WO2020259724A2 - 一种吡唑酮并嘧啶类化合物、其制备方法及应用 - Google Patents

一种吡唑酮并嘧啶类化合物、其制备方法及应用 Download PDF

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WO2020259724A2
WO2020259724A2 PCT/CN2020/112034 CN2020112034W WO2020259724A2 WO 2020259724 A2 WO2020259724 A2 WO 2020259724A2 CN 2020112034 W CN2020112034 W CN 2020112034W WO 2020259724 A2 WO2020259724 A2 WO 2020259724A2
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heterocycloalkyl
alkyl
independently
cycloalkyl
group
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PCT/CN2020/112034
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English (en)
French (fr)
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WO2020259724A3 (zh
Inventor
王倩
霍国永
夏广新
楼江松
舒思杰
葛辉
张霖
石辰
张智慧
毛煜
张冰宾
余建鑫
刘彦君
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上海医药集团股份有限公司
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Priority to CA3145348A priority Critical patent/CA3145348A1/en
Priority to EP20831960.8A priority patent/EP4008719A4/en
Priority to BR112021026620A priority patent/BR112021026620A2/pt
Priority to JP2021578137A priority patent/JP2022539460A/ja
Priority to US17/623,001 priority patent/US20220324868A1/en
Priority to MX2022000199A priority patent/MX2022000199A/es
Application filed by 上海医药集团股份有限公司 filed Critical 上海医药集团股份有限公司
Priority to KR1020227002020A priority patent/KR20230046270A/ko
Priority to AU2020304472A priority patent/AU2020304472A1/en
Publication of WO2020259724A2 publication Critical patent/WO2020259724A2/zh
Publication of WO2020259724A3 publication Critical patent/WO2020259724A3/zh
Priority to IL289395A priority patent/IL289395A/en
Priority to CONC2022/0000751A priority patent/CO2022000751A2/es

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to a pyrazolone and pyrimidine compound, its preparation method and application.
  • the cell cycle is closely related to the process of DNA damage repair.
  • the cell cycle refers to the entire process of cell division, which is divided into two phases: interphase and mitotic phase (M).
  • Cell cycle checkpoint (checkpoint) is a key point in regulating the cell cycle. Its main function is to ensure that each event in the cycle can be completed on time and orderly, and to adjust the cell state to adapt to the external environment.
  • the main checkpoints of cells are: 1) G1/S checkpoint: called R (restriction) point in mammals, which controls the cell to enter the DNA synthesis phase from the resting G1 phase; 2) S phase checkpoint: whether DNA replication is complete ; 3) G2/M check point: it is the control point that regulates the cell entering the division phase; 4) mid-late check point: also known as the spindle assembly check point. If the centromere is not correctly connected to the spindle, it will Causes interruption of the cell cycle. If there are abnormalities in some processes of the cell division cycle, such as DNA damage, the checkpoint will sense in time and initiate repair. P53 protein is an important protein that regulates the G1 checkpoint.
  • WEE1 kinase is a cell cycle regulatory protein, which can regulate the phosphorylation status of cyclin-dependent kinase 1 (cyclin-dependent kinase 1, CDK1), thereby regulating the activity of CDK1 and cyclin B (cyclinB) complex. Regulates the cell cycle and plays an important role in regulating DNA damage checkpoints.
  • WEE1 is a key gene for G2/M phase arrest and plays an important monitoring role. Overexpression in some cancers, and inhibition or down-regulation of WEE1 kinase can trigger mitotic disaster. Therefore, WEE1 kinase inhibitors play a key role in anti-cancer therapy. , Has become a hot spot for research and development of anticancer agents.
  • the technical problem to be solved by the present invention is that the structure of the existing compounds having inhibitory activity on WEE1 kinase is relatively simple. Therefore, the present invention provides a pyrazolone and pyrimidine compound, its preparation method and application. The inhibitory activity is better.
  • the present invention provides a pyrazolone and pyrimidine compound represented by formula I, its pharmaceutically acceptable salt, its solvate, or its pharmaceutically acceptable salt solvate:
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is - (CH 2) m -R 2 , C 3 ⁇ C 20 cycloalkyl, or a substituted 3 2 R C 3 ⁇ C 20 cycloalkyl group, C 3 ⁇ C 14 heterocycloalkyl, Or, C 3 ⁇ C 14 heterocycloalkyl substituted with 1 or 2 R 4 ;
  • n 0, 1, 2, 3 or 4;
  • R 2-1 and R 2-2 and the nitrogen atom connected thereto form a C 3 ⁇ C 14 heterocycloalkyl group optionally substituted with 1, 2 or 3 R 2-1-6 ;
  • One or two or more methylene groups in the C 3 to C 14 heterocycloalkyl group are optionally and independently substituted by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a vinylene group, or -N( R 2-1-7 ) -replacement of the group shown;
  • R 2-1-7 is independently C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-1-1 , R 2-1-2, and R 2-1-4 are independently hydrogen, -NR 2-1-1-1 R 2-1-1-2 , or, optionally one , 2 or 3 R 2- 1-1-3 substituted: C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-1-1-1 and R 2-1-1-2 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-1-1-3 are independently halogen, hydroxy, mercapto, cyano, amino, C 1 to C 7 alkyl, C 1 to C 7 alkoxy, C 1 to C 7 alkylthio, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-1-3 is selected from hydrogen, cyano, -OH, C 1 ⁇ C 7 alkyl or C 1 ⁇ C 7 alkoxy;
  • R 2-1-5 and R 2-1-6 are independently cyano, halogen, -NR 2-1-5-1 R 2-1-5-2 , -OR 2-1-5-3 ,- SR 2-1-5-4 or C 1 ⁇ C 7 alkyl;
  • R 2-1-5-1 , R 2-1-5-2 , R 2-1-5-3 and R 2-1-5-4 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-3 is independently hydrogen, -NR 2-3-1 R 2-3-2 , -OR 2-3-3 , or, optionally by 1, 2 or 3 R 2-3-4 Substituted: C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-3-1 and R 2-3-2 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl , C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-3-1 and R 2-3-2 and the nitrogen atom connected thereto form a C 3 ⁇ C 14 heterocyclic ring optionally substituted with 1, 2 or 3 R 2-3-1-1 Alkyl; one or more methylene groups in the C 3 to C 14 heterocycloalkyl group are optionally and independently substituted by oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, and sub Replacement of vinyl group or -N(R 2-3-1-2 )-; R 2-3-1-2 is independently C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl ;
  • R 2-3-1-1 is independently cyano, halogen, -NR 2-3-1-1-1 R 2-3-1-1-2 , -OR 2-3-1-1-3 , -SR 2-3-1-1-4 or C 1 ⁇ C 7 alkyl;
  • R 2-3-1-1-1 , R 2-3-1-1-2 , R 2-3-1-1-3 and R 2-3-1-1-4 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-3-3 is independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 hetero Cycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-3-4 is independently cyano, halogen, -NR 2-3-4-1 R 2-3-4-2 , -OR 2-3-4-3 , -SR 2-3-4- 4 or C 1 ⁇ C 7 alkyl;
  • R 2-3-4-1 , R 2-3-4-2 , R 2-3-4-3 and R 2-3-4-4 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-4 is independently hydrogen, -CN, -OR 2-4-1 or C 1 ⁇ C 7 alkyl;
  • R 2-4-1 is independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 hetero Cycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-5 is independently -NR 2-5-1 R 2-5-2 , -OR 2-5-3 , or, optionally substituted with 1, 2 or 3 R 2-5-4 : C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl Group or C 1 ⁇ C 7 heteroaryl group;
  • R 2-5-1 and R 2-5-2 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl , C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-5-1 and R 2-5-2 and the nitrogen atom connected thereto form a C 3 ⁇ C 14 heterocyclic ring optionally substituted with 1, 2 or 3 R 2-5-1-1 Alkyl; one or more methylene groups in the C 3 to C 14 heterocycloalkyl group are optionally and independently substituted by oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, and sub Replacement of vinyl group or -N(R 2-5-1-2 )-; R 2-5-1-2 is independently C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl ;
  • R 2-5-1-1 is independently cyano, halogen, -NR 2-5-1-1-1 R 2-5-1-1-2 , -OR 2-5-1-1-3 , -SR 2-5-1-1-4 or C 1 ⁇ C 7 alkyl;
  • R 2-5-1-1-1 , R 2-5-1-1-2 , R 2-5-1-1-3 and R 2-5-1-1-4 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-5-3 is independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 hetero Cycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-5-4 is independently cyano, halogen, -NR 2-5-4-1 R 2-5-4-2 , -OR 2-5-4-3 , -SR 2-5-4- 4 or C 1 ⁇ C 7 alkyl;
  • R 2-5-4-1 , R 2-5-4-2 , R 2-5-4-3 and R 2-5-4-4 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-6 is independently -NR 2-6-1 R 2-6-2 , -OR 2-6-3 , or, optionally substituted by 1, 2 or 3 R 2-6-4 :C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl Group or C 1 ⁇ C 7 heteroaryl group;
  • R 2-6-1 and R 2-6-2 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl , C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-6-1 and R 2-6-2 and the nitrogen atom connected thereto form a C 3 ⁇ C 14 heterocyclic ring optionally substituted with 1, 2 or 3 R 2-6-1-1 Alkyl; one or more methylene groups in the C 3 to C 14 heterocycloalkyl group are optionally and independently substituted by oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, and sub Replacement of vinyl group or -N(R 2-6-1-2 )-; R 2-6-1-2 is independently C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl ;
  • R 2-6-1-1 is independently cyano, halogen, -NR 2-6-1-1-1 R 2-6-1-1-2 , -OR 2-6-1-1-3 , -SR 2-6-1-1-4 or C 1 ⁇ C 7 alkyl;
  • R 2-6-1-1-1 , R 2-6-1-1-2 , R 2-6-1-1-3 and R 2-6-1-1-4 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-6-3 is independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 hetero Cycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-6-4 is independently cyano, halogen, -NR 2-6-4-1 R 2-6-4-2 , -OR 2-6-4-3 , -SR 2-6-4- 4 or C 1 ⁇ C 7 alkyl;
  • R 2-6-4-1 , R 2-6-4-2 , R 2-6-4-3 and R 2-6-4-4 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-7 and R 2-8 are independently hydrogen, or, optionally substituted by 1, 2 or 3 R 2-7-1 : C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkene Group, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-7-1 is independently cyano, halogen, -NR 2-7-1-1 R 2-7-1-2 , -OR 2-7-1-3 , -SR 2-7-1- 4 or C 1 ⁇ C 7 alkyl;
  • R 2-7-1-1 , R 2-7-1-2 , R 2-7-1-3 and R 2-7-1-4 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-9-1 , R 2-9-2 , R 2-9-3 and R 2-9-4 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl, or C 1 ⁇ C 7 heteroaryl;
  • R 2-9-5 is independently hydrogen, -NR 2-9-5-1 R 2-9-5-2 , -OR 2-9-5-3 or, optionally by 1, 2 or 3
  • R 2-9-5-1 , R 2-9-5-2 and R 2-9-5-3 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-9-5-4 is independently hydrogen, halogen, hydroxyl, mercapto, cyano, amino, C 1 to C 7 alkyl, C 1 to C 7 alkoxy, C 1 to C 7 alkylthio, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl base;
  • R 2-9-6 is independently hydrogen, -CN, -OR 2-9-6-1 or C 1 ⁇ C 7 alkyl;
  • R 2-9-6-1 is independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 Heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-9-7 is independently -NR 2-9-7-1 R 2-9-7-2 , -OR 2-9-7-3 , C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 Alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-9-7-1 and R 2-9-7-2 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-9-7-1 and R 2-9-7-2 and the nitrogen atom connected thereto form C optionally substituted with 1, 2, or 3 R 2-9-7-1-1 3 to C 14 heterocycloalkyl; one or two or more methylene groups in the C 3 to C 14 heterocycloalkyl are optionally and independently substituted by an oxygen atom, a sulfur atom, a sulfinyl group, Sulfonyl, carbonyl, vinylidene or -N(R 2-9-7-1-2 ) -replacement ; R 2-9-7-1-2 is independently C 1 ⁇ C 7 alkane Group or C 3 ⁇ C 14 cycloalkyl;
  • R 2-9-7-1-1 is independently halogen, hydroxyl, mercapto, cyano, amino, C 1 to C 7 alkyl, C 1 to C 7 alkoxy, C 1 to C 7 alkylthio, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl base;
  • R 2-9-7-3 is independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 Heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-9-8 is independently -NR 2-9-8-1 R 2-9-8-2 , -OR 2-9-8-3 , C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 Alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-9-8-1 and R 2-9-8-2 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • R 2-9-8-1 and R 2-9-8-2 and the nitrogen atom connected thereto form a C optionally substituted with 1, 2 or 3 R 2-9-8-1-1 3 to C 14 heterocycloalkyl; one or two or more methylene groups in the C 3 to C 14 heterocycloalkyl are optionally and independently covered by oxygen atoms, sulfur atoms, sulfinyl groups, Sulfonyl, carbonyl, vinylidene or -N(R 2-9-8-1-2 ) -replacement ; R 2-9-8-1-2 is independently C 1 ⁇ C 7 alkane Group or C 3 ⁇ C 14 cycloalkyl;
  • R 2-9-8-1-1 is independently halogen, hydroxyl, mercapto, cyano, amino, C 1 to C 7 alkyl, C 1 to C 7 alkoxy, C 1 to C 7 alkylthio, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl base;
  • R 2-9-8-3 is independently hydrogen, C 1 ⁇ C 7 alkyl, C 2 ⁇ C 7 alkenyl, C 2 ⁇ C 7 alkynyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 Heterocycloalkyl, C 6 ⁇ C 10 aryl or C 1 ⁇ C 7 heteroaryl;
  • the heteroatoms in the C 3 ⁇ C 14 heterocycloalkyl group and C 1 ⁇ C 7 heteroaryl group are independently selected from the group consisting of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more; the number of heteroatoms is independently 1, 2, 3, or 4.
  • the pyrazolo pyrimidine compound represented by formula I its pharmaceutically acceptable salt, its solvate, or the solvate of its pharmaceutically acceptable salt
  • substituents of may further have the following definitions, and the definitions of substituents not mentioned below are as described in any of the above schemes (hereinafter referred to as "in a certain scheme"):
  • said C 3 ⁇ C 20 cycloalkyl group such as C 3 ⁇ C 20 monocyclic cycloalkyl group, C 3 ⁇ C 20 spirocyclic cycloalkyl, C 3 ⁇ C 20 fused cyclic cycloalkyl or C 3 ⁇ C 20 bridged cyclic cycloalkyl.
  • the C 3 to C 20 monocyclic cycloalkyl group is, for example, a C 3 to C 6 monocyclic cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or cyclohexyl.
  • the C 3 ⁇ C 20 bridged cyclic cycloalkyl group is, for example, C 5 ⁇ C 8 bridged cyclic cycloalkyl group, for example
  • R 2-1 and R 2-2 are independently a C 1 ⁇ C 7 alkyl group
  • the C 1 ⁇ C 7 alkyl group is, for example, a C 1 ⁇ C 3 alkyl group, such as methyl, ethyl, n- Propyl or isopropyl, also for example methyl.
  • the C 3 ⁇ C 14 heterocycloalkyl group is, for example, a C 3 ⁇ C 14 monocyclic heterocycloalkyl group and a C 3 ⁇ C 14 spirocyclic heterocycloalkyl group , C 3 ⁇ C 14 fused ring heterocycloalkyl or C 3 ⁇ C 14 bridged ring heterocycloalkyl.
  • the C 3 ⁇ C 14 monocyclic heterocycloalkyl group is, for example, a C 3 ⁇ C 9 monocyclic group with one or two heteroatoms selected from one or two of N, O and S Heterocycloalkyl", another example is “C 3 ⁇ C 5 monocyclic heterocycloalkyl with one or two heteroatoms selected from one or two of N, O and S", and For example, "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or two of N, O and S C 3 ⁇ C 5 monocyclic heterocycloalkyl", and it passes through the nitrogen atom and the benzene ring Linkage is another example of morpholinyl, piperidinyl or piperazinyl.
  • the morpholino group is for example
  • the piperidinyl group is for example
  • the piperazinyl is for example
  • the C 3 ⁇ C 14 spirocyclic heterocycloalkyl group is, for example, a C 5 ⁇ C 9 spiro ring with one or two heteroatoms selected from one or two of N, O and S Heterocycloalkyl", another example is "C 7 -C 9 spirocycloheterocycloalkyl with one or two heteroatoms selected from one or two of N, O, and S", and For example, "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or two of N, O and S C 7 ⁇ C 9 spirocyclic heterocycloalkyl", and it passes through the nitrogen atom and the benzene ring Connection, another example Also for example
  • the C 3 ⁇ C 14 fused ring heterocycloalkyl group is, for example, a C 6 ⁇ C 8 fused ring with one or two heteroatoms selected from one or two of N, O and S Heterocycloalkyl", another example is "C 6 -C 8 fused ring heterocycloalkyl with one or two heteroatoms selected from one or two of N, O and S", and It is connected to the benzene ring through a nitrogen atom, for example Another example
  • the C 3 ⁇ C 14 bridged heterocycloalkyl group is, for example, a C 4 ⁇ C 6 bridged ring with one or two heteroatoms selected from one or two of N, O and S Heterocycloalkyl", another example is "C 4 ⁇ C 6 bridged cycloheterocycloalkyl with one or two heteroatoms selected from one or two of N, O and S", and It is connected to the benzene ring through a nitrogen atom, for example
  • the C 3 to C 14 heterocycloalkyl group is, for example, a C 3 to C 14 saturated heterocycloalkyl group.
  • L is a C 3 -C 14 heterocycloalkyl group
  • the heteroatom of the C 3 -C 14 heterocycloalkyl group may have no substituents.
  • C 3 ⁇ C 14 heterocycloalkyl group when L is substituted by 1 or 2 R C 3 ⁇ C 14 heterocycloalkyl group, said C 3 ⁇ C 14 heterocycloalkyl group, for example, C 3 ⁇ C 14 monocyclic heterocycloalkyl, C 3 to C 14 spirocyclic heterocycloalkyl, C 3 to C 14 condensed ring heterocycloalkyl, or C 3 to C 14 bridged ring heterocycloalkyl.
  • the C 3 ⁇ C 14 monocyclic heterocycloalkyl group is, for example, a C 3 ⁇ C 9 monocyclic group with one or two heteroatoms selected from one or two of N, O and S Heterocycloalkyl", another example is “C 3 ⁇ C 5 monocyclic heterocycloalkyl with one or two heteroatoms selected from one or two of N, O and S", and For example, "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or two of N, O and S C 3 ⁇ C 5 monocyclic heterocycloalkyl", and it passes through the nitrogen atom and the benzene ring Linkage is another example of morpholinyl, piperidinyl or piperazinyl.
  • the morpholino group is for example
  • the piperidinyl group is for example
  • the piperazinyl is for example
  • the C 3 ⁇ C 14 spirocyclic heterocycloalkyl group is, for example, a C 5 ⁇ C 9 spiro ring with one or two heteroatoms selected from one or two of N, O and S Heterocycloalkyl", another example is "C 7 -C 9 spirocycloheterocycloalkyl with one or two heteroatoms selected from one or two of N, O, and S", and For example, "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or two of N, O and S C 7 ⁇ C 9 spirocyclic heterocycloalkyl", and it passes through the nitrogen atom and the benzene ring Connection, another example Also for example
  • the C 3 ⁇ C 14 fused ring heterocycloalkyl group is, for example, a C 6 ⁇ C 8 fused ring with one or two heteroatoms selected from one or two of N, O and S Heterocycloalkyl", another example is "C 6 -C 8 fused ring heterocycloalkyl with one or two heteroatoms selected from one or two of N, O and S", and It is connected to the benzene ring through a nitrogen atom, for example Another example
  • the C 3 ⁇ C 14 bridged heterocycloalkyl group is, for example, a C 4 ⁇ C 6 bridged ring with one or two heteroatoms selected from one or two of N, O and S Heterocycloalkyl", another example is "C 4 ⁇ C 6 bridged cycloheterocycloalkyl with one or two heteroatoms selected from one or two of N, O and S", and It is connected to the benzene ring through a nitrogen atom, for example
  • L is a C 3 -C 14 heterocycloalkyl group substituted with one or two R 4 , except for R 4 , the heteroatom of the C 3 -C 14 heterocycloalkyl group may have no substituent.
  • L is a C 3 -C 14 heterocycloalkyl group substituted with 1 or 2 R 4
  • the methylene group in the C 3 -C 14 heterocycloalkyl group may not be substituted or replaced.
  • R 4 is optionally substituted with 1 R 2-9 is C 1 ⁇ C 7 alkyl
  • said C 1 ⁇ C 7 alkyl group for example, C 1 ⁇ C 3 alkyl group, and for example methyl, ethyl, , N-propyl or isopropyl, also for example methyl or ethyl.
  • R 4 is a C 3 ⁇ C 14 cycloalkyl group
  • the C 3 ⁇ C 14 cycloalkyl group is, for example, a C 3 ⁇ C 7 cycloalkyl group
  • another example is a C 3 ⁇ C 7 monocyclic cycloalkyl group, such as Cyclobutyl.
  • R 4 is a C 3 to C 14 cycloalkyl group
  • the C 3 to C 14 cycloalkyl group is, for example, a saturated C 3 to C 14 cycloalkyl group.
  • R 4 is an optionally 3 ⁇ C 14 heterocycloalkyl group substituted with 1 R 2-9 is C
  • said C 3 ⁇ C 14 heterocycloalkyl group for example, C 3 ⁇ C 7 heterocycloalkyl, and
  • C 3 ⁇ C 7 monocyclic heterocycloalkyl also for example azetidinyl, and for example
  • R 4 is optionally substituted with a 2-9 R C 3 ⁇ C 14 heterocycloalkyl group
  • said C 3 ⁇ C 14 heterocycloalkyl group for example a saturated C 3 ⁇ C 14 heterocycloalkyl.
  • R 4 is a C 3 ⁇ C 14 heterocycloalkyl group optionally substituted by one R 2-9 , in addition to R 2-9 , the heteroatom of the C 3 ⁇ C 14 heterocycloalkyl group may be No substituents.
  • R 4 is a C 3 -C 14 heterocycloalkyl group optionally substituted with one R 2-9 , the methylene group in the C 3 -C 14 heterocycloalkyl group may not be substituted or replaced.
  • R 2-9 is independently a C 3 ⁇ C 14 cycloalkyl group
  • the C 3 ⁇ C 14 cycloalkyl group is, for example, a C 3 ⁇ C 14 monocyclic cycloalkyl group, and another example is a C 3 ⁇ C 6 monocyclic ring group.
  • Cycloalkyl is also cyclopropyl.
  • R 2-9 is independently a C 3 to C 14 cycloalkyl group
  • the C 3 to C 14 cycloalkyl group is, for example, a C 3 to C 14 saturated cycloalkyl group.
  • R 2-9-2 and R 2-9-3 are independently a C 1 ⁇ C 7 alkyl group
  • the C 1 ⁇ C 7 alkyl group is, for example, a C 1 ⁇ C 3 alkyl group, such as methyl, Ethyl, n-propyl or isopropyl, also for example methyl.
  • R 4 when L is substituted by one of R C 3 ⁇ C 14 heterocycloalkyl group, R 4 is optionally substituted C 3 ⁇ C 14 heterocycloalkyl group substituted with 1 R 2-9 when said "are One R 4 substituted C 3 ⁇ C 14 heterocycloalkyl" is
  • R 2-3 is independently C 3 to C 14 heterocycloalkyl
  • the C 3 to C 14 heterocycloalkyl is, for example, C 3 to C 14 monocyclic heterocycloalkyl.
  • the C 3 ⁇ C 14 monocyclic heterocycloalkyl group is, for example, a C 3 ⁇ C 9 monocyclic group with one or two heteroatoms selected from one or two of N, O and S Heterocycloalkyl", another example is “C 3 ⁇ C 5 monocyclic heterocycloalkyl with one or two heteroatoms selected from one or two of N, O and S", and For example, "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or two of N, O and S C 3 ⁇ C 5 monocyclic heterocycloalkyl", and it passes through the nitrogen atom and the benzene ring Link, another example is tetrahydropyrrolyl.
  • the tetrahydropyrrolyl group is for example
  • R 2-3 is independently a C 3 to C 14 heterocycloalkyl group
  • the C 3 to C 14 heterocycloalkyl group is, for example, a C 3 to C 14 saturated heterocycloalkyl group.
  • R 2-3 is independently a C 3 to C 14 heterocycloalkyl group
  • the heteroatom of the C 3 to C 14 heterocycloalkyl group may have no substituent.
  • R 2-3 are independently C 3 ⁇ C 14 heterocycloalkyl group, C 3 ⁇ C 14 heterocycloalkyl group in the methylene group may be replaced or substituted.
  • the C 3 ⁇ C 14 monocyclic heterocycloalkyl group is, for example, "the number of heteroatoms is 1 or 2 One, the heteroatom is selected from one or two of N, O and S, C 3 ⁇ C 9 monocyclic heterocycloalkyl", another example is “the number of heteroatoms is 1 or 2, and the heteroatom is selected from N , O and S one or two of C 3 ⁇ C 5 monocyclic heterocycloalkyl", for example, "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one of N, O and S One or two kinds of C 3 ⁇ C 5 monocyclic heterocycloalkyl" and which are connected to the benzene ring through a nitrogen atom, such as piperazinyl.
  • the piperazinyl is for example
  • R 2 is optionally substituted C 3 ⁇ C 14 heterocycloalkyl group is substituted with one of R 2-9, said C 3 ⁇ C 14 heterocycloalkyl group, for example a saturated C 3 ⁇ C 14 heterocycloalkyl.
  • R 2 is a C 3 ⁇ C 14 heterocycloalkyl group optionally substituted by one R 2-9 , in addition to R 2-9 , the heteroatom of the C 3 ⁇ C 14 heterocycloalkyl group may be No substituents.
  • R 2 is a C 3 -C 14 heterocycloalkyl group optionally substituted with one R 2-9 , the methylene group in the C 3 -C 14 heterocycloalkyl group may not be replaced or substituted.
  • R 2-9 is independently a C 1 ⁇ C 7 alkyl group
  • the C 1 ⁇ C 7 alkyl group is, for example, a C 1 ⁇ C 3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl base.
  • the ratio of each isomer in the pyrazolo pyrimidine compound shown in formula I may be equal, for example, racemate.
  • the atom in the pyrazolone and pyrimidine compound shown in formula I, its pharmaceutically acceptable salt, its solvate, or the solvate of its pharmaceutically acceptable salt can all be Exist in the form of natural abundance.
  • R 1 is hydrogen or methyl.
  • n 1 or 2.
  • L is -(CH 2 ) m -R 2 , C 3 ⁇ C 20 cycloalkyl substituted with one R 3 , C 3 ⁇ C 14 heterocycloalkyl, or, C 3 ⁇ substituted with one R 4 C 14 heterocycloalkyl; m is 1 or 2, and can also be 3.
  • L is a C 3 to C 20 cycloalkyl group substituted with one R 3 , a C 3 to C 14 heterocycloalkyl group, or a C 3 to C 14 heterocycloalkyl group substituted with one R 4 .
  • L is -(CH 2 ) m -R 2 , C 3 ⁇ C 14 fused ring heterocycloalkyl substituted with 1 or 2 R 4 , or C 3 ⁇ C substituted with 1 or 2 R 4 14 Spirocyclic heterocycloalkyl;
  • the C 3 ⁇ C 14 fused ring heterocycloalkyl group is a C 5 ⁇ C 14 fused ring heterocycloalkyl group;
  • the C 3 -C 14 spirocyclic heterocycloalkyl group is a C 5 -C 14 spirocyclic heterocycloalkyl group.
  • R 2 is -NR 2-1 R 2-2 .
  • R 4 is -NR 2-1 R 2-2 or optionally substituted by 1, 2 or 3 R 2-9 : C 1 ⁇ C 7 alkyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl.
  • R 2-1 and R 2-2 are independently a C 1 -C 7 alkyl group.
  • R 2-9 is independently C 1 -C 7 alkyl or C 3 -C 14 heterocycloalkyl.
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-3 is independently C 3 ⁇ C 14 heterocycloalkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • R 3 and R 4 are independently -NR 2-1 R 2-2 , or, optionally substituted by one R 2-9 : C 1 -C 7 alkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 or C 3 ⁇ C 14 cycloalkyl
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • R 2-1 and R 2-2 are independently hydrogen, C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-3 is independently -NR 2-3-1 R 2-3-2 , -OR 2-3-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-3-1 and R 2-3-2 are independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-3-3 is independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-4 is independently hydrogen, -CN or -OR 2-4-1 ;
  • R 2-4-1 is independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-5 is independently -NR 2-5-1 R 2-5-2 or C 1 ⁇ C 7 alkyl
  • R 2-5-1 and R 2-5-2 are independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-6 is independently -NR 2-6-1 R 2-6-2 ;
  • R 2-6-1 and R 2-6-2 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 3 ⁇ C 14 cycloalkyl or C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently C 1 ⁇ C 7 alkyl
  • R 2-9-5 is independently hydrogen, -NR 2-9-5-1 R 2-9-5-2 , -OR 2-9-5-3 or C 1 ⁇ C 7 alkyl;
  • R 2-9-5-1 , R 2-9-5-2 and R 2-9-5-3 are independently hydrogen or C 1 ⁇ C 7 alkyl;
  • R 2-9-8 is independently -NR 2-9-8-1 R 2-9-8-2 ;
  • R 2-9-8-1 and R 2-9-8-2 are independently hydrogen, C 1 to C 7 alkyl, C 3 to C 14 cycloalkyl, or C 3 to C 14 heterocycloalkyl.
  • L is -(CH 2 ) m -R 2 , C 3 ⁇ C 20 cycloalkyl substituted with one R 3 , C 3 ⁇ C 14 heterocycloalkyl, or, C 3 ⁇ substituted with one R 4 C 14 heterocycloalkyl;
  • m is 1 or 2, and can also be 3;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-3 is independently C 3 ⁇ C 14 heterocycloalkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • L is a C 3 ⁇ C 20 cycloalkyl group, a C 3 ⁇ C 14 heterocycloalkyl group substituted by one R 3 , or a C 3 ⁇ C 14 heterocycloalkyl group substituted by one R 4 ;
  • R 3 and R 4 are independently -NR 2-1 R 2-2 , or, optionally substituted by one R 2-9 : C 1 -C 7 alkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 or C 3 ⁇ C 14 cycloalkyl
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • R 2 , R 3 and R 4 are independently -NR 2-1 R 2-2 , R 2-1 and R 2-2 are independently hydrogen, C 1 ⁇ C 7 alkyl or C 3 to C 14 cycloalkyl.
  • R 2 , R 3 and R 4 are independently -NR 2-1 R 2-2 , and R 2-1 and R 2-2 are independently C 1 -C 7 alkyl.
  • L is a C 3 ⁇ C 20 cycloalkyl group, or a C 3 ⁇ C 20 cycloalkyl group substituted by 1 or 2 R 3 .
  • L is C 3 ⁇ C 20 cycloalkyl substituted with 1 or 2 R 3 ;
  • R 3 is independently -NR 2-1 R 2-2 , or, optionally by 1 R 2-9 substituted: C 1 ⁇ C 7 alkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl;
  • R 2-9 are independently -NR 2-9-2 R 2 -9-3 or C 3 ⁇ C 14 cycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently C 1 ⁇ C 7 alkyl.
  • L is C 3 ⁇ C 14 heterocycloalkyl, or C 3 ⁇ C 14 heterocycloalkyl substituted with 1 or 2 R 4 ; said C 3 ⁇ C 14 heterocycle
  • the alkyl group is a C 3 to C 14 spirocyclic heterocycloalkyl group.
  • L is a C 3 ⁇ C 14 heterocycloalkyl group, or a C 3 ⁇ C 14 heterocycloalkyl group substituted by one R 4 ; the C 3 ⁇ C 14 heterocycloalkyl group is C 3 ⁇ C 14 spirocyclic heterocycloalkyl;
  • R 4 is independently -NR 2-1 R 2-2 , or, optionally substituted by one R 2-9 : C 1 ⁇ C 7 alkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl;
  • R 2-9 are independently -NR 2-9-2 R 2-9-3 or C 3 ⁇ C 14 cycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • L is C 3 ⁇ C 14 heterocycloalkyl, or C 3 ⁇ C 14 heterocycloalkyl substituted with 1 or 2 R 4 ; said C 3 ⁇ C 14 heterocycle
  • the alkyl group is a C 3 to C 14 condensed ring heterocycloalkyl group.
  • L is a C 3 ⁇ C 14 heterocycloalkyl group, or a C 3 ⁇ C 14 heterocycloalkyl group substituted by 1 R 4 ; the C 3 ⁇ C 14 heterocycloalkyl group C 3 ⁇ C 14 fused ring heterocycloalkyl;
  • R 4 is independently -NR 2-1 R 2-2 , or, optionally substituted by one R 2-9 : C 1 ⁇ C 7 alkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl;
  • R 2-9 are independently -NR 2-9-2 R 2-9-3 or C 3 ⁇ C 14 cycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • L is C 3 ⁇ C 14 heterocycloalkyl, or C 3 ⁇ C 14 heterocycloalkyl substituted with 1 or 2 R 4 ; said C 3 ⁇ C 14 heterocycle
  • the alkyl group is a C 3 to C 14 bridged ring heterocycloalkyl group.
  • L is a C 3 ⁇ C 14 heterocycloalkyl group, or a C 3 ⁇ C 14 heterocycloalkyl group substituted by one R 4 ; the C 3 ⁇ C 14 heterocycloalkyl group is C 3 ⁇ C 14 bridged cyclic heterocycloalkyl;
  • R 4 is independently -NR 2-1 R 2-2 , or, optionally substituted by one R 2-9 : C 1 ⁇ C 7 alkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl;
  • R 2-9 are independently -NR 2-9-2 R 2-9-3 or C 3 ⁇ C 14 cycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • L is -(CH 2 ) m -R 2 .
