 9、-NR 6SO 2R 9和R中的一个或多个取代基所取代；
所述的R选自环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基，所述的R各自独立地任选被选自卤素、烷基、卤代烷基、硝基、氰基、羟烷基、-(CH 2) yNR gR h、-OR 9、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基和杂芳基中的一个或多个取代基所取代；
R 2和R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷 氧基、环烷基、芳基、杂环基、杂芳基、环烷基烷基、芳基烷基、杂环基烷基和杂芳基烷基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自烷基、卤代烷基、卤素、氰基、硝基、-(CH 2) yNR gR h、-OR 9、-COR 9、-COOR 9、-OS(O) tR 9、-S(O) tR 9、-NR 6COR 9和-NR 6SO 2R 9中的一个或多个取代基所取代；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、氰基、硝基、-(CH 2) sNR 7R 8、-OR i、-COR i、-COOR i、-OS(O) xR i、-S(O) xR i、-NR 6COR i、-NR 6SO 2R i、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自烷基、卤代烷基、卤素、氰基、硝基、-(CH 2) yNR gR h、-OR 9、-COR 9、-COOR 9、-OS(O) tR 9、-S(O) tR 9、-NR 6COR 9和-NR 6SO 2R 9中的一个或多个取代基所取代；
或两个相邻的R 3与所连的碳原子一起形成环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自氢原子、烷基、卤素、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代；
R 6选自氢原子、烷基、环烷基和芳基，其中所述的烷基、环烷基和芳基各自独立地任选被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 7、R 8、R g和R h相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
或者R 7和R 8、R g和R h与相连的氮原子一起形成杂环基，所述的杂环基任选被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 9和R i相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、-(CH 2) sNR 7R 8、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基中的一个或多个取代基所取代；
n为1或2；
q为0、1、2、3或4；
s和y相同或不同，各自独立地选自0、1、2、3、4或5；且
t和x相同或不同，各自独立地选自0、1或2。
本公开的目的还在于提供一种通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
Figure PCTCN2021109205-appb-000002
其中：
R a、R b、R c、R d、R e和R f相同或不同，且各自独立地选自氢原子、烷基、卤素、烷氧基、卤代烷氧基、氰基、羟基、羟烷基、-(CH 2) sNR 7R 8、环烷基、环烷基烷基、环烷基氧基、杂环基、杂环基烷基、杂环基氧基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、卤代烷基、氰基、硝基、-(CH 2) yNR gR h和-OR 9中的一个或多个取代基所取代；
R 0、R 1与共同连接的碳原子一起在所连杂环上形成螺环，所述螺环任选被一个或多个R’取代；
R’相同或不同，且各自独立地选自氢原子、烷基、卤素、烷氧基、卤代烷氧基、氰基、羟基、羟烷基、-(CH 2) sNR 7R 8和硝基；
R 5选自氢原子、烷基、环烷基、杂环基、芳基和杂芳基；所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、硝基、氰基、羟烷基、-(CH 2) yNR gR h、-OR 9、-COR 9、-COOR 9、-OS(O) tR 9、-S(O) tR 9、-NR 6COR 9、-NR 6SO 2R 9和R中的一个或多个取代基所取代；
所述的R选自环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基，所述的R各自独立地任选被选自卤素、烷基、卤代烷基、硝基、氰基、羟烷基、-(CH 2) yNR gR h、-OR 9、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基和杂芳基中的一个或多个取代基所取代；
R 2和R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、环烷基、芳基、杂环基、杂芳基、环烷基烷基、芳基烷基、杂环基烷基和杂芳基烷基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自烷基、卤代烷基、卤素、氰基、硝基、-(CH 2) yNR gR h、-OR 9、-COR 9、-COOR 9、-OS(O) tR 9、-S(O) tR 9、-NR 6COR 9和-NR 6SO 2R 9中的一个或多个取代基所取代；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、氰基、硝基、-(CH 2) sNR 7R 8、-OR i、-COR i、-COOR i、-OS(O) xR i、-S(O) xR i、-NR 6COR i、-NR 6SO 2R i、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自烷基、卤代烷基、卤素、氰基、硝基、-(CH 2) yNR gR h、-OR 9、-COR 9、-COOR 9、-OS(O) tR 9、-S(O) tR 9、-NR 6COR 9和-NR 6SO 2R 9中的一个或多个取代基所取代；
或两个相邻的R 3与所连的碳原子一起形成环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自氢原子、烷基、 卤素、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代；
R 6选自氢原子、烷基、环烷基和芳基，其中所述的烷基、环烷基和芳基各自独立地任选被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 7、R 8、R g和R h相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
或者R 7和R 8、R g和R h与相连的氮原子一起形成杂环基，所述的杂环基任选被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 9和R i相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、-(CH 2) sNR 7R 8、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基中的一个或多个取代基所取代；
n为1或2；
q为0、1、2、3或4；
s和y相同或不同，且各自独立地选自0、1、2、3、4或5；且
t和x相同或不同，且各自独立地选自0、1或2。
在本公开的一些优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 0和R 1与所连的碳一起在所连杂环上形成螺环；优选地，形成螺3-6元环；更优选形成螺3-6元碳环；进一步优选形成螺环丙基。
在本公开的一些优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
Figure PCTCN2021109205-appb-000003
其中：m为0、1、2或3；
R’、R a-R f、R 2-R 5和q如通式(I)中所定义。
在本公开的一些优选的实施方案中，一种通式(I)或(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用 的盐，其中R 5为芳基或杂芳基，所述的芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、硝基、氰基、羟烷基、-(CH 2) yNR gR h、-OR 9、-COR 9、-COOR 9、-OS(O) tR 9、-S(O) tR 9、-NR 6COR 9、-NR 6SO 2R 9和R中的一个或多个取代基所取代；
所述的R选自环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基，所述的R各自独立地任选被选自卤素、烷基、卤代烷基和-OR 9中的一个或多个取代基所取代；
R 6、R 9、R g、R h、y和t如通式(I)或(II)中所定义。
在本公开的一些优选的实施方案中，一种通式(I)或(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 5为芳基或杂芳基，所述的芳基和杂芳基各自独立地任选被R所取代，所述的R选自环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基，所述的R各自独立地任选被选自卤素、烷基和卤代烷基中的一个或多个取代基所取代；
优选地，R 5为芳基，所述的芳基任选被杂环基烷基取代，所述的杂环基烷基任选被选自卤素、烷基和卤代烷基中的一个或多个取代基所取代；
进一步优选地，R 5为6-10元芳基，所述的6-10元芳基任选被3-8元杂环基C 1-6烷基取代，所述的3-8元杂环基C 1-6烷基任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个取代基所取代；
更优选地，R 5为苯基，所述的苯基被吗啉基甲基取代，甚至更优选地，R 5为
Figure PCTCN2021109205-appb-000004
在本公开的一些优选的实施方案中，一种通式(I)或(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
Figure PCTCN2021109205-appb-000005
其中：
R 10相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、硝基、氰基、羟烷基、-(CH 2) sNR 7R 8、-OR 9、环烷基、杂环基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氰基、硝基和-(CH 2) yNR gR h中的一个或多个取代基所 取代；
R 11相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、氰基、硝基、-(CH 2) yNR gR h、环烷基、环烷基氧基和环烷基烷基；
每个R 12相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、硝基、氰基、羟烷基、-(CH 2) yNR gR h、-OR 9、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基和杂芳基；当u大于等于2时，两个R 12可在吗啉环上形成螺环或桥环系统；
w为0、1、2、3或4；
u为0、1、2、3、4、5或6；
R’、R a-R h、R 2-R 4、R 7-R 9、s、m、y和q如通式(I)或(II)中所定义。
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R’相同或不同，且各自独立地选自氢原子、烷基和卤素；优选地，R’相同或不同，各自独立地选自氢原子、C 1-6烷基和卤素；更优选为氢原子。
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 2和R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、环烷基和环烷基烷基，其中所述的烷基和环烷基各自独立地任选地被选自烷基、卤代烷基、卤素、氰基和-OR 9中的一个或多个取代基所取代，R 9如通式(I)中所定义；
优选地，R 2和R 4相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；更优选地，R 2和R 4均为氢原子。
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、氰基、硝基、-(CH 2) sNR 7R 8和-OR i，R 7、R 8、R i、s如通式(I)中所定义；
优选地，R 3相同或不同，且各自独立地选自氢原子、卤素、卤代C 1-6烷基、C 1-6烷氧基和C 1-6烷基；
更优选地，R 3相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；进一步优选为氟。
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 6选自氢原子、烷基和环烷基，其中所述的烷基和环烷基各自独立地任选被选自烷基、烷氧基、卤素、羟基和羟烷基中的一个或多个取代基所取代；优选地，R 6为氢原子或C 1-6烷基。
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物、或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 7和R 8相同或不同，且各自独立地选自氢原子、烷基、卤代烷基和环烷基；或者R 7和R 8与相连的氮原子一起形成杂环基，所述的杂环基任选被选自烷基、烷氧基、卤素、羟烷基和环烷基中的一个或多个取代基所取代；
优选地，R 7和R 8相同或不同，且各自独立地选自氢原子、C 1-6烷基和C 1-6卤代烷基；或者R 7和R 8与相连的氮原子一起形成杂环基，所述的杂环基任选被选自C 1-6烷基、C 1-6烷氧基和卤素中的一个或多个取代基所取代。
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物、或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 9和R i相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、氰基和氨基中的一个或多个取代基所取代；
优选地，R 9和R i相同或不同，且各自独立地选自氢原子、烷基、卤代烷基和环烷基；其中所述的烷基和环烷基各自独立地任选被选自卤素、烷基、烷氧基和卤代烷基中的一个或多个取代基所取代；
更优选地，R 9和R i相同或不同，且各自独立地选自氢原子、C 1-6烷基和C 1-6卤代烷基。
