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WO2023109540A1 - Heterocyclic compound with akt kinase inhibitory activity, preparation method therefor and medical use thereof - Google Patents

Heterocyclic compound with akt kinase inhibitory activity, preparation method therefor and medical use thereof Download PDF

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Publication number
WO2023109540A1
WO2023109540A1 PCT/CN2022/136451 CN2022136451W WO2023109540A1 WO 2023109540 A1 WO2023109540 A1 WO 2023109540A1 CN 2022136451 W CN2022136451 W CN 2022136451W WO 2023109540 A1 WO2023109540 A1 WO 2023109540A1
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Prior art keywords
cycloalkyl
alkyl
alkenyl
membered
aryl
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PCT/CN2022/136451
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French (fr)
Chinese (zh)
Inventor
闫旭
陈振华
刘国标
蔡绪灿
尚飞
杜佩金
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中国医药研究开发中心有限公司
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Priority to CN202280050761.0A priority Critical patent/CN117677614A/en
Publication of WO2023109540A1 publication Critical patent/WO2023109540A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the technical field of medicine, and relates to a pyrimidine heterocyclic compound, a preparation method thereof, a pharmaceutical composition containing the same, and its use as an AKT kinase inhibitor for treating abnormal cell growth such as cancer.
  • AKT also known as protein kinase B (PKB)
  • PKA protein kinase B
  • AKT is an important member of the PI3K/Akt/mTOR signaling pathway. It affects biological processes such as development, glucose homeostasis, tumor growth and metastasis by regulating many downstream effector molecules. Over-activation of PI3K/AKT pathway exists in more than 50% of tumors, such as breast cancer, prostate cancer, pancreatic cancer, etc. Given AKT's role as a key signaling hub for tumor survival, efforts have been made for many years to develop drugs that target the AKT kinase.
  • AKT is divided into three subtypes, AKT1, AKT2, and AKT3.
  • AKT1 and AKT2 are distributed throughout the body, while AKT3 is mainly expressed in some organs such as the brain, breast, heart, and kidney (Masure et al., Eur J Biochem, 1999:265(1), 353-360; Yang et al., J Biol Chem, 2003:278(34), 32124-32131).
  • the three subtypes all belong to the AGC kinase family, and the homology of the kinase domain reaches more than 85% (Hanks et al., Faseb J, 1995:9(8), 576-596).
  • AKT ATP-binding kinase domain
  • CAT ATP-binding kinase domain
  • carboxy-terminal domain Kumar et al., Oncogene, 2005: 24(50) comprising a hydrophobic motif (HM) , 7493-7501).
  • HM hydrophobic motif
  • RTKs or G protein-coupled receptors activate PI3K, and then phosphorylate PIP2 to transform into PIP3; PIP3 binds to the PH domain, activates AKT through PDK1-mediated phosphorylation, and causes AKT to undergo a conformational change ( PH-out conformation) and translocates to the plasma membrane.
  • the PH-out conformation exposes the CAT and regulatory domains, leading to two major sites: the threonine residue of the CAT domain (Thr308 of AKT1, Thr309 of AKT2 and Thr305 of AKT3) and the serine residue of the HM domain (Chu et al.
  • PIK3CA amplification/mutation (Shimoi et al., Cancer Sci, 2018:109(8), 2558-2566), loss of PTEN (Milella et al., Front Oncol, 2015:5(24)), mutation of AKT itself (eg E17K mutation of the PH domain) (Kalinsky et al., JAMA Oncol, 2021: 7(2), 271-278), as well as hyperactivation of other RTKs lead to persistent activation of AKT signaling.
  • AKT AKT deactivation protein kinase kinase
  • PTEN PTEN
  • PP2A PHLPP
  • SHIP Shiongo et al., Cancers, 2019:11(8); Villalobos-Ayala et al., Cancers, 2020:12(12); Grzechnik et al. , Biochem Soc Trans, 2016:44(6), 1675-1682.
  • AKT kinase has been discovered more than 30 years ago, and no drug has been successfully marketed yet. Although a variety of PI3K inhibitors upstream of AKT have been approved for the treatment of tumors, both pan-PI3K inhibitors and selective PI3K subtype inhibitors have serious toxicity problems; and negative effects after inhibiting downstream mTOR The feedback mechanism will lead to the re-upregulation of pAKT levels, which in turn activates other downstream oncogenic effectors. Therefore, the development of ideal molecules that directly target AKT is expected to avoid the serious side effects caused by the inhibition of upstream PI3K, and also avoid the negative feedback mechanism caused by the inhibition of downstream mTOR.
  • the drugs can be divided into three categories: PH domain inhibitors, allosteric inhibitors and ATP competitive inhibitors.
  • the allosteric inhibitor MK-2206 is the first AKT inhibitor to enter clinical trials, and the early clinical results show good AKT signaling inhibition effect and good tolerance (Yap et al., J Clin Oncol, 2011:29(35) ,4688-4695), but due to serious side effects, it has been removed from the R&D company's pipeline.
  • ATP competitive inhibitors such as capIIIAasertib (AZD5363) and ipatasertib (GDC0068)
  • Phase III clinical trials have been conducted in HR+ and triple-negative breast cancer.
  • a recent phase III result of ipatasertib demonstrated that the combination of ipatasertib with abiraterone and prednisolone significantly improved radiographic progression-free survival in patients with PTEN-null, metastatic and castration-resistant prostate compared to placebo plus abiraterone Cancer (Sweeney et al., Lancet, 2021:398(10295), 131-142).
  • other AKT inhibitors such as afuresertib, uprosertib, and HZB0071 are also in clinical development.
  • AKT inhibitors still faces many challenges: low bioavailability, narrow therapeutic window, side effects in addition to diarrhea, rash, and hyperglycemia, because targeted inhibition of the PI3K/AKT pathway can disrupt glucose uptake in certain tissues and metabolism, leading to hyperglycemia (Fruman et al., Cell, 2017:170(4), 605-635).
  • inhibition of hepatic AKT may cause liver injury, inflammation and carcinogenesis in mice, and promote lung metastasis (Wang et al., Cancer Cell, 2016:29(4), 523-535).
  • Future research directions need to improve kinase selectivity and tolerance, and at the same time explore reasonable drug combinations to overcome the problem of PI3K/AKT inhibitor resistance.
  • the inventors designed and synthesized a series of pyrimidine compounds, which exhibit AKT1/2/3 kinase inhibitory activity, and can be developed as drugs for treating and/or preventing diseases related to AKT activity, such as cancer.
  • the object of the present invention is to provide a compound represented by general formula (I) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • Ring A is selected from C 3 -C 12 cycloalkyl, 3 to 14 membered heterocyclic group, C 6 -C 14 aryl and 6 to 14 membered heteroaryl; wherein said C 3 -C 12 cycloalkyl, 5 to 14-membered heteroaryl, C 6 -C 14 aryl, and 6 to 14-membered heteroaryl are each independently optionally substituted by one or more R 1 ;
  • L is a bond or -CH 2 -;
  • Ring B is selected from 5 to 8 membered saturated heterocyclic groups containing 1-2 nitrogen atoms; the heterocyclic group is optionally substituted by one or more R 3 ;
  • G is selected from hydrogen, phenyl, 5-6 membered heteroaryl, wherein the phenyl, 5-6 membered heteroaryl is optionally substituted by one or more R 4 ;
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl, heteroaryl, said alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano radical, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more groups are substituted; or,
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl, heteroaryl, said alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano , hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple groups substituted; or,
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl, heteroaryl, said alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano radical, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more groups are substituted; or,
  • Each R is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, -S(O) p R a , -NR a R b , -OR a , -C(O)R a , -C(O)NR a R b , -S(O) p NR a R b , cycloalkyl, heterocyclyl, aryl, heteroaryl, the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl , alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl
  • R a and R b are each independently selected from hydrogen, halogen, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy One or more groups of radical, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,
  • R a and R b and their connected nitrogen atoms together form a nitrogen-containing heterocyclic group, and the nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, Ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more groups;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1 or 2.
  • Each R 1 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (II) or their stereoisomers, tautomers, mesomers, Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • n 0, 1, 2, 3 or 4;
  • Each R 1 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • Ring B, L, G, R 2 and n are as defined in general formula (I).
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its stereoisomers, tautomers, mesomers, racemates isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein any two R 1 form C 3 -C 6 cycloalkyl or 3 together with the atoms they are connected to to 6-membered heterocyclic group, the C 3 -C 6 cycloalkyl or 3 to 6-membered heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, Ester group, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 - Substitution by one or more groups of C 6 al
  • Ring A is optionally substituted by one or more R 1 ; each R 1 is independently selected from the group consisting of hydrogen, halogen, amino, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; preferably R 1 is selected from hydrogen and amino, more preferably R 1 is hydrogen.
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its stereoisomers, tautomers, mesomers, racemates isomers, enantiomers, diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond.
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is represented by general formula (III-1), general formula (III-2) or general formula (III-3)
  • X 1 and X 2 are each independently selected from -CH 2 -, -O-, -NH-;
  • n 1 is 0 or 1
  • n2 is 0, 1 or 2;
  • Each R c is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;
  • q is 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • Ring B, G, R 2 and n are as defined in general formula (I).
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (IV-1) or (IV-2) or stereoisomers, interconversions thereof Isomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • Ring E 1 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group
  • Ring E 2 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group
  • Each R e is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;
  • t is 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • Ring B, G, R 2 and n are as defined in general formula (I).
  • the single wave line represents the position connected to the carbonyl, and the double wave line represents the position connected to the pyrimidine;
  • Ring B is optionally substituted by one or more R3 ;
  • Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • R3 is hydrogen
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (IIIA), general formula (IIIB) or general formula (IIIC) or a stereoisomer thereof isomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • X 1 and X 2 are each independently selected from -CH 2 -, -O-, -NH-;
  • n 1 is 0 or 1
  • n2 is 0, 1 or 2;
  • Each R c is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;
  • q is 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;
  • G, R 2 and n are as defined in general formula (I).
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (IVA) or (IVB) or stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • Ring E 1 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group
  • Ring E 2 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group
  • Each R e is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;
  • t is 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;
  • G, R 2 and n are as defined in general formula (I).
  • Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ;
  • R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,
  • R a and R b the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group
  • the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo
  • halogen amino, nitro, cyano, oxo
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (IIID), general formula (IIIE) or general formula (IIIF) or a stereoisomer thereof isomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • X 1 and X 2 are each independently selected from -CH 2 -, -O-, -NH-;
  • n 1 is 0 or 1
  • n2 is 0, 1 or 2;
  • Each R c is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;
  • q is 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;
  • Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ;
  • R is selected from halogen;
  • R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,
  • R a and R b the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replacement;
  • s 0, 1 or 2;
  • R 2 and n are as defined in general formula (I).
  • the compound represented by the general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, Enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (IVC) or (IVD) or their stereoisomers, tautomers isomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Ring E 1 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group
  • Ring E 2 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group
  • Each R e is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;
  • t is 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;
  • Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ;
  • R is selected from halogen;
  • R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,
  • R a and R b the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replacement;
  • s 0, 1 or 2;
  • R 2 and n are as defined in general formula (I).
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (V) or stereoisomers, tautomers, and mesomers thereof , racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Ring A is a 3 to 6 membered monocyclic heterocyclic group
  • Each R d is independently selected from hydrogen, halogen, amino, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl , C 1 -C 6 haloalkoxy; preferably hydrogen and amino;
  • t 0, 1 or 2;
  • Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;
  • Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ;
  • R is selected from halogen;
  • R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,
  • R a and R b the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replacement;
  • s 0, 1 or 2;
  • R 2 and n are as defined in general formula (I).
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (VI) or stereoisomers, tautomers, and mesomers thereof , racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Ring A is a 3 to 6 membered monocyclic heterocyclic group
  • R d is selected from hydrogen, halogen, amino, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; preferably hydrogen;
  • Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;
  • Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ;
  • R is selected from halogen;
  • R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,
  • R a and R b the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replacement;
  • s 0, 1 or 2;
  • R 2 and n are as defined in general formula (I).
  • the general formula ((IIIA), general formula (IIIB), general formula (C), general formula (D), general formula (E), general formula (F) according to the present invention
  • general formula (D), general formula (E), general formula (F), general formula (VIC), general formula (VID), general formula (V) according to the present invention
  • the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers , or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 haloalkyl, C 1 -C One or more groups of 6 haloalkyl, C 1
  • n 0, 1, 2, preferably 1 or 2, more preferably 2.
  • the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from hydroxyl and C 1 -C 6 alkyl.
  • the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 2, and each R 2 is independently selected from hydroxyl and C 1 -C 6 alkyl.
  • Typical compounds of the invention include, but are not limited to, the following compounds:
  • the present invention further provides a compound represented by general formula (IIIA) or general formula (IIIB) or general formula (IIIC) or its stereoisomer, tautomer, mesomer, racemate,
  • the compound of the formula IIIAa and the compound of the formula IIIAc obtain the compound of the formula IIIAb in the presence of a catalyst under alkaline conditions; compound;
  • the compound of formula IIIAa and the compound of formula IIIBc obtain the compound of formula IIIBb in the presence of catalyst coupling reaction under basic conditions; compound;
  • the compound of formula IIIAa and the compound of formula IIICc obtain the compound of formula IIICb in the presence of catalyst coupling reaction under basic conditions; compound;
  • the catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the alkaline condition is preferably N,N-diisopropylethylamine
  • the acidic condition is preferably hydrochloric acid
  • R x is an amino protecting group, preferably Boc
  • G, R 2 , R 3 , X 1 , X 2 , R c , n, n 1 , n 2 , q, r are as defined in general formula (IIIA), (IIIB) or (IIIC).
  • the present invention further relates to a compound represented by general formula (IIID) or general formula (IIIE) or general formula (IIIF) or its stereoisomer, tautomer, mesomer, racemate,
  • the compound of formula IIIAa and the compound of formula IIIDc obtain the compound of formula IIIDb in the presence of catalyst coupling reaction under basic conditions; compound;
  • the compound of the formula IIIAa and the compound of the formula IIIEc obtain the compound of the formula IIIEb in the presence of a catalyst under alkaline conditions in the coupling reaction; the compound of the formula IIIEb removes the protecting group under acidic conditions and obtains compound;
  • the compound of the formula IIIAa and the compound of the formula IIIFc obtain the compound of the formula IIIFb in the presence of a catalyst under alkaline conditions in the coupling reaction; the compound of the formula IIIFb removes the protecting group under acidic conditions and obtains compound;
  • the catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the alkaline condition is preferably N,N-diisopropylethylamine
  • the acidic condition is preferably hydrochloric acid
  • R x is an amino protecting group, preferably Boc
  • the present invention further relates to a compound represented by general formula (IVA) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer , or a mixture thereof, or a preparation method of a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the compound of the formula IIIAa and the compound of the formula IVAc obtain the compound of the formula IVAb in the presence of the catalyst in the presence of a catalyst under alkaline conditions; the compound of the formula IVAb removes the protecting group under acidic conditions to obtain compound;
  • the catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the alkaline condition is preferably N,N-diisopropylethylamine
  • the acidic condition is preferably hydrochloric acid
  • R x is an amino protecting group, preferably Boc
  • Ring E 1 , G, R 2 , R 3 , Re , n, r, t are as defined in general formula (IVA).
  • the present invention further relates to a compound represented by general formula (IVB) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a preparation method of a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the compound of formula IIIAa and the compound of formula IVBc obtain the compound of formula IVBb in the presence of catalyst coupling reaction under basic conditions; compound;
  • the catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the alkaline condition is preferably N,N-diisopropylethylamine
  • the acidic condition is preferably hydrochloric acid
  • R x is an amino protecting group, preferably Boc
  • Rings E 2 , G, R 2 , R 3 , R e , n, r, and t are as defined in general formula (IVB).
  • the present invention further relates to a compound represented by general formula (IVC) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a preparation method of a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the compound of formula IIIAa and the compound of formula IVCc obtain the compound of formula IVCb in the presence of catalyst coupling reaction under basic conditions; compound;
  • the catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the alkaline condition is preferably N,N-diisopropylethylamine
  • the acidic condition is preferably hydrochloric acid
  • R x is an amino protecting group, preferably Boc
  • Rings E 1 , R 2 , R 3 , R 4 , Re , n, r, s, t are as defined in general formula (IVC).
  • the present invention further relates to a compound represented by general formula (IVD) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a preparation method of a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the compound of the formula IIIAa and the compound of the formula IVDc obtain the compound of the formula IVDb in the presence of a catalyst under alkaline conditions; the compound of the formula IVDb removes the protecting group under acidic conditions to obtain compound;
  • the catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the alkaline condition is preferably N,N-diisopropylethylamine
  • the acidic condition is preferably hydrochloric acid
  • R x is an amino protecting group, preferably Boc
  • Rings E 2 , R 2 , R 3 , R 4 , Re , n, r, s, t are as defined in general formula (IVD).
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation of a medicament for inhibiting AKT1/2/3.
  • the present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, in the preparation of a medicament for preventing and/or treating a disease associated with AKT1/2/3 kinase activity, said disease being preferably cancer, particularly associated with A cancer characterized by amplification or overexpression of AKT1/2/3, preferably ovarian cancer, breast cancer, prostate cancer, glioma, glioblastoma, gastric cancer, fallopian tube cancer, lung cancer, peritoneal tumor, Melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer, skin cancer, neuroblastoma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck cancer, Multiple myelo
  • the present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used as an AKT1/2/3 inhibitor.
  • the present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, for use in a medicament for the treatment and/or prevention of diseases associated with AKT1/2/3 kinase activity, preferably Cancer, in particular cancer characterized by amplification or overexpression of AKT1/2/3, preferably ovarian cancer, breast cancer, prostate cancer, glioma, glioblastoma, gastric cancer, fallopian tube cancer, Lung cancer, peritoneal tumor, melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer, skin cancer, neuroblastoma, sarcoma, bone cancer, uterine cancer, endometrium Carcinoma, head and neck tumor
  • the present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used as a medicine, especially a medicine for preventing and/or treating diseases related to AKT1/2/3 kinase activity, and treating and/or preventing diseases associated with Use in medicine of a disease associated with AKT1/2/3 kinase activity, preferably cancer, in particular cancer characterized by amplification or overexpression of AKT1/2/3, preferably ovarian cancer, breast cancer Carcinoma, prostate cancer, glioma, glioma, gastric cancer, fallopian tube cancer, lung cancer, peritoneal cancer, melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer , skin cancer, neuroblastom
  • the present invention also relates to a method for inhibiting AKT1/2/3, which comprises administering an effective amount of the compound according to the present invention or its stereoisomer, tautomer, endo rotamers, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them.
  • the present invention also relates to a method for inhibiting cancer cell proliferation, inhibiting cancer cell invasion or inducing cancer cell apoptosis, which comprises administering an effective amount of the compound according to the present invention or its stereoisomer to a subject in need , tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present invention also relates to a method for preventing and/or treating diseases associated with AKT1/2/3 kinase activity, which comprises administering to a subject in need thereof an effective amount of a compound according to the present invention or a stereoisomer thereof isomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it,
  • the disease is preferably cancer, especially a cancer characterized by amplification or overexpression of AKT1/2/3, the cancer is preferably ovarian cancer, breast cancer, prostate cancer, glioma, glioma, gastric cancer , fallopian tube cancer, lung cancer, peritoneal tumor, melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer, skin cancer, neuroblastoma, sarcoma, bone cancer, uterine
  • Compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or A pharmaceutically acceptable salt or a pharmaceutical composition comprising the same may be administered simultaneously, separately or sequentially with another anticancer therapeutic agent or method of anticancer treatment.
  • Alkyl means a saturated aliphatic hydrocarbon group including straight and branched chain groups having the indicated number of carbon atoms.
  • the alkyl group usually contains 1-20 carbon atoms (C 1 -C 20 alkyl), preferably 1 to 12 carbon atoms (C 1 -C 12 alkyl), more preferably 1 to 8 carbon atoms (C 1 -C 8 alkyl) or 1 to 6 carbon atoms (C 1 -C 6 alkyl) or 1 to 4 carbon atoms (C 1 -C 4 alkyl).
  • Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropane base, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl base, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment.
  • an alkyl group is optionally substituted with one or more substituents, preferably 1-3 substituents.
  • Optionally substituted alkyl groups described herein may be substituted with one or more substituents, which are independently selected unless otherwise stated. To the extent such substitution is chemically significant, the total number of substituents can be equal to the total number of hydrogen atoms on the alkyl group.
  • Optionally substituted alkyl typically contains 1 to 6 optional substituents, sometimes 1 to 5 optional substituents, preferably 1 to 4 optional substituents, or more preferably 1 to 3 optional substituents Substituents.
  • an alkyl group may be substituted by one or more (up to the total number of hydrogen atoms present on the alkyl group) halo groups.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Alkenyl usually contains 2 to 20 carbon atoms (C 2 -C 20 alkenyl), preferably 2 to 12 carbon atoms (C 2 -C 12 alkenyl), more preferably 2 to 8 carbon atoms (C 2 -C 8 alkenyl) or 2 to 6 carbon atoms (C 2 -C 6 alkenyl) or 2 to 4 carbon atoms (C 2 -C 4 alkenyl).
  • alkenyl include ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, hetero Cyclosulfanyl.
  • alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkynyl group usually contains 2 to 20 carbon atoms (C 2 -C 20 alkynyl), preferably 2 to 12 carbon atoms (C 2 -C 12 alkynyl), more preferably 2 to 8 carbon atoms (C 2 -C 8 alkynyl) or 2 to 6 carbon atoms (C 2 -C 6 alkynyl) or 2 to 4 carbon atoms (C 2 -C 4 alkynyl).
  • Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, hetero Cyclosulfanyl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms.
  • monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene base, cyclooctyl, etc.
  • Multicyclic cycloalkyls include spiro, fused and bridged cycloalkyls.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, Benzocycloheptyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl Oxy group, cycloalkylthio group, heterocyclylthio group, oxo group, carboxyl group or carboxylate group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuryl , Dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 6 to 10 yuan.
  • the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclyls include:
  • fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring
  • the atom is carbon.
  • it is 6 to 14 yuan, more preferably 6 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond.
  • it is 6 to 14 yuan, more preferably 6 to 10 yuan.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where 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 substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl Oxy group, cycloalkylthio group, heterocyclylthio group, oxo group, carboxyl group or carboxylate group.
  • the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl,
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as benzene and naphthyl, more preferably phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane Oxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, Cycloalkylthio, heterocyclylthio, carboxyl or carboxylate.
  • 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.
  • Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; e.g. imidazolyl, furyl, thienyl, thiazolyl, pyrazole Base, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl Oxy group, cycloalkylthio group, heterocyclylthio group, carboxyl group or carboxylate group.
  • the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano,
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl Oxy group, cycloalkylthio group, heterocyclylthio group, carboxyl group or carboxylate group.
  • haloalkyl refers to an alkyl group substituted with one or more halo, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • alkylthio refers to -S-(alkyl), wherein alkyl is as defined above.
  • alkylamino refers to -NH-(alkyl), -N(alkyl) 2 -, -NH-(cycloalkyl) or -N-(cycloalkyl) 2 , wherein alkyl and cycloalkyl is defined as above.
  • cycloalkyloxy refers to -O-(cycloalkyl), wherein cycloalkyl is as defined above.
  • Non-limiting examples of cycloalkyloxy include: cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • cycloalkylthio refers to -S-(cycloalkyl), wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to -O-(heterocyclyl), wherein heterocyclyl is as defined above.
  • heterocyclylthio refers to -S-(heterocyclyl), wherein heterocyclyl is as defined above.
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • mercapto refers to -SH.
  • esters or “carboxylate” refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • amino-protecting group is used to protect the amino group with a group that can be easily removed in order to keep the amino group unchanged when other parts of the molecule react.
  • Non-limiting examples include tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.
  • the amino protecting group is preferably tert-butoxycarbonyl.
  • heterocyclyl optionally substituted with alkyl means that an alkyl group may but need not be present, and the description includes both cases where the heterocyclyl is substituted by an alkyl and cases where the heterocyclyl is not substituted by an alkyl.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients .
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • pharmaceutically acceptable salt and “pharmaceutically acceptable salt” can be used interchangeably and refer to the salts of the compounds of the present invention, which are safe and effective when used in mammals, and have due biological activity.
  • Cancer refers to any malignant and/or invasive growth or tumor (caused by abnormal cell growth). Cancers include solid tumors named for the type of cells that form them, cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Cancers of the blood include, but are not limited to, leukemias, lymphomas, and myelomas. Cancer also includes primary cancer that started in a specific part of the body, metastatic cancer that has spread from where it started to other parts of the body, recurrence from the original primary cancer after remission, and second primary cancer (This is a new primary cancer in a person with a history of previous cancer of a different type than the new primary cancer).
  • the cancer may be selected from breast cancer, ovarian cancer, prostate cancer, bladder cancer, uterine cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, and gastric cancer.
  • the cancer is characterized by amplification or overexpression of AKT1/2/3.
  • Stereoisomers described herein may include cis and trans isomers, optical isomers such as (R) and (S) enantiomers of the compounds of the invention (including compounds exhibiting more than one isomeric type) Isomers, diastereoisomers, geometric isomers, rotamers, atropisomers, conformers and tautomers; and mixtures thereof (such as racemates and asymmetric enantiomer pair).
  • optical isomers such as (R) and (S) enantiomers of the compounds of the invention (including compounds exhibiting more than one isomeric type) Isomers, diastereoisomers, geometric isomers, rotamers, atropisomers, conformers and tautomers; and mixtures thereof (such as racemates and asymmetric enantiomer pair).
  • the compounds of the present invention may exhibit tautomerism and structural isomerism.
  • compounds may exist in several tautomeric forms, including enol and imine forms and keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of the present invention.
  • Tautomers exist as a mixture of tautomeric sets in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the provided compounds.
  • enantiomeric purity of the compounds described herein can be described in terms of enantiomeric excess (ee), which means that a sample contains one enantiomer in a greater amount than the other Degree.
  • ee enantiomeric excess
  • the ee of a racemic mixture is 0%, while the ee of a single, completely pure enantiomer is 100%.
  • diastereomeric purity can be described in terms of diastereomeric excess (de).
  • the compounds of the present invention can form pharmaceutically acceptable base addition salts or acid addition salts with bases or acids.
  • the base includes inorganic bases and organic bases.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc.
  • Acceptable inorganic bases include aluminum hydroxide, hydroxide Calcium, Potassium Hydroxide, Sodium Carbonate and Sodium Hydroxide etc.
  • the acid includes inorganic acid and organic acid, acceptable inorganic acid includes hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and the like.
  • Acceptable organic acids include acetic acid, trifluoroacetic acid, formic acid, ascorbic acid, and the like.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir.
  • Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • water-soluble taste-masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • Hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in which the active ingredient is admixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil may also be used.
  • Soft gelatin capsules provide an oral formulation.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which may be natural
  • the resulting phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanylethyleneoxycetate Heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorb
  • Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweeteners.
  • preservatives such as ethyl or n-propylparaben
  • coloring agents such as ethyl or n-propylparaben
  • flavoring agents such as sucrose, saccharin, or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives for admixture. Suitable dispersing or wetting agents and suspending agents are mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of said partial esters with ethylene oxide Products such as polyethylene oxide sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • the pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then treated in a mixture of water and glycerol to form a microemulsion.
  • the injectable solution or microemulsion can be injected into the patient's bloodstream by local bolus injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
  • the pharmaceutical composition of the present invention may be in the form of sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are prepared as injectables.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's body weight, the patient's health status, the patient's behavior, the patient's Diet, administration time, administration method, excretion rate, drug combination, etc.
  • the optimal treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
  • the present invention may contain the compound represented by the general formula and its pharmaceutically acceptable salt, hydrate or solvate as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare a composition, and prepared into clinically acceptable dosage form.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like.
  • the compound of the present invention can be used as the only active ingredient, and can also be used in combination with other drugs for treating diseases related to AKT kinase activity. Combination therapy is achieved by the simultaneous, separate or sequential administration of the individual therapeutic components.
  • the present invention adopts the following synthetic scheme to prepare the compound of the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.
  • the compound of formula IIIAa and the compound of formula IIIDc obtain the compound of formula IIIDb in the presence of catalyst coupling reaction under basic conditions; compound;
  • the catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the alkaline condition is preferably N,N-diisopropylethylamine
  • the acidic condition is preferably hydrochloric acid.
  • Step 1 In the presence of activation such as pivaloyl chloride, compound a is condensed with a chiral auxiliary such as compound b to obtain compound c;
  • Step 2 In the presence of a catalyst such as 4-dimethylaminopyridine, compound d is reacted with a suitable compound such as tert-butyl dicarbonate to obtain amino-protected compound e;
  • a catalyst such as 4-dimethylaminopyridine
  • Step 3 reducing compound e using a reducing agent such as diisobutylaluminum hydride to obtain compound f;
  • Step 4 In the presence of a catalyst such as p-toluenesulfonic acid, compound f is reacted with methanol to obtain compound g;
  • a catalyst such as p-toluenesulfonic acid
  • Step 5 Compound g is condensed with compound c in the presence of a suitable Lewis acid such as titanium tetrachloride and a weak base such as N,N-diisopropylethylamine to give compound h, preferably at low temperature such as -78 °C to 0 °C to obtain acceptable diastereoselectivity in the reaction;
  • a suitable Lewis acid such as titanium tetrachloride
  • a weak base such as N,N-diisopropylethylamine
  • Step 6 Compound h is hydrolyzed in the presence of a base such as lithium hydroxide and a hydrolytic chiral auxiliary such as hydrogen peroxide to obtain a compound of formula IIIBc.
  • a base such as lithium hydroxide
  • a hydrolytic chiral auxiliary such as hydrogen peroxide
  • Compound Ik is prepared from hydroxypyrimidine Ij under standard conditions (eg, phosphorus oxychloride); compound Ik is reacted with the desired piperazine to give compound Il; compound Il is hydrolyzed with a base such as lithium hydroxide to give compound Im; Compound Im is reacted with benzyl bromide in the presence of a base such as cesium carbonate to give compound In; compound In is reacted with carbon monoxide to give compound Io; compound Io is cyclized to give compound Ip; benzyl is removed using palladium on carbon and an acid such as formic acid oxycarbonyl to provide compound Iq; asymmetric reduction of compound Iq using a chiral catalyst in the presence of a reducing agent such as formic acid affords Ir; Enantiomers; hydrolysis affords Compound It; compound It is then deprotected to afford Compound Iu.
  • a base such as lithium hydroxide to give compound Im
  • Compound Im is reacted with benzy
  • R x is an amino protecting group, preferably Boc
  • Figure 1 is the tumor growth curves in mice of each group in Test Example 4.
  • the compounds of the present invention are prepared utilizing convenient starting materials and general preparative procedures.
  • the present invention gives typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But unless otherwise specified, other reaction conditions can also be adopted. Optimum conditions may vary with specific reactants or solvents used, but in general, reaction optimization steps and conditions can be identified.
  • protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions.
  • Suitable protecting groups for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art.
  • Protecting Groups in Organic Preparations by T.W. Greene and G.M. Wuts (3rd Edition, Wiley, New York, 1999 and citations in the book) describes in detail the protection or deprotection of a large number of protecting groups.
  • the separation and purification of compounds and intermediates takes appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography or a combination of the above methods.
  • For its specific usage method please refer to the examples described in the present invention.
  • other similar separation and purification means can also be used. They can be characterized using conventional methods, including physical constants and spectral data.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined by LC (Waters 2695)/MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector).
  • Preparative high performance liquid chromatography uses lc6000 high performance liquid chromatography (manufacturer: Innovation Tongheng). Chromatographic column is DaisogelC18 10 ⁇ m 100A (30mm ⁇ 250mm), mobile phase: acetonitrile/water.
  • the thin-layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate.
  • the specification of the silica gel plate used for thin-layer chromatography (TLC) is 0.20mm-0.25mm, and the specification used for the preparation of thin-layer chromatography separation and purification products is 0.5mm.
  • the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Wanghua Mall, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Biide and other companies.
  • the reactions can all be carried out under a nitrogen atmosphere.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Reaction solvents organic solvents or inert solvents are each expressed as that the solvent used does not participate in the reaction under the described reaction conditions, including such as benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, Dichloromethane, ether, methanol, nitrogen-methylpyrrolidinone (NMP), pyridine, etc.
  • the solution refers to an aqueous solution.
  • the chemical reactions described in the present invention are generally carried out under normal pressure.
  • the reaction temperature is between -78°C and 200°C.
  • the reaction time and conditions are, for example, between -78°C and 200°C under one atmospheric pressure, and the reaction is completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin layer chromatography (TLC), and the system of developing agent used in the reaction has: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, C: acetone, The volume ratio of the solvent is adjusted according to the polarity of the compound.
  • TLC thin layer chromatography
  • the eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography include: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, the volume ratio of solvent is according to the compound It can be adjusted according to the polarity, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid.
  • Step 9 4-((5R,7R)-5-Methyl-7-(pivaloyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piper Preparation of tert-butylazine-1-carboxylate (1i)
  • Step 10 4-((5R,7R)-7-Hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylic acid Preparation of tert-butyl ester (1j)
  • Methyl 2-(diethoxyphosphoryl)acetate (32.5 g, 0.130 mol) was dissolved in anhydrous tetrahydrofuran (80 mL), and sodium hydride (3.71 g, 0.130 mol) was slowly added in batches under an ice bath, React at room temperature for 1 hour. Cyclopentanone (10.0 g, 0.120 mol) was then added and stirred at room temperature for 4 hours.
  • Step 16 Preparation of tert-butyl 3-hydroxy-2-azaspiro[4.4]nonane-2-carboxylate (1p)
  • tert-butyl 3-oxo-2-azaspiro[4.4]nonane-2-carboxylate (1.50g, 6.27mmol) and THF (23.0mL) were added to the reaction flask, cooled to -78 °C, DIBAL-H (10mL, 10.0mmol) was added dropwise, after the drop was completed, it was kept at -78°C for 30 minutes.
  • Step 17 Preparation of tert-butyl 3-methoxy-2-azaspiro[4.4]nonane-2-carboxylate (1q)
  • Step 19 (S)-3-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of tert-butyl -oxoethyl)-2-azaspiro[4.4]nonan-2-carboxylate (1s)
  • Step 20 (S)-2-((S)-2-(tert-butoxycarbonyl)-2-azaspiro[4.4]non-3-yl)-2-(4-chlorophenyl)acetic acid (1t ) preparation
  • Step 21 (S)-3-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2-azaspiro[4.4]nonan-2-carboxylic acid tert-butyl ester
  • Step 22 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-2-azaspiro[4.4]non-3-yl)ethan-1-one (1)
  • tert-butyl 8-oxo-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate (1.10 g, 4.56 mmol) and THF (20.0 mL) were added to the reaction flask , cooled to -78°C, added DIBAL-H (10mL, 10.0mmol) dropwise, and kept at -78°C for 30 minutes after dropping.
  • tert-butyl 8-hydroxy-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate 600 mg, 2.47 mmol
  • methanol (12 mL) and p-toluenesulfonic acid monohydrate 52.0 mg, 0.270mmol
  • the reaction system was poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to prepare a 29 wt% solution, which was directly used in the next step.
  • Step 7 (8S)-8-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate tert-butyl ester (2g)
  • Step 8 (2S)-2-((8S)-7-(tert-butoxycarbonyl)-2-oxa-7-azaspiro[4.4]non-8-yl)-2-(4-chlorobenzene Base) Preparation of acetic acid (2h)
  • Step 9 (8S)-8-((S)-1-(4-chlorophenyl)-2-(4-(((5R,7R)-7-hydroxy-5-methyl-6,7- Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2-oxa-7-azaspiro[4.4]nonane- Preparation of tert-butyl 7-carboxylate (2i)
  • Step 10 (2S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane And [d] pyrimidin-4-yl)piperazin-1-yl)-2-((8S)-2-oxygen-7-azaspiro[4.4]non-8-yl)ethan-1-one ( 2) Preparation
  • tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (10.2g, 50.0mmol) and ethyl acetate (250ml) were added to the reaction flask, and ruthenium dioxide- Hydrate (2.66g, 20.0mmol) and sodium periodate (53.5g, 250mmol) in aqueous solution (200ml), stirred for 12 hours.
  • the title compound as colorless oil, yield: 51.7%.
  • tert-butyl 2-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (6.66g, 32.3mmol) and methanol (70mL) were added to the reaction flask, and Toluenesulfonic acid (430mg, 2.26mmol), stirred for 2 hours.
  • reaction solution was concentrated to dryness, added with saturated sodium bicarbonate solution and ethyl acetate for extraction, the organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 5.63g
  • the title compound as a yellow oil was diluted with dichloromethane (20 mL) and used directly in the next step.
  • Step 5 (1S,2S)-2-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl) Preparation of -2-oxoethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (3e)
  • compound 1r (8.87g, 27.0mmol) and dichloromethane (90mL) were added to the reaction flask, the temperature was lowered to -78°C, titanium tetrachloride (5.12g, 27.0mmol) was added dropwise, and after 30 minutes of insulation DIPEA (4.74g, 36.8mmol) was added dropwise, and tert-butyl 2-methoxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (5.21g, 24.5mmol) was added dropwise after incubation for 30 minutes A dichloromethane solution (18 mL) was incubated for 30 minutes and then naturally rose to room temperature for 1.5 hours.
  • Step 8 (2S)-2-(((2S)-3-Azabicyclo[3.1.0]hex-2-yl)-2-(4-chlorophenyl)-1-(4-((5R ,7R)-7-Hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)ethan-1-one (3) preparation of
  • reaction solution was concentrated to dryness, diluted with dichloromethane, adjusted to pH 7-8 with DIPEA, concentrated under reduced pressure, and the residue was separated and purified by preparative high-performance liquid chromatography (column model: Daisogei 30mm*250mm , C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), 57.0 mg of the title compound was obtained as a white solid, and the yield was 61.2%.
  • methyl 3-cyanopropionate (7.91 g, 70.0 mmol) and tetrahydrofuran (200 mL) were added to the reaction flask, and tetraisopropyl titanate (3.98 g, 14.0 mmol) was added.
  • the temperature was lowered to below 10°C, under nitrogen atmosphere, ethylmagnesium bromide (3.0M, 51.4mL, 154mmol) was slowly added, after the addition was completed, the temperature was slowly raised to room temperature, and the reaction was stirred for 12 hours.
  • reaction solution was concentrated to dryness, added with saturated sodium bicarbonate solution and ethyl acetate for extraction, the organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 7.96g
  • the title compound as a brown oil was diluted with dichloromethane (20 mL) and used directly in the next step.
  • Step 5 (S)-5-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester (4e)
  • Step 8 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-4-azaspiro[2.4]hept-5-yl)ethan-1-one (4)
  • reaction solution was concentrated to dryness, diluted with dichloromethane, adjusted to pH 7-8 with DIPEA, concentrated under reduced pressure, and the residue was separated by preparative high-performance liquid chromatography (column model: Daisogei 30mm*250mm, C18 , 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), 34.0 mg of the title compound was obtained as a white solid, and the yield was 32.3%.
  • tert-butyl 1-oxo-2-azaspiro[4.5]decane-2-carboxylate 338mg, crude product
  • THF 23.0mL
  • DIBAL-H 2mL, 2.0mmol
  • tert-butyl 1-hydroxy-2-azaspiro[4.5]decane-2-carboxylate methanol (20mL)
  • p-toluenesulfonic acid monohydrate 52.0mg, 0.270mmol
  • the reaction system was poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to prepare a 29 wt% solution, which was directly used in the next step.
  • Step 4 (R)-1-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (5d)
  • Step 5 (S)-2-((R)-2-(tert-butoxycarbonyl)-2-azaspiro[4.5]dec-1-yl)-2-(4-chlorophenyl)acetic acid (5e ) preparation
  • Step 7 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-2-azaspiro[4.5]dec-1-yl)ethan-1-one (5)
  • methyl cyclopentanecarboxylate (1.02 g, 8.00 mmol), THF (20 mL) were added into the reaction flask. Cool down to -78°C, add LDA (4.4mL, 8.80mmol) dropwise, and stir for 1 hour. At -78°C, add bromoacetonitrile (1.14g, 9.60mmol) dropwise.
  • tert-butyl 1-oxo-2-azaspiro[4.4]nonan-2-carboxylate (460 mg, 1.92 mmol) and THF (10.0 mL) were added to the reaction flask at room temperature. Cool down to -78°C, add DIBAL-H (2.9mL, 2.88mmol) dropwise, and stir at -78°C for 30 minutes. After the reaction was completed, the reaction was quenched with saturated aqueous sodium acetate (5 mL), warmed to room temperature, added saturated aqueous ammonium chloride (5 mL) and ethyl acetate (10 mL) and stirred for 10 minutes, filtered, and the aqueous phase was extracted with ethyl acetate.
  • Step 6 (R)-1-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-2-azaspiro[4.4]nonan-2-carboxylate tert-butyl ester (6f)
  • Step 7 (S)-2-((R)-2-(tert-butoxycarbonyl)-2-azaspiro[4.4]non-1-yl)-2-(4-chlorophenyl)acetic acid (6g ) preparation
  • Step 8 (R)-1-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2-azaspiro[4.4]nonan-2-carboxylic acid tert-butyl ester
  • Step 9 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-2-azaspiro[4.4]non-1-yl)ethan-1-one (6)
  • dimethyl cyclopropane-1,1-dicarboxylate (10.0g, 63.3mmol) and THF (150mL) were added to the reaction flask, and lithium tris(tert-butoxy)aluminum hydride (35.4g , 139.2mmol), after the addition, the temperature was raised to 60°C for overnight reaction.
  • Step 2 Preparation of methyl 1-((p-toluenesulfonyloxy)methyl)cyclopropane-1-carboxylate (7b)
  • methyl 1-(hydroxymethyl)cyclopropane-1-carboxylate 5.0 g, 38.4 mmol
  • DCM 100 mL
  • TEA 7.76 g, 76.8 mmol
  • DMAP 468 mg, 3.84 mmol
  • TMSCN trimethyl Cyanosilane
  • TBAF tetrabutylammonium fluoride
  • tert-butyl 4-oxo-5-azaspiro[2.4]heptane-5-carboxylate 1.0 g, 4.74 mmol
  • THF 23.0 mL
  • DIBAL-H 10 mL, 10.0 mmol
  • tert-butyl 4-hydroxy-5-azaspiro[2.4]heptane-5-carboxylate 822mg, 3.86mmol
  • methanol (20mL) and p-toluenesulfonic acid monohydrate 36.6mg, 0.19mmol
  • the reaction system was poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to prepare a 29 wt% solution, which was directly used in the next step.
  • Step 8 (R)-4-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (7h)
  • Step 9 (S)-2-((R)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptan-4-yl)-2-(4-chlorophenyl)acetic acid ( 7i)
  • Step 11 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-5-azaspiro[2.4]heptane-4-yl)ethan-1-one (7)
  • Example 8 (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta Preparation of alkano[d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-6-azaspiro[3.4]oct-5-yl)ethan-1-one (8)
  • Methyl 1-(hydroxymethyl)cyclobutane-1-carboxylate (7.5 g, 52.0 mmol), DCM (100 mL), TEA (7.76 g, 76.8 mmol), DMAP (468 mg, 3.84 mmol) were mixed at room temperature Added to the reaction flask in turn, added p-toluenesulfonyl chloride (9.9 g, 52.0 mmol) in batches, and stirred overnight at room temperature.
  • methyl 1-((p-toluenesulfonyloxy)methyl)cyclobutane-1-carboxylate (11.0 g, 36.9 mmol) and THF (100 mL) were added to the reaction flask, and TMSCN ( 10.9g, 110.7mmol) and 1M TBAF in THF (110.7mL, 110.7mmol), stirred overnight at room temperature.
  • 6-azaspiro[3.4]octan-5-one (1.0g, 8.0mmol) was added into dichloromethane (25mL), followed by the addition of di-tert-butyl dicarbonate (3.7g, 16.8mmol) , triethylamine (3.4g, 33.6mmol) and 4-dimethylaminopyridine (68.3mg, 0.56mmol), stirred at room temperature for 2 hours.
  • Step 8 Preparation of tert-butyl 5-methoxy-6-azaspiro[3.4]octane-6-carboxylate (8h)
  • tert-butyl 5-hydroxy-6-azaspiro[3.4]octane-6-carboxylate 822mg, 3.62mmol
  • methanol 20mL
  • p-toluenesulfonic acid monohydrate 36.6mg, 0.19mmol
  • the reaction system was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to obtain a 29 wt% solution, which was directly used in the next step.
  • Step 9 (R)-5-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (8i)
  • Step 10 (S)-2-((R)-6-(tert-butoxycarbonyl)-6-azaspiro[3.4]octan-5-yl)-2-(4-chlorophenyl)acetic acid ( 8j) Preparation
  • Step 12 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-6-azaspiro[3.4]oct-5-yl)ethan-1-one (8)
  • tert-Butyl 6-oxo-5-azaspiro[2.4]heptane-5-carboxylate (1.4 g, 6.63 mmol) and THF (30 mL) were added to the reaction flask at room temperature. Cool down to -78°C, add DIBAL-H (10 mL, 10.0 mmol) dropwise, and stir at -78°C for 30 minutes.
  • Step 7 (S)-6-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (9g)
  • Step 8 (S)-2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptan-6-yl)-2-(4-chlorophenyl)acetic acid ( 9h)
  • Step 10 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-5-azaspiro[2.4]hept-6-yl)ethan-1-one (9)
  • 6-azaspiro[3.4]octan-7-one (1.1g, 8.79mmol) was added into dichloromethane (50mL), followed by di-tert-butyl dicarbonate (2.88g, 13.2mmol) , triethylamine (TEA) (2.67g, 26.4mmol) and 4-dimethylaminopyridine (DMAP) (53.7mg, 0.44mmol), stirred at room temperature for 2 hours.
  • TEA triethylamine
  • DMAP 4-dimethylaminopyridine
  • tert-butyl 7-oxo-6-azaspiro[3.4]octane-6-carboxylate 1.2 g, 5.33 mmol
  • THF 24 mL
  • DIBAL-H 10 mL, 10.0 mmol
  • Step 7 (S)-7-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (10g)
  • Step 8 (S)-2-((S)-6-(tert-butoxycarbonyl)-6-azaspiro[3.4]octan-7-yl)-2-(4-chlorophenyl)acetic acid ( 10h)
  • Step 10 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-6-azaspiro[3.4]oct-7-yl)ethan-1-one (10)
  • Step 5 2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d] Preparation of pyrimidin-4-yl)piperazin-1-yl)-3-(3-nitrooxetan-3-yl)propan-1-one (11e)
  • Step 6 3-(3-Aminoxetan-3-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl Preparation of -6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one (11)
  • Test Example 1 Inhibitory activity of compounds of the present invention on AKT1/AKT2/AKT3 kinases
  • the HTRF method was used to detect the inhibition of the activity of the compound on AKT kinase.
  • AKT1, AKT2, and AKT3 were purchased from Thermo Company, and the article numbers were P2999, PV3184, and PV3185, respectively.
  • the HTRF KinEASE-STK S3 kit was from Cisbio, Cat. No. 62ST3PEB.
  • Other reagents ATP solution (Sigma, R0441), MgCl 2 (Sigma, 7786-30-3), DMSO (Sigma, D2650-100ML), Ipatasertib (MCE, HY-15186).
  • Experimental process first dilute 5 ⁇ kinase buffer solution to prepare 1 ⁇ experimental working solution, and the final concentrations of MgCl 2 and DTT are 5mM and 1mM respectively.
  • the compound was diluted to 4 concentration points from the highest concentration point according to the 27-fold dilution method, and transferred to the Echo plate (Labcyte, LP0200).
  • Compounds were transferred to a 384-well plate (Greiner, 784075) with Echo, making the compounds into a 3-fold ratio dilution matrix with 11 concentration points.
  • IC50 values of the compounds of the present invention for the inhibition of AKT1, AKT2 and AKT3 kinases are shown in Table 1 below.
  • Table 1 The compounds of the present invention inhibit the IC50 values of AKT1, AKT2 and AKT3 kinases
  • Test Example 2 Inhibitory effect of compounds of the present invention on prostate cancer cells
  • the inhibitory level of the compound of the present invention on prostate cancer Lncap cells was detected by CTG method.
  • LNCaP cells (ATCC, CRL-1740) were cultured in RPMI-1640 medium (Gibco, C11875500BT), adding 10% FBS (Gibco, 10099141) and double antibodies (1% penicillin and streptomycin, Gibco, 15140122) . After the cells grew to a confluence of 70-80%, they were digested with trypsin substitute Tryple TM express enzyme (Invitrogen, 12604021) for 8 minutes. Cell suspension was prepared with RPMI-1640 culture medium supplemented with 10% FBS, counted, and the cell density was adjusted to 1.25 ⁇ 10 4 /ml.
  • the cell suspension was added to a 384-well plate, 40 ⁇ l per well, that is, 500 LNCaP cells per well.
  • Compound preparation starting from 10 mM, the compound was serially diluted 3 times in 100% DMSO with 10 concentration gradients. Then intermediate dilution was performed with medium containing 10% FBS, and 1 ⁇ l of the compound was added to 199 ⁇ l of medium, and diluted 200 times. The initial concentration of the experiment was 10 ⁇ M, and 10 ⁇ l of the compound diluted in the middle of the medium was added to the cells of the 384-well plate, 2 duplicate wells, a total of 50 ⁇ l of the reaction system, and the final concentration of DMSO was 0.1%.
  • IC 50 values of the compounds of the present invention for the inhibition of LNCaP cells are shown in Table 2 below.
  • Test example 3 mouse pharmacokinetic experiment of the compound of the present invention
  • the experimental animals were male ICR mice aged 7-8 weeks, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and raised in an SPF environment with a temperature of 20-26°C, a daily temperature difference of no more than 4°C, and a relative humidity of 40-70°C. %RH, 12h/12h alternate lighting every day.
  • the experimental animals went through an adaptation period of 3-5 days, and the animals administered orally were fasted overnight (>12h) one day before the experiment, without water.
  • the compound solution preparation process is as follows: dissolve the compound in DMSO first, and prepare a 10 mg/mL stock solution; take 100 ⁇ L of the stock solution, dilute it to 5 mL with 20% HP- ⁇ -CD, and obtain a concentration of 0.2 mg/mL for intravenous administration.
  • Drug solution take 100 ⁇ L of the stock solution, add solvent to make it up to 5 mL, vortex to disperse evenly, and obtain an intragastric administration solution with a compound concentration of 1 mg/mL.
  • Body weight was weighed before administration, and 0.1mL blood samples were collected through the ophthalmic venous plexus and added to heparin sodium anticoagulant tubes to prevent coagulation.
  • Each test compound was administered intravenously to 6 rats, and 6 rats were given oral administration, and food was given 2 hours after administration.
  • the sample collection time points are: gavage group: before administration and 15min, 30min, 1h, 2h, 4h, 8h after administration; intravenous group: before administration and after administration 5min, 15min, 30min, 1h, 2h, 4h , 8h.
  • Animal blood collection was divided into two parts, and cross-time point blood collection was adopted, and a maximum of 5 blood collection points were set for one mouse.
  • F% (AUC po x dose iv )/(AUC iv x dose po ) x 100%.
  • mice The pharmacokinetic parameters of the compounds of the present invention on mice are shown in Table 3 below.
  • Test Example 4 Pharmacodynamic experiments of compounds of the present invention on mouse prostate cancer model
  • mice aged 4-5 weeks were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and were raised in SPF environment. After 4-5 days of adaptive feeding, they were used to construct tumor models.
  • Cultivate human prostate cancer cell PC-3 (ATCC, CRL-1435; culture medium F12K+10% FBS), collect cells by centrifugation, prepare cell suspension with normal saline, mix with matrigel (Corning, Cat. No. 354234) at a ratio of 1:1 Mix well, and use a pre-cooled syringe to inoculate subcutaneously on the right forelimb of nude mice, with an inoculation volume of 100 ⁇ L for each animal, and inoculate 1 ⁇ 10 8 cells.
  • control group vehicle: 3% DMSO+97% (20% HP- ⁇ -CD)
  • compound 3 low dose group 25mg/kg, QD
  • compound 3 high dose group 50mg/kg, QD
  • compound 4 low dose group 25mg/kg, QD
  • compound 4 high dose group 50mg/kg, QD
  • TGI tumor growth inhibition rate
  • Table 4 shows the tumor volume and tumor growth inhibition rate of the animals after 21 days of treatment
  • Figure 1 shows the tumor growth curves in the mice of each group.
  • Table 4 The tumor volume and tumor growth inhibition rate of animals after treatment for 21 days