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is - (CH 2) m -R 2 , C 3 ⁇ C 20 cycloalkyl, or a substituted 3 2 R C 3 ⁇ C 20 cycloalkyl group, C 3 ⁇ C 14 heterocycloalkyl, Or, C 3 ⁇ C 14 heterocycloalkyl substituted with 1 or 2 R 4 ;
  • n 1, 2, 3 or 4;
  • R 2-1 and R 2-2 are independently hydrogen, C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-3 is independently -NR 2-3-1 R 2-3-2 , -OR 2-3-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-3-1 and R 2-3-2 are independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-3-3 is independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-4 is independently hydrogen, -CN or -OR 2-4-1 ;
  • R 2-4-1 is independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-5 is independently -NR 2-5-1 R 2-5-2 or C 1 ⁇ C 7 alkyl
  • R 2-5-1 and R 2-5-2 are independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-6 is independently -NR 2-6-1 R 2-6-2 ;
  • R 2-6-1 and R 2-6-2 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 3 ⁇ C 14 cycloalkyl or C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently C 1 ⁇ C 7 alkyl
  • R 2-9-5 is independently hydrogen, -NR 2-9-5-1 R 2-9-5-2 , -OR 2-9-5-3 or C 1 ⁇ C 7 alkyl;
  • R 2-9-5-1 , R 2-9-5-2 and R 2-9-5-3 are independently hydrogen or C 1 ⁇ C 7 alkyl;
  • R 2-9-8 is independently -NR 2-9-8-1 R 2-9-8-2 ;
  • R 2-9-8-1 and R 2-9-8-2 are independently hydrogen, C 1 to C 7 alkyl, C 3 to C 14 cycloalkyl, or C 3 to C 14 heterocycloalkyl.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is -(CH 2 ) m -R 2 , C 3 ⁇ C 20 cycloalkyl substituted with one R 3 , C 3 ⁇ C 14 heterocycloalkyl, or, C 3 ⁇ substituted with one R 4 C 14 heterocycloalkyl;
  • m is 1 or 2, and can also be 3;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-3 is independently C 3 ⁇ C 14 heterocycloalkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is a C 3 ⁇ C 20 cycloalkyl group, a C 3 ⁇ C 14 heterocycloalkyl group substituted by one R 3 , or a C 3 ⁇ C 14 heterocycloalkyl group substituted by one R 4 ;
  • R 3 and R 4 are independently -NR 2-1 R 2-2 , or, optionally substituted by one R 2-9 : C 1 -C 7 alkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 or C 3 ⁇ C 14 cycloalkyl
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is -(CH 2 ) m -R 2 , C 3 ⁇ C 20 cycloalkyl substituted by 1 or 2 R 3 , or C 3 ⁇ C 14 heterocycle substituted by 1 or 2 R 4 alkyl;
  • n 1, 2, 3 or 4;
  • R 2 , R 3 and R 4 are independently -NR 2-1 R 2-2 ;
  • R 2-1 and R 2-2 are independently hydrogen, C 1 -C 7 alkyl or C 3 -C 14 cycloalkyl.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is -(CH 2 ) m -R 2 , a C 3 ⁇ C 20 cycloalkyl group substituted by one R 3 or a C 3 ⁇ C 14 heterocycloalkyl group substituted by one R 4 ;
  • m is 1 Or 2, can also be 3;
  • R 2 , R 3 and R 4 are independently -NR 2-1 R 2-2 ;
  • R 2-1 and R 2-2 are independently a C 1 -C 7 alkyl group.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is a C 3 ⁇ C 20 cycloalkyl group substituted with one R 3 or a C 3 ⁇ C 14 heterocycloalkyl group substituted with one R 4 ;
  • R 3 and R 4 are independently -NR 2-1 R 2-2 ;
  • R 2-1 and R 2-2 are independently a C 1 -C 7 alkyl group.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is a C 3 ⁇ C 20 cycloalkyl group, or a C 3 ⁇ C 20 cycloalkyl group substituted by 1 or 2 R 3 ;
  • R 2-1 and R 2-2 are independently hydrogen, C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-3 is independently -NR 2-3-1 R 2-3-2 , -OR 2-3-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-3-1 and R 2-3-2 are independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-3-3 is independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-4 is independently hydrogen, -CN or -OR 2-4-1 ;
  • R 2-4-1 is independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-5 is independently -NR 2-5-1 R 2-5-2 or C 1 ⁇ C 7 alkyl
  • R 2-5-1 and R 2-5-2 are independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-6 is independently -NR 2-6-1 R 2-6-2 ;
  • R 2-6-1 and R 2-6-2 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 3 ⁇ C 14 cycloalkyl or C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently C 1 ⁇ C 7 alkyl
  • R 2-9-5 is independently hydrogen, -NR 2-9-5-1 R 2-9-5-2 , -OR 2-9-5-3 or C 1 ⁇ C 7 alkyl;
  • R 2-9-5-1 , R 2-9-5-2 and R 2-9-5-3 are independently hydrogen or C 1 ⁇ C 7 alkyl;
  • R 2-9-8 is independently -NR 2-9-8-1 R 2-9-8-2 ;
  • R 2-9-8-1 and R 2-9-8-2 are independently hydrogen, C 1 to C 7 alkyl, C 3 to C 14 cycloalkyl, or C 3 to C 14 heterocycloalkyl.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is a C 3 ⁇ C 20 cycloalkyl substituted by 1 R 3 ;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-3 is independently C 3 ⁇ C 14 heterocycloalkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is a C 3 ⁇ C 20 cycloalkyl substituted by 1 R 3 ;
  • R 3 is independently -NR 2-1 R 2-2 or, optionally substituted by one R 2-9 : C 1 ⁇ C 7 alkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 or C 3 ⁇ C 14 cycloalkyl
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is a C 3 ⁇ C 14 heterocycloalkyl group, or a C 3 ⁇ C 14 heterocycloalkyl group substituted by one or two R 4 ; the C 3 ⁇ C 14 heterocycloalkyl group is C 3 ⁇ C 14 spirocyclic heterocycloalkyl;
  • R 2-1 and R 2-2 are independently hydrogen, C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-3 is independently -NR 2-3-1 R 2-3-2 , -OR 2-3-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-3-1 and R 2-3-2 are independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-3-3 is independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-4 is independently hydrogen, -CN or -OR 2-4-1 ;
  • R 2-4-1 is independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-5 is independently -NR 2-5-1 R 2-5-2 or C 1 ⁇ C 7 alkyl
  • R 2-5-1 and R 2-5-2 are independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-6 is independently -NR 2-6-1 R 2-6-2 ;
  • R 2-6-1 and R 2-6-2 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 3 ⁇ C 14 cycloalkyl or C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently C 1 ⁇ C 7 alkyl
  • R 2-9-5 is independently hydrogen, -NR 2-9-5-1 R 2-9-5-2 , -OR 2-9-5-3 or C 1 ⁇ C 7 alkyl;
  • R 2-9-5-1 , R 2-9-5-2 and R 2-9-5-3 are independently hydrogen or C 1 ⁇ C 7 alkyl;
  • R 2-9-8 is independently -NR 2-9-8-1 R 2-9-8-2 ;
  • R 2-9-8-1 and R 2-9-8-2 are independently hydrogen, C 1 to C 7 alkyl, C 3 to C 14 cycloalkyl, or C 3 to C 14 heterocycloalkyl.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is a C 3 ⁇ C 14 heterocycloalkyl group, or a C 3 ⁇ C 14 heterocycloalkyl group substituted by one R 4 ; the C 3 ⁇ C 14 heterocycloalkyl group is a C 3 ⁇ C 14 spiro Cycloheterocycloalkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-3 is independently C 3 ⁇ C 14 heterocycloalkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is a C 3 ⁇ C 14 heterocycloalkyl group, or a C 3 ⁇ C 14 heterocycloalkyl group substituted by one R 4 ; the C 3 ⁇ C 14 heterocycloalkyl group is a C 3 ⁇ C 14 spiro Cycloheterocycloalkyl;
  • R 4 is independently -NR 2-1 R 2-2 or, optionally substituted by one R 2-9 : C 1 ⁇ C 7 alkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 or C 3 ⁇ C 14 cycloalkyl
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is a C 3 ⁇ C 14 heterocycloalkyl group, or a C 3 ⁇ C 14 heterocycloalkyl group substituted by one or two R 4 ; the C 3 ⁇ C 14 heterocycloalkyl group is C 3 ⁇ C 14 fused ring heterocycloalkyl;
  • R 2-1 and R 2-2 are independently hydrogen, C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-3 is independently -NR 2-3-1 R 2-3-2 , -OR 2-3-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-3-1 and R 2-3-2 are independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-3-3 is independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-4 is independently hydrogen, -CN or -OR 2-4-1 ;
  • R 2-4-1 is independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-5 is independently -NR 2-5-1 R 2-5-2 or C 1 ⁇ C 7 alkyl
  • R 2-5-1 and R 2-5-2 are independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-6 is independently -NR 2-6-1 R 2-6-2 ;
  • R 2-6-1 and R 2-6-2 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 3 ⁇ C 14 cycloalkyl or C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently C 1 ⁇ C 7 alkyl
  • R 2-9-5 is independently hydrogen, -NR 2-9-5-1 R 2-9-5-2 , -OR 2-9-5-3 or C 1 ⁇ C 7 alkyl;
  • R 2-9-5-1 , R 2-9-5-2 and R 2-9-5-3 are independently hydrogen or C 1 ⁇ C 7 alkyl;
  • R 2-9-8 is independently -NR 2-9-8-1 R 2-9-8-2 ;
  • R 2-9-8-1 and R 2-9-8-2 are independently hydrogen, C 1 to C 7 alkyl, C 3 to C 14 cycloalkyl, or C 3 to C 14 heterocycloalkyl.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is a C 3 ⁇ C 14 heterocycloalkyl group, or a C 3 ⁇ C 14 heterocycloalkyl group substituted by one R 4 ; the C 3 ⁇ C 14 heterocycloalkyl group is a C 3 ⁇ C 14 fused Cycloheterocycloalkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-3 is independently C 3 ⁇ C 14 heterocycloalkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is a C 3 ⁇ C 14 heterocycloalkyl group or a C 3 ⁇ C 14 heterocycloalkyl group substituted by one R 4 ; the C 3 ⁇ C 14 heterocycloalkyl group is C 3 ⁇ C 14 Condensed ring heterocycloalkyl;
  • R 4 is independently -NR 2-1 R 2-2 or, optionally substituted by one R 2-9 : C 1 ⁇ C 7 alkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 or C 3 ⁇ C 14 cycloalkyl
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is a C 3 ⁇ C 14 heterocycloalkyl group, or a C 3 ⁇ C 14 heterocycloalkyl group substituted by one or two R 4 ; the C 3 ⁇ C 14 heterocycloalkyl group is C 3 ⁇ C 14 bridged ring heterocycloalkyl;
  • R 2-1 and R 2-2 are independently hydrogen, C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-3 is independently -NR 2-3-1 R 2-3-2 , -OR 2-3-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-3-1 and R 2-3-2 are independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-3-3 is independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-4 is independently hydrogen, -CN or -OR 2-4-1 ;
  • R 2-4-1 is independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-5 is independently -NR 2-5-1 R 2-5-2 or C 1 ⁇ C 7 alkyl
  • R 2-5-1 and R 2-5-2 are independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-6 is independently -NR 2-6-1 R 2-6-2 ;
  • R 2-6-1 and R 2-6-2 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 3 ⁇ C 14 cycloalkyl or C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently C 1 ⁇ C 7 alkyl
  • R 2-9-5 is independently hydrogen, -NR 2-9-5-1 R 2-9-5-2 , -OR 2-9-5-3 or C 1 ⁇ C 7 alkyl;
  • R 2-9-5-1 , R 2-9-5-2 and R 2-9-5-3 are independently hydrogen or C 1 ⁇ C 7 alkyl;
  • R 2-9-8 is independently -NR 2-9-8-1 R 2-9-8-2 ;
  • R 2-9-8-1 and R 2-9-8-2 are independently hydrogen, C 1 to C 7 alkyl, C 3 to C 14 cycloalkyl, or C 3 to C 14 heterocycloalkyl.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is a C 3 ⁇ C 14 heterocycloalkyl group, or a C 3 ⁇ C 14 heterocycloalkyl group substituted by one R 4 ; the C 3 ⁇ C 14 heterocycloalkyl group is a C 3 ⁇ C 14 bridge Cycloheterocycloalkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-3 is independently C 3 ⁇ C 14 heterocycloalkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is a C 3 ⁇ C 14 heterocycloalkyl group, or a C 3 ⁇ C 14 heterocycloalkyl group substituted by one R 4 ; the C 3 ⁇ C 14 heterocycloalkyl group is a C 3 ⁇ C 14 bridge Cycloheterocycloalkyl;
  • R 4 is independently -NR 2-1 R 2-2 or, optionally substituted by one R 2-9 : C 1 ⁇ C 7 alkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 or C 3 ⁇ C 14 cycloalkyl
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is -(CH 2 ) m -R 2 ;
  • n 1, 2, 3 or 4;
  • R 2-1 and R 2-2 are independently hydrogen, C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-3 is independently -NR 2-3-1 R 2-3-2 , -OR 2-3-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-3-1 and R 2-3-2 are independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-3-3 is independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-4 is independently hydrogen, -CN or -OR 2-4-1 ;
  • R 2-4-1 is independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-5 is independently -NR 2-5-1 R 2-5-2 or C 1 ⁇ C 7 alkyl
  • R 2-5-1 and R 2-5-2 are independently hydrogen or C 1 ⁇ C 7 alkyl
  • R 2-6 is independently -NR 2-6-1 R 2-6-2 ;
  • R 2-6-1 and R 2-6-2 are independently hydrogen, C 1 ⁇ C 7 alkyl, C 3 ⁇ C 14 cycloalkyl or C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently C 1 ⁇ C 7 alkyl
  • R 2-9-5 is independently hydrogen, -NR 2-9-5-1 R 2-9-5-2 , -OR 2-9-5-3 or C 1 ⁇ C 7 alkyl;
  • R 2-9-5-1 , R 2-9-5-2 and R 2-9-5-3 are independently hydrogen or C 1 ⁇ C 7 alkyl;
  • R 2-9-8 is independently -NR 2-9-8-1 R 2-9-8-2 ;
  • R 2-9-8-1 and R 2-9-8-2 are independently hydrogen, C 1 to C 7 alkyl, C 3 to C 14 cycloalkyl, or C 3 to C 14 heterocycloalkyl.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is -(CH 2 ) m -R 2 ; m is 1 or 2, and can also be 3;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-3 is independently C 3 ⁇ C 14 heterocycloalkyl
  • R 2-9 is independently -NR 2-9-2 R 2-9-3 , C 1 ⁇ C 7 alkyl or C 3 ⁇ C 14 cycloalkyl;
  • R 2-9-2 and R 2-9-3 are independently a C 1 -C 7 alkyl group.
  • R 1 is hydrogen or methyl
  • n 1 or 2;
  • L is -(CH 2 ) m -R 2 , C 3 ⁇ C 14 fused ring heterocycloalkyl substituted with 1 or 2 R 4 , or C 3 ⁇ C substituted with 1 or 2 R 4 14 Spirocyclic heterocycloalkyl;
  • the C 3 ⁇ C 14 fused ring heterocycloalkyl group is a C 5 ⁇ C 14 fused ring heterocycloalkyl group;
  • the C 3 ⁇ C 14 spirocyclic heterocycloalkyl group is a C 5 ⁇ C 14 spirocyclic heterocycloalkyl group;
  • R 2 is -NR 2-1 R 2-2 ;
  • R 4 is -NR 2-1 R 2-2 or optionally substituted by 1, 2 or 3 R 2-9 : C 1 ⁇ C 7 alkyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl.
  • R 1 is hydrogen
  • n 1;
  • L is -(CH 2 ) m -R 2 , C 3 ⁇ C 14 fused ring heterocycloalkyl substituted with 1 or 2 R 4 , or C 3 ⁇ C substituted with 1 or 2 R 4 14 Spirocyclic heterocycloalkyl;
  • the C 3 ⁇ C 14 fused ring heterocycloalkyl group is a C 5 ⁇ C 14 fused ring heterocycloalkyl group;
  • the C 3 ⁇ C 14 spirocyclic heterocycloalkyl group is a C 5 ⁇ C 14 spirocyclic heterocycloalkyl group;
  • R 2 is -NR 2-1 R 2-2 ;
  • R 4 is -NR 2-1 R 2-2 or optionally substituted by 1, 2 or 3 R 2-9 : C 1 ⁇ C 7 alkyl, C 3 ⁇ C 14 cycloalkyl, C 3 ⁇ C 14 heterocycloalkyl;
  • R 2-1 and R 2-2 are independently C 1 ⁇ C 7 alkyl
  • R 2-9 is independently C 1 -C 7 alkyl or C 3 -C 14 heterocycloalkyl.
  • the pyrazolo pyrimidine compound represented by formula I has any of the following structures:
  • the pyrazolo pyrimidine compound represented by formula I is any of the following compounds:
  • the retention time is 9.66min under the following conditions (I-30-1): Agilent 1260 high performance liquid chromatograph; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; column time: 15min; column type: Waters company Xselect, 5 ⁇ m, 4.6 ⁇ 250mm ; Gradient elution, 5% mobile phase B ⁇ 50% mobile phase B;
  • the retention time is 10.04min under the following conditions (I-30-2): Agilent 1260 high performance liquid chromatograph; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; column time: 15min; column type: Waters Xselect, 5 ⁇ m, 4.6 ⁇ 250mm ; Gradient elution, 5% mobile phase B ⁇ 50% mobile phase B;
  • the retention time is 7.80min under the following conditions (I-36-1): Agilent 1260 high performance liquid chromatograph; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; column time: 15min; column type: Waters Xselect, 5 ⁇ m, 4.6 ⁇ 250mm ; Gradient elution, 5% mobile phase B ⁇ 95% mobile phase B;
  • the retention time is 7.97min under the following conditions (I-36-2): Agilent 1260 high performance liquid chromatograph; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; column time: 15 min; column type: Waters Xselect, 5 ⁇ m, 4.6 ⁇ 250mm ; Gradient elution, 5% mobile phase B ⁇ 95% mobile phase B;
  • the present invention also provides a method for preparing the aforementioned compound I, which includes the following steps: Step 1, Compound 1A and Compound 1B are reacted by CN coupling to obtain Compound 1C; Step 2, Compound 1C is first formed under the action of an oxidizing agent The intermediate sulfoxide with higher activity is then substituted with compound 1D to obtain compound I;
  • the conditions and steps of the reaction in the preparation method of Compound I can be conventional conditions and steps in the art.
  • the following conditions and steps are particularly preferred in the present invention:
  • the CN coupling reaction is a coupling method commonly used in the art to construct CN bonds, such as Ullmann reaction, Buchwald reaction, preferably Ullmann reaction, more preferably cuprous iodide/potassium carbonate/N,N-di Reaction conditions for isopropylethylamine/dioxane.
  • the oxidant is preferably m-chloroperoxybenzoic acid (m-CPBA);
  • the conditions of the substitution reaction are the reaction conditions commonly used in the field for substitution, such as alkaline conditions or acidic conditions, and alkaline conditions are preferred For diisopropylethylamine, trifluoroacetic acid is preferred for acidic conditions.
  • the compound 1A can also be obtained by the method shown in the following reaction formula 1: step 1, compound 1A1 is reacted with a bromination reagent in an organic solvent to obtain compound 1A2; step 2, compound 1A2 is oxidized to pyridine Oxidation is performed to obtain compound 1A3 with higher reactivity; in step three, compound 1A3 is reacted with a nucleophile to obtain compound 1A4; in step four, compound 1A4 is deacetylated under alkaline conditions to obtain compound 1A;
  • R 1 is hydrogen; n is 1 or 2.
  • reaction conditions and steps described in Reaction Formula 1 can be conventional conditions and steps in the field, and the following conditions are particularly preferred in the present invention:
  • the organic solvent is preferably a high boiling point solvent, such as toluene and acetonitrile;
  • the bromination reagent is preferably trimethylsilyl bromide and phosphorus oxybromide;
  • the reaction temperature is preferably 120°C to 150°C, and conventional heating reaction or microwave heating reaction.
  • the oxidizing agent can be an oxidizing agent commonly used in the art for the oxidation of nitrogen to nitrogen oxides, preferably m-chloroperoxybenzoic acid (m-CPBA).
  • m-CPBA m-chloroperoxybenzoic acid
  • the nucleophile is preferably acid anhydride, such as acetic anhydride.
  • the alkaline conditions are the conditions commonly used in the art to remove acetyl groups, preferably potassium hydroxide is used to remove acetyl groups in an ethanol solvent.
  • the compound 1A can also be obtained by the method shown in the following reaction formula 2: step one, compound 1A' is oxidized under the action of an oxidizing agent to form compound 1A5; step two, compound 1A5 is in the Grignard reagent Compound 1A was obtained under attack.
  • R 1 is a methyl group; n is 1 or 2.
  • the conditions and steps of the reaction in Reaction Formula 2 can be conventional conditions and steps in the field, and the following conditions are particularly preferred in the present invention:
  • the oxidant is a condition commonly used in the art for the oxidation of hydroxyl to form an aldehyde or ketone, preferably a Dess-Martin reagent.
  • Compound 1A' is prepared by the method of Reaction Formula 1 in the first method.
  • the Grignard reagent is a Grignard reagent commonly used in the field, preferably a methyl Grignard reagent.
  • the present invention also provides a compound represented by formula 1C:
  • R 1 is hydrogen or methyl; n is 1 or 2.
  • the compound represented by formula 1C can have any of the following structures:
  • the present invention also provides an application of substance X in the preparation of inhibitors of kinases (such as WEE1 kinase);
  • the substance X is the pyrazolone compound represented by formula I, its pharmaceutically acceptable salt, its solvate, or the solvate of its pharmaceutically acceptable salt.
  • the kinase inhibitor can be a kinase inhibitor used in vitro.
  • the invention also provides an application of substance X in the preparation of medicines
  • the substance X is the pyrazolone compound represented by formula I, its pharmaceutically acceptable salt, its solvate, or the solvate of its pharmaceutically acceptable salt.
  • the present invention also provides an application of substance X in the preparation of medicines; the medicines are used to treat and/or prevent diseases related to WEE1 kinase;
  • the substance X is the pyrazolone compound represented by formula I, its pharmaceutically acceptable salt, its solvate, or the solvate of its pharmaceutically acceptable salt.
  • the diseases related to WEEl kinase are cancers.
  • the cancer is, for example, brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, gastric cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , Ovarian cancer, villous epithelial cancer, uterine body cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonic cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblast Cell tumor, osteosarcoma, Ewing’s tumor, soft tissue tumor, acute leukemia, chronic lymphatic leukemia, chronic myelogenous leukemia, or, Hodgkin’s lymphoma, such as breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic leukemia, chronic my
  • the present invention also provides an application of substance X in the preparation of medicine; the medicine is used for the treatment and/or prevention of cancer;
  • the substance X is the pyrazolone compound represented by formula I, its pharmaceutically acceptable salt, its solvate, or the solvate of its pharmaceutically acceptable salt.
  • the cancer is, for example, brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, gastric cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , Ovarian cancer, villous epithelial cancer, uterine body cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonic cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblast Cell tumor, osteosarcoma, Ewing’s tumor, soft tissue tumor, acute leukemia, chronic lymphatic leukemia, chronic myelogenous leukemia, or, Hodgkin’s lymphoma, such as breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma,
  • the present invention also provides a method for treating and/or preventing diseases related to WEEl kinase, which comprises administering a therapeutically effective amount of substance X to a patient;
  • the substance X is the pyrazolone compound represented by formula I, its pharmaceutically acceptable salt, its solvate, or the solvate of its pharmaceutically acceptable salt.
  • the diseases related to WEEl kinase are cancers.
  • the cancer is, for example, brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, gastric cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , Ovarian cancer, villous epithelial cancer, uterine body cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonic cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblast Cell tumor, osteosarcoma, Ewing’s tumor, soft tissue tumor, acute leukemia, chronic lymphatic leukemia, chronic myelogenous leukemia, or, Hodgkin’s lymphoma, such as breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic leukemia, chronic my
  • the present invention also provides a method of treating and/or preventing cancer, which comprises administering to a patient a therapeutically effective amount of substance X;
  • the substance X is the pyrazolone compound represented by formula I, its pharmaceutically acceptable salt, its solvate, or the solvate of its pharmaceutically acceptable salt.
  • the cancer is, for example, brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, gastric cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , Ovarian cancer, villous epithelial cancer, uterine body cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonic cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblast Cell tumor, osteosarcoma, Ewing’s tumor, soft tissue tumor, acute leukemia, chronic lymphatic leukemia, chronic myelogenous leukemia, or, Hodgkin’s lymphoma, such as breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma,
  • the present invention also provides a pharmaceutical composition, which comprises substance X and (one or more) pharmaceutical excipients;
  • the substance X is the pyrazolone compound represented by formula I, its pharmaceutically acceptable salt, its solvate, or the solvate of its pharmaceutically acceptable salt.
  • the present invention also provides a combination comprising substance X and anticancer drugs,
  • the substance X is the pyrazolone compound represented by formula I, its pharmaceutically acceptable salt, its solvate, or the solvate of its pharmaceutically acceptable salt.
  • the anti-cancer drugs can be conventional anti-cancer drugs in the art (but not the above-mentioned substance X), such as anti-cancer alkylating agents, anti-cancer metabolic antagonists, anti-cancer antibiotics, and plant-derived Anticancer agents, anticancer platinum coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, mitoxantrone, L -Asparaginase, Procarbazine, dacarbazine, Hydroxyurea, Penstatin, Retinoic Acid, Alfaxet, Alfadarbetine, Anastrozole, Exemestane, Bicalutamide, Leuprolide, flutamide, fulvestrant, pegatanib sodium, diniinterleukin 2, aldesleukin, thyrotropin alpha, arsenic trioxide, bortezomib, capecitabine,
  • the anti-cancer alkylating agent can be a conventional anti-cancer alkylating agent in the art, such as nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, milfalin, busulfan, and two One or more of bromannitol, carbachol, cetepa, ramustine, nimustine, temozolomide, and carmustine.
  • the anti-cancer metabolic antagonist may be a conventional anti-cancer metabolic antagonist in the art, such as methotrexate, 6-mercaptopurine nucleoside, mercaptopurine, 5-fluorouracil, tegafur, and deoxyfluorouria
  • methotrexate 6-mercaptopurine nucleoside
  • mercaptopurine 5-fluorouracil
  • tegafur and deoxyfluorouria
  • 5-fluorouracil is an anti-cancer metabolic antagonist in the art, such as methotrexate, 6-mercaptopurine nucleoside, mercaptopurine, 5-fluorouracil, tegafur, and deoxyfluorouria
  • the anti-cancer antibiotics may be conventional anti-cancer antibiotics in the art, such as actinomycin D, doxorubicin, daunorubicin, neocarcinogen, bleomycin, pelomycin, One or more of mitomycin C, arubicin, pirarubicin, epirubicin, netstatin, idarubicin, sirolimus and valrubicin.
  • the plant-derived anti-cancer agent may be a conventional plant-derived anti-cancer agent in the art, such as vincristine, vinblastine, vindesine, etoposide, sobuzosan, docetaxel, One or more of paclitaxel and vinorelbine.
  • the anticancer platinum coordination compound may be a conventional anticancer platinum coordination compound, such as one or more of cisplatin, carboplatin, nedaplatin, and oxaliplatin.
  • the anti-cancer camptothecin derivative may be a conventional anti-cancer camptothecin derivative in the art, such as one or more of irinotecan, topotecan and camptothecin.
  • the anticancer tyrosine kinase inhibitor may be a conventional anticancer tyrosine kinase inhibitor in the art, such as one or more of gefitinib, imatinib and erlotinib .
  • the monoclonal antibody may be a conventional monoclonal antibody in the field, such as one or more of cetuximab, bevacizumab, rituximab, alemtuzumab and trastuzumab .
  • the interferon may be a conventional interferon in the art, such as one of interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a and interferon gamma-n1 Or multiple.
  • the biological response modifier can be a conventional biological response modifier in the art, such as one or more of Yunzhi polysaccharide, lentinan, cizoran, sapylin, and ubemex.
  • the components in the combination can be used simultaneously or separately (for example, sequentially); when the components in the combination are used at the same time, the components in the combination can be uniformly mixed (that is, the mixture).
  • Each component in the combination can be prepared into a single pharmaceutical composition for simultaneous use, or each component can be prepared into a single independent pharmaceutical composition (for example, in the form of a kit), these single independent pharmaceutical compositions Can be used simultaneously or separately (for example, sequential use).
  • the present invention also provides an application of the above-mentioned combination in the preparation of a medicine for preventing and/or treating cancer.
  • the cancer is, for example, brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, gastric cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , Ovarian cancer, villous epithelial cancer, uterine body cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonic cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblast Cell tumor, osteosarcoma, Ewing’s tumor, soft tissue tumor, acute leukemia, chronic lymphatic leukemia, chronic myelogenous leukemia, or, Hodgkin’s lymphoma, such as breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma,
  • the above-mentioned substance X and the above-mentioned anti-cancer drugs can be administered simultaneously or separately (for example, sequential administration).
  • the present invention also provides a method for treating and/or preventing cancer, which comprises administering to a patient a therapeutically effective amount of the above-mentioned combination.
  • the cancer is, for example, brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, gastric cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , Ovarian cancer, villous epithelial cancer, uterine body cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonic cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblast Cell tumor, osteosarcoma, Ewing’s tumor, soft tissue tumor, acute leukemia, chronic lymphatic leukemia, chronic myelogenous leukemia, or, Hodgkin’s lymphoma, such as breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma,
  • the present invention also provides an application of the above-mentioned substance X in the preparation of a medicine, which is "in combination with the above-mentioned anti-cancer medicine" for preventing and/or treating cancer.
  • the cancer is, for example, brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, gastric cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , Ovarian cancer, villous epithelial cancer, uterine body cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonic cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblast Cell tumor, osteosarcoma, Ewing’s tumor, soft tissue tumor, acute leukemia, chronic lymphatic leukemia, chronic myelogenous leukemia, or, Hodgkin’s lymphoma, such as breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma,
  • the anti-cancer drugs can be conventional anti-cancer drugs in the art (but not the above-mentioned substance X), such as anti-cancer alkylating agents, anti-cancer metabolic antagonists, anti-cancer antibiotics, and plant-derived Anticancer agents, anticancer platinum coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, mitoxantrone, L -Asparaginase, Procarbazine, dacarbazine, Hydroxyurea, Penstatin, Retinoic Acid, Alfaxet, Alfadarbetine, Anastrozole, Exemestane, Bicalutamide, Leuprolide, flutamide, fulvestrant, pegatanib sodium, diniinterleukin 2, aldesleukin, thyrotropin alpha, arsenic trioxide, bortezomib, capecitabine,
  • the anti-cancer alkylating agent can be a conventional anti-cancer alkylating agent in the art, such as nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, milfalin, busulfan, and two One or more of bromannitol, carbachol, cetepa, ramustine, nimustine, temozolomide, and carmustine.
  • the anti-cancer metabolic antagonist may be a conventional anti-cancer metabolic antagonist in the art, such as methotrexate, 6-mercaptopurine nucleoside, mercaptopurine, 5-fluorouracil, tegafur, and deoxyfluorouria
  • methotrexate 6-mercaptopurine nucleoside
  • mercaptopurine 5-fluorouracil
  • tegafur and deoxyfluorouria
  • 5-fluorouracil is an anti-cancer metabolic antagonist in the art, such as methotrexate, 6-mercaptopurine nucleoside, mercaptopurine, 5-fluorouracil, tegafur, and deoxyfluorouria
  • the anti-cancer antibiotics may be conventional anti-cancer antibiotics in the art, such as actinomycin D, doxorubicin, daunorubicin, neocarcinogen, bleomycin, pelomycin, One or more of mitomycin C, arubicin, pirarubicin, epirubicin, netstatin, idarubicin, sirolimus and valrubicin.
  • the plant-derived anti-cancer agent may be a conventional plant-derived anti-cancer agent in the art, such as vincristine, vinblastine, vindesine, etoposide, sobuzosan, docetaxel, One or more of paclitaxel and vinorelbine.
  • the anticancer platinum coordination compound may be a conventional anticancer platinum coordination compound, such as one or more of cisplatin, carboplatin, nedaplatin, and oxaliplatin.
  • the anti-cancer camptothecin derivative may be a conventional anti-cancer camptothecin derivative in the art, such as one or more of irinotecan, topotecan and camptothecin.
  • the anticancer tyrosine kinase inhibitor may be a conventional anticancer tyrosine kinase inhibitor in the art, such as one or more of gefitinib, imatinib and erlotinib .
  • the monoclonal antibody may be a conventional monoclonal antibody in the field, such as one or more of cetuximab, bevacizumab, rituximab, alemtuzumab and trastuzumab .
  • the interferon may be a conventional interferon in the art, such as one of interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a and interferon gamma-n1 Or multiple.
  • the biological response modifier can be a conventional biological response modifier in the art, for example, one or more of Yunzhi polysaccharide, lentinan, cizoran, sapylin, and ubemex.
  • the above-mentioned substance X and the above-mentioned anti-cancer drugs can be administered simultaneously or separately (for example, sequential administration).
  • the present invention also provides an application of the above-mentioned anti-cancer drug in the preparation of a drug, which is "in combination with the above-mentioned substance X" for preventing and/or treating cancer.
  • the cancer is, for example, brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, gastric cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , Ovarian cancer, villous epithelial cancer, uterine body cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonic cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblast Cell tumor, osteosarcoma, Ewing’s tumor, soft tissue tumor, acute leukemia, chronic lymphatic leukemia, chronic myelogenous leukemia, or, Hodgkin’s lymphoma, such as breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma,
  • the anti-cancer drugs can be conventional anti-cancer drugs in the art (but not the above-mentioned substance X), such as anti-cancer alkylating agents, anti-cancer metabolic antagonists, anti-cancer antibiotics, and plant-derived Anticancer agents, anticancer platinum coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, mitoxantrone, L -Asparaginase, Procarbazine, dacarbazine, Hydroxyurea, Penstatin, Retinoic Acid, Alfaxet, Alfadarbetine, Anastrozole, Exemestane, Bicalutamide, Leuprolide, flutamide, fulvestrant, pegatanib sodium, diniinterleukin 2, aldesleukin, thyrotropin alpha, arsenic trioxide, bortezomib, capecitabine,
  • the anti-cancer alkylating agent can be a conventional anti-cancer alkylating agent in the art, such as nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, milfalin, busulfan, and two One or more of bromannitol, carbachol, cetepa, ramustine, nimustine, temozolomide, and carmustine.
  • the anti-cancer metabolic antagonist may be a conventional anti-cancer metabolic antagonist in the art, such as methotrexate, 6-mercaptopurine nucleoside, mercaptopurine, 5-fluorouracil, tegafur, and deoxyfluorouria
  • methotrexate 6-mercaptopurine nucleoside
  • mercaptopurine 5-fluorouracil
  • tegafur and deoxyfluorouria
  • 5-fluorouracil is an anti-cancer metabolic antagonist in the art, such as methotrexate, 6-mercaptopurine nucleoside, mercaptopurine, 5-fluorouracil, tegafur, and deoxyfluorouria
  • the anti-cancer antibiotics may be conventional anti-cancer antibiotics in the art, such as actinomycin D, doxorubicin, daunorubicin, neocarcinogen, bleomycin, pelomycin, One or more of mitomycin C, arubicin, pirarubicin, epirubicin, netstatin, idarubicin, sirolimus and valrubicin.
  • the plant-derived anti-cancer agent may be a conventional plant-derived anti-cancer agent in the art, such as vincristine, vinblastine, vindesine, etoposide, sobuzosan, docetaxel, One or more of paclitaxel and vinorelbine.
  • the anticancer platinum coordination compound may be a conventional anticancer platinum coordination compound, such as one or more of cisplatin, carboplatin, nedaplatin, and oxaliplatin.
  • the anti-cancer camptothecin derivative may be a conventional anti-cancer camptothecin derivative in the art, such as one or more of irinotecan, topotecan and camptothecin.
  • the anticancer tyrosine kinase inhibitor may be a conventional anticancer tyrosine kinase inhibitor in the art, such as one or more of gefitinib, imatinib and erlotinib .
  • the monoclonal antibody may be a conventional monoclonal antibody in the field, such as one or more of cetuximab, bevacizumab, rituximab, alemtuzumab and trastuzumab .
  • the interferon may be a conventional interferon in the art, such as one of interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a and interferon gamma-n1 Or multiple.
  • the biological response modifier can be a conventional biological response modifier in the art, such as one or more of Yunzhi polysaccharide, lentinan, cizoran, sapylin, and ubemex.
  • the above-mentioned substance X and the above-mentioned anti-cancer drugs can be administered simultaneously or separately (for example, sequential administration).
  • the present invention also provides a pharmaceutical composition, which comprises the above-mentioned combination and (one or more) pharmaceutical excipients.
  • the pharmaceutical composition may consist of the combination and the pharmaceutical excipients.
  • the present invention also provides a combination medicine kit, which comprises a pharmaceutical composition A and a pharmaceutical composition B;
  • the pharmaceutical composition A includes the aforementioned substance X, and, (one or more) pharmaceutical excipients;
  • the pharmaceutical composition B includes the aforementioned anticancer drugs and (one or more) pharmaceutical excipients.