在本公开的一些优选的实施方案中，一种通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 10相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、硝基、氰基、羟烷基、-(CH 2) sNR 7R 8和-OR 9，R 7、R 8、R 9和s如通式(III)中所定义；
优选地，R 10相同或不同，且各自独立地为氢原子、卤素和C 1-6烷基；更优选为氢原子。
在本公开的一些优选的实施方案中，一种通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 11相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、氰基和-(CH 2) yNR gR h，R g、R h和y如通式(III)中所定义；
优选地，R 11相同或不同，且各自独立地为氢原子、卤素和C 1-6烷基；更优选为氢原子。
在本公开的一些优选的实施方案中，一种通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 12相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、硝基、氰基、羟烷基、-(CH 2) yNR gR h和-OR 9，R 9、R g、R h和y如通式(III)中所定义；
优选地，R 12相同或不同，且各自独立地为氢原子、卤素和C 1-6烷基；更优选为氢原子。
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物、或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R a-R f相同或不同，且各自独立地选自氢原子、卤素、烷基、氰基、羟基和羟烷基；
优选地，R a-R f相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；更优选地，R a-R f均为氢原子。
在本公开的一些优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中n为1。
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中q为0、1、2或3，优选为1。
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中s和y相同或不同，且各自独立地选自0或1，优选为0。
在本公开的一些优选的实施方案中，一种通式(I)、(II)或(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中t和x相同或不同，且各自独立地选自0或2，优选为2。
在本公开的一些优选的实施方案中，一种通式(II)或(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中m为0、1或2，优选为0或1，更优选为0。
在本公开的一些优选的实施方案中，一种通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中u为0、1、2或3，优选为0或1，更优选为0。
在本公开的一些优选的实施方案中，一种通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中w为0、1或2，优选为0或1，更优选为0。
在本公开的一些优选的实施方案中，一种通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R’、R 10、R 12、R a、R b、R c、R d、R e和R f相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；m为0或1；w为0或1；u为0或1；R 11、R 2和R 4相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；R 3相同或不同，且各自独立地选自氢原子、卤素、卤代C 1-6烷基、C 1-6烷氧基和C 1-6烷基；且q为1。
表A本公开的典型化合物包括但不限于：
Figure PCTCN2021109205-appb-000006
Figure PCTCN2021109205-appb-000007
Figure PCTCN2021109205-appb-000008
本公开的另一方面涉及一种制备通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括以下步骤：
Figure PCTCN2021109205-appb-000009
通式(IA)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐与通式(IB)的化合物或其可药用的盐反应，得到通式(I)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，
其中R 0-R 5、R a-R f、n和q如通式(I)中所定义。
本公开的另一方面涉及一种制备通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括以下步骤：
Figure PCTCN2021109205-appb-000010
通式(IA)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐与通式(IIB)的化合物或其可药用的盐反应，得到通式(II)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，
其中R’、R 2-R 5、R a-R f、m和q如通式(II)中所定义。
本公开的另一方面涉及一种制备通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括以下步骤：
Figure PCTCN2021109205-appb-000011
通式(IIIA)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐与通式(IIB)或其可药用的盐反应，得到通式(III)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，
其中R’、R 2-R 4、R a-R f、R 10-R 12、q、u、w和m如通式(III)中所定义。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、(II)、(III)或表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(I)、(II)、(III)或表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或者包含其的药物组合物在制备用于抑制PI3Kδ的药物中的用途。
本公开进一步涉及通式(I)、(II)、(III)或表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或者包含其的药物组合物在制备用于治疗和/或预防炎性疾病、自身免疫性疾病、癌症及相关疾病的药物中的用途；所述的癌症优选选自黑色素瘤、皮肤癌、肝癌、肾癌、肺癌、鼻咽癌、胃癌、食道癌、结肠直肠癌、胆囊癌、胆管癌、绒毛膜上皮癌、胰腺癌、真性红细胞增多症、儿科肿瘤、宫颈癌、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、输尿管肿瘤、前列腺癌、精原细胞瘤、睾丸肿瘤、白血病、头颈瘤、子宫内膜癌、甲状腺癌、淋巴瘤、肉瘤、骨瘤、成神经细胞瘤、神经母细胞瘤、神经内分泌癌、脑瘤、CNS癌、骨髓瘤、星形细胞瘤、胶质母细胞瘤和胶质瘤(以上所述的瘤均为相应的恶性肿瘤)，所述的白血病优选选自慢性淋巴细胞白血病、急性淋巴细胞性白血病(ALL)、急性髓细胞样白血病(AML)、慢性髓细胞样白血病(CML)和毛细胞性白血病，所述的淋巴瘤优选选自小淋巴细胞淋巴瘤、边缘带淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、非霍奇金淋巴瘤(NHL)、淋巴质浆细胞淋巴瘤、 结外边缘区淋巴瘤、T细胞淋巴瘤、B细胞淋巴瘤和弥漫性大B细胞淋巴瘤，所述的肺癌优选为非小细胞肺癌或小细胞肺癌，所述的骨髓瘤优选为多发性骨髓瘤(MM)，所述的自身免疫性疾病优选选自哮喘、类风湿性关节炎、急性播散性脑脊髓炎(ADEM)、艾迪生病、斑秃、僵直性脊椎炎、抗磷脂抗体综合征(APS)、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性内耳疾病、天疱疮、类天疱疮、白塞病、乳糜泻、抗-谷氨酰胺转胺酶、查加斯病、慢性阻塞性肺病、克罗恩病、皮肌炎、1型糖尿病、子宫内膜异位、肺出血-肾炎综合征、格雷夫斯病、格林-巴利综合征(GBS)、桥本氏病、化脓性汗腺炎、川崎病、甲型球蛋白肾病变、免疫性血小板减少紫斑症、特发性血小板减少性紫癜(ITP)、间质性膀胱炎、狼疮、狼疮性肾炎、膜性肾病、混合性结缔组织疾病、硬斑病、多发性硬化病(MS)、重肌无力症、猝睡症、神经性肌强直、恶性贫血、牛皮癣、银屑病关节炎、多发性肌炎、原发性胆汁性肝硬化、精神分裂症、硬皮症、口眼干燥综合症、舍格伦综合征、僵人综合征、颞动脉炎、溃疡性结肠炎、血管炎、白斑和韦格纳肉芽肿，所述的狼疮优选为红斑性狼疮或系统性红斑狼疮，所述的天疱疮优选为寻常性天疱疮，所述肝癌优选为肝细胞癌，所述头颈瘤优选为头颈鳞状细胞癌，所述肉瘤优选为骨肉瘤或软组织肉瘤，所述结肠直肠癌优选为结肠癌或直肠癌。
本公开还涉及一种抑制PI3Kδ的方法，其包括给予所需患者抑制有效量的通式(I)、(II)、(III)或表A或所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或包含其的药物组合物。
本公开还涉及一种治疗和/或预防PI3Kδ介导的疾病的方法，其包括给予所需患者治疗有效量的通式(I)、(II)、(III)或表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，或包含其的药物组合物。
本公开还涉及一种治疗和/或预防炎性疾病、自身免疫性疾病、癌症及相关疾病的方法，其包括给予所需患者治疗或预防有效量的通式(I)、(II)、(III)或表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，或包含其的药物组合物；所述的癌症优选选自黑色素瘤、皮肤癌、肝癌、肾癌、肺癌、鼻咽癌、胃癌、食道癌、结肠直肠癌、胆囊癌、胆管癌、绒毛膜上皮癌、胰腺癌、真性红细胞增多症、儿科肿瘤、宫颈癌、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、输尿管肿瘤、前列腺癌、精原细胞瘤、睾丸肿瘤、白血病、头颈瘤、子宫内膜癌、甲状腺癌、淋巴瘤、肉瘤、骨瘤、成神经细胞瘤、神经母细胞瘤、神经内分泌癌、脑瘤、CNS癌、骨髓瘤、星形细胞瘤、胶质母细胞瘤和胶质瘤，所述的白血病优选选自慢性淋巴细胞白血病、急性淋巴细胞性白血病(ALL)、急性髓细胞样白血病(AML)、慢性髓细胞样白血病(CML)和毛细胞性白血病，所述的淋巴瘤优选选自小淋巴细胞淋巴瘤、边缘带淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、非霍奇金淋巴瘤(NHL)、淋巴质浆细胞淋巴瘤、结外 边缘区淋巴瘤、T细胞淋巴瘤、B细胞淋巴瘤和弥漫性大B细胞淋巴瘤，所述的肺癌优选为非小细胞肺癌或小细胞肺癌，所述的骨髓瘤优选为多发性骨髓瘤(MM)，所述的自身免疫性疾病优选选自哮喘、类风湿性关节炎、急性播散性脑脊髓炎(ADEM)、艾迪生病、斑秃、僵直性脊椎炎、抗磷脂抗体综合征(APS)、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性内耳疾病、天疱疮、类天疱疮、白塞病、乳糜泻、抗-谷氨酰胺转胺酶、查加斯病、慢性阻塞性肺病、克罗恩病、皮肌炎、1型糖尿病、子宫内膜异位、肺出血-肾炎综合征、格雷夫斯病、格林-巴利综合征(GBS)、桥本氏病、化脓性汗腺炎、川崎病、甲型球蛋白肾病变、免疫性血小板减少紫斑症、特发性血小板减少性紫癜(ITP)、间质性膀胱炎、狼疮、狼疮性肾炎、膜性肾病、混合性结缔组织疾病、硬斑病、多发性硬化病(MS)、重肌无力症、猝睡症、神经性肌强直、恶性贫血、牛皮癣、银屑病关节炎、多发性肌炎、原发性胆汁性肝硬化、精神分裂症、硬皮症、口眼干燥综合症、舍格伦综合征、僵人综合征、颞动脉炎、溃疡性结肠炎、血管炎、白斑和韦格纳肉芽肿，所述的狼疮优选为红斑性狼疮或系统性红斑狼疮，所述的天疱疮优选为寻常性天疱疮，所述肝癌优选为肝细胞癌，所述头颈瘤优选为头颈鳞状细胞癌，所述肉瘤优选为骨肉瘤或软组织肉瘤，所述结肠直肠癌优选为结肠癌或直肠癌。
本公开进一步涉及一种通式(I)、(II)、(III)或表A示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或者包含其的药物组合物，其用作药物。
本公开还涉及通式(I)、(II)、(III)或表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，或包含其的药物组合物，其用作PI3Kδ抑制剂。
本公开还涉及通式(I)、(II)、(III)或表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，或包含其的药物组合物，其用于治疗和/或预防PI3Kδ介导的疾病。
本公开还涉及通式(I)、(II)、(III)或表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，或包含其的药物组合物，其用于治疗和/或预防炎性疾病、自身免疫性疾病、癌症及相关疾病；所述的癌症优选选自黑色素瘤、皮肤癌、肝癌、肾癌、肺癌、鼻咽癌、胃癌、食道癌、结肠直肠癌、胆囊癌、胆管癌、绒毛膜上皮癌、胰腺癌、真性红细胞增多症、儿科肿瘤、宫颈癌、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、输尿管肿瘤、前列腺癌、精原细胞瘤、睾丸肿瘤、白血病、头颈瘤、子宫内膜癌、甲状腺癌、淋巴瘤、肉瘤、骨瘤、成神经细胞瘤、神经母细胞瘤、神经内分泌癌、脑瘤、CNS癌、骨髓瘤、星形细胞瘤、胶质母细胞瘤和胶质瘤，所述的白血病优选选自慢性淋巴细胞白血病、急性淋巴细胞性白血病(ALL)、急性髓细胞样白血病(AML)、慢性髓细胞样白血病(CML)和毛细胞性白血病，所述的淋巴瘤优选选自小 淋巴细胞淋巴瘤、边缘带淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、非霍奇金淋巴瘤(NHL)、淋巴质浆细胞淋巴瘤、结外边缘区淋巴瘤、T细胞淋巴瘤、B细胞淋巴瘤和弥漫性大B细胞淋巴瘤，所述的肺癌优选为非小细胞肺癌或小细胞肺癌，所述的骨髓瘤优选为多发性骨髓瘤(MM)，所述的自身免疫性疾病优选选自哮喘、类风湿性关节炎、急性播散性脑脊髓炎(ADEM)、艾迪生病、斑秃、僵直性脊椎炎、抗磷脂抗体综合征(APS)、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性内耳疾病、天疱疮、类天疱疮、白塞病、乳糜泻、抗-谷氨酰胺转胺酶、查加斯病、慢性阻塞性肺病、克罗恩病、皮肌炎、1型糖尿病、子宫内膜异位、肺出血-肾炎综合征、格雷夫斯病、格林-巴利综合征(GBS)、桥本氏病、化脓性汗腺炎、川崎病、甲型球蛋白肾病变、免疫性血小板减少紫斑症、特发性血小板减少性紫癜(ITP)、间质性膀胱炎、狼疮、狼疮性肾炎、膜性肾病、混合性结缔组织疾病、硬斑病、多发性硬化病(MS)、重肌无力症、猝睡症、神经性肌强直、恶性贫血、牛皮癣、银屑病关节炎、多发性肌炎、原发性胆汁性肝硬化、精神分裂症、硬皮症、口眼干燥综合症、舍格伦综合征、僵人综合征、颞动脉炎、溃疡性结肠炎、血管炎、白斑和韦格纳肉芽肿，所述的狼疮优选为红斑性狼疮或系统性红斑狼疮，所述的天疱疮优选为寻常性天疱疮，所述肝癌优选为肝细胞癌，所述头颈瘤优选为头颈鳞状细胞癌，所述肉瘤优选为骨肉瘤或软组织肉瘤，所述结肠直肠癌优选为结肠癌或直肠癌。