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Abstract

Provided are a heterocyclic compound with AKT kinase inhibitory activity, a preparation method therefor and a medical use thereof. In particular, the invention relates to a compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing same, and a use thereof as an AKT kinase inhibitor in a drug for the prevention and/or treatment of abnormal cell growth such as cancer. The definitions of groups in general formula (I) are the same as that in the description.

Description

具有AKT激酶抑制活性的杂环化合物及其制备方法和医药用途Heterocyclic compound with AKT kinase inhibitory activity, preparation method and medical use thereof 技术领域technical field

本发明属于医药技术领域，涉及一种嘧啶杂环类化合物，其制备方法及含有其的药物组合物，以及其作为AKT激酶抑制剂用于治疗异常细胞生长如癌症的用途。The invention belongs to the technical field of medicine, and relates to a pyrimidine heterocyclic compound, a preparation method thereof, a pharmaceutical composition containing the same, and its use as an AKT kinase inhibitor for treating abnormal cell growth such as cancer.

背景技术Background technique

AKT，又称为蛋白激酶B(PKB)，是PI3K/Akt/mTOR信号通路重要成员，通过调控下游众多效应分子影响发育、葡萄糖稳态、肿瘤生长和转移等生物学过程。超过50％的肿瘤中存在PI3K/AKT通路过度活化，例如乳腺癌、前列腺癌、胰腺癌等。鉴于AKT作为肿瘤生存关键信号中枢的作用，多年来人们一直努力开发靶向AKT激酶的药物。AKT, also known as protein kinase B (PKB), is an important member of the PI3K/Akt/mTOR signaling pathway. It affects biological processes such as development, glucose homeostasis, tumor growth and metastasis by regulating many downstream effector molecules. Over-activation of PI3K/AKT pathway exists in more than 50% of tumors, such as breast cancer, prostate cancer, pancreatic cancer, etc. Given AKT's role as a key signaling hub for tumor survival, efforts have been made for many years to develop drugs that target the AKT kinase.

AKT分为三种亚型，AKT1、AKT2、AKT3。AKT1和AKT2分布于全身，而AKT3主要在脑、乳腺、心脏、肾脏等部分器官表达(Masure等人，Eur J Biochem,1999:265(1),353-360；Yang等人，J Biol Chem,2003:278(34),32124-32131)。三种亚型均属于AGC激酶家族，激酶结构域的同源性达85％以上(Hanks等人，Faseb J,1995:9(8),576-596)。结构上均是由三部分组成，氨基端PH结构域、结合ATP的激酶结构域(CAT)和包含疏水基序(HM)的羧基端结构域(Kumar等人，Oncogene,2005:24(50),7493-7501)。AKT的活性受磷酸化和去磷酸化调控，且依赖于AKT构象的变化。在没有信号刺激的情况下，AKT的PH域和CAT域通过分子内相互作用连接，从而维持胞质中AKT非活性状态(PH-In构象)(Calleja等人，PLoS Biol,2007:5(4),e95；Yudushkin等人，IUBMB Life,2020:72(6),1115-1125)。在细胞膜表面，RTKs或G蛋白偶联受体(GPCRs)活化PI3K，继而磷酸化PIP2，使转化为PIP3；PIP3结合PH结构域，通过PDK1介导的磷酸化激活AKT，使AKT发生构象变化(PH-out构象)并易位至质膜。PH-out构象暴露了CAT和调节域，导致两个主要位点：CAT域的苏氨酸残基(AKT1的Thr308、AKT2的Thr309和AKT3的Thr305)和HM域的丝氨酸残基(Chu等人，Elife,2020:3(9),e59151；Lucic等人，Proc Natl Acad Sci USA,2018:115(17),E3940-E3949)的磷酸化。此外，ATP对AKT核酸结合口袋的占据，减缓AKT的去磷酸化，促使充分激活(Chan等人，Cell Cycle,2012:11(3),475-478)。磷酸化的AKT通过TSC1/2激活下游效应分子mTOR，上调多种转录因子，促进蛋白质翻译、细胞生长、存活等。PIK3CA扩增/突变(Shimoi等人，Cancer Sci,2018:109(8),2558-2566)，PTEN的缺失(Milella等人，Front Oncol,2015:5(24))，AKT自身的突变(如PH结构域的E17K突变)(Kalinsky等人，JAMA Oncol,2021:7(2),271-278)，以及其他RTKs的过度激活均会导致AKT信号的持续活化。AKT的去活化主要由PTEN、PP2A、PHLPP、SHIP等磷酸化酶 控制(Luongo等人，Cancers,2019:11(8)；Villalobos-Ayala等人，Cancers,2020:12(12)；Grzechnik等人，Biochem Soc Trans,2016:44(6),1675-1682)。AKT is divided into three subtypes, AKT1, AKT2, and AKT3. AKT1 and AKT2 are distributed throughout the body, while AKT3 is mainly expressed in some organs such as the brain, breast, heart, and kidney (Masure et al., Eur J Biochem, 1999:265(1), 353-360; Yang et al., J Biol Chem, 2003:278(34), 32124-32131). The three subtypes all belong to the AGC kinase family, and the homology of the kinase domain reaches more than 85% (Hanks et al., Faseb J, 1995:9(8), 576-596). Structurally, they are composed of three parts, the amino-terminal PH domain, the ATP-binding kinase domain (CAT) and the carboxy-terminal domain (Kumar et al., Oncogene, 2005: 24(50) comprising a hydrophobic motif (HM) , 7493-7501). The activity of AKT is regulated by phosphorylation and dephosphorylation, and depends on the conformational changes of AKT. In the absence of signal stimulation, the PH and CAT domains of AKT are connected by intramolecular interactions, thereby maintaining the inactive state of AKT in the cytoplasm (PH-In conformation) (Calleja et al., PLoS Biol, 2007:5(4 ), e95; Yudushkin et al., IUBMB Life, 2020:72(6), 1115-1125). On the cell membrane surface, RTKs or G protein-coupled receptors (GPCRs) activate PI3K, and then phosphorylate PIP2 to transform into PIP3; PIP3 binds to the PH domain, activates AKT through PDK1-mediated phosphorylation, and causes AKT to undergo a conformational change ( PH-out conformation) and translocates to the plasma membrane. The PH-out conformation exposes the CAT and regulatory domains, leading to two major sites: the threonine residue of the CAT domain (Thr308 of AKT1, Thr309 of AKT2 and Thr305 of AKT3) and the serine residue of the HM domain (Chu et al. , Elife, 2020:3(9), e59151; Lucic et al., Proc Natl Acad Sci USA, 2018:115(17), E3940-E3949) phosphorylation. In addition, the occupation of the nucleic acid binding pocket of AKT by ATP slows down the dephosphorylation of AKT and promotes its full activation (Chan et al., Cell Cycle, 2012: 11(3), 475-478). Phosphorylated AKT activates the downstream effector molecule mTOR through TSC1/2, up-regulates various transcription factors, and promotes protein translation, cell growth, survival, etc. PIK3CA amplification/mutation (Shimoi et al., Cancer Sci, 2018:109(8), 2558-2566), loss of PTEN (Milella et al., Front Oncol, 2015:5(24)), mutation of AKT itself (eg E17K mutation of the PH domain) (Kalinsky et al., JAMA Oncol, 2021: 7(2), 271-278), as well as hyperactivation of other RTKs lead to persistent activation of AKT signaling. The deactivation of AKT is mainly controlled by phosphorylases such as PTEN, PP2A, PHLPP, SHIP (Luongo et al., Cancers, 2019:11(8); Villalobos-Ayala et al., Cancers, 2020:12(12); Grzechnik et al. , Biochem Soc Trans, 2016:44(6), 1675-1682).

AKT激酶发现已超过30年，目前并无药物成功上市。虽然AKT上游的PI3K抑制剂已有多款获批用于肿瘤的治疗，但无论是泛PI3K抑制剂还是选择性的PI3K亚型抑制剂都存在毒性较大问题；而抑制下游mTOR后出现的负反馈机制会导致pAKT水平重新上调，进而激活下游其他的致癌效应因子。因此，开发直接靶向AKT的理想分子，有希望避免抑制上游PI3K造成的严重副作用，也可避免抑制下游mTOR引起的负反馈机制。AKT kinase has been discovered more than 30 years ago, and no drug has been successfully marketed yet. Although a variety of PI3K inhibitors upstream of AKT have been approved for the treatment of tumors, both pan-PI3K inhibitors and selective PI3K subtype inhibitors have serious toxicity problems; and negative effects after inhibiting downstream mTOR The feedback mechanism will lead to the re-upregulation of pAKT levels, which in turn activates other downstream oncogenic effectors. Therefore, the development of ideal molecules that directly target AKT is expected to avoid the serious side effects caused by the inhibition of upstream PI3K, and also avoid the negative feedback mechanism caused by the inhibition of downstream mTOR.

根据抑制剂与AKT结合位点的不同，可将药物分为PH结构域抑制剂、变构抑制剂和ATP竞争性抑制剂3类。变构抑制剂MK-2206是最早进入临床试验的AKT抑制剂，早期临床结果显示出较好的AKT信号抑制效果和良好的耐受性(Yap等人，J Clin Oncol,2011:29(35),4688-4695)，但由于严重毒副作用已移出研发公司的管线。当前仍旧在研的主要以ATP竞争性抑制剂为主，如capIIIAasertib(AZD5363)和ipatasertib(GDC0068)的III期临床试验已在HR+和三阴性乳腺癌中进行。近期ipatasertib的一项III期结果表明，与安慰剂加abiraterone相比，ipatasertib与abiraterone和泼尼松龙的组合可显著改善PTEN缺失、转移性和去势抵抗性前列腺患者的放射学无进展生存期癌症(Sweeney等人，Lancet,2021:398(10295),131-142)。此外，其他AKT抑制剂如afuresertib、uprosertib和HZB0071也处于临床开发阶段。According to the different binding sites between inhibitors and AKT, the drugs can be divided into three categories: PH domain inhibitors, allosteric inhibitors and ATP competitive inhibitors. The allosteric inhibitor MK-2206 is the first AKT inhibitor to enter clinical trials, and the early clinical results show good AKT signaling inhibition effect and good tolerance (Yap et al., J Clin Oncol, 2011:29(35) ,4688-4695), but due to serious side effects, it has been removed from the R&D company's pipeline. The current research is mainly based on ATP competitive inhibitors, such as capIIIAasertib (AZD5363) and ipatasertib (GDC0068) Phase III clinical trials have been conducted in HR+ and triple-negative breast cancer. A recent phase III result of ipatasertib demonstrated that the combination of ipatasertib with abiraterone and prednisolone significantly improved radiographic progression-free survival in patients with PTEN-null, metastatic and castration-resistant prostate compared to placebo plus abiraterone Cancer (Sweeney et al., Lancet, 2021:398(10295), 131-142). In addition, other AKT inhibitors such as afuresertib, uprosertib, and HZB0071 are also in clinical development.

AKT抑制剂临床研究仍面临诸多挑战：生物利用度低，治疗窗口窄，副作用除了腹泻、皮疹之外，还有高血糖，这是由于靶向抑制PI3K/AKT通路会破坏某些组织的葡萄糖摄取和代谢，导致高血糖(Fruman等人，Cell,2017:170(4),605-635)。另外，肝脏AKT的抑制可能会导致小鼠肝损伤、炎症和癌变，并促进肺转移(Wang等人，Cancer Cell,2016:29(4),523-535)。未来研究方向需提高激酶选择性和耐受性，同时探索合理的药物组合以克服PI3K/AKT抑制剂耐药问题。The clinical research of AKT inhibitors still faces many challenges: low bioavailability, narrow therapeutic window, side effects in addition to diarrhea, rash, and hyperglycemia, because targeted inhibition of the PI3K/AKT pathway can disrupt glucose uptake in certain tissues and metabolism, leading to hyperglycemia (Fruman et al., Cell, 2017:170(4), 605-635). In addition, inhibition of hepatic AKT may cause liver injury, inflammation and carcinogenesis in mice, and promote lung metastasis (Wang et al., Cancer Cell, 2016:29(4), 523-535). Future research directions need to improve kinase selectivity and tolerance, and at the same time explore reasonable drug combinations to overcome the problem of PI3K/AKT inhibitor resistance.

发明内容Contents of the invention

本发明人经过潜心研究，设计合成了一系列嘧啶类化合物，其显示出AKT1/2/3激酶抑制活性，可以被开发为治疗和/或预防与AKT活性相关的疾病如癌症的药物。After painstaking research, the inventors designed and synthesized a series of pyrimidine compounds, which exhibit AKT1/2/3 kinase inhibitory activity, and can be developed as drugs for treating and/or preventing diseases related to AKT activity, such as cancer.