  • the combination kit can be composed of the pharmaceutical composition A and the pharmaceutical composition B.
  • the pharmaceutical composition A can be composed of substance X, and, pharmaceutical excipients;
  • the pharmaceutical composition B can be composed of the aforementioned anticancer drugs and pharmaceutical excipients.
  • the anti-cancer drugs can be conventional anti-cancer drugs in the art (but not the above-mentioned substance X), such as anti-cancer alkylating agents, anti-cancer metabolic antagonists, anti-cancer antibiotics, and plant-derived Anticancer agents, anticancer platinum coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, mitoxantrone, L -Asparaginase, Procarbazine, dacarbazine, Hydroxyurea, Penstatin, Retinoic Acid, Alfaxet, Alfadarbetine, Anastrozole, Exemestane, Bicalutamide, Leuprolide, flutamide, fulvestrant, pegatanib sodium, diniinterleukin 2, aldesleukin, thyrotropin alpha, arsenic trioxide, bortezomib, capecitabine,
  • the anti-cancer alkylating agent can be a conventional anti-cancer alkylating agent in the art, such as nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, milfalin, busulfan, and two One or more of bromomannitol, carbachol, cetepa, ramustine, nimustine, temozolomide, and carmustine.
  • the anti-cancer metabolic antagonist may be a conventional anti-cancer metabolic antagonist in the art, such as methotrexate, 6-mercaptopurine nucleoside, mercaptopurine, 5-fluorouracil, tegafur, and deoxyfluorouria
  • methotrexate 6-mercaptopurine nucleoside
  • mercaptopurine 5-fluorouracil
  • tegafur and deoxyfluorouria
  • 5-fluorouracil is an anti-cancer metabolic antagonist in the art, such as methotrexate, 6-mercaptopurine nucleoside, mercaptopurine, 5-fluorouracil, tegafur, and deoxyfluorouria
  • the anti-cancer antibiotics may be conventional anti-cancer antibiotics in the art, such as actinomycin D, doxorubicin, daunorubicin, neocarcinogen, bleomycin, pelomycin, One or more of mitomycin C, arubicin, pirarubicin, epirubicin, netstatin, idarubicin, sirolimus and valrubicin.
  • the plant-derived anti-cancer agent may be a conventional plant-derived anti-cancer agent in the art, such as vincristine, vinblastine, vindesine, etoposide, sobuzosan, docetaxel, One or more of paclitaxel and vinorelbine.
  • the anticancer platinum coordination compound may be a conventional anticancer platinum coordination compound, such as one or more of cisplatin, carboplatin, nedaplatin, and oxaliplatin.
  • the anti-cancer camptothecin derivative may be a conventional anti-cancer camptothecin derivative in the art, such as one or more of irinotecan, topotecan and camptothecin.
  • the anticancer tyrosine kinase inhibitor may be a conventional anticancer tyrosine kinase inhibitor in the art, such as one or more of gefitinib, imatinib and erlotinib .
  • the monoclonal antibody may be a conventional monoclonal antibody in the field, such as one or more of cetuximab, bevacizumab, rituximab, alemtuzumab and trastuzumab .
  • the interferon may be a conventional interferon in the art, such as one of interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a and interferon gamma-n1 Or multiple.
  • the biological response modifier can be a conventional biological response modifier in the art, such as one or more of Yunzhi polysaccharide, lentinan, cizoran, sapylin, and ubemex.
  • Each pharmaceutical composition in the combination kit can be used simultaneously or separately (for example, used sequentially).
  • pharmaceutically acceptable means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients.
  • the "patient” is preferably a mammal, more preferably a human.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • the compound of the present invention contains a relatively acidic functional group, it can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, diethanolamine salt.
  • the acid addition can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.
  • a pharmaceutically acceptable acid include inorganic acids, and the inorganic acids include, but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
  • the pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , Tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (ie 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid)), amino acids (e.g.
  • solvate refers to a substance formed by combining the compound of the present invention with a stoichiometric or non-stoichiometric solvent.
  • the solvent molecules in the solvate can exist in an ordered or non-ordered arrangement.
  • the solvent includes, but is not limited to: water, methanol, ethanol and the like.
  • pharmaceutically acceptable salt solvate and “solvate” in the term “pharmaceutically acceptable salt” and “solvate” are as described above, and refer to compound 1 of the present invention and a relatively non-toxic, pharmaceutically acceptable 2.
  • solvate of a pharmaceutically acceptable salt includes but is not limited to the hydrochloric acid monohydrate of the compound of the present invention.
  • crystal form means that the ions or molecules are arranged strictly and periodically in a three-dimensional space in a certain way, and have the regularity of periodic recurrence at intervals; due to the above-mentioned periodic arrangement, there may be many Crystal form, that is, polymorphism.
  • amorphous means that the ions or molecules present in a disorderly distribution state, that is, there is no periodic arrangement between the ions and molecules.
  • stereoisomer refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotation chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or salting (physical bonding, etc.).
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • the atoms in the terms “compound”, “pharmaceutically acceptable salt”, “solvate” and “solvate of pharmaceutically acceptable salt” may exist in their natural or non-natural abundance.
  • the form of its natural abundance means that about 99.995% of it is protium and about 0.015% is deuterium; the form of its unnatural abundance is, for example, about 95% of it is deuterium. That is, one or more of the atoms in the terms “compound”, “pharmaceutically acceptable salt”, “solvate” and “solvate of pharmaceutically acceptable salt” may be in unnatural abundance.
  • variable such as R 1-1-1
  • the definition in each position of the variable has nothing to do with the definition in the other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted by 1, 2, or 3 R 1-1-1 groups, that is, the group may be substituted by up to 3 R 1-1-1 , the position R 1 -The definition of 1-1 is independent of the definition of the other positions R 1-1-1 .
  • substituents and/or variables are only allowed if the combination produces a stable compound.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a saturated linear or branched monovalent hydrocarbon group having one to twelve carbon atoms (for example, a C 1 -C 6 alkyl group, for example a C 1 -C 4 alkyl group).
  • alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-butyl, 2-methyl-2 -Propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2 -Methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl , 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl,
  • alkenyl refers to a linear or branched monovalent hydrocarbon group of two to twelve carbon atoms with at least one position of unsaturation, that is, a carbon-carbon sp 2 double bond (for example, C 2 -C 6 alkenyl, and For example, C 2 -C 4 alkenyl), and includes groups having "cis” and “trans” orientations or "E” and “Z” orientations. Examples include but are not limited to vinyl and allyl.
  • alkynyl refers to a linear or branched monovalent hydrocarbon group of two to twelve carbon atoms with at least one position of unsaturation, that is, a carbon-carbon triple bond (such as C 2 -C 6 alkynyl, or C 2- C 4 alkynyl). Examples include, but are not limited to, ethynyl and propynyl.
  • cycloalkyl refers to a saturated or partially unsaturated (containing 1 or 2 double bonds), non-aromatic cyclic hydrocarbon radicals (e.g. C 3 -C 6 cycloalkyl) having three to twenty carbon atoms ), including monocyclic cycloalkyl and polycyclic cycloalkyl.
  • the cycloalkyl group contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl Alkyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 5-hexenyl, 1-cyclohex-1-enyl, 1 -Cyclohex-2-enyl, and 1-cyclohex-3-enyl.
  • Polycyclic cycloalkyls are polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, including spiro, fused, and bridged cycloalkyls.
  • spiro-cycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but no ring has a complete Conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl is divided into single spirocycloalkyl and dispirocycloalkane Group or polyspirocycloalkyl, preferably monospirocycloalkyl and bispirocycloalkyl. More preferably, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered Member/6 membered monospirocycloalkyl.
  • spirocycloalkyl examples include but are not limited to: "Fused ring cycloalkyl” refers to a 5- to 20-membered, all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, which may contain one or more double bonds , But no ring has a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • fused cycloalkyl groups include but are not limited to: "Bridged cycloalkyl” refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but none of the rings have Fully conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged cycloalkyl groups include but are not limited to:
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent having 3 to 20 ring atoms, wherein at least one ring atom is independently selected from boron, silicon, oxygen, Heteroatoms of sulfur, selenium, nitrogen and phosphorus, and the remaining ring atoms are C.
  • the group may be a carbon group or a heteroatom group (that is, it may be C-attached or N-attached, as long as it is possible).
  • heterocyclic groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 4-thiomorpholinyl, thio Oxalanyl and piperazinyl.
  • the group derived from tetrahydropyrrole may be tetrahydropyrrol-1-yl (N-attached) or tetrahydropyrrol-3-yl (C-attached).
  • the heterocyclic group may be a monovalent group or a divalent group, that is, a heterocyclylene group. Spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups are also included in the scope of this definition.
  • Spiroheterocyclic group refers to a polycyclic heteroalkane ring group with one atom (called spiro atom) between 5 to 20 membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, Heteroatoms of oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 12 yuan.
  • a spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered, and 6-membered/6-membered monospiro heterocyclic group.
  • Spiro heterocyclic groups include but are not limited to:
  • Condensed heterocyclic group 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, one or more rings May contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system, where one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) The other ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 12 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic ring base.
  • Condensed heterocyclic groups include but are not limited to:
  • Bridged heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but no A ring has a completely conjugated ⁇ -electron system, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 12 yuan.
  • Bridge heterocyclic groups include but are not limited to:
  • aryl refers to any stable monocyclic or bicyclic carbocyclic ring with up to 10 atoms in each ring, at least one of which is aromatic.
  • aryl unit examples include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthracenyl, or acenaphthyl. It is understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is made through the aromatic ring.
  • heteroaryl refers to a stable monocyclic or bicyclic ring with up to 7 atoms in each ring, at least one of which is an aromatic ring and contains 1-4 selected from boron, silicon, oxygen, sulfur, selenium, nitrogen And phosphorus heteroatoms.
  • Heteroaryl groups within the scope of this definition include but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl , Benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, Tetrahydroquinoline.
  • Heteroaryl should also be understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.
  • the heteroaryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or does not contain a heteroatom, it is understood that the connection is made through an aromatic ring, respectively.
  • Heteroaromatic and bicyclic heteroaromatic ring systems can form rings in a condensed form.
  • N, S, B, P or Se is optionally substituted by one or more oxygen atoms to obtain groups like NO, SO, SO 2 , BOH, PO, PO 2 , SeO, and N atoms can be quaternized .
  • the heteroaryl group can be attached to the main structure at any heteroatom or carbon atom to form a stable compound.
  • the heteroaryl group may be a monovalent group or a divalent group, that is, a heteroarylene group.
  • alkoxy refers to an alkyl group connected through an oxygen bridge; the alkyl group is as defined above.
  • alkylmercapto refers to an alkyl group connected through a sulfur bridge; the alkyl group is as defined above.
  • component refers to each component in the combination of the present invention, namely Compound I, its pharmaceutically acceptable salt, its solvate, the solvate of its pharmaceutically acceptable salt, its metabolite or its Prodrugs, or anticancer drugs.
  • pharmaceutical excipients refers to excipients and additives used in the production of drugs and formulating prescriptions, and are all substances contained in pharmaceutical preparations except for the active ingredients. Please refer to the Fourth Edition of the Pharmacopoeia of the People's Republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • treatment refers to therapeutic therapy.
  • treatment refers to: (1) alleviating one or more biological manifestations of the disease or disease, (2) interfering with (a) one or more points in the biological cascade causing or causing the disease, or (b) ) One or more biological manifestations of the disease, (3) Improve one or more symptoms, effects or side effects related to the disease, or one or more symptoms, effects or side effects related to the disease or its treatment, Or (4) to slow down the development of the disease or one or more biological manifestations of the disease.
  • prevention refers to a reduction in the risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound that is sufficient to effectively treat the diseases or conditions described herein when administered to a patient.
  • the “therapeutically effective amount” will vary according to the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted by those skilled in the art as needed.
  • patient refers to any animal that is about to or has received administration of the compound or composition according to an embodiment of the present invention, mammals are preferred, and humans are preferred.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • active ingredient refers to the active ingredient in the pharmaceutical composition or combination kit of the present invention, namely Compound I, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, Its metabolites or its prodrugs, anti-cancer drugs, or their combination of the above.
  • Use wedge keys and dotted keys Represents the absolute configuration of a three-dimensional center.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is that the compound of the present invention has better inhibitory activity on WEEl kinase and has better bioavailability.
  • the structures of all the compounds of the present invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
  • the 1 H NMR chemical shift ( ⁇ ) is recorded in PPM (10 -6 ).
  • NMR was performed by Bruker AVANCE-400 spectrometer.
  • LC-MS is measured by Agilent 1200HPLC/6120 mass spectrometer.
  • HPLC is measured by Agilent 1260 high performance liquid chromatograph. HPLC specific conditions: mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; column time: 15 min; column type: Waters Xselect, 5 ⁇ m, 4.6 ⁇ 250 mm.
  • the thin layer silica gel plate is Liangchen Silicon Source HSGF254 or Qingdao GF254 silica gel plate.
  • Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as a carrier.
  • the 2-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol (0.54g, 2.52mmol) (such as formula I-1-e), 2-allyl- 6-(Methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (0.56g, 2.52mmol) (I-1-f), sodium iodide Copper (0.482g, 2.52mmol), potassium carbonate (0.7g, 5.07mmol) and N1,N2-dimethylethylenediamine (0.46g, 5.2mmol) were added to 20ml of 1,4-dioxane, Under the protection of argon, stir overnight at 105°C.
  • reaction solution was adjusted to 9 with saturated sodium carbonate solution, water (50 mL) ethyl acetate (50 mL) was added, the layers were separated, the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered, evaporated to dryness, and the liquid phase was prepared and purified.
  • the reaction solution was concentrated to obtain a crude product, and the obtained crude product was prepared by high performance liquid phase to obtain 2-allyl-6-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino) -1-(8-hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-1-,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3- Ketoformate (I-28) 25mg, yellow solid, yield 42%.
  • reaction solution was adjusted to 9 with saturated sodium carbonate solution, water (50 mL) ethyl acetate (50 mL) was added, the layers were separated, the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered, evaporated to dryness, and the liquid phase was prepared and purified.
  • the obtained sulfoxide intermediate was dissolved in dimethyl sulfoxide (10 mL), and 4-(5-methylhexahydropyrrolo[3] ,4-c]pyrrole-2(1H)-yl)aniline (I-35-a) ((0.15mmol) and trifluoroacetic acid (0.3mL), the reaction solution was heated to 60°C and stirred for 16 hours.
  • reaction solution was concentrated, dissolved in ethyl acetate, washed twice with saturated sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate, filtered, and the crude product obtained after concentration was separated and purified by thin layer chromatography to obtain a yellow solid (I-38- e) (240mg, 0.835mmol), the yield is 65%.
  • reaction solution was concentrated, dissolved in ethyl acetate, washed twice with saturated sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate, filtered, and the crude product obtained after concentration was separated and purified by thin layer chromatography to obtain a yellow solid (I-39- a) (470mg, 1.21mmol), the yield is 94%.
  • the reaction solution was concentrated, dissolved with a mixture of dichloromethane and methanol (10/1, 20ml), washed twice with saturated sodium bicarbonate, and the organic layer was dried over anhydrous sodium sulfate and filtered.
  • reaction solution was concentrated, dissolved in ethyl acetate, washed twice with saturated sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate, filtered, and the crude product obtained after concentration was separated and purified by thin layer chromatography to obtain a yellow solid (I-41- a) (250mg, 0.830mmol), the yield is 65%.
  • test compound was screened on WEE1 kinase when the ATP concentration was Km. Three compounds were screened on WEEl kinase to evaluate the kinase inhibitory activity of the tested compounds.
  • the initial concentration of the test compound was selected as 100 nM, and each compound was selected at 6 gradient dilution concentrations, the gradient dilution ratio was 4 times, and each concentration was tested in 2 replicate wells, using MK1775 as a standard control.
  • WEE1 purchased from CarnaBiosciences, Inc., product number: 05-177; dimethyl sulfoxide, purchased from Sigma-Aldrich, product number: D8418; ATP, purchased from Sigma-Aldrich, product number: A7699; DTT solution, purchased from Sigma-Aldrich Aldrich, item number: 43816; protein tyrosine kinase (PTK) substrate (poly-Glu-Tyr), purchased from Sigma-Aldrich, item number: P4476; P-Tyr (PY99), purchased from Santa Cruz, item number: sc-7020; Anti -mouse IgG HRP-linked Antibody, purchased from Santa Cruz, item number: 7076S; TMB liquid Substrate System, purchased from Sigma-Aldrich, item number: T0440; Costa Stripwell Microplate No Lid 1 ⁇ 8 FlatBottom, Certified High Binding, purchased from Sigma -Aldrich, item number: 42592; 96-well compound plate
  • Coating substrate 1) Take an appropriate volume of the substrate storage solution protein tyrosine kinase (PTK) substrate (poly-Glu-Tyr), dilute it with PBS 10 times, and dilute the concentration from 250 mg/mL to 25 mg/mL . Add to high adsorption 96-well plate, 125 ⁇ L per well. Place it in a 37°C incubator overnight for coating. 2) After 24 hours, take out the 96-well plate, pour out the liquid in the 96-well plate, wash it 3 times with washing buffer, and dry it upside down in the 37°C incubator for 2 hours.
  • PTK protein tyrosine kinase
  • Compound preparation and transfer 1) Compound dilution: Take 10mM test compound stock solution, dilute the compound in multiple steps with DMSO in a 96-well compound plate to obtain a compound with an initial concentration of 100 ⁇ , and then This concentration of compound is the first concentration.
  • Enzyme reaction stage 1) Use 1 ⁇ reaction buffer to prepare WEE1 kinase and ATP into 2 ⁇ enzyme solution and 4 ⁇ ATP solution respectively. Among them, in this screening, the final concentration of WEE1 kinase is: 0.15ng/ ⁇ L, and the final concentration of ATP is: 12 ⁇ M; 2) Add 20 ⁇ L of 2 enzyme solution to the high adsorption 96-well plate; 3) to the high adsorption 96 well Add 10 ⁇ L of 4 ⁇ ATP solution to the plate, and add 10 ⁇ L of 1 ⁇ reaction buffer to the ATP-control blank; 4) Place the plate in a HERAEUS Multifuge X1R centrifuge at 2000 rpm for 20 seconds, then place it at room temperature for 60 minutes.
  • Reaction termination stage 1) Pour out the reaction solution in the plate, add 200 ⁇ L washing buffer to each well, wash 5 times; add the primary antibody P-Tyr (PY99) (dilution ratio 1:2000), 100 ⁇ L per well, room temperature 30min . 2) Pour out the primary antibody in the plate, add 200 ⁇ L washing buffer to each well, wash 5 times; add the secondary antibody Anti-mouse IgG HRP-linked Antibody (dilution ratio 1:2000), 100 ⁇ L per well, room temperature 30min. 3) Pour out the secondary antibody in the plate, wash 5 times with washing buffer, add TMB, 100 ⁇ L per well, develop color for 10-30min, depending on the color depth. Stop the reaction with 1N sulfuric acid before reading.
  • Detection and data processing 1) Read the light absorption at 450nM wavelength on ThermoScientific MultiScan GO, and read the background at 650nM. 2) Use Graphpad Prism 5.0 to fit the Log (inhibitor) vs. response-Variable slope (four parameters) curve to the data, and calculate the corresponding IC 50 (half maximal inhibitory concentration).
  • the compound inhibits the proliferation of COLO 205 cells and Hela cells.
  • COLO205 cells purchased from SIBS, generation P11; Hela purchased from ATCC, generation P13.
  • Cell culture and inoculation On the first day of the experiment, take the normally cultured cells, in their exponential growth state, after digestion and dispersion, adjust the cell density to 4.375 ⁇ 10 3 cells/mL, and inoculate 40 ⁇ l per well in a 96-well cell culture plate ; After inoculation, place the microtiter plate at 37 degrees Celsius and cultivate under the condition of 5% CO 2 ;
  • Dosing treatment of cells On the third day of the experiment, take out the microplate from the incubator, add 9 ⁇ compound to each well in the microplate, and add 5 ⁇ L to each well, of which each dosing concentration is 2 replicates. Well, each compound has a total of 10 dosing concentrations. According to different cell lines, the initial concentration of each compound is different. After completion, the microplate is placed at 37 degrees Celsius and 5% CO 2 for 72 hours;
  • Cell viability(%) signal value administration/signal value control ⁇ 100%.