可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药、吸入或吹入给药的各种剂型。本公开的化合物也可以配制成例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆等剂型。
作为一般性指导，本公开活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油、或矿物油、或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、疾病的严重性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷基，更优选为含有1至6个碳原子(例如1、2、3、4、5和6个)的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“亚烷基”指饱和的直链或支链脂肪族烃基，其为从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子，更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自烯基、炔基、烷氧基、卤代烷氧基、环烷基氧基、杂环基氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基。
术语“烯基”指分子中含有至少一个碳碳双键的烷基化合物，其中烷基的定 义如上所述。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。
术语“炔基”指分子中含有至少一个碳碳三键的烷基化合物，其中烷基的定义如上所述。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，优选包含3至8个(例如3、4、5、6、7和8个)碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元，单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元或6元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2021109205-appb-000012
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元的双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2021109205-appb-000013
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2021109205-appb-000014
所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括
Figure PCTCN2021109205-appb-000015
等；优选为
Figure PCTCN2021109205-appb-000016
Figure PCTCN2021109205-appb-000017
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基和丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个(例如3、4、5、6、7、8、9、10、11和12个)环原子，其中1～4个(例如1、2、3和4个)是杂原子；更优选包含3至8个环原子(例如3、4、5、6、7和8个)，其中1-3是杂原子(例如1、2和3个)；更优选包含3至6个环原子，其中1-3个是杂原子；最优选包含5或6个环原子，其中1-3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2.3.6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元或6元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2021109205-appb-000018
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2021109205-appb-000019
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数 目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2021109205-appb-000020
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2021109205-appb-000021
等。
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2021109205-appb-000022
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“杂芳基”指包含1至4个(例如1、2、3和4个)杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、 6、7、8、9或10元)，更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、三唑基、四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021109205-appb-000023
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
上述环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或从母体的相同或两个不同的环原子上除去两个氢原子所衍生的残基，即“二价环烷基”、“二价杂环基”、“亚芳基”、“亚杂芳基”。
术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变，用易于脱去的基团对氨基进行保护。非限制性实施例包含(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。
术语“羟基保护基”是本领域已知的适当的用于羟基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例，优选地，所述的羟基保护基可以是(C 1-10烷基或芳基) 3硅烷基，例如：三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基等；可以是C 1-10烷基或取代烷基，优选烷氧基或芳基取代的烷基，更优选C 1-6烷氧基取代的C 1-6烷基或苯基取代的C 1-6烷基，最优选C 1-4烷氧基取代的C 1-4烷基，例如：甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、2-四氢吡喃基(THP)等；可以是(C 1-10烷基或芳香基)酰基，例如：甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等；可以是(C 1-6烷基或C 6-10芳基)磺酰基；也可以是(C 1-6 烷氧基或C 6-10芳基氧基)羰基。
术语“芳基烷基”指芳基-亚烷基-，其中芳基和亚烷基如上所定义。
术语“杂芳基烷基”指杂芳基-亚烷基-，其中杂芳基和亚烷基如上所定义。
术语“环烷基烷基”指环烷基-亚烷基-，其中环烷基和亚烷基如上所定义。
术语“杂环基烷基”指杂环基-亚烷基-，其中杂环基和亚烷基如上所定义。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。
术语“烷硫基”指烷基-S-，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“巯基”指-SH。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”指“＝O”。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如上所定义。
本公开所述化合物的化学结构中，键
Figure PCTCN2021109205-appb-000024
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2021109205-appb-000025
可以为
Figure PCTCN2021109205-appb-000026
或
Figure PCTCN2021109205-appb-000027
或者同时包含
Figure PCTCN2021109205-appb-000028
和
Figure PCTCN2021109205-appb-000029
两种构型。
本公开的化合物还可包含其同位素衍生物。术语“同位素衍生物”指结构不同仅在于存在一种或多种同位素富集原子的化合物。例如，具有本公开的结构，除了用“氘”或“氚”代替氢，或者用 18F-氟标记( 18F同位素)代替氟，或者用 11C-、 13C-、或者 14C-富集的碳( 11C-、 13C-、或者 14C-碳标记； 11C-、 13C-、或者 14C-同位素)代替碳原子的化合物处于本公开的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。
本公开还包括各种氘化形式的式(I)、(II)、(III)或表A化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献 合成氘化形式的式(I)、(II)、(III)或表A化合物。在制备氘代形式的式(I)、(II)、(III)或表A化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留与未氘代的化合物相当的活性，并且当氘代在某些特定位点时可以取得更好的代谢稳定性，从而获得某些治疗优势。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为1～5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用的盐”是指本公开化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备盐。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键的时，通常仅出于说明目的给出数字，而不是限制。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐制备方法，包括以下步骤：
Figure PCTCN2021109205-appb-000030
通式(IA)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐与通式(IB)的化合物或其可药用的盐(优选盐酸盐)在碱性条件下，任选缩合剂存在下，进行反应，得到通式(I)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，
其中R 0-R 5、R a-R f、n和q如通式(I)中所定义。
方案二
本公开通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐制备方法，包括以下步骤：
Figure PCTCN2021109205-appb-000031
通式(IA)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐与通式(IIB)的化合物或其可药用的盐(优选盐酸盐)在碱性条件下，任选缩合剂存在下进行反应，得到通式(II)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，
其中R’、R 2-R 5、R a-R f、m和q如通式(II)中所定义。
方案三
本公开通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐制备方法，包括以下步骤：
Figure PCTCN2021109205-appb-000032
通式(IIIA)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐与通式(IIB)的化合物或其可药用的盐(优选盐酸盐)在碱性条件下，任选缩合剂存在下进行反应，得到通式(III)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，
其中R’、R 2-R 4、R a-R f、R 10-R 12、q、u、w和m如通式(III)中所定义。
上述反应提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、4-二甲氨基吡啶、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠、叔丁醇钾或1,8-二氮杂二环十一碳-7-烯，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、醋酸钠、醋酸钾、碳酸钾或碳酸铯、氢氧化钠、氢氧化锂和氢氧化钾；优选为N,N-二异丙基乙胺和/或4-二甲氨基吡啶；更优选为N,N-二异丙基乙胺和4-二甲氨基吡啶的组合。
上述反应中所述的缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU，又称N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲，O-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷；优选为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和/或1-羟基苯并三唑，或单独HATU；更优选为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑的组合。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水、甲苯、二甲苯、吡啶、二噁烷、N,N-二甲基乙酰胺或N,N-二甲基甲酰胺及其混合物。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE NEO 500M核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯 甲烷/甲醇体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
