WO2022166799A1 - 稠三环类细胞周期蛋白-依赖性激酶抑制剂及其制备方法和医药用途 - Google Patents

稠三环类细胞周期蛋白-依赖性激酶抑制剂及其制备方法和医药用途 Download PDF

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WO2022166799A1
WO2022166799A1 PCT/CN2022/074509 CN2022074509W WO2022166799A1 WO 2022166799 A1 WO2022166799 A1 WO 2022166799A1 CN 2022074509 W CN2022074509 W CN 2022074509W WO 2022166799 A1 WO2022166799 A1 WO 2022166799A1
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alkyl
cycloalkyl
formula
alkoxy
compound
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PCT/CN2022/074509
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English (en)
French (fr)
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李云飞
刘浩淼
邹昊
张瑱
庞夏明
龚红龙
张超
张芳
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上海拓界生物医药科技有限公司
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Priority to CA3206898A priority Critical patent/CA3206898A1/en
Priority to JP2023545857A priority patent/JP2024504452A/ja
Priority to EP22749078.6A priority patent/EP4289848A1/en
Priority to AU2022217309A priority patent/AU2022217309A1/en
Priority to US18/263,870 priority patent/US20240140963A1/en
Priority to MX2023008896A priority patent/MX2023008896A/es
Priority to CN202280008155.2A priority patent/CN116583524A/zh
Priority to KR1020237027643A priority patent/KR20230142735A/ko
Publication of WO2022166799A1 publication Critical patent/WO2022166799A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a fused tricyclic cyclin-dependent kinase inhibitor and its preparation method, composition and medical use.
  • Cyclin-dependent kinases are important cellular enzymes that play an important role in the regulation of eukaryotic cell division and proliferation. Cyclin-dependent kinase catalytic units are activated by regulatory subunits called cyclins. At least 16 mammalian cyclins have been identified (Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312). Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6 and possibly other heterodynes are important regulators of cell cycle progression. Other functions of cyclin/CDK heterodynes include transcriptional regulation, DNA repair, differentiation and apoptosis (Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).
  • CDK4 has been identified as a single oncogenic driver in many breast cancers. Therefore, since CDK4-selective inhibitors may offer improved safety or enhanced overall efficacy due to potentially higher and/or sequential doses compared to dual CDK4/6 inhibitors, the development of highly CDK4-selective molecules, in It has practical application value in clinical practice.
  • WO2019207463A discloses a class of cyclin-dependent kinase inhibitors.
  • the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl and C 3-8 cycloalkyl, the C 1-6 alkyl, C 1-6 haloalkyl and C 3-8
  • the cycloalkyl groups are each independently optionally substituted with one or more Ra ;
  • R 2 is the structure of formula II: R 9 is selected from H, OH and NH 2 optionally substituted with 1 or 2 Ra' or Ra ";
  • R 10 is each independently selected from OH, halogen, CN, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 Cycloalkyl and 3-12-membered heterocycloalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-12-membered heteroalkyl
  • the cycloalkyl groups are each independently optionally substituted with one or more R b ;
  • Q is NR 11 or O
  • Q is CR 12 R 13 , wherein R 12 , R 13 and the carbon atom to which they are attached form a 3-12 membered heterocycloalkyl group containing N or O in NR 11 as a ring atom, the heterocycloalkyl group is optionally is substituted by one or more R 10 ;
  • R 11 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, SO 2 R c , SO 2 NR d Re , COR f , COOR f and CONR g Rh , the C 1-6 Alkyl and Ci- 6 haloalkyl are each independently optionally selected from one or more of Ra , Rb , SO2Rc , SO2NRdRe , CORf , COORf , and CONRgRh Substituent substitution;
  • n 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • p 1, 2 or 3;
  • X is N or CH
  • Y is N or CR 7 , R 7 is selected from H, F, Cl, CN, C 1-6 alkyl and C 1-6 alkoxy, the C 1-6 alkyl and C 1-6 alkoxy each independently optionally substituted with one or more Ra ;
  • R 3 is selected from H, F, Cl, CN, CH 2 F, CHF 2 and CF 3 ;
  • R 4 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C3-8 cycloalkyl and 3-12-membered heterocycloalkyl, said C 1-6 alkyl, C 1- 6 alkoxy, C 3-8 cycloalkyl and 3-12 membered heterocycloalkyl are each independently optionally substituted with one or more R b or deuterium;
  • Z is O or CHR 8 , and R 8 is selected from hydrogen atom, deuterium atom and halogen;
  • L is -(CH 2 ) q -, the -(CH 2 )- is optionally selected from deuterium, CN, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy substituted with one or more substituents of the C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy and 3-12 membered heterocycles
  • the alkyl groups are each independently optionally substituted with one or more R or deuterium ;
  • q 1, 2, 3 or 4;
  • R 5 and R 6 are each independently selected from H, deuterium, CN, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy and 3-12 membered heterocycloalkyl, so Said C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy and 3-12 membered heterocycloalkyl are optionally each independently substituted with one or more R or deuterium ;
  • R a and R b are each independently selected from H, OH, CN, halogen (fluorine, chlorine, bromine, iodine), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-12-membered heterocycloalkyl and NR a' R a" substituted, the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-12 membered heterocycloalkyl are each independently optionally selected from NH 2 , NHCH 3 , N(CH 3 ) 2 , halogen, OH, C 1- Substituted with one or more substituents of 6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-12-membered heterocycloalkyl;
  • R a' and R a" are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-12 membered heterocycloalkyl, the C 1-6 6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-12 membered heterocycloalkyl are each independently optionally selected from NH 2 , NHCH 3 , N(CH 3 ) 2 , halogen, One of OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-12 membered heterocycloalkyl or more substituents;
  • Ra ' Ra " together with the N atom to which they are attached form a 3-12 membered heterocycloalkyl optionally selected from halogen, OH, C1-6 alkyl , C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-12-membered heterocycloalkyl substituted with one or more substituents;
  • R c , R d and R e are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and C 1-6 haloalkyl;
  • R f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-12 membered heterocycloalkyl
  • the C 1-6 alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and 3-12 membered heterocycloalkyl are each independently optionally selected from NH 2 , NHCH 3 , N(CH 3 ) 2 , halogen, OH, C 1-6 alkyl , C 1-6 alkoxy, C 1-6 haloalkyl, C 3-8 cycloalkyl and one or more substituents of 3-12-membered heterocycloalkyl;
  • R g and R h are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 3-8 cycloalkyl, the C 1-6 alkoxy , C 1-6 haloalkyl, and C 3-8 cycloalkyl are each independently optionally substituted with one or more R a or R b .
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein R 1 is H or C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein R 1 is H.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of
  • R 9 , R 10 , m and Q are as defined in the compound of formula I.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein R 2 is wherein, R 9 , R 10 , m and Q are as defined in the compound of formula I.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein R 2 is wherein R 9 , R 10 , R 11 and m are as defined in the compound of formula I.
  • the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 9 is OH or NH 2 , and the NH 2 is optionally separated by 1 or 2 R a' or R a" substituted, R a' and R a" are each independently C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein R 9 is OH.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein R 9 is NH 2 .
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein X is N.
  • the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein Y is CR 7 ; R 7 is selected from H, F, Cl and C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, F and Cl.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3 -8 cycloalkyl and 3-12 membered heterocycloalkyl; each of the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-12 membered heterocycloalkyl independently optionally substituted with one or more R b or deuterium, R b selected from H, OH, CN, halogen (fluorine, chlorine, bromine, iodine), C 1-6 alkyl, C 1-6 alkoxy , C 1-6 haloalkyl, C 1-6 haloalkoxy and C 3-8 cycloalkyl.
  • R 4 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3 -8 cycloalkyl and 3-12 membered heterocycloalkyl; each of the C 1-6 alkyl,
  • the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is a C 1-6 alkyl group, and the C 1-6 alkyl group is optionally replaced by a or more R b or deuterium substitution, R b is selected from OH, CN, halogen (fluorine, chlorine, bromine, iodine), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 3-8 cycloalkyl.
  • R 4 is a C 1-6 alkyl group
  • the C 1-6 alkyl group is optionally replaced by a or more R b or deuterium substitution
  • R b is selected from OH, CN, halogen (fluorine, chlorine, bromine, iodine), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 3-8 cycloalkyl.
  • the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is a C 1-6 alkyl group, and the C 1-6 alkyl group is optionally replaced by a or multiple R b or deuterium substitution, R b selected from OH, CN and halogen (fluorine, chlorine, bromine, iodine).
  • the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein L is -(CH 2 ) q -, and q is selected from 1 or 2; the -(CH 2 ) - optionally substituted by one or more selected from deuterium, CN, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy and 3-12 membered heterocycloalkyl base substitution.
  • L is -(CH 2 ) q -, and q is selected from 1; the -(CH 2 )-any is optionally substituted with one or more substituents selected from the group consisting of deuterium, CN, halogen, C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, and 3-12 membered heterocycloalkyl.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein L is -(CH 2 ) qa -, and q is selected from 1; the -(CH 2 )- Optionally substituted with one or more deuterium substituents.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 are each independently selected from H, deuterium, CN, halogen, C 1-6 alkyl and C 3-8 cycloalkyl.
  • the compound shown in formula I provided by the present disclosure or a pharmaceutically acceptable salt thereof is a compound shown in formula I-2 or a pharmaceutically acceptable salt thereof,
  • R 9 is OH or NH 2 , said NH 2 is optionally substituted with 1 or 2 R a' or R a" , and R a' and R a" are each independently C 1-6 alkyl;
  • R 10 is each independently selected from H, OH, halogen, CN, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;
  • n 0, 1 or 2;
  • R 11 is selected from SO 2 R c , SO 2 NR d Re , COR f , COOR f and CONR g Rh ;
  • R c , R d and R e are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and C 1-6 haloalkyl;
  • R f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-12 membered heterocycloalkyl;
  • R g and R h are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 3-8 cycloalkyl;
  • R 7 is selected from H, F, Cl and C 1-6 alkyl
  • R is selected from H, F and Cl
  • R 4 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-12-membered heterocycloalkyl; the C 1-6 alkyl, C 1 -6 alkoxy, C 3-8 cycloalkyl and 3-12 membered heterocycloalkyl are each independently optionally substituted with one or more R or deuterium selected from H, OH, CN and halogen ( Fluorine, chlorine, bromine, iodine);
  • R 5 and R 6 are each independently selected from H, deuterium, CN, halogen, C 1-6 alkyl and C 3-8 cycloalkyl;
  • Z is O or CHR 8
  • R 8 is selected from a hydrogen atom, a deuterium atom and a halogen.
  • the compound of formula I or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula I-2 or a pharmaceutically acceptable salt thereof 2, wherein Z is O.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound represented by formula I-2 or a pharmaceutically acceptable salt thereof, wherein Z is CHR 8 , R 8 is selected from a hydrogen atom, a deuterium atom and a halogen.
  • the compound shown in formula I provided by the present disclosure or a pharmaceutically acceptable salt thereof is a compound shown in formula I-2 or a pharmaceutically acceptable salt thereof,
  • R 9 is OH or NH 2 , said NH 2 is optionally substituted with 1 or 2 R a' or R a" , and R a' and R a" are each independently C 1-6 alkyl;
  • n 0;
  • R 11 is SO 2 R c ;
  • R c is selected from H, C 1-6 alkyl and C 1-6 haloalkyl
  • R 7 is selected from H, F, Cl and C 1-6 alkyl
  • R is selected from H, F and Cl
  • R 4 is selected from H, C 1-6 alkyl and C 1-6 alkoxy; said C 1-6 alkyl and C 1-6 alkoxy are each independently optionally replaced by one or more R b or deuterium substituted; R b is selected from H, OH, CN and halogen (fluorine, chlorine, bromine, iodine);
  • R 5 and R 6 are each independently selected from H, deuterium, CN, halogen and C 1-6 alkyl.
  • the compound shown in formula I provided by the present disclosure or a pharmaceutically acceptable salt thereof is a compound shown in formula I-2 or a pharmaceutically acceptable salt thereof,
  • R 9 is OH
  • n 0;
  • R 11 is SO 2 R c ;
  • R c is C 1-6 alkyl or C 1-6 haloalkyl
  • R 7 is F or Cl
  • R 3 is F or Cl
  • R 4 is H or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by one or more R b or deuterium, R b is selected from H, OH, CN and halogen (fluorine, chlorine, bromine, iodine);
  • R 5 and R 6 are each independently H or C 1-6 alkyl.