  • Graphpad Prism 5.0 was used to perform Log (inhibitor) vs. response-Variable slope (four parameters) curve fitting on the fluorescence signal value at each concentration, and the corresponding IC 50 (half maximal inhibitory concentration) was calculated.
  • Cell culture and seeding On the first day of the experiment, take the normally cultured cells, in their exponential growth state, after digestion and dispersion, adjust the cell density to 9 ⁇ 10 3 cells/mL, and seed 40 ⁇ l per well in a 384-well cell culture plate ; After inoculation, place the microtiter plate at 37 degrees Celsius and cultivate under the condition of 5% CO 2 ;
  • Dosing the cells On the second day of the experiment, take out the microplate from the incubator, and add 9 ⁇ compound to each well of the microplate, and add 5 ⁇ L to each well, with 2 replicates for each dose. Well, each compound has a total of 10 dosing concentrations. According to different cell lines, the initial concentration of each compound is different. After completion, the microplate is placed at 37 degrees Celsius and 5% CO 2 for 72 hours;
  • Cell viability(%) signal value administration/signal value control ⁇ 100%.
  • Graphpad Prism 5.0 was used to perform Log (inhibitor) vs. response-Variable slope (four parameters) curve fitting on the fluorescence signal value at each concentration, and the corresponding IC 50 (half maximal inhibitory concentration) was calculated.

Abstract

本发明公开了一种吡唑酮并嘧啶类化合物、其制备方法及应用。本发明提供了一种如式(I)所示的吡唑酮并嘧啶类化合物，该类化合物对WEE1激酶的抑制活性较佳。

Description

一种吡唑酮并嘧啶类化合物、其制备方法及应用
本申请要求申请日为2019年6月28日的中国专利申请CN201910578299.1的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种吡唑酮并嘧啶类化合物、其制备方法及应用。
背景技术
细胞周期与DNA损伤修复过程密切相关。细胞周期是指细胞***所经历的整个过程，分为细胞***间期(interphase)与***期(mitotic phase，M)两个阶段。细胞周期检验点(checkpoint)是调控细胞周期的一个关键点，主要作用是保证周期中每一事件能按时和有序完成，并且调节细胞状态与外界环境相适应。
细胞主要的检验点有：1)G1/S检验点：在哺乳动物中称作R(restriction)点，控制细胞由静止的G1期进入DNA合成期；2)S期检验点：DNA复制是否完成；3)G2/M检验点：是调节细胞进入***期的控制点；4)中-后期检验点：也称纺锤体组装检验点，如果着丝点没有正确的连接到纺锤体上，就会引起细胞周期的中断。如果细胞***周期某些过程存在异常如DNA损伤，检验点会及时感应并且启动修复。P53蛋白是调控G1检验点的重要蛋白，DNA受损伤时，阻止细胞进入S期，激活DNA修复机制，对于维护细胞基因组的完整性至关重要。但由于肿瘤细胞往往存在P53突变，使得G1检验点缺陷，故在P53突变的细胞中细胞***周期调控依赖G 2/M检验点。
WEE1激酶是一种细胞周期调节蛋白，能调控细胞周期蛋白依赖性激酶1(cyclin-dependent kinase 1，CDK1)的磷酸化状态，从而调节CDK1与细胞周期蛋白B(cyclinB)复合物的活性从而实现对细胞周期的调控，且对DNA损伤检查点具有重要的调节作用。WEE1是G2/M期阻滞的关键基因，起着重要的监测作用，在一些癌症中过表达，抑制或下调WEE1激酶均能引发有丝***灾难，因此WEE1激酶抑制剂在抗癌治疗中有关键作用，目前已成为抗癌剂的研发热点。
国际专利申请WO2019037678、WO2019028008、WO2018133829、WO2010098367、WO2010067886、WO2008115742、WO2008115738、WO2007126122、WO2007126128、WO2004007499等公开了部分小分子WEE1激酶抑制剂，但目前尚未有小分子WEE1激酶抑制剂上市，本领域还需要开发新的抗癌活性好、安全性高的WEE1激酶抑制剂。
发明内容
本发明所要解决的技术问题是现有对WEE1激酶具有抑制活性的化合物结构较为单一，故而，本发明提供了一种吡唑酮并嘧啶类化合物、其制备方法及应用，该类化合物对WEE1激酶的抑制活性较佳。
本发明提供了一种如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物：
Figure PCTCN2020112034-appb-000001
其中，R 1为氢或甲基；
n为1或2；
L为-(CH 2) m-R 2、C 3～C 20环烷基、被1个或2个R 3取代的C 3～C 20环烷基、C 3～C 14杂环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；
m为0、1、2、3或4；
R 2、R 3和R 4独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、-SR 2-8、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-1和R 2-2独立地为氢、-(C＝O)R 2-1-1、-S(＝O) 2R 2-1-2、-(C＝NR 2-1-3)R 2-1-4、或、任选被1个、2个或3个R 2-1-5取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
或者，R 2-1和R 2-2以及与其相连的氮原子形成任选被1个、2个或3个R 2-1-6取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基中的1个或2个以上的亚甲基任选地、独立地被氧原子、硫原子、亚磺酰基、磺酰基、羰基、亚乙烯基或-N(R 2-1-7)-所示的基团替换；R 2-1-7独立地为C 1～C 7烷基或C 3～C 14环烷基；
R 2-1-1、R 2-1-2和R 2-1-4独立地为氢、-NR 2-1-1-1R 2-1-1-2、或、任选被1个、2个或3个R 2- 1-1-3取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-1-1-1和R 2-1-1-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、 C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-1-1-3独立地为卤素、羟基、巯基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7烷硫基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-1-3选自氢、氰基、-OH、C 1～C 7烷基或C 1～C 7烷氧基；
R 2-1-5和R 2-1-6独立地为氰基、卤素、-NR 2-1-5-1R 2-1-5-2、-OR 2-1-5-3、-SR 2-1-5-4或C 1～C 7烷基；
R 2-1-5-1、R 2-1-5-2、R 2-1-5-3和R 2-1-5-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-3独立地为氢、-NR 2-3-1R 2-3-2、-OR 2-3-3、或、任选被1个、2个或3个R 2-3-4取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-3-1和R 2-3-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
或者，R 2-3-1和R 2-3-2以及与其相连的氮原子形成任选被1个、2个或3个R 2-3-1-1取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基中的1个或2个以上的亚甲基任选地、独立地被氧原子、硫原子、亚磺酰基、磺酰基、羰基、亚乙烯基或-N(R 2-3-1-2)-所示的基团替换；R 2-3-1-2独立地为C 1～C 7烷基或C 3～C 14环烷基；
R 2-3-1-1独立地为氰基、卤素、-NR 2-3-1-1-1R 2-3-1-1-2、-OR 2-3-1-1-3、-SR 2-3-1-1-4或C 1～C 7烷基；
R 2-3-1-1-1、R 2-3-1-1-2、R 2-3-1-1-3和R 2-3-1-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-3-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-3-4独立地为氰基、卤素、-NR 2-3-4-1R 2-3-4-2、-OR 2-3-4-3、-SR 2-3-4-4或C 1～C 7烷基；
R 2-3-4-1、R 2-3-4-2、R 2-3-4-3和R 2-3-4-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-4独立地为氢、-CN、-OR 2-4-1或C 1～C 7烷基；
R 2-4-1独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-5独立地为-NR 2-5-1R 2-5-2、-OR 2-5-3、或、任选被1个、2个或3个R 2-5-4取代的： C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-5-1和R 2-5-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
或者，R 2-5-1和R 2-5-2以及与其相连的氮原子形成任选被1个、2个或3个R 2-5-1-1取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基中的1个或2个以上的亚甲基任选地、独立地被氧原子、硫原子、亚磺酰基、磺酰基、羰基、亚乙烯基或-N(R 2-5-1-2)-所示的基团替换；R 2-5-1-2独立地为C 1～C 7烷基或C 3～C 14环烷基；
R 2-5-1-1独立地为氰基、卤素、-NR 2-5-1-1-1R 2-5-1-1-2、-OR 2-5-1-1-3、-SR 2-5-1-1-4或C 1～C 7烷基；
R 2-5-1-1-1、R 2-5-1-1-2、R 2-5-1-1-3和R 2-5-1-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-5-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-5-4独立地为氰基、卤素、-NR 2-5-4-1R 2-5-4-2、-OR 2-5-4-3、-SR 2-5-4-4或C 1～C 7烷基；
R 2-5-4-1、R 2-5-4-2、R 2-5-4-3和R 2-5-4-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-6独立地为-NR 2-6-1R 2-6-2、-OR 2-6-3、或、任选被1个、2个或3个R 2-6-4取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
或者，R 2-6-1和R 2-6-2以及与其相连的氮原子形成任选被1个、2个或3个R 2-6-1-1取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基中的1个或2个以上的亚甲基任选地、独立地被氧原子、硫原子、亚磺酰基、磺酰基、羰基、亚乙烯基或-N(R 2-6-1-2)-所示的基团替换；R 2-6-1-2独立地为C 1～C 7烷基或C 3～C 14环烷基；
R 2-6-1-1独立地为氰基、卤素、-NR 2-6-1-1-1R 2-6-1-1-2、-OR 2-6-1-1-3、-SR 2-6-1-1-4或C 1～C 7烷基；
R 2-6-1-1-1、R 2-6-1-1-2、R 2-6-1-1-3和R 2-6-1-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-6-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂 环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-6-4独立地为氰基、卤素、-NR 2-6-4-1R 2-6-4-2、-OR 2-6-4-3、-SR 2-6-4-4或C 1～C 7烷基；
R 2-6-4-1、R 2-6-4-2、R 2-6-4-3和R 2-6-4-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-7和R 2-8独立地为氢、或、任选被1个、2个或3个R 2-7-1取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-7-1独立地为氰基、卤素、-NR 2-7-1-1R 2-7-1-2、-OR 2-7-1-3、-SR 2-7-1-4或C 1～C 7烷基；
R 2-7-1-1、R 2-7-1-2、R 2-7-1-3和R 2-7-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-9独立地为-OR 2-9-1、-NR 2-9-2R 2-9-3、-SR 2-9-4、卤素、氰基、-(C＝O)R 2-9-5、-(C＝NR 2-9- 6)R 2-9-7、-S(＝O) 2R 2-9-8、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-9-1、R 2-9-2、R 2-9-3和R 2-9-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或、任选被1个、2个或3个R 2-9-5-4取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-9-5-4独立地为氢、卤素、羟基、巯基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7烷硫基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-9-6独立地为氢、-CN、-OR 2-9-6-1或C 1～C 7烷基；
R 2-9-6-1独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-9-7独立地为-NR 2-9-7-1R 2-9-7-2、-OR 2-9-7-3、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-9-7-1和R 2-9-7-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
或者，R 2-9-7-1和R 2-9-7-2以及与其相连的氮原子形成任选被1个、2个或3个R 2-9-7-1-1取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基中的1个或2个以上的亚甲基任选地、 独立地被氧原子、硫原子、亚磺酰基、磺酰基、羰基、亚乙烯基或-N(R 2-9-7-1-2)-所示的基团替换；R 2-9-7-1-2独立地为C 1～C 7烷基或C 3～C 14环烷基；
R 2-9-7-1-1独立地为卤素、羟基、巯基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7烷硫基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-9-7-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2、-OR 2-9-8-3、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
或者，R 2-9-8-1和R 2-9-8-2以及与其相连的氮原子形成任选被1个、2个或3个R 2-9-8-1-1取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基中的1个或2个以上的亚甲基任选地、独立地被氧原子、硫原子、亚磺酰基、磺酰基、羰基、亚乙烯基或-N(R 2-9-8-1-2)-所示的基团替换；R 2-9-8-1-2独立地为C 1～C 7烷基或C 3～C 14环烷基；
R 2-9-8-1-1独立地为卤素、羟基、巯基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7烷硫基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
R 2-9-8-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
以上任一种情况下，所述C 3～C 14杂环烷基、C 1～C 7杂芳基中的杂原子独立地选自硼、硅、氧、硫、硒、氮和磷中的一种或多种；杂原子数独立地为1个、2个、3个或4个。
在某一方案中，所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物里的某些取代基可进一步具有下述的定义，下文未涉及的取代基的定义如上任一方案所述(以下简称为“在某一方案中”)：
当L为被1个或2个R 3取代的C 3～C 20环烷基时，所述的C 3～C 20环烷基例如C 3～C 20单环环烷基、C 3～C 20螺环环烷基、C 3～C 20稠环环烷基或C 3～C 20桥环环烷基。
所述的C 3～C 20单环环烷基例如C 3～C 6单环环烷基，又例如环丙基、环丁基、环戊基或环己基，还例如环己基。
所述的C 3～C 20桥环环烷基例如C 5～C 8桥环环烷基，又例如
Figure PCTCN2020112034-appb-000002
在某一方案中：
当L为被1个或2个R 3取代的C 3～C 20环烷基时，所述的C 3～C 20环烷基例如C 3～C 20饱和环烷基。
在某一方案中：
当R 2-1和R 2-2独立地为C 1～C 7烷基时，所述的C 1～C 7烷基例如C 1～C 3烷基，又例如甲基、乙基、正丙基或异丙基，还例如甲基。
在某一方案中：
当L为被1个R 3取代的C 3～C 20环烷基、R 3为-NR 2-1R 2-2时，所述的“被1个R 3取代的C 3～C 20环烷基”例如
Figure PCTCN2020112034-appb-000003
在某一方案中：
当L为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基例如C 3～C 14单环杂环烷基、C 3～C 14螺环杂环烷基、C 3～C 14稠环杂环烷基或C 3～C 14桥环杂环烷基。
所述的C 3～C 14单环杂环烷基例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 3～C 9单环杂环烷基”，又例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 3～C 5单环杂环烷基”，还例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 3～C 5单环杂环烷基”、且其通过氮原子与苯环连接，再例如吗啉基、哌啶基或哌嗪基。
所述的吗啉基例如
Figure PCTCN2020112034-appb-000004
所述的哌啶基例如
Figure PCTCN2020112034-appb-000005
所述的哌嗪基例如
Figure PCTCN2020112034-appb-000006
所述的C 3～C 14螺环杂环烷基例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 5～C 9螺环杂环烷基”，又例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 7～C 9螺环杂环烷基”，还例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 7～C 9螺环杂环烷基”、且其通过氮原子与苯环连接， 再例如
Figure PCTCN2020112034-appb-000007
还例如
Figure PCTCN2020112034-appb-000008
所述的C 3～C 14稠环杂环烷基例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 6～C 8稠环杂环烷基”，又例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 6～C 8稠环杂环烷基”、且其通过氮原子与苯环连接，还例如
Figure PCTCN2020112034-appb-000009
再例如
Figure PCTCN2020112034-appb-000010
所述的C 3～C 14桥环杂环烷基例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 4～C 6桥环杂环烷基”，又例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 4～C 6桥环杂环烷基”、且其通过氮原子与苯环连接，还例如
Figure PCTCN2020112034-appb-000011
在某一方案中：
当L为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基例如C 3～C 14饱和杂环烷基。
在某一方案中：
当L为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基的杂原子上可无取代基。
在某一方案中：
当L为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基中的亚甲基可不被替代或替换。
在某一方案中：
当L为被1个或2个R 4取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基例如C 3～C 14单环杂环烷基、C 3～C 14螺环杂环烷基、C 3～C 14稠环杂环烷基或C 3～C 14桥环杂环烷基。
所述的C 3～C 14单环杂环烷基例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 3～C 9单环杂环烷基”，又例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 3～C 5单环杂环烷基”，还例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 3～C 5单环杂环烷基”、且其通过氮原子与苯环连接， 再例如吗啉基、哌啶基或哌嗪基。
所述的吗啉基例如
Figure PCTCN2020112034-appb-000012
所述的哌啶基例如
Figure PCTCN2020112034-appb-000013
所述的哌嗪基例如
Figure PCTCN2020112034-appb-000014
所述的C 3～C 14螺环杂环烷基例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 5～C 9螺环杂环烷基”，又例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 7～C 9螺环杂环烷基”，还例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 7～C 9螺环杂环烷基”、且其通过氮原子与苯环连接，再例如
Figure PCTCN2020112034-appb-000015
还例如
Figure PCTCN2020112034-appb-000016
所述的C 3～C 14稠环杂环烷基例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 6～C 8稠环杂环烷基”，又例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 6～C 8稠环杂环烷基”、且其通过氮原子与苯环连接，还例如
Figure PCTCN2020112034-appb-000017
再例如
Figure PCTCN2020112034-appb-000018
所述的C 3～C 14桥环杂环烷基例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 4～C 6桥环杂环烷基”，又例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 4～C 6桥环杂环烷基”、且其通过氮原子与苯环连接，还例如
Figure PCTCN2020112034-appb-000019
在某一方案中：
当L为被1个或2个R 4取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基例如C 3～C 14饱和杂环烷基。
在某一方案中：
当L为被1个或2个R 4取代的C 3～C 14杂环烷基时，除R 4外，所述的C 3～C 14杂环烷 基的杂原子上可无取代基。
在某一方案中：
当L为被1个或2个R 4取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基中的亚甲基可不被替代或替换。
在某一方案中：
当R 4为任选被1个R 2-9取代的C 1～C 7烷基时，所述的C 1～C 7烷基例如C 1～C 3烷基，又例如甲基、乙基、正丙基或异丙基，还例如甲基或乙基。
在某一方案中：
当R 4为C 3～C 14环烷基时，所述的C 3～C 14环烷基例如C 3～C 7环烷基，又例如C 3～C 7单环环烷基，还例如环丁基。
在某一方案中：
当R 4为C 3～C 14环烷基时，所述的C 3～C 14环烷基例如饱和C 3～C 14环烷基。
在某一方案中：
当R 4为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基例如C 3～C 7杂环烷基，又例如C 3～C 7单环杂环烷基，还例如氮杂环丁基，再例如
Figure PCTCN2020112034-appb-000020
在某一方案中：
当R 4为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基例如C 3～C 14饱和杂环烷基。
在某一方案中：
当R 4为任选被1个R 2-9取代的C 3～C 14杂环烷基时，除R 2-9外，所述的C 3～C 14杂环烷基的杂原子上可无取代基。
在某一方案中：
当R 4为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基中的亚甲基可不被替代或替换。
在某一方案中：
当R 2-9独立地为C 3～C 14环烷基时，所述的C 3～C 14环烷基例如C 3～C 14单环环烷基，又例如C 3～C 6单环环烷基，还例如环丙基。
在某一方案中：
当R 2-9独立地为C 3～C 14环烷基时，所述的C 3～C 14环烷基例如C 3～C 14饱和环烷基。
在某一方案中：
当R 2-9-2和R 2-9-3独立地为C 1～C 7烷基时，所述的C 1～C 7烷基例如C 1～C 3烷基，又例如甲基、乙基、正丙基或异丙基，还例如甲基。
在某一方案中：
当L为被1个R 4取代的C 3～C 14杂环烷基、R 4为任选被1个R 2-9取代的C 1～C 7烷基时，所述的“被1个R 4取代的C 3～C 14杂环烷基”例如
Figure PCTCN2020112034-appb-000021
Figure PCTCN2020112034-appb-000022
还例如
Figure PCTCN2020112034-appb-000023
Figure PCTCN2020112034-appb-000024
在某一方案中：
当L为被1个R 4取代的C 3～C 14杂环烷基、R 4为任选被1个R 2-9取代的C 3～C 14环烷基时，所述的“被1个R 4取代的C 3～C 14杂环烷基”为
Figure PCTCN2020112034-appb-000025
在某一方案中：
当L为被1个R 4取代的C 3～C 14杂环烷基、R 4为任选被1个R 2-9取代的C 3～C 14杂环 烷基时，所述的“被1个R 4取代的C 3～C 14杂环烷基”为
Figure PCTCN2020112034-appb-000026
在某一方案中：
当L为被1个R 4取代的C 3～C 14杂环烷基、R 4为-NR 2-1R 2-2时，所述的“被1个R 4取代的C 3～C 14杂环烷基”为
Figure PCTCN2020112034-appb-000027
在某一方案中：
当R 2-3独立地为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基例如C 3～C 14单环杂环烷基。
所述的C 3～C 14单环杂环烷基例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 3～C 9单环杂环烷基”，又例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 3～C 5单环杂环烷基”，还例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 3～C 5单环杂环烷基”、且其通过氮原子与苯环连接，再例如四氢吡咯基。
所述的四氢吡咯基例如
Figure PCTCN2020112034-appb-000028
在某一方案中：
当R 2-3独立地为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基例如C 3～C 14饱和杂环烷基。
在某一方案中：
当R 2-3独立地为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基的杂原子上可无取代基。
在某一方案中：
当R 2-3独立地为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基中的亚甲基可不被替换或替代。
在某一方案中：
当R 2为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的C 3～C 14单环杂环烷基例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 3～C 9单环杂环烷基”，又例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 3～C 5单环杂环烷基”，还例如“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 3～C 5单环杂环烷基”、且其通过氮原子与苯环连接，再例如哌嗪基。
所述的哌嗪基例如
Figure PCTCN2020112034-appb-000029
在某一方案中：
当R 2为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基例如C 3～C 14饱和杂环烷基。
在某一方案中：
当R 2为任选被1个R 2-9取代的C 3～C 14杂环烷基时，除R 2-9外，所述的C 3～C 14杂环烷基的杂原子上可无取代基。
在某一方案中：
当R 2为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基中的亚甲基可不被替换或替代。
在某一方案中：
当R 2-9独立地为C 1～C 7烷基时，所述的C 1～C 7烷基例如C 1～C 3烷基，还例如甲基、乙基、正丙基或异丙基。
在某一方案中：
所述的如式I所示的吡唑酮并嘧啶类化合物中的各异构体的比例可均等，例如外消旋体。
在某一方案中：
所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物中的原子可以均以其天然丰度的形式存在。
在某一方案中：
R 1为氢或甲基。
在某一方案中：
n为1或2。
在某一方案中：
L为-(CH 2) m-R 2、被1个R 3取代的C 3～C 20环烷基、C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；m为1或2，还可为3。
在某一方案中：
L为被1个R 3取代的C 3～C 20环烷基、C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基。
在某一方案中：
L为-(CH 2) m-R 2、被1个或2个R 4取代的C 3～C 14稠环杂环烷基、或、被1个或2个R 4取代的C 3～C 14螺环杂环烷基；
当L为C 3～C 14稠环杂环烷基时，所述的C 3～C 14稠环杂环烷基为C 5～C 14稠环杂环烷基；
当L为C 3～C 14螺环杂环烷基时，所述的C 3～C 14螺环杂环烷基为C 5～C 14螺环杂环烷基。
在某一方案中：
R 2为-NR 2-1R 2-2。
在某一方案中：
R 4为-NR 2-1R 2-2或任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基。
在某一方案中：
R 2-1和R 2-2独立地为C 1～C 7烷基。
在某一方案中：
R 2-9独立地为C 1～C 7烷基或C 3～C 14杂环烷基。
在某一方案中：
L为
Figure PCTCN2020112034-appb-000030
Figure PCTCN2020112034-appb-000031
在某一方案中：
R 2、R 3和R 4独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-3独立地为C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：
R 3和R 4独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：
R 2、R 3和R 4独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基、或、C 1～C 7杂芳基；
R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基；
R 2-3独立地为-NR 2-3-1R 2-3-2、-OR 2-3-3、C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-3-1和R 2-3-2独立地为氢或C 1～C 7烷基；
R 2-3-3独立地为氢或C 1～C 7烷基；
R 2-4独立地为氢、-CN或-OR 2-4-1；
R 2-4-1独立地为氢或C 1～C 7烷基；
R 2-5独立地为-NR 2-5-1R 2-5-2或C 1～C 7烷基；
R 2-5-1和R 2-5-2独立地为氢或C 1～C 7烷基；
R 2-6独立地为-NR 2-6-1R 2-6-2；
R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、卤素、氰基、-(C＝O)R 2-9-5、-S(＝O) 2R 2-9-8、C 1～C 7烷基、 C 3～C 14环烷基或C 3～C 14杂环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或C 1～C 7烷基；
R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢或C 1～C 7烷基；
R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2；
R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基。
在某一方案中：
L为-(CH 2) m-R 2、被1个R 3取代的C 3～C 20环烷基、C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；m为1或2，还可为3；
R 2、R 3和R 4独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-3独立地为C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：
L为被1个R 3取代的C 3～C 20环烷基、C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；
R 3和R 4独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：R 2、R 3和R 4独立地为-NR 2-1R 2-2，R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基。
在某一方案中：R 2、R 3和R 4独立地为-NR 2-1R 2-2，R 2-1和R 2-2独立地为C 1～C 7烷基。
在某一方案中：L为C 3～C 20环烷基、或、被1个或2个R 3取代的C 3～C 20环烷基。
在某一方案中：L为被1个或2个R 3取代的C 3～C 20环烷基；R 3独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；R 2-1和R 2-2独立地为C 1～C 7烷基；R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：L为C 3～C 14杂环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14螺环杂环烷基。
在某一方案中：L为C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14螺环杂环烷基；R 4独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；R 2-1和R 2-2独立地为C 1～C 7烷基；R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：L为C 3～C 14杂环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14稠环杂环烷基。
在某一方案中：L为被C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14稠环杂环烷基；R 4独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；R 2-1和R 2-2独立地为C 1～C 7烷基；R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：L为C 3～C 14杂环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14桥环杂环烷基。
在某一方案中：L为C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14桥环杂环烷基；R 4独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；R 2-1和R 2-2独立地为C 1～C 7烷基；R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：L为-(CH 2) m-R 2。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为-(CH 2) m-R 2、C 3～C 20环烷基、被1个或2个R 3取代的C 3～C 20环烷基、C 3～C 14杂环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；
m为1、2、3或4；
R 2、R 3和R 4独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基、或、C 1～C 7杂芳基；
R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基；
R 2-3独立地为-NR 2-3-1R 2-3-2、-OR 2-3-3、C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-3-1和R 2-3-2独立地为氢或C 1～C 7烷基；
R 2-3-3独立地为氢或C 1～C 7烷基；
R 2-4独立地为氢、-CN或-OR 2-4-1；
R 2-4-1独立地为氢或C 1～C 7烷基；
R 2-5独立地为-NR 2-5-1R 2-5-2或C 1～C 7烷基；
R 2-5-1和R 2-5-2独立地为氢或C 1～C 7烷基；
R 2-6独立地为-NR 2-6-1R 2-6-2；
R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、卤素、氰基、-(C＝O)R 2-9-5、-S(＝O) 2R 2-9-8、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或C 1～C 7烷基；
R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢或C 1～C 7烷基；
R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2；
R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为-(CH 2) m-R 2、被1个R 3取代的C 3～C 20环烷基、C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；m为1或2，还可为3；
R 2、R 3和R 4独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-3独立地为C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为被1个R 3取代的C 3～C 20环烷基、C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；
R 3和R 4独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为-(CH 2) m-R 2、被1个或2个R 3取代的C 3～C 20环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；
m为1、2、3或4；
R 2、R 3和R 4独立地为-NR 2-1R 2-2；
R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为-(CH 2) m-R 2、被1个R 3取代的C 3～C 20环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；m为1或2，还可为3；
R 2、R 3和R 4独立地为-NR 2-1R 2-2；
R 2-1和R 2-2独立地为C 1～C 7烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为被1个R 3取代的C 3～C 20环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；
R 3和R 4独立地为-NR 2-1R 2-2；
R 2-1和R 2-2独立地为C 1～C 7烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为C 3～C 20环烷基、或、被1个或2个R 3取代的C 3～C 20环烷基；
R 3独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基、或、C 1～C 7杂芳基；
R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基；
R 2-3独立地为-NR 2-3-1R 2-3-2、-OR 2-3-3、C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-3-1和R 2-3-2独立地为氢或C 1～C 7烷基；
R 2-3-3独立地为氢或C 1～C 7烷基；
R 2-4独立地为氢、-CN或-OR 2-4-1；
R 2-4-1独立地为氢或C 1～C 7烷基；
R 2-5独立地为-NR 2-5-1R 2-5-2或C 1～C 7烷基；
R 2-5-1和R 2-5-2独立地为氢或C 1～C 7烷基；
R 2-6独立地为-NR 2-6-1R 2-6-2；
R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、卤素、氰基、-(C＝O)R 2-9-5、-S(＝O) 2R 2-9-8、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或C 1～C 7烷基；
R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢或C 1～C 7烷基；
R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2；
R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为被1个R 3取代的C 3～C 20环烷基；
R 3独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-3独立地为C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为被1个R 3取代的C 3～C 20环烷基；
R 3独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为C 3～C 14杂环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14螺环杂环烷基；
R 4独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基、或、C 1～C 7杂芳基；
R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基；
R 2-3独立地为-NR 2-3-1R 2-3-2、-OR 2-3-3、C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-3-1和R 2-3-2独立地为氢或C 1～C 7烷基；
R 2-3-3独立地为氢或C 1～C 7烷基；
R 2-4独立地为氢、-CN或-OR 2-4-1；
R 2-4-1独立地为氢或C 1～C 7烷基；
R 2-5独立地为-NR 2-5-1R 2-5-2或C 1～C 7烷基；
R 2-5-1和R 2-5-2独立地为氢或C 1～C 7烷基；
R 2-6独立地为-NR 2-6-1R 2-6-2；
R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、卤素、氰基、-(C＝O)R 2-9-5、-S(＝O) 2R 2-9-8、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或C 1～C 7烷基；
R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢或C 1～C 7烷基；
R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2；
R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环 烷基为C 3～C 14螺环杂环烷基；
R 4独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-3独立地为C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14螺环杂环烷基；
R 4独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为C 3～C 14杂环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14稠环杂环烷基；
R 4独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基、或、C 1～C 7杂芳基；
R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基；
R 2-3独立地为-NR 2-3-1R 2-3-2、-OR 2-3-3、C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-3-1和R 2-3-2独立地为氢或C 1～C 7烷基；
R 2-3-3独立地为氢或C 1～C 7烷基；
R 2-4独立地为氢、-CN或-OR 2-4-1；
R 2-4-1独立地为氢或C 1～C 7烷基；
R 2-5独立地为-NR 2-5-1R 2-5-2或C 1～C 7烷基；
R 2-5-1和R 2-5-2独立地为氢或C 1～C 7烷基；
R 2-6独立地为-NR 2-6-1R 2-6-2；
R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、卤素、氰基、-(C＝O)R 2-9-5、-S(＝O) 2R 2-9-8、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或C 1～C 7烷基；
R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢或C 1～C 7烷基；
R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2；
R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14稠环杂环烷基；
R 4独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-3独立地为C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为被C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14稠环杂环烷基；
R 4独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为C 3～C 14杂环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14桥环杂环烷基；
R 4独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基、或、C 1～C 7杂芳基；
R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基；
R 2-3独立地为-NR 2-3-1R 2-3-2、-OR 2-3-3、C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-3-1和R 2-3-2独立地为氢或C 1～C 7烷基；
R 2-3-3独立地为氢或C 1～C 7烷基；
R 2-4独立地为氢、-CN或-OR 2-4-1；
R 2-4-1独立地为氢或C 1～C 7烷基；
R 2-5独立地为-NR 2-5-1R 2-5-2或C 1～C 7烷基；
R 2-5-1和R 2-5-2独立地为氢或C 1～C 7烷基；
R 2-6独立地为-NR 2-6-1R 2-6-2；
R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、卤素、氰基、-(C＝O)R 2-9-5、-S(＝O) 2R 2-9-8、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或C 1～C 7烷基；
R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢或C 1～C 7烷基；
R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2；
R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14桥环杂环烷基；
R 4独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-3独立地为C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14桥环杂环烷基；
R 4独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为-(CH 2) m-R 2；
m为1、2、3或4；
R 2、R 3和R 4独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基、或、C 1～C 7杂芳基；
R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基；
R 2-3独立地为-NR 2-3-1R 2-3-2、-OR 2-3-3、C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-3-1和R 2-3-2独立地为氢或C 1～C 7烷基；
R 2-3-3独立地为氢或C 1～C 7烷基；
R 2-4独立地为氢、-CN或-OR 2-4-1；
R 2-4-1独立地为氢或C 1～C 7烷基；