因此，本发明的目的是提供一种通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，Therefore, the object of the present invention is to provide a compound represented by general formula (I) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

Figure PCTCN2022136451-appb-000001
Figure PCTCN2022136451-appb-000001

其中：in:

环A选自C 3-C 12环烷基、3至14元杂环基、C 6-C 14芳基和6至14元杂芳基；其中所述C 3-C 12环烷基、5至14元杂芳基、C 6-C 14芳基和6至14元杂芳基各自独立地任选被一个或多个R 1所取代； Ring A is selected from C 3 -C 12 cycloalkyl, 3 to 14 membered heterocyclic group, C 6 -C 14 aryl and 6 to 14 membered heteroaryl; wherein said C 3 -C 12 cycloalkyl, 5 to 14-membered heteroaryl, C 6 -C 14 aryl, and 6 to 14-membered heteroaryl are each independently optionally substituted by one or more R 1 ;

L为键或-CH 2-； L is a bond or -CH 2 -;

环B选自包含1-2个氮原子的5至8元饱和杂环基；所述杂环基任选被一个或多个R 3所取代； Ring B is selected from 5 to 8 membered saturated heterocyclic groups containing 1-2 nitrogen atoms; the heterocyclic group is optionally substituted by one or more R 3 ;

G选自氢、苯基、5-6元杂芳基，其中所述苯基、5-6元杂芳基任选被一个或多个R 4所取代； G is selected from hydrogen, phenyl, 5-6 membered heteroaryl, wherein the phenyl, 5-6 membered heteroaryl is optionally substituted by one or more R 4 ;

每个R 1各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，所述烷基、烷氧基、、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团所取代；或者， Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl, heteroaryl, said alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano radical, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more groups are substituted; or,

任意两个R 1与他们连接的原子一起形成环烷基、杂环基、芳基和杂芳基，所述环烷基、杂环基、芳基和杂芳基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代； Any two R together with the atoms to which they are attached form cycloalkyl, heterocyclyl, aryl and heteroaryl which are optionally selected from the group consisting of halogen, heterocyclyl, aryl and heteroaryl Amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl One or more groups of radicals and heteroaryls are substituted;

每个R 2各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团所取代；或者， Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl, heteroaryl, said alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano , hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple groups substituted; or,

任意两个R 2与他们连接的原子一起形成环烷基、杂环基、芳基和杂芳基，所述环烷基、杂环基、芳基和杂芳基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、 环烷基、杂环基、芳基和杂芳基的一个或多个基团取代； Any two R 2 together with the atoms to which they are attached form cycloalkyl, heterocyclyl, aryl and heteroaryl, which are optionally selected from the group consisting of halogen, heterocyclyl, aryl and heteroaryl Amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl One or more groups of radicals and heteroaryls are substituted;

每个R 3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，所述烷基、烷氧基、、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团所取代；或者， Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl, heteroaryl, said alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano radical, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more groups are substituted; or,

任意两个R 3与他们连接的原子一起形成环烷基、杂环基、芳基和杂芳基，所述环烷基、杂环基、芳基和杂芳基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代； Any two R 3 together with the atoms to which they are attached form cycloalkyl, heterocyclyl, aryl and heteroaryl, which are optionally selected from the group consisting of halogen, heterocyclyl, aryl and heteroaryl Amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl One or more groups of radicals and heteroaryls are substituted;

每个R 4各自独立地选自氢、卤素、硝基、氰基、羟基、巯基、烷基、烯基、炔基、-S(O) pR a、-NR aR b、-OR a、-C(O)R a、-C(O)NR aR b、-S(O) pNR aR b、环烷基、杂环基、芳基、杂芳基，所述烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团所取代； Each R is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, -S(O) p R a , -NR a R b , -OR a , -C(O)R a , -C(O)NR a R b , -S(O) p NR a R b , cycloalkyl, heterocyclyl, aryl, heteroaryl, the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl , alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more groups;

R a和R b各自独立地选自氢、卤素、羟基、巯基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，所述烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团所取代；或者， R a and R b are each independently selected from hydrogen, halogen, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy One or more groups of radical, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,

R a和R b他们连接的氮原子一起形成含氮杂环基，所述含氮杂环基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代； R a and R b and their connected nitrogen atoms together form a nitrogen-containing heterocyclic group, and the nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, Ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more groups;

n为0、1、2、3或4；n is 0, 1, 2, 3 or 4;

p为0、1或2。p is 0, 1 or 2.

在一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环A选自C 3-C 12环烷基和3至14元杂环基，优选3至14元杂环基，更优选3至6元单环杂环基、6至11元双环杂环基，进一步优选6至10元稠杂环基、6至10元螺杂环基；所述环烷基或杂环基各自独立地任选被一个或多个R 1所取代； In a preferred embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring A is selected from C 3 -C 12 cycloalkyl and 3 to 14 membered heterocyclic groups, preferably 3 to 14 membered heterocyclic groups Cyclic group, more preferably 3 to 6 membered monocyclic heterocyclic group, 6 to 11 membered bicyclic heterocyclic group, further preferably 6 to 10 membered condensed heterocyclic group, 6 to 10 membered spiro heterocyclic group; the cycloalkyl or Each heterocyclyl group is independently optionally substituted by one or more R 1 ;

每个R 1各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、 C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代；或者， Each R 1 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclic group, C 6 -C 10 aryl group, 5 to 10-membered heteroaryl group substituted by one or more groups; or,

任意两个R 1与他们连接的原子一起形成环烷基、杂环基、芳基和杂芳基，所述环烷基、杂环基、芳基和杂芳基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基的一个或多个基团取代。 Any two R together with the atoms to which they are attached form cycloalkyl, heterocyclyl, aryl and heteroaryl which are optionally selected from the group consisting of halogen, heterocyclyl, aryl and heteroaryl Amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 -C 10 aryl and 5 to 10 membered One or more groups of heteroaryl are substituted.

在一个具体的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环A为3至6元单环杂环基；所述3至6元单环杂环基任选被一个或多个R 1所取代；每个R 1各自独立地选自氢、卤素、氨基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选R 1选自氢和氨基。 In a specific embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer body, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 3 to 6-membered monocyclic heterocyclic group; the 3 to 6-membered monocyclic heterocyclic group is optionally One or more R 1 are substituted; each R 1 is independently selected from hydrogen, halogen, amino, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy radical, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; preferably R 1 is selected from hydrogen and amino.

在另一个具体的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环A为6至10元稠杂环基或6至10元螺杂环基，所述6至10元稠杂环基或6至10元螺杂环基任选被一个或多个R 1所取代；每个R 1各自独立地选自氢、卤素、氨基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选R 1选自氢。 In another specific embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is a 6-10 membered condensed heterocyclic group or a 6-10 membered spiroheterocyclic group, and said 6-10 A membered fused heterocyclic group or a 6- to 10-membered spiroheterocyclic group is optionally substituted by one or more R 1 ; each R 1 is independently selected from hydrogen, halogen, amino, cyano, oxo, hydroxyl, Mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; preferably R 1 is selected from hydrogen.

在一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In a preferred embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (II) or their stereoisomers, tautomers, mesomers, Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

Figure PCTCN2022136451-appb-000002
Figure PCTCN2022136451-appb-000002

其中：in:

m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;

每个R 1各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代；或者， Each R 1 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 -C 10 aryl, 5 to 10-membered heteroaryl by one or more groups; or,

任意两个R 1与他们连接的原子一起形成环烷基、杂环基、芳基和杂芳基，所述环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基的一个或多个基团取代； Any two R together with the atoms to which they are attached form cycloalkyl, heterocyclyl, aryl and heteroaryl which are optionally further selected from the group consisting of halogen , amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 - C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, C 6 -C 10 aryl Substituted with one or more groups of 5 to 10 membered heteroaryl;

环B、L、G、R 2、n如通式(I)所定义。 Ring B, L, G, R 2 and n are as defined in general formula (I).

在一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中任意两个R 1与他们连接的原子一起形成C 3-C 6环烷基或3至6元杂环基，所述C 3-C 6环烷基或3至6元杂环基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基的一个或多个基团取代。 In a preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention or its stereoisomers, tautomers, mesomers, racemates isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein any two R 1 form C 3 -C 6 cycloalkyl or 3 together with the atoms they are connected to to 6-membered heterocyclic group, the C 3 -C 6 cycloalkyl or 3 to 6-membered heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, Ester group, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 - Substitution by one or more groups of C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl and 5 to 10 membered heteroaryl.

在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中R 1选自氢和氨基，优选氢。 In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention or its stereoisomer, tautomer, mesomer, racemate isomers, enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is selected from hydrogen and amino, preferably hydrogen.

在一个具体的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环A选自：In a specific embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Ring A is selected from:

Figure PCTCN2022136451-appb-000003
Figure PCTCN2022136451-appb-000003

环A任选被一个或多个R 1所取代；每个R 1各自独立地选自氢、卤素、氨基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选R 1选自氢和氨基，更优选R 1为氢。 Ring A is optionally substituted by one or more R 1 ; each R 1 is independently selected from the group consisting of hydrogen, halogen, amino, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; preferably R 1 is selected from hydrogen and amino, more preferably R 1 is hydrogen.

在一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中L为键。In a preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention or its stereoisomers, tautomers, mesomers, racemates isomers, enantiomers, diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中L为-CH 2-。 In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention or its stereoisomer, tautomer, mesomer, racemate rotamers, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein L is -CH 2 -.

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III-1)、通式(III-2)或通式(III-3)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、 非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is represented by general formula (III-1), general formula (III-2) or general formula (III-3) A compound or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

Figure PCTCN2022136451-appb-000004
Figure PCTCN2022136451-appb-000004

其中，in,

X 1和X 2各自独立地选自-CH 2-、-O-、-NH-； X 1 and X 2 are each independently selected from -CH 2 -, -O-, -NH-;

n 1为0或1； n 1 is 0 or 1;

n 2为0、1或2； n2 is 0, 1 or 2;

每个R c各自独立地选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基； Each R c is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;

q为0、1或2，优选0或1，更优选0；q is 0, 1 or 2, preferably 0 or 1, more preferably 0;

环B、G、R 2和n如通式(I)所定义。 Ring B, G, R 2 and n are as defined in general formula (I).

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IV-1)或(IV-2)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (IV-1) or (IV-2) or stereoisomers, interconversions thereof Isomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

Figure PCTCN2022136451-appb-000005
Figure PCTCN2022136451-appb-000005

其中，in,

环E 1为C 3-C 6环烷基或3至6元杂环基； Ring E 1 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group;

环E 2为C 3-C 6环烷基或3至6元杂环基； Ring E 2 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group;

每个R e各自独立地选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基； Each R e is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;

t为0、1或2，优选0或1，更优选0；t is 0, 1 or 2, preferably 0 or 1, more preferably 0;

环B、G、R 2和n如通式(I)所定义。 Ring B, G, R 2 and n are as defined in general formula (I).

在另一个优选的实施方案中，根据本发明所述的通式(I)、通式(II)、通式(III-1)、通式(III-2)、通式(III-3)、通式(IV-1)或通式(IV-2)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中环B为包含1-2个氮原子的6至8元饱和杂环基；环B优选自以下基团：In another preferred embodiment, according to the general formula (I), general formula (II), general formula (III-1), general formula (III-2), general formula (III-3) of the present invention , the compound represented by general formula (IV-1) or general formula (IV-2) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring B is a 6- to 8-membered saturated heterocyclic group containing 1-2 nitrogen atoms; ring B is preferably selected from the following groups:

Figure PCTCN2022136451-appb-000006
Figure PCTCN2022136451-appb-000006

其中单波线表示连接至羰基的位置，双波线表示连接至嘧啶的位置；Wherein the single wave line represents the position connected to the carbonyl, and the double wave line represents the position connected to the pyrimidine;

环B任选被一个或多个R 3所取代； Ring B is optionally substituted by one or more R3 ;

每个R 3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代； Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 Substituted by one or more groups from 6-membered heterocyclic group, C 6 -C 10 aryl group, 5- to 10-membered heteroaryl group;

优选R 3为氢。 Preferably R3 is hydrogen.

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IIIA)、通式(IIIB)或通式(IIIC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIIA), general formula (IIIB) or general formula (IIIC) or a stereoisomer thereof isomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

Figure PCTCN2022136451-appb-000007
Figure PCTCN2022136451-appb-000007

其中，in,

X 1和X 2各自独立地选自-CH 2-、-O-、-NH-； X 1 and X 2 are each independently selected from -CH 2 -, -O-, -NH-;

n 1为0或1； n 1 is 0 or 1;

n 2为0、1或2； n2 is 0, 1 or 2;

每个R c各自独立地选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基； Each R c is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;

q为0、1或2，优选0或1，更优选0；q is 0, 1 or 2, preferably 0 or 1, more preferably 0;

每个R 3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代；优选R 3为氢； Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclic group, C 6 -C 10 aryl group, 5 to 10-membered heteroaryl group substituted by one or more groups; preferably R 3 is hydrogen;

r为0、1、2、3或4，优选0、1或2，更优选0或1；r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;

G、R 2和n如通式(I)所定义。 G, R 2 and n are as defined in general formula (I).

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IVA)或(IVB)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (IVA) or (IVB) or stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

Figure PCTCN2022136451-appb-000008
Figure PCTCN2022136451-appb-000008

其中，in,

环E 1为C 3-C 6环烷基或3至6元杂环基； Ring E 1 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group;

环E 2为C 3-C 6环烷基或3至6元杂环基； Ring E 2 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group;

每个R e各自独立地选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基； Each R e is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;

t为0、1或2，优选0或1，更优选0；t is 0, 1 or 2, preferably 0 or 1, more preferably 0;

每个R 3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代；优选R 3为氢； Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclic group, C 6 -C 10 aryl group, 5 to 10-membered heteroaryl group substituted by one or more groups; preferably R 3 is hydrogen;

r为0、1、2、3或4，优选0、1或2，更优选0或1；r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;

G、R 2和n如通式(I)所定义。 G, R 2 and n are as defined in general formula (I).

在另一个优选的实施方案中，根据本发明所述的通式(I)、通式(II)、通式(III-1)、通式(III-2)、通式(III-3)、通式(IV-1)、通式(IV-2)、通式(IIIA)、通式(IIIB)、通式(IIIC)、通式(IVA)或通式(IVB)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中G选自苯基，所述苯基任选被任选被一个或多个R 4所取代； In another preferred embodiment, according to the general formula (I), general formula (II), general formula (III-1), general formula (III-2), general formula (III-3) of the present invention , general formula (IV-1), general formula (IV-2), general formula (IIIA), general formula (IIIB), general formula (IIIC), general formula (IVA) or the compound shown in general formula (IVB) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein G selected from phenyl, which is optionally substituted by one or more R4 ;

每个R 4各自独立地选自卤素、氰基、羟基、巯基、C 1-C 6烷基、-NR aR b、-OR a，所述C 1-C 6烷基任选被卤素取代； Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ;

R a和R b各自独立地选自氢和C 1-C 6烷基；或者， R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,

R a和R b他们连接的氮原子一起形成含5-6元氮杂环基，所述5-6元含氮杂环基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷 基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代。 R a and R b , the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replaced.

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IIID)、通式(IIIE)或通式(IIIF)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIID), general formula (IIIE) or general formula (IIIF) or a stereoisomer thereof isomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

Figure PCTCN2022136451-appb-000009
Figure PCTCN2022136451-appb-000009

其中，in,

X 1和X 2各自独立地选自-CH 2-、-O-、-NH-； X 1 and X 2 are each independently selected from -CH 2 -, -O-, -NH-;

n 1为0或1； n 1 is 0 or 1;

n 2为0、1或2； n2 is 0, 1 or 2;

每个R c各自独立地选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基； Each R c is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;

q为0、1或2，优选0或1，更优选0；q is 0, 1 or 2, preferably 0 or 1, more preferably 0;

每个R 3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代；优选R 3为氢； Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclic group, C 6 -C 10 aryl group, 5 to 10-membered heteroaryl group substituted by one or more groups; preferably R 3 is hydrogen;

r为0、1、2、3或4，优选0、1或2，更优选0或1；r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;

每个R 4各自独立地选自卤素、氰基、羟基、巯基、C 1-C 6烷基、-NR aR b、-OR a，所述C 1-C 6烷基任选被卤素取代；优选R 4选自卤素； Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ; Preferably R is selected from halogen;

R a和R b各自独立地选自氢和C 1-C 6烷基；或者， R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,

R a和R b他们连接的氮原子一起形成含5-6元氮杂环基，所述5-6元含氮杂环基任 选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代； R a and R b , the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replacement;

s为0、1或2；s is 0, 1 or 2;

R 2和n如通式(I)所定义。 R 2 and n are as defined in general formula (I).

在另一个优选的实施方案中，根据本发明所述的所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IVC)或(IVD)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, Enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (IVC) or (IVD) or their stereoisomers, tautomers isomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

Figure PCTCN2022136451-appb-000010
Figure PCTCN2022136451-appb-000010

其中，in,

环E 1为C 3-C 6环烷基或3至6元杂环基； Ring E 1 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group;

环E 2为C 3-C 6环烷基或3至6元杂环基； Ring E 2 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group;

每个R e各自独立地选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基； Each R e is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;

t为0、1或2，优选0或1，更优选0；t is 0, 1 or 2, preferably 0 or 1, more preferably 0;

每个R 3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代；优选R 3为氢； Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclic group, C 6 -C 10 aryl group, 5 to 10-membered heteroaryl group substituted by one or more groups; preferably R 3 is hydrogen;

r为0、1、2、3或4，优选0、1或2，更优选0或1；r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;

每个R 4各自独立地选自卤素、氰基、羟基、巯基、C 1-C 6烷基、-NR aR b、-OR a，所述C 1-C 6烷基任选被卤素取代；优选R 4选自卤素； Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ; Preferably R is selected from halogen;

R a和R b各自独立地选自氢和C 1-C 6烷基；或者， R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,

R a和R b他们连接的氮原子一起形成含5-6元氮杂环基，所述5-6元含氮杂环基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代； R a and R b , the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replacement;

s为0、1或2；s is 0, 1 or 2;

R 2和n如通式(I)所定义。 R 2 and n are as defined in general formula (I).

在一个优选的实施方案中，根据本发明所述的通式(IV-1)、通式(IVA)、通式(IVC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环E 1为C 3-C 6环烷基，优选环丙基、环丁基或环戊基。 In a preferred embodiment, according to the compound represented by general formula (IV-1), general formula (IVA), general formula (IVC) or its stereoisomers, tautomers, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring E1 is C3 - C6cycloalkyl , Preference is given to cyclopropyl, cyclobutyl or cyclopentyl.

在另一个优选的实施方案中，根据本发明所述的通式(IV-2)、通式(IVB)、通式(IVD)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环E 2为C 3-C 6环烷基，优选环丙基、环丁基或环戊基。 In another preferred embodiment, according to the compound represented by general formula (IV-2), general formula (IVB), general formula (IVD) of the present invention or its stereoisomers, tautomers , mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring E 2 is C 3 -C 6 cycloalkyl , preferably cyclopropyl, cyclobutyl or cyclopentyl.

在另一个优选的实施方案中，根据本发明所述的通式(IV-1)、通式(IV-2)、通式(IVA)、通式(IVB)、通式(IVC)或通式(IVD)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R e为氢，t为1。 In another preferred embodiment, according to the general formula (IV-1), general formula (IV-2), general formula (IVA), general formula (IVB), general formula (IVC) or general formula according to the present invention A compound represented by formula (IVD) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein, Re is hydrogen, t is 1.

在另一个优选的实施方案中，根据本发明所述的通式(IV-1)、通式(IV-2)、通式(IVA)、通式(IVB)、通式(IVC)或通式(IVD)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，t为0。In another preferred embodiment, according to the general formula (IV-1), general formula (IV-2), general formula (IVA), general formula (IVB), general formula (IVC) or general formula according to the present invention A compound represented by formula (IVD) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein, t is 0.

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(V)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (V) or stereoisomers, tautomers, and mesomers thereof , racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

Figure PCTCN2022136451-appb-000011
Figure PCTCN2022136451-appb-000011

其中：in:

环A为3至6元单环杂环基；Ring A is a 3 to 6 membered monocyclic heterocyclic group;

每个R d各自独立地选自氢、卤素、氨基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选氢和氨基； Each R d is independently selected from hydrogen, halogen, amino, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl , C 1 -C 6 haloalkoxy; preferably hydrogen and amino;

t为0、1或2；t is 0, 1 or 2;

每个R 3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代；优选R 3为氢； Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclic group, C 6 -C 10 aryl group, 5 to 10-membered heteroaryl group substituted by one or more groups; preferably R 3 is hydrogen;

r为0、1、2、3或4，优选0、1或2，更优选0或1；r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;

每个R 4各自独立地选自卤素、氰基、羟基、巯基、C 1-C 6烷基、-NR aR b、-OR a，所述C 1-C 6烷基任选被卤素取代；优选R 4选自卤素； Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ; Preferably R is selected from halogen;

R a和R b各自独立地选自氢和C 1-C 6烷基；或者， R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,

R a和R b他们连接的氮原子一起形成含5-6元氮杂环基，所述5-6元含氮杂环基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代； R a and R b , the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replacement;

s为0、1或2；s is 0, 1 or 2;

R 2和n如通式(I)所定义。 R 2 and n are as defined in general formula (I).

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(VI)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (VI) or stereoisomers, tautomers, and mesomers thereof , racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

Figure PCTCN2022136451-appb-000012
Figure PCTCN2022136451-appb-000012

其中：in:

环A为3至6元单环杂环基；Ring A is a 3 to 6 membered monocyclic heterocyclic group;

R d选自氢、卤素、氨基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧 基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选氢； R d is selected from hydrogen, halogen, amino, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; preferably hydrogen;

每个R 3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代；优选R 3为氢； Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclic group, C 6 -C 10 aryl group, 5 to 10-membered heteroaryl group substituted by one or more groups; preferably R 3 is hydrogen;

r为0、1、2、3或4，优选0、1或2，更优选0或1；r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;

每个R 4各自独立地选自卤素、氰基、羟基、巯基、C 1-C 6烷基、-NR aR b、-OR a，所述C 1-C 6烷基任选被卤素取代；优选R 4选自卤素； Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ; Preferably R is selected from halogen;

R a和R b各自独立地选自氢和C 1-C 6烷基；或者， R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,

R a和R b他们连接的氮原子一起形成含5-6元氮杂环基，所述5-6元含氮杂环基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代； R a and R b , the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replacement;

s为0、1或2；s is 0, 1 or 2;

R 2和n如通式(I)所定义。 R 2 and n are as defined in general formula (I).

在一个具体的实施方案中，根据本发明所述的通式(III-1)、通式(III-2)、通式(III-3)、通式(IIIA)、通式(IIIB)、通式(IIIC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中X 1选自-CH 2-和-O-。 In a specific embodiment, according to the general formula (III-1), general formula (III-2), general formula (III-3), general formula (IIIA), general formula (IIIB), The compound represented by the general formula (IIIC) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 is selected from -CH 2 - and -O-.

在另一个具体的实施方案中，根据本发明所述的通式(III-1)、通式(III-2)、通式(III-3)、通式(IIIA)、通式(IIIB)、通式(IIIC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中X 2选自-CH 2-。 In another specific embodiment, according to the general formula (III-1), general formula (III-2), general formula (III-3), general formula (IIIA), general formula (IIIB) of the present invention , the compound represented by the general formula (IIIC) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof, wherein X 2 is selected from -CH 2 -.

在另一个具体的实施方案中，根据本发明所述的通式(III-1)、通式(III-2)、通式(III-3)、通式(IIIA)、通式(IIIB)、通式(IIIC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中X 1和X 2均为-CH 2-。 In another specific embodiment, according to the general formula (III-1), general formula (III-2), general formula (III-3), general formula (IIIA), general formula (IIIB) of the present invention , the compound represented by the general formula (IIIC) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof, wherein both X 1 and X 2 are -CH 2 -.

在另一个具体的实施方案中，根据本发明所述的通式(III-1)、通式(III-2)、通式(III-3)、通式(IIIA)、通式(IIIB)、通式(IIIC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中n 1为0或1。 In another specific embodiment, according to the general formula (III-1), general formula (III-2), general formula (III-3), general formula (IIIA), general formula (IIIB) of the present invention , the compound represented by the general formula (IIIC) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof, wherein n 1 is 0 or 1.

在另一个具体的实施方案中，根据本发明所述的通式(III-1)、通式(III-2)、通式(III-3)、通式(IIIA)、通式(IIIB)、通式(IIIC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混 合物形式、或其可药用盐，其中n 2为0、1或2。 In another specific embodiment, according to the general formula (III-1), general formula (III-2), general formula (III-3), general formula (IIIA), general formula (IIIB) of the present invention , the compound represented by the general formula (IIIC) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof, wherein n 2 is 0, 1 or 2.

在另一个具体的实施方案中，根据本发明所述的通式(III-1)、通式(III-2)、通式(III-3)、通式(IIIA)、通式(IIIB)、通式(IIIC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中R c为氢且q为1。 In another specific embodiment, according to the general formula (III-1), general formula (III-2), general formula (III-3), general formula (IIIA), general formula (IIIB) of the present invention , the compound represented by the general formula (IIIC) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof, wherein R c is hydrogen and q is 1.

在另一个具体的实施方案中，根据本发明所述的通式(III-1)、通式(III-2)、通式(III-3)、通式(IIIA)、通式(IIIB)、通式(IIIC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中q为0。In another specific embodiment, according to the general formula (III-1), general formula (III-2), general formula (III-3), general formula (IIIA), general formula (IIIB) of the present invention , the compound represented by the general formula (IIIC) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof, wherein q is 0.

在另一个具体的实施方案中，根据本发明所述的通式(IIIA)、通式(IIIB)、通式(C)、通式(D)、通式(E)、通式(F)、通式(VIA)、通式(VIB)、通式(VIC)、通式(VID)、通式(V)或通式(VI)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中R 3为氢且r为1。 In another specific embodiment, according to the general formula (IIIA), general formula (IIIB), general formula (C), general formula (D), general formula (E), general formula (F) of the present invention , the general formula (VIA), the general formula (VIB), the general formula (VIC), the general formula (VID), the general formula (V) or the compound represented by the general formula (VI) or its stereoisomers, tautomerism isomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen and r is 1.

在另一个具体的实施方案中，根据本发明所述的通式((IIIA)、通式(IIIB)、通式(C)、通式(D)、通式(E)、通式(F)、通式(VIA)、通式(VIB)、通式(VIC)、通式(VID)、通式(V)或通式(VI)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中r为0。In another specific embodiment, the general formula ((IIIA), general formula (IIIB), general formula (C), general formula (D), general formula (E), general formula (F) according to the present invention ), the general formula (VIA), the general formula (VIB), the general formula (VIC), the general formula (VID), the general formula (V) or the compound represented by the general formula (VI) or its stereoisomers, interconversion Isomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein r is zero.

在另一个具体的实施方案中，根据本发明所述的通式(D)、通式(E)、通式(F)、通式(VIC)、通式(VID)、通式(V)或通式(VI)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中R 4为氢或卤素，优选卤素，且s为1。 In another specific embodiment, the general formula (D), general formula (E), general formula (F), general formula (VIC), general formula (VID), general formula (V) according to the present invention Or the compound represented by general formula (VI) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its mixture form , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen or halogen, preferably halogen, and s is 1.

在一个优选的实施方案中，根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中每个R 2各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团所取代；优选每个R 2各自独立地选自氢、羟基和C 1-C 6烷基； In a preferred embodiment, the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers , or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 haloalkyl, C 1 -C One or more groups of 6 haloalkoxy are substituted; preferably each R 2 is independently selected from hydrogen, hydroxyl and C 1 -C 6 alkyl;

n为0、1、2，优选1或2，更优选2。n is 0, 1, 2, preferably 1 or 2, more preferably 2.

在另一个优选的实施方案中，根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中每个R 2各自独立地选自羟基和C 1-C 6烷基。 In another preferred embodiment, the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from hydroxyl and C 1 -C 6 alkyl.

在另一个优选的实施方案中，根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、 或其可药用盐，其中，n为2，且每个R 2各自独立地选自羟基和C 1-C 6烷基。 In another preferred embodiment, the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 2, and each R 2 is independently selected from hydroxyl and C 1 -C 6 alkyl.

本发明典型的化合物包括但不限于以下化合物：Typical compounds of the invention include, but are not limited to, the following compounds:

Figure PCTCN2022136451-appb-000013
Figure PCTCN2022136451-appb-000013

Figure PCTCN2022136451-appb-000014
Figure PCTCN2022136451-appb-000014

Figure PCTCN2022136451-appb-000015
Figure PCTCN2022136451-appb-000015

或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用盐。Stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers thereof, or a mixture thereof or a pharmaceutically acceptable salt thereof.

本发明进一步提供一种通式(IIIA)或通式(IIIB)或通式(IIIC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：The present invention further provides a compound represented by general formula (IIIA) or general formula (IIIB) or general formula (IIIC) or its stereoisomer, tautomer, mesomer, racemate, A method for preparing enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Figure PCTCN2022136451-appb-000016
Figure PCTCN2022136451-appb-000016

式IIIAa的化合物与式IIIAc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IIIAb的化合物；式IIIAb的化合物在酸性条件下脱除保护基得到通式(IIIA)所示的化合物；The compound of the formula IIIAa and the compound of the formula IIIAc obtain the compound of the formula IIIAb in the presence of a catalyst under alkaline conditions; compound;

Figure PCTCN2022136451-appb-000017
Figure PCTCN2022136451-appb-000017

式IIIAa的化合物与式IIIBc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IIIBb的化合物；式IIIBb的化合物在酸性条件下脱除保护基得到通式(IIIB)所示的化合物；The compound of formula IIIAa and the compound of formula IIIBc obtain the compound of formula IIIBb in the presence of catalyst coupling reaction under basic conditions; compound;

Figure PCTCN2022136451-appb-000018
Figure PCTCN2022136451-appb-000018

式IIIAa的化合物与式IIICc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IIICb的化合物；式IIICb的化合物在酸性条件下脱除保护基得到通式(IIIC)所示的化合物；The compound of formula IIIAa and the compound of formula IIICc obtain the compound of formula IIICb in the presence of catalyst coupling reaction under basic conditions; compound;

其中：in:

所述催化剂优选苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐；The catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate;

所述碱性条件优选N,N-二异丙基乙胺；The alkaline condition is preferably N,N-diisopropylethylamine;

所述酸性条件优选盐酸；The acidic condition is preferably hydrochloric acid;

R x为氨基保护基，优选Boc； R x is an amino protecting group, preferably Boc;

G、R 2、R 3、X 1、X 2、R c、n、n 1、n 2、q、r如通式(IIIA)、(IIIB)或(IIIC)所定义。 G, R 2 , R 3 , X 1 , X 2 , R c , n, n 1 , n 2 , q, r are as defined in general formula (IIIA), (IIIB) or (IIIC).

本发明进一步涉及一种通式(IIID)或通式(IIIE)或通式(IIIF)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：The present invention further relates to a compound represented by general formula (IIID) or general formula (IIIE) or general formula (IIIF) or its stereoisomer, tautomer, mesomer, racemate, A method for preparing enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Figure PCTCN2022136451-appb-000019
Figure PCTCN2022136451-appb-000019

式IIIAa的化合物与式IIIDc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IIIDb的化合物；式IIIDb的化合物在酸性条件下脱除保护基得到通式(IIID)所示的化合物；The compound of formula IIIAa and the compound of formula IIIDc obtain the compound of formula IIIDb in the presence of catalyst coupling reaction under basic conditions; compound;

Figure PCTCN2022136451-appb-000020
Figure PCTCN2022136451-appb-000020

式IIIAa的化合物与式IIIEc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IIIEb的化合物；式IIIEb的化合物在酸性条件下脱除保护基得到通式(IIIE)所示的化合物；The compound of the formula IIIAa and the compound of the formula IIIEc obtain the compound of the formula IIIEb in the presence of a catalyst under alkaline conditions in the coupling reaction; the compound of the formula IIIEb removes the protecting group under acidic conditions and obtains compound;

Figure PCTCN2022136451-appb-000021
Figure PCTCN2022136451-appb-000021

式IIIAa的化合物与式IIIFc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IIIFb的化合物；式IIIFb的化合物在酸性条件下脱除保护基得到通式(IIIF)所示的化合物；The compound of the formula IIIAa and the compound of the formula IIIFc obtain the compound of the formula IIIFb in the presence of a catalyst under alkaline conditions in the coupling reaction; the compound of the formula IIIFb removes the protecting group under acidic conditions and obtains compound;

其中：in:

所述催化剂优选苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐；The catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate;

所述碱性条件优选N,N-二异丙基乙胺；The alkaline condition is preferably N,N-diisopropylethylamine;

所述酸性条件优选盐酸；The acidic condition is preferably hydrochloric acid;

R x为氨基保护基，优选Boc； R x is an amino protecting group, preferably Boc;

G、R 2、R 3、R 4、X 1、X 2、R c、n、n 1、n 2、q、r、s如通式(IIID)或通式(IIIE)或通式(IIIF)所定义。 G, R 2 , R 3 , R 4 , X 1 , X 2 , R c , n, n 1 , n 2 , q, r, s such as general formula (IIID) or general formula (IIIE) or general formula (IIIF ) as defined.