  • the compound shown in formula I provided by the present disclosure or a pharmaceutically acceptable salt thereof is a compound shown in formula I-2 or a pharmaceutically acceptable salt thereof,
  • R 9 is OH
  • n 0;
  • R 11 is SO 2 R c ;
  • R c is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl;
  • R 7 is F or Cl
  • R 3 is F or Cl
  • R 4 is H or C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by one or more R b or deuterium, and R b is H or OH;
  • R5 and R6 are each independently selected from H, methyl, ethyl, n - propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
  • the compound shown in formula I provided by the present disclosure or a pharmaceutically acceptable salt thereof is a compound shown in formula I-2 or a pharmaceutically acceptable salt thereof,
  • R 9 is OH
  • n 0;
  • R 11 is SO 2 R c ;
  • R c is selected from methyl, ethyl and n-propyl
  • R 7 is F or Cl
  • R 3 is F or Cl
  • R 4 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, said methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl and tert-butyl are each independently optionally substituted with one or more Rb , Rb being H or OH;
  • R5 and R6 are each independently selected from H, methyl, ethyl, n - propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
  • the compound shown in formula I provided by the present disclosure or a pharmaceutically acceptable salt thereof is a compound shown in formula I-2 or a pharmaceutically acceptable salt thereof,
  • R 9 is OH
  • n 0;
  • R 11 is SO 2 R c ;
  • R c is methyl
  • R 7 is F or Cl
  • R 3 is F or Cl
  • R4 is selected from H, methyl, ethyl, n - propyl and isopropyl;
  • R5 and R6 are each independently selected from H, methyl, ethyl, n - propyl and isopropyl.
  • the compound shown in formula I or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound shown in formula I-3 or a pharmaceutically acceptable salt thereof,
  • R 9 is OH or NH 2 , said NH 2 is optionally substituted with 1 or 2 R a' or R a" , and R a' and R a" are each independently C 1-6 alkyl;
  • R 10 is each independently selected from OH, halogen, CN, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;
  • n 0, 1 or 2;
  • R 7 is selected from H, F, Cl and C 1-6 alkyl
  • R is selected from H, F and Cl
  • R 4 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-12 membered heterocycloalkyl, said C 1-6 alkyl, C 1 -6 alkoxy, C3-8 cycloalkyl and 3-12 membered heterocycloalkyl are each independently optionally substituted with one or more R or deuterium ;
  • R is selected from H, OH, CN and halogen ( fluoro , chlorine, bromine, iodine);
  • R 5 and R 6 are each independently selected from H, deuterium, CN, halogen, C 1-6 alkyl and C 3-8 cycloalkyl;
  • Z is O or CHR 8
  • R 8 is selected from a hydrogen atom, a deuterium atom and a halogen.
  • the compound of formula I or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula I-3 or a pharmaceutically acceptable salt thereof, wherein Z is O.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound represented by formula I-3 or a pharmaceutically acceptable salt thereof, wherein Z is CHR 8 , R 8 is a hydrogen atom, a deuterium atom or a halogen.
  • the compound of formula I provided by the present disclosure or a pharmaceutically acceptable salt thereof is a compound of formula I-3 or a pharmaceutically acceptable salt thereof,
  • R 9 is OH or NH 2 , said NH 2 is optionally substituted with 1 or 2 R a' or R a" , and R a' and R a" are each independently C 1-6 alkyl;
  • n 0;
  • R 7 is selected from H, F, Cl and C 1-6 alkyl
  • R is selected from H, F and Cl
  • R 4 is selected from H, C 1-6 alkyl and C 1-6 alkoxy; said C 1-6 alkyl and C 1-6 alkoxy are each independently optionally replaced by one or more R b or deuterium substituted, R b is selected from H, OH, CN and halogen (fluorine, chlorine, bromine, iodine);
  • R 5 and R 6 are each independently selected from H, deuterium, CN, halogen and C 1-6 alkyl.
  • the compound of formula I provided by the present disclosure or a pharmaceutically acceptable salt thereof is a compound of formula I-3 or a pharmaceutically acceptable salt thereof,
  • R 9 is OH
  • n 0;
  • R 7 is F or Cl
  • R 3 is F or Cl
  • R 4 is H or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by one or more R b or deuterium, R b is selected from H, OH, CN and halogen (fluorine, chlorine, bromine, iodine);
  • R 5 and R 6 are each independently H or C 1-6 alkyl.
  • the compound of formula I provided by the present disclosure or a pharmaceutically acceptable salt thereof is a compound of formula I-3 or a pharmaceutically acceptable salt thereof,
  • R 9 is OH
  • n 0;
  • R 7 is F or Cl
  • R 3 is F or Cl
  • R 4 is H or C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by one or more R b or deuterium, and R b is H or OH;
  • R5 and R6 are each independently selected from H, methyl, ethyl, n - propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
  • the compound of formula I provided by the present disclosure or a pharmaceutically acceptable salt thereof is a compound of formula I-3 or a pharmaceutically acceptable salt thereof,
  • R 9 is OH
  • n 0;
  • R 7 is F or Cl
  • R 3 is F Hu Cl
  • R 4 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, said methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl and tert-butyl are each independently optionally substituted with one or more R b ;
  • R b is H or OH;
  • R5 and R6 are each independently selected from H, methyl, ethyl, n - propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
  • the compound shown in the formula I provided by the present disclosure or a pharmaceutically acceptable salt thereof is a compound shown in the formula I-3 or a pharmaceutically acceptable salt thereof,
  • R 9 is OH
  • n 0;
  • R 7 is F or Cl
  • R 3 is F or Cl
  • R4 is selected from H, methyl, ethyl, n - propyl and isopropyl;
  • R5 and R6 are each independently selected from H, methyl, ethyl, n - propyl and isopropyl.
  • the compound of formula I provided by the present disclosure or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • Another aspect of the present disclosure provides an isotopic substitution of the aforementioned compounds represented by formula I, I-2, and I-3 or a pharmaceutically acceptable salt thereof, in an optional embodiment, the isotopic substitution For the deuterium atom substitution.
  • the abundance of the deuterium atom is greater than 20%.
  • the abundance of the deuterium atom is greater than 50%.
  • the abundance of the deuterium atom is greater than 90%.
  • the abundance of the deuterium atom is greater than 95%.
  • the present disclosure also provides a method for preparing a compound of formula I, comprising the steps of reacting a compound of formula I-B with a compound of formula I-C to form a compound of formula I,
  • LG 1 is a leaving group, and the leaving group is preferably halogen, sulfonate, boronic acid and boronic ester;
  • X, Y, Z, L, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the compound of formula I.
  • the reaction is carried out in the presence of a catalyst, which is metallic palladium or metallic nickel.
  • the catalyst is selected from the group consisting of palladium on carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)bis ferrocene]palladium dichloride, 1,1'-[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium and 2- Bicyclohexylphosphine-2',6'-dimethoxybiphenyl, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride and 2-biscyclohexylphosphine-2', 6'-dimethoxybiphenyl.
  • Another aspect of the present disclosure provides a compound of formula I-B or a pharmaceutically acceptable salt thereof,
  • LG 1 is a leaving group selected from halogen, sulfonic acid ester, boronic acid and boronic acid ester;
  • X, Y, Z, L, R 3 , R 4 , R 5 , R 6 are such as as defined in the compound of formula I.
  • the present disclosure also provides a pharmaceutical composition, comprising at least one therapeutically effective amount of the compounds represented by the aforementioned formulas I, I-2, and I-3, or their pharmaceutically acceptable salts or the aforementioned isotopic substitutions, and a pharmaceutically acceptable amount thereof. acceptable excipients.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound represented by formula I, I-2, I-3 or a pharmaceutically acceptable salt thereof or the aforementioned isotopic substitution.
  • the pharmaceutical composition contains 0.1-99.9% of the compounds represented by the aforementioned formulas I, I-2, and I-3, or their pharmaceutically acceptable salts or the aforementioned isotopic substitutions. .
  • the pharmaceutical composition contains 0.5%-99.5% of the compounds represented by the aforementioned formulas I, I-2, and I-3, or their pharmaceutically acceptable salts or the aforementioned isotopic substitutions.
  • the pharmaceutical composition contains 1%-99% of the compounds represented by the aforementioned formulas I, I-2, and I-3, or their pharmaceutically acceptable salts or the aforementioned isotopic substitutions.
  • the pharmaceutical composition contains 2%-98% of the compounds represented by the aforementioned formulas I, I-2, and I-3, or their pharmaceutically acceptable salts or the aforementioned isotopic substitutions.
  • the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition.
  • the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient.
  • the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient.
  • the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient.
  • the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.
  • the present disclosure also provides a method for preventing and/or treating a cyclin-dependent kinase-related disease, comprising administering to a patient in need thereof a therapeutically effective amount of the compounds represented by the aforementioned formulae I, I-2, and I-3 or a pharmaceutically acceptable salt thereof or the aforementioned isotopic substitution, or the aforementioned pharmaceutical composition.
  • the present disclosure also provides a method for preventing and/or treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the compound represented by the aforementioned formulas I, I-2, I-3 or a pharmaceutically acceptable salt thereof or The aforementioned isotopic substitution, or the aforementioned pharmaceutical composition.
  • the present disclosure also provides the compounds represented by the aforementioned formulas I, I-2, and I-3 or their pharmaceutically acceptable salts or the aforementioned isotopic substitutions, or the aforementioned pharmaceutical compositions in preparation for prevention and/or treatment and cell cycle Use in medicine for protein-dependent kinase-related diseases.
  • the present disclosure also provides the compounds represented by the aforementioned formulas I, I-2, and I-3, or their pharmaceutically acceptable salts or the aforementioned isotopic substitutions, or the aforementioned pharmaceutical compositions in the preparation of preparations for the prevention and/or treatment of and cancer. use in medicine.
  • the cyclin-dependent kinase-related disease is selected from the group consisting of cell proliferative diseases, cancer and immune diseases.
  • the cancer described in this disclosure is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, bowel cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic, gastric and thyroid cancers.
  • the cyclin-dependent kinase described in the present disclosure is CDK4.
  • Another aspect of the present disclosure provides a compound represented by the aforementioned formulas I, I-2, and I-3 or a pharmaceutically acceptable salt thereof
  • the compounds represented by the aforementioned formulas I, I-2, and I-3 or their pharmaceutically acceptable salts or the aforementioned isotopic substitutions, or the aforementioned pharmaceutical compositions provided by the present disclosure have reduced gastrointestinal and/or hematological toxicity.
  • the pharmaceutically acceptable salts of the compounds described in this disclosure are inorganic or organic salts.
  • Compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or both Two configurations.
  • key Indicates unspecified configuration, including cis (E) or trans (Z) configuration.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton tautomers
  • proton transfer such as keto-enol and imine-enamine, lactam-lactam isomerizations .
  • An example of a lactam-lactam equilibrium is between A and B as shown below.
  • the present disclosure also includes certain isotopically-labeled compounds of the present disclosure which are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic weight or mass number different from that normally found in nature.
  • isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (ie, at least 1000 times greater than the natural abundance of deuterium (which is 0.015%)) % of deuterium incorporated).
  • Exemplary compounds having natural abundance greater than deuterium may be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 4000 times more abundant 5000 times more abundant deuterium, at least 6000 times more abundant deuterium or more abundant deuterium.
  • the present disclosure also includes compounds of formula (I) in various deuterated forms.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to relevant literature to synthesize the compound of formula (I) in deuterated form.
  • Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • “Pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener that has been approved by the U.S. Food and Drug Administration for use in humans or livestock animals , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • Alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 12 carbon atoms is preferred, and an alkyl group containing 1 to 6 carbon atoms is more preferred.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and their various branched isomers Wait.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, Nitro group, cyano group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-7 cycloalkyl group, 3-12 membered heterocyclic group and the like.
  • Alkenyl includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups.
  • C 2-6 alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, Nitro group, cyano group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-7 cycloalkyl group, 3-12 membered heterocyclic group and the like.
  • Alkynyl includes branched and straight chain alkynyl groups having from 2 to 12 carbon atoms or alkenes containing aliphatic hydrocarbon groups, or if a specified number of carbon atoms is specified, that specific number is meant. Examples are ethynyl, propynyl (eg 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, Nitro group, cyano group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-7 cycloalkyl group, 3-12 membered heterocyclic group and the like.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring linked to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-7 cycloalkyl group, 3-12 membered heterocyclic group and the like.
  • heterocyclyl also expressed as heterocycloalkyl, refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is optional Heteroatoms from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms are carbon.
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • Non-limiting examples of "heterocyclyl" include:
  • heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-7 cycloalkyl group, 3-12 membered heterocyclic group and the like.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 12 membered, such as benzene base and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 3-12 membered heterocyclic group, etc., preferably phenyl.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 6- to 12-membered, more preferably 5- or 6-membered.
  • Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, and many more.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-7 cycloalkyl group, 3-12 membered heterocyclic group and the like.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-7 cycloalkyl group, 3-12 membered heterocyclic group and the like.
  • hydroxyl refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, with other chemical components, together with other components such as a physiologically acceptable carrier and excipient.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • experimental methods without specific conditions are generally based on conventional conditions or conditions suggested by raw material or commodity manufacturers.
  • Reagents with no specific source indicated are conventional reagents purchased in the market.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS was measured with a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer.
  • HPLC uses Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200 LC high pressure liquid chromatograph (Ultimate XB-C18 3.0*150mm chromatographic column or Xtimate C18 2.1*30mm chromatographic column).