(6-氟-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮1
Figure PCTCN2021109205-appb-000033
第一步
1-(4-(吗啉基甲基)苯基)肼-1-羧酸叔丁酯2b
在氩气氛下，将化合物4-(4-碘代苄基)吗啉2a(51g，168.24mmol，采用专利申请“WO200832191A2”中说明书第59页实施例17.1公开的方法制备而得)和肼基甲酸叔丁酯(23.347g，176.66mmol，韶远)溶解于400mL二甲亚砜中，搅拌10分钟，再加入碘化亚铜(1.603g，8.42mmol)，升温至50℃，搅拌反应17小时。加入400mL水，水相用乙酸乙酯(300mL×6)萃取，合并有机相，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物2b(51g，产率98.6％)。
MS m/z(ESI)：308.1[M+1]。
第二步
4-(4-肼基苄基)吗啉2c的盐酸盐
在0℃，将化合物2b(51g，165.91mmol)溶解于80mL甲醇中，滴加氯化氢的1,4-二氧六环溶液(350mL，4.0M，研峰科技)，自然升温至室温，搅拌反应17小时。减压浓缩，得到粗品标题化合物2c的盐酸盐(45.4g)，产品不经纯化直接用于下一步反应。
第三步
3-((2-氟苯基)硫基)丙酸1e
将2-氟苯硫酚1d(50g，390.11mmol，韶远)、碳酸钾(70g，507.14mmol,国药)溶于N,N-二甲基甲酰胺(500mL)中，60℃搅拌1小时，加入3-溴丙酸(65.6g，429.15mmol，韶远)，继续在60℃反应3小时。反应完成后，向反应液中加入1000mL水，乙酸乙酯萃取(300mL x 2)，水相用浓盐酸调节pH约等于3，乙酸乙酯萃取(400mL x 3)，合并有机相，依次用水(400mL x 3)、饱和食盐水溶液(400mL x 2)洗涤，用无水硫酸钠干燥15分钟，过滤，减压浓缩，得到粗品标题化合物1e(70g)，产品不经纯化直接用于下一步反应。
MS m/z(ESI)：198.9[M-1]。
第四步
8-氟硫代色烷-4-酮1f
将化合物1e(70g，356.65mmol)溶于浓硫酸(200mL)中，在0℃搅拌3小时，反应完成后，反应液倒入1000mL冰水中，乙酸乙酯萃取(400mL x 3)，合并有机相，用饱和食盐水溶液(400mL x 2)洗涤，无水硫酸钠干燥15分钟，过滤，滤液减压浓缩，得到粗品标题化合物1f(30g)，产品不经纯化直接用于下一步反应。
第五步
2-(8-氟-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯1g
将乙醇钠(52g，152.59mmol，20％w/w乙醇溶液，阿达马斯)加入到500mL三口烧瓶中，于0℃，缓慢滴加入草酸二乙酯(16.7g，114.47mmol，溶于100mL甲苯中，韶远)，随后缓慢滴加化合物1f(13.9g，76.28mmol，溶于100mL甲苯中)。反应液减压浓缩，残余物中加入400mL水，用二氯甲烷萃取(200mL x 2)，水相用5M HCl溶液调节pH约为2，用乙酸乙酯萃取(250mLx 3)，合并有机相，用饱和食盐水溶液(200mL x 2)洗涤，无水硫酸钠干燥15分钟，过滤，滤液减压浓缩，得到粗品标题化合物1g(22g)，产品不经纯化直接用于下一步反应。
MS m/z(ESI)：280.9[M-1]。
第六步
2-(8-氟-1,1-二氧化-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯1h
将化合物1g(22g，77.93mmol)溶解于250mL二氯甲烷中，冰浴冷却下分批加入间氯过氧苯甲酸(34.8g，171.46mmol，沃凯)，室温搅拌17小时。过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化 合物1h(24.5g，产率100％)。
MS m/z(ESI)：313.0[M-1]。
第七步
6-氟-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸乙酯5,5-二氧化物1i
将化合物1h(9.4g，29.90mmol)、化合物2c的盐酸盐(6.8g，75％)和冰乙酸(3.6g，59.94mmol，沪试)溶解于200mL无水乙醇中，升温至回流，搅拌3小时。加入300mL饱和碳酸氢钠溶液，混合液用乙酸乙酯(250mL×3)萃取，合并有机相，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物1i(7.5g，产率51.6％)。
MS m/z(ESI)：486.1[M+1]。
第八步
6-氟-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸5,5-二氧化物1a
将化合物1i(14g，29.07mmol)溶解于150mL四氢呋喃中，加入氢氧化钠水溶液(58.2mL，2M)，搅拌4小时。加入浓盐酸溶液，调节pH约等于3，减压浓缩，得到粗品标题化合物1a(21.2g)，产品不经纯化直接用于下一步反应。
MS m/z(ESI)：458.0[M+1]。
第九步
(6-氟-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮1
将化合物1a(100mg，218.59mmol)和4-氧杂-7-氮杂螺[2.5]辛烷盐酸盐(33mg，220.77mmol，江苏艾康)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(251mg，651.77mmol)、1-羟基苯并三唑(99mg，655.77mmol)、N,N-二异丙基乙胺(110mg，1.09mmol)、4-二甲氨基吡啶(53mg，437.18mmol)溶于二氯甲烷(30mL)中，室温搅拌16小时。加入50mL水，二氯甲烷和甲醇(v:v＝10:1)混合溶剂(60mL)萃取，合并有机相，依次用水(60mL)和饱和食盐水溶液(60mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物1(60mg,产率：49.6％)。
MS m/z(ESI)：553.3[M+1]。
1H NMR(500MHz,DMSO-d 6):δ7.62-7.44(m,6H),6.66(d,1H),4.99(d,2H),4.07(t,1H),3.90(s,1H),3.76-3.59(m,9H),3.32(s,1H),2.42(s,4H),0.73-0.60(m,4H)。
实施例2
(6-氯-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮2
Figure PCTCN2021109205-appb-000034
第一步
1-(4-(吗啉基甲基)苯基)肼-1-羧酸叔丁酯2b
在氩气氛下，将化合物4-(4-碘代苄基)吗啉2a(51g，168.24mmol，采用专利申请“WO200832191A2”中说明书第59页实施例17.1公开的方法制备而得)和肼基甲酸叔丁酯(23.347g，176.66mmol，韶远)溶解于400mL二甲亚砜中，搅拌10分钟，再加入碘化亚铜(1.603g，8.42mmol)，升温至50℃，搅拌反应17小时。加入400mL水，水相用乙酸乙酯(300mL×6)萃取，合并有机相，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物2b(51g，产率98.6％)。
MS m/z(ESI)：308.1[M+1]。
第二步
4-(4-肼基苄基)吗啉2c的盐酸盐
在0℃，将化合物2b(51g，165.91mmol)溶解于80mL甲醇中，滴加氯化氢的1,4-二氧六环溶液(350mL，4.0M，研峰科技)，自然升温至室温，搅拌反应17小时。减压浓缩，得到粗品标题化合物2c的盐酸盐(45.4g)，产品不经纯化直接用于下一步反应。
第三步
2-(8-氯-1,1-二氧化-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯2e
将化合物2-(8-氯-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯2d(25.7g，86.03mmol，采用专利“CN102695710B”中说明书第169页中间体E4公开的方法制备而得)溶解于250mL二氯甲烷中，冰浴冷却下分批加入间氯过氧苯甲酸(43.664g，215.07mmol)，室温搅拌17小时。过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物2e(28.323g，产率99.5％)。
MS m/z(ESI)：330.9[M+1]。
第四步
6-氯-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸乙酯5,5-二氧化物2f
将化合物2e(10g，30.24mmol)、化合物2c的盐酸盐(9.192g，75％)和冰乙酸(3.632g，60.48mmol，沪试)溶解于300mL无水乙醇中，升温至回流，搅拌3小时。加入300mL饱和碳酸氢钠溶液，混合液用乙酸乙酯(250mL×3)萃取，合并有机相，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物2f(10g，产率65.9％)。
MS m/z(ESI)：502.0[M+1]。
第五步
6-氯-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸5,5-二氧化物2g
将化合物2f(10g，19.92mmol)溶解于150mL四氢呋喃中，加入氢氧化钠水溶液(39.8mL，2.5M)，搅拌4小时。加入浓盐酸溶液，调节pH约等于3，减压浓缩，得到粗品标题化合物2g(17.028g)，产品不经纯化直接用于下一步反应。
MS m/z(ESI)：474.0[M+1]。
第六步
(6-氯-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮2
将化合物2g(544mg，633.61μmol，55.2％)、4-氧杂-7-氮杂螺[2.5]辛烷盐酸盐(97mg，648.32μmol，药石)、HATU(290mg，762.70μmol)和N,N-二异丙基乙胺(411mg，3.18mmol)溶解于60mL N,N-二甲基甲酰胺中，室温搅拌17小时。加入50mL饱和碳酸氢钠溶液，水相用乙酸乙酯(50mL×3)萃取，合并有机相，减压浓缩，所得残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物2(108mg，产率：30.0％)。
MS m/z(ESI)：569.0[M+1]。
1H NMR(500MHz,DMSO-d 6):δ7.66-7.64(m,1H),7.54-7.40(m,5H),6.83-6.81(m,1H),5.02-5.00(m,2H),4.08(s,1H),3.92(s,1H),3.75-3.58(m,10H),2.46-2.41(m,4H),0.73-0.61(m,4H)。
实施例3
(9-甲氧基-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮3
Figure PCTCN2021109205-appb-000035
第一步
5-甲氧基硫代色烷-4-酮3b
将3-(3-甲氧基苯基硫代)甲酸3a(12g，56.53mmol，采用“Organic Letters,2020,22(3),1155-1159”公开的方法制备而得)、硫酸(40mL)加入100mL单口瓶中，常温搅拌3小时。反应液倒入100mL冰水中，乙酸乙酯萃取(100mL×3)，有机相用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到目标产物3b(300mg，产率：2.73％)。
第二步
2-(5-甲氧基-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯3c
将乙醇钠(1.44g，4.23mmol，20％w/w乙醇溶液)溶于20mL甲苯中，冷却至0℃，滴加入草酸二乙酯(463mg，3.166mmol)的20mL甲苯溶液，再加入化合物3b(410mg，2.11mmol)，室温反应17小时。反应液减压浓缩，残余物中加入100mL水，二氯甲烷萃取(50mL)，水相用5M盐酸溶液调节pH约为2，乙酸乙酯萃取(50mL×3)，合并有机相用饱和食盐水(20mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到标题化合物3c(900mg)，产品不经纯化直接进行下一步反应。
第三步
2-(5-甲氧基-1,1-二氧化-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯3d
将粗品3c(900mg，3.058mmol)溶于30mL二氯甲烷中，加入3-氯过氧苯甲酸(1.2g，6.95mmol)，室温搅拌17小时。减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题化合物3d(550mg，产率：55.1％)。
第四步
9-甲氧基-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸乙酯5,5-二氧化物3e
将化合物3d(550mg，1.68mmol)溶于30mL乙醇中，加入化合物2c的盐酸盐(384mg)、冰乙酸(203mg，3.3804mmol)，反应在90℃搅拌2小时。减压浓缩，用乙醇打浆，过滤，滤饼干燥得标题产物3e(700mg)，产率：83.4％。
第五步
9-甲氧基-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸5,5-二氧化物3f
将化合物3e(10.2g，20.5mmol)溶于50mL四氢呋喃中，加入氢氧化钠水溶液(3M，2.8mL)，常温搅拌4小时。反应液用5.0M盐酸溶液调节pH约为2，减压浓缩，得到粗品标题产物3f(1g，60％纯度)，产品不经纯化直接用于下一步反应。
第六步
(9-甲氧基-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮3
将粗品化合物3f(300mg，332.26μmol，纯度60％)、4-氧杂-7-氮杂螺[2.5]辛烷盐酸盐(50mg，334.18μmol，药石)、HATU(152mg，399.76μmol)和N,N-二异丙基乙胺(215mg，1.66mmol)溶解于60mL N,N-二甲基甲酰胺中，室温搅拌17小时。加入50mL饱和碳酸氢钠溶液，水相用乙酸乙酯(50mL×3)萃取，合并有机相，减压浓缩，所得残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物3(40mg，产率：21.3％)。
MS m/z(ESI)：565.0[M+1]。