本发明进一步涉及一种通式(IVA)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：The present invention further relates to a compound represented by general formula (IVA) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer , or a mixture thereof, or a preparation method of a pharmaceutically acceptable salt thereof, comprising the following steps:

Figure PCTCN2022136451-appb-000022
Figure PCTCN2022136451-appb-000022

式IIIAa的化合物与式IVAc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IVAb的化合物；式IVAb的化合物在酸性条件下脱除保护基得到通式(IVA)所示的化合物；The compound of the formula IIIAa and the compound of the formula IVAc obtain the compound of the formula IVAb in the presence of the catalyst in the presence of a catalyst under alkaline conditions; the compound of the formula IVAb removes the protecting group under acidic conditions to obtain compound;

所述催化剂优选苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐；The catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate;

所述碱性条件优选N,N-二异丙基乙胺；The alkaline condition is preferably N,N-diisopropylethylamine;

所述酸性条件优选盐酸；The acidic condition is preferably hydrochloric acid;

其中：in:

R x为氨基保护基，优选Boc； R x is an amino protecting group, preferably Boc;

环E 1、G、R 2、R 3、R e、n、r、t如通式(IVA)所定义。 Ring E 1 , G, R 2 , R 3 , Re , n, r, t are as defined in general formula (IVA).

本发明进一步涉及一种通式(IVB)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：The present invention further relates to a compound represented by general formula (IVB) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a preparation method of a pharmaceutically acceptable salt thereof, comprising the following steps:

Figure PCTCN2022136451-appb-000023
Figure PCTCN2022136451-appb-000023

式IIIAa的化合物与式IVBc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IVBb的化合物；式IVBb的化合物在酸性条件下脱除保护基得到通式(IVB)所示的化合物；The compound of formula IIIAa and the compound of formula IVBc obtain the compound of formula IVBb in the presence of catalyst coupling reaction under basic conditions; compound;

所述催化剂优选苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐；The catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate;

所述碱性条件优选N,N-二异丙基乙胺；The alkaline condition is preferably N,N-diisopropylethylamine;

所述酸性条件优选盐酸；The acidic condition is preferably hydrochloric acid;

其中：in:

R x为氨基保护基，优选Boc； R x is an amino protecting group, preferably Boc;

环E 2、G、R 2、R 3、R e、n、r、t如通式(IVB)所定义。 Rings E 2 , G, R 2 , R 3 , R e , n, r, and t are as defined in general formula (IVB).

本发明进一步涉及一种通式(IVC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：The present invention further relates to a compound represented by general formula (IVC) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a preparation method of a pharmaceutically acceptable salt thereof, comprising the following steps:

Figure PCTCN2022136451-appb-000024
Figure PCTCN2022136451-appb-000024

式IIIAa的化合物与式IVCc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IVCb的化合物；式IVCb的化合物在酸性条件下脱除保护基得到通式(IVC)所示的化合物；The compound of formula IIIAa and the compound of formula IVCc obtain the compound of formula IVCb in the presence of catalyst coupling reaction under basic conditions; compound;

所述催化剂优选苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐；The catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate;

所述碱性条件优选N,N-二异丙基乙胺；The alkaline condition is preferably N,N-diisopropylethylamine;

所述酸性条件优选盐酸；The acidic condition is preferably hydrochloric acid;

其中：in:

R x为氨基保护基，优选Boc； R x is an amino protecting group, preferably Boc;

环E 1、R 2、R 3、R 4、R e、n、r、s、t如通式(IVC)所定义。 Rings E 1 , R 2 , R 3 , R 4 , Re , n, r, s, t are as defined in general formula (IVC).

本发明进一步涉及一种通式(IVD)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：The present invention further relates to a compound represented by general formula (IVD) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a preparation method of a pharmaceutically acceptable salt thereof, comprising the following steps:

Figure PCTCN2022136451-appb-000025
Figure PCTCN2022136451-appb-000025

式IIIAa的化合物与式IVDc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IVDb的化合物；式IVDb的化合物在酸性条件下脱除保护基得到通式(IVD)所示的化合物；The compound of the formula IIIAa and the compound of the formula IVDc obtain the compound of the formula IVDb in the presence of a catalyst under alkaline conditions; the compound of the formula IVDb removes the protecting group under acidic conditions to obtain compound;

所述催化剂优选苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐；The catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate;

所述碱性条件优选N,N-二异丙基乙胺；The alkaline condition is preferably N,N-diisopropylethylamine;

所述酸性条件优选盐酸；The acidic condition is preferably hydrochloric acid;

其中：in:

R x为氨基保护基，优选Boc； R x is an amino protecting group, preferably Boc;

环E 2、R 2、R 3、R 4、R e、n、r、s、t如通式(IVD)所定义。 Rings E 2 , R 2 , R 3 , R 4 , Re , n, r, s, t are as defined in general formula (IVD).

本发明还提供一种药物组合物，其包含根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。The present invention also provides a pharmaceutical composition comprising the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

本发明还涉及根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物在制备用于抑制AKT1/2/3的药物中的用途。The present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation of a medicament for inhibiting AKT1/2/3.

本发明还涉及根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物在制备用于预防和/或治疗与AKT1/2/3激酶活性相关的疾病的药物中的用途，所述疾病优选癌症，特别是与以AKT1/2/3的扩增或过表达为特 征的癌症，所述癌症优选卵巢癌、乳腺癌、前列腺癌、神经胶质瘤、胶质细胞瘤、胃癌、输卵管癌、肺癌、腹膜肿瘤、黑色素瘤、脑癌、食管癌、肝癌、胰腺癌、结直癌、肺癌、肾癌、宫颈癌、皮肤癌、神经母细胞瘤、肉瘤、骨癌、子宫癌、子宫内膜癌、头颈肿瘤、多发性骨髓瘤、淋巴瘤、非霍奇金淋巴瘤、非小细胞肺癌、真性红细胞增多症、白血病、甲状腺肿瘤、膀胱癌和胆囊癌，特别优选卵巢癌、乳腺癌和前列腺癌。The present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, in the preparation of a medicament for preventing and/or treating a disease associated with AKT1/2/3 kinase activity, said disease being preferably cancer, particularly associated with A cancer characterized by amplification or overexpression of AKT1/2/3, preferably ovarian cancer, breast cancer, prostate cancer, glioma, glioblastoma, gastric cancer, fallopian tube cancer, lung cancer, peritoneal tumor, Melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer, skin cancer, neuroblastoma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck cancer, Multiple myeloma, lymphoma, non-Hodgkin's lymphoma, non-small cell lung cancer, polycythemia vera, leukemia, thyroid tumors, bladder cancer and gallbladder cancer, especially ovarian cancer, breast cancer and prostate cancer.

本发明还涉及根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物，其用作AKT1/2/3抑制剂。The present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used as an AKT1/2/3 inhibitor.

本发明还涉及根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐或包含其的药物组合物，其用于治疗和/或预防与AKT1/2/3激酶活性相关的疾病的药物中的用途，所述疾病优选癌症，特别是与以AKT1/2/3的扩增或过表达为特征的癌症，所述癌症优选卵巢癌、乳腺癌、前列腺癌、神经胶质瘤、胶质细胞瘤、胃癌、输卵管癌、肺癌、腹膜肿瘤、黑色素瘤、脑癌、食管癌、肝癌、胰腺癌、结直癌、肺癌、肾癌、宫颈癌、皮肤癌、神经母细胞瘤、肉瘤、骨癌、子宫癌、子宫内膜癌、头颈肿瘤、多发性骨髓瘤、淋巴瘤、非霍奇金淋巴瘤、非小细胞肺癌、真性红细胞增多症、白血病、甲状腺肿瘤、膀胱癌和胆囊癌，特别优选卵巢癌、乳腺癌和前列腺癌。The present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, for use in a medicament for the treatment and/or prevention of diseases associated with AKT1/2/3 kinase activity, preferably Cancer, in particular cancer characterized by amplification or overexpression of AKT1/2/3, preferably ovarian cancer, breast cancer, prostate cancer, glioma, glioblastoma, gastric cancer, fallopian tube cancer, Lung cancer, peritoneal tumor, melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer, skin cancer, neuroblastoma, sarcoma, bone cancer, uterine cancer, endometrium Carcinoma, head and neck tumors, multiple myeloma, lymphoma, non-Hodgkin's lymphoma, non-small cell lung cancer, polycythemia vera, leukemia, thyroid tumors, bladder cancer and gallbladder cancer, particularly preferably ovarian cancer, breast cancer and prostate cancer cancer.

本发明还涉及根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物，其用作药物，特别是用于预防和/或治疗与AKT1/2/3激酶活性相关的疾病的药物，治疗和/或预防与AKT1/2/3激酶活性相关的疾病的药物中的用途，所述疾病优选癌症，特别是与以AKT1/2/3的扩增或过表达为特征的癌症，所述癌症优选卵巢癌、乳腺癌、前列腺癌、神经胶质瘤、胶质细胞瘤、胃癌、输卵管癌、肺癌、腹膜肿瘤、黑色素瘤、脑癌、食管癌、肝癌、胰腺癌、结直癌、肺癌、肾癌、宫颈癌、皮肤癌、神经母细胞瘤、肉瘤、骨癌、子宫癌、子宫内膜癌、头颈肿瘤、多发性骨髓瘤、淋巴瘤、非霍奇金淋巴瘤、非小细胞肺癌、真性红细胞增多症、白血病、甲状腺肿瘤、膀胱癌和胆囊癌，特别优选卵巢癌、乳腺癌和前列腺癌。The present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used as a medicine, especially a medicine for preventing and/or treating diseases related to AKT1/2/3 kinase activity, and treating and/or preventing diseases associated with Use in medicine of a disease associated with AKT1/2/3 kinase activity, preferably cancer, in particular cancer characterized by amplification or overexpression of AKT1/2/3, preferably ovarian cancer, breast cancer Carcinoma, prostate cancer, glioma, glioma, gastric cancer, fallopian tube cancer, lung cancer, peritoneal cancer, melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer , skin cancer, neuroblastoma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck cancer, multiple myeloma, lymphoma, non-Hodgkin's lymphoma, non-small cell lung cancer, polycythemia vera, Leukemias, thyroid tumors, bladder and gallbladder cancers, ovarian, breast and prostate cancers are particularly preferred.

本发明还涉及一种抑制AKT1/2/3的方法，其包含向有需要的受试者施用有效量的根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物。The present invention also relates to a method for inhibiting AKT1/2/3, which comprises administering an effective amount of the compound according to the present invention or its stereoisomer, tautomer, endo rotamers, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them.

本发明还涉及一种抑制癌细胞增值、抑制癌细胞侵袭或诱导癌细胞凋亡的方法，其包含向有需要的受试者施用有效量的根据本发明所述的化合物或其立体异 构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物。The present invention also relates to a method for inhibiting cancer cell proliferation, inhibiting cancer cell invasion or inducing cancer cell apoptosis, which comprises administering an effective amount of the compound according to the present invention or its stereoisomer to a subject in need , tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

本发明还涉及一种预防和/或治疗与AKT1/2/3激酶活性相关的疾病的方法，其包含向有需要的受试者施用有效量的根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物，所述疾病优选癌症，特别是与以AKT1/2/3的扩增或过表达为特征的癌症，所述癌症优选卵巢癌、乳腺癌、前列腺癌、神经胶质瘤、胶质细胞瘤、胃癌、输卵管癌、肺癌、腹膜肿瘤、黑色素瘤、脑癌、食管癌、肝癌、胰腺癌、结直癌、肺癌、肾癌、宫颈癌、皮肤癌、神经母细胞瘤、肉瘤、骨癌、子宫癌、子宫内膜癌、头颈肿瘤、多发性骨髓瘤、淋巴瘤、非霍奇金淋巴瘤、非小细胞肺癌、真性红细胞增多症、白血病、甲状腺肿瘤、膀胱癌和胆囊癌，特别优选卵巢癌、乳腺癌和前列腺癌。The present invention also relates to a method for preventing and/or treating diseases associated with AKT1/2/3 kinase activity, which comprises administering to a subject in need thereof an effective amount of a compound according to the present invention or a stereoisomer thereof isomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, The disease is preferably cancer, especially a cancer characterized by amplification or overexpression of AKT1/2/3, the cancer is preferably ovarian cancer, breast cancer, prostate cancer, glioma, glioma, gastric cancer , fallopian tube cancer, lung cancer, peritoneal tumor, melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer, skin cancer, neuroblastoma, sarcoma, bone cancer, uterine cancer , endometrial cancer, head and neck tumors, multiple myeloma, lymphoma, non-Hodgkin's lymphoma, non-small cell lung cancer, polycythemia vera, leukemia, thyroid tumors, bladder cancer and gallbladder cancer, particularly preferably ovarian cancer, Breast and prostate cancer.

根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物可以与另外一种抗癌治疗剂或抗癌治疗方法同时、分开或相继施用。Compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or A pharmaceutically acceptable salt or a pharmaceutical composition comprising the same may be administered simultaneously, separately or sequentially with another anticancer therapeutic agent or method of anticancer treatment.

术语说明Glossary

除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

“烷基”是指饱和的脂族烃基，其包括具有指定碳原子数的直链和支链基团。烷基通常含有1-20个碳原子(C 1-C 20烷基)，优选1至12个碳原子(C 1-C 12烷基)，更优选1至8个碳原子(C 1-C 8烷基)或1至6个碳原子(C 1-C 6烷基)或1至4个碳原子(C 1-C 4烷基)。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代。适用于烷基的任选的取代基包括但不限于卤素、氨基、硝基、氰基(-CN)、羟基(-OH)、巯基(-SH)、羧基(-COOH)、酯基、氧代基(＝O)、硫代基(＝S)、＝N-CN、烷氧基、芳基氧基、杂芳基氧基、卤代烷基、卤代烷氧基、羟基烷基、烷基氨基、烯基、炔基、环烷基、杂环基、芳基、杂芳基。在一些实 施方案中，烷基任选被一个或多个取代基，优选被1-3个取代基取代。 "Alkyl" means a saturated aliphatic hydrocarbon group including straight and branched chain groups having the indicated number of carbon atoms. The alkyl group usually contains 1-20 carbon atoms (C 1 -C 20 alkyl), preferably 1 to 12 carbon atoms (C 1 -C 12 alkyl), more preferably 1 to 8 carbon atoms (C 1 -C 8 alkyl) or 1 to 6 carbon atoms (C 1 -C 6 alkyl) or 1 to 4 carbon atoms (C 1 -C 4 alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropane base, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl base, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2- Dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethyl Hexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl- 3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment. Optional substituents suitable for alkyl groups include, but are not limited to, halogen, amino, nitro, cyano (-CN), hydroxyl (-OH), mercapto (-SH), carboxyl (-COOH), ester, oxygen Substitute (=O), Thio (=S), =N-CN, Alkoxy, Aryloxy, Heteroaryloxy, Haloalkyl, Haloalkoxy, Hydroxyalkyl, Alkylamino, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl. In some embodiments, an alkyl group is optionally substituted with one or more substituents, preferably 1-3 substituents.

本文所述的任选取代的烷基可以被一个或多个取代基取代，除非另有说明，否则这些取代基是独立选择的。在这种取代具有化学意义的程度上，取代基的总数可以等于烷基基团上的氢原子总数。任选取代的烷基通常含有1至6个任选的取代基，有时1至5个任选的取代基，优选1至4个任选的取代基，或更优选1至3个任选的取代基。特别地，除非另外指出，烷基可以被一个或多个(直至烷基基团上存在的氢原子总数)卤素基团取代。Optionally substituted alkyl groups described herein may be substituted with one or more substituents, which are independently selected unless otherwise stated. To the extent such substitution is chemically significant, the total number of substituents can be equal to the total number of hydrogen atoms on the alkyl group. Optionally substituted alkyl typically contains 1 to 6 optional substituents, sometimes 1 to 5 optional substituents, preferably 1 to 4 optional substituents, or more preferably 1 to 3 optional substituents Substituents. In particular, unless otherwise indicated, an alkyl group may be substituted by one or more (up to the total number of hydrogen atoms present on the alkyl group) halo groups.

术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基。烯基通常含有2-20个碳原子(C 2-C 20烯基)，优选2至12个碳原子(C 2-C 12烯基)，更优选2至8个碳原子(C 2-C 8烯基)或2至6个碳原子(C 2-C 6烯基)或2至4个碳原子(C 2-C 4烯基)。烯基的非限定性实例包括乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷基氧基、杂环基氧基、环烷基硫基、杂环基硫基。 The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Alkenyl usually contains 2 to 20 carbon atoms (C 2 -C 20 alkenyl), preferably 2 to 12 carbon atoms (C 2 -C 12 alkenyl), more preferably 2 to 8 carbon atoms (C 2 -C 8 alkenyl) or 2 to 6 carbon atoms (C 2 -C 6 alkenyl) or 2 to 4 carbon atoms (C 2 -C 4 alkenyl). Non-limiting examples of alkenyl include ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, hetero Cyclosulfanyl.

术语“炔基”指由至少由两个碳原子和至少一个碳-碳三键组成的如上定义的烷基。炔基通常含有2-20个碳原子(C 2-C 20炔基)，优选2至12个碳原子(C 2-C 12炔基)，更优选2至8个碳原子(C 2-C 8炔基)或2至6个碳原子(C 2-C 6炔基)或2至4个碳原子(C 2-C 4炔基)。炔基的非限定性实例包括乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷基氧基、杂环基氧基、环烷基硫基、杂环基硫基。 The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkynyl group usually contains 2 to 20 carbon atoms (C 2 -C 20 alkynyl), preferably 2 to 12 carbon atoms (C 2 -C 12 alkynyl), more preferably 2 to 8 carbon atoms (C 2 -C 8 alkynyl) or 2 to 6 carbon atoms (C 2 -C 6 alkynyl) or 2 to 4 carbon atoms (C 2 -C 4 alkynyl). Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, hetero Cyclosulfanyl.

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。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene base, cyclooctyl, etc. Multicyclic cycloalkyls include spiro, fused and bridged cycloalkyls.

术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The π-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

Figure PCTCN2022136451-appb-000026
Figure PCTCN2022136451-appb-000026

术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include:

Figure PCTCN2022136451-appb-000027
Figure PCTCN2022136451-appb-000027

术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated π-electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

Figure PCTCN2022136451-appb-000028
Figure PCTCN2022136451-appb-000028

所述环烷基环可以稠合于芳基、杂芳基或杂环基环上，其中与母体结构相连接的环为环烷基，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，其独立地选自烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷基氧基、杂环基氧基、环烷基硫基、杂环基硫基、氧代基、羧基或羧酸酯基。The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, Benzocycloheptyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl Oxy group, cycloalkylthio group, heterocyclylthio group, oxo group, carboxyl group or carboxylate group.

术语“杂环基”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14个环原子，其中1～4个是杂原子；或者包含3至8个环原子，其中1～3个是杂原子；或者包含5至7个环原子，其中1～2或1～3个是杂原子；或者包含3至6个环原子，其中1～2个是杂原子。单环杂环基的非限制性实例包括氧杂环丁烷基、氮杂环丁烷基、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、吡喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably contain 3 to 14 ring atoms, of which 1 to 4 are heteroatoms; or contain 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; or contain 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms; or contain 3 to 6 ring atoms, of which 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuryl , Dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环 杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为6至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括： The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclyls include:

Figure PCTCN2022136451-appb-000029
Figure PCTCN2022136451-appb-000029

术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为6至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括： The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated π-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring The atom is carbon. Preferably it is 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

Figure PCTCN2022136451-appb-000030
Figure PCTCN2022136451-appb-000030

术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为6至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括： The term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond. A pi-electron system of a yoke wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

Figure PCTCN2022136451-appb-000031
Figure PCTCN2022136451-appb-000031

所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构相连接的环为杂环基，其非限制性实例包括：The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

Figure PCTCN2022136451-appb-000032
等。
Figure PCTCN2022136451-appb-000032
wait.

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，其独立地选自烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷基氧基、杂环基氧基、环烷基硫基、杂环基硫基、氧代基、羧基或羧酸酯基。Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl Oxy group, cycloalkylthio group, heterocyclylthio group, oxo group, carboxyl group or carboxylate group.

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10元，例如苯基和萘基，更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构相连接的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as benzene and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

Figure PCTCN2022136451-appb-000033
Figure PCTCN2022136451-appb-000033

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，其独立地选自烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷基氧基、杂环基氧基、环烷基硫基、杂环基硫基、羧基或羧酸酯基。Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane Oxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, Cycloalkylthio, heterocyclylthio, carboxyl or carboxylate.

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5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；例如咪唑基、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、吡嗪基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构相连接的环为杂芳基环，其非限制性实例包括：The term "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. Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; e.g. imidazolyl, furyl, thienyl, thiazolyl, pyrazole Base, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Figure PCTCN2022136451-appb-000034
Figure PCTCN2022136451-appb-000034

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，其独立地选自烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷基氧基、杂环基氧基、环烷基硫基、杂环基硫基、羧基或羧酸酯基。Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl Oxy group, cycloalkylthio group, heterocyclylthio group, carboxyl group or carboxylate group.

术语“烷氧基”指-O-(烷基)，其中烷基定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基。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，其独立地选自烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷基氧基、杂环基氧基、环烷基硫基、杂环基硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl Oxy group, cycloalkylthio group, heterocyclylthio group, carboxyl group or carboxylate group.

术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halo, wherein alkyl is as defined above.

术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.

术语“烷硫基”指-S-(烷基)，其中烷基的定义如上所述。The term "alkylthio" refers to -S-(alkyl), wherein alkyl is as defined above.

术语“烷基氨基”指-NH-(烷基)、-N(烷基) 2-、-NH-(环烷基)或-N-(环烷基) 2，其中烷基和环烷基的定义如上所述。 The term "alkylamino" refers to -NH-(alkyl), -N(alkyl) 2 -, -NH-(cycloalkyl) or -N-(cycloalkyl) 2 , wherein alkyl and cycloalkyl is defined as above.

术语“环烷基氧基”指-O-(环烷基)，其中环烷基定义如上所述。环烷基氧基的非限制性实例包括：环丙氧基、环丁氧基、环戊氧基、环己氧基。The term "cycloalkyloxy" refers to -O-(cycloalkyl), wherein cycloalkyl is as defined above. Non-limiting examples of cycloalkyloxy include: cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.

术语“环烷基硫基”指-S-(环烷基)，其中环烷基定义如上所述。The term "cycloalkylthio" refers to -S-(cycloalkyl), wherein cycloalkyl is as defined above.

术语“杂环基氧基”指-O-(杂环基)，其中杂环基定义如上所述。The term "heterocyclyloxy" refers to -O-(heterocyclyl), wherein heterocyclyl is as defined above.

术语“杂环基硫基”指-S-(杂环基)，其中杂环基定义如上所述。The term "heterocyclylthio" refers to -S-(heterocyclyl), wherein heterocyclyl is as defined above.

术语“羟基”指-OH基团。The term "hydroxyl" refers to a -OH group.

术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.

术语“氨基”指-NH 2。 The term "amino" refers to -NH2 .

术语“氰基”指-CN。The term "cyano" refers to -CN.

术语“硝基”指-NO 2。 The term "nitro" refers to -NO2 .

术语“氧代基”指＝O。The term "oxo" refers to =O.

术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.

术语“巯基”指-SH。The term "mercapto" refers to -SH.

术语“酯基”或“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基和环烷基如上所定义。The term "ester" or "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

术语“酰基”指含有-C(O)R基团的化合物，其中R为烷基、环烷基、杂环基、芳基、杂芳基。The term "acyl" refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变，用易于脱去的基团对氨基进行保护。非限制性实施例包含叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。所述氨基保护基优选为叔丁氧羰基。The term "amino-protecting group" is used to protect the amino group with a group that can be easily removed in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro. The amino protecting group is preferably tert-butoxycarbonyl.

“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基”意味着烷基可以但不必须存在，该说明包括杂环基被烷基取代的情形和杂环基不被烷基取代的情形。"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 does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that an alkyl group may but need not be present, and the description includes both cases where the heterocyclyl is substituted by an alkyl and cases where the heterocyclyl is not substituted by an alkyl.

“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。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.

“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐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。"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients . The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.

术语“可药用盐”与“药学上可接受的盐”可以互换使用，是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。The terms "pharmaceutically acceptable salt" and "pharmaceutically acceptable salt" can be used interchangeably and refer to the salts of the compounds of the present invention, which are safe and effective when used in mammals, and have due biological activity.

“癌症”是指任何恶性和/或侵袭性生长或肿瘤(由异常细胞生长引起)。癌症包括以形成它们的细胞类型命名的实体瘤，血液、骨髓或淋巴系统的癌症。实体瘤的实例包括肉瘤和癌。血液癌症包括但不限于白血病、淋巴瘤和骨髓瘤。癌症还包括起源于身体具体部位的原发性癌症，已经从其开始的部位扩散到身体的其它部位的转移性癌症，缓解后从原始的原发性癌症的复发，以及第二原发性癌症(这是在具有与新的原发性癌症不同类型的先前癌症病史的人中的新的原发性癌症)。在本文提供的一些实施方案中，癌症可以选自乳腺癌、卵巢癌、前列腺癌、膀胱癌、子宫癌、肺癌、食道癌、肝癌、胰腺癌和胃癌。在一些这种实施方案中，癌症的特征在于AKT1/2/3的扩增或过表达。"Cancer" refers to any malignant and/or invasive growth or tumor (caused by abnormal cell growth). Cancers include solid tumors named for the type of cells that form them, cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Cancers of the blood include, but are not limited to, leukemias, lymphomas, and myelomas. Cancer also includes primary cancer that started in a specific part of the body, metastatic cancer that has spread from where it started to other parts of the body, recurrence from the original primary cancer after remission, and second primary cancer (This is a new primary cancer in a person with a history of previous cancer of a different type than the new primary cancer). In some embodiments provided herein, the cancer may be selected from breast cancer, ovarian cancer, prostate cancer, bladder cancer, uterine cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, and gastric cancer. In some such embodiments, the cancer is characterized by amplification or overexpression of AKT1/2/3.

本文所述的立体异构体可包括本发明化合物(包括表现出超过一种异构类型的化合物)的顺式和反式异构体、光学异构体如(R)和(S)对映异构体、非对映异构体、几何异构体、旋转异构体、阻转异构体、构象异构体和互变异构体；及其混合物(如外消旋体和非对映异构体对)。Stereoisomers described herein may include cis and trans isomers, optical isomers such as (R) and (S) enantiomers of the compounds of the invention (including compounds exhibiting more than one isomeric type) Isomers, diastereoisomers, geometric isomers, rotamers, atropisomers, conformers and tautomers; and mixtures thereof (such as racemates and asymmetric enantiomer pair).

本发明化合物可以表现出互变异构现象和结构异构现象。例如，化合物可以数种互变异构形式，包括烯醇和亚胺形式以及酮和烯胺形式，和几何异构体及其混合物存在。所有这种互变异构形式都包括在本发明化合物的范围内。互变异构体作为在溶液中的互变异构组的混合物存在。在固体形式中，通常一种互变异构体占优势。即使可以描述一种互变异构体，但本发明包括所提供的化合物的所有互变异构体。The compounds of the present invention may exhibit tautomerism and structural isomerism. For example, compounds may exist in several tautomeric forms, including enol and imine forms and keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of the present invention. Tautomers exist as a mixture of tautomeric sets in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the provided compounds.

用于制备/分离单一的对映异构体的常规技术包括由合适的光学纯的前体手性合成或利用例如手性高压液相色谱(HPLC)或超临界流体色谱(SFC)拆分外消旋体(或盐或衍生物的外消旋体)。Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution using, for example, chiral high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). Racemate (or racemate of salt or derivative).

本文所述化合物的对映异构体纯度可以用对映异构体过量(ee)来描述，其表示样品以比另一种对映异构体更大的量含有一种对映异构体的程度。外消旋混合物的ee为0％，而单一的完全纯的对映异构体的ee为100％。类似地，非对映异构体纯 度可以用非对映异构体过量(de)来描述。The enantiomeric purity of the compounds described herein can be described in terms of enantiomeric excess (ee), which means that a sample contains one enantiomer in a greater amount than the other Degree. The ee of a racemic mixture is 0%, while the ee of a single, completely pure enantiomer is 100%. Similarly, diastereomeric purity can be described in terms of diastereomeric excess (de).

按照本发明所属领域的常规方法，本发明化合物可以与碱或者酸生成药学上可接受的碱式加成盐或酸式加成盐。所述碱包括无机碱和有机碱，可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等，可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠等。所述酸包括无机酸和有机酸，可接受的无机酸包括盐酸、硫酸、硝酸、磷酸、氢溴酸等。可接受的有机酸包括乙酸、三氟乙酸、甲酸、抗环血酸等。According to conventional methods in the field to which the present invention belongs, the compounds of the present invention can form pharmaceutically acceptable base addition salts or acid addition salts with bases or acids. The base includes inorganic bases and organic bases. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, hydroxide Calcium, Potassium Hydroxide, Sodium Carbonate and Sodium Hydroxide etc. The acid includes inorganic acid and organic acid, acceptable inorganic acid includes hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and the like. Acceptable organic acids include acetic acid, trifluoroacetic acid, formic acid, ascorbic acid, and the like.

含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir. Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time. For example, water-soluble taste-masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending materials such as ethylcellulose, cellulose acetate butyrate may be used.

也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。Hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in which the active ingredient is admixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil may also be used. Soft gelatin capsules provide an oral formulation.

水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和阿拉伯胶；分散剂或湿润剂，可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which may be natural The resulting phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanylethyleneoxycetate Heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweeteners. Flavoring agents such as sucrose, saccharin, or aspartame.

油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油混悬液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

通过加入水，适用于制备水混悬液的可分散粉末和颗粒可以提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂如上所述。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives for admixture. Suitable dispersing or wetting agents and suspending agents are mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.

本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制的糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of said partial esters with ethylene oxide Products such as polyethylene oxide sorbitan monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.

本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒和溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated in a mixture of water and glycerol to form a microemulsion. The injectable solution or microemulsion can be injected into the patient's bloodstream by local bolus injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.

本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如在1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。The pharmaceutical composition of the present invention may be in the form of sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are prepared as injectables.

本领域技术人员熟知，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、排泄的速率、药物的组合等。另外，最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。It is well known to those skilled in the art that the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's body weight, the patient's health status, the patient's behavior, the patient's Diet, administration time, administration method, excretion rate, drug combination, etc. In addition, the optimal treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.

本发明可以含有通式所示的化合物及其药学上可接受的盐、水合物或溶剂化物作为活性成分，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型。本发明的衍生物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应等。本发明化合物可作为唯一的活性成分，也可以与其它治疗与AKT激酶活性相关的疾病的药物联合使用。联合治疗通过将各个治疗组分同时、分开或相继给药来实现。The present invention may contain the compound represented by the general formula and its pharmaceutically acceptable salt, hydrate or solvate as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare a composition, and prepared into clinically acceptable dosage form. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like. The compound of the present invention can be used as the only active ingredient, and can also be used in combination with other drugs for treating diseases related to AKT kinase activity. Combination therapy is achieved by the simultaneous, separate or sequential administration of the individual therapeutic components.

本发明化合物的合成方法The synthetic method of compound of the present invention

为了完成本发明的目的，本发明采用如下合成方案制备本发明的化合物或其 立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐。In order to accomplish the purpose of the present invention, the present invention adopts the following synthetic scheme to prepare the compound of the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

本发明通式(IIID)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐可以通过以下方案1制备：The compound represented by the general formula (IIID) of the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, can be prepared by the following Scheme 1:

Figure PCTCN2022136451-appb-000035
Figure PCTCN2022136451-appb-000035

方案1plan 1

式IIIAa的化合物与式IIIDc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IIIDb的化合物；式IIIDb的化合物在酸性条件下脱除保护基得到通式(IIID)所示的化合物；The compound of formula IIIAa and the compound of formula IIIDc obtain the compound of formula IIIDb in the presence of catalyst coupling reaction under basic conditions; compound;

所述催化剂优选苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐；The catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate;

所述碱性条件优选N,N-二异丙基乙胺；The alkaline condition is preferably N,N-diisopropylethylamine;

所述酸性条件优选盐酸。The acidic condition is preferably hydrochloric acid.