  • Chiralpak IC-3 100 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 150 ⁇ 4.6mm for chiral HPLC analysis I.D.,3um, Chiralpak AS-3 100 ⁇ 4.6mm I.D.,3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm I.D.,3um, Chiralcel OD-3 100 ⁇ 4.6mm I.D.,3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm I.D., 5um, Chiralcel OJ-3 150 ⁇ 4.6mm I.D., 3um chromatographic column;
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • the chiral preparative column used DAICEL CHIRALPAK IC (250mm*30mm, 10 ⁇ m) or Phenomenex-Amylose-1 (250mm*30mm, 5 ⁇ m).
  • the CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).
  • the average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC),
  • reaction solution was concentrated, 100 mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (100 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Purification by eluting with petroleum ether, ethyl acetate gave the title compound 1c (2.0 g, yield: 59%).
  • reaction solution was poured into 20 mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Purification by eluting with petroleum ether, ethyl acetate gave the title compound 1e (105 mg, yield: 73%).
  • the reaction solution was cooled to room temperature, filtered, and the filtrate was collected. After concentration under reduced pressure, the residue was purified by C-18 reverse phase chromatography to obtain a crude product mixture.
  • the crude product was resolved by chirality (column: DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m), Conditions: 45% EtOH (0.1% NH3 ⁇ H2O ) in CO2 ; flow rate: 80 mL/min) to give isomer 1 (3.8 mg, yield: 17%) and isomer 2 (4.4 mg, Yield: 20%).
  • compound 2a (30 mg, 0.08 mmol), (3R, 4R)-4-amino-1-(methylsulfonyl)piperidin-3-ol (19.4 mg, 0.10 mmol) were successively prepared using the patent application "WO 2019/207463 A1 "prepared by the disclosed method), (S)-(-)-2,2"-bis(diphenylphosphino)-1,1"-binaphthalene (10mg, 0.02mmol), palladium acetate (4.4 mg, 0.02 mmol) dissolved in 2 mL of tetrahydrofuran. Cesium carbonate (52 mg, 0.16 mmol) was added, and the mixture was reacted at 80°C for 1 hour.
  • the reaction solution was cooled to room temperature, filtered, and the filtrate was collected. After concentration under reduced pressure, the residue was purified by C-18 reverse phase chromatography to obtain a crude product mixture.
  • the crude product was resolved by chirality (column: DAICEL CHIRALCEL OD-H (250mm*30mm, 5 ⁇ m ), 50% EtOH (0.1% NH3 ⁇ H2O ) in CO2 ; flow rate: 80 mL/min) to give isomer 1 (4.4 mg, yield: 10%) and isomer 2 (3.3 mg, Yield: 8%).
  • compound 4a (930 mg, 3.1 mmol) was dissolved in 20 mL of tetrahydrofuran. The temperature was lowered to -20°C, methylmagnesium bromide tetrahydrofuran solution (3mol/L, 1.5ml, 4.5mmol) was added dropwise, and the reaction was carried out at -20°C for 4 hours. 5 ml of water was added to quench the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by C-18 reverse phase chromatography to obtain the title compound 4b (830 mg, yield: 85%).
  • reaction solution was cooled to room temperature, 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoramantane (58 mg, 0.2 mmol), potassium carbonate ( 221 mg, 1.6 mmol), 2,4-dichloro-5-fluoropyrimidine (220 mg, 1.2 mmol), tris(dibenzylideneacetone) dipalladium (183 mg, 0.2 mmol) and 1 mL of water, reaction 1 at 80 °C Hour.
  • the reaction solution was cooled to room temperature, filtered, the filtrate was collected, concentrated under reduced pressure, and the residue was purified by C-18 reverse phase chromatography to obtain the title compound 4e (129 mg, yield: 41%).
  • Compound A is Example A94 of WO 2019/207463A1, which was synthesized with reference to the method disclosed in this patent application.
  • kinase into 1-fold kinase buffer to prepare 2.5-fold enzyme solution; prepare 5-fold compound dilution (1-fold kinase buffer, 10% DMSO) corresponding to the test concentration of the compound; add an appropriate amount of FAM-labeled polypeptide and ATP to 1-fold kinase buffer to prepare a 2.5x substrate solution.
  • X compound concentration log value
  • Y compound inhibition percentage
  • the initial concentration of in vitro CDK (CDK2, CDK9) kinase activity test was 1 ⁇ M, 3-fold dilution, a total of 10 concentrations, and repeated well test.
  • Compound PHA-793887 was used as a control compound.
  • % inhibition 100-(Signalcmpd-SignalAve_PC)/(SignalAve_VC-SignalAve_PC) ⁇ 100.
  • SignalAve_PC Average of all positive control wells in the entire plate.
  • SignalAve_VC Average of all negative control wells in the entire plate.
  • Signalcmpd Average value of the corresponding well for the test compound.
  • X compound concentration log value
  • Y compound inhibition percentage
  • CDK CDK1, CDK4, CDK6, CDK9 kinase biochemical inhibitory activities of the compounds of the present disclosure were determined by the above experiments, and the measured IC50 values are shown in Table 1, Table 2 and Table 3.
  • CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 were used to assess representative substrate metabolism responses of the five major human CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4). Determination of different concentrations of test compounds for phenacetin (CYP1A2), diclofenac sodium (CYP2C9), S-mephentoin (CYP2C19), bufurolol hydrochloride by liquid chromatography tandem mass spectrometry (LC/MS/MS) Effects of salt (CYP2D6) and midazolam (CYP3A4/5) on metabolic responses.
  • CYP1A2A2C9, CYP2C19, CYP2D6, CYP3A4 were used to assess representative substrate metabolism responses of the five major human CYP isoforms (CYP1A2, CYP2C9,
  • test compound concentration of 0.1, 0.3, 1, 3, 10, 30 ⁇ mol/L or positive compound or blank control and mixed human liver microsomes (0.2mg/mL) in a reaction system of 200 ⁇ L (100mmol/L phosphate buffer, pH 7.4, containing 0.3% by volume respectively) DMSO, 0.6% acetonitrile, 0.1% methanol) were incubated at 37°C for 5 minutes.
  • Peak area ratio metabolite peak area/internal standard peak area
  • Residual activity ratio (%) peak area ratio of the test compound group / peak area ratio of the blank group
  • CYP median inhibitory concentration (IC 50 ) was calculated by Excel XLfit 5.3.1.3.
  • thermodynamic solubility of compounds in phosphate buffer pH 7.4 was determined. Both sample supernatants and standards of known concentration were detected by LC/MS/MS.
  • Compound A is Example A94 of WO 2019207463A, synthesized with reference to the method disclosed in this patent application.
  • NaH 2 PO 4 ⁇ 2H 2 O analytical grade
  • NaH 2 PO 4 analytical grade
  • NaOH analytical grade
  • the pipette tip was washed with acetonitrile for 5 seconds and then with pure water for 5 seconds. Then the first 50 ⁇ L of waste liquid was drained, and the remaining 700 ⁇ L was added to another 96-well sample plate with a glass tube, and then centrifuged for 30 minutes (25°C, 4000, rpm), and 10 ⁇ L of the second centrifuged sample was added to 990 ⁇ L of In the mixture of the target acetonitrile and water (1:1) (100 times the sample), pipette 10 ⁇ L of the diluted solution and add it to 990 ⁇ L of the mixture of acetonitrile and water (1:1) containing the internal standard (10,000 times the sample). Sample dilutions may vary based on solubility values and LC/MS signal responses.
  • Test compounds were measured by in vitro activation of PXR at different concentrations of test compounds (30, 10, 3.33, 1.11, 0.370 and 0.123 ⁇ M) to obtain EC 50 values.
  • concentrations of positive control rifampicin were 20, 5, 1.25, 0.312, 0.0781 and 0.195 ⁇ M.
  • DPX2 human PXR gene and fluorescent reporter gene and stably transfected into HepG2 cells
  • the entrusting party provided the test compound, and the reference drug (rifampicin) was purchased from Sigma (St. Louis, MO).
  • CellTiter-Fluor TM cell viability detection kit and One-Glo fluorescence detection kit were purchased from Promega (Madison, WI), fetal bovine serum (FBS) was purchased from Corning (Manassas, VA), and MTS3 oscillator was purchased from IKA Labortechnik (Staufen, Germany), DMEM, penicillin and streptomycin were purchased from local suppliers, hygromycin B and G418 were purchased from Merck (Darmstadt, Germany), cell culture medium and DPX2 cells were purchased from Puracyp Inc.
  • FBS fetal bovine serum
  • MTS3 oscillator was purchased from IKA Labortechnik (Staufen, Germany)
  • DMEM penicillin and streptomycin were purchased from local suppliers
  • hygromycin B and G418 were purchased from Merck (Darmstadt, Germany)
  • cell culture medium and DPX2 cells were purchased from Puracyp Inc.
  • DPX2 cells were cultured in a T-75 culture flask in an incubator at 37° C., 5% CO 2 , and 95% relative humidity, and the cells were digested when the cells covered 80-90% of the bottom of the flask.
  • Test compounds and positive compounds were prepared in DMSO, and the compounds were diluted in serum-free medium at 37°C.
  • the final concentrations of the positive control rifampicin were 20, 5, 1.25, 0.312, 0.0781 and 0.195 ⁇ M, and the final concentrations of the test compounds were 30, 10, 3.33, 1.11, 0.370 and 0.123 ⁇ M.
  • the final concentration of DMSO was 0.1%. 1 ⁇ L of DMSO was added to the medium containing 1 mL of preincubation as a solvent control.
  • the culture After 2 days of drug treatment, the culture can be quantitatively detected by PXR activation.
  • I is the fluorescence intensity of the sample
  • I (carrier) is the fluorescence intensity of the cells with 0.1% DMSO.
  • RFU/RLU The activity of luciferase is expressed as RFU/RLU
  • RLU is the average luminescence intensity value of two parallels for each concentration of each compound
  • RFU is the average fluorescence intensity of two parallels for each concentration of each compound.