1H NMR(500MHz,CDCl 3)δ7.77-7.75(m,1H),7.59-7.56(m,1H),7.42-7.39(m,2H),7.35-7.33(m,1H),7.31-7.30(m,1H),7.03-7.01(m,1H),4.73-4.71(m,2H),4.33-4.32(m,1H),4.19(s,1H),3.89-3.82(m,3H),3.79-3.74(m,5H),3.57(s,2H),3.13(s,3H),2.50-2.48(m,4H),0.87-0.85(m,2H),0.74-0.72(m,2H)。
实施例4
(7-甲氧基-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮4
Figure PCTCN2021109205-appb-000036
Figure PCTCN2021109205-appb-000037
第一步
2-(7-甲氧基-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯4b
将乙醇钠(19.267g，56.62mmol,20％w/w乙醇溶液)加入500mL单口瓶中，于0℃加入草酸二乙酯(6.207g，42.47mmol)的甲苯溶液300mL，再加入7-甲氧基硫代色烷-4-酮4a(5.5g，28.31mmol，采用“Organic Letters,2020,22(3)，1155-1159”公开的方法制备而得)，常温搅拌17小时。反应液减压浓缩，残余物中加入400mL水，二氯甲烷萃取(200mL×2)，水相用5M盐酸溶液调节pH约为2，乙酸乙酯萃取(200mL×3)，合并有机相用饱和食盐水(200mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品标题化合物4b(8.3g)，产品不经纯化直接进行下一步反应。
第二步
2-(7-甲氧基-1,1-二氧化-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯4c
将粗品化合物4b(8.3g，28.20mmol)溶于200mL二氯甲烷中，冰浴冷却下分批加入间氯过氧苯甲酸(12.166g，70.50mmol)，常温搅拌17小时。过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题化合物4c(8.8g，产率：95.6％)。
第三步
7-甲氧基-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸乙酯5,5-二氧化物4d
将化合物4c(8.8g，26.96mmol)溶于200mL乙醇中，加入2c的盐酸盐(6.7g)、冰乙酸(3.239g，53.93mmol)，反应在90℃搅拌2小时。减压浓缩，用乙醇打浆，过滤，滤饼干燥得到标题产物4d(10.2g)，产率：76.0％。
第四步
7-甲氧基-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸5,5-二氧化物4e
将化合物4d(10.2g，20.5mmol)溶于100mL四氢呋喃中，加入氢氧化钠水溶液(1.0M，102.5mL)，常温搅拌4小时。反应液用5.0M盐酸溶液调节pH约为2，减压浓缩，得标题产物4e(16.3g，5纯度8.8％)。
第五步
(7-甲氧基-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮4
将化合物4e(300mg，332.26μmol，58.8％)、4-氧杂-7-氮杂螺[2.5]辛烷盐酸盐(50mg，334.18μmol，药石)、HATU(151mg，397.13μmol)和N,N-二异丙基乙胺(215mg，1.66mmol)溶解于5mL N,N-二甲基甲酰胺中，室温搅拌17小时。加入10mL饱和碳酸氢钠溶液，水相用乙酸乙酯(20mL×3)萃取，合并有机相，减压浓缩，所得残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物4(47mg)，产率：25.1％)。
MS m/z(ESI)：565.1[M+1]。
1H NMR(500MHz,CDCl 3)δ7.62-7.60(m,1H),7.53-7.49(m,2H),7.46-7.40(m,2H),7.07-6.89(m,1H),6.83-6.81(m,1H),4.76-4.75(m,2H),4.31-4.29(m,1H),4.18-4.16(m,1H),3.91-3.88(m,5H),3.83-3.78(m,6H),3.63-3.60(m,2H),2.54-2.51(m,4H),0.87-0.84(m,2H),0.72-0.68(m,2H)。
实施例5
(6-甲氧基-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮5
Figure PCTCN2021109205-appb-000038
第一步
3-((2-甲氧基苯基)硫代)丙酸5b
将2-甲氧基苯硫酚5a(25.0g，178.31mmol，韶远)和碳酸钾(36.9g，267.50mmol，国药)溶于200mL N,N-二甲基甲酰胺中，氮气氛下，60℃搅拌30分钟，冷却至室温，加入3-溴丙酸(28.6g，187.28mmol，阿德马斯)，继续在氮气氛下60℃搅拌3小时。反应液中加入1000mL水，乙酸乙酯萃取(300mL×2)，水相用浓盐酸调节pH约等于3，乙酸乙酯萃取(400mL×2)，合并有机相依次用水(400mL×2)、饱和食盐水(400mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到标题产物5b(37g)，产率：98％。
MS m/z(ESI)：213.1[M-1]。
第二步
8-甲氧基硫代色烷-4-酮5c
将化合物5b(37g,174.3mmol)溶于浓硫酸(200mL)中，0℃搅拌2小时。反应液倒入1000mL冰水中，乙酸乙酯萃取(300mL x 3)，有机相用饱和食盐水(300mLx 2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化得到标题产物5c(1.74g，产率：4.3％)。
MS m/z(ESI)：194.9[M+1]。
第三步
2-(8-甲氧基-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯5d
将乙醇钠(6.10g，17.92mmol，20％w/w乙醇溶液)加入100mL三口烧瓶中，0℃加入草酸二乙酯(1.97g，13.49mmol，溶于30mL甲苯中)和化合物5c(1.74g，8.95mmol，溶于30mL甲苯中)，室温反应16小时。反应液减压浓缩，残余物中加入80ml水，二氯甲烷萃取(80mL×2)，水相用5M盐酸溶液调节pH约为2，乙酸乙酯萃取(70mL×3)，合并有机相，用饱和食盐水(60mL×2)洗涤，再用无水硫酸钠干燥15分钟，过滤，滤液减压浓缩，得到标题产物5d(2.6g)，产率：98.6％。
MS m/z(ESI)：295.0[M+1]。
第四步
2-(8-甲氧基-1,1-二氧化-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯5e
将化合物5d(2.6g，8.83mmol)溶解于250mL二氯甲烷中，冰浴冷却下分批加入间氯过氧苯甲酸(3.9g，19.47mmol)，室温搅拌17小时。过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物5e(2.8g，产率97.1％)。
MS m/z(ESI)：326.9[M+1]。
第五步
6-甲氧基-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸乙酯5,5-二氧化物5f
将化合物5e(1.3g，3.98mmol)、化合物2c的盐酸盐(825.7mg)和冰乙酸(478.4m g，7.96mmol)溶解于60mL无水乙醇中，升温至回流，搅拌3小时。加入60mL饱和碳酸氢钠溶液，混合液用乙酸乙酯(80mL×3)萃取，合并有机相，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物5f(1.63g，产率82.2％)。
MS m/z(ESI)：498.0[M+1]。
第六步
6-甲氧基-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸5,5-二氧化物5g
将化合物5f(1.63g，3.27mmol)溶解于30mL四氢呋喃中，加入氢氧化钠水溶液(6.5mL，2.5M)，搅拌4小时。加入浓盐酸溶液，调节pH约等于3，减压浓缩，得到粗品标题化合物5g(2.4g，产率156.0％)，产品不经纯化直接用于下一步反应。
MS m/z(ESI)：470.0[M+1]。
第七步
(6-甲氧基-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮5
将粗品化合物5g(330mg，421.71μmol，60％纯度)、4-氧杂-7-氮杂螺[2.5]辛烷盐酸盐(63mg，421.74μmol，江苏艾康)和HATU(297.6mg，1.26mmol)溶解于30mL N,N-二甲基甲酰胺中，再加入N,N-二异丙基乙胺(326mg，2.53mmol)，搅拌反应2小时。加入60mL水淬灭反应，水相用乙酸乙酯(80mL×3)萃取，合并有机相，用饱和食盐水溶液洗涤(80mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物5(102mg，产率42.8％)。
MS m/z(ESI)：565.1[M+1]。
1H NMR(500MHz,DMSO-d 6):δ7.53-7.50(m,2H),7.45-7.37(m,3H),7.25(d,1H),6.39-6.37(m,1H),4.80(d,2H),4.07(m,2H),3.91(s,3H),3.74-3.57(m,9H),3.32(s,1H),2.41(t,4H),0.74-0.59(m,4H)。
实施例6
(6-甲基-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮6
Figure PCTCN2021109205-appb-000039
Figure PCTCN2021109205-appb-000040
第一步
3-(o-甲苯基硫代)丙酸6b
将2-甲基苯硫酚6a(25.0g，201.2mmol，韶远)和碳酸钾(41.7g，301.9mmol)溶于200mL N,N-二甲基甲酰胺中，氮气氛下60℃搅拌30分钟。冷却至室温，加入3-溴丙酸(32.3g，211.4mmol，阿德马斯)，继续在氮气氛下60℃搅拌3小时。反应液中加入1000mL水，乙酸乙酯萃取(300mL×2)，水相用浓盐酸调节pH约等于3，乙酸乙酯萃取(400mL×2)，合并有机相依次用水(400mL×2)、饱和食盐水(400mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到标题产物6b(39g)，产率：98％。
MS m/z(ESI)：195.2[M-1]。
第二步
8-甲基硫代色烷-4-酮6c
将化合物6b(39g，198.6mmol)溶于浓硫酸(200mL)中，0℃搅拌2小时。反应液倒入1000mL冰水中，乙酸乙酯萃取(300mL x 3)，有机相用饱和食盐水(300mLx2)洗涤，有机相用无水硫酸钠干燥，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化得到标题产物6c(15.5g，产率：43％)。
MS m/z(ESI)：178.9[M+1]。
第三步
2-(8-甲基-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯6d
将乙醇钠(59g，173.93mmol，20％w/w乙醇溶液)加入500mL三口烧瓶中，0℃加入草酸二乙酯(19g，130.49mmol，溶于100mL甲苯中)和化合物6c(15.5g，86.9mmol，溶于100mL甲苯中)，室温反应16小时。反应液减压浓缩，残余物中加入400mL水，二氯甲烷萃取(200mL×2)，水相用5M盐酸溶液调节pH约为2，乙酸乙酯萃取(200mL×3)，合并有机相，用饱和食盐水(200mL×2)洗涤，再用无水硫酸钠干燥15min，过滤，滤液减压浓缩，得到标题产物6d(24g)，产率：99.0％。
MS m/z(ESI)：279.0[M+1]。
第四步
2-(8-甲基-1,1-二氧化-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯6e
将化合物6d(24g，86.23mmol)溶解于250mL二氯甲烷中，冰浴冷却下分批加入间氯过氧苯甲酸(29g，172.5mmol)，室温搅拌17小时。过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物6e(26g，产率97.1％)。
MS m/z(ESI)：310.9[M+1]。
第五步
6-甲基-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸乙酯5,5-二氧化物6f
将化合物6e(15g，49.01mmol)、化合物2c的盐酸盐(10g)和冰乙酸(5.9g，98.11mmol)溶解于300mL无水乙醇中，升温至回流，搅拌3小时。加入300mL饱和碳酸氢钠溶液，混合液用乙酸乙酯(250mL×3)萃取，合并有机相，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物6f(20g，产率86.9％)。
MS m/z(ESI)：482.0[M+1]。
第六步
6-甲基-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸5,5-二氧化物6g
将化合物6f(14g，29.07mmol)溶解于150mL四氢呋喃中，加入氢氧化钠水溶液(58.2mL，2.5M)，搅拌4小时。加入浓盐酸溶液，调节pH约等于3，减压浓缩，得到粗品标题化合物6g(21.2g)，产品不经纯化直接用于下一步反应。
MS m/z(ESI)：454.0[M+1]。
第七步
(6-甲基-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮6
将化合物6g(250mg，330.75μmol)、4-氧杂-7-氮杂螺[2.5]辛烷盐酸盐(49.5mg，330.77μmol)和HATU(233.4mg，992.28μmol)溶解于30mL N,N-二甲基甲酰胺中，再加入N,N-二异丙基乙胺(256mg，1.98mmol)，搅拌反应2小时。加入60mL水淬灭反应，水相用乙酸乙酯(80mL×3)萃取，合并有机相，用饱和食盐水溶液洗涤(80mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物6(40mg，产率22％)。
MS m/z(ESI)：549.1[M+1]。
1H NMR(500MHz,DMSO-d 6):δ7.52-7.49(m,2H),7.42-7.35(m,4H),6.71-6.68(m,1H),4.89(d,2H),4.09(t,2H),3.92(s,3H),3.74-3.57(m,9H),3.29(s,1H),2.41(t, 4H),0.72-0.61(m,4H)。
实施例7