R 2-5独立地为-NR 2-5-1R 2-5-2或C 1～C 7烷基；
R 2-5-1和R 2-5-2独立地为氢或C 1～C 7烷基；
R 2-6独立地为-NR 2-6-1R 2-6-2；
R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、卤素、氰基、-(C＝O)R 2-9-5、-S(＝O) 2R 2-9-8、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或C 1～C 7烷基；
R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢或C 1～C 7烷基；
R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2；
R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基。
在某一方案中：
R 1为氢或甲基；
n为1或2；
L为-(CH 2) m-R 2；m为1或2，还可为3；
R 2独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-3独立地为C 3～C 14杂环烷基；
R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；
R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
在某一方案中，
R 1为氢或甲基；
n为1或2；
L为-(CH 2) m-R 2、被1个或2个R 4取代的C 3～C 14稠环杂环烷基、或、被1个或2个R 4取代的C 3～C 14螺环杂环烷基；
当L为C 3～C 14稠环杂环烷基时，所述的C 3～C 14稠环杂环烷基为C 5～C 14稠环杂环烷基；
当L为C 3～C 14螺环杂环烷基时，所述的C 3～C 14螺环杂环烷基为C 5～C 14螺环杂环烷基；
R 2为-NR 2-1R 2-2；
R 4为-NR 2-1R 2-2或任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基。
在某一方案中，
R 1为氢；
n为1；
L为-(CH 2) m-R 2、被1个或2个R 4取代的C 3～C 14稠环杂环烷基、或、被1个或2个R 4取代的C 3～C 14螺环杂环烷基；
当L为C 3～C 14稠环杂环烷基时，所述的C 3～C 14稠环杂环烷基为C 5～C 14稠环杂环烷基；
当L为C 3～C 14螺环杂环烷基时，所述的C 3～C 14螺环杂环烷基为C 5～C 14螺环杂环烷基；
R 2为-NR 2-1R 2-2；
R 4为-NR 2-1R 2-2或任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基；
R 2-1和R 2-2独立地为C 1～C 7烷基；
R 2-9独立地为C 1～C 7烷基或C 3～C 14杂环烷基。
在某一方案中，所述的如式I所示的吡唑酮并嘧啶类化合物不为
Figure PCTCN2020112034-appb-000032
Figure PCTCN2020112034-appb-000033
Figure PCTCN2020112034-appb-000034
在某一方案中，所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物里，如式I所示的吡唑酮并嘧啶类化合物为下述任一结构：
Figure PCTCN2020112034-appb-000035
Figure PCTCN2020112034-appb-000036
Figure PCTCN2020112034-appb-000037
在某一方案中，所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物里，如式I所示的吡唑酮并嘧啶类化合物为如下任一化合物：
在下述条件下保留时间为9.66min的
Figure PCTCN2020112034-appb-000038
(I-30-1)：Agilent 1260高效液相色谱仪；流动相A:水(0.1％甲酸)，流动相B:乙腈；柱时间：15min；柱型：Waters公司Xselect，5μm，4.6×250mm；梯度洗脱,5％流动相B→50％流动相B；
在下述条件下保留时间为10.04min的
Figure PCTCN2020112034-appb-000039
(I-30-2)：Agilent 1260高效液相色谱仪；流动相A:水(0.1％甲酸)，流动相B:乙腈；柱时间：15min；柱型：Waters公司Xselect，5μm，4.6×250mm；梯度洗脱,5％流动相B→50％流动相B；
在下述条件下保留时间为7.80min的
Figure PCTCN2020112034-appb-000040
(I-36-1)：Agilent 1260高效液相色谱仪；流动相A:水(0.1％甲酸)，流动相B:乙腈；柱时间：15min；柱型：Waters公司Xselect，5μm，4.6×250mm；梯度洗脱,5％流动相B→95％流动相B；
在下述条件下保留时间为7.97min的
Figure PCTCN2020112034-appb-000041
(I-36-2)：Agilent 1260高效液相色谱仪；流动相A:水(0.1％甲酸)，流动相B:乙腈；柱时间：15min；柱型：Waters公司Xselect，5μm，4.6×250mm；梯度洗脱,5％流动相B→95％流动相B；
其中，
Figure PCTCN2020112034-appb-000042
是指顺反构型不定。
本发明还提供了一种上述的化合物I的制备方法，其包括下述步骤：步骤一，化合物1A与化合物1B经C-N偶联反应得到化合物1C；步骤二，化合物1C先在氧化剂的作用下形成活性较高的中间体亚砜，然后再与化合物1D进行取代反应得到化合物I；
Figure PCTCN2020112034-appb-000043
化合物I的制备方法中所述反应的条件和步骤可为本领域常规的条件和步骤，本发明特别优选下述条件步骤：
步骤一中，所述C-N偶联反应为本领域惯常用于构建C-N键的偶联方法，例如Ullmann反应，Buchwald反应，优选Ullmann反应，更优选碘化亚铜/碳酸钾/N,N-二异丙基乙胺/二氧六环的反应条件。
步骤二中，所述氧化剂优选为间氯过氧苯甲酸(m-CPBA)；所述取代反应的条件为本领域惯常用于取代的反应条件，例如碱性条件或酸性条件，碱性条件优选二异丙基乙胺，酸性条件优选三氟乙酸。
上述的化合物I的制备方法中，所述化合物1A还可由如下反应式1所示方法得到：步骤一，化合物1A1在有机溶剂与溴化试剂反应得到化合物1A2；步骤二，化合物1A2经氧化剂对吡啶进行氧化得到反应活性较高的化合物1A3；步骤三，化合物1A3与亲核试剂反应得到化合物1A4；步骤四，化合物1A4在碱性条件下脱除乙酰基得到化合物1A；
Figure PCTCN2020112034-appb-000044
其中，所述R 1为氢；n为1或2。
反应式1中所述反应的条件和步骤可为本领域常规的条件和步骤，本发明特别优选下述条件：
步骤一中，所述有机溶剂优选高沸点溶剂，如甲苯、乙腈；所述溴化试剂优选三甲基 溴硅烷、三溴氧磷；反应温度优选120℃～150℃，常规加热反应或微波加热反应。
步骤二中，所述氧化剂可为本领域惯常用于氮氧化成氮氧化物之氧化剂，优选为间氯过氧苯甲酸(m-CPBA)。
步骤三中，所述亲核试剂优选酸酐，例如乙酸酐。
步骤四中，所述碱性条件为本领域惯常用于脱除乙酰基之条件，优选在乙醇溶剂中用氢氧化钾脱除乙酰基。
上述的化合物I的制备方法中，所述化合物1A还可由如下反应式2所示方法得到：步骤一，化合物1A’在氧化剂的作用下氧化形成化合物1A5；步骤二，化合物1A5在格氏试剂的进攻下得到化合物1A。
Figure PCTCN2020112034-appb-000045
其中，R 1为甲基；n为1或2。
反应式2中所述反应的条件和步骤可为本领域常规的条件和步骤，本发明特别优选下述条件：
步骤一中，所述氧化剂为本领域惯常用于羟基氧化形成醛或酮之条件，优选为戴斯-马丁试剂。化合物1A’由所述方法一中反应式1的方法制备获得。
步骤二中，所述的格氏试剂为本领域常用之格氏试剂，优先甲基格氏试剂。
本发明还提供了一种如式1C所示的化合物：
Figure PCTCN2020112034-appb-000046
其中，R 1为氢或甲基；n为1或2。
在某一方案中，如式1C所示的化合物可为如下任一结构：
Figure PCTCN2020112034-appb-000047
本发明还提供了一种物质X在制备激酶(例如WEE1激酶)抑制剂中的应用；
所述的物质X为上述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
在所述的应用中，所述的激酶抑制剂可为在体外使用的激酶抑制剂。
本发明还提供了一种物质X在制备药物中的应用；
所述的物质X为上述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
本发明还提供了一种物质X在制备药物中的应用；所述的药物用于治疗和/或预防与WEE1激酶有关的疾病；
所述的物质X为上述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
所述的与WEE1激酶有关的疾病例如癌症。所述的癌症例如脑癌、头颈部癌、食道癌、甲状腺癌、小细胞癌、非小细胞癌、乳腺癌、肺癌、胃癌、胆囊-胆管癌、肝癌、胰腺癌、结肠癌、直肠癌、卵巢癌、绒毛上皮癌、子宫体癌、***、肾盂-输尿管癌、膀胱癌、***癌、***癌、睾丸癌、胚胎性癌、肾母细胞瘤、皮肤癌、恶性黑色素瘤、成神经细胞瘤、骨肉瘤、尤文瘤、软组织瘤、急性白血病、慢性淋巴性白血病、慢性骨髓性白血病、或、何杰金氏淋巴瘤，又例如乳腺癌、肺癌、胰腺癌、结肠癌、卵巢癌、急性白血病、慢性淋巴性白血病、慢性骨髓型白血病、何杰金氏淋巴瘤，还例如结肠癌或卵巢癌，更例如结肠癌或***。
本发明还提供了一种物质X在制备药物中的应用；所述的药物用于治疗和/或预防癌症；
所述的物质X为上述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
所述的癌症例如脑癌、头颈部癌、食道癌、甲状腺癌、小细胞癌、非小细胞癌、乳腺癌、肺癌、胃癌、胆囊-胆管癌、肝癌、胰腺癌、结肠癌、直肠癌、卵巢癌、绒毛上皮癌、子宫体癌、***、肾盂-输尿管癌、膀胱癌、***癌、***癌、睾丸癌、胚胎性癌、肾母细胞瘤、皮肤癌、恶性黑色素瘤、成神经细胞瘤、骨肉瘤、尤文瘤、软组织瘤、急性白血病、慢性淋巴性白血病、慢性骨髓性白血病、或、何杰金氏淋巴瘤，又例如乳腺癌、肺癌、胰腺癌、结肠癌、卵巢癌、急性白血病、慢性淋巴性白血病、慢性骨髓型白血病、何杰金氏淋巴瘤，还例如结肠癌或卵巢癌，更例如结肠癌或***。
本发明还提供了一种治疗和/或预防与WEE1激酶有关的疾病的方法，其包括向患者 施用治疗有效量的物质X；
所述的物质X为上述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
所述的与WEE1激酶有关的疾病例如癌症。所述的癌症例如脑癌、头颈部癌、食道癌、甲状腺癌、小细胞癌、非小细胞癌、乳腺癌、肺癌、胃癌、胆囊-胆管癌、肝癌、胰腺癌、结肠癌、直肠癌、卵巢癌、绒毛上皮癌、子宫体癌、***、肾盂-输尿管癌、膀胱癌、***癌、***癌、睾丸癌、胚胎性癌、肾母细胞瘤、皮肤癌、恶性黑色素瘤、成神经细胞瘤、骨肉瘤、尤文瘤、软组织瘤、急性白血病、慢性淋巴性白血病、慢性骨髓性白血病、或、何杰金氏淋巴瘤，又例如乳腺癌、肺癌、胰腺癌、结肠癌、卵巢癌、急性白血病、慢性淋巴性白血病、慢性骨髓型白血病、何杰金氏淋巴瘤，还例如结肠癌或卵巢癌，更例如结肠癌或***。
本发明还提供了一种治疗和/或预防癌症的方法，其包括向患者施用治疗有效量的物质X；
所述的物质X为上述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
所述的癌症例如脑癌、头颈部癌、食道癌、甲状腺癌、小细胞癌、非小细胞癌、乳腺癌、肺癌、胃癌、胆囊-胆管癌、肝癌、胰腺癌、结肠癌、直肠癌、卵巢癌、绒毛上皮癌、子宫体癌、***、肾盂-输尿管癌、膀胱癌、***癌、***癌、睾丸癌、胚胎性癌、肾母细胞瘤、皮肤癌、恶性黑色素瘤、成神经细胞瘤、骨肉瘤、尤文瘤、软组织瘤、急性白血病、慢性淋巴性白血病、慢性骨髓性白血病、或、何杰金氏淋巴瘤，又例如乳腺癌、肺癌、胰腺癌、结肠癌、卵巢癌、急性白血病、慢性淋巴性白血病、慢性骨髓型白血病、何杰金氏淋巴瘤，还例如结肠癌或卵巢癌，更例如结肠癌或***。
本发明还提供了一种药物组合物，其包含物质X和(一种或多种)药用辅料；
所述的物质X为上述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
本发明还提供了一种组合，其包含物质X和抗癌药物，
所述的物质X为上述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
所述的抗癌药物可为本领域中常规的抗癌药物(但不为上述的物质X)，例如抗癌性烷基化剂、抗癌性代谢拮抗剂、抗癌性抗生素、来源于植物的抗癌剂、抗癌性铂配位化合物、抗癌性喜树碱衍生物、抗癌性酪氨酸激酶抑制剂、单克隆抗体、干扰素、生物反应调 节物、米托蒽醌、L-天冬酰胺酶、丙卡巴肼、达卡巴嗪、羟基脲、喷司他丁、维甲酸、阿法赛特、阿法达贝汀、阿那曲唑、依西美坦、比卡鲁胺、亮丙瑞林、氟他胺、氟维司群、哌加他尼钠、地尼白介素2、阿地白介素、促甲状腺素α、三氧化二砷、硼替佐米、卡培他滨和戈舍瑞林中的一种或多种，又例如抗癌性代谢拮抗剂。
所述的抗癌性烷基化剂可为本领域常规的抗癌性烷基化剂，例如氮芥N-氧化物、环磷酰胺、异环磷酰胺、米尔法兰、白消安、二溴甘露醇、卡巴醌、塞替派、雷莫司汀、尼莫司汀、替莫唑胺和卡莫司汀中的一种或多种。
所述的抗癌性代谢拮抗剂可为本领域常规的抗癌性代谢拮抗剂，例如甲氨蝶呤、6-巯基嘌呤核苷、巯嘌呤、5-氟尿嘧啶、替加氟、去氧氟尿苷、卡莫氟、阿糖胞苷、阿糖胞苷十八烷基磷酸钠、依诺他滨、S-1、吉西他滨、氟达拉滨和培美曲塞二钠中的一种或多种，又例如5-氟尿嘧啶。
所述的抗癌性抗生素可为本领域常规的抗癌性抗生素，例如放线菌素D、多柔比星、柔红霉素、新制癌菌素、博来霉素、培洛霉素、丝裂霉素C、阿柔比星、吡柔比星、表柔比星、净司他丁斯酯、伊达比星、西罗莫司和戊柔比星中的一种或多种。
所述的来源于植物的抗癌剂可为本领域常规的来源于植物的抗癌剂，例如长春新碱、长春碱、长春地辛、足叶乙苷、索布佐生、多西他赛、紫杉醇和长春瑞滨中的一种或多种。
所述的抗癌性铂配位化合物可为本领域常规的抗癌性铂配位化合物，例如顺铂、卡铂、奈达铂和奥沙利铂中的一种或多种。
所述的抗癌性喜树碱衍生物可为本领域常规的抗癌性喜树碱衍生物，例如伊立替康、托泊替康和喜树碱中的一种或多种。
所述的抗癌性酪氨酸激酶抑制剂可为本领域常规的抗癌性酪氨酸激酶抑制剂，例如吉非替尼、伊马替尼和埃罗替尼中的一种或多种。
所述的单克隆抗体可为本领域常规的单克隆抗体，例如西妥昔单抗、贝伐单抗、利妥昔单抗、阿仑单抗和曲妥单抗中的一种或多种。
所述的干扰素可为本领域常规的干扰素，例如干扰素α、干扰素α-2a、干扰素α-2b、干扰素β、干扰素γ-1a和干扰素γ-n1中的一种或多种。
所述的生物反应调节物可为本领域常规的生物反应调节物，例如云芝多糖、香菇多糖、西佐喃、沙培林和乌苯美司中的一种或多种。
所述组合中的各组分可同时使用或分开使用(例如顺序使用)；当所述组合中的各组分同时使用时，所述组合中的各组分可均匀混合(即各组分的混合物)。
所述组合中的各组分可以制备成一个单一的药物组合物同时使用，也可以将各组分分别制成单个独立的药物组合物(例如以套装的形式)，这些单个独立的药物组合物可同时使用或分开使用(例如顺序使用)。
本发明还提供了一种上述的组合在制备用于预防和/或治疗癌症的药物中的应用。
所述的癌症例如脑癌、头颈部癌、食道癌、甲状腺癌、小细胞癌、非小细胞癌、乳腺癌、肺癌、胃癌、胆囊-胆管癌、肝癌、胰腺癌、结肠癌、直肠癌、卵巢癌、绒毛上皮癌、子宫体癌、***、肾盂-输尿管癌、膀胱癌、***癌、***癌、睾丸癌、胚胎性癌、肾母细胞瘤、皮肤癌、恶性黑色素瘤、成神经细胞瘤、骨肉瘤、尤文瘤、软组织瘤、急性白血病、慢性淋巴性白血病、慢性骨髓性白血病、或、何杰金氏淋巴瘤，又例如乳腺癌、肺癌、胰腺癌、结肠癌、卵巢癌、急性白血病、慢性淋巴性白血病、慢性骨髓型白血病、何杰金氏淋巴瘤，还例如结肠癌或卵巢癌，更例如结肠癌或***。
在本发明所述的应用中，上述的物质X，和，上述的抗癌药物可以同时或者分开施用(例如顺序施用)。
本发明还提供了一种治疗和/或预防癌症的方法，其包括向患者施用治疗有效量的上述的组合。
所述的癌症例如脑癌、头颈部癌、食道癌、甲状腺癌、小细胞癌、非小细胞癌、乳腺癌、肺癌、胃癌、胆囊-胆管癌、肝癌、胰腺癌、结肠癌、直肠癌、卵巢癌、绒毛上皮癌、子宫体癌、***、肾盂-输尿管癌、膀胱癌、***癌、***癌、睾丸癌、胚胎性癌、肾母细胞瘤、皮肤癌、恶性黑色素瘤、成神经细胞瘤、骨肉瘤、尤文瘤、软组织瘤、急性白血病、慢性淋巴性白血病、慢性骨髓性白血病、或、何杰金氏淋巴瘤，又例如乳腺癌、肺癌、胰腺癌、结肠癌、卵巢癌、急性白血病、慢性淋巴性白血病、慢性骨髓型白血病、何杰金氏淋巴瘤，还例如结肠癌或卵巢癌，更例如结肠癌或***。
本发明还提供了一种上述的物质X在制备药物中的应用，所述的药物“和上述的抗癌药物联合”用于预防和/或治疗癌症。
所述的癌症例如脑癌、头颈部癌、食道癌、甲状腺癌、小细胞癌、非小细胞癌、乳腺癌、肺癌、胃癌、胆囊-胆管癌、肝癌、胰腺癌、结肠癌、直肠癌、卵巢癌、绒毛上皮癌、子宫体癌、***、肾盂-输尿管癌、膀胱癌、***癌、***癌、睾丸癌、胚胎性癌、肾母细胞瘤、皮肤癌、恶性黑色素瘤、成神经细胞瘤、骨肉瘤、尤文瘤、软组织瘤、急性白血病、慢性淋巴性白血病、慢性骨髓性白血病、或、何杰金氏淋巴瘤，又例如乳腺癌、肺癌、胰腺癌、结肠癌、卵巢癌、急性白血病、慢性淋巴性白血病、慢性骨髓型白血病、何杰金氏淋巴瘤，还例如结肠癌或卵巢癌，更例如结肠癌或***。
所述的抗癌药物可为本领域中常规的抗癌药物(但不为上述的物质X)，例如抗癌性烷基化剂、抗癌性代谢拮抗剂、抗癌性抗生素、来源于植物的抗癌剂、抗癌性铂配位化合物、抗癌性喜树碱衍生物、抗癌性酪氨酸激酶抑制剂、单克隆抗体、干扰素、生物反应调节物、米托蒽醌、L-天冬酰胺酶、丙卡巴肼、达卡巴嗪、羟基脲、喷司他丁、维甲酸、阿法赛特、阿法达贝汀、阿那曲唑、依西美坦、比卡鲁胺、亮丙瑞林、氟他胺、氟维司群、哌加他尼钠、地尼白介素2、阿地白介素、促甲状腺素α、三氧化二砷、硼替佐米、卡培他滨和戈舍瑞林中的一种或多种，又例如抗癌性代谢拮抗剂。
所述的抗癌性烷基化剂可为本领域常规的抗癌性烷基化剂，例如氮芥N-氧化物、环磷酰胺、异环磷酰胺、米尔法兰、白消安、二溴甘露醇、卡巴醌、塞替派、雷莫司汀、尼莫司汀、替莫唑胺和卡莫司汀中的一种或多种。
所述的抗癌性代谢拮抗剂可为本领域常规的抗癌性代谢拮抗剂，例如甲氨蝶呤、6-巯基嘌呤核苷、巯嘌呤、5-氟尿嘧啶、替加氟、去氧氟尿苷、卡莫氟、阿糖胞苷、阿糖胞苷十八烷基磷酸钠、依诺他滨、S-1、吉西他滨、氟达拉滨和培美曲塞二钠中的一种或多种，又例如5-氟尿嘧啶。
所述的抗癌性抗生素可为本领域常规的抗癌性抗生素，例如放线菌素D、多柔比星、柔红霉素、新制癌菌素、博来霉素、培洛霉素、丝裂霉素C、阿柔比星、吡柔比星、表柔比星、净司他丁斯酯、伊达比星、西罗莫司和戊柔比星中的一种或多种。
所述的来源于植物的抗癌剂可为本领域常规的来源于植物的抗癌剂，例如长春新碱、长春碱、长春地辛、足叶乙苷、索布佐生、多西他赛、紫杉醇和长春瑞滨中的一种或多种。
所述的抗癌性铂配位化合物可为本领域常规的抗癌性铂配位化合物，例如顺铂、卡铂、奈达铂和奥沙利铂中的一种或多种。
所述的抗癌性喜树碱衍生物可为本领域常规的抗癌性喜树碱衍生物，例如伊立替康、托泊替康和喜树碱中的一种或多种。
所述的抗癌性酪氨酸激酶抑制剂可为本领域常规的抗癌性酪氨酸激酶抑制剂，例如吉非替尼、伊马替尼和埃罗替尼中的一种或多种。
所述的单克隆抗体可为本领域常规的单克隆抗体，例如西妥昔单抗、贝伐单抗、利妥昔单抗、阿仑单抗和曲妥单抗中的一种或多种。
所述的干扰素可为本领域常规的干扰素，例如干扰素α、干扰素α-2a、干扰素α-2b、干扰素β、干扰素γ-1a和干扰素γ-n1中的一种或多种。
所述的生物反应调节物可为本领域常规的生物反应调节物，例如云芝多糖、香菇多 糖、西佐喃、沙培林和乌苯美司中的一种或多种。
在本发明所述的应用中，上述的物质X，和，上述的抗癌药物可以同时或者分开施用(例如顺序施用)。
本发明还提供了一种上述的抗癌药物在制备药物中的应用，所述的药物“和上述的物质X联合”用于预防和/或治疗癌症。
所述的癌症例如脑癌、头颈部癌、食道癌、甲状腺癌、小细胞癌、非小细胞癌、乳腺癌、肺癌、胃癌、胆囊-胆管癌、肝癌、胰腺癌、结肠癌、直肠癌、卵巢癌、绒毛上皮癌、子宫体癌、***、肾盂-输尿管癌、膀胱癌、***癌、***癌、睾丸癌、胚胎性癌、肾母细胞瘤、皮肤癌、恶性黑色素瘤、成神经细胞瘤、骨肉瘤、尤文瘤、软组织瘤、急性白血病、慢性淋巴性白血病、慢性骨髓性白血病、或、何杰金氏淋巴瘤，又例如乳腺癌、肺癌、胰腺癌、结肠癌、卵巢癌、急性白血病、慢性淋巴性白血病、慢性骨髓型白血病、何杰金氏淋巴瘤，还例如结肠癌或卵巢癌，更例如结肠癌或***。
所述的抗癌药物可为本领域中常规的抗癌药物(但不为上述的物质X)，例如抗癌性烷基化剂、抗癌性代谢拮抗剂、抗癌性抗生素、来源于植物的抗癌剂、抗癌性铂配位化合物、抗癌性喜树碱衍生物、抗癌性酪氨酸激酶抑制剂、单克隆抗体、干扰素、生物反应调节物、米托蒽醌、L-天冬酰胺酶、丙卡巴肼、达卡巴嗪、羟基脲、喷司他丁、维甲酸、阿法赛特、阿法达贝汀、阿那曲唑、依西美坦、比卡鲁胺、亮丙瑞林、氟他胺、氟维司群、哌加他尼钠、地尼白介素2、阿地白介素、促甲状腺素α、三氧化二砷、硼替佐米、卡培他滨和戈舍瑞林中的一种或多种，又例如抗癌性代谢拮抗剂。
所述的抗癌性烷基化剂可为本领域常规的抗癌性烷基化剂，例如氮芥N-氧化物、环磷酰胺、异环磷酰胺、米尔法兰、白消安、二溴甘露醇、卡巴醌、塞替派、雷莫司汀、尼莫司汀、替莫唑胺和卡莫司汀中的一种或多种。
所述的抗癌性代谢拮抗剂可为本领域常规的抗癌性代谢拮抗剂，例如甲氨蝶呤、6-巯基嘌呤核苷、巯嘌呤、5-氟尿嘧啶、替加氟、去氧氟尿苷、卡莫氟、阿糖胞苷、阿糖胞苷十八烷基磷酸钠、依诺他滨、S-1、吉西他滨、氟达拉滨和培美曲塞二钠中的一种或多种，又例如5-氟尿嘧啶。
所述的抗癌性抗生素可为本领域常规的抗癌性抗生素，例如放线菌素D、多柔比星、柔红霉素、新制癌菌素、博来霉素、培洛霉素、丝裂霉素C、阿柔比星、吡柔比星、表柔比星、净司他丁斯酯、伊达比星、西罗莫司和戊柔比星中的一种或多种。
所述的来源于植物的抗癌剂可为本领域常规的来源于植物的抗癌剂，例如长春新碱、长春碱、长春地辛、足叶乙苷、索布佐生、多西他赛、紫杉醇和长春瑞滨中的一种或多 种。
所述的抗癌性铂配位化合物可为本领域常规的抗癌性铂配位化合物，例如顺铂、卡铂、奈达铂和奥沙利铂中的一种或多种。
所述的抗癌性喜树碱衍生物可为本领域常规的抗癌性喜树碱衍生物，例如伊立替康、托泊替康和喜树碱中的一种或多种。
所述的抗癌性酪氨酸激酶抑制剂可为本领域常规的抗癌性酪氨酸激酶抑制剂，例如吉非替尼、伊马替尼和埃罗替尼中的一种或多种。
所述的单克隆抗体可为本领域常规的单克隆抗体，例如西妥昔单抗、贝伐单抗、利妥昔单抗、阿仑单抗和曲妥单抗中的一种或多种。
所述的干扰素可为本领域常规的干扰素，例如干扰素α、干扰素α-2a、干扰素α-2b、干扰素β、干扰素γ-1a和干扰素γ-n1中的一种或多种。
所述的生物反应调节物可为本领域常规的生物反应调节物，例如云芝多糖、香菇多糖、西佐喃、沙培林和乌苯美司中的一种或多种。
在本发明所述的应用中，上述的物质X，和，上述的抗癌药物可以同时或者分开施用(例如顺序施用)。
本发明还提供了一种药物组合物，其包含上述的组合和(一种或多种)药用辅料。
所述药物组合物可由所述组合和所述药用辅料组成。
本发明还提供了一种组合药盒，其包含药物组合物A和药物组合物B；
所述的药物组合物A包括上述的物质X，和，(一种或多种)药用辅料；
所述的药物组合物B包括上述的抗癌药物和(一种或多种)药用辅料。
所述的组合药盒可由所述的药物组合物A和所述的药物组合物B组成。
所述的药物组合物A可由物质X，和，药用辅料组成；
所述的药物组合物B可由上述的抗癌药物和药用辅料组成。
所述的抗癌药物可为本领域中常规的抗癌药物(但不为上述的物质X)，例如抗癌性烷基化剂、抗癌性代谢拮抗剂、抗癌性抗生素、来源于植物的抗癌剂、抗癌性铂配位化合物、抗癌性喜树碱衍生物、抗癌性酪氨酸激酶抑制剂、单克隆抗体、干扰素、生物反应调节物、米托蒽醌、L-天冬酰胺酶、丙卡巴肼、达卡巴嗪、羟基脲、喷司他丁、维甲酸、阿法赛特、阿法达贝汀、阿那曲唑、依西美坦、比卡鲁胺、亮丙瑞林、氟他胺、氟维司群、哌加他尼钠、地尼白介素2、阿地白介素、促甲状腺素α、三氧化二砷、硼替佐米、卡培他滨和戈舍瑞林中的一种或多种，又例如抗癌性代谢拮抗剂。
所述的抗癌性烷基化剂可为本领域常规的抗癌性烷基化剂，例如氮芥N-氧化物、环 磷酰胺、异环磷酰胺、米尔法兰、白消安、二溴甘露醇、卡巴醌、塞替派、雷莫司汀、尼莫司汀、替莫唑胺和卡莫司汀中的一种或多种。
所述的抗癌性代谢拮抗剂可为本领域常规的抗癌性代谢拮抗剂，例如甲氨蝶呤、6-巯基嘌呤核苷、巯嘌呤、5-氟尿嘧啶、替加氟、去氧氟尿苷、卡莫氟、阿糖胞苷、阿糖胞苷十八烷基磷酸钠、依诺他滨、S-1、吉西他滨、氟达拉滨和培美曲塞二钠中的一种或多种，又例如5-氟尿嘧啶。
所述的抗癌性抗生素可为本领域常规的抗癌性抗生素，例如放线菌素D、多柔比星、柔红霉素、新制癌菌素、博来霉素、培洛霉素、丝裂霉素C、阿柔比星、吡柔比星、表柔比星、净司他丁斯酯、伊达比星、西罗莫司和戊柔比星中的一种或多种。
所述的来源于植物的抗癌剂可为本领域常规的来源于植物的抗癌剂，例如长春新碱、长春碱、长春地辛、足叶乙苷、索布佐生、多西他赛、紫杉醇和长春瑞滨中的一种或多种。
所述的抗癌性铂配位化合物可为本领域常规的抗癌性铂配位化合物，例如顺铂、卡铂、奈达铂和奥沙利铂中的一种或多种。
所述的抗癌性喜树碱衍生物可为本领域常规的抗癌性喜树碱衍生物，例如伊立替康、托泊替康和喜树碱中的一种或多种。
所述的抗癌性酪氨酸激酶抑制剂可为本领域常规的抗癌性酪氨酸激酶抑制剂，例如吉非替尼、伊马替尼和埃罗替尼中的一种或多种。
所述的单克隆抗体可为本领域常规的单克隆抗体，例如西妥昔单抗、贝伐单抗、利妥昔单抗、阿仑单抗和曲妥单抗中的一种或多种。
所述的干扰素可为本领域常规的干扰素，例如干扰素α、干扰素α-2a、干扰素α-2b、干扰素β、干扰素γ-1a和干扰素γ-n1中的一种或多种。
所述的生物反应调节物可为本领域常规的生物反应调节物，例如云芝多糖、香菇多糖、西佐喃、沙培林和乌苯美司中的一种或多种。
所述组合药盒中的各个药物组合物可以同时使用或分开使用(例如顺序使用)。
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全，并且适合于患者使用。所述的“患者”优选哺乳动物，更优选为人类。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获 得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于：水、甲醇、乙醇等。
术语“药学上可接受的盐的溶剂合物”中的“药学上可接受的盐”和“溶剂合物”如上所述，是指本发明化合物1、与相对无毒的、药学上可接受的酸或碱制备得到的，且2、与化学计量或非化学计量的溶剂结合形成的物质。所述的“药学上可接受的盐的溶剂合物”包括但不限于本发明化合物的盐酸一水合物。
术语“化合物”、“药学上可接受的盐”、“溶剂合物”和“药学上可接受的盐的溶剂合物”可以以晶型或无定型的形式存在。术语“晶型”是指其中的离子或分子是按照一种确定的方式在三维空间作严格周期性排列，并具有间隔一定距离周期重复出现规律；因上述周期性排列的不同，可存在多种晶型，也即多晶型现象。术语“无定型”是指其中的离子或分子呈现杂乱无章的分布状态，即离子、分子间不具有周期性排列规律。
术语“化合物”、“药学上可接受的盐”、“溶剂合物”和“药学上可接受的盐的溶剂合物”如存在立体异构体，则可以以单一的立体异构体或它们的混合物(例如外消旋体)的形式存在。术语“立体异构体”是指顺反异构体或旋光异构体。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成 盐(物理结合等)等方式进行手性拆分获得。术语“单一的立体异构体”是指本发明化合物的一种立体异构体相对于该化合物的所有立体异构体的质量含量不低于95％。
术语“化合物”、“药学上可接受的盐”、“溶剂合物”和“药学上可接受的盐的溶剂合物”如存在互变异构体，则可以以单一的互变异构体或它们的混合物的形式存在，较佳地以较稳定的互变异构体为主的形式存在。
术语“化合物”、“药学上可接受的盐”、“溶剂合物”和“药学上可接受的盐的溶剂合物”中的原子可以以其天然丰度或非天然丰度的形式存在。以氢原子为例，其天然丰度的形式是指其中约99.985％为氕、约0.015％为氘；其非天然丰度的形式例如其中约95％为氘。也即，术语“化合物”、“药学上可接受的盐”、“溶剂合物”和“药学上可接受的盐的溶剂合物”中的一个或多个原子可为以非天然丰度的形式存在的原子。
当任意变量(例如R 1-1-1)在化合物的定义中多次出现时，该变量每一位置出现的定义与其余位置出现的定义无关，它们的含义互相独立、互不影响。因此，若某基团被1个、2个或3个R 1-1-1基团取代，也就是说，该基团可能会被最多3个R 1-1-1取代，该位置R 1- 1-1的定义与其余位置R 1-1-1的定义是互相独立的。另外，取代基及/或变量的组合只有在该组合产生稳定的化合物时才被允许。
术语“任选取代”是指可被取代，也可不被取代。
术语“卤素”是指氟、氯、溴或碘。
术语“烷基”是指具有一个到十二个碳原子的饱和的直链或支链的一价烃基(例如C 1-C 6烷基，又例如C 1-C 4烷基)。烷基的实例包括但不仅限于甲基、乙基、1-丙基、2-丙基、1-丁基、2-甲基-1-丁基、2-丁基、2-甲基-2-丙基、1-戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、1-庚基和1-辛基。
术语“烯基”是指具有至少一个不饱和位置即碳-碳sp 2双键的二到十二个碳原子的直链或支链的一价烃基(例如C 2-C 6烯基，又例如C 2-C 4烯基)，并且包括具有“顺式”和“反式”取向或者“E”和“Z”取向的基团。其实例包括但不仅限于乙烯基、烯丙基。
术语“炔基”是指具有至少一个不饱和位置即碳-碳sp三键的二到十二个碳原子的直链或支链的单价烃基(例如C 2-C 6炔基，又例如C 2-C 4炔基)。其实例包括但不仅限于乙炔基和丙炔基。
术语“环烷基”是指具有三到二十个碳原子的饱和或部分不饱和(包含1或2个双键)的、非芳香族的环烃原子团(例如C 3-C 6环烷基)，包括单环环烷基和多环环烷基。环烷 基包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。
单环环烷基实例包括但不仅限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、5-己烯基、1-环己-1-烯基、1-环己-2-烯基、和1-环己-3-烯基。
多环环烷基为多环的(例如，二环和三环)环烷基结构，包括螺环、稠环和桥环的环烷基。其中，螺环的环烷基”指5至20元的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，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至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4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基实例包括但不仅限于：
Figure PCTCN2020112034-appb-000048
“稠环的环烷基”指5至20元，***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，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至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5元/5元或5元/6元双环烷基。稠环烷基实例包括但不仅限于：
Figure PCTCN2020112034-appb-000049
Figure PCTCN2020112034-appb-000050
“桥环的环烷基”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，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至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，更有选为双环或三环。桥环烷基实例包括但不仅限于：
Figure PCTCN2020112034-appb-000051
术语“杂环烷基”是指具有3到20个环原子的饱和或部分不饱和的单环或多环环状烃取代基，其中至少一个环原子为独立地选自硼、硅、氧、硫、硒、氮和磷的杂原子，其余的环原子为C。该基团可为碳基团或杂原子基团(也即其可为C-连接的或N-连接的，只要其是可能的即可)。杂环基的实例包括但不仅限于吡咯烷基、四氢呋喃基、四氢噻吩基、 四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、4-硫代吗啉基、噻恶烷基和哌嗪基。例如，由四氢吡咯衍生的基团可为四氢吡咯-1-基(N-连接的)或四氢吡咯-3-基(C-连接的)。例如是3-7元环的单环(1-6个碳原子和选自N，O，P，B，Si，S和Se的1-3个杂原子，在此N，B、P或Se任选地被一个或多个氧原子所取代得到像NO，BOH，PO，PO 2，SeO的基团；N可以任选地季铵化；S原子可以任选地被一个或多个氧原子或氮原子所取代得到像SO、SO 2、S(＝O)(＝NR a),S(＝NR b)或S(＝NR c) 2的基团，同时，R a、R b和R c独立地为氰基、C 1～C 7烷基、C 3～C 14环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 14杂环烷基”、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 6～C 10芳基或C 1～C 7烷氧基；同时，-CH 2-基团可以任选地被-C(＝O)-、-C(＝S)-或-C(＝NR d)-替代，R d独立地为氰基、C 1～C 7烷基、C 3～C 14环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 14杂环烷基”、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 6～C 10芳基或C 1～C 7烷氧基；当所述的环为三元环时，其中只有一个杂原子)、或、7-10个原子组成的双环(4-9个碳原子和选自N，O，P，B，Si，S、Se的1-3个杂原子，在此N，S，B，Se或P任选地被一个或多个氧原子所取代得到像NO，BOH，SO，SO 2，PO，PO 2，SeO的基团，同时，-CH 2-基团可以任选地被-C(＝O)-替代)。视结构而定，杂环基可为单价基团或二价基团，即亚杂环基。螺杂环基、稠合杂环基、桥杂环基也被包括在该定义的范围内。
螺杂环基(螺环杂环烷基)是指5至20元的单环之间共一个原子(称螺原子)多环杂烷环基团，其中一个多个环原子为选自氮、氧或S(O) m(其中m是0至2的整数)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至12元。根据环与环之间共用螺原子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4元/4元、4元/5元、4元/6元、5元/5元、5元/6元、6元/6元单螺杂环基。螺杂环基包括但不仅限于：
Figure PCTCN2020112034-appb-000052
稠合杂环基(稠环杂环烷基)指5至20元，***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，但没有一个 环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为更优选为7至12元。根据组成环的数目可以分为双环、三环、四环或多环稠合杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠合杂环基。稠合杂环基包括但不仅限于：
Figure PCTCN2020112034-appb-000053
桥杂环基(桥环杂环烷基)指5至20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，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为更优选为7至12元。根据组成环的数目可以分为双环、三环、四环或多环杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基包括但不仅限于：
Figure PCTCN2020112034-appb-000054
术语“芳基”是指任何稳定的在各环中可高达10个原子的单环或者双环碳环，其中至少一个环是芳香环。上述芳基单元的实例包括苯基、萘基、四氢萘基、2,3-二氢化茚基、联苯基、菲基、蒽基或者苊基(acenaphthyl)。可以理解，在芳基取代基是二环取代基，且其中一个环是非芳香环的情况中，连接是通过芳环进行的。
术语“杂芳基”是指各环中可高达7个原子的稳定单环或者二环，其中至少一个环是芳香环并且含有1-4个选自硼、硅、氧、硫、硒、氮和磷的杂原子。在此定义范围内的杂芳基包括但不限于：吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并***基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四氢喹啉。“杂芳基”还应当理解为包括任何含氮杂芳基的N-氧化物衍生物。在其中杂芳基取代基是二环取代基并且一个环是非芳香环或者不包含杂原子的情况下，可以理解，连接分别通过芳环进行。杂芳环并芳环、双环杂芳环体系可以以稠合的形式成环。其中，N、S、B、P或Se任选地被一个或多个氧原子所取代得到像NO、SO、SO 2、BOH、PO、PO 2、SeO的基团，N原子可以季铵化。杂芳基可以在任何杂原子或者碳原子上连接到主结构上从而形成稳定的化合物。 视结构而定，杂芳基可为单价基团或二价基团，即亚杂芳基。
术语“烷氧基”是指通过氧桥连接的烷基；所述的烷基的定义同上。
术语“烷巯基”是指通过硫桥连接的烷基；所述的烷基的定义同上。
术语“组分”是指本发明组合中的各组分，即化合物I、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、其代谢产物或其药物前体，或者抗癌药物。
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009 Sixth Edition)。
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“治疗有效量”是指在给予患者时，足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化，但可由本领域技术人员根据需要进行调整。
术语“患者”是指根据本发明的实施例，即将或已经接受了该化合物或组合物给药的任何动物，哺乳动物为优，人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。
术语“活性成分”是指本发明药物组合物或组合药盒中的活性成分，即化合物I、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、其代谢产物或其药物前体，抗癌药物，或者，它们所形成的上述组合。
用楔形键和虚线键
Figure PCTCN2020112034-appb-000055
表示一个立体中心的绝对构型。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的化合物对WEE1激酶的抑制活性较佳，且具有较佳的生物利用度。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本发明所有化合物的结构可通过核磁共振( 1H NMR)和/或质谱检测(MS)鉴定。 1H NMR化学位移(δ)以PPM记录(10 -6)。NMR通过Bruker AVANCE-400光谱仪进行。
LC-MS由Agilent 1200HPLC/6120质谱仪测定。
HPLC由Agilent 1260高效液相色谱仪测定。HPLC具体条件：流动相A:水(0.1％甲酸)，流动相B:乙腈；柱时间：15min；柱型：Waters公司Xselect，5μm，4.6×250mm。
薄层硅胶板是良臣硅源HSGF254或青岛GF254硅胶板。柱层析一般使用烟台黄海200-300目硅胶作为载体。
实施例1
Figure PCTCN2020112034-appb-000056
第一步：
将1,2-氯-6,7-二氢-5H-环戊二烯并[b]吡啶(1g,6.51mmol)(I-1-a)加入到30mL甲苯中，然后加入三溴氧磷(4g,13.95mmol)，130℃加热搅拌三天。反应液冷却浓缩后慢慢加入饱和的碳酸氢钠溶液,直到PH值约等于10,然后用二氯甲烷萃取三次(3*30ml),无水硫酸钠干燥后浓缩得粗品，过柱纯化(乙酸乙酯:石油醚＝0-15％)，得到2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶(I-1-b)0.84g，棕色固体，收率：65％。LC-MS:m/z:(M+H) +＝198。
第二步：
将2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶(I-1-b)(0.8g,4mmol)加入到25ml二氯甲烷中，然后77％的间氯过氧苯甲酸(1.34g，6mmol)也加入到25ml二氯甲烷中，将此溶液加入到上述化合物如式I-1-b的溶液中，室温搅拌过夜。反应液用饱和的酸氢钠溶液溶液洗涤,水相再用二氯甲烷萃取三次(3*30ml)，合并后的有机层无水硫酸钠干燥后浓缩得粗品,过柱纯化(乙酸乙酯:石油醚＝0-60％)得到2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶1-氧化物(如式I-1-c)0.74g，白色固体,收率:90％。LC-MS:m/z:(M+H) +＝214。
第三步：
将2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶1-氧化物(如式I-1-c)(0.74g,3.5mmol)溶于20ml乙酸酐中，120℃搅拌过夜。反应液浓缩后加入30ml二氯甲烷，用饱和的酸氢钠溶液溶液洗涤两次(2*10ml)，再用10ml饱和的食盐水洗一次，无水硫酸钠干燥后浓缩过柱(乙酸乙酯:石油醚＝0-30％)，得到2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶-7-基乙酸酯(I-1-d)0.74g，无色油状物，收率84％。LC-MS:m/z:(M+H) +＝256。
第四步：
将2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶-7-基乙酸酯(I-1-d)(0.74g,2.9mmol)加入到6ml的乙醇中,然后加入15ml氢氧化钾(172mg,3.07mmol)的乙醇溶液。室温搅拌3h。往反应液中加入25ml水，将大部分的乙醇蒸除,二氯甲烷萃取(3*25ml),再用20ml饱和的食盐水洗一次，无水硫酸钠干燥后浓缩过柱(乙酸乙酯:石油醚＝0-30％)，得到2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶-7-醇(I-1-e)0.57g，无色油状物，收率92％。 1H NMR(400MHz,CDCl3)δ7.45(d,J＝8.0Hz,1H),7.35(d,J＝8.0Hz,1H),5.22(td,J＝7.5,3.3Hz,1H),3.26(d,J＝3.4Hz,1H),3.01(m,1H),2.80(m,1H),2.63–2.50(m,1H),2.09(m,1H).LC-MS:m/z:(M+H) +＝214。
第五步：
将2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶-7-醇(0.54g,2.52mmol)(如式I-1-e),2-烯丙基-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(0.56g,2.52mmol)(I-1-f),碘化亚铜(0.482g，2.52mmol),碳酸钾(0.7g,5.07mmol)和N1，N2-二甲基乙二胺(0.46g,5.2mmol)加入到20ml的1，4-二氧六环中，在氩气保护下，105℃搅拌过夜。反应物冷却后过滤浓缩得粗品，过柱纯化(甲醇:二氯甲烷＝0-10％)，得到2-烯丙基1-(7-羟基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4d]嘧啶-3-酮(I-1-g)0.42g，白色固体，收率46％。LC-MS:m/z:(M+H) +＝356。
第六步：
将2-烯丙基1-(7-羟基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4d]嘧啶-3-酮(142mg,0.4mmol)(I-1-g)在30ml甲苯的溶液中加入间氯过氧苯甲酸(108mg,0.48mmol),所得溶液室温搅拌2h。将上述反应液中加入4-(4-甲基哌嗪-1-基)苯胺(100mg,0.52mmol)(I-1-h)和2ml N,N-二异丙基乙胺室温搅拌过夜。将反应液浓缩得粗品，所得粗产物过柱纯化(甲醇二氯甲烷＝0-20％),然后通过高效液相制备得到2-烯丙基1-(7-羟基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-1)95mg，黄色固体，收率47％。 1H NMR(400MHz,CDCl 3)δ8.73(s,1H),8.39(s,1H),7.76(d,J＝8.2Hz,1H),7.59(d,J＝8.1Hz,1H),7.44(d,J＝8.0Hz,2H),6.81(d,J＝8.8Hz,2H),5.68(ddd,J＝16.5,12.1,6.1Hz,1H),5.25(t,J＝6.7Hz,1H),5.03(d,J＝10.1Hz,1H),4.94(d,J＝17.2Hz,1H),4.77–4.60(m,2H),3.34(s,4H),3.11(m,5H),2.96–2.85(m,1H),2.64(m,4H),2.12(m,1H).LC-MS:m/z:(M+H) +＝499。
实施例2
Figure PCTCN2020112034-appb-000057
将2-烯丙基1-(7-羟基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4d]嘧啶-3-酮(40mg,0.11mmol)(I-1-g)和3-氯苯基过氧羧酸(30.2mg,0.135mmol)溶于15ml甲苯中,所得溶液室温搅拌2h。将4-(4-乙基哌嗪-1-基)苯胺(30mg,0.14mmol)和N,N-二异丙基乙胺(29.0mg,0.22mmol)加入到上述溶液中，反应液在90℃氮气保护下搅拌16小时。反应液浓缩，得到的固体用薄层层析板分离(二氯甲烷:甲醇＝10:1)得到粗品，再用制备HPLC分离得到得到2-烯丙基-6-((4-(4-乙基哌嗪-1-基)苯基)氨基)-1-(7-羟基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)--1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-2)38.6mg，白色固体，收率66.9％。1H NMR(400MHz,CDCl3)δ8.68(d,J＝34.2Hz,1H),8.49(s,1H),7.87(d,J＝8.1Hz,1H),7.66(d,J＝8.1Hz,1H),7.52(d,J＝8.8Hz,2H),6.89(d,J＝8.9Hz,2H),5.73(ddd,J＝12.8,8.2,3.9Hz,1H),5.14(dd,J＝7.1,5.7Hz,1H),5.04(dd,J＝10.2,1.0Hz,1H),4.97(d,J＝1.2Hz,1H),4.80–4.66(m,2H),3.49–3.27(m,8H),3.19(dd,J＝14.0,6.8Hz,2H),3.10(ddd,J＝16.1,8.6,4.6Hz,1H),2.98–2.80(m,1H),2.56(dtd,J＝13.0,8.1,4.7Hz,1H),2.15–1.96(m,1H),1.38(t,J＝7.0Hz,3H).LC-MS: m/z:(M+H) +＝513。
实施例5
Figure PCTCN2020112034-appb-000058
第一步：
将67mg(0.25mmol)N,N-二甲基-1-(1-(4-硝基苯)哌啶-4-基)甲胺(I-5-a)溶解在5ml甲醇中，在氢气，钯碳催化的条件下反应半小时。反应液经过滤，浓缩得到4-(4-(二甲胺)甲基)哌啶-1-基)苯胺(I-5-b)56mg，黄色固体,产率97％。LC-MS:m/z:(M+H) +＝234。
第二步：
将2-烯丙基-1-(7-羟基6,7-5H-环戊[b]吡啶-2-基)-6-(甲基硫代)-1,2-二氢-3H-吡唑[3,4-d]吡啶-3-酮(I-1-g)溶解到10ml甲苯中，加入30mg(0.17mol,77％)3-氯过氧苯甲酸，室温搅拌15分钟后将甲苯旋干，再加入40mg(0.11mmol)4-(4-(二甲胺)甲基)哌啶-1-基)苯胺(I-5-b)溶于5ml二甲基亚砜，加入0.4ml三氟醋酸，升温至60℃并搅拌约18小时。反应液冷却后用水和乙酸乙酯萃取。经浓缩，然后经薄层色谱(DCM/CH 3OH/NH 3.CH 3OH＝100/10/1.5)纯化三次后得2-烯丙基-6-((4-((二甲胺)甲基哌啶-1-基)苯氨基)-1-(7-羟基6-7-二氢-5H-环戊[b]吡啶-2-基)-1,2-二氢-3H-吡唑[3,4-d]嘧啶-3-1(I-5)29mg，黄色固体，产率32％。 1H NMR(400MHz,Chloroform-d)δ8.79(s,1H),7.73(d,J＝8.2Hz,1H),7.63(d,J＝8.4Hz,1H),7.41(d,J＝8.4Hz,2H),6.93–6.79(m,2H),5.68(ddt,J＝16.6,10.2,6.2Hz,1H),5.22(t,J＝6.8Hz,1H),5.02(dd,J＝10.2,1.3Hz,1H),4.94(dt,J＝17.1,1.4Hz,1H),4.68(s,2H),3.64(d,J＝12.2Hz,2H),3.09(ddd,J＝16.7,9.1,3.8Hz,1H),2.88(dd,J＝16.2,7.9Hz,1H),2.69(td,J＝12.4,2.7Hz,2H),2.63–2.56(m,1H),2.40(s,6H),2.24–2.18(m,1H),2.09(ddt,J＝13.3,8.7,6.7Hz,3H),2.00(d,J＝6.6Hz,1H),1.94(d,J＝13.1Hz,3H),1.41(tt,J＝12.1,6.2Hz,2H).LC-MS:m/z:(M+H) +＝541。
实施例9
Figure PCTCN2020112034-appb-000059
第一步：
将2-烯丙基1-(7-羟基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4d]嘧啶-3-酮(I-1-g)(40mg,0.11mmol)溶于10ml甲苯中,加入3-氯苯基过氧羧酸(30mg,0.13mmol)，反应液在20℃搅拌2小时。加入二异丙基乙胺(30mg,0.23mmol)和3-(4-氨基苯基)-3,9-二氮杂螺[5.5]十一烷-9-羧酸叔丁酯(40mg,0.12mmol)，反应液在20℃搅拌24小时。反应液浓缩，TLC制备(二氯甲烷/甲醇＝10/1)得到9-(4-((2-烯丙基-1-(7-羟基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-3-氧代-2,3-二氢-叔丁基-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)苯基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸甲酯(I-9-a)(30mg，40.83％)，黄色固体。LC-MS:m/z:(M+H) +＝653.
第二步：
将9-(4-((2-烯丙基-1-(7-羟基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-3-氧代-2,3-二氢-叔丁基-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)苯基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸甲酯(I-9-a)(30mg,0.046mmol)溶于4ml二氯甲烷中,加入1mL三氟乙酸，反应液在20℃搅拌1小时。反应液浓缩得到6-((4-(3,9-二氮杂螺[5.5]十一烷-3-基)苯基)氨基)-2-烯丙基-1-(7-羟基-6,7-二氢-5H-环戊二烯并[b]吡啶吡啶-2-基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-9-b)(30mg，118.1％)，黄棕色固体。LC-MS:m/z:(M+H) +＝553.
第三步：
将6-((4-(3,9-二氮杂螺[5.5]十一烷-3-基)苯基)氨基)-2-烯丙基-1-(7-羟基-6,7-二氢-5H-环戊二烯并[b]吡啶吡啶-2-基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-9-b)(30mg,0.054mmol)溶于2ml甲醇中,加入37％甲醛水溶液(88mg,1.08mmol)，反应液在20℃搅拌2小时。加入三乙酰氧基硼氢化钠(17mg,0.081mmol)，反应液在20℃搅拌24小时。反应液用饱和碳酸氢钠水溶液淬灭，用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩，TLC制备(二氯甲烷/甲醇＝10/1)得到2-烯丙基1-(7-羟基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-((4-(9-甲基-3,9-二氮杂螺[5.5]十一碳-3-基)苯基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-9)黄色固体(10.77mg,35.01％)。 1H NMR(400MHz,CDCl 3)δ1H NMR(400MHz,MeOD)δ8.79(d,J＝3.1Hz,1H),7.89(d,J＝8.2Hz, 1H),7.71(d,J＝8.1Hz,1H),7.50(dd,J＝22.7,8.8Hz,2H),6.96(t,J＝6.2Hz,2H),5.74(ddt,J＝16.4,10.3,6.1Hz,1H),5.16–5.10(m,1H),5.06(dd,J＝10.3,1.2Hz,1H),4.99(d,J＝1.3Hz,1H),4.76(d,J＝6.0Hz,2H),3.38–3.28(m,4H),3.07(d,J＝4.8Hz,1H),2.96–2.79(m,1H),2.64–2.45(m,5H),2.28(s,3H),2.12–1.97(m,1H),1.75–1.54(m,8H).LC-MS:m/z:(M+H) +＝567.