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Abstract

提供稠三环类细胞周期蛋白-依赖性激酶抑制剂及其制备方法和医药用途。特别地，所述稠三环类细胞周期蛋白-依赖性激酶抑制剂结构如式I所示，其中各取代基定义见说明书。所述稠三环类细胞周期蛋白-依赖性激酶抑制剂用于预防和/或治疗与细胞周期蛋白-依赖性激酶相关疾病，特别是癌症。

Description

稠三环类细胞周期蛋白-依赖性激酶抑制剂及其制备方法和医药用途 技术领域
本公开属于医药领域，涉及一种稠三环类细胞周期蛋白-依赖性激酶抑制剂及其制备方法、组合物和医药用途。
背景技术
细胞周期蛋白-依赖性激酶(CDK)是重要的细胞酶，其在调节真核细胞分裂和增殖中发挥重要作用。细胞周期蛋白-依赖性激酶催化单元被称为细胞周期蛋白的调节亚基激活。已经鉴定出至少16种哺乳动物细胞周期蛋白(Annu.Rev.Pharmacol.Toxicol.(1999)39:295-312)。细胞周期蛋白B/CDK1、细胞周期蛋白A/CDK2、细胞周期蛋白E/CDK2、细胞周期蛋白D/CDK4、细胞周期蛋白D/CDK6和可能的其他heterodynes是细胞周期进展的重要调节因子。细胞周期蛋白/CDK heterodynes的其他功能包括转录调节、DNA修复、分化和凋亡(Annu.Rev.Cell.Dev.Biol.(1997)13:261-291)。
近年来，乳腺癌治疗领域最大的进展无疑是CDK4/6单用或联合内分泌治疗在激素受体阳性晚期乳腺癌，如帕博西尼(palbociclib)、瑞博西尼(ribociclib)和玻玛西尼(abemaciclib)已被批准与芳香酶抑制剂组合用于治疗绝经后妇女的激素受体(HR)-阳性、人类表皮生长因子受体2(HER2)-阴性晚期或转移性乳腺癌，并且帕博西尼和玻玛西尼(abemaciclib)已被批准与氟维司群组合用于在内分泌疗法后疾病进展后治疗绝经后妇女的激素受体(HR)-阳性、人类表皮生长因子受体2(HER2)-阴性晚期或转移性乳腺癌(Nature Reviews(2016)13:417-430、J Clin Oncol 2017,35,2875-2884)。尽管CDK4/6抑制剂在雌激素受体ER阳性转移性乳腺癌中显示出显著的临床功效，但与其他激酶一样，它们的作用可能随着时间的推移被原发性或获得性抗性的发展限制。
用CDK4/6抑制剂治疗已在临床中被证明会导致不良反应，例如胃肠道和/或血液学毒性，并且随着时间的流逝可能会产生获得性耐药。新兴数据表明，细胞周期蛋白D3-CDK6可能与所观察到的血液学毒性有关。(Malumbres等人，Mammalian Cells Cycle without the D-Type Cyclin-Dependent Kinases Cdk4 and Cdk6，(2004)Cell 118(4)：493-504；Sicinska等人,Essential Role for Cyclin D3 in Granulocyte Colony-Stimulating Factor-Driven Expansion of Neutrophil Granulocytes(2006)，Mol.Cell Biol 26(21)：8052-8060；Cooper等人,A unique function for cyclin D3 in early B cell development，(2006)，Nat.Immunol.5(7)：489-497)。CDK4已被确定为许多乳腺癌中的单一致癌驱动因子。因此，由于与双重CDK4/6抑制剂相比潜在的更高和/或连续的剂量，CDK4选择性抑制剂可提供改善的安全性或增强的总体功效，故开发CDK4选择性高的分子，在临床 上有实际应用价值。WO2019207463A公开了一类细胞周期蛋白-依赖性激酶抑制剂。
发明内容
本公开提供一种式I所示的化合物或其药学上可接受的盐，
Figure PCTCN2022074509-appb-000001
其中，R 1选自H、C 1-6烷基、C 1-6卤代烷基和C 3-8环烷基，所述C 1-6烷基、C 1-6卤代烷基和C 3-8环烷基各自独立地任选被一个或多个R a取代；
R 2为式II的结构：
Figure PCTCN2022074509-appb-000002
R 9选自H、OH和NH 2，所述NH 2任选被1或2个R a’或R a”取代；
R 10各自独立地选自OH、卤素、CN、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 3-8环烷基和3-12元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基各自独立地任选被一个或多个R b取代；
Q为NR 11或O；
或者Q为CR 12R 13，其中R 12、R 13与其连接的碳原子形成3-12元的含有NR 11中的N或O作为环原子的杂环烷基，所述杂环烷基任选被一个或多个R 10取代；
R 11选自H、C 1-6烷基、C 1-6卤代烷基、SO 2R c、SO 2NR dR e、COR f、COOR f和CONR gR h，所述的C 1-6烷基和C 1-6卤代烷基各自独立地任选被选自R a、R b、SO 2R c、SO 2NR dR e、COR f、COOR f和CONR gR h的一个或多个取代基取代；
m为0、1或2；
n为0、1、2、3或4；
p为1、2或3；
X为N或CH；
Y为N或CR 7，R 7选自H，F、Cl、CN、C 1-6烷基和C 1-6烷氧基，所述C 1-6烷基和C 1-6烷氧基各自独立地任选被一个或多个R a取代；
R 3选自H、F、Cl、CN、CH 2F、CHF 2和CF 3；
R 4选自H、C 1-6烷基、C 1-6烷氧基、C3-8环烷基和3-12元杂环烷基，所述的 C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和3-12元杂环烷基各自独立地任选被一个或多个R b或氘取代；
Z为O或CHR 8，R 8选自氢原子、氘原子和卤素；
L为-(CH 2) q-，所述-(CH 2)-任选被选自氘、CN、卤素、C 1-6烷基、C 3-8环烷基、C 1-6烷氧基和3-12元杂环烷基的一个或多个取代基取代，所述C 1-6烷基、C 3-8环烷基、C 1-6烷氧基和3-12元杂环烷基各自独立地任选被一个或多个R b或氘取代；
q为1、2、3或4；
R 5和R 6各自独立选自H、氘、CN、卤素、C 1-6烷基、C 3-8环烷基、C 1-6烷氧基和3-12元杂环烷基，所述C 1-6烷基、C 3-8环烷基、C 1-6烷氧基和3-12元杂环烷基任选各自独立地被一个或多个R b或氘取代；
R a和R b各自独立地选自H、OH、CN、卤素(氟、氯、溴、碘)、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 3-8环烷基、3-12元杂环烷基和NR a’R a”取代，所述C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基各自独立地任选被选自NH 2、NHCH 3、N(CH 3) 2、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基的一个或多个取代基取代；
R a’和R a”各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基，所述C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基各自独立地任选被选自NH 2、NHCH 3、N(CH 3) 2、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 3-8环烷基和3-12元杂环烷基的一个或多个取代基取代；
或者R a’、R a”与它们连接的N原子一起形成3-12元杂环烷基，所述3-12元杂环烷基任选被选自卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 3-8环烷基和3-12元杂环烷基的一个或多个取代基取代；
R c、R d和R e各自独立地选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和C 1-6卤代烷基；
R f选自H、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基，所述C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基各自独立地任选被选自NH 2、NHCH 3、N(CH 3) 2、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基的一或多个取代基取代；
R g和R h各自独立地选自H、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 3-8环烷基，所述C 1-6烷氧基、C 1-6卤代烷基和C 3-8环烷基各自独立地任选被一个或者多个R a或R b取代。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中R 1为H或C 1-6烷基。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐， 其中R 1为H。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中，R 2选自
Figure PCTCN2022074509-appb-000003
其中，R 9、R 10、m和Q如式I所示的化合物中定义。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中，R 2为
Figure PCTCN2022074509-appb-000004
其中，R 9、R 10、m和Q如式I所示的化合物中定义。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中，R 2为
Figure PCTCN2022074509-appb-000005
其中R 9、R 10、R 11和m如式I所示的化合物中定义。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中，R 9为OH或NH 2，所述NH 2任选被1或2个R a’或R a”取代，R a’和R a”各自独立地为C 1-6烷基。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中，R 9为OH。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中，R 9为NH 2。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中X为N。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中Y为CR 7；R 7选自H，F、Cl和C 1-6烷基。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中R 3选自H、F和Cl。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中R 4选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和3-12元杂环烷基；所述的 C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和3-12元杂环烷基各自独立地任选被一个或多个R b或氘取代，R b选自H、OH、CN、卤素(氟、氯、溴、碘)、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 3-8环烷基。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中R 4为C 1-6烷基，所述的C 1-6烷基任选被一个或多个R b或氘取代，R b选自OH、CN、卤素(氟、氯、溴、碘)、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 3-8环烷基。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中R 4为C 1-6烷基，所述的C 1-6烷基任选被一个或多个R b或氘取代，R b选自OH、CN和卤素(氟、氯、溴、碘)。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中L为-(CH 2) q-，q选自1或2；所述-(CH 2)-任选被选自氘、CN、卤素、C 1-6烷基、C 3-8环烷基、C 1-6烷氧基和3-12元杂环烷基的一或多个取代基取代。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，L为-(CH 2) q-，q选自1；所述-(CH 2)-任选被选自氘、CN、卤素、C 1-6烷基、C 3-8环烷基、C 1-6烷氧基和3-12元杂环烷基的一或多个取代基取代。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中L为-(CH 2) qa-，q选自1；所述-(CH 2)-任选被一个或多个氘的取代基取代。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，其中R 5和R 6各自独立选自H、氘、CN、卤素、C 1-6烷基和C 3-8环烷基。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐为式I-2所示的化合物或其药学上可接受的盐，
Figure PCTCN2022074509-appb-000006
其中R 9为OH或NH 2，所述NH 2任选被1或2个R a’或R a”取代，R a’和R a”各自独立地为C 1-6烷基；
R 10各自独立地选自H、OH、卤素、CN、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；
m为0、1或2；
R 11选自SO 2R c、SO 2NR dR e、COR f、COOR f和CONR gR h；
R c、R d和R e各自独立地选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和C 1-6卤代烷基；
R f选自H、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基；
R g、R h各自独立地选自H、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 3-8环烷基；
R 7选自H，F、Cl和C 1-6烷基；
R 3选自H、F和Cl；
R 4选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和3-12元杂环烷基；所述的C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和3-12元杂环烷基各自独立地任选被一个或多个R b或氘取代，R b选自H、OH、CN和卤素(氟、氯、溴、碘)；
R 5和R 6各自独立选自H、氘、CN、卤素、C 1-6烷基和C 3-8环烷基；
Z为O或CHR 8，R 8选自氢原子、氘原子和卤素。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐为式I-2所示的化合物或其药学上可接受的盐2，其中Z为O。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐，为式I-2所示的化合物或其药学上可接受的盐，其中Z为CHR 8，R 8选自氢原子、氘原子和卤素。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐为式I-2所示的化合物或其药学上可接受的盐，
其中R 9为OH或NH 2，所述NH 2任选被1或2个R a’或R a”取代，R a’和R a”各自独立地为C 1-6烷基；
m为0；
R 11为SO 2R c；
R c选自H、C 1-6烷基和C 1-6卤代烷基；
R 7选自H，F、Cl和C 1-6烷基；
R 3选自H、F和Cl；
R 4选自H、C 1-6烷基和C 1-6烷氧基；所述的C 1-6烷基和C 1-6烷氧基各自独立地任选被一个或多个R b或氘取代；R b选自H、OH、CN和卤素(氟、氯、溴、碘)；
R 5和R 6各自独立选自H、氘、CN、卤素和C 1-6烷基。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐为式I-2所示的化合物或其药学上可接受的盐，
其中R 9为OH；
m为0；
R 11为SO 2R c；
R c为C 1-6烷基或C 1-6卤代烷基；
R 7为F或Cl；
R 3为F或Cl；
R 4为H或C 1-6烷基，所述的C 1-6烷基任选被一个或多个R b或氘取代，R b选自H、OH、CN和卤素(氟、氯、溴、碘)；
R 5和R 6各自独立为H或C 1-6烷基。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐为式I-2所示的化合物或其药学上可接受的盐，
其中R 9为OH；
m为0；
R 11为SO 2R c；
R c选自甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基；
R 7为F或Cl；
R 3为F或Cl；