式IIIDc的化合物可以通过以下方案2制备：Compounds of formula IIIDc can be prepared by the following Scheme 2:

Figure PCTCN2022136451-appb-000036
Figure PCTCN2022136451-appb-000036

方案2Scenario 2

步骤1：在活化例如特戊酰氯的存在下，化合物a与手性助剂例如化合物b缩 合得到化合物c；Step 1: In the presence of activation such as pivaloyl chloride, compound a is condensed with a chiral auxiliary such as compound b to obtain compound c;

步骤2：在催化剂例如4-二甲氨基吡啶的存在下，化合物d与适合的化合物例如二碳酸而叔丁酯反应，得到氨基保护的化合物e；Step 2: In the presence of a catalyst such as 4-dimethylaminopyridine, compound d is reacted with a suitable compound such as tert-butyl dicarbonate to obtain amino-protected compound e;

步骤3：使用还原剂例如二异丁基氢化铝还原化合物e以得到化合物f；Step 3: reducing compound e using a reducing agent such as diisobutylaluminum hydride to obtain compound f;

步骤4：在催化剂例如对甲苯磺酸的存在下，化合物f与甲醇反应得到化合物g；Step 4: In the presence of a catalyst such as p-toluenesulfonic acid, compound f is reacted with methanol to obtain compound g;

步骤5：在适合的路易斯酸例如四氯化钛和弱碱例如N,N-二异丙基乙胺的存在下，化合物g与化合物c缩合，得到化合物h，该反应优选在低温例如-78℃至0℃进行，以在反应中获得可接受的非对映异构选择性；Step 5: Compound g is condensed with compound c in the presence of a suitable Lewis acid such as titanium tetrachloride and a weak base such as N,N-diisopropylethylamine to give compound h, preferably at low temperature such as -78 °C to 0 °C to obtain acceptable diastereoselectivity in the reaction;

步骤6：在碱例如氢氧化锂和水解手性助剂例如双氧水的存在下，将化合物h水解，得到式IIIBc的化合物。Step 6: Compound h is hydrolyzed in the presence of a base such as lithium hydroxide and a hydrolytic chiral auxiliary such as hydrogen peroxide to obtain a compound of formula IIIBc.

当每个R 2各自独立地为甲基和羟基，且n为2时，式IIIAa的化合物可以通过以下方案3制备，当R 2选自其它基团时，本领域技术人员可容易地参照此方法进行制备： When each R 2 is independently methyl and hydroxyl, and n is 2, the compound of formula IIIAa can be prepared by the following scheme 3, when R 2 is selected from other groups, those skilled in the art can easily refer to this Method for preparation:

Figure PCTCN2022136451-appb-000037
Figure PCTCN2022136451-appb-000037

方案3Option 3

在标准条件下(例如，三氯氧磷)由羟基嘧啶Ij制得化合物Ik；使化合物Ik与需要的哌嗪进行反应，得到化合物Il；化合物Il用碱如氢氧化锂水解，得到化合物Im；在碱如碳酸铯的存在下使化合物Im与溴化苄反应，得到化合物In；化合物In与一氧化碳反应得到化合物Io；化合物Io发生环化反应，得到化合物Ip；使用钯碳和酸如甲酸除去苄氧羰基以提供化合物Iq；在还原剂如甲酸的存在下，使用手性催化剂对化合物Iq进行不对称还原得到Ir；；然后通过用大位阻的特戊酰氯衍生化得到化合物Is来分离非对映异构体；水解得到化合物It；然后使化合物It脱保护以提供化合物Iu。Compound Ik is prepared from hydroxypyrimidine Ij under standard conditions (eg, phosphorus oxychloride); compound Ik is reacted with the desired piperazine to give compound Il; compound Il is hydrolyzed with a base such as lithium hydroxide to give compound Im; Compound Im is reacted with benzyl bromide in the presence of a base such as cesium carbonate to give compound In; compound In is reacted with carbon monoxide to give compound Io; compound Io is cyclized to give compound Ip; benzyl is removed using palladium on carbon and an acid such as formic acid oxycarbonyl to provide compound Iq; asymmetric reduction of compound Iq using a chiral catalyst in the presence of a reducing agent such as formic acid affords Ir; Enantiomers; hydrolysis affords Compound It; compound It is then deprotected to afford Compound Iu.

其中，in,

R x为氨基保护基，优选Boc； R x is an amino protecting group, preferably Boc;

G、R 2、R 3、R 4、X 1、X 2、R c、n、n 1、n 2、q、r、s如通式(IIID)所定义。 G, R 2 , R 3 , R 4 , X 1 , X 2 , R c , n, n 1 , n 2 , q, r, s are as defined in the general formula (IIID).

附图说明Description of drawings

图1为试验例4中各组小鼠中的肿瘤生长曲线。Figure 1 is the tumor growth curves in mice of each group in Test Example 4.

具体实施方式Detailed ways

进一步通过实施例来理解本发明的化合物及其制备，这些实施例说明了一些制备或使用所述化合物的方法。然而，要理解的是，这些实施例并不限制本发明的范围。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和要求保护的本发明范围之内。The compounds of the invention and their preparation are further understood by the examples, which illustrate some of the methods of making or using the compounds. However, it is to be understood that these examples do not limit the scope of the present invention. Variations of the invention now known or further developed are considered to fall within the scope of the invention described and claimed herein.

本发明化合物是利用便利的起始原料和通用的制备步骤来完成制备的。本发明给出了典型的或倾向性的反应条件，诸如反应温度、时间、溶剂、压力、反应物的摩尔比。但是除非特殊说明，其他反应条件也能采纳。优化条件可能随着具体的反应物或溶剂的使用而改变，但在通常情况下，反应优化步骤和条件都能得到确定。The compounds of the present invention are prepared utilizing convenient starting materials and general preparative procedures. The present invention gives typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But unless otherwise specified, other reaction conditions can also be adopted. Optimum conditions may vary with specific reactants or solvents used, but in general, reaction optimization steps and conditions can be identified.

另外，本发明中可能用到了一些保护基团来保护某些官能团避免不必要的反应。适宜于各种官能团的保护基以及它们的保护或脱保护条件已经为本领域技术人员广泛熟知。例如T.W.Greene和G.M.Wuts的《有机制备中的保护基团》(第3版,Wiley,New York,1999和书中的引用文献)详细描述了大量的保护基团的保护或脱保护。In addition, some protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions. Suitable protecting groups for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, "Protecting Groups in Organic Preparations" by T.W. Greene and G.M. Wuts (3rd Edition, Wiley, New York, 1999 and citations in the book) describes in detail the protection or deprotection of a large number of protecting groups.

化合物和中间体的分离和纯化依据具体的需求采取适当的方法和步骤，例如过滤、萃取、蒸馏、结晶、柱层析、制备薄层色谱、制备高效液相色谱或上述方法的混合使用。其具体使用方法可参阅本发明描述的实例。当然，其他类似的分离和纯化手段也是可以采用的。可以使用常规方法(包括物理常数和波谱数据)对其进行表征。The separation and purification of compounds and intermediates takes appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography or a combination of the above methods. For its specific usage method, please refer to the examples described in the present invention. Of course, other similar separation and purification means can also be used. They can be characterized using conventional methods, including physical constants and spectral data.

化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10 -6(ppm)的单位给出。NMR的测定是用Brukerdps 300型核磁仪，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)。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts are given in units of 10 -6 (ppm). The determination of NMR is a Brukerdps 300 type nuclear magnetic analyzer, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethyl sulfoxide. trimethylsilane (TMS).

MS的测定用LC(Waters 2695)/MS(Quattro Premier xE)质谱仪(生产商：沃特世)(Photodiode Array Detector)。MS was determined by LC (Waters 2695)/MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector).

制备高效液相色谱法使用lc6000高效液相色谱仪(生产商：创新通恒)。色谱柱为DaisogelC18 10μm 100A(30mm×250mm)，流动相：乙腈/水。Preparative high performance liquid chromatography uses lc6000 high performance liquid chromatography (manufacturer: Innovation Tongheng). Chromatographic column is DaisogelC18 10μm 100A (30mm×250mm), mobile phase: acetonitrile/water.

薄层层析硅胶板使用青岛海洋化工GF254硅胶板，薄层色谱法(TLC)使用的硅 胶板采用的规格是0.20mm～0.25mm，制备薄层层析分离纯化产品采用的规格是0.5mm。The thin-layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate. The specification of the silica gel plate used for thin-layer chromatography (TLC) is 0.20mm-0.25mm, and the specification used for the preparation of thin-layer chromatography separation and purification products is 0.5mm.

柱层析一般使用青岛海洋硅胶100～200目、200～300目和300～400目硅胶为载体。Column chromatography generally uses Qingdao Marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

本发明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，或可购买自网化商城、北京偶合、Sigma、百灵威、易世明、上海书亚、上海伊诺凯、安耐吉化学、上海毕得等公司。The known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Wanghua Mall, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Biide and other companies.

实施例中无特殊说明，反应能够均在氮气氛下进行。Unless otherwise specified in the examples, the reactions can all be carried out under a nitrogen atmosphere.

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。Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.

反应溶剂、有机溶剂或惰性溶剂各自表述为使用的该溶剂在所描述的反应条件下不参与反应，包括如苯、甲苯、乙腈、四氢呋喃(THF)、二甲基甲酰胺(DMF)、氯仿、二氯甲烷、乙醚、甲醇、氮-甲基吡咯碄酮(NMP)、吡啶等。实施例中无特殊说明，溶液是指水溶液。Reaction solvents, organic solvents or inert solvents are each expressed as that the solvent used does not participate in the reaction under the described reaction conditions, including such as benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, Dichloromethane, ether, methanol, nitrogen-methylpyrrolidinone (NMP), pyridine, etc. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

本发明中所描述的化学反应一般在常压下进行。反应温度在-78℃至200℃之间。反应时间和条件为，例如，一个大气压下，-78℃至200℃之间，大约1至24小时内完成。如果反应过夜，则反应时间一般为16小时。实施例中无特殊说明，反应的温度为室温，为20℃～30℃。The chemical reactions described in the present invention are generally carried out under normal pressure. The reaction temperature is between -78°C and 200°C. The reaction time and conditions are, for example, between -78°C and 200°C under one atmospheric pressure, and the reaction is completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.

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的体系有：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，C：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。The monitoring of the reaction process in the embodiment adopts thin layer chromatography (TLC), and the system of developing agent used in the reaction has: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, C: acetone, The volume ratio of the solvent is adjusted according to the polarity of the compound.

纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，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三氟乙酸等碱性或酸性试剂进行调节。The eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography include: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, the volume ratio of solvent is according to the compound It can be adjusted according to the polarity, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid.

除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention.

根据本文提供的示例性程序及其本领域技术人员已知的改变来制备本发明的化合物。Compounds of the invention are prepared according to the exemplary procedures provided herein and variations thereof known to those skilled in the art.

实施例Example

实施例1：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((S)-2-氮杂螺[4.4]壬-3-基)乙-1-酮(1)的制备Example 1: (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta Preparation of alkano[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-2-azaspiro[4.4]non-3-yl)ethan-1-one (1)

Figure PCTCN2022136451-appb-000038
Figure PCTCN2022136451-appb-000038

步骤1：(R)-3-(4,6-二氯嘧啶-5-基)丁酸甲酯(1a)的制备Step 1: Preparation of (R)-methyl 3-(4,6-dichloropyrimidin-5-yl)butanoate (1a)

于室温，将(R)-3-(4,6-二羟基嘧啶-5-基)丁酸甲酯(40.0g,189mmol)、乙腈(400mL)加入至反应瓶中，一次性加入2,6-二甲基吡啶(20.0g,187mmol)，冰浴降温至5℃左右，滴加三氯氧磷(86.4g,564mmol)，滴毕加热至75℃反应10小时。反应结束后以6mol/L NaOH水溶液淬灭反应，浓缩后以乙酸乙酯和水稀释，水相以乙酸乙酯萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(PE:EA＝10:1)，得33.2g无色油状的标题产物，直接用于下一步，产率70.9％。 At room temperature, (R)-3-(4,6-dihydroxypyrimidin-5-yl)butanoic acid methyl ester (40.0g, 189mmol) and acetonitrile (400mL) were added to the reaction flask, and 2,6 -Lutidine (20.0g, 187mmol), cooled to about 5°C in an ice bath, added dropwise phosphorus oxychloride (86.4g, 564mmol), and heated to 75°C for 10 hours after dropping. After the reaction was completed, the reaction was quenched with 6mol/L NaOH aqueous solution, diluted with ethyl acetate and water after concentration, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (PE:EA=10:1) to obtain 33.2 g of the title product as a colorless oil, which was directly used in the next step with a yield of 70.9%.

LCMS:m/z 249.01[M+H] +。 LCMS: m/z 249.01 [M+H] + .

步骤2：(R)-4-(6-氯-5-(4-甲氧基-4-氧代丁烷-2-基)嘧啶-4-基)哌嗪-1-羧酸叔丁 酯(1b)的制备Step 2: (R)-tert-butyl 4-(6-chloro-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate Preparation of (1b)

于室温，将(R)-3-(4,6-二氯嘧啶-5-基)丁酸甲酯(30.0g,120.6mmol)、甲醇(300mL)、N-Boc-哌嗪(24.6g,132mmol)、DIPEA(23.4g,181mmol)依次加入至反应瓶中，60℃反应10小时。反应结束后直接浓缩，以乙酸乙酯和饱和氯化铵水溶液稀释，水相以乙酸乙酯萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(PE:EA＝5:1)，得46.8g无色油状的标题产物，直接用于下一步，产率97.5％。 At room temperature, (R)-3-(4,6-dichloropyrimidin-5-yl)butanoic acid methyl ester (30.0g, 120.6mmol), methanol (300mL), N-Boc-piperazine (24.6g, 132mmol), DIPEA (23.4g, 181mmol) were sequentially added into the reaction flask, and reacted at 60°C for 10 hours. Concentrate directly after the reaction, dilute with ethyl acetate and saturated aqueous ammonium chloride, extract the aqueous phase with ethyl acetate, combine the organic phases, dry over anhydrous Na2SO4 , filter, concentrate the filtrate under reduced pressure , and pass the residue through the column layer Separation and purification by chromatography (PE:EA=5:1) gave 46.8 g of the title product as a colorless oil, which was directly used in the next step with a yield of 97.5%.

LCMS:m/z 399.17[M+H] +。 LCMS: m/z 399.17 [M+H] + .

步骤3：(R)-3-(4-(4-(叔丁氧羰基)哌嗪-1-基)-6-氯嘧啶-5-基)丁酸(1c)的制备Step 3: Preparation of (R)-3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloropyrimidin-5-yl)butanoic acid (1c)

于室温，将(R)-4-(6-氯-5-(4-甲氧基-4-氧代丁烷-2-基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯(46.8g,118mmol)、四氢呋喃(480mL)、水(150mL)加入至反应瓶中，冰浴降温至5℃左右，分批加入氢氧化锂(14.8g,353mmol)，室温反应10小时。反应结束以4mol/L盐酸调节pH＝3.5，析出白色固体，过滤烘干得42.0g白色固态的标题产物，直接用于下一步，产率93.3％。At room temperature, (R)-4-(6-chloro-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl Ester (46.8g, 118mmol), tetrahydrofuran (480mL), and water (150mL) were added to the reaction flask, cooled to about 5°C in an ice bath, lithium hydroxide (14.8g, 353mmol) was added in batches, and reacted at room temperature for 10 hours. At the end of the reaction, the pH was adjusted to 3.5 with 4 mol/L hydrochloric acid, and a white solid was precipitated. After filtration and drying, 42.0 g of the title product was obtained as a white solid, which was directly used in the next step with a yield of 93.3%.

LCMS:m/z 385.16[M+H] +。 LCMS: m/z 385.16 [M+H] + .

步骤4：(R)-4-(5-(4-(苄氧基)-4-氧代丁烷-2-基)-6-氯嘧啶-4-基)哌嗪-1-羧酸叔丁酯(1d)的制备Step 4: (R)-4-(5-(4-(Benzyloxy)-4-oxobutan-2-yl)-6-chloropyrimidin-4-yl)piperazine-1-carboxylic acid tert Preparation of butyl ester (1d)

于室温，将(R)-3-(4-(4-(叔丁氧羰基)哌嗪-1-基)-6-氯嘧啶-5-基)丁酸(33.9g，83.4mmol)、DMF(510mL)加入至反应瓶中，分批加入碳酸铯(30.0g,91.8mmol)，滴加溴化苄(15.0g,87.6mmol)，加毕室温10小时。反应结束后将反应体系倒入水中，水相以乙酸乙酯萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(PE:EA＝5:1)，得34.2g无色油状的标题产物，直接用于下一步，产率82.6％。 At room temperature, (R)-3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloropyrimidin-5-yl)butanoic acid (33.9g, 83.4mmol), DMF (510 mL) was added to the reaction flask, cesium carbonate (30.0 g, 91.8 mmol) was added in batches, benzyl bromide (15.0 g, 87.6 mmol) was added dropwise, and the addition was completed at room temperature for 10 hours. After the reaction, the reaction system was poured into water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE: EA=5:1), 34.2 g of the title product was obtained as a colorless oil, which was directly used in the next step with a yield of 82.6%.

LCMS:m/z 475.2[M+H] +。 LCMS: m/z 475.2 [M+H] + .

步骤5：(R)-5-(4-(苄氧基)-4-氧代丁烷-2-基)-6-(4-(叔丁氧羰基)哌嗪-1-基)嘧啶-4-羧酸异丙酯(1e)的制备Step 5: (R)-5-(4-(Benzyloxy)-4-oxobutan-2-yl)-6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine- Preparation of isopropyl 4-carboxylate (1e)

于室温，将(R)-4-(5-(4-(苄氧基)-4-氧代丁烷-2-基)-6-氯嘧啶-4-基)哌嗪-1-羧酸叔丁酯(24g,50.4mmol)、醋酸钯(1.70g,7.56mmol)、dppp(3.42g,8.28mmol)、碳酸钠(5.88g,55.5mmol)、异丙醇(360mL)加入至反应釜中，一氧化碳置换釜内空气，加压至0.80MPa，75℃反应10小时。反应结束后直接浓缩，残余物通过柱层析色谱法分离纯化(PE:EA＝5:1)，得19.2g淡黄色油状的标题产物，直接用于下一步，产率72.7％。At room temperature, (R)-4-(5-(4-(benzyloxy)-4-oxobutan-2-yl)-6-chloropyrimidin-4-yl)piperazine-1-carboxylic acid Tert-butyl ester (24g, 50.4mmol), palladium acetate (1.70g, 7.56mmol), dppp (3.42g, 8.28mmol), sodium carbonate (5.88g, 55.5mmol), and isopropanol (360mL) were added to the reaction kettle , replace the air in the kettle with carbon monoxide, pressurize to 0.80MPa, and react at 75°C for 10 hours. Concentrate directly after the reaction, and the residue is separated and purified by column chromatography (PE:EA=5:1) to obtain 19.2 g of the title product as light yellow oil, which is directly used in the next step with a yield of 72.7%.

LCMS:m/z 527.28[M+H] +。 LCMS: m/z 527.28 [M+H] + .

步骤6：(S)-4-(4-(叔丁氧羰基)哌嗪-1-基)-7-羟基-5-甲基-5H-环戊烷并[d]嘧啶-6-羧酸苄基酯(1f)的制备Step 6: (S)-4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidine-6-carboxylic acid Preparation of benzyl ester (1f)

于室温，将(R)5-(4-(苄氧基)-4-氧代丁烷-2-基)-6-(4-(叔丁氧羰基)哌嗪-1-基)嘧 啶-4-羧酸异丙酯(15.0g,28.4mmol)、四氢呋喃(225mL)加入至反应瓶中，冰浴降温至5℃左右，分批加入叔丁醇钾(4.80g，42.9mmol)，加毕室温反应3小时。反应结束后以甲酸调节pH＝5，浓缩后得8.70g粗品，直接用于下一步。At room temperature, (R) 5-(4-(benzyloxy)-4-oxobutan-2-yl)-6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine- Add isopropyl 4-carboxylate (15.0g, 28.4mmol) and tetrahydrofuran (225mL) into the reaction flask, cool down to about 5°C in an ice bath, add potassium tert-butoxide (4.80g, 42.9mmol) in batches, and complete the addition React at room temperature for 3 hours. After the reaction, the pH was adjusted to 5 with formic acid, and 8.70 g of crude product was obtained after concentration, which was directly used in the next step.

LCMS:m/z 467.2[M+H] +。 LCMS: m/z 467.2 [M+H] + .

步骤7：(R)-4-(5-甲基-7-氧代-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(1g)的制备Step 7: (R)-4-(5-Methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert Preparation of butyl ester (1g)

于室温，将(S)-4-(4-(叔丁氧羰基)哌嗪-1-基)-7-羟基-5-甲基-5H-环戊烷并[d]嘧啶-6-羧酸苄基酯(13.5g粗品)、四氢呋喃(225mL)、钯碳(1.50g)、甲酸(15mL)加入至反应瓶中，在氮气氛下，室温反应48小时。反应结束后以饱和碳酸氢钠水溶液淬灭反应，过滤滤液以二氯甲烷萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(DCM:MeOH＝20:1)，得8.70g褐色油状的标题产物，直接用于下一步，两步产率91.8％。 At room temperature, (S)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidine-6-carboxy Acetate benzyl ester (13.5g crude product), tetrahydrofuran (225mL), palladium carbon (1.50g), formic acid (15mL) were added into the reaction flask, and reacted at room temperature for 48 hours under nitrogen atmosphere. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate solution, the filtered filtrate was extracted with dichloromethane, the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM:MeOH=20:1), 8.70 g of the title product in the form of brown oil was obtained, which was directly used in the next step, and the yield of the two steps was 91.8%.

LCMS:m/z 333.18[M+H] +。 LCMS: m/z 333.18 [M+H] + .

步骤8：4-((5R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(1h)的制备Step 8: tert-butyl 4-((5R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate Preparation of ester (1h)

于室温，将(R)-4-(5-甲基-7-氧代-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(7.89g,23.8mmol)、二氯甲烷(100mL)加入至反应瓶中，在氮气氛下，一次性加入三乙胺(2.90g,28.7mmol)，冰浴降温至5℃左右，滴加甲酸(1.65g,35.8mmol)，一次性加入对伞花烃CAS:192139-92-7(142mg,0.230mmol)，室温反应10小时。反应结束后直接浓缩，残余物通过柱层析色谱法分离纯化(DCM:MeOH＝20:1)，得9.15g黄色油状粗品，直接用于下一步。At room temperature, (R)-4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylic acid Tert-butyl ester (7.89g, 23.8mmol) and dichloromethane (100mL) were added to the reaction flask, under a nitrogen atmosphere, triethylamine (2.90g, 28.7mmol) was added at one time, and the temperature was cooled to about 5°C in an ice bath. Formic acid (1.65g, 35.8mmol) was added dropwise, p-cymene CAS: 192139-92-7 (142mg, 0.230mmol) was added in one go, and the reaction was carried out at room temperature for 10 hours. After the reaction was completed, it was directly concentrated, and the residue was separated and purified by column chromatography (DCM:MeOH=20:1) to obtain 9.15 g of a yellow oily crude product, which was directly used in the next step.

LCMS:m/z 335.20[M+H] +。 LCMS: m/z 335.20 [M+H] + .

步骤9：4-((5R,7R)-5-甲基-7-(新戊酰氧基)-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(1i)的制备Step 9: 4-((5R,7R)-5-Methyl-7-(pivaloyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piper Preparation of tert-butylazine-1-carboxylate (1i)

于室温，将4-((5R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(9.15g,27.4mmol)、二氯甲烷(130mL)加入至反应瓶中，氮气氛下，一次性加入TEA(3.32g,32.9mmol)，冰浴降温至5℃左右，滴加特戊酰氯(3.63g,30.2mmol)，室温反应10小时。反应结束后将反应体系倒入水中，水相以二氯甲烷萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(PE:EA＝5:1)，得8.50g(TLC上点)淡褐色油状的标题产物，直接用于下一步，产率74.2％。 At room temperature, 4-((5R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert Butyl ester (9.15g, 27.4mmol) and dichloromethane (130mL) were added to the reaction flask, under nitrogen atmosphere, TEA (3.32g, 32.9mmol) was added at one time, the temperature was cooled to about 5°C in an ice bath, and pentapentyl was added dropwise Acyl chloride (3.63g, 30.2mmol), react at room temperature for 10 hours. After the reaction, the reaction system was poured into water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE: EA=5:1), to obtain 8.50 g (TLC spot) of the title product as light brown oil, which was directly used in the next step with a yield of 74.2%.

LCMS:m/z 419.26[M+H] +。 LCMS: m/z 419.26 [M+H] + .

步骤10：4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(1j)的制备Step 10: 4-((5R,7R)-7-Hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylic acid Preparation of tert-butyl ester (1j)

于室温，将4-((5R,7R)-5-甲基-7-(新戊酰氧基)-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(3.50g,8.37mmol)、四氢呋喃(24mL)、水(12mL)加入 至反应瓶中，冰浴降温至5℃左右，分批加入氢氧化锂(1.05g,25.0mmol)，加毕室温反应10小时。反应结束以4mol/L盐酸调节pH＝3.5，以二氯甲烷萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(DCM:MeOH＝20:1)，得2.70g淡褐色油状的标题产物，直接用于下一步，产率96.7％。 At room temperature, 4-((5R,7R)-5-methyl-7-(pivaloyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl) Piperazine-1-carboxylate tert-butyl ester (3.50g, 8.37mmol), tetrahydrofuran (24mL) and water (12mL) were added to the reaction flask, cooled to about 5°C in an ice bath, and lithium hydroxide (1.05g , 25.0mmol), and reacted at room temperature for 10 hours after addition. After the reaction was completed, the pH was adjusted to 3.5 with 4 mol/L hydrochloric acid, extracted with dichloromethane, the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM: MeOH=20:1), 2.70 g of the title product in the form of pale brown oil was obtained, which was directly used in the next step with a yield of 96.7%.

LCMS:m/z 335.2[M+H] +。 LCMS: m/z 335.2 [M+H] + .

步骤11：(5R,7R)-5-甲基-4-(哌嗪-1-基)-6,7-二氢-5H-环戊烷并[d]嘧啶-7-醇二盐酸盐(1k)的制备Step 11: (5R,7R)-5-Methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride Preparation of (1k)

于室温，将4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(200mg,0.600mmol)、无水乙醇(3mL)加入至反应瓶中，冰浴降温至5℃左右，滴加盐酸/二氧六环溶液(0.45mL,1.80mmol)，室温反应10小时。反应结束浓缩得162mg粗品直接用于下一步。At room temperature, 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxy Add tert-butyl acetate (200mg, 0.600mmol) and absolute ethanol (3mL) into the reaction flask, cool down to about 5°C in an ice bath, add hydrochloric acid/dioxane solution (0.45mL, 1.80mmol) dropwise, and react at room temperature 10 hours. After the reaction was completed and concentrated, 162 mg of the crude product was directly used in the next step.

LCMS:m/z 235.15[M+H] +。 LCMS: m/z 235.15 [M+H] + .

步骤12：2-环戊亚基乙酸甲酯(1l)的制备Step 12: Preparation of methyl 2-cyclopentylene acetate (1l)

将2-(二乙氧基磷酰基)乙酸甲酯(32.5g，0.130mol)溶于无水四氢呋喃(80mL)中，于冰浴下，分批缓慢加入氢化钠(3.71g，0.130mol)，于室温反应1小时。然后加入环戊酮(10.0g，0.120mol)，并于室温搅拌4小时。将反应液减压浓缩，残余物用乙酸乙酯和水萃取，有机相干燥并减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝0:1-1:10)，得到油状标题化合物11.9g，收率：70.8％。Methyl 2-(diethoxyphosphoryl)acetate (32.5 g, 0.130 mol) was dissolved in anhydrous tetrahydrofuran (80 mL), and sodium hydride (3.71 g, 0.130 mol) was slowly added in batches under an ice bath, React at room temperature for 1 hour. Cyclopentanone (10.0 g, 0.120 mol) was then added and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was extracted with ethyl acetate and water, the organic phase was dried and concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (mobile phase: EA/PE=0:1-1: 10) to obtain 11.9 g of the title compound as an oil, yield: 70.8%.

LCMS：m/z 141[M+H] +。 LCMS: m/z 141 [M+H] + .

步骤13：2-(1-(硝基甲基)环戊基)乙酸甲酯(1m)的制备Step 13: Preparation of methyl 2-(1-(nitromethyl)cyclopentyl)acetate (1m)

于室温，将2-环亚戊基乙酸甲酯(11.9g，0.850mol)加入二甲基亚砜(50mL)中，然后依次加入碳酸铯(5.59，0.17mol)和硝基甲烷(7.33g，1.19mol)，于80℃搅拌过夜。反应液用冰醋酸(2.04g，0.340mol)淬灭，用甲基叔丁基醚萃取，有机相干燥，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝0:1-1:10)，得到标题化合物16.5g，收率：96.6％。At room temperature, methyl 2-cyclopentylene acetate (11.9 g, 0.850 mol) was added into dimethyl sulfoxide (50 mL), then cesium carbonate (5.59, 0.17 mol) and nitromethane (7.33 g, 1.19mol), stirred overnight at 80°C. The reaction solution was quenched with glacial acetic acid (2.04g, 0.340mol), extracted with methyl tert-butyl ether, the organic phase was dried, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: EA/PE =0:1-1:10), to obtain 16.5 g of the title compound, yield: 96.6%.

LCMS：m/z 202[M+H] +。 LCMS: m/z 202 [M+H] + .

步骤14：2-氮杂螺[4.4]壬烷-3-酮(1n)的制备Step 14: Preparation of 2-azaspiro[4.4]nonan-3-one (1n)

于室温，将2-(1-(硝基甲基)环戊基)乙酸甲酯(1.00g，4.98mmol)加入乙酸乙酯(5mL)中，然后加入钯炭催化剂(200mg)。于室温，氢气氛下，搅拌过夜。反应液过滤，有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：MeOH/DCM＝0:1-1:50)，得标题化合物550mg，收率：79.4％。Methyl 2-(1-(nitromethyl)cyclopentyl)acetate (1.00 g, 4.98 mmol) was added to ethyl acetate (5 mL) at room temperature, followed by palladium on carbon catalyst (200 mg). Stir overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered, the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: MeOH/DCM=0:1-1:50) to obtain 550 mg of the title compound, yield: 79.4%.

LCMS：m/z 140[M+H] +。 LCMS: m/z 140 [M+H] + .

步骤15：3-氧代-2-氮杂螺[4.4]壬烷-2-羧酸叔丁酯(1o)的制备Step 15: Preparation of tert-butyl 3-oxo-2-azaspiro[4.4]nonane-2-carboxylate (1o)

于室温，将2-氮杂螺[4.4]壬烷-3-酮(8.13g，58.4mmol)加入二氯甲烷(50mL) 中，然后依次加入二碳酸二叔丁酯(31.9g，146mmol)、三乙胺(17.8g，175mmol)和4-二甲氨基吡啶(DMAP)(1.43g，11.7mmol)，于室温搅拌2小时。反应液用二氯甲烷萃取，有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：MTBE/DCM＝0:1-1:10)，得标题化合物12.0g，收率：85.9％。At room temperature, 2-azaspiro[4.4]nonan-3-one (8.13g, 58.4mmol) was added into dichloromethane (50mL), and then di-tert-butyl dicarbonate (31.9g, 146mmol) was added successively, Triethylamine (17.8 g, 175 mmol) and 4-dimethylaminopyridine (DMAP) (1.43 g, 11.7 mmol) were stirred at room temperature for 2 hours. The reaction solution was extracted with dichloromethane, the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: MTBE/DCM=0:1-1:10) to obtain 12.0 g of the title compound, with a yield of : 85.9%.

LCMS：m/z 184[M-55] +。 LCMS: m/z 184 [M-55] + .

1H NMR(400MHz,DMSO-d6)δ3.55(d,J＝44.0Hz,2H),2.43(d,J＝44.0Hz,2H),1.68-1.60(m,8H),1.53(s,9H)。 1 H NMR (400MHz, DMSO-d6) δ3.55 (d, J = 44.0Hz, 2H), 2.43 (d, J = 44.0Hz, 2H), 1.68-1.60 (m, 8H), 1.53 (s, 9H ).