实施例12
Figure PCTCN2020112034-appb-000060
第一步：
将5-(4-硝基苯基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(64mg,0.2mmol)(I-12-a)和10％的钯炭(30mg)加入到25ml的甲醇中，反应瓶用氢气球换气三次,反应液在氢气环境中室温搅拌3h。反应液过滤蒸干，得到5-(4-氨基苯基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(I-12-b)55mg，棕色固体，直接用于下一步。收率95％LC-MS:m/z:(M+H) +＝290。.
第二步：
将2-烯丙基-1-(7-羟基-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(35mg,0.095mmol)(I-16-h)在20ml甲苯的溶液中加入间氯过氧苯甲酸(25mg,0.112mmol),所得溶液室温搅拌15min。将上述反应液中加入5-(4-氨基苯基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(55mg,0.19mmol)(I-12-b)所示的化合物)和0.2ml N,N-二异丙基乙胺室温搅拌过夜。将反应液浓缩得粗品，所得粗产物粗产物用薄层层析法纯化{7M氨甲醇:(二氯甲烷:乙酸乙酯＝8:2)}＝1:18,得到5-(4-((2-烯丙基-1-(7-羟基-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-3-氧代-2,3-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)苯基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(I-12-c)40mg，黄色固体，收率69％。LC-MS:m/z:(M+H) +＝611。
第三步：
将5-(4-((2-烯丙基-1-(7-羟基-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-3-氧代-2,3-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)苯基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(30mg,0.049mmol)(I-12-c)加入到10ml二氯甲烷中，然后加入溴化锌(40mg,0.178mmol)室 温搅拌0.5h。将反应液浓缩后加入30ml二氯甲烷和1ml甲醇和饱和的碳酸氢钠溶液(3ml)，搅拌10分钟,有机层用无水硫酸钠干燥后用薄层层析法纯化{7M氨甲醇:(二氯甲烷:乙酸乙酯＝9:1)}＝1:8,得到6-((4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)苯基)氨基)-2-烯丙基-1-(7-羟基-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-12)黄色固体14mg，收率55％。 1H NMR(400MHz,CDCl 3)δ8.71(d,1H),7.70(m,2H),7.34(d,J＝6.4Hz,2H),6.47(d,J＝8.6Hz,2H),5.79–5.59(m,1H),5.01(d,J＝10.2Hz,1H),4.92(d,J＝17.1Hz,1H),4.75(m,2H),4.30(s,1H),3.88(d,J＝6.5Hz,1H),3.63(d,J＝7.4Hz,1H),3.21–2.98(m,4H),2.93–2.82(m,2H),2.42–2.25(m,2H),2.02–1.84(m,2H),1.63(d,3H)。LC-MS:m/z:(M+H) +＝511.
实施例13
Figure PCTCN2020112034-appb-000061
第一步：
将7-(4-硝基苯基)-2,7-二氮杂螺[3-4]壬烷-2-羧酸叔丁酯(80mg,0.23mmol)(I-13-a)加入到5ml二氯甲烷和5ml三氟乙酸组成的混合溶剂中，室温搅拌2h。将反应液浓缩后得到粗产物黄色固体(I-13-b),直接用于下一步。LC-MS:m/z:(M+H) +＝248.
第二步：
将7-(4-硝基苯基)-2,7-二氮杂螺[3.5]壬烷(55mg,0.22mmol)(I-13-b),0.5ml N,N-二异丙基乙胺,0.4ml的甲醛水溶液和醋酸硼氢化钠(240mg,1.13mol)加入到15ml的甲醇中，室温搅拌过夜。将反应液浓缩后加入20ml二氯甲烷和1ml甲醇，所得混合溶液用饱和的碳酸钠溶液(5ml)洗涤，有机层用无水硫酸钠干燥后浓缩得到2-甲基-7-(4-硝基苯基)-2,7-二氮杂螺[3.5]壬烷(I-13-c)50mg，黄色固体，收率86％。LC-MS:m/z:(M+H) +＝262.
第三步：
将2-甲基-7-(4-硝基苯基)-2,7-二氮杂螺[3.5]壬烷(60mg,0.23mmol)(I-13-c)和10％的钯炭(30mg)加入到20ml的甲醇中，反应瓶用氢气球换气三次,反应液在氢气环境中室温搅拌2h。反应液过滤蒸干，得到4-(2-甲基-2,7-二氮杂螺[3.5]壬-7-基)苯胺(I-13-d)50mg，棕色固体，直接用于下一步。收率94％。LC-MS:m/z:(M+H) +＝232。
第四步：
将2-烯丙基-1-(7-羟基-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(35mg,0.09mmol)(I-16-h)在15ml甲苯的溶液中加入含量77％的间氯过氧苯甲酸(22mg,0.1mmol),所得溶液室温搅拌15min。将上述反应液中4-(2-甲基-2,7-二氮杂螺[3.5]壬-7-基)苯胺(50mg,0.22mmol)(I-13-d)和0.2ml N,N-二异丙基乙胺在3ml二氯甲烷中的混合溶液,室温搅拌过夜。将反应液浓缩得粗品，所得粗产物用薄层层析法纯化{7M氨甲醇:(二氯甲烷:乙酸乙酯＝8:2)}＝1:20,得到2-烯丙基-1-(7-羟基-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-((4-(2-甲基-2,7-二氮杂螺[3.5]壬-7-基)苯基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-13)7mg,黄色固体，收率13％。 1H NMR(400MHz,CDCl 3)δ8.73(s,1H),7.69(m,2H),7.43(d,J＝8.8Hz,2H),6.88(d,J＝9.0Hz,2H),5.69(ddt,J＝16.8,10.2,6.3Hz,1H),5.01(dd,J＝10.2,1.0Hz,1H),4.92(dd,J＝17.1,1.2Hz,1H),4.84(dd,J＝15.6,5.5Hz,1H),4.72(dd,J＝15.7,6.6Hz,1H),3.22(d,J＝13.5Hz,4H),3.11–3.02(m,5H),2.92–2.83(m,1H),2.50–2.42(s,3H),2.42–2.26(m,2H),1.96–1.87(m,4H),1.63(s,3H).LC-MS:m/z:(M+H) +＝553。
实施例14
Figure PCTCN2020112034-appb-000062
将2-烯丙基-1-(7-羟基-7-甲基-5,6-二氢环戊二烯并[b]吡啶-2-基)-6-甲硫基-吡唑并[3,4-d]嘧啶-3-酮(I-16-h)(40mg,0.11mmol)溶于10ml甲苯中,加入3-氯苯基过氧羧酸(30mg,0.13mmol)，反应液在20℃搅拌2小时。加入二异丙基乙胺(30mg,0.23mmol)和4-(7-甲基-2,7-二氮杂螺[3.5]壬-2-基)苯胺(I-14-a)(30mg,0.13mmol)，反应液在20℃搅拌24小时。反应液过滤，浓缩，TLC制备(二氯甲烷/甲醇＝10/1)得到2-烯丙基-1-(7-羟基-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-((4-(7-甲基-2,7-二氮杂螺[3.5]壬-2-基)苯基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(如式I-14)(28mg，46.78％)，黄色固体。 1H NMR(400MHz,CDCl 3)δ1H NMR(400MHz,MeOD)δ8.71(d,J＝40.7Hz,1H),7.86(dd,J＝15.2,7.9Hz,1H),7.71(d,J＝8.1Hz,1H),7.41(ddd,J＝29.8,17.3,7.9Hz,2H),6.46(d,J＝8.9Hz,2H),5.73(ddt,J＝16.4,10.3,6.1Hz,1H),5.04(dd,J＝ 10.2,1.1Hz,1H),4.98–4.91(m,2H),4.76(dt,J＝23.8,14.4Hz,2H),3.62(s,4H),3.06(dt,J＝16.0,6.9Hz,1H),2.95–2.67(m,5H),2.55(s,3H),2.25(dt,J＝15.2,7.4Hz,2H),1.98(t,J＝5.3Hz,4H),1.59(s,3H).LC-MS:m/z:(M+H)+＝553.
实施例16
Figure PCTCN2020112034-appb-000063
第一步：
将2-氯-6,7-二氢-5H-环戊二烯并[b]吡啶(I-16-a)(23.0mmol)溶于甲苯(30mL)，向反应液中加入三溴氧磷(46mmol)，将反应液加热至回流，反应液搅拌16小时。向反应液中加入饱和碳酸氢钠水溶液调节至pH＝9，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，蒸干的粗品，粗品柱层析纯化(石油醚/乙酸乙酯＝100/0-50/50)得目标化合物2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶(I-16-b)(4.0g，89％)，灰色固体。LC-MS:m/z:(M+H) +＝198.
第二步：
将2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶(I-16-b)(18.0mmol)溶于二氯甲烷(20mL)，向反应液中加入3-氯苯并过氧酸(27.0mmol，70％)，将反应液室温下搅拌16小时。反应完后，向反应液中加入饱和碳酸氢钠水溶液调节至pH＝9，二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，蒸干的粗品，粗品柱层析纯化(二氯甲烷/甲醇＝100/0-97/3)得目标化合物2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶1-氧化物(I-16-c)(3.2g，84％)白色固体。LC-MS:m/z:(M+H) +＝216。
第三步：
将2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶1-氧化物(I-16-c)(15.0mmol)溶于乙酸酐(30mL)，反应液在110℃下搅拌16小时，将反应液蒸干。向反应液中加入饱和碳酸氢钠水溶液调节至pH＝9，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，蒸干的粗品，粗品柱层析纯化(石油醚/乙酸乙酯＝100/0-50/50)得目标化合物2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶-7-基乙酸酯(I-16-d)(2.7g，71％)，黄色固体。LC-MS:m/z:(M+H) +＝256。
第四步：
将2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶-7-基乙酸酯(I-16-d)(11.0mmol)溶于乙醇(15mL)和水(10mL)，加入氢氧化钾(12.0mmol)，反应液室温下搅拌3小时。反应液用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，蒸干的粗品，粗品柱层析纯化(石油醚/乙酸乙酯＝100/0-50/50)目标化合物2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶-7-醇(I-16-e)(1.50g，66％)，白色固体。LC-MS:m/z:(M+H) +＝214。
第五步：
将2-溴-6,7-二氢-5H-环戊二烯并[b]吡啶-7-醇(I-16-e)(7.0mmol)溶于二氯甲烷(50mL)，加入3-氧代-115-苯并[d][1,2]碘唑-1,1,1(3H)-三乙酸三酯(14.0mmol)，反应液室温下搅拌3小时。将反应液过滤，滤液蒸干得粗品，粗品柱层析纯化(石油醚/乙酸乙酯＝100/0-50/50)目标化合物2-溴-5,6-二氢-7H-环戊二烯并[b]吡啶-7-酮(I-16-f)(1.20g，81％)，白色固体。LC-MS:m/z:(M+H) +＝212。
第六步：
将2-溴-5,6-二氢-7H-环戊二烯并[b]吡啶-7-酮(I-16-f)(3.54mmol)溶于无水四氢呋喃(10mL)，将反应液冷却至0℃，加入甲基溴化镁(7.07mmol)，反应液室温下搅1小时。相反应液中加入水，淬灭反应，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液蒸得粗品，粗品柱层析纯化(石油醚/乙酸乙酯＝100/0-50/50)目标化合物2-溴-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-醇(I-16-g)(320mg，39.7％)，白色固体。LC-MS:m/z:(M+H) +＝229。
第七步：
将2-烯丙基-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-1-f)(1.54mmol)溶于无水1,4-二恶烷(20mL)，向反应液中加入N1，N2-二甲基乙-1,2-二胺(2.81mmol)，碘化亚铜(1.40mmol)，碳酸钾(1.96mmol)和2-溴-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-醇(I-16-g)(1.40mmol)。将反应液在氮气保护下加热至110℃，并搅拌反应16小时。将反应液过滤，滤液蒸得粗品，粗品柱层析纯化(石油醚/乙酸乙酯＝100/0-50/50) 目标化合物2-烯丙基-1-(7-羟基-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-16-h)(170mg，32.8％)，白色固体。LC-MS:m/z:(M+H) +＝370。
第八步：
将2-烯丙基-1-(7-羟基-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-16-h)(0.23mmol)溶于甲苯(15mL)，加入3-氯苯氧基甲酸(0.25mmol)，反应液室温下搅拌0.5小时，将反应液蒸干，所得亚砜中间体溶于二甲亚砜(10mL)，加入4-(4-甲基哌嗪-1-基)苯胺(I-16-f)(0.25mmol)和三氟乙酸(0.3mL)，将反应液加热至60℃下搅拌16小时。反应液用饱和碳酸钠溶液调pH＝9，加入水(50mL)乙酸乙酯(50mL)，分层，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，蒸干，液相制备纯化得目标化合物2-烯丙基-1-(7-羟基-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-((4-(4-甲基哌嗪-1-基)苯基基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-16)(25mg，21.2％)，白色固体。 1H NMR(400MHz,DMSO)δ10.11(s,1H),8.83(s,1H),8.27(s,2H),7.94(d,J＝7.3Hz,1H),7.77-7.53(m,3H),6.92(d,J＝8.9Hz,2H),5.76-5.63(m,1H),5.00(d,J＝10.2Hz,1H),4.87(d,J＝17.1Hz,1H),4.81-4.54(m,3H),3.11(s,4H),3.04-2.92(m,1H),2.81(dd,J＝15.1,8.0Hz,1H),2.48(s,4H),2.24(s,3H),2.14(t,J＝6.9Hz,2H),2.01(dd,J＝15.3,7.7Hz,1H),1.46(s,3H).LC-MS:m/z:(M+H) +＝513。
实施例17
Figure PCTCN2020112034-appb-000064
第一步：
将3-(4-硝基苯基)丙酸(300mg,1.54mmol)和吡咯烷(I-17-a)(131mg,1.84mmol)溶于5ml二氯甲烷中,加入丙基磷酸三环酸酐溶液(1.47g,50％，2.31mmol)，反应液在15℃反应1小时。反应液浓缩，过柱子纯化(甲醇/二氯甲烷＝0-10％)，得到白色固体(I-17-b)(300mg，78.6％)。LC-MS:m/z:(M+H) +＝249。
第二步：
将3-(4-硝基苯基)-1-吡咯烷-1-基-丙-1-酮(I-17-b)(50mg,0.20mmol)溶于10 ml甲醇中,加入10％Pd/C(30mg)，反应液在15℃加氢气(15psi)搅拌2小时。过滤并浓缩，得到白色固体(I-17-c)(40mg，91％)。LC-MS:m/z:(M+H) +＝219。
第三步：
将2-烯丙基-1-(8-羟基-8-甲基-6,7-二氢-5H-喹啉-2-基)-6-甲硫基-吡唑并[3,4-d]嘧啶-3-酮(I-18-h)(40mg,0.10mmol)溶于10ml甲苯中,加入3-氯苯基过氧羧酸(32mg,0.14mmol)，反应液在20℃搅拌2小时。加入二异丙基乙胺(30mg,0.23mmol)和3-(4-氨基苯基)-1-吡咯烷-1-基-丙-1-酮(I-17-c)(27mg,0.13mmol)，反应液在20℃搅拌24小时。反应液用二氯甲烷(50mL)稀释，饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩，TLC制备(二氯甲烷/甲醇＝10/1)得到2-烯丙基-1-(8-羟基-8-甲基-5,6,7,8-四氢喹啉-2-基)-6-((4-(3-氧代-3-(吡咯烷-1-基)丙基)苯基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-17)(28.55mg，49％)，黄色固体。 1H NMR(400MHz,CDCl 3)δ1H NMR(400MHz,MeOD)δ8.83(s,1H),7.74(dd,J＝18.0,8.3Hz,2H),7.61(d,J＝8.5Hz,2H),7.20(d,J＝8.6Hz,2H),5.81–5.66(m,1H),5.05(dd,J＝10.2,1.1Hz,1H),4.94(ddd,J＝14.9,10.8,3.6Hz,2H),4.81–4.68(m,1H),3.39(dd,J＝11.5,4.8Hz,2H),3.30(s,3H),2.91(dt,J＝10.7,7.3Hz,4H),2.63(t,J＝7.5Hz,2H),2.14–1.93(m,3H),1.92–1.75(m,5H),1.62(d,J＝8.4Hz,3H).LC-MS:m/z:(M+H) +＝554。
实施例18
Figure PCTCN2020112034-appb-000065
第一步：
将2-氯-5,6,7,8-四氢喹啉(2g,11.93mmol)(I-18-a)溶于40ml乙腈中,加入溴(三甲基)硅烷(7.3g,43.7mmol)，反应液在150℃微波搅拌2小时。反应液浓缩，将残余物用二氯甲烷(30mL)稀释，并用饱和碳酸氢钠水溶液(20mL×3)洗涤。将有机层用无水硫酸钠干燥，过滤并浓缩，得到粗产物，过柱子纯化(乙酸乙酯/石油醚＝0-100％)，得到无色油状的产物2-溴-5,6,7,8-四氢喹啉(I-18-b)(2.4g，95％)。LC-MS:m/z:(M+H) +＝554。
第二步：
将2-溴-5,6,7,8-四氢喹啉(I-18-b)(2.4g,11mmol)溶于20ml二氯甲烷中,加入3-氯苯基过氧羧酸(3.3g,70％，14mmol)，反应液在15℃搅拌16小时。反应液用饱和碳酸氢钠水溶液淬灭，用二氯甲烷(30mL×2)萃取。将有机层用无水硫酸钠干燥，过滤并浓缩，得到粗产物，过柱子纯化(乙酸乙酯/石油醚＝0-50％)，得到2-溴-5,6,7,8-四氢喹啉1-氧化物(I-18-c)(2.36g，91％)白色固体。LC-MS:m/z:(M+H) +＝228。
第三步：
将2-溴-5,6,7,8-四氢喹啉1-氧化物(I-18-c)(2.36g,10.3mmol)溶于50ml乙酸酐中,反应液在110℃搅拌16小时。反应液浓缩，过柱子纯化(乙酸乙酯/石油醚＝0-50％)，得到无色油状的产物2-溴-5,6,7,8-四氢喹啉-8-基乙酸酯(I-18-d)(2.2g，79％)。LC-MS:m/z:(M+H) +＝270。
第四步：
将2-溴-5,6,7,8-四氢喹啉-8-基乙酸酯(I-18-d)(2.2g,8.17mmol)溶于20ml乙醇中,加入溶于50ml乙醇的KOH(500mg，8.93mmol)溶液，反应液在15℃搅拌3小时。反应液浓缩，残余物加入50ml水，用二氯甲烷(50mL×2)萃取，将有机层用无水硫酸钠干燥，过滤并浓缩，得到无色油状的产物2-溴-5,6,7,8-四氢喹啉-8-醇(I-18-e)(1.6g，86％)。LC-MS:m/z:(M+H) +＝228。
第五步：
将2-溴-5,6,7,8-四氢喹啉-8-醇(I-18-e)(1.6g,7.0mmol)溶于50ml二氯甲烷中,加入戴斯-马丁试剂(8g,18.86mmol)，反应液在15℃搅拌3小时。反应液用饱和碳酸氢钠水溶液和硫代硫酸钠水溶液洗涤，用二氯甲烷(30mL×2)萃取，有机层用无水硫酸钠干燥，，过滤并浓缩，得到粗产物，过柱子纯化(乙酸乙酯/石油醚＝0-50％)，得到2-溴-6,7-二氢喹啉-8(5H)-酮(I-18-f)(760mg，59％)，白色固体。LC-MS:m/z:(M+H) +＝242。
第六步：
将2-溴-6,7-二氢喹啉-8(5H)-酮(I-18-f)(1.2g,5.3mmol)溶于50ml四氢呋喃 中,0℃下加入3M甲基溴化镁(2.6mL,7.8mmol)，加毕搅拌10min。反应液用饱和氯化铵水溶液淬灭，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩，得到粗产物，过柱子纯化(乙酸乙酯/石油醚＝0-50％)，得到2-溴-8-甲基-5,6,7,8-四氢喹啉-8-醇(I-18-g)(1.3g，82％)，白色固体。LC-MS:m/z:(M+H) +＝226。
第七步：
将2-溴-8-甲基-5,6,7,8-四氢喹啉-8-醇(I-18-g)(750mg,3.10mmol)、2-烯丙基-6-甲硫基-1H-吡唑并[1]的混合物[3,4-d]嘧啶-3-酮(I-1-f)(688mg,3.10mmol)、碘化亚酮(592mg，3.0978mmol)，碳酸钾(855mg，6.1955mmol)和N1，N2-二甲基乙烷-1,2-二胺(410mg，4.65mmol，)悬浮于20ml二氧六环中,95℃下搅拌16小时。反应液过滤并浓缩，得到粗产物，过柱子纯化(乙酸乙酯/石油醚＝0-60％)，得到2-烯丙基-1-(8-羟基-8-甲基-5,6,7,8-四氢喹啉-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4d]嘧啶-3-酮(I-18-h)(430mg，36.2％)，白色固体。LC-MS:m/z:(M+H) +＝384。
第八步：
将2-烯丙基-1-(8-羟基-8-甲基-5,6,7,8-四氢喹啉-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4d]嘧啶-3-酮(I-18-h)(40mg,0.10mmol)溶于10ml甲苯中,加入3-氯苯基过氧羧酸(30mg,0.14mmol)，反应液在20℃搅拌2小时。加入二异丙基乙胺(30mg,0.23mmol)和4-(4-氨基苯基)哌嗪-1-羧酸叔丁酯(33mg,0.12mmol)，反应液在20℃搅拌24小时。反应液浓缩，TLC制备(二氯甲烷/甲醇＝10/1)得到4-(4-((2-烯丙基-1-(8-羟基-8-甲基-5,6,7,8-四氢喹啉-2-基)-3-氧代-2,3-二氢-叔丁基-4-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)苯基)哌嗪-1-羧酸叔丁酯(I-18-i)(25mg，39.12％),黄色固体。LC-MS:m/z:(M+H) +＝613.
第九步：
将4-(4-((2-烯丙基-1-(8-羟基-8-甲基-5,6,7,8-四氢喹啉-2-基)-3-氧代-2,3-二氢-叔丁基-4-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)苯基)哌嗪-1-羧酸叔丁酯(I-18-i)(25mg,0.041mmol)溶于3ml二氯甲烷中,加入盐酸/二氧六环溶液(3ml,4M)，反应液在15℃搅拌1小时。反应液浓缩，HPLC制备得到偏白色固体2-烯丙基-1-(8-羟基-8-甲基-5,6,7,8-四氢喹啉-2-基)-6-((4-(哌嗪-1-基)苯基)氨基)-1，-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-18)(19mg，94.14％)。 1H NMR(400MHz,CDCl 3)δ1H NMR(400MHz,MeOD)δ8.81(d,J＝4.6Hz,1H),8.45(s,1H),7.80–7.70(m,2H),7.62(d,J＝9.0Hz,2H),7.18–6.92(m,2H),5.81–5.60(m,1H),5.05(dd,J＝10.2,1.2Hz,1H),4.99–4.91(m,2H),4.79(dd,J＝16.1,6.3Hz,1H),3.38(d,J＝10.4Hz,8H),2.99–2.79(m,2H),2.18–1.93(m,3H), 1.92–1.77(m,1H),1.63(s,3H).LC-MS:m/z:(M+H) +＝513。
实施例19
Figure PCTCN2020112034-appb-000066
将2-烯丙基-1-(8-羟基-8-甲基-5,6,7,8-四氢喹啉-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4d]嘧啶-3-酮(I-18-h)(40mg,0.11mmol)溶于10ml甲苯中,加入3-氯苯基过氧羧酸(30mg,0.13mmol)，反应液在20℃搅拌2小时。加入二异丙基乙胺(30mg,0.23mmol)和4-(4-甲基哌嗪-1-基)苯胺(30mg,0.16mmol)，反应液在20℃搅拌24小时。反应液过滤，浓缩，TLC制备(二氯甲烷/甲醇＝10/1)得到2-烯丙基-1-(8-羟基-8-甲基-5,6,7,8-四氢喹啉-2-基)-6-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-19)(26mg，47.34％)，黄色固体。 1H NMR(400MHz,CDCl 3)δ1H NMR(400MHz,MeOD)δ8.78(s,1H),7.83–7.65(m,2H),7.54(d,J＝8.9Hz,2H),6.95(d,J＝9.1Hz,2H),5.90–5.61(m,1H),5.05(dd,J＝10.2,0.9Hz,1H),4.95(dd,J＝12.2,6.2Hz,2H),4.79(dd,J＝16.1,6.3Hz,1H),3.26–3.11(m,4H),2.97–2.76(m,2H),2.76–2.58(m,4H),2.39(s,3H),2.15–1.92(m,3H),1.92–1.76(m,1H),1.61(d,J＝8.9Hz,3H).LC-MS:m/z:(M+H) +＝527。
实施例20和实施例21
Figure PCTCN2020112034-appb-000067
第一步：
将7-(4-硝基苯基)-2,7-二氮杂螺[3-4]壬烷-2-羧酸叔丁酯(80mg,0.23mmol)(如式I-20-a)和10％的钯炭(30mg)加入到25ml的甲醇中，反应瓶用氢气球换气三次,反应液在氢气环境中室温搅拌3h。反应液过滤蒸干，得到7-(4-氨基苯基)-2,7-二氮杂螺[3-4]壬烷-2-羧酸叔丁酯(I-20-b)70mg，棕色固体，直接用于下一步。收率95％。LC-MS:m/z:(M+H) +＝318。
第二步：
将2-烯丙基-1-(8-羟基-5,6,7,8-四氢喹啉-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(53mg,0.143mmol)(I-23-f)在15ml甲苯的溶液中加入间氯过氧苯甲酸(38mg,0.17mmol),所得溶液室温搅拌2h。将上述反应液中加入7-(4-氨基苯基)-2,7-二氮杂螺[3-4]壬烷-2-羧酸叔丁酯(60mg,0.189mmol)(I-20-b)和0.2ml N,N-二异丙基乙胺在3ml二氯甲烷中的混合溶液,室温搅拌过夜。将反应液浓缩得粗品，所得粗产物用薄层层析法纯化{7M氨甲醇:(二氯甲烷:乙酸乙酯＝8:2)}＝1:13,得到7-(4-((2-烯丙基-1-(8-羟基-5,6,7,8-四氢喹啉-2-基)-3-氧代-2,3-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)苯基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸甲酯(I-20-c)70mg，黄色固体，收率76％。LC-MS:m/z:(M+H) +＝639。
第三步：
将7-(4-((2-烯丙基-1-(8-羟基-5,6,7,8-四氢喹啉-2-基)-3-氧代-2,3-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)苯基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸甲酯(I-20-c)(70mg,0.11mmol)加入到5ml二氯甲烷和5ml三氟乙酸组成的混合溶剂中，室温搅拌2h。将反应液浓缩后加入30ml 二氯甲烷和2ml甲醇，所得混合溶液用饱和的碳酸钠溶液(10ml)洗涤，有机层用无水硫酸钠干燥后用薄层层析法纯化{7M氨甲醇:(二氯甲烷:乙酸乙酯＝8:1)}＝1:9,得到6-((4-(2,7-二氮杂螺[3.5]壬-7-基)苯基)氨基)-2-烯丙基-1-(8-羟基-5,6,7,8-四氢喹啉-2-基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-21)45mg，黄色固体，收率76％。 1H NMR(400MHz,CDCl 3)δ8.78(s,1H),7.65(d,J＝8.2Hz,1H),7.58(d,J＝8.3Hz,1H),7.43(d,J＝8.7Hz,2H),6.90(d,J＝9.1Hz,2H),5.73(ddt,J＝16.3,10.3,6.0Hz,1H),5.07(dd,J＝10.2,1.1Hz,1H),5.00(dd,J＝17.1,1.2Hz,1H),4.73(t,J＝6.5Hz,1H),4.69–4.67(d,J＝5.5Hz,2H),3.46(d,J＝8.2Hz,4H),3.13–3.05(m,4H),2.94–2.78(m,2H),2.35–2.20(m,1H),2.06(m,1H),1.99–1.78(m,6H).LC-MS:m/z:(M+H) +＝539。
第四步：
将6-((4-(2,7-二氮杂螺[3.5]壬-7-基)苯基)氨基)-2-烯丙基-1-(8-羟基-5,6,7,8-四氢喹啉-2-基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(25mg,0.046mmol)(I-21),0.1ml的甲醛水溶液和醋酸硼氢化钠(30mg,0.14mmol)加入到8ml的甲醇中,室温搅拌过夜。将反应液浓缩后加入20ml二氯甲烷和1ml甲醇，所得混合溶液用饱和的碳酸钠溶液(5ml)洗涤，有机层用无水硫酸钠干燥后用薄层层析法纯化{7M氨甲醇:(二氯甲烷:乙酸乙酯＝8:2)}＝1:10,得到2-烯丙基-1-(8-羟基-5,6,7,8-四氢喹啉-2-基)-6-((4-(2-甲基-2,7-二氮杂螺[3.5]壬-7-基基)苯基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-20)黄色固体15mg，收率58％。 1H NMR(400MHz,CDCl 3)δ8.79(s,1H),7.66(d,J＝8.2Hz,1H),7.59(d,J＝8.3Hz,1H),7.43(d,J＝8.8Hz,2H),6.90(t,J＝6.2Hz,2H),5.74(ddt,J＝16.3,10.3,6.0Hz,1H),5.08(dd,J＝10.2,1.0Hz,1H),5.00(dd,J＝17.1,1.2Hz,1H),4.77–4.63(m,3H),3.18–3.04(m,8H),2.96–2.78(m,2H),2.40(s,3H),2.35–2.21(m,1H),2.12–2.00(m,1H),1.98–1.79(m,6H).LC-MS:m/z:(M+H) +＝553。
实施例23
Figure PCTCN2020112034-appb-000068
第一步：
将2-氯-5,6,7,8-四氢喹啉(I-23-a)(0.71g,4.23mmol)和三甲基溴硅烷(3g,19.6mmol)加入到15mL乙腈中,微波条件下150度加热搅拌3h。反应液冷却浓缩后慢慢加入10ml饱和的碳酸氢钠溶液,直到PH值约等于10,然后用二氯甲烷萃取三次(3*30ml),无水硫酸钠干燥后浓缩得粗品，过柱纯化(乙酸乙酯:石油醚＝0-15％)，得到2-溴-5,6,7,8-四氢喹啉(I-23-b)0.82g，无色油状物，收率：91％。LC-MS:m/z:(M+H) +＝212。
第二步：
将2-溴-5,6,7,8-四氢喹啉(I-23-b)(0.82g,3.9mmol)加入到25ml二氯甲烷中,然后77％的间氯过氧苯甲酸(1.32g,5.9mmol)也加入到25ml二氯甲烷中,将此溶液加入到上述化合物2的溶液中,室温搅拌过夜。反应液用饱和的酸氢钠溶液溶液洗涤,水相再用二氯甲烷萃取三次(3*30ml)，合并后的有机层无水硫酸钠干燥后浓缩得粗品,过柱纯化(乙酸乙酯:石油醚＝0-80％)得到2-溴-5,6,7,8-四氢喹啉1-氧化物(I-23-c)0.82g，白色固体,收率:93％。LC-MS:m/z:(M+H) +＝228。
第三步：
将2-溴-5,6,7,8-四氢喹啉1-氧化物(I-23-c)(0.82g,3.6mmol)溶于20ml乙酸酐中，120℃搅拌过夜。反应液浓缩后加入30ml二氯甲烷，用饱和的酸氢钠溶液溶液洗涤两次(2*10ml)，再用10ml饱和的食盐水洗一次，无水硫酸钠干燥后浓缩过柱(乙酸乙酯:石油醚＝0-30％)，得到2-溴-5,6,7,8-四氢喹啉-8-基乙酸酯(I-23-d)0.74g，无色油状物，收率76％。LC-MS:m/z:(M+H) +＝270。
第四步：
将2-溴-5,6,7,8-四氢喹啉-8-基乙酸酯(I-23-d)(0.74g,2.7mmol)加入到20ml的乙醇中,然后加入20ml氢氧化钾(154mg,2.75mmol)的乙醇溶液。室温搅拌3h。往反应液中加入25ml水，将大部分的乙醇蒸除,二氯甲烷萃取(3*25ml),再用20ml饱和的食盐水洗一次，无水硫酸钠干燥后浓缩过柱(乙酸乙酯:石油醚＝0-50％)，得到2-溴-5,6,7,8-四氢喹啉-8-醇(I-23-e)0.58g，无色油状物，收率93％。 1H NMR(400MHz,CDCl 3)δ7.31(t,J＝5.1Hz,1H),4.71(t,J＝6.6Hz,0H),3.55(s,0H),2.87–2.68(m,2H),2.32–2.18(m,1H),2.09–1.95(m,1H),1.90–1.74(m,2H).LC-MS:m/z:(M+H) +＝227。
第五步：
将2-溴-5,6,7,8-四氢喹啉-8-醇(I-23-e)(0.58g,2.54mmol),2-烯丙基-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(0.58g,2.61mmol)(I-1-f),碘化亚铜(0.5g，2.6mmol),碳酸钾(0.72g,5.22mmol)和N1，N2-二甲基乙二胺(0.46g,5.2mmol)加入到20ml的1，4-二氧六环中，在氩气保护下，100度搅拌过夜。反应物冷却后过滤浓缩得粗品，过柱纯化(甲醇:二氯甲烷＝0-10％)，得到2-烯丙基-1-(8-羟基-5,6,7,8-四氢喹啉-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-23-f)0.50g白色固体,收率50％。LC-MS:m/z:(M+H) +＝370。
第六步：
将2-烯丙基-1-(8-羟基-5,6,7,8-四氢喹啉-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(53mg,0.14mmol)(I-23-f)在20ml甲苯的溶液中加入间氯过氧苯甲酸(38mg,0.17mmol),所得溶液室温搅拌2h。将上述反应液中加入4-(4-甲基哌嗪-1-基)苯胺(35mg,0.18mmol)(I-1-h)和0.2ml N,N-二异丙基乙胺室温搅拌过夜。将反应液浓缩得粗品，所得粗产物过柱纯化(甲醇二氯甲烷＝0-20％),然后通过高效液相制备得到2-烯丙基-1-(8-羟基-5,6,7,8-四氢喹啉-2-基)-6-((4-(4-甲基哌嗪-1-基(苯基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-23)34mg，黄色固体，收率34％。 1H NMR(400MHz,CDCl 3)δ8.78(s,1H),8.04(s,1H),7.64(d,J＝8.2Hz,1H),7.58(t,J＝8.1Hz,1H),7.43(d,J＝8.8Hz,2H),6.89(d,J＝9.0Hz,2H),5.72(ddt,J＝16.4,10.3,6.0Hz,1H),5.06(dd,J＝10.2,0.9Hz,1H),4.99(dd,J＝17.1,1.2Hz,1H),4.72(t,J＝6.5Hz,1H),4.67(d,J＝5.9Hz,2H),3.90(s,1H),3.24–3.13(m,4H),2.94–2.75(m,2H),2.67–2.55(m,4H),2.36(s,3H),2.33–2.24(m,1H),2.06–2.03(m,1H),1.91–1.77(m,2H).LC-MS:m/z:(M+H) +＝513.
实施例28
Figure PCTCN2020112034-appb-000069
第一步：
将N，N-二甲基-1-(4-硝基苯基)哌啶-4-胺(60mg,0.24mmol)(I-28-a)和10％的钯炭(30mg)加入到25ml的甲醇中，反应瓶用氢气球换气三次,反应液在氢气环境中室温搅拌3h。反应液过滤蒸干，得到1-(4-氨基苯基)-N，N-二甲基哌啶-4-胺(I-28-b)50mg，棕色固体，直接用于下一步。收率95％。LC-MS:m/z:(M+H) +＝220.