R 4为H或C 1-6烷基，所述的C 1-6烷基任选被一个或多个R b或氘取代，R b为H或OH；
R 5和R 6各自独立选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐为式I-2所示的化合物或其药学上可接受的盐，
其中R 9为OH；
m为0；
R 11为SO 2R c；
R c选自甲基、乙基和正丙基；
R 7为F或Cl；
R 3为F或Cl；
R 4选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基，所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基各自独立地任选被一个或多个R b取代，R b为H或OH；
R 5和R 6各自独立选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐为式I-2所示的化合物或其药学上可接受的盐，
其中R 9为OH；
m为0；
R 11为SO 2R c；
R c为甲基；
R 7为F或Cl；
R 3为F或Cl；
R 4选自H、甲基、乙基、正丙基和异丙基；
R 5和R 6各自独立选自H、甲基、乙基、正丙基和异丙基。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐为式I-3所示的化合物或其药学上可接受的盐，
Figure PCTCN2022074509-appb-000007
其中R 9为OH或NH 2，所述NH 2任选被1或2个R a’或R a”取代，R a’和R a”各自独立地为C 1-6烷基；
R 10各自独立地选自OH、卤素、CN、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；
m为0、1或2；
R 7选自H、F、Cl和C 1-6烷基；
R 3选自H、F和Cl；
R 4选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和3-12元杂环烷基，所述的C 1-6烷基、C 1-6烷氧基、C3-8环烷基和3-12元杂环烷基各自独立地任选被一个或多个R b或氘取代；R b选自H、OH、CN和卤素(氟、氯、溴、碘)；
R 5和R 6各自独立选自H、氘、CN、卤素、C 1-6烷基和C 3-8环烷基；
Z为O或CHR 8，R 8选自氢原子、氘原子和卤素。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐为式I-3所示的化合物或其药学上可接受的盐，其中，Z为O。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐为式I-3所示的化合物或其药学上可接受的盐，其中，Z为CHR 8，R 8为氢原子、氘原子或卤素。
可选的实施方案中，本公开提供的本公开提供的式I所示的化合物或其药学上可接受的盐为式I-3所示的化合物或其药学上可接受的盐，
其中R 9为OH或NH 2，所述NH 2任选被1或2个R a’或R a”取代，R a’和R a”各自独立地为C 1-6烷基；
m为0；
R 7选自H，F、Cl和C 1-6烷基；
R 3选自H、F和Cl；
R 4选自H、C 1-6烷基和C 1-6烷氧基；所述的C 1-6烷基和C 1-6烷氧基各自独立地任选被一个或多个R b或氘取代，R b选自H、OH、CN和卤素(氟、氯、溴、碘)；
R 5和R 6各自独立选自H、氘、CN、卤素和C 1-6烷基。
可选的实施方案中，本公开提供的本公开提供的式I所示的化合物或其药学上可接受的盐为式I-3所示的化合物或其药学上可接受的盐，
其中R 9为OH；
m为0；
R 7为F或Cl；
R 3为F或Cl；
R 4为H或C 1-6烷基，所述的C 1-6烷基任选被一个或多个R b或氘取代，R b选自H、OH、CN和卤素(氟、氯、溴、碘)；
R 5和R 6各自独立为H或C 1-6烷基。
可选的实施方案中，本公开提供的本公开提供的式I所示的化合物或其药学上可接受的盐为式I-3所示的化合物或其药学上可接受的盐，
其中R 9为OH；
m为0；
R 7为F或Cl；
R 3为F或Cl；
R 4为H或C 1-6烷基，所述的C 1-6烷基任选被一个或多个R b或氘取代，R b为H或OH；
R 5和R 6各自独立选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。
可选的实施方案中，本公开提供的本公开提供的式I所示的化合物或其药学上可接受的盐为式I-3所示的化合物或其药学上可接受的盐，
其中R 9为OH；
m为0；
R 7为F或Cl；
R 3为F胡Cl；
R 4选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基，所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基各自独立地任选被一个或多个R b取代；R b为H或OH；
R 5和R 6各自独立选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。
可选的实施方案中，本公开提供的本公开提供的式I所示的化合物或其药学 上可接受的盐为式I-3所示的化合物或其药学上可接受的盐，
其中R 9为OH；
m为0；
R 7为F或Cl；
R 3为F或Cl；
R 4选自H、甲基、乙基、正丙基和异丙基；
R 5和R 6各自独立选自H、甲基、乙基、正丙基和异丙基。
可选的实施方案中，本公开提供的式I所示的化合物或其药学上可接受的盐选自
Figure PCTCN2022074509-appb-000008
Figure PCTCN2022074509-appb-000009
Figure PCTCN2022074509-appb-000010
本公开另一方面提供一种前述式I、I-2、I-3所示的化合物或其药学上可接受的盐的同位素取代物，在可选的实施方案中，所述的同位素取代物为氘原子取代物。
可选的实施方案中，式I所示的化合物或其药学上可接受的盐，所述氘原子的丰度大于20％。
可选的实施方案中，式I所示的化合物或其药学上可接受的盐，所述氘原子的丰度大于50％。
可选的实施方案中，式I所示的化合物或其药学上可接受的盐，所述氘原子的丰度大于90％。
可选的实施方案中，式I所示的化合物或其药学上可接受的盐，所述氘原子的丰度大于95％。
本公开还提供制备式I所示化合物的方法，包括式I-B所示化合物与式I-C所示化合物反应以形成式I化合物的步骤，
Figure PCTCN2022074509-appb-000011
其中，LG 1为离去基团，所述离去基团优选卤素、磺酸酯、硼酸和硼酸酯；
X、Y、Z、L、R 1、R 2、R 3、R 4、R 5和R 6如式I所示化合物中定义。
在一些实施方案中，所述反应在催化剂存在下进行，所述催化剂为金属钯或金属镍。
在一些实施方案中，所述催化剂选自钯/碳、雷尼镍、四-三苯基膦钯、二氯化钯、醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1’-[1,1'-双(二叔丁基膦基)二茂铁]二氯化钯、三(二亚苄基丙酮)二钯和2-双环己基膦-2',6'-二甲氧基联苯，优选[1,1'-双(二苯基膦基)二茂铁]二氯化钯和2-双环己基膦-2',6'-二甲氧基联苯。
本公开另一方面提供一种式I-B所示化合物或其药学上可接受的盐，
Figure PCTCN2022074509-appb-000012
其中，LG 1为离去基团，所述离去基团选自卤素、磺酸酯、硼酸和硼酸酯；X、Y、Z、L、R 3、R 4、R 5、R 6如式I所示化合物中定义。
本公开中还提供了一种药物组合物，包括至少一种治疗有效量的前述式I、I-2、I-3所示化合物或其药学上可接受的盐或前述同位素取代物以及药学上可接受的赋形剂。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述式I、I-2、I-3所示化合物或其药学上可接受的盐或前述同位素取代物。
在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述式I、I-2、I-3所示化合物或其药学上可接受的盐或前述同位素取代物。。
在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述式I、I-2、I-3所示化合物或其药学上可接受的盐或前述同位素取代物。
在某些实施方案中，所述的药物组合物含有1％-99％的前述式I、I-2、I-3所示化合物或其药学上可接受的盐或前述同位素取代物。
在某些实施方案中，所述的药物组合物含有2％-98％的前述式I、I-2、I-3所示化合物或其药学上可接受的盐或前述同位素取代物。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。
在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。
在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。
在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。
在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。
本公开还提供一种预防和/或治疗与细胞周期蛋白-依赖性激酶相关疾病的方法，其包括向需要其的患者施用治疗有效量的前述式I、I-2、I-3所示化合物或其药学上可接受的盐或前述同位素取代物、或前述药物组合物。
本公开还提供一种预防和/或治疗癌症的方法，其包括向需要其的患者施用治疗有效量的前述式I、I-2、I-3所示化合物或其药学上可接受的盐或前述同位素取代物、或前述药物组合物。
本公开还提供了前述式I、I-2、I-3所示化合物或其药学上可接受的盐或前述同位素取代物、或前述药物组合物在制备用于预防和/或治疗与细胞周期蛋白-依赖性激酶相关疾病的药物中的用途。
本公开还提供了前述式I、I-2、I-3所示化合物或其药学上可接受的盐或前述同位素取代物、或前述药物组合物在制备用于预防和/或治疗与癌症的药物中的用途。
可选的实施方案中，所述与细胞周期蛋白-依赖性激酶相关疾病选自细胞增殖性疾病、癌症和免疫性疾病。
本公开中所述癌症选自乳腺癌、卵巢癌、膀胱癌、子宫癌、前列腺癌、肺癌(包括NSCLC、SCLC、鳞状细胞癌或腺癌)、食道癌、头颈癌、肠癌、肾癌(包括RCC)、肝癌(包括HCC)、胰腺癌、胃癌和甲状腺癌。
可选的实施方案中，本公开中所述的细胞周期蛋白-依赖性激酶为CDK4。
本公开另一方面提供一种前述式I、I-2、I-3所示化合物或其药学上可接受的盐
或前述同位素取代物用作药物的用途。
本公开提供的前述式I、I-2、I-3所示化合物或其药学上可接受的盐或前述同位素取代物，或前述药物组合物，降低了胃肠道和/或血液学毒性。
另一方面，本公开中所述化合物可药用盐为无机盐或有机盐。
本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物， 均包括在本公开的范围之内。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本公开某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本公开所述化合物的化学结构中，键
Figure PCTCN2022074509-appb-000013
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022074509-appb-000014
可以为
Figure PCTCN2022074509-appb-000015
或者同时包含
Figure PCTCN2022074509-appb-000016
两种构型。键
Figure PCTCN2022074509-appb-000017
表示未指定构型，包括顺式(E)或反式(Z)构型。
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
Figure PCTCN2022074509-appb-000018
本公开中的所有化合物可以被画成A型或B型。所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至 少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
术语解释：
“药学上可接受的赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基，及其各种支链异构体等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-12元杂环基等。
“烯基”包括具有2至12个碳原子的支链和直链烯烃或含有脂族烃基团的烯烃。例如“C 2-6烯基”表示具有2、3、4、5或6个碳原子的烯基。烯基的实例包括但不限于，乙烯基、烯丙基、1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基丁-2-烯基、3-甲基丁-1-烯基、1-戊烯基、3-戊烯基及4-己烯基。烯基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-12元杂环基等。
“炔基”包括具有2至12个碳原子的支链和直链炔基或含有脂族烃基的烯烃，或若规定指定碳原子数，则意指该特定数目。例如乙炔基、丙炔基(例如1-丙炔基、2-丙炔基)、3-丁炔基、戊炔基、己炔基及1-甲基戊-2-炔基。炔基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-12元杂环基等。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环 己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-12元杂环基等。
术语“杂环基”同样被表述为杂环烷基，指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。“杂环基”非限制性实例包括：
Figure PCTCN2022074509-appb-000019
Figure PCTCN2022074509-appb-000020
等等。
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2022074509-appb-000021
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧 基、C 3-7环烷基、3-12元杂环基等。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2022074509-appb-000022
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-12元杂环基等，优选苯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为6至12元，更优选为5元或6元。例如。其非限制性实例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪，
Figure PCTCN2022074509-appb-000023
等等。
所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2022074509-appb-000024
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-12元杂环基等。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、硝基、 氰基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-12元杂环基等。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代”指＝O取代基。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上药学上可接受的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。
本公开实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Shimadzu 2010 Mass Spectrometer或Agilent 6110A MSD质谱仪。
HPLC的测定使用Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200 LC高压液相色谱仪(Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.,3um、Chiralpak AD-3 150×4.6mm I.D.,3um、Chiralpak AD-3 50×4.6mm I.D.,3um、Chiralpak AS-3  150×4.6mm I.D.,3um、Chiralpak AS-3 100×4.6mm I.D.,3μm、ChiralCel OD-3 150×4.6mm I.D.,3um、Chiralcel OD-3 100×4.6mm I.D.,3μm、ChiralCel OJ-H 150×4.6mm I.D.,5um、Chiralcel OJ-3 150×4.6mm I.D.,3um色谱柱；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10μm)或Phenomenex-Amylose-1(250mm*30mm,5μm)。