(7-氯-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮7
Figure PCTCN2021109205-appb-000041
第一步
2-(7-氯-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯7b
将乙醇钠(62.0g，182.2mmol，20％w/w乙醇溶液)加入500mL单口瓶中，于0℃加入草酸二乙酯(19.9g，136.2mmol)的甲苯溶液300mL，再加入7-氯硫代色烷-4-酮7a(18.0g,90.6mmol，采用“Organic Letters,2020,22(3),1155-1159”公开的方法制备而得)，常温搅拌17h。反应液减压浓缩，残余物中加入400mL水，二氯甲烷萃取(200mL×2)，水相用5M盐酸溶液调节pH约为2，乙酸乙酯萃取(200mL×3)，合并有机相用饱和食盐水(200mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到标题化合物7b(13.7g)，产品不经纯化直接进行下一步反应。
第二步
2-(7-氯-1,1-二氧化-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯7c
将粗品化合物7b(11.80g，36.15mmol)溶于150mL二氯甲烷中，加入3-氯过氧苯甲酸(17.2g，81.79mmol)，室温搅拌17小时。减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题化合物7c(12.3g)，产率：98.3％。
第三步
7-氯-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸乙酯5,5-二氧化物7d
将化合物7c(11.3g，33.6mmol)溶于80mL乙醇中，加入化合物2c的盐酸盐(9.0g)、冰乙酸(20mL)，反应在80℃搅拌2小时。减压浓缩，用乙醇打浆，过滤， 滤饼真空干燥得标题产物7d(13.9g)，产率：83.2％。
第四步
7-氯-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸5,5-二氧化物7e
将化合物7d(13.9g，28.3mmol)溶于100mL四氢呋喃中，加入氢氧化钠(3M，5.5mL)水溶液，室温搅拌16小时。反应液用5.0M盐酸溶液调节pH约为2，减压浓缩，得到标题产物7e(16.1g)，产品不经纯化直接用于下一步反应。
第五步
(7-氯-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮7
将粗品化合物7e(200mg，255.2μmol)、4-氧杂-7-氮杂螺[2.5]辛烷盐酸盐(49.5mg，330.77μmol)和HATU(233.4mg，992.28μmol)溶解于10mL N,N-二甲基甲酰胺中，再加入N,N-二异丙基乙胺(256mg，1.98mmol)，搅拌反应3小时。加入60mL水淬灭反应，水相用乙酸乙酯(80mL×3)萃取，合并有机相，用饱和食盐水溶液洗涤(80mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物7(55mg，产率32.7％)。
MS m/z(ESI)：569.1[M+1]。
1H NMR(500MHz,DMSO-d 6):δ8.00(s,1H),7.72(d,1H),7.61-7.47(m,4H),6.89(d,1H),4.94(d,2H),4.05(s,1H),3.90(s,1H),3.76-3.59(m,10H),2.42(brs,4H),0.68-0.64(m,4H)。
实施例8
(1-(4-(吗啉基甲基)苯基)-5,5-二氧化-6-(三氟甲基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮8
Figure PCTCN2021109205-appb-000042
Figure PCTCN2021109205-appb-000043
第一步
3-((2-(三氟甲基)苯基)硫代)丙酸8b
将化合物8a(10.4g，58.3mmol)溶于N,N-二甲基甲酰胺(60mL)中，加入碳酸钾(16.1g，116.5mmol)，60℃搅拌30分钟。冷却后，加入溴丙酸(9.8g，64.3mmol)，60℃继续搅拌3小时。冷却，倒入水中，2M盐酸调节至pH＝2，乙酸乙酯萃取三次，合并有机相，饱和食盐水溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题化合物8b(11.0g)，产率：75.3％。
第二步
8-(三氟甲基)硫代色烷-4-酮8c
将化合物8b(11.0g,46.5mmol)加入浓硫酸(150mL)中，室温搅拌3小时。反应液倒入冰水中，搅拌均匀。过滤，用水洗涤，固体溶于乙酸乙酯后，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体A纯化，得到标题化合物8c(8.0g)，产率：71.8％。
第三步
2-(8-(三氟甲基)-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯8d
将乙醇钠(23.5g，69.1mmol，20％w/w乙醇溶液)加入500mL单口瓶中，0℃加入草酸二乙酯(7.6g，51.7mmol)的甲苯溶液200mL，再加入化合物8c(8.0g，34.5mmol)，常温搅拌17h。反应液减压浓缩，残余物中加入300mL水，二氯甲烷萃取(100mL×2)，水相用5M盐酸溶液调节pH约为2，乙酸乙酯萃取(100mL×3)，合并有机相用饱和食盐水(200mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品标题化合物8d(9.1g)，产品不经纯化直接用于下一步。
第四步
2-(8-(三氟甲基)-1,1-二氧化-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯8e
将化合物8d(9.1g，27.2mmol)溶于150mL二氯甲烷中，加入3-氯过氧苯甲酸(11.6g，57.2mmol)，室温搅拌17小时。减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题化合物8e(9.8g)，产率：99.3％。
第五步
6-(三氟甲基)-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸乙酯5,5-二氧化物8f
将化合物8e(9.8g，26.9mmol)溶于80mL乙醇中，加入化合物2c的盐酸盐(7.0g)、冰乙酸(20mL)，反应在80℃搅拌2小时。减压浓缩，用乙醇打浆，过滤，滤饼干燥得标题产物8f(8.0g)，产率：55.5％。
第六步
6-(三氟甲基)-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-羧酸5,5-二氧化物8g
将化合物8f(8.0g，14.9mmol)溶于100mL四氢呋喃中，加入氢氧化钠(3M，5.5mL)水溶液，室温搅拌16小时。反应液用5.0M盐酸溶液调节pH约为2，减压浓缩，得到标题产物8g(10.5g，纯度70％)，产品不经纯化直接用于下一步反应。
第七步
(1-(4-(吗啉基甲基)苯基)-5,5-二氧化-6-(三氟甲基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮8
将粗品化合物8g(200mg，255.2μmol)、4-氧杂-7-氮杂螺[2.5]辛烷盐酸盐(49.5mg,330.77μmol)和HATU(233.4mg，992.28μmol)溶解于10mL N,N-二甲基甲酰胺中，再加入N,N-二异丙基乙胺(172.9mg，1.34mmol)，搅拌反应3小时。加入60mL水淬灭反应，水相用乙酸乙酯(50mL×3)萃取，合并有机相，用饱和食盐水溶液洗涤(80mL×2)，无水硫酸钠干燥。过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物8(60mg，产率37.2％)。
MS m/z(ESI)：603.1[M+1]。
1H NMR(500MHz,DMSO-d 6):δ8.01(d,1H),7.72(t,1H),7.52(t,2H),7.46-7.41(m,2H),7.19(d,1H),5.00(d,2H),4.11(s,1H),3.95(s,1H),3.75-3.52(m,10H),2.41(brs,4H),0.69-0.65(m,4H)。
实施例9
(7-甲基-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮9
Figure PCTCN2021109205-appb-000044
Figure PCTCN2021109205-appb-000045
第一步
3-(m-甲苯基硫代)丙酸9b
将3-甲基苯硫酚9a(10g，80.5mmol)溶于100mL的N,N-二甲基甲酰胺中，加入碳酸钾(16g，115.7mmol)，室温搅拌下加入3-溴丙酸，室温搅拌反应2小时。加500mL水淬灭，水相用乙酸乙酯(80mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物9b(8.94g，产率：56.5％)，产品不经纯化直接用于下一步反应。
MS m/z(ESI)：195.0[M-1]。
第二步
7-甲基硫代色烷-4-酮9c
将粗品化合物9b(8.94g，45.5mmol)溶于100mL的浓硫酸中，室温搅拌3小时。反应液小心倒入500g冰水淬灭，水相用乙酸乙酯(80mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用柱层析色谱法以展开剂体系B纯化所得残余物，得到标题化合物9c(5.17g，产率：63.7％)。
1H NMR(500MHz,CDCl 3)δ7.30(t,1H),7.20(d,1H),7.03(d,1H),3.27-3.21(m,2H),2.93-2.85(m,2H),2.49(s,3H)。
第三步
2-(7-甲基-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯9e
单口瓶中加入乙醇钠(20g，58.78mmol，20％w/w乙醇溶液)，冰浴冷却，再加入草酸二乙酯(4.5g，30.79mmol，溶于50mL甲苯)，搅拌下加入化合物9c(5.17g，29.00mmol，溶于50mL甲苯)，室温搅拌18小时。反应液减压浓缩，加入200mL水淬灭反应，用3M的盐酸水溶液调节pH至中性，水相用乙酸乙酯(100mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物9e(7.87g，产率：97.5％)。
MS m/z(ESI)：279.0[M+1]。
第四步
2-(7-甲基-1,1-二氧化-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯9f
将化合物9e(7.78g，28.28mmol)溶于240mL二氯甲烷中，冰浴冷却下分批加入间氯过氧苯甲酸(14g，68.96mmol)，室温搅拌3小时。过滤掉不溶物，滤液减压浓缩，残余物经柱层析色谱法以A体系纯化得标题化合物9f(6.88g，收率78.2％)。
MS m/z(ESI)：310.9[M+1]。
第五步
7-甲基-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-甲酸乙酯5,5-二氧化物9g
将化合物9f(6.88g，22.17mmol)和化合物2c的盐酸盐(4.5g，21.71mmol)溶于150mL的乙醇中，加入冰乙酸(2.5g，41.63mmol)，回流搅拌6小时。待反应液冷却至室温后，过滤出黄色固体，收集固体真空干燥，得粗品标题产物9g(14.7g)，产品不经纯化直接进行下一步反应。
MS m/z(ESI)：482.2[M+1]。
第六步
7-甲基-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-甲酸5,5-二氧化物9h
将粗品化合物9g(5g，10.38mmol)溶于60mL四氢呋喃中，加入氢氧化钠水溶液(2.5M，10mL)，60℃加热搅拌1小时。待反应冷却至室温后，用3M盐酸调节pH至中性，减压除去有机溶剂，剩余水相冻干，得粗品标题产物9h(9g)，产品不经纯化直接进行下一步反应。
MS m/z(ESI)：452.1[M-1]。
第七步
(7-甲基-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮9
将粗品化合物9h(200mg，0.22mmol)、4-氧杂-7-氮杂螺[2.5]辛烷盐酸盐(40mg，0.27mmol)和HATU(120mg,0.32mmol)溶解于5mL N,N-二甲基甲酰胺中，再加入N,N-二异丙基乙胺(100mg，0.77mmol，0.13mL)，搅拌反应2小时。加入150mL水淬灭反应，水相用乙酸乙酯(50mL×3)萃取，合并有机相，用饱和食盐水溶液洗涤(50mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法以洗脱剂体系A纯化得标题产物9(32mg，产率26.5％)。
MS m/z(ESI)：549.1[M+1]。
1H NMR(500MHz,DMSO-d 6)δ7.84(s,1H),7.54(t,2H),7.49(d,1H),7.45(d,1H),7.38(d,1H),6.73(d,1H),4.84(d,2H),4.10-4.03(m,1H),3.91(s,1H),3.73(d,2H),3.70-3.64(m,2H),3.64-3.56(m,6H),2.44-2.36(m,7H),0.75-0.66(m,2H), 0.66-0.58(m,2H)。
对照例10
(6-氟-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(7-氧杂-4-氮杂螺[2.5]辛-4-基)甲酮10
Figure PCTCN2021109205-appb-000046
将化合物1a和7-氧杂-4-氮杂螺[2.5]辛烷盐酸盐(33mg，220.77mmol，江苏艾康)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(251mg，651.77mmol)、1-羟基苯并三唑(99mg，655.77mmol)、N,N-二异丙基乙胺(110mg，1.09mmol)、4-二甲氨基吡啶(53mg，437.18mmol)溶于二氯甲烷(30mL)中，室温搅拌16小时。加入50mL水，二氯甲烷和甲醇(V:V＝10:1)混合溶剂(60mL)萃取，合并有机相，依次用水(60mL)和饱和食盐水溶液(60mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物10(25mg，产率：20.6％)。
MS m/z(ESI)：553.3[M+1]。
1H NMR(500MHz,DMSO-d 6):δ7.60-7.44(m,6H),6.65(d,1H),4.95(d,2H),3.99-3.56(m,9H),2.41(s,4H),1.27-0.72(m,7H)。
实施例11