步骤16：3-羟基-2-氮杂螺[4.4]壬烷-2-羧酸叔丁酯(1p)的制备Step 16: Preparation of tert-butyl 3-hydroxy-2-azaspiro[4.4]nonane-2-carboxylate (1p)

于室温，将3-氧代-2-氮杂螺[4.4]壬烷-2-羧酸叔丁酯(1.50g,6.27mmol)和THF(23.0mL)加入至反应瓶中，降温至-78℃，滴加DIBAL-H(10mL,10.0mmol)，滴毕，于-78℃保温30分钟。反应结束后，以饱和乙酸钠水溶液(5mL)淬灭反应，升至室温，加入饱和氯化铵水溶液(5mL)和乙酸乙酯(10mL)搅拌10分钟，过滤，水相以乙酸乙酯萃取，合并有机相后减压浓缩，得1.38g黄色油状标题产物，直接用于下一步，产率91.4％。At room temperature, tert-butyl 3-oxo-2-azaspiro[4.4]nonane-2-carboxylate (1.50g, 6.27mmol) and THF (23.0mL) were added to the reaction flask, cooled to -78 ℃, DIBAL-H (10mL, 10.0mmol) was added dropwise, after the drop was completed, it was kept at -78℃ for 30 minutes. After the reaction was completed, the reaction was quenched with saturated aqueous sodium acetate (5 mL), warmed to room temperature, added saturated aqueous ammonium chloride (5 mL) and ethyl acetate (10 mL) and stirred for 10 minutes, filtered, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain 1.38 g of the title product as a yellow oil, which was directly used in the next step with a yield of 91.4%.

LCMS:m/z 242.17[M+H] +。 LCMS: m/z 242.17 [M+H] + .

步骤17：3-甲氧基-2-氮杂螺[4.4]壬烷-2-羧酸叔丁酯(1q)的制备Step 17: Preparation of tert-butyl 3-methoxy-2-azaspiro[4.4]nonane-2-carboxylate (1q)

于室温，将3-羟基-2-氮杂螺[4.4]壬烷-2-羧酸叔丁酯(1.38g,5.72mmol)、甲醇(20mL)和一水合对甲苯磺酸(52.0mg,0.270mmol)加入至反应瓶中，室温反应2小时。反应结束后，将反应体系倒入饱和碳酸氢钠水溶液中，以乙酸乙酯萃取，合并有机相，减压浓缩后以二氯甲烷稀释配成29wt％溶液，直接用于下一步。At room temperature, tert-butyl 3-hydroxy-2-azaspiro[4.4]nonane-2-carboxylate (1.38g, 5.72mmol), methanol (20mL) and p-toluenesulfonic acid monohydrate (52.0mg, 0.270 mmol) was added to the reaction flask, and reacted at room temperature for 2 hours. After the reaction, the reaction system was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, concentrated under reduced pressure and diluted with dichloromethane to prepare a 29 wt% solution, which was directly used in the next step.

LCMS:m/z 256.18[M+H] +。 LCMS: m/z 256.18 [M+H] + .

步骤18：(R)-4-苄基-3-(2-(4-氯苯基)乙酰基)噁唑烷-2-酮(1r)的制备Step 18: Preparation of (R)-4-benzyl-3-(2-(4-chlorophenyl)acetyl)oxazolidin-2-one (1r)

于室温，将2-(4-氯苯基)乙酸(10.0g,58.6mmol)、(R)-4-苄基噁唑烷-2-酮(10.4g,58.6mmol)、甲苯(150mL)加入至反应瓶中，滴加三乙胺(23.7g,235mmol)。冰浴降温至5℃左右，滴加特戊酰氯(PVIC)(9.10g,75mmol)，回流反应10小时。反应结束后将反应体系倒入水中，水相以乙酸乙酯萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(PE:EA＝5:1)，得8.70g黄色油状的目标产物，直接用于下一步，产率45％。 At room temperature, 2-(4-chlorophenyl)acetic acid (10.0g, 58.6mmol), (R)-4-benzyloxazolidin-2-one (10.4g, 58.6mmol), toluene (150mL) were added To the reaction flask, triethylamine (23.7 g, 235 mmol) was added dropwise. The temperature was cooled to about 5°C in an ice bath, pivaloyl chloride (PVIC) (9.10 g, 75 mmol) was added dropwise, and the reaction was refluxed for 10 hours. After the reaction, the reaction system was poured into water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE: EA=5:1), 8.70 g of the target product in the form of yellow oil was obtained, which was directly used in the next step with a yield of 45%.

LCMS:m/z 330.08[M+H] +。 LCMS: m/z 330.08 [M+H] + .

步骤19：(S)-3-((S)-2-((R)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-2-氮杂螺[4.4]壬-2-羧酸叔丁酯(1s)的制备Step 19: (S)-3-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of tert-butyl -oxoethyl)-2-azaspiro[4.4]nonan-2-carboxylate (1s)

于室温，将(R)-4-苄基-3-(2-(4-氯苯基)乙酰基)噁唑烷-2-酮(1.86g,5.64mmol)、二氯甲烷(30mL)加入至反应瓶中，降温至-78℃，滴加四氯化钛(1.18g,6.23mmol)，保温30分钟后滴加DIPEA(878mg,6.79mmol)，保温30分钟后滴加3-甲氧基-2-氮杂螺[4.4]壬烷-2-羧酸叔丁酯的二氯甲烷溶液，保温30分钟后自然升至室温反应 1.5小时。反应结束后将反应体系倒入水中，水相以二氯甲烷萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(PE:EA＝5:1)，得1.18g黄色油状的目标产物，直接用于下一步，产率59.6％。 At room temperature, (R)-4-benzyl-3-(2-(4-chlorophenyl)acetyl)oxazolidin-2-one (1.86g, 5.64mmol), dichloromethane (30mL) were added To the reaction flask, cool down to -78°C, add titanium tetrachloride (1.18g, 6.23mmol) dropwise, add DIPEA (878mg, 6.79mmol) dropwise after keeping warm for 30 minutes, add 3-methoxyl dropwise after keeping warm for 30 minutes - Dichloromethane solution of tert-butyl 2-azaspiro[4.4]nonane-2-carboxylate, warmed for 30 minutes, then naturally raised to room temperature for 1.5 hours. After the reaction, the reaction system was poured into water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE: EA=5:1), 1.18 g of the target product in the form of yellow oil was obtained, which was directly used in the next step with a yield of 59.6%.

LCMS:m/z 553.24[M+H] +。 LCMS: m/z 553.24 [M+H] + .

步骤20：(S)-2-((S)-2-(叔丁氧羰基)-2-氮杂螺[4.4]壬-3-基)-2-(4-氯苯基)乙酸(1t)的制备Step 20: (S)-2-((S)-2-(tert-butoxycarbonyl)-2-azaspiro[4.4]non-3-yl)-2-(4-chlorophenyl)acetic acid (1t ) preparation

于室温，将LiOH(38mg,0.904mmol)、水(2mL)、THF(4mL)加入至反应瓶中，冰浴降温至5℃左右，滴加30％双氧水(82.1mg,0.724mmol)，分批加入(S)-3-((S)-2-((R)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-2-氮杂螺[4.4]壬-2-羧酸叔丁酯(200mg,0.362mmol)，冰浴反应30小时。反应结束后以12.5wt％亚硫酸钠水溶液淬灭反应，27.0wt％硫酸氢钾溶液调节PH为2，水相用乙酸乙酯萃取，合并有机相浓缩后，残余物经柱层析色谱法分离纯化(PE:EA＝10:1)，得105mg黄色油状的目标产物，直接用于下一步，产率73.6％。At room temperature, LiOH (38mg, 0.904mmol), water (2mL) and THF (4mL) were added to the reaction flask, the temperature was cooled to about 5°C in an ice bath, and 30% hydrogen peroxide (82.1mg, 0.724mmol) was added dropwise. Add (S)-3-((S)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2-oxo Ethyl)-2-azaspiro[4.4]nonan-2-carboxylate tert-butyl ester (200mg, 0.362mmol), react in ice bath for 30 hours. Quenching reaction with 12.5wt% sodium sulfite aqueous solution after reaction finishes, 27.0wt% potassium bisulfate solution adjusts pH to be 2, aqueous phase is extracted with ethyl acetate, after merging organic phase concentration, residue is separated and purified through column chromatography ( PE:EA=10:1), 105 mg of the target product was obtained as a yellow oil, which was directly used in the next step with a yield of 73.6%.

LCMS:m/z 394.91[M+H] +。 LCMS: m/z 394.91 [M+H] + .

步骤21：(S)-3-((S)-1-(4-氯苯基)-2-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-氧代乙基)-2-氮杂螺[4.4]壬-2-羧酸叔丁酯(1u)的制备Step 21: (S)-3-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2-azaspiro[4.4]nonan-2-carboxylic acid tert-butyl ester Preparation of (1u)

于室温，将(5R,7R)-5-甲基-4-(哌嗪-1-基)-6,7-二氢-5H-环戊烷并[d]嘧啶-7-醇二盐酸盐(1k)(200mg,0.854mmol)、二氯甲烷(5mL)加到反应瓶中，加入N,N-二异丙基乙胺(DIPEA)(412mg,3.10mmol)，搅拌5分钟，加入(S)-2-((S)-2-(叔丁氧羰基)-2-氮杂螺[4.4]壬-3-基)-2-(4-氯苯基)乙酸(1t)(105mg,0.267mmol)，搅拌1分钟，加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)(204mg,0.540mmol)，搅拌反应12小时。反应结束后，减压浓缩，残余物经柱层析色谱法分离纯化(DCM:MeOH＝10:1)，得230mg白色固体状的粗品标题化合物。At room temperature, (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride Salt (1k) (200mg, 0.854mmol), dichloromethane (5mL) were added to the reaction flask, N,N-diisopropylethylamine (DIPEA) (412mg, 3.10mmol) was added, stirred for 5 minutes, and ( S)-2-((S)-2-(tert-butoxycarbonyl)-2-azaspiro[4.4]non-3-yl)-2-(4-chlorophenyl)acetic acid (1t) (105mg, 0.267mmol), stirred for 1 minute, added benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) (204mg, 0.540mmol), stirred for 12 hours. After the reaction, it was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM:MeOH=10:1) to obtain 230 mg of the crude title compound as a white solid.

LCMS:m/z 610.31[M+H] +。 LCMS: m/z 610.31 [M+H] + .

步骤22：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((S)-2-氮杂螺[4.4]壬-3-基)乙-1-酮(1)的制备Step 22: (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-2-azaspiro[4.4]non-3-yl)ethan-1-one (1)

于室温，将化合物1u(230mg,粗品)、二氯甲烷(DCM)(3mL)加入至反应瓶中，冰浴降温至5℃左右，滴加盐酸/二氧六环溶液(0.33mL，1.32mmol)，加毕室温反应10小时。反应结束后减压浓缩，残余物用制备高效液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得54mg白色固体标题化合物，两步产率39.7％。At room temperature, compound 1u (230mg, crude product) and dichloromethane (DCM) (3mL) were added to the reaction flask, cooled to about 5°C in an ice bath, and hydrochloric acid/dioxane solution (0.33mL, 1.32mmol ), add and react at room temperature for 10 hours. Concentrate under reduced pressure after the reaction, and the residue is separated by preparative high-performance liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), to obtain 54 mg of the title compound as a white solid, 39.7% yield over two steps.

LCMS:m/z 510.26[M+H] +。 LCMS: m/z 510.26 [M+H] + .

1H NMR(400MHz,CDCl 3)δ8.48(s,1H),7.31(d,J＝8.4,2H),7.22(d,J＝8.3,2H),5.08(t,J＝7.0,1H),4.00-3.75(m,4H),3.70(d,J＝12.2,1H),3.58(d,J＝9.6,1H),3.55-3.26(m,5H),3.12(s,1H),2.89(s,2H),2.24-2.05(m,2H),1.54(d,J＝18.6,7H), 1.48-1.20(m,4H),1.12(d,J＝6.8,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.48(s,1H),7.31(d,J=8.4,2H),7.22(d,J=8.3,2H),5.08(t,J=7.0,1H) ,4.00-3.75(m,4H),3.70(d,J=12.2,1H),3.58(d,J=9.6,1H),3.55-3.26(m,5H),3.12(s,1H),2.89( s, 2H), 2.24-2.05 (m, 2H), 1.54 (d, J = 18.6, 7H), 1.48-1.20 (m, 4H), 1.12 (d, J = 6.8, 3H).

实施例2：(2S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((8S)-2-氧基-7-氮杂螺[4.4]壬-8-基)乙-1-酮(2)的制备Example 2: (2S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta Alkano[d]pyrimidin-4-yl)piperazin-1-yl)-2-((8S)-2-oxyl-7-azaspiro[4.4]non-8-yl)ethan-1-one (2) Preparation

Figure PCTCN2022136451-appb-000039
Figure PCTCN2022136451-appb-000039

步骤1：(E)-2-(二氢呋喃-3(2H)-亚基)乙酸甲酯(2a)的制备Step 1: Preparation of (E)-methyl 2-(dihydrofuran-3(2H)-ylidene)acetate (2a)

将2-(二乙氧基磷酰基)乙酸甲酯(13.4g，63.9mmol)加入THF(50mL)中，于0℃，分批加入氢化钠(2.55g，63.9mmol)，加毕升至室温，搅拌1小时。加入二氢呋喃-3(2H)-酮(5.00g，58.1mmol)，室温反应4小时。将反应液减压浓缩，乙酸乙酯萃取，有机相用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/DCM＝1:50)，得黄色油状标题化合物4.89g，收率：60％。Add methyl 2-(diethoxyphosphoryl)acetate (13.4g, 63.9mmol) into THF (50mL), add sodium hydride (2.55g, 63.9mmol) in batches at 0°C, and warm to room temperature , and stirred for 1 hour. Add dihydrofuran-3(2H)-one (5.00 g, 58.1 mmol) and react at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: EA /DCM=1:50), to obtain 4.89 g of the title compound as yellow oil, yield: 60%.

步骤2：2-(3-(硝基甲基)四氢呋喃-3-基)乙酸甲酯(2b)的制备Step 2: Preparation of methyl 2-(3-(nitromethyl)tetrahydrofuran-3-yl)acetate (2b)

于室温，将(E)-2-(二氢呋喃-3(2H)-亚基)乙酸甲酯(2.00g，14.1mmol)加入DMSO(10mL)中，然后加入碳酸铯(918mg，2.81mmol)和硝基甲烷(1.20g，19.7mmol)。于80℃搅拌过夜。用冰乙酸(0.322mL，5.60mmol)淬灭反应，用二甲基叔丁基醚萃取，有机相用水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：MeOH/DCM＝1:20)，得到浅黄色油状标题化合物1.11g，收率：38.9％。(E)-Methyl 2-(dihydrofuran-3(2H)-ylidene)acetate (2.00 g, 14.1 mmol) was added to DMSO (10 mL) followed by cesium carbonate (918 mg, 2.81 mmol) at room temperature and nitromethane (1.20 g, 19.7 mmol). Stir overnight at 80°C. The reaction was quenched with glacial acetic acid (0.322 mL, 5.60 mmol), extracted with dimethyl tert-butyl ether, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase: MeOH/DCM = 1:20) to obtain 1.11 g of the title compound as light yellow oil, yield: 38.9%.

步骤3：2-氧杂-7-氮杂螺[4.4]壬烷-8-酮(2c)的制备Step 3: Preparation of 2-oxa-7-azaspiro[4.4]nonan-8-one (2c)

于室温，将2-(3-(硝基甲基)四氢呋喃-3-基)乙酸甲酯(388mg，1.91mmol)加 入甲醇(5mL)中，然后加入Pd/C(38.8mg)，在氢气氛下，室温搅拌过夜。反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：MeOH/DCM＝1:20)，得到红色油状标题化合物100mg，收率：37％。At room temperature, methyl 2-(3-(nitromethyl)tetrahydrofuran-3-yl)acetate (388mg, 1.91mmol) was added into methanol (5mL), then Pd/C (38.8mg) was added, and the Stir overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: MeOH/DCM=1:20) to obtain 100 mg of the title compound as a red oil, yield: 37%.

步骤4：8-氧代-2-氧杂-7-氮杂螺[4.4]壬烷-7-羧酸叔丁酯(2d)的制备Step 4: Preparation of tert-butyl 8-oxo-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate (2d)

于室温，将2-氧杂-7-氮杂螺[4.4]壬烷-8-酮(100mg，0.708mmol)加入四氢呋喃(10mL)中，然后加入三乙胺(0.31mL，2.10mmol)、DMAP(8.60mg，0.071mmol)、二碳酸二叔丁酯(387mg,1.77mmol)，在氮气氛下，室温搅拌过夜。反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：MeOH/DCM＝1:50)，得到淡黄色固体状标题化合物80mg，收率：46.7％。At room temperature, 2-oxa-7-azaspiro[4.4]nonan-8-one (100mg, 0.708mmol) was added into tetrahydrofuran (10mL), then triethylamine (0.31mL, 2.10mmol), DMAP (8.60mg, 0.071mmol), di-tert-butyl dicarbonate (387mg, 1.77mmol), under nitrogen atmosphere, stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: MeOH/DCM=1:50) to obtain 80 mg of the title compound as a pale yellow solid, yield: 46.7%.

LCMS：m/z 264[M+Na] +。 LCMS: m/z 264 [M+Na] + .

1H NMR(400MHz,CDCl3)δ3.94-3.91(m,2H),3.84(d,J＝8.8Hz,1H),3.64-3.58(m,3H),2.48(s,2H),2.12-1.98(m,2H),1.53(s,9H)。 1 H NMR (400MHz, CDCl3) δ3.94-3.91 (m, 2H), 3.84 (d, J = 8.8Hz, 1H), 3.64-3.58 (m, 3H), 2.48 (s, 2H), 2.12-1.98 (m,2H), 1.53(s,9H).

步骤5:8-羟基-2-氧杂-7-氮杂螺[4.4]壬烷-7-羧酸叔丁酯(2e)的制备Step 5: Preparation of tert-butyl 8-hydroxy-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate (2e)

于室温，将8-氧代-2-氧杂-7-氮杂螺[4.4]壬烷-7-羧酸叔丁酯(1.10g,4.56mmol)和THF(20.0mL)加入至反应瓶中，降温至-78℃，滴加DIBAL-H(10mL,10.0mmol)，滴毕，于-78℃保温30分钟。反应结束后，以饱和乙酸钠水溶液(5mL)淬灭反应，升至室温，加入饱和氯化铵水溶液(5mL)和乙酸乙酯(10mL)搅拌10分钟，过滤，水相以乙酸乙酯萃取，合并有机相后减压浓缩，得600mg黄色油状粗品标题产物，直接用于下一步。At room temperature, tert-butyl 8-oxo-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate (1.10 g, 4.56 mmol) and THF (20.0 mL) were added to the reaction flask , cooled to -78°C, added DIBAL-H (10mL, 10.0mmol) dropwise, and kept at -78°C for 30 minutes after dropping. After the reaction was completed, the reaction was quenched with saturated aqueous sodium acetate (5 mL), warmed to room temperature, added saturated aqueous ammonium chloride (5 mL) and ethyl acetate (10 mL) and stirred for 10 minutes, filtered, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain 600 mg of the crude title product as a yellow oil, which was directly used in the next step.

LCMS:m/z 244.15[M+H] +。 LCMS: m/z 244.15 [M+H] + .

步骤6:8-甲氧基-2-氧杂-7-氮杂螺[4.4]壬烷-7-羧酸叔丁酯(2f)的制备Step 6: Preparation of tert-butyl 8-methoxy-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate (2f)

于室温，将8-羟基-2-氧杂-7-氮杂螺[4.4]壬烷-7-羧酸叔丁酯(600mg,2.47mmol)甲醇(12mL)和一水合对甲苯磺酸(52.0mg,0.270mmol)加入至反应瓶中，室温反应2小时。反应结束后将反应体系倒入饱和碳酸氢钠水溶液中，以乙酸乙酯萃取，合并有机相，减压浓缩后，残余物以二氯甲烷稀释配成29wt％溶液，直接用于下一步。At room temperature, tert-butyl 8-hydroxy-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate (600 mg, 2.47 mmol) methanol (12 mL) and p-toluenesulfonic acid monohydrate (52.0 mg, 0.270mmol) was added to the reaction flask, and reacted at room temperature for 2 hours. After the reaction, the reaction system was poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to prepare a 29 wt% solution, which was directly used in the next step.

LCMS:m/z 258.16[M+H] +。 LCMS: m/z 258.16 [M+H] + .

步骤7：(8S)-8-((S)-2-((R)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-2-氧杂-7-氮杂螺[4.4]壬烷-7-羧酸叔丁酯(2g)的制备Step 7: (8S)-8-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate tert-butyl ester (2g)

于室温，将(R)-4-苄基-3-(2-(4-氯苯基)乙酰基)噁唑烷-2-酮(1r)(814mg,2.47mmol)、二氯甲烷(16mL)加入至反应瓶中，降温至-78℃，滴加四氯化钛(515mg,2.72mmol)，保温30分钟后滴加DIPEA(383mg,2.96mmol)，保温30分钟后滴加8-甲氧基-2-氧杂-7-氮杂螺[4.4]壬烷-7-羧酸叔丁酯的二氯甲烷溶液，保温30分钟后自然升至室温反应1.5小时。反应结束后将反应体系倒入水中，水相以二氯甲烷萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(PE:EA＝5:1)，得165mg黄色油状的目标产物，直接用于下一 步，三步产率10.7％。 At room temperature, (R)-4-benzyl-3-(2-(4-chlorophenyl)acetyl)oxazolidin-2-one (1r) (814mg, 2.47mmol), dichloromethane (16mL ) was added to the reaction flask, cooled to -78°C, titanium tetrachloride (515mg, 2.72mmol) was added dropwise, DIPEA (383mg, 2.96mmol) was added dropwise after 30 minutes of heat preservation, and 8-methoxyl was added dropwise after 30 minutes of heat preservation Dichloromethane solution of tert-butyl-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate was incubated at room temperature for 1.5 hours after incubation for 30 minutes. After the reaction, the reaction system was poured into water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE: EA=5:1), 165 mg of the target product in the form of yellow oil was obtained, which was directly used in the next step, and the three-step yield was 10.7%.

LCMS:m/z 555.22[M+H] +。 LCMS: m/z 555.22 [M+H] + .

步骤8：(2S)-2-((8S)-7-(叔丁氧羰基)-2-氧杂-7-氮杂螺[4.4]壬-8-基)-2-(4-氯苯基)乙酸(2h)的制备Step 8: (2S)-2-((8S)-7-(tert-butoxycarbonyl)-2-oxa-7-azaspiro[4.4]non-8-yl)-2-(4-chlorobenzene Base) Preparation of acetic acid (2h)

于室温，将LiOH(38mg,0.904mmol)、水(2mL)、THF(4mL)加入至反应瓶中，冰浴降温至5℃左右，滴加30％双氧水(82.1mg,0.724mmol)，分批加入(8S)-8-((S)-2-((S)-5-苄基-2-氧杂噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-2-氧杂-7-氮杂螺[4.4]壬烷-7-羧酸叔丁酯(200mg,0.361mmol)，冰浴反应30小时。反应结束后以12.5wt％亚硫酸钠水溶液淬灭反应，27.0wt％硫酸氢钾溶液调节PH为2，水相用乙酸乙酯萃取，合并有机相，减压浓缩后，残余物经柱层析色谱法分离纯化(PE:EA＝10:1)，得105mg黄色油状的目标产物，直接用于下一步，产率73.6％。At room temperature, LiOH (38mg, 0.904mmol), water (2mL) and THF (4mL) were added to the reaction flask, the temperature was cooled to about 5°C in an ice bath, and 30% hydrogen peroxide (82.1mg, 0.724mmol) was added dropwise. Add (8S)-8-((S)-2-((S)-5-benzyl-2-oxazolidin-3-yl)-1-(4-chlorophenyl)-2-oxo Ethyl)-2-oxa-7-azaspiro[4.4]nonane-7-carboxylic acid tert-butyl ester (200mg, 0.361mmol), react in ice bath for 30 hours. After the reaction was finished, quench the reaction with 12.5wt% sodium sulfite aqueous solution, adjust the pH to 2 with 27.0wt% potassium hydrogensulfate solution, extract the aqueous phase with ethyl acetate, combine the organic phases, concentrate under reduced pressure, and the residue was subjected to column chromatography After separation and purification (PE:EA=10:1), 105 mg of the target product was obtained as a yellow oil, which was directly used in the next step with a yield of 73.6%.

LCMS:m/z 396.15[M+H] +。 LCMS: m/z 396.15 [M+H] + .

步骤9：(8S)-8-((S)-1-(4-氯苯基)-2-(4-(((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-氧代乙基)-2-氧杂-7-氮杂螺[4.4]壬烷-7-羧酸叔丁酯(2i)的制备Step 9: (8S)-8-((S)-1-(4-chlorophenyl)-2-(4-(((5R,7R)-7-hydroxy-5-methyl-6,7- Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2-oxa-7-azaspiro[4.4]nonane- Preparation of tert-butyl 7-carboxylate (2i)

于室温，将化合物1k(100mg,0.427mmol)、二氯甲烷(2.5mL)加到反应瓶中，加入N,N-二异丙基乙胺(DIPEA)(206mg,1.55mmol)，搅拌5分钟，加入(2S)-2-((8S)-7-(叔丁氧羰基)-2-氧杂-7-氮杂螺[4.4]壬-8-基)-2-(4-氯苯基)乙酸(2h)(100mg，粗品)，搅拌1分钟，加入HBTU(102mg,0.270mmol)，搅拌反应12小时。反应结束后，减压浓缩，残余物经柱层析色谱法分离纯化(DCM:MeOH＝10:1)，得140mg白色固体状的粗品标题化合物。At room temperature, compound 1k (100mg, 0.427mmol), dichloromethane (2.5mL) were added to the reaction flask, N,N-diisopropylethylamine (DIPEA) (206mg, 1.55mmol) was added, stirred for 5 minutes , add (2S)-2-((8S)-7-(tert-butoxycarbonyl)-2-oxa-7-azaspiro[4.4]non-8-yl)-2-(4-chlorophenyl ) acetic acid (2h) (100mg, crude product), stirred for 1 minute, added HBTU (102mg, 0.270mmol), stirred and reacted for 12 hours. After the reaction, it was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM:MeOH=10:1) to obtain 140 mg of the crude title compound as a white solid.

LCMS:m/z 612.29[M+H] +。 LCMS: m/z 612.29 [M+H] + .

步骤10：(2S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((8S)-2-氧基-7-氮杂螺[4.4]壬-8-基)乙-1-酮(2)的制备Step 10: (2S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane And [d] pyrimidin-4-yl)piperazin-1-yl)-2-((8S)-2-oxygen-7-azaspiro[4.4]non-8-yl)ethan-1-one ( 2) Preparation

于室温，将化合物2i(140mg,粗品)、二氯甲烷(2mL)加入至反应瓶中，冰浴降温至5℃左右，滴加盐酸/二氧六环溶液(0.33mL，1.32mmol)，加毕室温反应10小时。反应结束后直接浓缩，残余物用制备高效液相色谱法分离纯化(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得14mg白色固体标题化合物，三步产率14.0％。At room temperature, compound 2i (140 mg, crude product) and dichloromethane (2 mL) were added to the reaction flask, cooled to about 5 °C in an ice bath, hydrochloric acid/dioxane solution (0.33 mL, 1.32 mmol) was added dropwise, and Complete reaction at room temperature for 10 hours. Concentrate directly after the reaction, and the residue is separated and purified by preparative high-performance liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), to obtain 14 mg of the title compound as a white solid, 14.0% yield over three steps.

LCMS:m/z 512.24[M+H] +。 LCMS: m/z 512.24 [M+H] + .

1H NMR(400MHz,DMSO)δ8.43(s,1H),7.39(s,4H),5.38(s,1H),4.83(s,1H),3.90(d,J＝9.4Hz,1H),3.78-3.61(m,5H),3.61-3.51(m,3H),3.47(dd,J＝12.9,5.7Hz,3H),3.28-3.12(m,3H),2.80(d,J＝10.1Hz,1H),2.71(d,J＝10.2Hz,1H),2.05-1.85(m,2H),1.78(dd,J＝10.1,4.4Hz,2H),1.34(ddd,J＝19.3,12.5,8.2Hz,2H),1.03(d,J＝6.9Hz,3H)。 1 H NMR (400MHz,DMSO)δ8.43(s,1H),7.39(s,4H),5.38(s,1H),4.83(s,1H),3.90(d,J=9.4Hz,1H), 3.78-3.61(m,5H),3.61-3.51(m,3H),3.47(dd,J=12.9,5.7Hz,3H),3.28-3.12(m,3H),2.80(d,J=10.1Hz, 1H), 2.71(d, J=10.2Hz, 1H), 2.05-1.85(m, 2H), 1.78(dd, J=10.1, 4.4Hz, 2H), 1.34(ddd, J=19.3, 12.5, 8.2Hz , 2H), 1.03 (d, J=6.9Hz, 3H).

实施例3：(2S)-2-(((2S)-3-氮杂双环[3.1.0]己-2-基)-2-(4-氯苯 基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)乙-1-酮(3)的制备Example 3: (2S)-2-(((2S)-3-azabicyclo[3.1.0]hex-2-yl)-2-(4-chlorophenyl)-1-(4-(( 5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)ethan-1-one (3 ) preparation

Figure PCTCN2022136451-appb-000040
Figure PCTCN2022136451-appb-000040

步骤1：3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(3a)的制备Step 1: Preparation of tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (3a)

于室温，将3-氮杂双环[3.1.0]己烷(6.00g,50.0mmol)、四氢呋喃(50ml)、水(100ml)加入到反应瓶中，加入二碳酸二叔丁酯(12.0g,55.0mmol)、碳酸钠(13.3g,125mmol)，搅拌反应5小时。反应结束后，向反应瓶中加入乙酸乙酯、水萃取，有机相用饱和氯化钠溶液洗涤，有机相浓缩至干，得到10.2g黄色油状的标题化合物，直接用于下一步。At room temperature, 3-azabicyclo[3.1.0]hexane (6.00g, 50.0mmol), tetrahydrofuran (50ml), water (100ml) were added to the reaction flask, and di-tert-butyl dicarbonate (12.0g, 55.0mmol), sodium carbonate (13.3g, 125mmol), stirred and reacted for 5 hours. After the reaction was completed, ethyl acetate was added to the reaction flask and extracted with water, the organic phase was washed with saturated sodium chloride solution, and the organic phase was concentrated to dryness to obtain 10.2 g of the title compound as a yellow oil, which was directly used in the next step.

LCMS:m/z 184.13[M+H] +。 LCMS: m/z 184.13 [M+H] + .

步骤2：2-氧代-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(3b)的制备Step 2: Preparation of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (3b)

于室温，将3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(10.2g,50.0mmol)、乙酸乙酯(250ml)加入到反应瓶中，缓慢加入二氧化钌一水合物(2.66g,20.0mmol)和高碘酸钠(53.5g,250mmol)的水溶液(200ml)，搅拌反应12小时。反应结束后，过滤，滤液中加入乙酸乙酯、水萃取，有机相浓缩至干，残余物通过柱层析色谱法(洗脱剂：二氯甲烷：甲醇＝80：1)纯化，得到5.10g无色油状的标题化合物，收率：51.7％。At room temperature, tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (10.2g, 50.0mmol) and ethyl acetate (250ml) were added to the reaction flask, and ruthenium dioxide- Hydrate (2.66g, 20.0mmol) and sodium periodate (53.5g, 250mmol) in aqueous solution (200ml), stirred for 12 hours. After the reaction, filter, add ethyl acetate and water to the filtrate, concentrate the organic phase to dryness, and purify the residue by column chromatography (eluent: dichloromethane:methanol=80:1) to obtain 5.10g The title compound as colorless oil, yield: 51.7%.

LCMS:m/z 198.11[M+H] +。 LCMS: m/z 198.11 [M+H] + .

步骤3：2-羟基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(3c)的制备Step 3: Preparation of tert-butyl 2-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (3c)

于室温，将2-氧代-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(5.79g,29.4mmol)、四氢呋喃(60mL)加入到反应瓶中，降温至-78℃，氮气氛围下滴加DIBAL-H(1.0M,49mL,49.0mmol)，滴毕于-78℃保温30分钟。反应结束后，用饱和乙酸钠溶液(30mL)淬灭反应，自然升温至30℃，加入饱和氯化铵溶液(100mL)，搅拌10分钟，加入乙酸乙酯(150mL)，过滤，水相用乙酸乙酯萃取，合并有机相，用 饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到6.66g淡黄色油状的标题化合物，直接用于下一步。At room temperature, add tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (5.79g, 29.4mmol) and tetrahydrofuran (60mL) into the reaction flask, and cool down to - At 78°C, DIBAL-H (1.0M, 49mL, 49.0mmol) was added dropwise under a nitrogen atmosphere, and kept at -78°C for 30 minutes after the drop was completed. After the reaction, quench the reaction with saturated sodium acetate solution (30mL), naturally warm up to 30°C, add saturated ammonium chloride solution (100mL), stir for 10 minutes, add ethyl acetate (150mL), filter, and wash the aqueous phase with acetic acid Extract with ethyl ester, combine the organic phases, wash with saturated sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 6.66 g of the title compound as light yellow oil, which is directly used in the next step.