CombiFlash快速制备仪使用Combiflash Rf150(TELEDYNE ISCO)。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，
反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
(3S,4R)-4-((5-氟-4-(8-氟-2,3-二甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-6-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇异构体1
(3S,4R)-4-((5-氟-4-(-8-氟-2,3-二甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-6-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇异构体2
Figure PCTCN2022074509-appb-000025
第一步
6-溴-4-氟-2,3-二硝基苯酚1b
将化合物1a(3.5g，14.8mmol)溶于16mL二氯甲烷中。加入硝酸的二氯甲烷溶液(2mol/L，16mL)。在室温下反应20分钟。将反应液倒入50mL冰水中，分离有机相，水相用二氯甲烷萃取(50mL×2)，合并有机相，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩得到标题化合物1b(3.8g，产率：91％)。
MS(ESI)m/z 279.0,281.0[M-H] -
第二步
2-氨基-6-溴-4-氟-3-硝基苯酚1c
将化合物1b(3.8g，13.5mmol)溶于60mL甲醇中。加入25mL浓盐酸，分批加入氯化亚锡二水合物(9.2g，40.6mmol)。在室温下反应20分钟。将反应液浓缩，加入100mL饱和碳酸氢钠溶液,用乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩，残余物用硅胶柱色谱法以石油醚、乙酸乙酯洗脱纯化，得到标题化合物1c(2.0g，产率：59％)。
MS(ESI)m/z 249.1,251.1[M-H] -
第三步
8-溴-6-氟-3-甲基-5-硝基-3,4-二氢-2H-苯并[b][1,4]噁嗪1d
将化合物1c(200mg，0.8mmol)溶于4mL丙酮中并降温至0℃。在0℃下加入碳酸钾(121mg，0.9mmol)和溴丙酮(120mg，0.9mmol)，在室温下反应2小时。加入20mL水，用乙酸乙酯萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩，残余物溶于5mL四氢呋喃中。加入0.5mL三氟乙酸，分批加入氰基硼氢化钠(75mg，1.2mmol)。在室温下反应2小时。将反应液倒入20mL饱和碳酸氢钠溶液中，用乙酸乙酯萃取(20mL×3)，合并有机相，无水硫酸 钠干燥，过滤，收集滤液，滤液减压浓缩，残余物用硅胶柱色谱法以石油醚、乙酸乙酯洗脱纯化，得到标题化合物1d(160mg，产率：69％)。
MS(ESI)m/z 291.2,293.2[M+H] +
第四步
8-溴-6-氟-3-甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪-5-胺1e
将化合物1d(160mg，0.5mmol)溶于4mL甲醇中。加入2mL浓盐酸，分批加入氯化亚锡二水合物(496mg，2.2mmol)。在室温下反应2小时。将反应液倒入20mL饱和碳酸氢钠溶液中，用乙酸乙酯萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩，残余物用硅胶柱色谱法以石油醚、乙酸乙酯洗脱纯化，得到标题化合物1e(105mg，产率：73％)。
MS(ESI)m/z 261.3,263.3[M+H] +
第五步
6-溴-8-氟-2,3-二甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯1f
将化合物1e(105mg，0.4mmol)溶于2mL浓盐酸中。加入0.5mL乙酸，在120℃下反应2小时。将反应液浓缩，加入30mL饱和碳酸氢钠溶液，用乙酸乙酯萃取(30mL×3)，合并有机相，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩，残余物用C-18反相色谱法纯化得到标题化合物1f(17mg，产率：15％)。
MS(ESI)m/z 241.3,243.3[M+H] +
第六步
6-(2-氯-5-氟嘧啶-4-基)-8-氟-2,3-二甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯1g
氮气氛下，依次将化合物1f(40mg，0.14mmol)、联硼酸频那醇酯(57mg，0.22mmol)、醋酸钾(29mg,0.29mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(21mg,0.03mmol)溶于2mL 1,4-二氧六环中。100℃条件下反应1小时。反应液冷却至室温，加入1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷酰金刚烷(8mg，0.03mmol)、碳酸钾(41mg，0.29mmol)、2,4-二氯-5-氟嘧啶(35mg,0.21mmol)、三(二亚苄基丙酮)二钯(26mg,0.03mmol)和0.5mL水，80℃条件下反应1小时。反应液冷却至室温，过滤，收集滤液，减压浓缩后残余物用C-18反相色谱法纯化得到标题化合物1g(18mg，产率：38％)。
MS(ESI)m/z 337.2[M+H] +
第七步
(3S,4R)-4-((5-氟-4-(8-氟-2,3-二甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-6-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇异构体1
(3S,4R)-4-((5-氟-4-(-8-氟-2,3-二甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-6-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇异构体2
氮气氛下，依次将化合物1g(18mg，0.05mmol)、(3S,4R)-4-氨基四氢-2H-吡喃-3-醇(7.5mg，0.06mmol)、(S)-(-)-2,2”-双(二苯膦基)-1,1”-联萘(6.2mg，0.01mmol)、 醋酸钯(2.2mg，0.01mmol)溶于2mL四氢呋喃中。加入碳酸铯(41mg，0.13mmol)，80℃条件下反应1小时。
反应液冷却至室温，过滤，收集滤液，减压浓缩后残余物用C-18反相色谱法纯化得到粗品混合物，粗品通过手性拆分(柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm),条件:45％EtOH(0.1％NH 3·H 2O)在CO 2中；流速:80mL/min)得到异构体1(3.8mg，产率：17％)和异构体2(4.4mg，产率：20％)。
分析方法
柱：DAICEL CHIRALPAK AD-3(150mm*4.6mm,3μm)；
条件：CO 2条件下，40％EtOH(0.05％DEA)；
流速：2.5mL/min；
ABPR：1500psi；
温度:35℃。
将保留时间为2.903min的化合物定义为异构体1；MS(ESI)m/z 418.3[M+H] +
将保留时间为3.997min的化合物定义为异构体2；MS(ESI)m/z 418.3[M+H] +
实施例2
(3R,4R)-4-((5-氯-4-(8-氟-2,3-二甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-6-基)嘧啶-2-基)氨基)-1-(甲磺酰)哌啶-3-醇异构体1
(3R,4R)-4-((5-氯-4-(8-氟-2,3-二甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-6-基)嘧啶-2-基)氨基)-1-(甲磺酰)哌啶-3-醇异构体2
Figure PCTCN2022074509-appb-000026
第一步
6-(2,5-二氯嘧啶-4-基)-8-氟-2,3-二甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯2a
氮气氛下，依次将化合物1f(50mg，0.18mmol)、联硼酸频那醇酯(67mg，0.26mmol)、醋酸钾(37mg,0.38mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(26 mg,0.04mmol)溶于2mL 1,4-二氧六环中。100℃条件下反应1小时。反应液冷却至室温，加入1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷酰金刚烷(10mg，0.04mmol)、碳酸钾(51mg，0.37mmol)、2,4-二氯-5-氟嘧啶(52mg,0.28mmol)、三(二亚苄基丙酮)二钯(32mg,0.04mmol)和0.5mL水，80℃条件下反应1小时。反应液冷却至室温，过滤，收集滤液，减压浓缩后残余物用C-18反相色谱法纯化得到标题化合物2a(30mg，产率：48％)。
MS(ESI)m/z 353.1[M+H] +
第二步
(3R,4R)-4-((5-氯-4-(8-氟-2,3-二甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-6-基)嘧啶-2-基)氨基)-1-(甲磺酰)哌啶-3-醇异构体1
(3R,4R)-4-((5-氯-4-(8-氟-2,3-二甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-6-基)嘧啶-2-基)氨基)-1-(甲磺酰)哌啶-3-醇异构体2
氮气氛下，依次将化合物2a(30mg，0.08mmol)、(3R,4R)-4-氨基-1-(甲磺酰)哌啶-3-醇(19.4mg，0.10mmol，采用专利申请“WO 2019/207463 A1”公开的方法制备而得)、(S)-(-)-2,2”-双(二苯膦基)-1,1”-联萘(10mg，0.02mmol)、醋酸钯(4.4mg，0.02mmol)溶于2mL四氢呋喃中。加入碳酸铯(52mg，0.16mmol)，80℃条件下反应1小时。反应液冷却至室温，过滤，收集滤液，减压浓缩后残余物用C-18反相色谱法纯化得到粗品混合物，粗品通过手性拆分(柱:DAICEL CHIRALCEL OD-H(250mm*30mm,5μm),50％EtOH(0.1％NH 3·H 2O)在CO 2中；流速:80mL/min)得到异构体1(4.4mg，产率：10％)和异构体2(3.3mg，产率：8％)。
分析方法
柱：DAICEL CHIRALPAK AD-3(50mm*4.6mm,3μm)；
流动相：A:CO 2B:异丙醇(0.05％DEA),梯度:2min内5％至40％的B，维持40％的B 1.2min，然后5％的B 0.8min；
流速:4mL/min；
ABPR:1500psi；
温度:35℃。
将保留时间为2.094min的化合物定义为异构体1；
MS(ESI)m/z 511.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ＝8.38(s,1H),7.48(br s,1H),6.91(br d,J＝11.0Hz,1H),5.21(br s,1H),4.86(br d,J＝6.5Hz,1H),4.52-4.44(m,1H),4.24(br d,J＝10.8Hz,1H),3.77(br s,1H),3.64-3.55(m,2H),3.48(br d,J＝13.6Hz,1H),2.89(s,3H),2.69-2.63(m,1H),2.60(s,3H),1.39(d,J＝6.8Hz,3H),1.24(br s,2H),1.18-1.04(m,1H)。
将保留时间为2.499min的化合物定义为异构体2；
MS(ESI)m/z 511.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ＝8.38(s,1H),7.47(br s,1H),6.91(br d,J＝11.5 Hz,1H),5.21(br d,J＝4.0Hz,1H),4.86(br d,J＝6.5Hz,1H),4.48(dd,J＝1.8,11.5Hz,1H),4.36(t,J＝5.0Hz,2H),4.24(br d,J＝9.5Hz,1H),3.76(br s,1H),3.59(br d,J＝8.0Hz,2H),2.89(s,3H),2.67(br d,J＝9.3Hz,1H),2.60(s,3H),1.58-1.46(m,1H),1.39(d,J＝6.8Hz,3H),1.24(br s,1H)。
实施例3
(3S,4R)-4-((5-氯-4-((S)-8-氟-2,3-二甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-6-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇异构体1
(3S,4R)-4-((5-氯-4-((R)-8-氟-2,3-二甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-6-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇异构体2
Figure PCTCN2022074509-appb-000027
氮气氛下，依次将化合物2a(55mg，0.16mmol)、(3S,4R)-4-氨基四氢-2H-吡喃-3-醇(18mg，0.16mmol)、(S)-(-)-2,2”-双(二苯膦基)-1,1”-联萘(20mg，0.03mmol)、醋酸钯(6.7mg，0.03mmol)溶于3mL四氢呋喃中。加入碳酸铯(104mg，0.32mmol)，85℃条件下反应3小时。反应液冷却至室温，过滤，收集滤液，减压浓缩后残余物用C-18反相色谱法纯化得到粗品混合物。粗品通过手性拆分[柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm),条件:0.1％NH 3 .H 2O IPA,以B:45％开始；以B:45％结束；流速(ml/min):70)]得到异构体1(6.2mg，产率：9.2％)和异构体2(7.7mg，产率：11％)。
分析方法
柱：DAICEL CHIRALCEL OD-3(100mm*4.6mm,3μm)；
流动相：A:CO 2B:乙醇(0.05％DEA),梯度:4min内5％至40％的B，维持40％的B 2.5min，然后5％的B 1.5min；
流速:2.8mL/min；
ABPR:1500psi；
温度:35℃。
将保留时间为3.518min的化合物定义为异构体1；
MS(ESI)m/z 434.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ＝8.37(s,1H),7.45(br s,1H),6.90(d,J＝11.5Hz,1H),4.93(d,J＝5.3Hz,1H),4.86(br d,J＝6.8Hz,1H),4.48(dd,J＝1.6,11.7Hz,1H),4.24(br d,J＝9.3Hz,1H),3.84-3.74(m,3H),3.53-3.40(m,2H),3.03(br t,J＝10.2Hz,1H),2.60(s,3H),2.01-1.90(m,1H),1.54-1.44(m,1H),1.38(d,J＝6.5Hz,3H)。
将保留时间为4.165min的化合物定义为异构体2；
MS(ESI)m/z 434.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ＝8.37(s,1H),7.46(br s,1H),6.91(br d,J＝11.5Hz,1H),4.93(d,J＝5.3Hz,1H),4.86(br d,J＝6.5Hz,1H),4.47(br d,J＝10.5Hz,1H),4.23(br d,J＝9.8Hz,1H),3.86-3.74(m,3H),3.54-3.44(m,1H),3.32-3.27(m,1H),3.03(br t,J＝10.3Hz,1H),2.60(s,3H),1.95(br d,J＝13.1Hz,1H),1.54-1.43(m,1H),1.38(d,J＝6.5Hz,3H)。
实施例4
(3S,4R)-4-((5-氯-4-((S)-8-氟-2-(2-羟基丙烷-2-基)-3-甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-6-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇异构体1
(3S,4R)-4-((5-氯-4-((R)-8-氟-2-(2-羟基丙烷-2-基)-3-甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-6-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇异构体2
Figure PCTCN2022074509-appb-000028
第一步
6-溴-8-氟-3-甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-2-甲醛4a