(7-氯-6-氟-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮11
Figure PCTCN2021109205-appb-000047
Figure PCTCN2021109205-appb-000048
第一步
3-((3-氯-2-氟代苯基)硫代)丙酸11b
将3-氯-2氟苯硫酚11a(8g，49.20mmol，无锡科华)溶于100mL的N,N-二甲基甲酰胺中，加入碳酸钾(8.840g，63.96mmol)，60℃搅拌30分钟，加入3-溴丙酸(8.279g，54.12mmol)，60℃搅拌反应2小时。加500mL水淬灭，用乙酸乙酯(200mL×1)萃取，水相用浓盐酸调节pH约等于3，水相再用乙酸乙酯(300mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物11b(11.166g，产率：96.7％)，产品不经纯化直接用于下一步反应。
第二步
7-氯-8-氟硫代色烷-4-酮11c
将粗品化合物11b(11.116g，47.37mmol)溶于100mL的浓硫酸中，室温搅拌3小时。反应液小心倒入500mL冰水淬灭，水相用乙酸乙酯(200mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到标题化合物11c(8.731g，产率：85.1％)，产品不经纯化直接用于下一步反应。
第三步
2-(7-氯-8-氟-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯11d
单口瓶中加入乙醇钠(27.423g，80.60mmol，20％w/w乙醇溶液，TCI)和125mL甲苯，冰浴冷却，再加入草酸二乙酯(8.834g，60.45mmol)，搅拌下加入粗品化合物11c(8.731g，40.30mmol)，室温搅拌17小时。反应液减压浓缩，加入600mL水淬灭反应，用浓盐酸调节pH约为3，水相用乙酸乙酯(250mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物11d(11.919g，产率：93.4％)。
MS m/z(ESI)：316.9[M+1]。
第四步
2-(7-氯-8-氟-1,1-二氧化-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯11e
将化合物11d(11.919g，37.63mmol)溶于130mL二氯甲烷中，冰浴冷却下分批加入间氯过氧苯甲酸(19.100g，94.08mmol)，室温搅拌17小时。过滤掉不溶物，滤液浓缩，残余物经柱层析色谱法以A体系纯化得标题化合物11e(11.5g，收率：87.6％)。
MS m/z(ESI)：347.0[M-1]。
第五步
7-氯-6-氟-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-甲酸乙酯5,5-二氧化物11f
将化合物11e(11.5g，32.98mmol)和化合物2c的盐酸盐(10.024g)溶于250mL的乙醇中，加入冰乙酸(3.961g，65.96mmol)，回流搅拌3小时。反应液中加入300mL饱和碳酸氢钠溶液，用乙酸乙酯(250mL×4)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物11f(16g，收率：93.3％)，产品不经纯化直接进行下一步反应。
MS m/z(ESI)：520.0[M+1]。
第六步
7-氯-6-氟-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-甲酸5,5-二氧化物11g
将粗品化合物11f(16g，30.77mmol)溶于250mL四氢呋喃中，加入氢氧化钠水溶液(2.5M，62mL)，室温搅拌4小时。反应液用3M盐酸调节pH约为3，减压浓缩得粗品标题产物11g(15g，收率：99.1％)，产品不经纯化直接进行下一步反应。
MS m/z(ESI)：491.9[M+1]。
第七步
(7-氯-6-氟-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮11
将粗品化合物11g(506mg，0.52mmol)、4-氧杂-7-氮杂螺[2.5]辛烷盐酸盐(80mg，0.53mmol)和HATU(240mg,0.63mmol)溶解于25mL N,N-二甲基甲酰胺中，再加入N,N-二异丙基乙胺(340mg，2.63mmol)，搅拌反应17小时。加入50mL饱和碳酸氢钠溶液淬灭反应，水相用乙酸乙酯(50mL×3)萃取，合并有机相，滤液减压浓缩，用硅胶柱层析色谱法以洗脱剂体系A纯化得标题产物11(72.6mg，产率：23.6％)。
MS m/z(ESI)：587.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ7.85(s,1H),7.53-7.46(m,4H),6.68-6.66(m,1H),5.05-5.03(m,2H),4.06-3.47(m,12H),2.50-2.42(m,4H),0.73-0.60(m,4H)。
实施例12
(9-甲基-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮12
Figure PCTCN2021109205-appb-000049
第一步
5-甲基硫代色烷-4-酮12a
将粗品化合物9b(8.94g，45.5mmol)溶于100mL的浓硫酸中，室温搅拌3小时。反应液小心倒入500g冰水淬灭，分液，水相用乙酸乙酯(80mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用柱层析色谱法以展开剂体系B纯化所得残余物，得到标题化合物12a(5.17g，产率：41.6％)。
1H NMR(500MHz,CDCl 3)δ7.30(t,1H),7.20(d,1H),7.03(d,1H),3.27-3.21(m,2H),2.93-2.85(m,2H),2.49(s,3H)。
第二步
2-(5-甲基-4-氧代硫代色烷-3-基)-2-氧代乙酸乙酯12b
单口瓶中加入乙醇钠(13g，38.21mmol，20％w/w乙醇溶液)，冰浴冷却，再加入草酸二乙酯(3.0g，20.53mmol，溶于50mL甲苯)，搅拌下加入化合物12a(3.38g，18.93mmol，溶于50mL甲苯)，室温搅拌18小时。反应液减压浓缩，加入200ml水淬灭反应，用3M的盐酸水溶液调节pH至中性，水相用乙酸乙酯(100mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物12b(3.66g，产率：69.56％)，产品不经纯化直接进行下一步反应。
MS m/z(ESI)：279.0[M+1]。
第三步
2-(5-甲基-1,1-二氧化-4-氧代硫代色烷-3-基)-2氧代乙酸乙酯12c
将化合物12b(3.66g，13.17mmol)溶于50mL二氯甲烷中，冰浴冷却下分批加入间氯过氧苯甲酸(6g，29.55mmol，含量85％)，室温搅拌3小时。过滤掉不溶物，滤液减压浓缩，残余物经柱层析色谱法以A体系纯化得粗品标题化合物12c(7.3g，粗品)。
MS m/z(ESI)：310.9[M+1]。
第四步
9-甲基-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-甲酸乙酯5,5-二氧化物12d
将粗品化合物12c(7.3g，12.94mmol)和化合物2c的盐酸盐(3.6g)溶于50mL的乙醇中，加入冰乙酸(1.5g，24.98mmol)，回流搅拌6小时。待反应液冷却至室温后，过滤，收集滤饼真空干燥，得到标题产物12d(6.8g)，产品不经纯化直接进行下一步反应。
MS m/z(ESI)：482.2[M+1]。
第五步
9-甲基-1-(4-(吗啉基甲基)苯基)-1,4-二氢硫代色烯并[4,3-c]吡唑-3-甲酸5,5-二氧化物12e
将粗品化合物12d(1.35g，1.54mmol)溶于15mL四氢呋喃中，加入氢氧化钠水溶液(2.5M，3mL)，60℃加热搅拌1小时。待反应冷却至室温后，用3M盐酸调节pH至中性，减压除去有机溶剂，剩余水相冻干，得到粗品标题产物12e(2.2g)，产品不经纯化直接进行下一步反应。
MS m/z(ESI)：452.1[M-1]。
第六步
(9-甲基-1-(4-(吗啉基甲基)苯基)-5,5-二氧化-1,4-二氢硫代色烯并[4,3-c]吡唑-3-基)(4-氧杂-7-氮杂螺[2.5]辛-7-基)甲酮12
硫代将粗品化合物12e(200mg，0.22mmol)、4-氧杂-7-氮杂螺[2.5]辛烷盐酸盐(45mg，0.30mmol)和HATU(150mg,0.40mmol)溶解于5mL N,N-二甲基甲酰胺中，再加入N,N-二异丙基乙胺(150mg,1.16mmol,0.19mL)，搅拌反应2小时。加入150mL水淬灭反应，水相用乙酸乙酯(50mL×3)萃取，合并有机相，用饱和食盐水溶液洗涤(50mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法以洗脱剂体系A纯化得标题产物12(62mg，产率43.7％)。
MS m/z(ESI)：549.1[M+H]。
1H NMR(500MHz,DMSO-d 6)δ7.89(d,1H),7.64(t,1H),7.53(d,1H),7.45(t,2H),7.27(d,2H),4.79(s,2H),4.06(t,1H),3.93(s,1H),3.79-3.47(m,9H),3.29(s,1H),2.37(s,4H),1.61(d,3H),0.75-0.52(m,4H)。
测试例：
生物学评价
测试例1、本公开化合物对PI3Kδ酶的抑制活性和选择性测试
一、实验目的
本实验的目的是为了测试化合物对PI3Kδ酶学活性的抑制作用和选择性，根据IC 50大小评价化合物的体外活性。
二、实验原理
本实验使用ADP-Glo TM激酶检测试剂盒(Kinase Assay Kit)，在酶的作用下，底物被磷酸化同时产生ADP，加入ADP-Glo试剂(ADP-Glo Reagent)除去反应体系中未反应的ATP，激酶检测试剂(Kinase detection reagent)检测反应产生的ADP。在化合物存在的条件下，通过测量信号值算出化合物的抑制率。
三、实验材料
1、仪器
仪器名称 供货公司 型号
离心机 Eppendorf 5430
酶标仪 Perkin Elmer Envision，SN.1050214
Echo 550 Labcyte Echo 550
2、试剂和耗材
试剂名称 供货公司 货号
PIK3CD/PIK3R1 Carna 11-103
PI103 selleckchem S1038
DMSO Sigma D8418-1L
384-孔白色板 PerkinElmer 6007290
四、实验方法
受试化合物测试浓度为10000nM起始，3倍稀释，11个浓度，复孔测试。在384孔板中梯度稀释成100倍终浓度的11个不同浓度的溶液。用Echo转移50nL到384孔板的化合物孔；阴性对照孔加50nL的DMSO。用1×激酶缓冲液(Kinase buffer)配制2倍终浓度的激酶溶液。在化合物孔加2.5μL的2倍终浓度的激酶溶液；在阴性对照孔中加2.5μL的1×激酶缓冲液(Kinase buffer)。1000rpm离心30秒，振荡混匀后室温孵育10分钟。用1×激酶缓冲液(Kinase buffer)配制2倍终浓度的ATP和底物P1P2的混合溶液。加入2.5μL的2倍终浓度的ATP和底物的混合溶液，起始反应。将384孔板1000rpm离心30秒，振荡混匀后室温反应120分钟。加入5μL ADP-Glo试剂，1000rpm离心30秒，振荡混匀后室温孵育40分钟。加入10μL激酶检测试剂(Kinase Detection Reagent)，1000rpm离心30秒，振荡混匀后室温孵育30分钟。用Envision酶标仪读取发光值RLU。
五、数据分析
用Graphpad Prism软件计算化合物抑制活性的IC 50值，结果参见下表1。
表1本公开化合物对PI3Kδ酶的抑制和选择性活性数据(单位nM)
实施例编号 PI3Kδ酶IC 50 PI3Kα酶IC 50 PI3Kβ酶IC 50 PI3Kγ酶IC 50
1 13 467.6 1316.0 6210.0
2 18.4 - - -
3 5.6 - - -
4 7.9 - - -
5 19 2329 2791 >10000
6 68 2570 7058 >10000
7 26.5 1523 1743 >10000
9 25.0 1761 1551 >10000
11 10.5 441 736 8918
12 5.8 - - -
10(对照例) >10000 - - -
结论：本公开化合物相对于对照例，对PI3Kδ酶具有较强的抑制活性和选择性。

Claims (17)

  1. 一种通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
    Figure PCTCN2021109205-appb-100001
    其中：
    R a、R b、R c、R d、R e和R f相同或不同，且各自独立地选自氢原子、烷基、卤素、烷氧基、卤代烷氧基、氰基、羟基、羟烷基、-(CH 2) sNR 7R 8、环烷基、环烷基烷基、环烷基氧基、杂环基、杂环基烷基、杂环基氧基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、卤代烷基、氰基、硝基、-(CH 2) yNR gR h和-OR 9中的一个或多个取代基所取代；
    R 0、R 1与共同连接的碳原子一起在所连杂环上形成螺环，所述螺环任选被一个或多个R’取代；
    R’相同或不同，且各自独立地选自氢原子、烷基、卤素、烷氧基、卤代烷氧基、氰基、羟基、羟烷基、-(CH 2) sNR 7R 8和硝基；
    R 5选自氢原子、烷基、环烷基、杂环基、芳基和杂芳基；所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、硝基、氰基、羟烷基、-(CH 2) yNR gR h、-OR 9、-COR 9、-COOR 9、-OS(O) tR 9、-S(O) tR 9、-NR 6COR 9、-NR 6SO 2R 9和R中的一个或多个取代基所取代；
    所述的R选自环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基，所述的R各自独立地任选被选自卤素、烷基、卤代烷基、硝基、氰基、羟烷基、-(CH 2) yNR gR h、-OR 9、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基和杂芳基中的一个或多个取代基所取代；
    R 2和R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、环烷基、芳基、杂环基、杂芳基、环烷基烷基、芳基烷基、杂环基烷基和杂芳基烷基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自烷基、卤代烷基、卤素、氰基、硝基、-(CH 2) yNR gR h、-OR 9、-COR 9、-COOR 9、-OS(O) tR 9、-S(O) tR 9、-NR 6COR 9和-NR 6SO 2R 9中的一个或多个取代基所取代；