第二步：
将2-烯丙基-1-(8-羟基-5,6,7,8-四氢喹啉-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(40mg,0.108mmol)(I-23-f)在15ml甲苯的溶液中加入间氯过氧苯甲酸(30mg,0.134mmol),所得溶液室温搅拌2h。将上述反应液中加入1-(4-氨基苯基)-N，N-二甲基哌啶-4-胺(50mg,0.228mmol)(I-28-b)和0.2ml N,N-二异丙基乙胺室温搅拌过夜。将反应液浓缩得粗品，所得粗产物用高效液相制备,得到2-烯丙基-6-((4-(4-(二甲基氨基)哌啶-1-基)苯基)氨基)-1-(8-羟基-5,6,7,8-四氢喹啉-2-基)-1-，2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮甲酸盐(I-28)25mg，黄色固体，收率42％。 1H NMR(400MHz,CDCl 3)δ8.78(s,1H),8.52(s,1H),7.61(q,J＝8.3Hz,2H),7.46(d,J＝8.3Hz,2H),6.88(d,J＝8.8Hz,2H),5.78–5.65(m,1H),5.07(d,J＝10.2Hz,1H),4.98(d,J＝17.1Hz,1H),4.72(t,J＝7.3Hz,1H),4.66(d,J＝5.4Hz,2H),3.72(d,J＝12.0Hz,2H),3.06(t,J＝11.7Hz,1H),2.95–2.81(m,2H),2.75(t,J＝11.9Hz,2H),2.66(s,6H),2.30(m,1H),2.18–1.98(m,3H),1.85(m,4H).LC-MS:m/z:(M+H) +＝541。
实施例32和实施例33
Figure PCTCN2020112034-appb-000070
第一步：
将2-烯丙基-1-(8-羟基-8-甲基-6,7-二氢-5H-喹啉-2-基)-6-甲硫基-吡唑并[3,4-d]嘧啶-3-酮(40mg,0.104mmol)(I-18-h)溶于10ml甲苯中,加入3-氯苯基过氧羧酸(30mg,0.13mmol)，反应液在20℃搅拌2小时。加入二异丙基乙胺(30mg,0.23mmol)和叔丁基(3aR，6aS)-2-(4-氨基苯基)-1,3,3a，4,6,6a-六氢吡咯并[3,4-c]吡咯-5-羧酸叔丁酯(30mg,0.10mmol)，反应液在20℃搅拌24小时。反应液过滤，浓缩，TLC制备(二氯甲烷/甲醇＝10/1)得到叔丁基(3aR，6aS)-5-(4-((2-烯丙基-1-(8-羟基-8-甲基-5,6,7,8-四氢喹啉-2-基)-3-氧代-2,3-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)苯基)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(I-32-a)(35mg，52.53％)，黄色固体。LC-MS:m/z:(M+H) +＝639.
第二步：
将叔丁基(3aR，6aS)-5-(4-((2-烯丙基-1-(8-羟基-8-甲基-5,6,7,8-四氢喹啉-2-基)-3-氧代-2,3-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)苯基)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(I-32-a)((35mg,0.055mmol)溶于3ml二氯甲烷中,加入6mL4M盐酸二氧六环溶液，反应液在20℃搅拌1小时。反应液浓缩得到2-烯丙基-6-((4-((3AR，6AS)六氢吡咯并[3,4-c]吡咯-2(1H)-基)苯基)氨基)-1-(8-羟基-8-甲基-5,6,7,8-四氢喹啉-2-基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-33)(30mg，95.21％)，黄棕色固体。 1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,MeOD)δ8.76(s,1H),7.71(s,2H),7.50(d,J＝7.9Hz,2H),6.75(d,J＝8.7Hz,2H),5.89–5.56(m,1H),5.05(d,J＝10.1Hz,1H),4.96(s,1H),4.80(d,J＝6.1Hz,2H),3.61(s,2H),3.49(d,J＝7.6Hz,2H),3.26(s,5H),3.24(s,1H),2.89(d,J＝6.3Hz,2H),2.16–1.95(m,4H),1.86(d,J＝6.3Hz,1H),1.63(s,3H).LC-MS:m/z:(M+H) +＝539.
第三步：
将2-烯丙基-6-((4-((3AR，6AS)六氢吡咯并[3,4-c]吡咯-2(1H)-基)苯基)氨基)-1-(8-羟基-8-甲基-5,6,7,8-四氢喹啉-2-基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-33)(30mg,0.052mmol)溶于2ml甲醇中,加入37％甲醛水溶液(21mg,0.26mmol)，反应液在20℃搅拌2小时。加入三乙酰氧基硼氢化钠(22mg,0.10mmol)，反应液在20℃搅拌24小时。反应液浓缩，TLC制备(二氯甲烷/甲醇＝10/1)得到黄色固体20mg,再经制备液相得到2-烯丙基-1-(8-羟基-8-甲基-5,6,7,8-四氢喹啉-2-基)-6-((4-((3AR，6AS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)苯基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-32)(8.5mg,29％)，黄色固体。 1H NMR(400MHz,CDCl 3)δ1H NMR(400MHz,MeOD)δ8.78(s,1H),7.72(s,2H),7.52(d,J＝8.2Hz,2H),6.79(d,J＝8.9Hz,2H),5.73(ddd,J＝16.7,10.2,6.0Hz,1H),5.05(d,J＝9.3Hz,1H),4.99–4.92(m,2H),4.79(dd,J＝16.1,6.3Hz,1H),3.53–3.38(m,4H),3.18(d,J＝7.1Hz,4H),3.03(d,J＝10.4Hz,2H),2.96–2.83(m,2H),2.74(s,3H),2.13–1.97(m,4H),1.93–1.80(m,1H),1.63(s,3H).LC-MS:m/z:(M+H) +＝553.
实施例34
Figure PCTCN2020112034-appb-000071
第一步，
将4-溴苯胺(I-34-a)(58.1mmol)溶于甲苯(250mL)，向反应液中加入碳酸钾(87.2mmol)和氯化苄基酯(87.2mmol)，将反应液在氮气保护下搅拌16小时。将反应液过滤，滤液蒸干的粗品，粗品用少量乙酸乙酯洗涤得目标化合物(苄基(4-溴苯基)氨基甲酸酯(I-34-b)15.2g，白色固体，85.4％。LC-MS:m/z:(M+H) +＝306.
第二步，
将((苄基(4-溴苯基)氨基甲酸酯(I-34-b)(16.0mmol)溶于1,2-二甲氧基乙烷(50 mL)，向反应液中加入4,4,5,5-四甲基-2-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)-1,3,2-二氧杂硼烷(如式I-34-c)(16.0mmoL)，碳酸钾(42.0mmol)和四三苯基瞵钯(1.6mmol)，将反应液加热至80℃下搅拌16小时。将反应液过滤，滤液蒸干得到粗品，粗品柱层析纯化(二氯甲烷/甲醇＝100/0-95/5)得目标化合物苄基(4-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)苯基)氨基甲酸酯(I-34-d)5.6g，白色固体，产率94％。LC-MS:m/z:(M+H) +＝367。
第三步：
将苄基(4-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)苯基)氨基甲酸酯(I-34-d)(15.0mmol)溶于四氢呋喃(30mL)。向反应液中加入盐酸(20mL,4mmol/L)，将反应液加热至45℃下搅拌16小时。向反应液中加入碳酸钾，调节pH＝9，二氯甲烷萃取，有机相用食盐水洗涤，有机相用无水硫酸钠干燥，过滤，蒸干得粗品目标化合物苄基(4'-氧代-2'，3'，4'，5'-四氢-[1,1'-联苯]-4-基)氨基甲酸酯(I-34-e)4.0g，黄色固体，产率81％。LC-MS:m/z:(M+H) +＝322。
第四步：
将苄基(4'-氧代-2'，3'，4'，5'-四氢-[1,1'-联苯]-4-基)氨基甲酸酯(I-34-e)(12.0mmol)溶于二氯甲烷(25mL)，向反应液中加入二甲胺盐酸盐(25.0mmol)，二异丙基乙基胺(25.0mmol)和三乙酰氧基硼氢化钠(37.0mmol)。将反应液室温下搅拌16小时，将反应液液蒸干得粗品，粗品柱层析纯化(二氯甲烷/甲醇＝100/0-95/5)得目标化合物苄基(4'-(二甲基氨基)-2'，3'，4'，5'-四氢-[1,1'-联苯]-4-基)氨基甲酸酯(I-34-f)3.5g，黄色固体，产率80％。LC-MS:m/z:(M+H) +＝351。
第五步：
将苄基(4'-(二甲基氨基)-2'，3'，4'，5'-四氢-[1,1'-联苯]-4-基)氨基甲酸酯(I-34-f)(10.0mmol)溶于甲醇(20mL)，加入钯碳(350mg)，反应液室温下在氢气下搅拌16小时，将反应液过滤，滤液蒸干得粗品，粗品用少量的乙酸乙酯洗涤得目标化合物4-(4-(二甲基氨基)环己基)苯胺(I-34-g)1.2g，白色固体，产率55％。LC-MS:m/z:(M+H) +＝219。
第六步：
将2-烯丙基-1-(7-羟基-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-16-h)(0.14mmol)溶于甲苯(10mL)，加入3-氯苯氧基甲酸(0.15mmol)，反应液室温下搅拌0.5小时，将反应液蒸干，所得亚砜中间体溶于二甲亚砜(10mL)，加入4-(4-(二甲基氨基)环己基)苯胺(I-34-g)(0.15mmol)和三氟乙酸(0.3mL)，将反应液加热至60℃下搅拌16小时。反应液用饱和碳酸钠溶液 调pH＝9，加入水(50mL)乙酸乙酯(50mL)，分层，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，蒸干，液相制备纯化得目标化合物2-烯丙基-6-((4-(4-(二甲基氨基)环己基)苯基)氨基)-1-(7-羟基-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-34)25mg，白色固体，产率34.2％。 1H NMR(400MHz,CDCl3)δ8.86(s,0H),7.72(dd,J＝24.0,8.0Hz,1H),7.54(d,J＝7.8Hz,3H),7.18(d,J＝8.2Hz,1H),5.72(d,J＝6.4Hz,0H),5.37(s,0H),4.99(dd,J＝39.8,13.5Hz,1H),4.79(d,J＝23.4Hz,1H),3.07(s,0H),2.91(d,J＝7.6Hz,0H),2.54(s,2H),2.36(d,J＝5.9Hz,1H),2.20(s,1H),2.04(s,1H),1.64(s,1H),1.55(s,1H).LC-MS:m/z:(M+H) +＝540。
实施例35
Figure PCTCN2020112034-appb-000072
将2-烯丙基-1-(7-羟基-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮)(I-16-h)(0.14mmol)溶于甲苯(10mL)，加入3-氯苯氧基甲酸(0.15mmol)，反应液室温下搅拌0.5小时，将反应液蒸干，所得亚砜中间体溶于二甲亚砜(10mL)，加入4-(5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)苯胺(I-35-a)((0.15mmol)和三氟乙酸(0.3mL)，将反应液加热至60℃下搅拌16小时。反应液用饱和碳酸钠溶液调pH＝9，加入水(50mL)乙酸乙酯(50mL)，分层，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，蒸干，液相制备纯化得目标化合物2-烯丙基-1-(7-羟基-7-甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-((4-(5-甲基六氢吡咯并[3,4-C]吡咯-2(1H)-基)苯基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-35)12.5mg，黄色固体，产率17.1％。 1H NMR(400MHz,CDCl3)δ8.74(s,1H),8.44(s,1H),7.68(dd,J＝23.7,8.0Hz,2H),7.41(d,J＝7.8Hz,2H),6.64(d,J＝8.1Hz,2H),5.75-5.63(m,1H),5.25(s,1H),4.97(dd,J＝39.0,13.6Hz,2H),4.85-4.63(m,2H),3.67(s,2H),3.39(d,J＝9.3Hz,2H),3.30-3.00(m,5H),2.96-2.62(m,6H),2.42-2.24(m,2H),1.63(s,3H)。LC-MS:m/z:(M+H) +＝539。
实施例38
Figure PCTCN2020112034-appb-000073
第一步：
将对氟硝基苯(如式I-38-a)(1.0g,7.09mmol)溶于20mL DMSO中,然后加入(3aR,6aS)-六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(I-38-b)(1.5g,7.09mmol)和碳酸钾(2.9g,21mmol)，60℃搅拌反应24h。反应结束后加入30ml水，每次用30ml的乙酸乙酯萃取两次。合并有机相，用30ml饱和食盐水进行洗涤，用无水硫酸钠干燥后浓缩，所得粗品直接用于下一步。得到黄色固体(I-38-c)(2.34g,7.02mmol)，收率99％。
第二步：
将(3aR,6aS)-5-(4-硝基苯基)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(I-38-c)(2.34g,7.02mmol)溶于20ml二氯甲烷中，加入4N氯化氢二氧六环溶液0.5mL,室温搅拌16h。减压浓缩，所得粗产物先用水溶解，二氯甲烷萃取。取水层用2N NaOH溶液调至pH＝10，过滤得到黄色固体(I-38-d)(1.6g,6.90mmol)，收率98％。
第三步：
将(3aR,6aS)-2-(4-硝基苯基)八氢吡咯并[3,4-c]吡咯(I-38-d)(300mg,1.29mmol)溶解到甲醇(10ml)中，然后加入环丁酮(270mg,3.86mmol)和三乙酰基硼氢化钠(1.37g,6.45mmol)，室温搅拌16h。反应液浓缩，用乙酸乙酯溶解，饱和碳酸氢钠洗两次，有机层经无水硫酸钠干燥后，过滤，浓缩所得粗产物用薄层层析法分离纯化得到黄色固体(I-38-e)(240mg,0.835mmol)，收率65％。
第四步：
将(3aR，6aS)-2-环丁基-5-(4-硝基苯基)八氢吡咯并[3,4-c]吡咯(如式I-38-e)(240mg,0.835mmol)和钯碳(10mg)溶于10ml甲醇中,氢气球下室温搅拌反应3h。反应结束后硅藻土过滤，得到黄色固体(I-38-f)(176mg,0.684mmol)直接用于下一步，收率82％。 LC-MS:m/z:(M+H) +＝258.1。
第五步：
将2-烯丙基-1-(7-羟基-6,7-二氢-5H-环戊[b]吡啶-2-基)-6-(甲硫基)-1，2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-1-g)(60mg,0.168mmol)在15ml甲苯的溶液中加入间氯过氧苯甲酸(42mg，0.185mmol),所得溶液室温搅拌1h得到2-烯丙基-1-(7-羟基-6,7-二氢-5H-环戊[b]吡啶-2-基)-6-(甲基亚磺酰基)-1，2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮的甲苯溶液。在上述所得溶液中加入4-((3aR，6aS)-5-环丁基六氢吡咯并[3,4-c]吡咯-2(1H)-基)苯胺(I-38-f)(48mg,0.185mmol)和0.1ml N,N-二异丙基乙胺,室温搅拌16h。减压浓缩，所得粗产物用薄层层析法分离纯化(7M氨甲醇:二氯甲烷＝0-10％)得到目标化合物21mg，黄色固体(I-38)，收率21％。 1H NMR(400MHz,CDCl 3)δ8.80(s,1H),7.74(d,J＝8.2Hz,1H),7.66(d,J＝7.9Hz,1H),7.41(d,J＝7.5Hz,2H),6.65(d,J＝8.9Hz,2H),5.81–5.64(m,1H),5.28–5.20(m,1H),5.08–4.92(m,2H),4.71(s,1H),3.28(s,4H),3.11(ddd,J＝16.0,8.8,3.7Hz,3H),2.91(dt,J＝15.9,7.8Hz,1H),2.68–2.57(m,1H),2.35(s,1H),2.21–2.00(m,4H).LC-MS:m/z:(M+H) +＝565.3。
实施例39
Figure PCTCN2020112034-appb-000074
第一步：
将(3aR,6aS)-2-(4-硝基苯基)八氢吡咯并[3,4-c]吡咯(I-38-d)(300mg,1.29mmol)溶解到甲醇(10ml)中，然后加入3-氧杂氮杂环丁烷-1-羧酸叔丁酯(660mg,3.86mmol)和三乙酰基硼氢化钠(1.37g,6.45mmol)，室温搅拌16h。反应液浓缩，用乙酸乙酯溶解，饱和碳酸氢钠洗两次，有机层经无水硫酸钠干燥后，过滤，浓缩所得粗产物用薄层层析法分离纯化得到黄色固体(I-39-a)(470mg,1.21mmol)，收率94％。
第二步：
将3-(((3aR，6aS)-5-(4-硝基苯基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)氮杂环丁烷-1-羧酸叔丁酯(I-39-a)(470mg,1.21mmol)和钯碳(10mg)溶于10ml甲醇中,氢气球下室温室温搅拌反应3h。反应结束后硅藻土过滤，得到黄色固体(I-39-b)(320mg,0.892mmol)直接用于下一步，收率74％。LC-MS:m/z:(M+H) +＝359.2。
第三步：
将2-烯丙基-1-(7-羟基-6,7-二氢-5H-环戊[b]吡啶-2-基)-6-(甲硫基)-1，2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-1-g)(84mg,0.236mmol)在15ml甲苯的溶液中加入间氯过氧苯甲酸(55mg，0.24mmol),所得溶液室温搅拌1h得到2-烯丙基-1-(7-羟基-6,7-二氢-5H-环戊[b]吡啶-2-基)-6-(甲基亚磺酰基)-1，2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮的甲苯溶液。在上述所得溶液中加入3-(((3aR，6aS)-5-(4-氨基苯基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)氮杂环丁烷-1-羧酸叔丁酯(I-39-b)(93mg,0.26mmol)和0.1ml N,N-二异丙基乙胺,室温搅拌16h。减压浓缩，所得粗产物用薄层层析法分离纯化(7M氨甲醇:二氯甲烷＝0-10％)得到Boc保护的目标化合物，溶于20ml二氯甲烷中，加入4N氯化氢二氧六环溶液0.5mL,室温搅拌16h。减压浓缩，所得粗产物先用水溶解，二氯甲烷萃取。取水层用2N NaOH溶液调至pH＝10，过滤得到目标化合物76mg，黄色固体(I-39)，收率57％。 1H NMR(400MHz,MeOD)δ8.85–8.72(m,1H),7.97(t,J＝7.9Hz,1H),7.78(d,J＝7.8Hz,1H),7.64(dd,J＝7.7,0.7Hz,1H),7.48(d,J＝8.3Hz,2H),6.70(d,J＝9.0Hz,2H),5.72(ddt,J＝16.4,10.3,6.1Hz,1H),5.05(dd,J＝10.2,1.1Hz,1H),4.94(d,J＝1.3Hz,1H),4.82(d,J＝6.1Hz,1H),3.80–3.44(m,2H),3.44–3.36(m,0H),3.31–3.15(m,2H),2.97(s,1H),2.89–2.71(m,1H),2.37(dd,J＝9.1,4.1Hz,1H),1.59(s,3H).LC-MS:m/z:(M+H) +＝566.3。
实施例40
Figure PCTCN2020112034-appb-000075
将2-烯丙基-6-(((4-((3aR，6aS)-5-(氮杂环丁烷-3-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基) 苯基)氨基)-1-(7-羟基-6,7-二氢-5H-环戊[b]吡啶-2-基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-39)(70mg,0.124mmol)溶解到甲醇(10ml)中，然后加入甲醛溶液(0.1mL)和三乙酰基硼氢化钠(52mg，0.248mmol)，室温搅拌16小时。反应液浓缩，用二氯甲烷和甲醇的混合液(10/1,20ml)溶解，饱和碳酸氢钠洗两次，有机层经无水硫酸钠干燥后，过滤，浓缩所得粗产物用薄层层析法分离纯化(7M氨甲醇:二氯甲烷＝0-10％)得到目标化合物(I-40)14mg，收率20％。1H NMR(400MHz,CDCl3)δ8.80(s,1H),7.73(d,J＝8.0Hz,1H),7.66(s,1H),7.39(s,2H),6.63(d,J＝8.9Hz,2H),5.71(ddd,J＝16.5,11.3,5.1Hz,1H),5.30–5.17(m,1H),5.01(dd,J＝32.2,13.5Hz,2H),4.71(s,2H),3.71(s,2H),3.44–3.31(m,2H),3.21(dd,J＝14.9,6.6Hz,4H),3.10(ddd,J＝16.4,9.0,3.9Hz,1H),2.99(s,1H),2.89(dd,J＝16.2,8.0Hz,1H),2.85–2.75(m,1H),2.63(ddd,J＝11.9,9.9,5.8Hz,1H),2.49(s,1H),2.35(d,J＝6.3Hz,1H),2.20–2.07(m,2H).LC-MS:m/z:(M+H)+＝580.0。
实施例41
Figure PCTCN2020112034-appb-000076
第一步：
将(3aR,6aS)-2-(4-硝基苯基)八氢吡咯并[3,4-c]吡咯(I-38-d)(300mg,1.29mmol)溶解到甲醇(10ml)中，然后加入1-环丙基乙-1-酮(325mg,3.86mmol)和三乙酰基硼氢化钠(1.37g,6.45mmol)，室温搅拌16h。反应液浓缩，用乙酸乙酯溶解，饱和碳酸氢钠洗两次，有机层经无水硫酸钠干燥后，过滤，浓缩所得粗产物用薄层层析法分离纯化得到黄色固体(I-41-a)(250mg,0.830mmol)，收率65％。
第二步：
将(3aR，6aS)-2-(1-环丙基乙基)-5-(4-硝基苯基)八氢吡咯并[3,4-c]吡咯(I-41-a)(250mg, 0.830mmol)和钯碳(10mg)溶于10ml甲醇中,氢气球下室温室温搅拌反应3h。反应结束后硅藻土过滤，得到黄色固体(I-41-b)(185mg,0.682mmol)直接用于下一步，收率82％。LC-MS:m/z:(M+H) +＝272.2。
第三步：
将2-烯丙基-1-(7-羟基-6,7-二氢-5H-环戊[b]吡啶-2-基)-6-(甲硫基)-1，2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(I-1-g)(80mg,0.22mmol)在15ml甲苯的溶液中加入间氯过氧苯甲酸(55mg，0.24mmol),所得溶液室温搅拌1h得到2-烯丙基-1-(7-羟基-6,7-二氢-5H-环戊[b]吡啶-2-基)-6-(甲基亚磺酰基)-1，2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮的甲苯溶液。在上述所得溶液中加入4-((3aR，6aS)-5-(1-环丙基乙基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)苯胺(I-41-b)(65mg,0.24mmol)和0.1ml N,N-二异丙基乙胺,室温搅拌16h。减压浓缩，所得粗产物用薄层层析法分离纯化(7M氨甲醇:二氯甲烷＝0-10％)得到目标化合物25mg，黄色固体(I-41)，收率19％。1H NMR(400MHz,CDCl3)δ8.78(s,1H),7.73(d,J＝8.2Hz,1H),7.64(s,1H),7.39(d,J＝5.9Hz,2H),6.64(d,J＝8.9Hz,2H),5.70(ddt,J＝16.5,10.2,6.2Hz,1H),5.24(t,J＝6.8Hz,1H),5.00(dd,J＝34.2,13.6Hz,2H),4.69(s,2H),3.59(s,1H),3.44(s,1H),3.32(t,J＝7.7Hz,2H),3.28–3.18(m,2H),3.15–3.04(m,3H),2.95–2.82(m,2H),2.62(ddd,J＝11.8,8.7,4.1Hz,2H),2.53(s,3H),2.19–2.06(m,1H),1.70(s,1H),1.34(d,J＝6.4Hz,3H),0.95(s,1H),0.69(s,1H),0.59–0.51(m,1H),0.37(dd,J＝9.5,4.7Hz,1H),0.10(dd,J＝9.8,4.9Hz,1H).LC-MS:m/z:(M+H)+＝579.0。
实施例42
Figure PCTCN2020112034-appb-000077
第一步：
将N，N-二甲基-2-(4-硝基苯基)-2-氮杂螺[3.3]庚-6-胺(100mg,0.383mmol)(I-42-a)和10％的钯炭(30mg)加入到30ml的二氯甲烷中，反应瓶用氢气球换气三次,反应液在氢气环境中室温搅拌过夜。反应液中加入5ml甲醇过滤蒸干，得到棕色固体(I-42-b)85mg，直接用于下一步。收率96％。LC-MS:m/z:(M+H)+＝232。
第二步：
将2-烯丙基1-(7-羟基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(107mg,0.3mmol)(I-42-b)在15ml甲苯的溶液中加入85％间氯过氧苯甲酸(75mg,0.37mmol),所得溶液室温搅拌1h。
将上述反应液中加入2-(4-氨基苯基)-N,N-二甲基-2-氮杂螺[3.3]庚-6-胺(I-42-b)(85mg,0.21mmol),0.5mlN,N-二异丙基乙胺和6ml二甲基亚砜，室温搅拌过夜。往上述反应液中加入5ml饱和的碳酸钠水溶液和25ml水，用二氯甲烷萃取三次(3*20ml),合并有机相，分别用20ml水和20ml饱和的氯化钠溶液洗涤，无水硫酸钠干燥后浓缩得粗品，所得粗产物用薄层层析板分离{7M氨甲醇:(二氯甲烷:乙酸乙酯＝8:1)＝1:9}得到黄色固体(I-42)40mg，收率24％。LC-MS:m/z:(M+H)+＝539,1H NMR(400MHz,CDCl3)δ8.77(s,1H),7.72(d,J＝8.2Hz,1H),7.65(s,1H),7.35(d,J＝6.6Hz,2H),6.40(d,J＝8.8Hz,2H),5.69(ddt,J＝16.5,10.2,6.2Hz,1H),5.28–5.19(m,1H),5.03(d,J＝10.1Hz,1H),4.95(d,J＝17.1Hz,1H),4.70(s,2H),3.88(s,2H),3.79(s,2H),3.09(ddd,J＝16.2,8.9,3.8Hz,1H),2.95–2.83(m,1H),2.62(m,2H),2.43–2.34(m,2H),2.22–2.11(m,9H).