氮气氛下，依次将化合物1f(2.0g，7mmol)、二氧化硒(3.1g，28mmol)加入到30mL 1,4-二氧六环中。95℃条件下反应8小时。反应液冷却至室温，过滤，收集滤液，减压浓缩后残余物用C-18反相色谱法纯化得到标题化合物4a(930mg，产率：44％)。
MS(ESI)m/z 299.1,301.1[M+H] +
第二步
1-(6-溴-8-氟-3-甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-2-基)乙烷-1-醇4b
氮气氛下，将化合物4a(930mg，3.1mmol)溶于20mL四氢呋喃中。降温至-20℃，滴加甲基溴化镁四氢呋喃溶液(3mol/L,1.5ml,4.5mmol)，并在-20℃条件下反应4小时。加入5ml水淬灭反应，反应液减压浓缩后残余物用C-18反相色谱法纯化得到标题化合物4b(830mg，产率：85％)。
MS(ESI)m/z 315.2,317.2[M+H] +
第三步
1-(6-溴-8-氟-3-甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-2-基)乙烷-1-酮4c
室温下，将化合物4b(600mg，1.9mmol)溶于20mL四氢呋喃中，加入戴斯马丁氧化剂(2.0g，4.8mmol)。加热至80℃并反应2小时，反应液冷却至室温，过滤，收集滤液，减压浓缩后残余物用C-18反相色谱法纯化得到标题化合物4c(350mg，产率：59％)。
MS(ESI)m/z 313.1,315.1[M+H] +
第四步
2-(6-溴-8-氟-3-甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-2-基)丙烷-2-醇4d
氮气氛下，将化合物4c(350mg，1.1mmol)溶于20mL四氢呋喃中。降温至-20℃，滴加甲基溴化镁四氢呋喃溶液(3mol/L,0.7ml,2.1mmol)，并在-20℃条件下反应4小时。加入5ml水淬灭反应，反应液减压浓缩后残余物用C-18反相色谱法纯化得到标题化合物4d(260mg，产率：71％)。
MS(ESI)m/z 329.2,331.2[M+H] +
第五步
2-(6-(2,5-二氯嘧啶-4-基)-8-氟-3-甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-2-基)丙烷-2-醇4e
氮气氛下，依次将化合物4d(260mg，0.8mmol)、联硼酸频那醇酯(305mg，1.2mmol)、醋酸钾(157mg,1.6mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(117mg,0.2mmol)溶于5mL 1,4-二氧六环中。100℃条件下反应2小时。反应液冷却至室温，加入1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷酰金刚烷(58mg，0.2mmol)、碳酸钾(221mg，1.6mmol)、2,4-二氯-5-氟嘧啶(220mg,1.2mmol)、三(二亚苄基丙酮)二钯(183mg，0.2mmol)和1mL水，80℃条件下反应1小时。反应液冷却至室温，过滤，收集滤液，减压浓缩后残余物用C-18反相色谱法纯化得到标题化合 物4e(129mg，产率：41％)。
MS(ESI)m/z 397.3[M+H] +
第六步
(3S,4R)-4-((5-氯-4-((S)-8-氟-2-(2-羟基丙烷-2-基)-3-甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-6-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇异构体1
(3S,4R)-4-((5-氯-4-((R)-8-氟-2-(2-羟基丙烷-2-基)-3-甲基-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-6-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇异构体2
氮气氛下，依次将化合物4e(124mg，0.31mmol)、(3S,4R)-4-氨基四氢-2H-吡喃-3-醇(19mg，0.16mmol)、(S)-(-)-2,2”-双(二苯膦基)-1,1”-联萘(118mg，0.5mmol)、醋酸钯(14mg，0.06mmol)溶于5mL四氢呋喃中。加入碳酸铯(202mg，0.62mmol)，85℃条件下反应3小时。反应液冷却至室温，过滤，收集滤液，减压浓缩后残余物用C-18反相色谱法纯化得到粗品混合物4f，粗品通过手性拆分[柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm),条件:0.1％NH 3 .H 2O ETOH,Begin B:40％；End B:40％；流速(ml/min):60)]得到标题化合物异构体1(25.2mg，产率：17％)和标题化合物异构体2(22mg，产率：15％)。
分析方法
柱：DAICEL CHIRALCEL AD-3(100mm*4.6mm,3μm)；
流动相：A:CO 2B:乙醇(0.05％DEA),梯度:2min内5％至40％的B，维持40％的B 1.2min，然后5％的B 0.8min；
流速:4mL/min；
ABPR:1500psi；
温度:35℃。
将保留时间为1.887min的化合物定义为异构体2；
MS(ESI)m/z 478.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ＝8.37(s,1H),7.45(br s,1H),6.92(d,J＝11.3Hz,1H),5.82(br s,1H),5.23(q,J＝6.4Hz,1H),4.93(d,J＝5.3Hz,1H),4.47(d,J＝11.0Hz,1H),4.22(br d,J＝11.3Hz,1H),3.89-3.67(m,3H),3.39-3.25(m,2H),3.03(br t,J＝10.2Hz,1H),1.95(br d,J＝10.5Hz,1H),1.68(s,3H),1.62(s,3H),1.54-1.47(m,1H),1.45(d,J＝6.5Hz,3H)。
将保留时间为2.078min的化合物定义为异构体1；
MS(ESI)m/z 478.1[M+H] +
1H NMR(400MHz,DMSO-d6)δ＝8.37(s,1H),7.45(br s,1H),6.92(d,J＝11.5Hz,1H),5.82(s,1H),5.29-5.19(m,1H),4.93(d,J＝5.5Hz,1H),4.47(d,J＝11.3Hz,1H),4.21(br d,J＝10.3Hz,1H),3.85-3.75(m,3H),3.53-3.40(m,2H),3.03(br t,J＝10.4Hz,1H),1.94(br s,1H),1.67(s,3H),1.62(s,3H),1.53-1.47(m,1H),1.45(d,J＝6.5Hz,3H)。
生物学评价
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
测试例1、公开化合物对细胞周期蛋白-依赖性激酶活性检测
1、实验材料
Figure PCTCN2022074509-appb-000029
化合物A为WO 2019/207463A1的实施例A94，参照该专利申请公开的方法合成得到。
2、激酶活性测试(CDK4/细胞周期蛋白D1,CDK6/细胞周期蛋白D3)
体外CDK激酶活性通过流动性转变分析(Mobility Shift Assay)的方法进行测试。实验中，受试化合物对CDK活性抑制的测试的起始浓度为300nM，3倍稀释，共10个浓度，复孔测试。采用化合物星孢菌素作为标准对照。
配制1倍激酶缓冲液(CDK2)(50mM HEPES，pH 7.5,0.0015％Brij-35)，1倍激酶缓冲液(CDK4)(20mM HEPES,pH 7.5,0.01％Triton X-100)，终止液(100mM HEPES,pH 7.5,0.015％Brij-35,0.2％Coating Reagent#3,50mM EDTA)。将适量激酶加入1倍激酶缓冲液中配制2.5倍酶溶液；配制化合物测试浓度相应5倍化合物稀释液(1倍激酶缓冲液，10％DMSO)；将适量FAM标记的多肽和ATP加入1倍激酶缓冲液，配制2.5倍底物溶液。在384孔反应板的反应孔中加入5μl 5倍化合物稀释液及10μl 2.5倍酶溶液，混匀后室温孵育10分钟；然后向384孔板中加 入10μl 2.5倍底物溶液，1000rpm离心1分钟；反应板在28℃下孵育60分钟(生化培养箱型号：SPX-100B-Z)；向384孔反应板中加30μl终止液终止反应，1000rpm离心1分钟；最后在Caliper EZ ReaderⅡ上读取转化率数据(激发波长：400nm，发射波长：445nm和520nm)。
化合物的IC 50值用XLFit excel add-in version 5.4.0.8拟合。拟合公式:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。
X:化合物浓度log值；Y:化合物抑制百分率。
3、激酶活性测试(CDK1/细胞周期蛋白B,CDK9/细胞周期蛋白T1)
体外CDK(CDK2、CDK9)激酶活性测试的起始浓度为1μM，3倍稀释，共10个浓度，复孔测试。采用化合物PHA-793887作为对照化合物。
配制1x激酶反应缓冲液(40mM Tris-HCl,pH7.4,20mM Mg2Cl2,0.1mg/ml BSA,50μM DTT)，1倍体积的5x激酶反应缓冲液和4倍体积的水，并加入DTT(终浓度50μM)。用Echo655向反应板(784075,Greiner)每孔转移稀释好的化合物工作液50nL(DMSO终浓度为1％)。用封板膜封住反应板，1000g离心1分钟。用1x激酶反应缓冲液配制2x酶(0.3ng/uL CDK2/细胞周期蛋白E1或CDK9/细胞周期蛋白T1)，每孔加入2.5uL上述激酶溶液，用封板莫封住反应板，1000g离心1分钟，室温放置10分钟。用1×激酶反应缓冲液配制2×激酶底物和ATP混合液，2×CDK2/CylinE1激酶底物为0.4mg/ml组蛋白H1和30μM ATP。向反应板中加入2.5μL 2×组蛋白H1和ATP混合液，1000g离心30秒，开始反应。激酶测试室温反应120分钟后，加入4μl ADP-Glo试剂，室温反应40分钟。然后加入8μl激酶检测试剂，室温反应40分钟，用Envision 2104读发光信号。数据分析如下
a)抑制百分率:％抑制＝100-(Signalcmpd-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)×100。
SignalAve_PC:整板所有阳性对照孔的平均值。
SignalAve_VC:整板所有阴性对照孔的平均值。
Signalcmpd:测试化合物对应孔的平均值。
b)化合物IC 50：用GraphPad 8.0，利用以下非线性拟合公式来计算得到。
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:化合物浓度log值；Y:化合物抑制百分率。
本公开化合物的CDK(CDK1、CDK4、CDK6、CDK9)激酶生化抑制活性通过以上的试验进行测定，测得的IC 50值见表1、表2和表3。
表1.
Figure PCTCN2022074509-appb-000030
Figure PCTCN2022074509-appb-000031
表2.
Figure PCTCN2022074509-appb-000032
表3.
Figure PCTCN2022074509-appb-000033
测试例2、CYP抑制实验
使用150个供体混合人肝微粒体(购自Corning,货号452117)评估人主要5个CYP亚型(CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4)的代表性底物代谢反应。通过液相色谱串联质谱(LC/MS/MS)测定不同浓度待测化合物对非那西丁(CYP1A2)、双氯芬酸钠(CYP2C9)、S-美芬妥英(CYP2C19)、丁呋洛尔盐酸盐(CYP2D6)、咪达唑仑(CYP3A4/5)代谢反应的影响。
将30μM非那西丁、10μM双氯芬酸钠、35μM S-美芬妥英、5μM丁呋洛尔盐酸盐、3μM咪达唑仑、1mM NADPH、待测化合物(浓度分别为0.1、0.3、1、3、10、30μmol/L)或阳性化合物或空白对照与混合人肝微粒体(0.2mg/mL)的反应体系200μL(100mmol/L磷酸盐缓冲液，pH 7.4，含体积比分别为0.3％的DMSO、0.6％ 的乙腈、0.1％的甲醇)在37℃孵育5分钟。然后加入200μL含3％甲酸及40nM内标维拉帕米的乙腈溶液，4000rpm离心50分钟。置于冰上冷却20分钟，再4000rpm离心20分钟析出蛋白。取200μL上清液进行LC/MS/MS分析。
峰面积根据色谱图计算。残余活性比例(％)用如下公式进行计算：
峰面积比例＝代谢产物峰面积/内标峰面积
残余活性比例(％)＝待测化合物组的峰面积比例/空白组的峰面积比例
CYP半数抑制浓度(IC 50)通过Excel XLfit 5.3.1.3计算得到。
测得的CYP半数抑制浓度(IC 50)数值见下表4。
表4.本公开化合物对CYP的半数抑制浓度(IC 50)
Figure PCTCN2022074509-appb-000034
测试例3、溶解度测试实验
测定化合物在pH7.4的磷酸盐缓冲液中的热动力学溶解度。样品上清液和已知浓度的标准品都通过LC/MS/MS来检测。
1、材料和试剂
化合物A(化合物A为WO 2019207463A的实施例A94，参照该专利申请公开的方法合成得到)。
NaH 2PO 4·2H 2O(分析纯)，NaH 2PO 4(分析纯)，NaOH(分析纯)。
1.5mL平底玻璃管(BioTech Solutions)；模塑的聚四氟乙烯盖子(BioTech
Solutions)，聚四氟乙烯包被的搅拌棒(BioTech Solutions)，Eppendorf舒适型恒温混匀器及96孔深孔板。
2、pH7.4的0.01M磷酸纳缓冲液的制备
称量15.6g的NaH 2PO 4·2H 2O放入1L玻璃瓶内，加入1L去离子水溶解。溶液PH大概为4.7，然后用10M NaOH调节PH值到7.4。
3、溶解度测定过程
每个化合物准确称量1mg的粉末，放入玻璃管内，上述玻璃管内加入PH7.4的磷酸盐缓冲液，加入量为每毫克加1mL。每个玻璃管加入一个搅拌棒，再盖上 盖子，把装有玻璃管的样品盘放入Eppendorf舒适型恒温混匀器中，25℃，1100rpm孵育24小时，孵育结束后打开盖子，用磁铁吸出搅拌棒，并记录每个玻璃管内的现象，将板子25℃，4000rpm离心30分钟。吸取750μL上清液。枪头用乙腈洗5秒，再用纯水洗5秒。然后排出前50μL废液，剩下700μL加入到另一个装有玻璃管的96孔样品盘中，再离心30分钟(25℃，4000，rpm)，吸取10μL二次离心的样品加入990μL的含内标的乙腈和水(1:1)的混合液中(100倍样品)，吸取10μL稀释溶液加入990μL的含内标的乙腈和水(1:1)的混合液中(10,000倍样品)。样品稀释倍数可能会根据溶解度值和LC/MS信号响应而改变。
表5.现象的记录和稀释倍数
Figure PCTCN2022074509-appb-000035
4、标准品的制备
准确称量1mg化合物粉末，各加入一只玻璃管内，每个玻璃管内加入DMSO，加入量为每毫克加1mL。每个玻璃管加入一个搅拌棒，再盖上盖子，把装有标准品玻璃管的盘放入Eppendorf舒适型恒温混匀器中，25℃，1,100转孵育2小时让粉末充分溶解，观察固体是否完全溶解，记录下化合物在DMSO溶液中不能完全溶解的。吸取10μL 1mg/mL的标准品加入990μL的含内标的乙腈和水(1:1)的混合液中，得到10μg/mL的标准品。吸取10μL 10μg/mL的标准品加入99 0μL的含内标的乙腈和水(1:1)的混合液中，得到0.1μg/mL的标准品。样品稀释倍数可能会根据LC/MS信号响应而改变。样品通过LC/MS/MS进行分析。所有化合物单独进行测试。
5、数据计算
所有计算通过Microsoft Excel进行。
样品通过LC/MS/MS进行分析，根据已知浓度的标准品来定量。通过以下公式计算待测化合物的溶解度：[样品]＝面积比样品×DF样品×[STD]/面积比STD
DF：稀释倍数。
STD：待测化合物标准品。
表6.本公开化合物溶解度
实施例编号 溶解度(μM)
化合物A 16
实施例4中保留时间为1.887min的异构体2 2126
实施例4中保留时间为2.078min的异构体1 2203
测试例4、PXR诱导实验
1、评估待测化合物通过体外激活PXR从而诱导药物代谢酶活力的潜力。待测化合物通过体外激活PXR测量不同浓度的测试化合物(30、10、3.33、1.11、0.370和0.123μM)得到EC 50值。阳性对照利福平的浓度为20、5、1.25、0.312、0.0781和0.195μM。
2、材料和试剂
1)DPX2(人类PXR基因和荧光报告基因与稳定转染到HepG2细胞中)细胞购自Puracyp(Carlsbad,CA)。
2)委托方提供待测化合物，对照药(利福平)购自Sigma(St.Louis,MO)。
3)CellTiter-Fluor TM细胞活力检测试剂盒和One-Glo荧光检测试剂盒购自Promega(Madison,WI)，胎牛血清(FBS)购自Corning(Manassas,VA)，MTS3振荡器购自IKA Labortechnik(Staufen,Germany)，DMEM、青霉素和链霉素购自本地供应商，潮霉素B和G418购自Merck(Darmstadt,Germany)，细胞培养基和DPX2细胞购自Puracyp Inc。