    R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、氰基、硝基、-(CH 2) sNR 7R 8、-OR i、-COR i、-COOR i、-OS(O) xR i、-S(O) xR i、-NR 6COR i、-NR 6SO 2R i、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自烷基、卤代烷基、卤素、氰基、硝基、-(CH 2) yNR gR h、-OR 9、-COR 9、-COOR 9、-OS(O) tR 9、-S(O) tR 9、-NR 6COR 9和-NR 6SO 2R 9 中的一个或多个取代基所取代；
    或两个相邻的R 3与所连的碳原子一起形成环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自氢原子、烷基、卤素、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代；
    R 6选自氢原子、烷基、环烷基和芳基，其中所述的烷基、环烷基和芳基各自独立地任选被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 7、R 8、R g和R h相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    或者R 7和R 8、R g和R h与相连的氮原子一起形成杂环基，所述的杂环基任选被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 9和R i相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、-(CH 2) sNR 7R 8、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基中的一个或多个取代基所取代；
    n为1或2；
    q为0、1、2、3或4；
    s和y相同或不同，且各自独立地选自0、1、2、3、4或5；且
    t和x相同或不同，且各自独立地选自0、1或2。
  2. 根据权利要求1所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 0和R 1与所连的碳一起在所连杂环上形成螺3-6元环，优选形成螺3-6元碳环，更优选形成螺环丙基。
  3. 根据权利要求1或2中所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
    Figure PCTCN2021109205-appb-100002
    其中：m为0、1、2或3；
    R’、R a-R f、R 2-R 5和q如权利要求1中所定义。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 5为芳基或杂芳基，所述的芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、硝基、氰基、羟烷基、-(CH 2) yNR gR h、-OR 9、-COR 9、-COOR 9、-OS(O) tR 9、-S(O) tR 9、-NR 6COR 9、-NR 6SO 2R 9和R中的一个或多个取代基所取代；
    所述的R选自环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基，所述的R各自独立地任选被选自卤素、烷基、卤代烷基和-OR 9中的一个或多个取代基所取代；
    R 6、R 9、R g、R h、y和t如权利要求1中所定义。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 5为芳基或杂芳基，所述的芳基和杂芳基各自独立地任选被R所取代，所述的R选自环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基，所述的R各自独立地任选被选自卤素、烷基和卤代烷基中的一个或多个取代基所取代。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
    Figure PCTCN2021109205-appb-100003
    其中：
    R 10相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、硝基、氰基、羟烷基、-(CH 2) sNR 7R 8、-OR 9、环烷基、杂环基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氰基、硝基和-(CH 2) yNR gR h中的一个或多个取代基所取代；
    R 11相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、 卤代烷氧基、羟基、羟烷基、氰基、硝基、-(CH 2) yNR gR h、环烷基、环烷基氧基和环烷基烷基；
    每个R 12相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、硝基、氰基、羟烷基、-(CH 2) yNR gR h、-OR 9、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基和杂芳基；当u大于等于2时，两个R 12可在吗啉环上形成螺环或桥环系统；
    w为0、1、2、3或4；
    u为0、1、2、3、4、5或6；
    R’、R a-R h、R 2-R 4、R 7-R 9、s、m、y和q如权利要求3中所定义。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 2和R 4相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；优选地，R 2和R 4均为氢原子。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 3相同或不同，且各自独立地选自氢原子、卤素、卤代C 1-6烷基、C 1-6烷氧基和C 1-6烷基；
    优选地，R 3相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基。
  9. 根据权利要求6至8中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 10相同或不同，且各自独立地为氢原子、卤素和C 1-6烷基；优选地，R 10为氢原子。
  10. 根据权利要求6至9中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 11相同或不同，且各自独立地为氢原子、卤素和C 1-6烷基；优选地，R 11为氢原子。
  11. 根据权利要求6至10中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 12相同或不同，且各自独立地为氢原子、卤素和C 1-6烷基；优选地，R 12为氢原子。
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其互变异构 体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R a-R f各自独立地为氢原子。
  13. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其选自以下化合物：
    Figure PCTCN2021109205-appb-100004
  14. 一种制备权利要求1所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括以下步骤：
    Figure PCTCN2021109205-appb-100005
    通式(IA)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与通式(IB)的化合物或其可药用的盐反应，得到通式(I)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，
    其中R 0-R 5、R a-R f、n和q如权利要求1中所定义。
  15. 一种药物组合物，所述药物组合物含有根据权利要求1至13中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  16. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求15所述的药物组合物在制备用于抑制PI3Kδ的药物中的用途。
  17. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求15所述的药物组合物在制备用于治疗和/或预防炎性疾病、自身免疫性疾病、癌症及相关疾病的药物中的用途；所述的癌症优选选自黑色素瘤、皮肤癌、肝癌、肾癌、肺癌、鼻咽癌、胃癌、食道癌、结肠直肠癌、胆囊癌、胆管癌、绒毛膜上皮癌、胰腺癌、真性红细胞增多症、儿科肿瘤、宫颈癌、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、输尿管肿瘤、前列腺癌、精原细胞瘤、睾丸肿瘤、白血病、头颈瘤、子宫内膜癌、甲状腺癌、淋巴瘤、肉瘤、骨瘤、成神经细胞瘤、神经母细胞瘤、神经内分泌癌、脑瘤、CNS癌、骨髓瘤、星形细胞瘤、胶质母细胞瘤和胶质瘤，所述的白血病优选选自慢性淋巴细胞白血病、急性淋巴细胞性白血病(ALL)、急性髓细胞样白血病(AML)、慢性髓细胞样白血病(CML)和毛细胞性白血病，所述的淋巴瘤优选选自小淋巴细胞淋巴瘤、边缘带淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、非霍奇金淋巴瘤(NHL)、淋巴质浆细胞淋巴瘤、结外边缘区淋巴瘤、T细胞淋巴瘤、B细胞淋巴瘤和弥漫性大B细胞淋巴瘤，所述的肺癌优选为非小细胞肺癌或小细胞肺癌，所述的骨髓瘤优选为多发性骨髓瘤(MM)，所述的 自身免疫性疾病优选选自哮喘、类风湿性关节炎、急性播散性脑脊髓炎(ADEM)、艾迪生病、斑秃、僵直性脊椎炎、抗磷脂抗体综合征(APS)、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性内耳疾病、天疱疮、类天疱疮、白塞病、乳糜泻、抗-谷氨酰胺转胺酶、查加斯病、慢性阻塞性肺病、克罗恩病、皮肌炎、1型糖尿病、子宫内膜异位、肺出血-肾炎综合征、格雷夫斯病、格林-巴利综合征(GBS)、桥本氏病、化脓性汗腺炎、川崎病、甲型球蛋白肾病变、免疫性血小板减少紫斑症、特发性血小板减少性紫癜(ITP)、间质性膀胱炎、狼疮、狼疮性肾炎、膜性肾病、混合性结缔组织疾病、硬斑病、多发性硬化病(MS)、重肌无力症、猝睡症、神经性肌强直、恶性贫血、牛皮癣、银屑病关节炎、多发性肌炎、原发性胆汁性肝硬化、精神分裂症、硬皮症、口眼干燥综合症、舍格伦综合征、僵人综合征、颞动脉炎、溃疡性结肠炎、血管炎、白斑和韦格纳肉芽肿，所述的狼疮优选为红斑性狼疮或系统性红斑狼疮，所述的天疱疮优选为寻常性天疱疮，所述肝癌优选为肝细胞癌，所述头颈瘤优选为头颈鳞状细胞癌，所述肉瘤优选为骨肉瘤或软组织肉瘤，所述结肠直肠癌优选为结肠癌或直肠癌。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004069824A1 (ja) 2003-02-07 2004-08-19 Daiichi Pharmaceutical Co., Ltd. ピラゾール誘導体
WO2008032191A2 (en) 2006-09-13 2008-03-20 Astrazeneca Ab Spiro-oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators
WO2011058149A1 (en) 2009-11-13 2011-05-19 Merck Serono S.A. Tricyclic pyrazol amine derivatives
WO2014121901A1 (en) 2013-02-07 2014-08-14 Merck Patent Gmbh Polymorphic forms
WO2014209980A1 (en) 2013-06-24 2014-12-31 Merck Patent Gmbh Pyrazole compounds as modulators of fshr and uses thereof
WO2015196759A1 (en) 2014-06-23 2015-12-30 Tocopherx, Inc. Pyrazole compounds as modulators of fshr and uses thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004069824A1 (ja) 2003-02-07 2004-08-19 Daiichi Pharmaceutical Co., Ltd. ピラゾール誘導体
WO2008032191A2 (en) 2006-09-13 2008-03-20 Astrazeneca Ab Spiro-oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators
WO2011058149A1 (en) 2009-11-13 2011-05-19 Merck Serono S.A. Tricyclic pyrazol amine derivatives
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 (en) 2013-02-07 2014-08-14 Merck Patent Gmbh Polymorphic forms
WO2014209980A1 (en) 2013-06-24 2014-12-31 Merck Patent Gmbh Pyrazole compounds as modulators of fshr and uses thereof
WO2015196759A1 (en) 2014-06-23 2015-12-30 Tocopherx, Inc. Pyrazole compounds as modulators of fshr and uses thereof
WO2015196335A1 (en) 2014-06-23 2015-12-30 Tocopherx, Inc. Pyrazole compounds as modulators of fshr and uses thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CANCER IMMUNOL RES,, vol. 2, pages 1080 - 1089
CANCER RES, vol. 77, pages 4135 - 4145
CELL, vol. 170, no. 4, pages 605 - 635
N ENGLJ MED, vol. 379, pages 2052 - 2062
ORGANIC LETTERS, vol. 22, no. 3, 2020, pages 1155 - 1159

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