参照上述实施例，制备出表1所示的化合物，其结构表征见下：
表1化合物列表
Figure PCTCN2020112034-appb-000078
Figure PCTCN2020112034-appb-000079
Figure PCTCN2020112034-appb-000080
Figure PCTCN2020112034-appb-000081
Figure PCTCN2020112034-appb-000082
Figure PCTCN2020112034-appb-000083
Figure PCTCN2020112034-appb-000084
效果实施例1
一、化合物对WEE1激酶体外抑制作用
测试方法：
采用ELISA方法，在ATP浓度为Km情况下在WEE1激酶上对受试化合物进行筛 选。在WEE1激酶上进行了3个化合物的筛选，以评价受试化合物的激酶抑制活性。检测过程中，受试化合物初始浓度均选择为100nM，各化合物均选择6个梯度稀释浓度，梯度稀释倍数为4倍，每浓度2个复孔进行检测，采用MK1775作为标准对照。
WEE1，购自CarnaBiosciences,Inc.，货号：05-177；二甲基亚砜，购自Sigma-Aldrich，货号：D8418；ATP，购自Sigma-Aldrich，货号：A7699；DTT溶液，购自Sigma-Aldrich，货号：43816；protein tyrosine kinase(PTK)substrate(poly–Glu-Tyr)，购自Sigma-Aldrich，货号：P4476；P-Tyr(PY99)，购自Santa Cruz，货号：sc-7020；Anti-mouse IgG HRP-linked Antibody，购自Santa Cruz，货号：7076S；TMB liquid Substrate System，购自Sigma-Aldrich，货号：T0440；Costar Stripwell Microplate No Lid 1×8 Flat Bottom，Certified High Binding，购自Sigma-Aldrich，货号：42592；96孔化合物板，购自Thermo Scientific，货号：267245。
测试步骤：
1、包被底物：1)取适当体积的底物储存液protein tyrosine kinase(PTK)substrate(poly–Glu-Tyr)，用PBS稀释10倍，将浓度从250mg/mL的稀释为25mg/mL。加入到高吸附96孔板中，每孔125μL。放置到37℃孵育箱过夜包被。2)24h后，取出96孔板，倒掉96孔板中的液体，用washing buffer清洗3次，37℃孵育箱倒置烘干2h。
2、化合物的配制与转移：1)化合物稀释：取10mM的受试化合物储存液，在96孔化合物板中，用DMSO将化合物分多步稀释，获得为初始浓度100×的化合物，之后再以此浓度化合物为第一个浓度，采用DMSO进行4倍梯度稀释，共稀释6个浓度；之后分别取2μL的梯度稀释液加入48μL的1×反应缓冲液中，配制成4×化合物备用；2)4×化合物的转移：从上步配置的96孔化合物板中转移10μL的4×化合物进入烘干的高吸附96孔板中；无化合物对照孔和ATP-对照孔中加入10μL的如下液体：2μL的DMSO加入48μL的1×反应缓冲液。
3、酶反应阶段：1)采用1×反应缓冲液将WEE1激酶、ATP分别配制成2×的酶溶液和4×的ATP溶液。其中在本次筛选中，WEE1激酶的终浓度为：0.15ng/μL，ATP终浓度为：12μM；2)向高吸附96孔板中加入20μL的2的酶溶液；3)向高吸附96孔板中加入10μL的4×ATP溶液，ATP-对照空加入10μL1×反应缓冲液；4)将板放于HERAEUS Multifuge X1R离心机中2000rpm离心20s后，放置于室温反应60min。
4、反应终止阶段：1)倒掉板中的反应液，每孔加入200μL washing buffer，清洗5遍；加入一抗P-Tyr(PY99)(稀释比例1：2000)，每孔100μL，室温30min。2)倒掉板中的一抗，每孔加入200μL washing buffer，清洗5遍；加入二抗Anti-mouse IgG HRP- linked Antibody(稀释比例1：2000)，每孔100μL，室温30min。3)倒掉板中的二抗，用washing buffer洗5遍，加入TMB，每孔100μL，显色10～30min，视颜色深浅而定。读数前用1N硫酸终止反应。
5、检测与数据处理：1)于ThermoScientific MultiScan GO上读取波长450nM处的光吸收，同时在650nM处读取背景。2)采用Graphpad Prism 5.0对数据进行Log(inhibitor)vs.response-Variable slope(four parameters)曲线拟合，计算相应的IC 50(half maximal inhibitory concentration)。
二、测试结果数据
测试中使用的对照样品结构见表2。
表2对照样品结构
Figure PCTCN2020112034-appb-000085
测试结果详见表3。
表3 WEE1酶抑制活性测试结果
Figure PCTCN2020112034-appb-000086
Figure PCTCN2020112034-appb-000087
结论：通过表3可以看出，本发明化合物对Wee1激酶具有很好的抑制作用。
效果实施例2
一、化合物对COLO 205细胞及对Hela细胞的增殖抑制。
测试方法：
采用Luminescence ATP Detection方法，检测化合物对p53缺失细胞株COLO 205及对Hela细胞增殖的抑制作用。COLO205细胞，购自SIBS，代数P11；Hela购自ATCC，代数P13。
测试步骤：
1、对COLO 205细胞的增殖抑制
细胞培养与接种：实验第一天，取正常培养的细胞，在其指数生长状态下，消化分散 后，调整细胞密度至4.375×10 3cells/mL，每孔40μl接种于96孔细胞培养板中；接种完成后将微孔板放置于37摄氏度，5％CO 2的条件下培养；
加药处理细胞：实验的第三天，从培养箱中取出微孔板，向微孔板中的每个孔中各加入9×化合物，每孔加入5μL，其中每个给药浓度2个复孔，每个化合物共10个给药浓度。根据不同的细胞株，各化合物的起始浓度有所不同，完成后将微孔板放置于37摄氏度，5％CO 2的条件下培养72h；
数据的采集：将微孔板从培养箱中取出，室温平衡30分钟。于每孔中加入100μl室温平衡后的ATPlite反应液，1300rpm室温震荡2分钟，之后将微孔板放置于HERAEUS Multifuge X1R离心机中2000rpm离心1分钟；室温平衡10分钟后，于EnVisionTM上测定荧光信号值。
按下列公式对化合物的体外抑制活性进行计算：细胞增殖抑制率：抑制率(％)＝(信号值对照－信号值给药)/信号值对照×100％。并根据各浓度的抑制率，采用LOGIT法计算50％抑制浓度(50％inhibitory concentration，IC 50)。
细胞存活率计算：Cell viability(％)＝信号值给药/信号值对照×100％。采用Graphpad Prism 5.0对各浓度下的荧光信号值进行Log(inhibitor)vs.response-Variable slope(four parameters)曲线拟合，计算相应的IC 50(half maximal inhibitory concentration)。
2、对Hela细胞的增殖抑制
细胞培养与接种：实验第一天，取正常培养的细胞，在其指数生长状态下，消化分散后，调整细胞密度至9×10 3cells/mL，每孔40μl接种于384孔细胞培养板中；接种完成后将微孔板放置于37摄氏度，5％CO 2的条件下培养；
加药处理细胞：实验的第二天，从培养箱中取出微孔板，向微孔板中的每个孔中各加入9×化合物，每孔加入5μL，其中每个给药浓度2个复孔，每个化合物共10个给药浓度。根据不同的细胞株，各化合物的起始浓度有所不同，完成后将微孔板放置于37摄氏度，5％CO 2的条件下培养72h；
数据的采集：将微孔板从培养箱中取出，室温平衡30分钟。于每孔中加入40μl室温平衡后的ATPlite反应液，1300rpm室温震荡2分钟，之后将微孔板放置于HERAEUS Multifuge X1R离心机中2000rpm离心1分钟；室温平衡10分钟后，于EnVisionTM上测定荧光信号值。
按下列公式对化合物的体外抑制活性进行计算：细胞增殖抑制率：抑制率(％)＝(信号值对照－信号值给药)/信号值对照×100％。并根据各浓度的抑制率，采用LOGIT法计算50％抑制浓度(50％inhibitory concentration，IC 50)。
细胞存活率计算：Cell viability(％)＝信号值给药/信号值对照×100％。采用Graphpad Prism 5.0对各浓度下的荧光信号值进行Log(inhibitor)vs.response-Variable slope(four parameters)曲线拟合，计算相应的IC 50(half maximal inhibitory concentration)。
二、实验结果
表4
化合物编号 COLO 205 IC 50(nM) Hela IC 50(nM)
I-1 1882 495
I-2 1735 345
I-3 5152 434
I-4 1971 395
I-5 2552 392
I-7 - 2903
I-9 614 191
I-10 920 206
I-11 1194 317
I-13 886 190
I-14 363 192
I-16 1615 316
I-19 944 170
I-23 1669 534
I-32 541 148
I-33 891 200
I-34 1581 214
I-35 473 147
I-38 451 134
I-41 786 224
I-42 - 322
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (25)

  1. 一种如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物；
    Figure PCTCN2020112034-appb-100001
    其中，R 1为氢或甲基；
    n为1或2；
    L为-(CH 2) m-R 2、C 3～C 20环烷基、被1个或2个R 3取代的C 3～C 20环烷基、C 3～C 14杂环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；
    m为0、1、2、3或4；
    R 2、R 3和R 4独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、-SR 2-8、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-1和R 2-2独立地为氢、-(C＝O)R 2-1-1、-S(＝O) 2R 2-1-2、-(C＝NR 2-1-3)R 2-1-4、或、任选被1个、2个或3个R 2-1-5取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    或者，R 2-1和R 2-2以及与其相连的氮原子形成任选被1个、2个或3个R 2-1-6取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基中的1个或2个以上的亚甲基任选地、独立地被氧原子、硫原子、亚磺酰基、磺酰基、羰基、亚乙烯基或-N(R 2-1-7)-所示的基团替换；R 2-1-7独立地为C 1～C 7烷基或C 3～C 14环烷基；
    R 2-1-1、R 2-1-2和R 2-1-4独立地为氢、-NR 2-1-1-1R 2-1-1-2、或、任选被1个、2个或3个R 2- 1-1-3取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-1-1-1和R 2-1-1-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-1-1-3独立地为卤素、羟基、巯基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7烷硫基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7 杂芳基；
    R 2-1-3选自氢、氰基、-OH、C 1～C 7烷基或C 1～C 7烷氧基；
    R 2-1-5和R 2-1-6独立地为氰基、卤素、-NR 2-1-5-1R 2-1-5-2、-OR 2-1-5-3、-SR 2-1-5-4或C 1～C 7烷基；
    R 2-1-5-1、R 2-1-5-2、R 2-1-5-3和R 2-1-5-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-3独立地为氢、-NR 2-3-1R 2-3-2、-OR 2-3-3、或、任选被1个、2个或3个R 2-3-4取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-3-1和R 2-3-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    或者，R 2-3-1和R 2-3-2以及与其相连的氮原子形成任选被1个、2个或3个R 2-3-1-1取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基中的1个或2个以上的亚甲基任选地、独立地被氧原子、硫原子、亚磺酰基、磺酰基、羰基、亚乙烯基或-N(R 2-3-1-2)-所示的基团替换；R 2-3-1-2独立地为C 1～C 7烷基或C 3～C 14环烷基；
    R 2-3-1-1独立地为氰基、卤素、-NR 2-3-1-1-1R 2-3-1-1-2、-OR 2-3-1-1-3、-SR 2-3-1-1-4或C 1～C 7烷基；
    R 2-3-1-1-1、R 2-3-1-1-2、R 2-3-1-1-3和R 2-3-1-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-3-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-3-4独立地为氰基、卤素、-NR 2-3-4-1R 2-3-4-2、-OR 2-3-4-3、-SR 2-3-4-4或C 1～C 7烷基；
    R 2-3-4-1、R 2-3-4-2、R 2-3-4-3和R 2-3-4-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-4独立地为氢、-CN、-OR 2-4-1或C 1～C 7烷基；
    R 2-4-1独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-5独立地为-NR 2-5-1R 2-5-2、-OR 2-5-3、或、任选被1个、2个或3个R 2-5-4取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-5-1和R 2-5-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、 C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    或者，R 2-5-1和R 2-5-2以及与其相连的氮原子形成任选被1个、2个或3个R 2-5-1-1取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基中的1个或2个以上的亚甲基任选地、独立地被氧原子、硫原子、亚磺酰基、磺酰基、羰基、亚乙烯基或-N(R 2-5-1-2)-所示的基团替换；R 2-5-1-2独立地为C 1～C 7烷基或C 3～C 14环烷基；
    R 2-5-1-1独立地为氰基、卤素、-NR 2-5-1-1-1R 2-5-1-1-2、-OR 2-5-1-1-3、-SR 2-5-1-1-4或C 1～C 7烷基；
    R 2-5-1-1-1、R 2-5-1-1-2、R 2-5-1-1-3和R 2-5-1-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-5-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-5-4独立地为氰基、卤素、-NR 2-5-4-1R 2-5-4-2、-OR 2-5-4-3、-SR 2-5-4-4或C 1～C 7烷基；
    R 2-5-4-1、R 2-5-4-2、R 2-5-4-3和R 2-5-4-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-6独立地为-NR 2-6-1R 2-6-2、-OR 2-6-3、或、任选被1个、2个或3个R 2-6-4取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    或者，R 2-6-1和R 2-6-2以及与其相连的氮原子形成任选被1个、2个或3个R 2-6-1-1取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基中的1个或2个以上的亚甲基任选地、独立地被氧原子、硫原子、亚磺酰基、磺酰基、羰基、亚乙烯基或-N(R 2-6-1-2)-所示的基团替换；R 2-6-1-2独立地为C 1～C 7烷基或C 3～C 14环烷基；
    R 2-6-1-1独立地为氰基、卤素、-NR 2-6-1-1-1R 2-6-1-1-2、-OR 2-6-1-1-3、-SR 2-6-1-1-4或C 1～C 7烷基；
    R 2-6-1-1-1、R 2-6-1-1-2、R 2-6-1-1-3和R 2-6-1-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-6-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-6-4独立地为氰基、卤素、-NR 2-6-4-1R 2-6-4-2、-OR 2-6-4-3、-SR 2-6-4-4或C 1～C 7烷基；
    R 2-6-4-1、R 2-6-4-2、R 2-6-4-3和R 2-6-4-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、 C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-7和R 2-8独立地为氢、或、任选被1个、2个或3个R 2-7-1取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-7-1独立地为氰基、卤素、-NR 2-7-1-1R 2-7-1-2、-OR 2-7-1-3、-SR 2-7-1-4或C 1～C 7烷基；
    R 2-7-1-1、R 2-7-1-2、R 2-7-1-3和R 2-7-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-9独立地为-OR 2-9-1、-NR 2-9-2R 2-9-3、-SR 2-9-4、卤素、氰基、-(C＝O)R 2-9-5、-(C＝NR 2-9- 6)R 2-9-7、-S(＝O) 2R 2-9-8、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-9-1、R 2-9-2、R 2-9-3和R 2-9-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或、任选被1个、2个或3个R 2-9-5-4取代的：C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-9-5-4独立地为氢、卤素、羟基、巯基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7烷硫基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-9-6独立地为氢、-CN、-OR 2-9-6-1或C 1～C 7烷基；
    R 2-9-6-1独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-9-7独立地为-NR 2-9-7-1R 2-9-7-2、-OR 2-9-7-3、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-9-7-1和R 2-9-7-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    或者，R 2-9-7-1和R 2-9-7-2以及与其相连的氮原子形成任选被1个、2个或3个R 2-9-7-1-1取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基中的1个或2个以上的亚甲基任选地、独立地被氧原子、硫原子、亚磺酰基、磺酰基、羰基、亚乙烯基或-N(R 2-9-7-1-2)-所示的基团替换；R 2-9-7-1-2独立地为C 1～C 7烷基或C 3～C 14环烷基；
    R 2-9-7-1-1独立地为卤素、羟基、巯基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7 烷硫基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-9-7-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2、-OR 2-9-8-3、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    或者，R 2-9-8-1和R 2-9-8-2以及与其相连的氮原子形成任选被1个、2个或3个R 2-9-8-1-1取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基中的1个或2个以上的亚甲基任选地、独立地被氧原子、硫原子、亚磺酰基、磺酰基、羰基、亚乙烯基或-N(R 2-9-8-1-2)-所示的基团替换；R 2-9-8-1-2独立地为C 1～C 7烷基或C 3～C 14环烷基；
    R 2-9-8-1-1独立地为卤素、羟基、巯基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7烷硫基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    R 2-9-8-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 14环烷基、C 3～C 14杂环烷基、C 6～C 10芳基或C 1～C 7杂芳基；
    以上任一种情况下，所述C 3～C 14杂环烷基、C 1～C 7杂芳基中的杂原子独立地选自硼、硅、氧、硫、硒、氮和磷中的一种或多种；杂原子数独立地为1个、2个、3个或4个。
  2. 如权利要求1所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物，其特征在于，当L为被1个或2个R 3取代的C 3～C 20环烷基时，所述的C 3～C 20环烷基为C 3～C 20单环环烷基、C 3～C 20螺环环烷基、C 3～C 20稠环环烷基或C 3～C 20桥环环烷基；
    和/或，当L为被1个或2个R 3取代的C 3～C 20环烷基时，所述的C 3～C 20环烷基为C 3～C 20饱和环烷基；
    和/或，当R 2-1和R 2-2独立地为C 1～C 7烷基时，所述的C 1～C 7烷基为C 1～C 3烷基；
    和/或，当L为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基为C 3～C 14单环杂环烷基、C 3～C 14螺环杂环烷基、C 3～C 14稠环杂环烷基或C 3～C 14桥环杂环烷基；
    和/或，当L为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基为C 3～C 14饱和杂环烷基；
    和/或，当L为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基的杂原子上无取代基；
    和/或，当L为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基中的亚甲基不被替代或 替换；
    和/或，当L为被1个或2个R 4取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基为C 3～C 14单环杂环烷基、C 3～C 14螺环杂环烷基、C 3～C 14稠环杂环烷基或C 3～C 14桥环杂环烷基；
    和/或，当L为被1个或2个R 4取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基为C 3～C 14饱和杂环烷基；
    和/或，当L为被1个或2个R 4取代的C 3～C 14杂环烷基时，除R 4外，所述的C 3～C 14杂环烷基的杂原子上无取代基；
    和/或，当L为被1个或2个R 4取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基中的亚甲基不被替代或替换；
    和/或，当R 4为任选被1个R 2-9取代的C 1～C 7烷基时，所述的C 1～C 7烷基为C 1～C 3烷基；
    和/或，当R 4为C 3～C 14环烷基时，所述的C 3～C 14环烷基为C 3～C 7环烷基；
    和/或，当R 4为C 3～C 14环烷基时，所述的C 3～C 14环烷基为饱和C 3～C 14环烷基；
    和/或，当R 4为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基为C 3～C 7杂环烷基；
    和/或，当R 4为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基为C 3～C 14饱和杂环烷基；
    和/或，当R 4为任选被1个R 2-9取代的C 3～C 14杂环烷基时，除R 2-9外，所述的C 3～C 14杂环烷基的杂原子上无取代基；
    和/或，当R 4为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基中的亚甲基不被替代或替换；
    和/或，当R 2-9独立地为C 3～C 14环烷基时，所述的C 3～C 14环烷基为C 3～C 14单环环烷基；
    和/或，当R 2-9独立地为C 3～C 14环烷基时，所述的C 3～C 14环烷基为C 3～C 14饱和环烷基；
    和/或，当R 2-9-2和R 2-9-3独立地为C 1～C 7烷基时，所述的C 1～C 7烷基为C 1～C 3烷基；
    和/或，当R 2-3独立地为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基为C 3～C 14单环杂环烷基；
    和/或，当R 2-3独立地为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基为C 3～C 14饱和杂环烷基；
    和/或，当R 2-3独立地为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基的杂原子上无取代基；
    和/或，当R 2-3独立地为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基中的亚甲基不被替换或替代；
    和/或，当R 2为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的C 3～C 14单环杂环烷基为“杂原子数为1个或2个，杂原子选自N、O和S中的一种或两种的C 3～C 9单环杂环烷基”；
    和/或，当R 2为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基为C 3～C 14饱和杂环烷基；
    和/或，当R 2为任选被1个R 2-9取代的C 3～C 14杂环烷基时，除R 2-9外，所述的C 3～C 14杂环烷基的杂原子上无取代基；
    和/或，当R 2为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基中的亚甲基不被替换或替代；
    和/或，当R 2-9独立地为C 1～C 7烷基时，所述的C 1～C 7烷基为C 1～C 3烷基；
    和/或，所述的如式I所示的吡唑酮并嘧啶类化合物中的各异构体的比例均等；
    和/或，所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物中的原子均以其天然丰度的形式存在。
  3. 如权利要求2所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物，其特征在于，当L为被1个或2个R 3取代的C 3～C 20环烷基、所述的C 3～C 20环烷基为C 3～C 20单环环烷基时，所述的C 3～C 20单环环烷基为环丙基、环丁基、环戊基或环己基；
    和/或，当L为被1个或2个R 3取代的C 3～C 20环烷基、所述的C 3～C 20环烷基为C 3～C 20桥环环烷基时，所述的C 3～C 20桥环环烷基为
    Figure PCTCN2020112034-appb-100002
    和/或，当R 2-1和R 2-2独立地为C 1～C 7烷基时，所述的C 1～C 7烷基为甲基、乙基、正丙基或异丙基；
    和/或，当L为C 3～C 14杂环烷基、所述的C 3～C 14杂环烷基为C 3～C 14单环杂环烷基时，所述的C 3～C 14单环杂环烷基为
    Figure PCTCN2020112034-appb-100003
    和/或，当L为C 3～C 14杂环烷基、所述的C 3～C 14杂环烷基为C 3～C 14螺环杂环烷基时，所述的C 3～C 14螺环杂环烷基为
    Figure PCTCN2020112034-appb-100004
    还可为
    Figure PCTCN2020112034-appb-100005
    和/或，当L为C 3～C 14杂环烷基、所述的C 3～C 14杂环烷基为C 3～C 14稠环杂环烷基时，所述的C 3～C 14稠环杂环烷基为
    Figure PCTCN2020112034-appb-100006
    和/或，当L为C 3～C 14杂环烷基、所述的C 3～C 14杂环烷基为C 3～C 14桥环杂环烷基时，所述的C 3～C 14桥环杂环烷基为
    Figure PCTCN2020112034-appb-100007
    和/或，当L为被1个或2个R 4取代的C 3～C 14杂环烷基、所述的C 3～C 14杂环烷基为C 3～C 14单环杂环烷基时，所述的C 3～C 14单环杂环烷基为
    Figure PCTCN2020112034-appb-100008
    和/或，当L为被1个或2个R 4取代的C 3～C 14杂环烷基、所述的C 3～C 14杂环烷基为C 3～C 14螺环杂环烷基时，所述的C 3～C 14螺环杂环烷基为
    Figure PCTCN2020112034-appb-100009
    Figure PCTCN2020112034-appb-100010
    还可为
    Figure PCTCN2020112034-appb-100011
    和/或，当L为被1个或2个R 4取代的C 3～C 14杂环烷基、所述的C 3～C 14杂环烷基为C 3～C 14稠环杂环烷基时，所述的C 3～C 14稠环杂环烷基为
    Figure PCTCN2020112034-appb-100012
    和/或，当L为被1个或2个R 4取代的C 3～C 14杂环烷基、所述的C 3～C 14杂环烷基为C 3～C 14桥环杂环烷基时，所述的C 3～C 14桥环杂环烷基为
    Figure PCTCN2020112034-appb-100013
    和/或，当R 4为任选被1个R 2-9取代的C 1～C 7烷基时，所述的C 1～C 7烷基为甲基、乙基、正丙基或异丙基；
    和/或，当R 4为C 3～C 14环烷基时，所述的C 3～C 14环烷基为C 3～C 7单环环烷基，例如环丁基；
    和/或，当R 4为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基为C 3～C 7单环杂环烷基，例如氮杂环丁基，又例如
    Figure PCTCN2020112034-appb-100014
    和/或，当R 2-9独立地为C 3～C 14环烷基时，所述的C 3～C 14环烷基为环丙基；
    和/或，当R 2-9-2和R 2-9-3独立地为C 1～C 7烷基时，所述的C 1～C 7烷基为甲基、乙基、正丙基或异丙基；
    和/或，当R 2-3独立地为C 3～C 14杂环烷基时，所述的C 3～C 14杂环烷基为
    Figure PCTCN2020112034-appb-100015
    和/或，当R 2为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的C 3～C 14单环杂环烷基为
    Figure PCTCN2020112034-appb-100016
    和/或，当R 2-9独立地为C 1～C 7烷基时，所述的C 1～C 7烷基为甲基、乙基、正丙基或异丙基。
  4. 如权利要求3所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物，其特征在于，当L为被1个R 3取代 的C 3～C 20环烷基、R 3为-NR 2-1R 2-2时，所述的“被1个R 3取代的C 3～C 20环烷基”为
    Figure PCTCN2020112034-appb-100017
    和/或，当L为被1个R 4取代的C 3～C 14杂环烷基、R 4为任选被1个R 2-9取代的C 1～C 7烷基时，所述的“被1个R 4取代的C 3～C 14杂环烷基”为
    Figure PCTCN2020112034-appb-100018
    Figure PCTCN2020112034-appb-100019
    还可为
    Figure PCTCN2020112034-appb-100020
    Figure PCTCN2020112034-appb-100021
    和/或，当L为被1个R 4取代的C 3～C 14杂环烷基、R 4为任选被1个R 2-9取代的C 3～C 14环烷基时，所述的“被1个R 4取代的C 3～C 14杂环烷基”为
    Figure PCTCN2020112034-appb-100022
    和/或，当L为被1个R 4取代的C 3～C 14杂环烷基、R 4为任选被1个R 2-9取代的C 3～C 14杂环烷基时，所述的“被1个R 4取代的C 3～C 14杂环烷基”为
    Figure PCTCN2020112034-appb-100023
    和/或，当L为被1个R 4取代的C 3～C 14杂环烷基、R 4为-NR 2-1R 2-2时，所述的“被1个R 4取代的C 3～C 14杂环烷基”为
    Figure PCTCN2020112034-appb-100024
  5. 如权利要求1所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物，其特征在于，R 1为氢或甲基；
    和/或，n为1或2；
    和/或，L为-(CH 2) m-R 2、被1个R 3取代的C 3～C 20环烷基、C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；m为1或2，还可为3；
    和/或，R 2、R 3和R 4独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；R 2-1和R 2-2独立地为C 1～C 7烷基；R 2-3独立地为C 3～C 14杂环烷基；R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    和/或，所述的如式I所示的吡唑酮并嘧啶类化合物不为
    Figure PCTCN2020112034-appb-100025
    Figure PCTCN2020112034-appb-100026
    Figure PCTCN2020112034-appb-100027
  6. 如权利要求5所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物，其特征在于，L为被1个R 3取代的C 3～C 20环烷基、C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；
    和/或，R 3和R 4独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；R 2-1和R 2-2独立地为C 1～C 7烷基；R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
  7. 如权利要求2所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物，其特征在于，L为-(CH 2) m-R 2、被1个或2个R 4取代的C 3～C 14稠环杂环烷基、或、被1个或2个R 4取代的C 3～C 14螺环杂环烷基；
    当L为C 3～C 14稠环杂环烷基时，所述的C 3～C 14稠环杂环烷基为C 5～C 14稠环杂环烷基；
    当L为C 3～C 14螺环杂环烷基时，所述的C 3～C 14螺环杂环烷基为C 5～C 14螺环杂环烷基。
  8. 如权利要求7所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物，其特征在于，R 2为-NR 2-1R 2-2；
    和/或，R 4为-NR 2-1R 2-2或任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基；
    和/或，R 2-1和R 2-2独立地为C 1～C 7烷基；
    和/或，R 2-9独立地为C 1～C 7烷基或C 3～C 14杂环烷基。
  9. 如权利要求8所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物，其特征在于，L为
    Figure PCTCN2020112034-appb-100028
    Figure PCTCN2020112034-appb-100029
  10. 如权利要求1所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物，其特征在于，如式I所示的吡唑酮并嘧啶类化合物为下述任一方案：
    方案(1)：
    R 1为氢或甲基；
    n为1或2；
    L为-(CH 2) m-R 2、C 3～C 20环烷基、被1个或2个R 3取代的C 3～C 20环烷基、C 3～C 14杂环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；
    m为1、2、3或4；
    R 2、R 3和R 4独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基、或、C 1～C 7杂芳基；
    R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基；
    R 2-3独立地为-NR 2-3-1R 2-3-2、-OR 2-3-3、C 1～C 7烷基或C 3～C 14杂环烷基；
    R 2-3-1和R 2-3-2独立地为氢或C 1～C 7烷基；
    R 2-3-3独立地为氢或C 1～C 7烷基；
    R 2-4独立地为氢、-CN或-OR 2-4-1；
    R 2-4-1独立地为氢或C 1～C 7烷基；
    R 2-5独立地为-NR 2-5-1R 2-5-2或C 1～C 7烷基；
    R 2-5-1和R 2-5-2独立地为氢或C 1～C 7烷基；
    R 2-6独立地为-NR 2-6-1R 2-6-2；
    R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3、卤素、氰基、-(C＝O)R 2-9-5、-S(＝O) 2R 2-9-8、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或C 1～C 7烷基；
    R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢或C 1～C 7烷基；
    R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2；
    R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    方案(2)：
    R 1为氢或甲基；
    n为1或2；
    L为-(CH 2) m-R 2、被1个R 3取代的C 3～C 20环烷基、C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；m为1或2，还可为3；
    R 2、R 3和R 4独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；
    R 2-1和R 2-2独立地为C 1～C 7烷基；
    R 2-3独立地为C 3～C 14杂环烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    方案(3)：
    R 1为氢或甲基；
    n为1或2；
    L为被1个R 3取代的C 3～C 20环烷基、C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；
    R 3和R 4独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；
    R 2-1和R 2-2独立地为C 1～C 7烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    方案(4)：
    R 1为氢或甲基；
    n为1或2；
    L为-(CH 2) m-R 2、被1个或2个R 4取代的C 3～C 14稠环杂环烷基、或、被1个或2个R 4取代的C 3～C 14螺环杂环烷基；
    当L为C 3～C 14稠环杂环烷基时，所述的C 3～C 14稠环杂环烷基为C 5～C 14稠环杂环烷基；
    当L为C 3～C 14螺环杂环烷基时，所述的C 3～C 14螺环杂环烷基为C 5～C 14螺环杂环烷 基；
    R 2为-NR 2-1R 2-2；
    R 4为-NR 2-1R 2-2或任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基；
    方案(5)：
    R 1为氢；
    n为1；
    L为-(CH 2) m-R 2、被1个或2个R 4取代的C 3～C 14稠环杂环烷基、或、被1个或2个R 4取代的C 3～C 14螺环杂环烷基；
    当L为C 3～C 14稠环杂环烷基时，所述的C 3～C 14稠环杂环烷基为C 5～C 14稠环杂环烷基；
    当L为C 3～C 14螺环杂环烷基时，所述的C 3～C 14螺环杂环烷基为C 5～C 14螺环杂环烷基；R 2为-NR 2-1R 2-2；
    R 4为-NR 2-1R 2-2或任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基；
    R 2-1和R 2-2独立地为C 1～C 7烷基；
    R 2-9独立地为C 1～C 7烷基或C 3～C 14杂环烷基；
    方案(6)：
    R 1为氢或甲基；
    n为1或2；
    L为-(CH 2) m-R 2、被1个或2个R 3取代的C 3～C 20环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；
    m为1、2、3或4；
    R 2、R 3和R 4独立地为-NR 2-1R 2-2；
    R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基；
    方案(7)：
    R 1为氢或甲基；
    n为1或2；
    L为-(CH 2) m-R 2、被1个R 3取代的C 3～C 20环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；m为1或2，还可为3；
    R 2、R 3和R 4独立地为-NR 2-1R 2-2；
    R 2-1和R 2-2独立地为C 1～C 7烷基；
    方案(8)：
    R 1为氢或甲基；
    n为1或2；
    L为被1个R 3取代的C 3～C 20环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；
    R 3和R 4独立地为-NR 2-1R 2-2；
    R 2-1和R 2-2独立地为C 1～C 7烷基；
    方案(9)：
    R 1为氢或甲基；
    n为1或2；
    L为C 3～C 20环烷基、或、被1个或2个R 3取代的C 3～C 20环烷基；
    R 3独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基、或、C 1～C 7杂芳基；
    R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基；
    R 2-3独立地为-NR 2-3-1R 2-3-2、-OR 2-3-3、C 1～C 7烷基或C 3～C 14杂环烷基；
    R 2-3-1和R 2-3-2独立地为氢或C 1～C 7烷基；
    R 2-3-3独立地为氢或C 1～C 7烷基；
    R 2-4独立地为氢、-CN或-OR 2-4-1；
    R 2-4-1独立地为氢或C 1～C 7烷基；
    R 2-5独立地为-NR 2-5-1R 2-5-2或C 1～C 7烷基；
    R 2-5-1和R 2-5-2独立地为氢或C 1～C 7烷基；
    R 2-6独立地为-NR 2-6-1R 2-6-2；
    R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3、卤素、氰基、-(C＝O)R 2-9-5、-S(＝O) 2R 2-9-8、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或C 1～C 7烷基；
    R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢或C 1～C 7烷基；
    R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2；
    R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    方案(10)：
    R 1为氢或甲基；
    n为1或2；
    L为被1个R 3取代的C 3～C 20环烷基；
    R 3独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；
    R 2-1和R 2-2独立地为C 1～C 7烷基；
    R 2-3独立地为C 3～C 14杂环烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    方案(11)：
    R 1为氢或甲基；
    n为1或2；
    L为被1个R 3取代的C 3～C 20环烷基；
    R 3独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；
    R 2-1和R 2-2独立地为C 1～C 7烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    方案(12)：
    R 1为氢或甲基；
    n为1或2；
    L为C 3～C 14杂环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14螺环杂环烷基；
    R 4独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基、或、C 1～C 7杂芳基；
    R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基；
    R 2-3独立地为-NR 2-3-1R 2-3-2、-OR 2-3-3、C 1～C 7烷基或C 3～C 14杂环烷基；
    R 2-3-1和R 2-3-2独立地为氢或C 1～C 7烷基；
    R 2-3-3独立地为氢或C 1～C 7烷基；
    R 2-4独立地为氢、-CN或-OR 2-4-1；
    R 2-4-1独立地为氢或C 1～C 7烷基；
    R 2-5独立地为-NR 2-5-1R 2-5-2或C 1～C 7烷基；
    R 2-5-1和R 2-5-2独立地为氢或C 1～C 7烷基；
    R 2-6独立地为-NR 2-6-1R 2-6-2；
    R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3、卤素、氰基、-(C＝O)R 2-9-5、-S(＝O) 2R 2-9-8、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或C 1～C 7烷基；
    R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢或C 1～C 7烷基；
    R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2；
    R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    方案(13)：
    R 1为氢或甲基；
    n为1或2；
    L为C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14螺环杂环烷基；
    R 4独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；
    R 2-1和R 2-2独立地为C 1～C 7烷基；
    R 2-3独立地为C 3～C 14杂环烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    方案(14)：
    R 1为氢或甲基；
    n为1或2；
    L为C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14螺环杂环烷基；
    R 4独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；
    R 2-1和R 2-2独立地为C 1～C 7烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    方案(15)：
    R 1为氢或甲基；
    n为1或2；
    L为C 3～C 14杂环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14稠环杂环烷基；
    R 4独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基、或、C 1～C 7杂芳基；
    R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基；
    R 2-3独立地为-NR 2-3-1R 2-3-2、-OR 2-3-3、C 1～C 7烷基或C 3～C 14杂环烷基；
    R 2-3-1和R 2-3-2独立地为氢或C 1～C 7烷基；
    R 2-3-3独立地为氢或C 1～C 7烷基；
    R 2-4独立地为氢、-CN或-OR 2-4-1；
    R 2-4-1独立地为氢或C 1～C 7烷基；
    R 2-5独立地为-NR 2-5-1R 2-5-2或C 1～C 7烷基；
    R 2-5-1和R 2-5-2独立地为氢或C 1～C 7烷基；
    R 2-6独立地为-NR 2-6-1R 2-6-2；
    R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3、卤素、氰基、-(C＝O)R 2-9-5、-S(＝O) 2R 2-9-8、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或C 1～C 7烷基；
    R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢或C 1～C 7烷基；
    R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2；
    R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    方案(16)：
    R 1为氢或甲基；
    n为1或2；
    L为C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14稠环杂环烷基；
    R 4独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；
    R 2-1和R 2-2独立地为C 1～C 7烷基；
    R 2-3独立地为C 3～C 14杂环烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    方案(17)：
    R 1为氢或甲基；
    n为1或2；
    L为被C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14稠环杂环烷基；
    R 4独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；
    R 2-1和R 2-2独立地为C 1～C 7烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    方案(18)：
    R 1为氢或甲基；
    n为1或2；
    L为C 3～C 14杂环烷基、或、被1个或2个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14桥环杂环烷基；
    R 4独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基、或、C 1～C 7杂芳基；
    R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基；
    R 2-3独立地为-NR 2-3-1R 2-3-2、-OR 2-3-3、C 1～C 7烷基或C 3～C 14杂环烷基；
    R 2-3-1和R 2-3-2独立地为氢或C 1～C 7烷基；
    R 2-3-3独立地为氢或C 1～C 7烷基；
    R 2-4独立地为氢、-CN或-OR 2-4-1；
    R 2-4-1独立地为氢或C 1～C 7烷基；
    R 2-5独立地为-NR 2-5-1R 2-5-2或C 1～C 7烷基；
    R 2-5-1和R 2-5-2独立地为氢或C 1～C 7烷基；
    R 2-6独立地为-NR 2-6-1R 2-6-2；
    R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3、卤素、氰基、-(C＝O)R 2-9-5、-S(＝O) 2R 2-9-8、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或C 1～C 7烷基；
    R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢或C 1～C 7烷基；
    R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2；
    R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    方案(19)：
    R 1为氢或甲基；
    n为1或2；
    L为C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14桥环杂环烷基；
    R 4独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；
    R 2-1和R 2-2独立地为C 1～C 7烷基；
    R 2-3独立地为C 3～C 14杂环烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    方案(20)：
    R 1为氢或甲基；
    n为1或2；
    L为C 3～C 14杂环烷基、或、被1个R 4取代的C 3～C 14杂环烷基；所述的C 3～C 14杂环烷基为C 3～C 14桥环杂环烷基；
    R 4独立地为-NR 2-1R 2-2、或、任选被1个R 2-9取代的：C 1～C 7烷基；
    R 2-1和R 2-2独立地为C 1～C 7烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3或C 3～C 14环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    方案(21)：
    R 1为氢或甲基；
    n为1或2；
    L为-(CH 2) m-R 2；
    m为1、2、3或4；
    R 2、R 3和R 4独立地为-CN、-NR 2-1R 2-2、-(C＝O)R 2-3、-(C＝NR 2-4)R 2-5、-S(＝O) 2R 2-6、-OR 2-7、或、任选被1个、2个或3个R 2-9取代的：C 1～C 7烷基、C 3～C 14环烷基、C 3～C 14杂环烷基、或、C 1～C 7杂芳基；
    R 2-1和R 2-2独立地为氢、C 1～C 7烷基或C 3～C 14环烷基；
    R 2-3独立地为-NR 2-3-1R 2-3-2、-OR 2-3-3、C 1～C 7烷基或C 3～C 14杂环烷基；
    R 2-3-1和R 2-3-2独立地为氢或C 1～C 7烷基；
    R 2-3-3独立地为氢或C 1～C 7烷基；
    R 2-4独立地为氢、-CN或-OR 2-4-1；
    R 2-4-1独立地为氢或C 1～C 7烷基；
    R 2-5独立地为-NR 2-5-1R 2-5-2或C 1～C 7烷基；
    R 2-5-1和R 2-5-2独立地为氢或C 1～C 7烷基；
    R 2-6独立地为-NR 2-6-1R 2-6-2；
    R 2-6-1和R 2-6-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3、卤素、氰基、-(C＝O)R 2-9-5、-S(＝O) 2R 2-9-8、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基；
    R 2-9-5独立地为氢、-NR 2-9-5-1R 2-9-5-2、-OR 2-9-5-3或C 1～C 7烷基；
    R 2-9-5-1、R 2-9-5-2和R 2-9-5-3独立地为氢或C 1～C 7烷基；
    R 2-9-8独立地为-NR 2-9-8-1R 2-9-8-2；
    R 2-9-8-1和R 2-9-8-2独立地为氢、C 1～C 7烷基、C 3～C 14环烷基或C 3～C 14杂环烷基；
    方案(22)：
    R 1为氢或甲基；
    n为1或2；
    L为-(CH 2) m-R 2；m为1或2，还可为3；
    R 2独立地为-NR 2-1R 2-2、-(C＝O)R 2-3、或、任选被1个R 2-9取代的：C 1～C 7烷基或C 3～C 14杂环烷基；
    R 2-1和R 2-2独立地为C 1～C 7烷基；
    R 2-3独立地为C 3～C 14杂环烷基；
    R 2-9独立地为-NR 2-9-2R 2-9-3、C 1～C 7烷基或C 3～C 14环烷基；
    R 2-9-2和R 2-9-3独立地为C 1～C 7烷基。
  11. 如权利要求1所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物，其特征在于，如式I所示的吡唑酮并嘧啶类化合物为下述任一结构：
    Figure PCTCN2020112034-appb-100030
    Figure PCTCN2020112034-appb-100031
    Figure PCTCN2020112034-appb-100032
  12. 如权利要求1所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物，其特征在于，如式I所示的吡唑酮并嘧啶类化合物为如下任一化合物：
    在下述条件下保留时间为9.66min的
    Figure PCTCN2020112034-appb-100033
    (I-30-1)：Agilent 1260高效液相色谱仪；流动相A:水(0.1％甲酸)，流动相B:乙腈；柱时间：15min；柱型：Waters公司Xselect，5μm，4.6×250mm；梯度洗脱,5％流动相B→50％流动相B；
    在下述条件下保留时间为10.04min的
    Figure PCTCN2020112034-appb-100034
    (I-30-2)：Agilent 1260高效液相色谱仪；流动相A:水(0.1％甲酸)，流动相B:乙腈；柱时间：15min；柱型：Waters公司Xselect，5μm，4.6×250mm；梯度洗脱,5％流动相B→50％流动相B；
    在下述条件下保留时间为7.80min的
    Figure PCTCN2020112034-appb-100035
    (I-36-1)：Agilent 1260高效液相色谱仪；流动相A:水(0.1％甲酸)，流动相B:乙腈；柱时间：15min；柱型：Waters公司Xselect，5μm，4.6×250mm；梯度洗脱,5％流动相B→95％流动相B；
    在下述条件下保留时间为7.97min的
    Figure PCTCN2020112034-appb-100036
    (I-36-2)：Agilent 1260高效液相色谱仪；流动相A:水(0.1％甲酸)，流动相B:乙腈；柱时间：15min；柱型：Waters公司Xselect，5μm，4.6×250mm；梯度洗脱,5％流动相B→95％流动相B；
    其中，
    Figure PCTCN2020112034-appb-100037
    是指顺反构型不定。
  13. 一种如权利要求1～12中至少一项所述的如式I所示的吡唑酮并嘧啶类化合物的制备方法，其包括下述步骤：步骤一，化合物1A与化合物1B经C-N偶联反应得到化合物1C；步骤二，化合物1C先在氧化剂的作用下形成活性较高的中间体亚砜，然后再与化合物1D进行取代反应得到化合物I；
    Figure PCTCN2020112034-appb-100038
  14. 一种如式1C所示的化合物：
    Figure PCTCN2020112034-appb-100039
    其中，R 1为氢或甲基；n为1或2；
    较佳地为如下任一结构：
    Figure PCTCN2020112034-appb-100040
  15. 一种物质X在制备激酶抑制剂或药物中的应用；
    所述的物质X为如权利要求1～12中至少一项所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
  16. 一种物质X在制备药物中的应用；所述的药物用于治疗和/或预防与WEE1激酶有关的疾病，或者，所述的药物用于治疗和/或预防癌症；
    所述的物质X为如权利要求1～12中至少一项所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
  17. 一种药物组合物，其包含物质X和药用辅料；
    所述的物质X为如权利要求1～12中至少一项所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
  18. 一种组合，其包含物质X和抗癌药物，
    所述的物质X为如权利要求1～12中至少一项所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
  19. 一种如权利要求18所述的组合在制备用于预防和/或治疗癌症的药物中的应用。
  20. 一种物质X在制备药物中的应用，所述的药物和抗癌药物联合用于预防和/或治疗癌症；
    所述的物质X为如权利要求1～12中至少一项所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
  21. 一种抗癌药物在制备药物中的应用，所述的药物和物质X联合用于预防和/或治 疗癌症；
    所述的物质X为如权利要求1～12中至少一项所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
  22. 一种药物组合物，其包含如权利要求18所述的组合和药用辅料。
  23. 一种组合药盒，其包含药物组合物A和药物组合物B；
    所述的药物组合物A包括物质X和药用辅料；
    所述的药物组合物B包括抗癌药物和药用辅料；
    所述的物质X为如权利要求1～12中至少一项所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物。
  24. 一种治疗和/或预防疾病的方法，其包括向患者施用治疗有效量的物质X；所述的疾病为与WEE1激酶有关的疾病或癌症；
    所述的物质X为如权利要求1～12中至少一项所述的如式I所示的吡唑酮并嘧啶类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、其代谢产物或其药物前体。
  25. 一种治疗和/或预防癌症的方法，其包括向患者施用治疗有效量的如权利要求18所述的组合。
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