3、实验步骤
3.1种板准备
1)加50mL FBS到450mL细胞培养基中。
2)DPX2细胞用T-75培养瓶在37℃，5％CO 2，95％的相对湿度的孵箱中培养，在细胞长满培养瓶瓶底80-90％时消化细胞。
3)用8mL PBS清洗T-75培养的细胞表层，吸弃PBS，加入3mL胰酶，在37℃消化5分钟左右，或者直到细胞被消化下来悬浮在胰酶中，加入10mL过剩的含血清培养基中和胰酶。
4)将细胞悬液转至锥形底的离心管中，120g离心10分钟。用种板培养基将细胞悬浮并调浓度为4x 10 5细胞/mL。在96孔细胞培养板中每孔加入稀释好的细胞100μL。将培养板放入孵箱，37℃孵育24小时，然后准备PXR激活实验。
3.2加药处理
1)用DMSO准备测试化合物和阳性化合物(利福平)，用37℃的不含有血清的培养基稀释化合物。阳性对照利福平的终浓度是20、5、1.25、0.312、0.0781和0.195μM，待测化合物的最终浓度为30、10、3.33、1.11、0.370和0.123μM。DMSO的终浓度为0.1％。向含有1mL预孵育的培养基中加入1μL的DMSO做 为溶剂对照组。
2)从孵箱中拿出细胞培养板，弃去培养基，在合适的孔加入100μL的待测化合物和阳性化合物，每组两个平行，将细胞板放入孵化器中孵育24小时。
3.3 PXR激活的定量测定
1)药物处理2天后，培养物可以做PXR激活定量检测。
2)将CellTiter-Fluor TM细胞活力检测试剂盒和One-Glo荧光素酶试剂平衡至室温。将GF-AFC(10μL)底物加入检测缓冲液(10mL)形成2X试剂，然后用10ml PBS稀释至1X；将ONE-Glo底物加入ONE-Glo荧光素酶检测缓冲液。
3)从孵箱中取出细胞培养板，弃去每个孔中的培养基，用PBS洗2遍，将1X的CellTiter-Fluor TM试剂加入灭菌的加样槽，用排枪吸取50μL加入每个孔中，37℃孵育30分钟。
4)从孵化器中移出96孔细胞板，用酶标仪在激发波长400nm，发射波长505nm的荧光模式下进行测定每个孔的荧光值。
5)将ONE-Glo试剂倒入加样槽，然后用排枪取50uL加入每孔，轻轻混匀试剂，放置室温下孵育混匀5分钟。孵育完成后使用光度计读取每个孔的发光值。
4、细胞诱导值计算
4.1细胞活力
细胞活率计算公式:
细胞活力百分比(％)＝I(样品)/(I(载体)x 100
I(样品)是样品的荧光强度,I(载体)是指0.1％DMSO对细胞的荧光强度。
4.2细胞诱导值计算
所有的数据都用Microsoft Excel来计算。
荧光素酶的活力用RFU/RLU来体现，RLU是每个化合物每个浓度的两个平行的平均发光强度值，RFU是每个化合物每个浓度的两个平行的平均荧光强度。诱导倍数计算公式：
Figure PCTCN2022074509-appb-000036
表7.部分测得PXR诱导值
Figure PCTCN2022074509-appb-000037
Figure PCTCN2022074509-appb-000038

Claims (22)

  1. 一种式I所示的化合物或其药学上可接受的盐，
    Figure PCTCN2022074509-appb-100001
    其中，R 1选自H、C 1-6烷基、C 1-6卤代烷基和C 3-8环烷基，所述C 1-6烷基、C 1-6卤代烷基和C 3-8环烷基各自独立地任选被一个或多个R a取代；
    R 2为式II的结构：
    Figure PCTCN2022074509-appb-100002
    R 9选自H、OH和NH 2，所述NH 2任选被1或2个R a’或R a”取代；
    R 10各自独立地选自OH、卤素、CN、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 3-8环烷基和3-12元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基各自独立地任选被一个或多个R b取代；
    Q为NR 11或O；
    或者Q为CR 12R 13，其中R 12、R 13与其连接的碳原子形成3-12元的含有NR 11中的N或O作为环原子的杂环烷基，所述杂环烷基任选被一个或多个R 10取代；
    R 11选自H、C 1-6烷基、C 1-6卤代烷基、SO 2R c、SO 2NR dR e、COR f、COOR f和CONR gR h，所述的C 1-6烷基和C 1-6卤代烷基各自独立地任选被选自R a、R b、SO 2R c、SO 2NR dR e、COR f、COOR f和CONR gR h的一个或多个取代基取代；
    m为0、1或2；
    n为0、1、2、3或4；
    p为1、2或3；
    X为N或CH；
    Y为N或CR 7；
    R 7选自H，F、Cl、CN、C 1-6烷基和C 1-6烷氧基，所述C 1-6烷基和C 1-6烷氧基各自独立地任选被一个或多个R a取代；
    R 3选自H、F、Cl、CN、CH 2F、CHF 2和CF 3；
    R 4选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和3-12元杂环烷基，所述的 C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和3-12元杂环烷基各自独立地任选被一个或多个R b或氘取代；
    Z为O或CHR 8，R 8选自氢原子、氘原子和卤素；
    L为-(CH 2) q-，所述-(CH 2)-任选被选自氘、CN、卤素、C 1-6烷基、C 3-8环烷基、C 1-6烷氧基和3-12元杂环烷基的一个或多个取代基取代，所述C 1-6烷基、C 3-8环烷基、C 1-6烷氧基和3-12元杂环烷基各自独立地任选被一个或多个R b或氘取代；
    q为1、2、3或4；
    R 5和R 6各自独立选自H、氘、CN、卤素、C 1-6烷基、C 3-8环烷基、C 1-6烷氧基和3-12元杂环烷基，所述C 1-6烷基、C 3-8环烷基、C 1-6烷氧基和3-12元杂环烷基各自独立地任选被一个或多个R b或氘取代；
    R a和R b各自独立地选自H、OH、CN、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 3-8环烷基、3-12元杂环烷基和NR a’R a”，所述C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基各自独立地任选被选自NH 2、NHCH 3、N(CH 3) 2、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基的一个或多个取代基取代；
    R a’和R a”各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基，所述C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基各自独立地任选被选自NH 2、NHCH 3、N(CH 3) 2、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 3-8环烷基和3-12元杂环烷基的一个或多个取代基取代；
    或者R a’、R a”与它们连接的N原子一起形成3-12元杂环烷基，所述3-12元杂环烷基任选被选自卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 3-8环烷基和3-12元杂环烷基的一个或多个取代基取代；
    R c、R d和R e各自独立地选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和C 1-6卤代烷基；
    R f选自H、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基，所述C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基各自独立地任选被选自NH 2、NHCH 3、N(CH 3) 2、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-8环烷基和3-12元杂环烷基的一或多个取代基取代；
    R g和R h各自独立地选自H、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 3-8环烷基，所述C 1-6烷氧基、C 1-6卤代烷基和C 3-8环烷基各自独立地任选被一个或者多个R a或R b取代。
  2. 根据权利要求1所述的式I所示的化合物或其药学上可接受的盐，其中R 1为H或C 1-6烷基，优选为H。
  3. 根据权利要求1所述的式I所示的化合物或其药学上可接受的盐，其中，R 2选自
    Figure PCTCN2022074509-appb-100003
    Figure PCTCN2022074509-appb-100004
    优选
    Figure PCTCN2022074509-appb-100005
    R 9、R 10、m和Q如权利要求1中所定义。
  4. 根据权利要求3所述的式I所示的化合物或其药学上可接受的盐，其中，R 2为
    Figure PCTCN2022074509-appb-100006
    R 9、R 10、m和R 11如权利要求1中所定义。
  5. 根据权利要求3或4所述的式I所示的化合物或其药学上可接受的盐，其中，R 9为OH或NH 2，所述NH 2任选被1或2个R a’或R a”取代，R a’和R a”各自独立地为C 1-6烷基。
  6. 根据权利要求1所述的式I所示的化合物或其药学上可接受的盐，其中X为N。
  7. 根据权利要求1所述的式I所示的化合物或其药学上可接受的盐，其中Y为CR 7；R 7选自H、F、Cl和C 1-6烷基，优选F或Cl。
  8. 根据权利要求1所述的式I所示的化合物或其药学上可接受的盐，其中R 3选自H、F和Cl，优选F或Cl。
  9. 根据权利要求1所述的式I所示的化合物或其药学上可接受的盐，其中R 4选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和3-12元杂环烷基，所述的C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和3-12元杂环烷基各自独立地任选被一个或多个R b或氘取代，R b选自OH、CN、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 3-8环烷基；优选地，R 4为C 1-6烷基，所述的C 1-6烷基任选被一个或多 个R b或氘取代，R b为OH或卤素。
  10. 根据权利要求1所述的式I所示的化合物或其药学上可接受的盐，其中L为-(CH 2) q-，q选自1或2；所述-(CH 2)-任选被选自氘、CN、卤素、C 1-6烷基、C 3-8环烷基、C 1-6烷氧基和3-12元杂环烷基的一个或多个取代基取代；
    优选的，q选自1；所述-(CH 2)-任选被选自H、氘、CN、卤素、C 1-6烷基、C 3-8环烷基、C 1-6烷氧基和3-12元杂环烷基的一个或多个取代基取代；
    最优选，q选自1；所述-(CH 2)-任选被一个或多个氘取代。
  11. 根据权利要求1所述的式I所示的化合物或其药学上可接受的盐，其中R 5和R 6各自独立选自H、氘、CN、卤素、C 1-6烷基和C 3-8环烷基。
  12. 根据权利要求1-11中任一项所述的式I所示的化合物或其药学上可接受的盐，其为式I-3所示的化合物或其药学上可接受的盐，
    Figure PCTCN2022074509-appb-100007
    其中R 9为OH或NH 2，所述NH 2任选被1或2个R a’或R a”取代，R a’和R a”各自独立地为C 1-6烷基；
    R 10各自独立地选自OH、卤素、CN、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；
    m为0、1或2；
    R 7选自H、F、Cl和C 1-6烷基；
    R 3选自H、F和Cl；
    R 4选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和3-12元杂环烷基，所述的C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和3-12元杂环烷基各自独立地任选被一个或多个R b或氘取代；R b选自H、OH、CN和卤素；
    R 5和R 6各自独立选自H、氘、CN、卤素、C 1-6烷基和C 3-8环烷基；
    Z为O或CHR 8，R 8选自氢原子、氘原子和卤素。
  13. 根据权利要求12所述的式I所示的化合物或其药学上可接受的盐，其中Z为O。
  14. 根据权利要求12所述的式I所示的化合物或其药学上可接受的盐，其中，Z为CHR 8，R 8选自氢原子、氘原子和卤素。
  15. 根据权利要求13或14所述的式I所示的化合物或其药学上可接受的盐，
    其中R 9为OH或NH 2，所述NH 2任选被1或2个R a’或R a”取代，R a’和R a”各自独立地为C 1-6烷基；
    m为0；
    R 7选自H、F、Cl和C 1-6烷基；
    R 3选自H、F和Cl；
    R 4选自H、C 1-6烷基和C 1-6烷氧基，所述的C 1-6烷基和C 1-6烷氧基各自独立地任选被一个或多个R b或氘取代，R b选自H、OH、CN和卤素；
    R 5和R 6各自独立选自H、氘、CN、卤素和C 1-6烷基；
    优选的，
    其中R 9为OH；
    m为0；
    R 7为F或Cl；
    R 3为F或Cl；
    R 4为H或C 1-6烷基，所述的C 1-6烷基任选被一个或多个R b或氘取代，R b选自OH、CN和卤素；
    R 5和R 6各自独立为H或C 1-6烷基；
    更优选的，
    其中R 9为OH；
    m为0；
    R 7为F或Cl；
    R 3为F或Cl；
    R 4为H或C 1-6烷基，所述的C 1-6烷基任选被一个或多个R b或氘取代，R b为OH；
    R 5和R 6各自独立选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基；
    甚至优选的，
    其中R 9为OH；
    m为0；
    R 7为F或Cl；
    R 3为F或Cl；
    R 4选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基，所述 的甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基各自独立地任选被一个或多个R b取代；R b为OH；
    R 5和R 6各自独立选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基；
    特别优选的，
    其中R 9为OH；
    m为0；
    R 7为F或Cl；
    R 3为F或Cl；
    R 4选自H、甲基、乙基、正丙基和异丙基；
    R 5和R 6各自独立选自H、甲基、乙基、正丙基和异丙基。
  16. 根据权利要求1-15中任一项所述的式I所示的化合物或其药学上可接受的盐，其选自
    Figure PCTCN2022074509-appb-100008
    Figure PCTCN2022074509-appb-100009
    Figure PCTCN2022074509-appb-100010
  17. 一种根据权利要求1-16中任一项所述的式I所示的化合物或其药学上可接受的盐的同位素取代物，优选地，所述的同位素取代物为氘原子取代物。
  18. 一种制备根据权利要求1-16中任一项所述的式I所示的化合物或其药学上可接受的盐的方法，包括式I-B所示的化合物与式I-C所示的化合物反应以形成式I所示的化合物的步骤，
    Figure PCTCN2022074509-appb-100011
    其中，LG 1为离去基团，所述离去基团选自卤素、磺酸酯、硼酸和硼酸酯；X、Y、Z、L、R 1、R 2、R 3、R 4、R 5和R 6如权利要求1中定义。
  19. 一种药物组合物，其包含根据权利要求1-16中任一项所述的式I所示的化合物或其药学上可接受的盐、或根据权利要求17所述的同位素取代物，以及药学上可接受的赋形剂。
  20. 根据权利要求1-16中任一项所述的式I所示的化合物或其药学上可接受的盐、或根据权利要求17所述的同位素取代物、或根据权利要求19所述的药物组合物在制备用于预防和/或治疗与细胞周期蛋白-依赖性激酶相关疾病的药物中的用途。
  21. 根据权利要求1-16任一项所述的式I所示的化合物或其药学上可接受的盐、或根据权利要求17所述的同位素取代物、或根据权利要求19所述的药物组合物在制备用于预防和/或治疗癌症的药物中的用途，所述癌症选自乳腺癌、卵巢癌、膀胱癌、子宫癌、前列腺癌、肺癌、食道癌、头颈癌、肠癌、肾癌、肝癌、胰腺癌、胃癌和甲状腺癌。
  22. 一种式I-B所示的化合物或其药学上可接受的盐，
    Figure PCTCN2022074509-appb-100012
    其中，LG 1为离去基团，所述离去基团选自卤素、磺酸酯、硼酸和硼酸酯；X、Y、Z、L、R 3、R 4、R 5和R 6如权利要求1中定义。
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