LCMS:m/z 200.12[M+H] +。 LCMS: m/z 200.12 [M+H] + .

步骤4：2-甲氧基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(3d)的制备Step 4: Preparation of tert-butyl 2-methoxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (3d)

于室温，将2-羟基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(6.66g,32.3mmol)、甲醇(70mL)加入到反应瓶中，加入一水合对甲苯磺酸(430mg,2.26mmol)，搅拌反应2小时。反应结束后，将反应液浓缩至干，加入饱和碳酸氢钠溶液、乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到5.63g黄色油状的标题化合物，用二氯甲烷(20mL)稀释，直接用于下一步。At room temperature, tert-butyl 2-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (6.66g, 32.3mmol) and methanol (70mL) were added to the reaction flask, and Toluenesulfonic acid (430mg, 2.26mmol), stirred for 2 hours. After the reaction, the reaction solution was concentrated to dryness, added with saturated sodium bicarbonate solution and ethyl acetate for extraction, the organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 5.63g The title compound as a yellow oil was diluted with dichloromethane (20 mL) and used directly in the next step.

LCMS:m/z 214.14[M+H] +。 LCMS: m/z 214.14 [M+H] + .

步骤5：(1S,2S)-2-((S)-2-((R)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(3e)的制备Step 5: (1S,2S)-2-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl) Preparation of -2-oxoethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (3e)

于室温，将化合物1r(8.87g,27.0mmol)、二氯甲烷(90mL)加入到反应瓶中，降温至-78℃，滴加四氯化钛(5.12g,27.0mmol)，保温30分钟后滴加DIPEA(4.74g,36.8mmol)，保温30分钟后滴加2-甲氧基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(5.21g,24.5mmol)的二氯甲烷溶液(18mL)，保温30分钟后自然升至室温反应1.5小时。反应结束后，加入饱和碳酸氢钠溶液，二氯甲烷萃取，有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷)纯化，得到4.61g白色固体状的标题化合物，收率36.9％。At room temperature, compound 1r (8.87g, 27.0mmol) and dichloromethane (90mL) were added to the reaction flask, the temperature was lowered to -78°C, titanium tetrachloride (5.12g, 27.0mmol) was added dropwise, and after 30 minutes of insulation DIPEA (4.74g, 36.8mmol) was added dropwise, and tert-butyl 2-methoxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (5.21g, 24.5mmol) was added dropwise after incubation for 30 minutes A dichloromethane solution (18 mL) was incubated for 30 minutes and then naturally rose to room temperature for 1.5 hours. After completion of the reaction, add saturated sodium bicarbonate solution, extract with dichloromethane, wash the organic phase with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is passed through column chromatography (washing Removal agent: dichloromethane) was purified to obtain 4.61 g of the title compound as a white solid, with a yield of 36.9%.

LCMS:m/z 511.19[M+H] +。 LCMS: m/z 511.19 [M+H] + .

步骤6：(2S)-2-((2S)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-2-基)-2-(4-氯苯基)乙酸(3f)的制备Step 6: (2S)-2-((2S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-2-yl)-2-(4-chlorophenyl) Preparation of acetic acid (3f)

于室温，将氢氧化锂一水合物(104mg,2.45mmol)、四氢呋喃(3mL)、水(3.5mL)加入到反应瓶中，加入30％过氧化氢(66.7mg,1.96mmol)，降温至0℃，加入(1S,2S)-2-((S)-2-((R)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(3e)(500mg,0.980mmol)的四氢呋喃溶液(4mL)，0℃搅拌反应3小时。于10℃，向反应液中加入12.5wt％亚硫酸钠溶液(1.2mL)，搅拌0.5小时，加入27.0wt％硫酸氢钾溶液调pH至2～3，加入乙酸乙酯萃取，有机相浓缩至干，残余物通过制备高效液相色谱法分离纯化(色谱柱型号：Daisogei30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得到215mg白色固体状的标题化合物，收率62.6％。At room temperature, lithium hydroxide monohydrate (104mg, 2.45mmol), tetrahydrofuran (3mL), water (3.5mL) were added to the reaction flask, 30% hydrogen peroxide (66.7mg, 1.96mmol) was added, and the temperature was lowered to 0 ℃, add (1S,2S)-2-((S)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl) -2-Oxoethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (3e) (500mg, 0.980mmol) in THF (4mL), stirred at 0°C for reaction 3 Hour. At 10°C, add 12.5wt% sodium sulfite solution (1.2mL) to the reaction solution, stir for 0.5 hours, add 27.0wt% potassium bisulfate solution to adjust the pH to 2-3, add ethyl acetate for extraction, and concentrate the organic phase to dryness. The residue was separated and purified by preparative high-performance liquid chromatography (column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%) to obtain 215 mg of the title compound as a white solid , yield 62.6%.

LCMS:m/z 352.12[M+H] +。 LCMS: m/z 352.12 [M+H] + .

步骤7：(2S)-2-((S)-1-(4-氯苯基)-2-(4-(((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-氧代乙基)-3-氮杂双环[3.1.0]己-3-羧酸叔丁酯 (3g)的制备Step 7: (2S)-2-((S)-1-(4-chlorophenyl)-2-(4-(((5R,7R)-7-hydroxy-5-methyl-6,7- Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-3-azabicyclo[3.1.0]hexan-3-carboxylic acid Preparation of tert-butyl ester (3g)

于室温，将化合物1k(90.0mg,0.384mmol)、二氯甲烷(4mL)加入到反应瓶中，加入DIPEA(258mg,2.00mmol)，搅拌10分钟，加入(2S)-2-((2S)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-2-基)-2-(4-氯苯基)乙酸(3f)(70.0mg,0.200mmol)，搅拌5分钟，加入HBTU(91.0mg,0.240mmol)，搅拌反应12小时。反应结束后，将反应液浓缩至干，残余物通过柱层析色谱法(洗脱剂：二氯甲烷：甲醇＝40：1)纯化，得到176mg白色固体状的标题化合物，直接用于下一步。At room temperature, compound 1k (90.0mg, 0.384mmol), dichloromethane (4mL) were added to the reaction flask, DIPEA (258mg, 2.00mmol) was added, stirred for 10 minutes, (2S)-2-((2S) -3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-yl)-2-(4-chlorophenyl)acetic acid (3f) (70.0mg, 0.200mmol), stirring After 5 minutes, HBTU (91.0 mg, 0.240 mmol) was added, and the reaction was stirred for 12 hours. After the reaction, the reaction solution was concentrated to dryness, and the residue was purified by column chromatography (eluent: dichloromethane: methanol = 40:1) to obtain 176 mg of the title compound as a white solid, which was directly used in the next step .

LCMS:m/z 568.26[M+H] +。 LCMS: m/z 568.26 [M+H] + .

步骤8：(2S)-2-(((2S)-3-氮杂双环[3.1.0]己-2-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)乙-1-酮(3)的制备Step 8: (2S)-2-(((2S)-3-Azabicyclo[3.1.0]hex-2-yl)-2-(4-chlorophenyl)-1-(4-((5R ,7R)-7-Hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)ethan-1-one (3) preparation of

于室温，将化合物3g(164mg,0.200mmol)、二氯甲烷(5mL)加入到反应瓶中，加入氯化氢的1,4-二氧六环溶液(4.0M,0.5ml,2.00mmol)，25℃搅拌反应12小时。反应结束后，将反应液浓缩至干，加入二氯甲烷稀释，用DIPEA调pH至7～8，减压浓缩，残余物用制备高效液相色谱法分离纯化(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得到57.0mg白色固体状的标题化合物，收率61.2％。At room temperature, compound 3g (164mg, 0.200mmol) and dichloromethane (5mL) were added to the reaction flask, and a solution of hydrogen chloride in 1,4-dioxane (4.0M, 0.5ml, 2.00mmol) was added, at 25°C The reaction was stirred for 12 hours. After the reaction, the reaction solution was concentrated to dryness, diluted with dichloromethane, adjusted to pH 7-8 with DIPEA, concentrated under reduced pressure, and the residue was separated and purified by preparative high-performance liquid chromatography (column model: Daisogei 30mm*250mm , C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), 57.0 mg of the title compound was obtained as a white solid, and the yield was 61.2%.

LCMS:m/z 468.21[M+H] +。 LCMS: m/z 468.21 [M+H] + .

1H NMR(400MHz,DMSO)δ8.44(s,1H),7.44(dd,J＝35.1,8.5Hz,4H),5.37(d,J＝5.6Hz,1H),4.84(dd,J＝12.8,6.3Hz,1H),3.87(d,J＝10.2Hz,1H),3.67(dd,J＝31.4,10.4Hz,5H),3.56-3.34(m,6H),2.86(dd,J＝11.0,2.9Hz,1H),2.71(d,J＝11.1Hz,1H),2.03-1.84(m,2H),1.31-1.19(m,1H),1.06(d,J＝6.9Hz,3H),0.83-0.70(m,1H),0.26(td,J＝7.7,4.3Hz,1H),0.17(q,J＝4.0Hz,1H)。 1 H NMR (400MHz, DMSO) δ8.44(s, 1H), 7.44(dd, J=35.1, 8.5Hz, 4H), 5.37(d, J=5.6Hz, 1H), 4.84(dd, J=12.8 ,6.3Hz,1H),3.87(d,J=10.2Hz,1H),3.67(dd,J=31.4,10.4Hz,5H),3.56-3.34(m,6H),2.86(dd,J=11.0, 2.9Hz, 1H), 2.71(d, J=11.1Hz, 1H), 2.03-1.84(m, 2H), 1.31-1.19(m, 1H), 1.06(d, J=6.9Hz, 3H), 0.83- 0.70(m, 1H), 0.26(td, J=7.7, 4.3Hz, 1H), 0.17(q, J=4.0Hz, 1H).

实施例4：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((S)-4-氮杂螺[2.4]庚-5-基)乙-1-酮(4)的制备Example 4: (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta Preparation of alkano[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-4-azaspiro[2.4]hept-5-yl)ethan-1-one (4)

Figure PCTCN2022136451-appb-000041
Figure PCTCN2022136451-appb-000041

Figure PCTCN2022136451-appb-000042
Figure PCTCN2022136451-appb-000042

步骤1：4-氮杂螺[2.4]庚烷-5-酮(4a)的制备Step 1: Preparation of 4-azaspiro[2.4]heptan-5-one (4a)

于室温，将3-氰基丙酸甲酯(7.91g,70.0mmol)、四氢呋喃(200mL)加入到反应瓶中，加入钛酸四异丙酯(3.98g,14.0mmol)。降温至10℃以下，氮气氛围下，缓慢加入乙基溴化镁(3.0M,51.4mL,154mmol)，加毕缓慢升至室温，搅拌反应12小时。反应结束后，向反应瓶中加入水(3.5mL)，搅拌20分钟，过滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷：甲醇＝20：1)纯化，得到10.3g褐色油状的标题化合物，直接用于下一步。At room temperature, methyl 3-cyanopropionate (7.91 g, 70.0 mmol) and tetrahydrofuran (200 mL) were added to the reaction flask, and tetraisopropyl titanate (3.98 g, 14.0 mmol) was added. The temperature was lowered to below 10°C, under nitrogen atmosphere, ethylmagnesium bromide (3.0M, 51.4mL, 154mmol) was slowly added, after the addition was completed, the temperature was slowly raised to room temperature, and the reaction was stirred for 12 hours. After the reaction, add water (3.5mL) to the reaction flask, stir for 20 minutes, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (eluent: dichloromethane:methanol=20:1) , to obtain 10.3 g of the title compound as a brown oil, which was directly used in the next step.

LCMS:m/z 112.07[M+H] +。 LCMS: m/z 112.07 [M+H] + .

步骤2：5-氧代-4-氮杂螺[2.4]庚烷-4-羧酸叔丁酯(4b)的制备Step 2: Preparation of tert-butyl 5-oxo-4-azaspiro[2.4]heptane-4-carboxylate (4b)

于室温，将4-氮杂螺[2.4]庚烷-5-酮(8.83g,60.0mmol)、二碳酸二叔丁酯(19.7g,90.0mmol)、四氢呋喃(90mL)加入到反应瓶中，降温至5℃以下，加入三乙胺(18.2g,180mmol)、DMAP(366mg,3.00mmol)，搅拌反应12小时。反应结束后，向反应瓶中加入乙酸乙酯、水萃取，有机相浓缩至干，残余物通过柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝5：1)纯化，得到4.92g淡黄色固体状的标题化合物，收率：33.5％。At room temperature, add 4-azaspiro[2.4]heptan-5-one (8.83g, 60.0mmol), di-tert-butyl dicarbonate (19.7g, 90.0mmol), tetrahydrofuran (90mL) into the reaction flask, Cool down to below 5°C, add triethylamine (18.2g, 180mmol), DMAP (366mg, 3.00mmol), and stir for 12 hours. After the reaction was completed, ethyl acetate was added to the reaction flask, extracted with water, the organic phase was concentrated to dryness, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 4.92 g The title compound as a pale yellow solid, yield: 33.5%.

LCMS:m/z 212.12[M+H] +。 LCMS: m/z 212.12 [M+H] + .

步骤3：5-羟基-4-氮杂螺[2.4]庚烷-4-羧酸叔丁酯(4c)的制备Step 3: Preparation of tert-butyl 5-hydroxy-4-azaspiro[2.4]heptane-4-carboxylate (4c)

于室温，将5-氧代-4-氮杂螺[2.4]庚烷-4-羧酸叔丁酯(7.81g,37.0mmol)、四氢呋喃(90mL)加入到反应瓶中，降温至-78℃，氮气氛围下滴加DIBAL-H(1.0M,44.4mL,44.4mmol)，滴毕，-78℃保温30分钟。反应结束后，用饱和乙酸钠溶液(20mL)淬灭反应，自然升温至30℃，加入饱和氯化铵溶液(70mL)搅拌10分钟，加入乙酸乙酯(120mL)，过滤，水相用乙酸乙酯萃取，合并有机相，用饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到8.12g黄色油状的标题化合物，直接用于下一步。At room temperature, add tert-butyl 5-oxo-4-azaspiro[2.4]heptane-4-carboxylate (7.81g, 37.0mmol) and tetrahydrofuran (90mL) into the reaction flask and cool to -78°C , DIBAL-H (1.0M, 44.4mL, 44.4mmol) was added dropwise under a nitrogen atmosphere, after the drop was completed, it was incubated at -78°C for 30 minutes. After the reaction, quench the reaction with saturated sodium acetate solution (20mL), naturally warm up to 30°C, add saturated ammonium chloride solution (70mL) and stir for 10 minutes, add ethyl acetate (120mL), filter, and wash the aqueous phase with ethyl acetate The ester was extracted, the organic phases were combined, washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 8.12 g of the title compound as a yellow oil, which was directly used in the next step.

LCMS:m/z 214.14[M+H] +。 LCMS: m/z 214.14 [M+H] + .

步骤4：5-甲氧基-4-氮杂螺[2.4]庚烷-4-羧酸叔丁酯(4d)的制备Step 4: Preparation of tert-butyl 5-methoxy-4-azaspiro[2.4]heptane-4-carboxylate (4d)

于室温，将5-羟基-4-氮杂螺[2.4]庚烷-4-羧酸叔丁酯(8.12g,37.0mmol)、甲醇(90mL)加入到反应瓶中，加入对一水合甲苯磺酸(493mg,2.59mmol)，搅 拌反应2小时。反应结束后，将反应液浓缩至干，加入饱和碳酸氢钠溶液、乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到7.96g褐色油状的标题化合物，用二氯甲烷(20mL)稀释，直接用于下一步。At room temperature, tert-butyl 5-hydroxy-4-azaspiro[2.4]heptane-4-carboxylate (8.12g, 37.0mmol) and methanol (90mL) were added to the reaction flask, and p-toluenesulfonate monohydrate was added Acid (493mg, 2.59mmol), stirred for 2 hours. After the reaction, the reaction solution was concentrated to dryness, added with saturated sodium bicarbonate solution and ethyl acetate for extraction, the organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 7.96g The title compound as a brown oil was diluted with dichloromethane (20 mL) and used directly in the next step.

LCMS:m/z 228.15[M+H] +。 LCMS: m/z 228.15 [M+H] + .

步骤5：(S)-5-((S)-2-((R)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-4-氮杂螺[2.4]庚烷-4-羧酸叔丁酯(4e)的制备Step 5: (S)-5-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester (4e)

于室温，将化合物1r(9.71g,29.5mmol)、二氯甲烷(110mL)加入到反应瓶中，降温至-78℃，滴加四氯化钛(5.61g,29.5mmol)，保温30分钟后滴加DIPEA(5.71g,44.3mmol)，保温30分钟后滴加5-甲氧基-4-氮杂螺[2.4]庚烷-4-羧酸叔丁酯(8.70g,38.4mmol)的二氯甲烷溶液(18mL)，保温30分钟后自然升至室温反应1.5小时。反应结束后，加入饱和碳酸氢钠溶液、二氯甲烷萃取，有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝10：1)纯化，得到12.3g白色固体状的标题化合物，收率79.8％。At room temperature, compound 1r (9.71g, 29.5mmol) and dichloromethane (110mL) were added to the reaction flask, the temperature was lowered to -78°C, titanium tetrachloride (5.61g, 29.5mmol) was added dropwise, and after 30 minutes of insulation DIPEA (5.71g, 44.3mmol) was added dropwise, and after 30 minutes of incubation, a solution of tert-butyl 5-methoxy-4-azaspiro[2.4]heptane-4-carboxylate (8.70g, 38.4mmol) was added dropwise. Chloromethane solution (18mL) was incubated for 30 minutes and then allowed to rise to room temperature for 1.5 hours. After the reaction was finished, add saturated sodium bicarbonate solution and dichloromethane for extraction, the organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was passed through column chromatography (washing Removal agent: petroleum ether: ethyl acetate = 10: 1) Purification to obtain 12.3 g of the title compound as a white solid with a yield of 79.8%.

LCMS:m/z 525.21[M+H] +。 LCMS: m/z 525.21 [M+H] + .

步骤6：(S)-2-((S)-4-(叔丁氧羰基)-4-氮杂螺[2.4]庚烷-5-基)-2-(4-氯苯基)乙酸(4f)的制备Step 6: (S)-2-((S)-4-(tert-butoxycarbonyl)-4-azaspiro[2.4]heptan-5-yl)-2-(4-chlorophenyl)acetic acid ( 4f) Preparation

于室温，将氢氧化锂一水合物(106mg,2.50mmol)、四氢呋喃(5mL)、水(3.5mL)加入到反应瓶中，加入30％过氧化氢(68.0mg,2.00mmol)，降温至0℃以下，加入(S)-5-((S)-2-((R)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-4-氮杂螺[2.4]庚烷-4-羧酸叔丁酯(4e)(524mg,1.00mmol)的四氢呋喃溶液(2mL)，0℃左右搅拌反应3小时。反应结束后，于10℃以下，向反应液中加入12.5wt％亚硫酸钠溶液(1.2mL)，搅拌0.5小时，加入27.0wt％硫酸氢钾溶液调pH至2～3，加入乙酸乙酯萃取，有机相浓缩至干，残余物通过制备高效液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得到233mg白色固体状的标题化合物，收率63.8％。At room temperature, add lithium hydroxide monohydrate (106mg, 2.50mmol), tetrahydrofuran (5mL), water (3.5mL) into the reaction flask, add 30% hydrogen peroxide (68.0mg, 2.00mmol), cool to 0 Below ℃, add (S)-5-((S)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)- 2-Oxoethyl)-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester (4e) (524mg, 1.00mmol) in tetrahydrofuran (2mL), stirred at about 0°C for 3 hours. After the reaction, below 10°C, add 12.5wt% sodium sulfite solution (1.2mL) to the reaction solution, stir for 0.5 hours, add 27.0wt% potassium bisulfate solution to adjust the pH to 2-3, add ethyl acetate for extraction, organic The phase was concentrated to dryness, and the residue was separated by preparative high-performance liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), to obtain 233mg white The title compound as a solid, yield 63.8%.

LCMS:m/z 366.14[M+H] +。 LCMS: m/z 366.14 [M+H] + .

步骤7：(S)-5-((S)-1-(4-氯苯基)-2-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-氧代乙基)-4-氮杂螺[2.4]庚烷-4-羧酸叔丁酯(4g)的制备Step 7: (S)-5-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl Preparation of ester (4g)

于室温，将化合物1k(115mg,0.491mmol)、二氯甲烷(4mL)加入到反应瓶中，加入DIPEA(284mg,2.20mmol)，搅拌10分钟，加入(S)-2-((S)-4-(叔丁氧羰基)-4-氮杂螺[2.4]庚烷-5-基)-2-(4-氯苯基)乙酸(83.0mg,0.220mmol)，搅拌5分钟，加入HBTU(101mg,0.264mmol)，搅拌反应12小时。反应结束后，将反应液浓缩至干，残余物通过柱层析色谱法(洗脱剂：二氯甲烷：甲醇＝20：1)纯化， 得到173mg白色固体状的标题化合物，直接用于下一步。At room temperature, compound 1k (115mg, 0.491mmol), dichloromethane (4mL) were added to the reaction flask, DIPEA (284mg, 2.20mmol) was added, stirred for 10 minutes, and (S)-2-((S)- 4-(tert-butoxycarbonyl)-4-azaspiro[2.4]heptane-5-yl)-2-(4-chlorophenyl)acetic acid (83.0mg, 0.220mmol), stirred for 5 minutes, added HBTU ( 101mg, 0.264mmol), stirred for 12 hours. After the reaction, the reaction solution was concentrated to dryness, and the residue was purified by column chromatography (eluent: dichloromethane:methanol=20:1) to obtain 173 mg of the title compound as a white solid, which was directly used in the next step .

LCMS:m/z 582.28[M+H] +。 LCMS: m/z 582.28 [M+H] + .

步骤8：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((S)-4-氮杂螺[2.4]庚-5-基)乙-1-酮(4)的制备Step 8: (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-4-azaspiro[2.4]hept-5-yl)ethan-1-one (4)

于室温，将化合物4g(157mg,0.220mmol)、二氯甲烷(5mL)加入到反应瓶中，加入氯化氢的1,4-二氧六环溶液(4.0M,0.25mL,1.00mmol)，25℃搅拌反应12小时。反应结束后，将反应液浓缩至干，加入二氯甲烷稀释，用DIPEA调pH至7～8，减压浓缩，残余物用制备高效液相色谱法分离(色谱柱型号：Daisogei30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得到34.0mg白色固体状的标题化合物，收率32.3％。At room temperature, compound 4g (157mg, 0.220mmol) and dichloromethane (5mL) were added to the reaction flask, and a solution of hydrogen chloride in 1,4-dioxane (4.0M, 0.25mL, 1.00mmol) was added, at 25°C The reaction was stirred for 12 hours. After the reaction, the reaction solution was concentrated to dryness, diluted with dichloromethane, adjusted to pH 7-8 with DIPEA, concentrated under reduced pressure, and the residue was separated by preparative high-performance liquid chromatography (column model: Daisogei 30mm*250mm, C18 , 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), 34.0 mg of the title compound was obtained as a white solid, and the yield was 32.3%.

LCMS:m/z 482.22[M+H] +。 LCMS: m/z 482.22 [M+H] + .

1H NMR(400MHz,DMSO)δ8.44(s,1H),7.40(q,J＝8.7Hz,4H),5.38(d,J＝5.6Hz,1H),4.84(dd,J＝12.9,6.3Hz,1H),4.53(q,J＝7.3Hz,1H),3.99(d,J＝9.2Hz,1H),3.66(dd,J＝16.9,12.3Hz,3H),3.58-3.36(m,6H),2.35-2.16(m,4H),2.06-1.83(m,2H),1.73-1.54(m,1H),1.28(ddd,J＝16.3,12.6,8.4Hz,1H),1.10-0.91(m,6H)。 1 H NMR (400MHz, DMSO) δ8.44 (s, 1H), 7.40 (q, J = 8.7Hz, 4H), 5.38 (d, J = 5.6Hz, 1H), 4.84 (dd, J = 12.9, 6.3 Hz, 1H), 4.53(q, J=7.3Hz, 1H), 3.99(d, J=9.2Hz, 1H), 3.66(dd, J=16.9, 12.3Hz, 3H), 3.58-3.36(m, 6H ),2.35-2.16(m,4H),2.06-1.83(m,2H),1.73-1.54(m,1H),1.28(ddd,J＝16.3,12.6,8.4Hz,1H),1.10-0.91(m ,6H).

实施例5：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((R)-2-氮杂螺[4.5]癸-1-基)乙-1-酮(5)的制备Example 5: (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta Preparation of alkano[d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-2-azaspiro[4.5]dec-1-yl)ethan-1-one (5)

Figure PCTCN2022136451-appb-000043
Figure PCTCN2022136451-appb-000043

步骤1:1-氧代-2-氮杂螺[4.5]癸烷-2-羧酸叔丁酯(5a)的制备Step 1: Preparation of tert-butyl 1-oxo-2-azaspiro[4.5]decane-2-carboxylate (5a)

于室温，将2-氮杂螺[4.5]癸烷-1-酮(200mg,1.31mmol)、DCM(10mL)、TEA(331mg,3.3mmol)、DMAP(16mg,0.13mmol)加入至反应瓶中，降温至0℃，滴加Boc 2O(343mg,1.57mmol)，搅拌反应30小时。反应结束后倒入水中，水相 以二氯甲烷萃取，合并有机相后减压浓缩得338mg黄色油粗品状标题产物，直接用于下一步。 At room temperature, 2-azaspiro[4.5]decane-1-one (200mg, 1.31mmol), DCM (10mL), TEA (331mg, 3.3mmol), DMAP (16mg, 0.13mmol) were added to the reaction flask , cooled to 0°C, added Boc 2 O (343mg, 1.57mmol) dropwise, and stirred for 30 hours. After the reaction was completed, it was poured into water, and the aqueous phase was extracted with dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain 338 mg of the title product as crude yellow oil, which was directly used in the next step.

LCMS:m/z 254.17[M+H] +。 LCMS: m/z 254.17 [M+H] + .

步骤2:1-羟基-2-氮杂螺[4.5]癸烷-2-羧酸叔丁酯(5b)的制备Step 2: Preparation of tert-butyl 1-hydroxy-2-azaspiro[4.5]decane-2-carboxylate (5b)

于室温，将1-氧代-2-氮杂螺[4.5]癸烷-2-羧酸叔丁酯(338mg,粗品)、THF(23.0mL)加入至反应瓶中，降温至-78℃，滴加DIBAL-H(2mL,2.0mmol)，滴毕，-78℃保温30分钟。反应结束后，以饱和乙酸钠水溶液(5mL)淬灭反应，升至室温，加入饱和氯化铵水溶液(5mL)和乙酸乙酯(10mL)搅拌10分钟，过滤，水相以乙酸乙酯萃取，合并有机相后减压浓缩得270mg黄色油状标题产物，直接用于下一步，产率81％。At room temperature, tert-butyl 1-oxo-2-azaspiro[4.5]decane-2-carboxylate (338mg, crude product) and THF (23.0mL) were added to the reaction flask, cooled to -78°C, DIBAL-H (2mL, 2.0mmol) was added dropwise, and the solution was kept at -78°C for 30 minutes. After the reaction was completed, the reaction was quenched with saturated aqueous sodium acetate (5 mL), warmed to room temperature, added saturated aqueous ammonium chloride (5 mL) and ethyl acetate (10 mL) and stirred for 10 minutes, filtered, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain 270 mg of the title product as a yellow oil, which was directly used in the next step with a yield of 81%.

LCMS:m/z 256.18[M+H] +。 LCMS: m/z 256.18 [M+H] + .

步骤3:1-甲氧基-2-氮杂螺[4.5]癸烷-2-羧酸叔丁酯(5c)的制备Step 3: Preparation of tert-butyl 1-methoxy-2-azaspiro[4.5]decane-2-carboxylate (5c)

于室温，将1-羟基-2-氮杂螺[4.5]癸烷-2-羧酸叔丁酯(270mg,1.06mmol)甲醇(20mL)和一水合对甲苯磺酸(52.0mg,0.270mmol)加入至反应瓶中，室温反应2小时。反应结束后将反应体系倒入饱和碳酸氢钠水溶液中，以乙酸乙酯萃取，合并有机相，减压浓缩后，残余物以二氯甲烷稀释配成29wt％溶液，直接用于下一步。At room temperature, tert-butyl 1-hydroxy-2-azaspiro[4.5]decane-2-carboxylate (270mg, 1.06mmol) methanol (20mL) and p-toluenesulfonic acid monohydrate (52.0mg, 0.270mmol) Add it to the reaction flask, and react at room temperature for 2 hours. After the reaction, the reaction system was poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to prepare a 29 wt% solution, which was directly used in the next step.

LCMS:m/z 270.39[M+H] +。 LCMS: m/z 270.39 [M+H] + .

步骤4：(R)-1-((S)-2-((R)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-2-氮杂螺[4.5]癸烷-2-羧酸叔丁酯(5d)的制备Step 4: (R)-1-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (5d)

于室温，将化合物1r(1.86g,5.64mmol)、二氯甲烷(30mL)加入至反应瓶中，降温至-78℃，滴加四氯化钛(1.18g,6.23mmol)，保温30分钟后，滴加DIPEA(878mg,6.79mmol)，保温30分钟后滴加1-甲氧基-2-氮杂螺[4.5]癸烷-2-羧酸叔丁酯的二氯甲烷溶液，保温30分钟后自然升至室温反应1.5小时。反应结束后将反应体系倒入水中，水相以二氯甲烷萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(PE:EA＝5:1)，得294mg黄色油状的目标产物，直接用于下一步，两步产率49％。 At room temperature, compound 1r (1.86g, 5.64mmol) and dichloromethane (30mL) were added to the reaction flask, the temperature was lowered to -78°C, titanium tetrachloride (1.18g, 6.23mmol) was added dropwise, and after 30 minutes of insulation , DIPEA (878mg, 6.79mmol) was added dropwise, and after 30 minutes of incubation, a dichloromethane solution of 1-methoxy-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl was added dropwise, and incubated for 30 minutes Then naturally rise to room temperature and react for 1.5 hours. After the reaction, the reaction system was poured into water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE: EA=5:1), to obtain 294 mg of the target product in the form of yellow oil, which was directly used in the next step, and the two-step yield was 49%.

LCMS:m/z 567.25[M+H] +。 LCMS: m/z 567.25 [M+H] + .

步骤5：(S)-2-((R)-2-(叔丁氧羰基)-2-氮杂螺[4.5]癸-1-基)-2-(4-氯苯基)乙酸(5e)的制备Step 5: (S)-2-((R)-2-(tert-butoxycarbonyl)-2-azaspiro[4.5]dec-1-yl)-2-(4-chlorophenyl)acetic acid (5e ) preparation

于室温，将LiOH(48.9mg,1.164mmol)、水(2.5mL)、THF(5mL)加入至反应瓶中，冰浴降温至5℃左右，滴加30％双氧水(105.6mg,0.932mmol)，分批加入(R)-1-((S)-2-((S)-5-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-2-氮杂螺[4.5]癸烷-2-羧酸叔丁酯(264mg,0.466mmol)，冰浴反应3小时。反应结束后以12.5wt％亚硫酸钠水溶液淬灭反应，27.0wt％硫酸氢钾溶液调节PH为2，水相用乙酸乙酯萃取，合并有机相，减压浓缩后残余物经柱层析色谱法分离 (PE:EA＝10:1)，得84mg黄色油状的目标产物，直接用于下一步，产率44.2％。At room temperature, LiOH (48.9mg, 1.164mmol), water (2.5mL), and THF (5mL) were added to the reaction flask, cooled to about 5°C in an ice bath, and 30% hydrogen peroxide (105.6mg, 0.932mmol) was added dropwise, Add (R)-1-((S)-2-((S)-5-benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 in batches -Oxoethyl)-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (264mg, 0.466mmol), react in ice bath for 3 hours. After the reaction was completed, the reaction was quenched with 12.5wt% sodium sulfite aqueous solution, 27.0wt% potassium bisulfate solution was used to adjust the pH to 2, the aqueous phase was extracted with ethyl acetate, the organic phase was combined, and the residue was separated by column chromatography after concentrating under reduced pressure. (PE:EA=10:1), 84 mg of the target product was obtained as a yellow oil, which was directly used in the next step with a yield of 44.2%.

LCMS:m/z 408.19[M+H] +。 LCMS: m/z 408.19 [M+H] + .

步骤6：(R)-1-((S)-1-(4-氯苯基)-2-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-氧代乙基)-2-氮杂螺[4.5]癸烷-2-羧酸叔丁酯(5f)的制备Step 6: (R)-1-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl Preparation of ester (5f)

于室温，将化合物1k(70mg,0.299mmol)、二氯甲烷(5mL)加到反应瓶中，加入N,N-二异丙基乙胺(412mg,3.10mmol)，搅拌5分钟，加入(S)-2-((R)-2-(叔丁氧羰基)-2-氮杂螺[4.5]癸-1-基)-2-(4-氯苯基)乙酸(84mg,0.206mmol)，搅拌1分钟，加入HBTU(204mg,0.540mmol)，搅拌反应12小时。反应结束后，减压浓缩，残余物经柱层析色谱法分离纯化(DCM:MeOH＝10:1)，得137mg白色固体状的粗品标题化合物。At room temperature, compound 1k (70mg, 0.299mmol) and dichloromethane (5mL) were added to the reaction flask, N,N-diisopropylethylamine (412mg, 3.10mmol) was added, stirred for 5 minutes, and (S )-2-((R)-2-(tert-butoxycarbonyl)-2-azaspiro[4.5]dec-1-yl)-2-(4-chlorophenyl)acetic acid (84mg, 0.206mmol), After stirring for 1 minute, HBTU (204 mg, 0.540 mmol) was added and the reaction was stirred for 12 hours. After the reaction, it was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM:MeOH=10:1) to obtain 137 mg of the crude title compound as a white solid.

LCMS:m/z 624.32[M+H] +。 LCMS: m/z 624.32 [M+H] + .

步骤7：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((R)-2-氮杂螺[4.5]癸-1-基)乙-1-酮(5)的制备Step 7: (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-2-azaspiro[4.5]dec-1-yl)ethan-1-one (5)

于室温，将化合物5f(137mg,粗品)、二氯甲烷(3mL)加入至反应瓶中，冰浴降温至5℃左右，滴加盐酸/二氧六环溶液(0.33mL，1.32mmol)，加毕室温反应10小时。反应结束后直接浓缩，残余物用制备高效液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得35mg白色固体标题化合物，产率31.9％。At room temperature, compound 5f (137mg, crude product) and dichloromethane (3mL) were added to the reaction flask, cooled to about 5°C in an ice bath, hydrochloric acid/dioxane solution (0.33mL, 1.32mmol) was added dropwise, and Complete reaction at room temperature for 10 hours. Concentrate directly after the reaction, and the residue is separated by preparative high-performance liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%) to obtain 35mg The title compound as a white solid, 31.9% yield.

LCMS:m/z 524.27[M+H] +。 LCMS: m/z 524.27 [M+H] + .

1H NMR(400MHz,CDCl 3)δ8.49(s,1H),7.44-7.28(m,4H),5.07(t,J＝7.1,1H),4.12(d,J＝8.9,1H),3.86-3.73(m,2H),3.74-3.48(m,5H),3.42(ddd,J＝27.2,15.4,5.9,2H),3.24(s,1H),2.97(d,J＝4.5,2H),2.24-2.08(m,2H),2.09-1.92(m,1H),1.71(d,J＝9.0,1H),1.64-1.46(m,3H),1.47-1.23(m,3H),1.22-1.04(m,4H),0.94(d,J＝13.5,1H),0.81(dd,J＝17.1,7.9,1H),0.33(td,J＝13.1,3.9,1H)。 1 H NMR (400MHz, CDCl 3 )δ8.49(s,1H),7.44-7.28(m,4H),5.07(t,J=7.1,1H),4.12(d,J=8.9,1H),3.86 -3.73(m,2H),3.74-3.48(m,5H),3.42(ddd,J=27.2,15.4,5.9,2H),3.24(s,1H),2.97(d,J=4.5,2H), 2.24-2.08(m,2H),2.09-1.92(m,1H),1.71(d,J=9.0,1H),1.64-1.46(m,3H),1.47-1.23(m,3H),1.22-1.04 (m, 4H), 0.94 (d, J = 13.5, 1H), 0.81 (dd, J = 17.1, 7.9, 1H), 0.33 (td, J = 13.1, 3.9, 1H).

实施例6：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((R)-2-氮杂螺[4.4]壬-1-基)乙-1-酮(6)的制备Example 6: (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta Preparation of alkano[d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-2-azaspiro[4.4]non-1-yl)ethan-1-one (6)

Figure PCTCN2022136451-appb-000044
Figure PCTCN2022136451-appb-000044

Figure PCTCN2022136451-appb-000045
Figure PCTCN2022136451-appb-000045

步骤1:1-(氰甲基)环戊烷-1-羧酸甲酯(6a)的制备Step 1: Preparation of methyl 1-(cyanomethyl)cyclopentane-1-carboxylate (6a)

于室温，将环戊烷羧酸甲酯(1.02g,8.00mmol)、THF(20mL)加入至反应瓶中。降温至-78℃，滴加LDA(4.4mL,8.80mmol)，搅拌1小时，于-78℃，滴加溴乙腈(1.14g,9.60mmol)，加毕，升至室温，搅拌10小时。反应结束后，将反应液倒入饱和氯化铵水溶液中，水相以乙酸乙酯萃取，合并有机相，减压浓缩后，残余物经柱层析色谱法分离纯化(PE:EA＝10:)得900mg白色固体状标题产物，直接用于下一步，产率67.7％。At room temperature, methyl cyclopentanecarboxylate (1.02 g, 8.00 mmol), THF (20 mL) were added into the reaction flask. Cool down to -78°C, add LDA (4.4mL, 8.80mmol) dropwise, and stir for 1 hour. At -78°C, add bromoacetonitrile (1.14g, 9.60mmol) dropwise. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE:EA=10: ) to obtain 900 mg of the title product as a white solid, which was directly used in the next step with a yield of 67.7%.

LCMS:m/z 168.09[M+H] +。 LCMS: m/z 168.09 [M+H] + .

步骤2:2-氮杂螺[4,4]壬-1-酮(6b)的制备Step 2: Preparation of 2-azaspiro[4,4]nonan-1-one (6b)

于室温，将1-(氰甲基)环戊烷-1-羧酸甲酯(850mg,5.09mmol)、THF(20.0mL)、水(10.0mL)、六水合氯化钴(607mg,2.55mmol)加入至反应瓶中搅拌溶解。降温至0℃，分批加入NaBH 4(962mg,25.44mmol)，加毕，升至室温搅拌10小时。反应结束后，加入水(5mL)和乙酸乙酯(10mL)搅拌10分钟，过滤，水相以乙酸乙酯萃取，合并有机相，减压浓缩，残余物经柱层析色谱法分离纯化(PE:EA＝2:1)，得298mg白色固体状标题产物，直接用于下一步，产率42.1％。 At room temperature, methyl 1-(cyanomethyl)cyclopentane-1-carboxylate (850mg, 5.09mmol), THF (20.0mL), water (10.0mL), cobalt chloride hexahydrate (607mg, 2.55mmol ) into the reaction flask and stirred to dissolve. The temperature was lowered to 0°C, and NaBH 4 (962 mg, 25.44 mmol) was added in batches. After the addition was complete, the mixture was raised to room temperature and stirred for 10 hours. After the reaction, add water (5mL) and ethyl acetate (10mL) and stir for 10 minutes, filter, extract the aqueous phase with ethyl acetate, combine the organic phases, concentrate under reduced pressure, and the residue is separated and purified by column chromatography (PE :EA=2:1), 298 mg of the title product was obtained as a white solid, which was directly used in the next step with a yield of 42.1%.

LCMS:m/z 140.10[M+H] +。 LCMS: m/z 140.10 [M+H] + .

步骤3:1-氧代-2-氮杂螺[4.4]壬-2-羧酸叔丁酯(6c)的制备Step 3: Preparation of tert-butyl 1-oxo-2-azaspiro[4.4]nonan-2-carboxylate (6c)

于室温，将2-氮杂螺[4,4]壬-1-酮(270mg,1.94mmol)、DCM(10mL)、TEA(588.1mg,5.82mmol)、DMAP(11.8mg,0.097mmol)加入至反应瓶中。降温至0℃，滴加Boc 2O(634.7mg,2.91mmol)，搅拌30小时。反应结束后，将反应液倒入水中，水相以二氯甲烷萃取，合并有机相，减压浓缩，残余物经柱层析色谱法分离纯化(PE:EA＝5:1)，得460mg白色固体状标题产物，直接用于下一步，产 率99％。 At room temperature, 2-azaspiro[4,4]nonan-1-one (270mg, 1.94mmol), DCM (10mL), TEA (588.1mg, 5.82mmol), DMAP (11.8mg, 0.097mmol) were added to in the reaction vial. Cool down to 0°C, add Boc 2 O (634.7 mg, 2.91 mmol) dropwise, and stir for 30 hours. After the reaction, the reaction solution was poured into water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE:EA=5:1) to obtain 460 mg of white The title product was used as a solid in the next step in 99% yield.

LCMS:m/z 240.15[M+H] +。 LCMS: m/z 240.15 [M+H] + .

步骤4:1-羟基-2-氮杂螺[4.4]壬-2-羧酸叔丁酯(6d)的制备Step 4: Preparation of tert-butyl 1-hydroxy-2-azaspiro[4.4]nonan-2-carboxylate (6d)

于室温，将1-氧代-2-氮杂螺[4.4]壬-2-羧酸叔丁酯(460mg,1.92mmol)和THF(10.0mL)加入至反应瓶中。降温至-78℃，滴加DIBAL-H(2.9mL,2.88mmol)，滴毕，于-78℃搅拌30分钟。反应结束后，以饱和乙酸钠水溶液(5mL)淬灭反应，升至室温，加入饱和氯化铵水溶液(5mL)和乙酸乙酯(10mL)搅拌10分钟，过滤，水相以乙酸乙酯萃取，合并有机相，减压浓缩，残余物经柱层析色谱法分离纯化(PE:EA＝5:1)，得460mg黄色油状标题产物，直接用于下一步，产率99％。tert-butyl 1-oxo-2-azaspiro[4.4]nonan-2-carboxylate (460 mg, 1.92 mmol) and THF (10.0 mL) were added to the reaction flask at room temperature. Cool down to -78°C, add DIBAL-H (2.9mL, 2.88mmol) dropwise, and stir at -78°C for 30 minutes. After the reaction was completed, the reaction was quenched with saturated aqueous sodium acetate (5 mL), warmed to room temperature, added saturated aqueous ammonium chloride (5 mL) and ethyl acetate (10 mL) and stirred for 10 minutes, filtered, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE:EA=5:1) to obtain 460 mg of the title product as a yellow oil, which was directly used in the next step with a yield of 99%.

LCMS:m/z 242.17[M+H] +。 LCMS: m/z 242.17 [M+H] + .

步骤5:1-甲氧基-2-氮杂螺[4.4]壬-2-羧酸叔丁酯(6e)的制备Step 5: Preparation of tert-butyl 1-methoxy-2-azaspiro[4.4]nonan-2-carboxylate (6e)

于室温，将1-羟基-2-氮杂螺[4.4]壬-2-羧酸叔丁酯(412mg,1.71mmol)、甲醇(20mL)和对一水合对甲苯磺酸(16.2mg,0.09mmol)加入至反应瓶中，室温反应2小时。反应结束后，将反应体系倒入饱和碳酸氢钠水溶液中，以乙酸乙酯萃取，合并有机相，减压浓缩，残余物以二氯甲烷稀释配成29wt％溶液，直接用于下一步。At room temperature, tert-butyl 1-hydroxy-2-azaspiro[4.4]nonan-2-carboxylate (412mg, 1.71mmol), methanol (20mL) and p-toluenesulfonic acid monohydrate (16.2mg, 0.09mmol ) was added to the reaction flask, and reacted at room temperature for 2 hours. After the reaction, the reaction system was poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to prepare a 29 wt% solution, which was directly used in the next step.

LCMS:m/z 256.18[M+H] +。 LCMS: m/z 256.18 [M+H] + .

步骤6：(R)-1-((S)-2-((R)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-2-氮杂螺[4.4]壬-2-羧酸叔丁酯(6f)的制备Step 6: (R)-1-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-2-azaspiro[4.4]nonan-2-carboxylate tert-butyl ester (6f)

于室温，将化合物1r(627.9mg,1.91mmol)、二氯甲烷(30mL)加入至反应瓶中，降温至-78℃，滴加四氯化钛(398.4mg,2.10mmol)，搅拌30分钟后滴加DIPEA(295.4mg,2.29mmol)，保温30分钟后滴加1-甲氧基-2-氮杂螺[4.4]壬-2-羧酸叔丁酯的二氯甲烷溶液，保温30分钟后自然升至室温反应1.5小时。反应结束后，将反应体系倒入水中，水相以二氯甲烷萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(PE:EA＝5:1)得543mg黄色油状的目标产物，直接用于下一步，两步产率59.9％。 At room temperature, compound 1r (627.9mg, 1.91mmol) and dichloromethane (30mL) were added to the reaction flask, cooled to -78°C, titanium tetrachloride (398.4mg, 2.10mmol) was added dropwise, and stirred for 30 minutes DIPEA (295.4mg, 2.29mmol) was added dropwise, and after 30 minutes of incubation, a dichloromethane solution of 1-methoxy-2-azaspiro[4.4]nonane-2-tert-butyl carboxylate was added dropwise, and after 30 minutes of incubation, Naturally rise to room temperature and react for 1.5 hours. After the reaction, the reaction system was poured into water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous Na2SO4 , filtered, the filtrate was concentrated under reduced pressure , and the residue was separated and purified by column chromatography (PE :EA=5:1) 543 mg of the target product in the form of yellow oil was obtained, which was directly used in the next step, and the two-step yield was 59.9%.

LCMS:m/z 553.24[M+H] +。 LCMS: m/z 553.24 [M+H] + .

步骤7：(S)-2-((R)-2-(叔丁氧羰基)-2-氮杂螺[4.4]壬-1-基)-2-(4-氯苯基)乙酸(6g)的制备Step 7: (S)-2-((R)-2-(tert-butoxycarbonyl)-2-azaspiro[4.4]non-1-yl)-2-(4-chlorophenyl)acetic acid (6g ) preparation

于室温，将LiOH(103mg,2.45mmol)、水(5mL)、THF(10mL)加入至反应瓶中。冰浴降温至5℃左右，滴加30％双氧水(222mg,1.96mmol)，分批加入(R)-1-((S)-2-((S)-5-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-2-氮杂螺[4.4]壬-2-羧酸叔丁酯(543mg,0.982mmol)，冰浴反应3小时。反应结束后，以12.5wt％亚硫酸钠水溶液淬灭反应，27.0wt％硫酸氢钾溶液调节PH为2，水相用乙酸乙酯萃取，合并有机相，减压浓缩，残余物经柱层析色谱法分离纯化 (PE:EA＝10:1)，得102mg黄色油状的目标产物，直接用于下一步，产率31％。LiOH (103 mg, 2.45 mmol), water (5 mL), THF (10 mL) were added to the reaction flask at room temperature. Cool down to about 5°C in an ice bath, add 30% hydrogen peroxide (222 mg, 1.96 mmol) dropwise, and add (R)-1-((S)-2-((S)-5-benzyl-2-oxo Oxazolidin-3-yl)-1-(4-chlorophenyl)-2-oxoethyl)-2-azaspiro[4.4]nonan-2-carboxylic acid tert-butyl ester (543mg, 0.982mmol) , react in ice bath for 3 hours. After the reaction, quench the reaction with 12.5wt% sodium sulfite aqueous solution, adjust the pH to 2 with 27.0wt% potassium hydrogensulfate solution, extract the aqueous phase with ethyl acetate, combine the organic phases, concentrate under reduced pressure, and the residue is subjected to column chromatography After separation and purification (PE:EA=10:1), 102 mg of the target product was obtained as a yellow oil, which was directly used in the next step with a yield of 31%.

LCMS:m/z 394.17[M+H] +。 LCMS: m/z 394.17 [M+H] + .

步骤8：(R)-1-((S)-1-(4-氯苯基)-2-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-氧代乙基)-2-氮杂螺[4.4]壬-2-羧酸叔丁酯(6h)的制备Step 8: (R)-1-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2-azaspiro[4.4]nonan-2-carboxylic acid tert-butyl ester Preparation of (6h)

于室温，将化合物1k(68.7mg,0.293mmol)、二氯甲烷(5mL)加到反应瓶中，加入N,N-二异丙基乙胺(327.7mg,2.54mmol)，搅拌5分钟，加入(S)-2-((R)-2-(叔丁氧羰基)-2-氮杂螺[4.4]壬-1-基)-2-(4-氯苯基)乙酸(100mg,0.254mmol)，搅拌1分钟，加入HBTU(115.6mg,0.305mmol)，搅拌反应12小时。反应结束后，减压浓缩，残余物经柱层析色谱法分离纯化(DCM:MeOH＝10:1)得163mg白色固体状的粗品标题化合物。At room temperature, compound 1k (68.7mg, 0.293mmol), dichloromethane (5mL) were added to the reaction flask, N,N-diisopropylethylamine (327.7mg, 2.54mmol) was added, stirred for 5 minutes, added (S)-2-((R)-2-(tert-butoxycarbonyl)-2-azaspiro[4.4]non-1-yl)-2-(4-chlorophenyl)acetic acid (100mg, 0.254mmol ), stirred for 1 minute, added HBTU (115.6mg, 0.305mmol), and stirred for 12 hours. After the reaction, it was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM:MeOH=10:1) to obtain 163 mg of the crude title compound as a white solid.

LCMS:m/z 610.31[M+H] +。 LCMS: m/z 610.31 [M+H] + .

步骤9：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((R)-2-氮杂螺[4.4]壬-1-基)乙-1-酮(6)的制备Step 9: (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-2-azaspiro[4.4]non-1-yl)ethan-1-one (6)

于室温，将化合物6h(163mg,粗品)、二氯甲烷(3mL)加入至反应瓶中，冰浴降温至5℃左右，滴加盐酸/二氧六环溶液(0.67mL，2.68mmol)，加毕室温反应10小时。反应结束后直接浓缩，残余物用制备高效液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得51mg白色固体标题化合物，产率39.4％。At room temperature, compound 6h (163 mg, crude product) and dichloromethane (3 mL) were added to the reaction flask, cooled to about 5 °C in an ice bath, hydrochloric acid/dioxane solution (0.67 mL, 2.68 mmol) was added dropwise, and Complete reaction at room temperature for 10 hours. Concentrate directly after the reaction, and the residue is separated by preparative high-performance liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), and 51mg is obtained The title compound as a white solid, 39.4% yield.

LCMS:m/z 510.26[M+H] +。 LCMS: m/z 510.26 [M+H] + .

1H NMR(400MHz,DMSO)δ＝8.43(s,1H),7.50(d,J＝8.5,2H),7.37(d,J＝8.5,2H),5.36(d,J＝5.6,1H),4.90-4.78(m,1H),4.06(d,J＝9.6,1H),3.76(d,J＝4.7,1H),3.68(d,J＝15.6,1H),3.62(d,J＝9.5,2H),3.59-3.52(m,2H),3.52-3.42(m,2H),2.87-2.76(m,1H),2.72(dd,J＝12.1,4.9,1H),1.94(ddd,J＝9.6,8.9,4.0,2H),1.62(td,J＝7.0,3.6,1H),1.56-1.45(m,2H),1.45-1.40(m,1H),1.40-1.31(m,2H),1.31-1.20(m,2H),1.19-1.08(m,2H),1.05(d,J＝6.9,3H),0.83-0.70(m,1H)。 1 H NMR (400MHz, DMSO) δ=8.43(s,1H),7.50(d,J=8.5,2H),7.37(d,J=8.5,2H),5.36(d,J=5.6,1H), 4.90-4.78(m,1H),4.06(d,J=9.6,1H),3.76(d,J=4.7,1H),3.68(d,J=15.6,1H),3.62(d,J=9.5, 2H), 3.59-3.52(m, 2H), 3.52-3.42(m, 2H), 2.87-2.76(m, 1H), 2.72(dd, J=12.1, 4.9, 1H), 1.94(ddd, J=9.6 ,8.9,4.0,2H),1.62(td,J=7.0,3.6,1H),1.56-1.45(m,2H),1.45-1.40(m,1H),1.40-1.31(m,2H),1.31- 1.20 (m, 2H), 1.19-1.08 (m, 2H), 1.05 (d, J = 6.9, 3H), 0.83-0.70 (m, 1H).

实施例7：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((R)-5-氮杂螺[2.4]庚-4-基)乙-1-酮(7)的制备Example 7: (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta Preparation of alkano[d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-5-azaspiro[2.4]hept-4-yl)ethan-1-one (7)

Figure PCTCN2022136451-appb-000046
Figure PCTCN2022136451-appb-000046

Figure PCTCN2022136451-appb-000047
Figure PCTCN2022136451-appb-000047

步骤1：1-(羟甲基)环丙烷-1-羧酸甲酯(7a)的制备Step 1: Preparation of methyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (7a)

于室温，将环丙烷-1,1-二甲酸二甲酯(10.0g，63.3mmol)、THF(150mL)加入至反应瓶中，分批加入三(叔丁氧基)氢化铝锂(35.4g，139.2mmol)，加毕升温至60℃反应过夜。降至室温，以10％KHSO 4水溶液淬灭反应，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝0:1-1:10)，得到标题化合物5.8g，收率：70.7％。 At room temperature, dimethyl cyclopropane-1,1-dicarboxylate (10.0g, 63.3mmol) and THF (150mL) were added to the reaction flask, and lithium tris(tert-butoxy)aluminum hydride (35.4g , 139.2mmol), after the addition, the temperature was raised to 60°C for overnight reaction. Cool down to room temperature, quench the reaction with 10% KHSO aqueous solution, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: EA/ PE=0:1-1:10), to obtain 5.8g of the title compound, yield: 70.7%.

LCMS：m/z 131.06[M+H] +。 LCMS: m/z 131.06 [M+H] + .

步骤2：1-((对甲苯磺酰氧基)甲基)环丙烷-1-羧酸甲酯(7b)的制备Step 2: Preparation of methyl 1-((p-toluenesulfonyloxy)methyl)cyclopropane-1-carboxylate (7b)

于室温，将1-(羟甲基)环丙烷-1-羧酸甲酯(5.0g，38.4mmol)、DCM(100mL)、TEA(7.76g，76.8mmol)、DMAP(468mg，3.84mmol)依次加入至反应瓶中，分批加入对甲苯磺酰氯(8.8g，46.08mmol)，室温反应过夜。将反应体系倒入冰水中淬灭反应，，水相用DCM萃取，合并有机相，无水硫酸钠干燥，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝0:1-1:10)，得到标题化合物6.0g，收率：55.0％。At room temperature, methyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (5.0 g, 38.4 mmol), DCM (100 mL), TEA (7.76 g, 76.8 mmol), DMAP (468 mg, 3.84 mmol) were sequentially Add it to the reaction flask, add p-toluenesulfonyl chloride (8.8 g, 46.08 mmol) in batches, and react overnight at room temperature. The reaction system was poured into ice water to quench the reaction, the aqueous phase was extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: EA/PE =0:1-1:10), to obtain 6.0 g of the title compound, yield: 55.0%.

LCMS：m/z 285.07[M+H] +。 LCMS: m/z 285.07 [M+H] + .

步骤3：1-(氰甲基)环丙烷-1-羧酸甲酯(7c)的制备Step 3: Preparation of methyl 1-(cyanomethyl)cyclopropane-1-carboxylate (7c)

于室温，将1-((对甲苯磺酰氧基)甲基)环丙烷-1-羧酸甲酯(5.0g，17.6mmol)和THF(100mL)加入至反应瓶中，滴加1M三甲基氰硅烷(TMSCN)(5.24g，52.8mmol)和1M四丁基氟化铵(TBAF)的THF溶液(52.8mL，52.8mmol)，室温反应过夜。将反应体系倒入冰水和乙酸乙酯中淬灭反应，水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝0:1-1:10)，得到标题化合物2.25g，收率：92.2％。At room temperature, 1-((p-toluenesulfonyloxy)methyl)cyclopropane-1-carboxylic acid methyl ester (5.0g, 17.6mmol) and THF (100mL) were added to the reaction flask, and 1M trimethyl Cyanosilane (TMSCN) (5.24g, 52.8mmol) and 1M tetrabutylammonium fluoride (TBAF) in THF (52.8mL, 52.8mmol) were reacted overnight at room temperature. The reaction system was poured into ice water and ethyl acetate to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography Purification (mobile phase: EA/PE=0:1-1:10) gave 2.25 g of the title compound, yield: 92.2%.

LCMS：m/z 140.06[M+H] +。 LCMS: m/z 140.06 [M+H] + .

步骤4：5-氮杂螺[2.4]庚烷-4-酮(7d)的制备Step 4: Preparation of 5-azaspiro[2.4]heptan-4-one (7d)

于室温，将1-(氰甲基)环丙烷-1-羧酸甲酯(2.2g，15.82mmol)、THF(44mL)、H 2O(22mL)加入至反应瓶中，加入六水合氯化钴(1.88g，7.91mmol)。冰浴降温至0℃，分批加入硼氢化钠(2.99g，79.09mmol)，加毕室温反应过夜。将反应体系倒入冰水和乙酸乙酯中淬灭反应，水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝0:1-1:1)，得到标题化合物1.34g白色固体，收率：76.2％。 At room temperature, add methyl 1-(cyanomethyl)cyclopropane-1-carboxylate (2.2g, 15.82mmol), THF (44mL), H 2 O (22mL) into the reaction flask, add chloride hexahydrate Cobalt (1.88 g, 7.91 mmol). Cool down to 0°C in an ice bath, add sodium borohydride (2.99 g, 79.09 mmol) in batches, and react overnight at room temperature after addition. The reaction system was poured into ice water and ethyl acetate to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase: EA/PE=0:1-1:1) gave the title compound as a white solid (1.34 g, yield: 76.2%).

LCMS：m/z 112.07[M+H] +。 LCMS: m/z 112.07 [M+H] + .

步骤5：4-氧代-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(7e)的制备Step 5: Preparation of tert-butyl 4-oxo-5-azaspiro[2.4]heptane-5-carboxylate (7e)

于室温，将5-氮杂螺[2.4]庚烷-4-酮(1.24g，11.2mmol)加入二氯甲烷(25mL)中，然后依次加入二碳酸二叔丁酯(3.7g，16.8mmol)、TEA(3.4g，33.6mmol)和4-二甲氨基吡啶(68.3mg，0.56mmol)，于室温搅拌2小时。反应液用二氯甲烷萃取，有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：MTBE/DCM＝0:1-1:10)，得标题化合物2.24g，收率：95.3％。At room temperature, 5-azaspiro[2.4]heptan-4-one (1.24g, 11.2mmol) was added into dichloromethane (25mL), followed by di-tert-butyl dicarbonate (3.7g, 16.8mmol) , TEA (3.4g, 33.6mmol) and 4-dimethylaminopyridine (68.3mg, 0.56mmol), stirred at room temperature for 2 hours. The reaction solution was extracted with dichloromethane, the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: MTBE/DCM=0:1-1:10) to obtain 2.24 g of the title compound. The yield was : 95.3%.

LCMS：m/z 156.12[M-55] +。 LCMS: m/z 156.12 [M-55] + .

步骤6：4-羟基-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(7f)的制备Step 6: Preparation of tert-butyl 4-hydroxy-5-azaspiro[2.4]heptane-5-carboxylate (7f)

于室温，将4-氧代-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(1.0g,4.74mmol)和THF(23.0mL)加入至反应瓶中。降温至-78℃，滴加DIBAL-H(10mL,10.0mmol)，滴毕，于-78℃搅拌30分钟。反应结束后，以饱和乙酸钠水溶液(5mL)淬灭反应，升至室温，加入饱和氯化铵水溶液(5mL)和乙酸乙酯(10mL)搅拌10分钟，过滤，水相以乙酸乙酯萃取，合并有机相后，减压浓缩，得865mg黄色油状标题产物，直接用于下一步，产率86.5％。tert-butyl 4-oxo-5-azaspiro[2.4]heptane-5-carboxylate (1.0 g, 4.74 mmol) and THF (23.0 mL) were added to the reaction flask at room temperature. Cool down to -78°C, add DIBAL-H (10 mL, 10.0 mmol) dropwise, and stir at -78°C for 30 minutes. After the reaction was completed, the reaction was quenched with saturated aqueous sodium acetate (5 mL), warmed to room temperature, added saturated aqueous ammonium chloride (5 mL) and ethyl acetate (10 mL) and stirred for 10 minutes, filtered, and the aqueous phase was extracted with ethyl acetate. After combining the organic phases, they were concentrated under reduced pressure to obtain 865 mg of the title product as a yellow oil, which was directly used in the next step with a yield of 86.5%.

LCMS:m/z 214.14[M+H] +。 LCMS: m/z 214.14 [M+H] + .

步骤7：4-甲氧基-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(7g)的制备Step 7: Preparation of tert-butyl 4-methoxy-5-azaspiro[2.4]heptane-5-carboxylate (7 g)

于室温，将4-羟基-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(822mg,3.86mmol)、甲醇(20mL)和一水合对甲苯磺酸(36.6mg,0.19mmol)加入至反应瓶中，室温反应2小时。反应结束后，将反应体系倒入饱和碳酸氢钠水溶液中，以乙酸乙酯萃取，合并有机相，减压浓缩后，残余物以二氯甲烷稀释配成29wt％溶液，直接用于下一步。At room temperature, tert-butyl 4-hydroxy-5-azaspiro[2.4]heptane-5-carboxylate (822mg, 3.86mmol), methanol (20mL) and p-toluenesulfonic acid monohydrate (36.6mg, 0.19mmol ) was added to the reaction flask, and reacted at room temperature for 2 hours. After the reaction, the reaction system was poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to prepare a 29 wt% solution, which was directly used in the next step.

LCMS:m/z 228.15[M+H] +。 LCMS: m/z 228.15 [M+H] + .

步骤8：(R)-4-((S)-2-((R)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-5-氮杂螺环[2.4]庚烷-5-羧酸叔丁酯(7h)的制备Step 8: (R)-4-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (7h)

于室温，将化合物1r(1.7g,5.28mmol)、二氯甲烷(30mL)加入至反应瓶中。降温至-78℃，滴加四氯化钛(1.1g,5.81mmol)，保温30分钟后滴加DIPEA(818mg,6.34mmol)，保温30分钟后滴加4-甲氧基-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯的二氯甲烷溶液，保温30分钟后自然升至室温反应1.5小时。反应结束后，将反应体系倒入水中，水相以二氯甲烷萃取，合并有机相，无水Na 2SO 4干燥，过 滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(PE:EA＝5:1)，得1.3g黄色固体目标产物，直接用于下一步，产率48.1％。 Compound 1r (1.7 g, 5.28 mmol), dichloromethane (30 mL) were added into the reaction flask at room temperature. Cool down to -78°C, add titanium tetrachloride (1.1g, 5.81mmol) dropwise, add DIPEA (818mg, 6.34mmol) dropwise after 30 minutes of insulation, and add 4-methoxy-5-aza The dichloromethane solution of spiro[2.4]heptane-5-tert-butyl carboxylate was incubated for 30 minutes and then naturally raised to room temperature for 1.5 hours of reaction. After the reaction, the reaction system was poured into water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous Na2SO4 , filtered, the filtrate was concentrated under reduced pressure , and the residue was separated and purified by column chromatography (PE :EA=5:1), 1.3g of the target product as a yellow solid was obtained, which was directly used in the next step with a yield of 48.1%.

LCMS:m/z 525.21[M+H] +。 LCMS: m/z 525.21 [M+H] + .

步骤9：(S)-2-((R)-5-(叔丁氧羰基)-5-氮杂螺[2.4]庚烷-4-基)-2-(4-氯苯基)乙酸(7i)的制备Step 9: (S)-2-((R)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptan-4-yl)-2-(4-chlorophenyl)acetic acid ( 7i) Preparation

于室温，将LiOH(247mg,5.88mmol)、水(13mL)、THF(25mL)加入至反应瓶中。冰浴降温至5℃左右，滴加30％双氧水(533mg,4.70mmol)，分批加入(R)-4-((S)-2-((S)-5-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(1.3g,2.35mmol)，冰浴反应30小时。反应结束后，以12.5wt％亚硫酸钠水溶液淬灭反应，27.0wt％硫酸氢钾溶液调节PH为2，水相用乙酸乙酯萃取，合并有机相，减压浓缩后，经柱层析色谱法分离(PE:EA＝10:1)，得90mg白色固体目标产物，直接用于下一步，产率9.9％。LiOH (247 mg, 5.88 mmol), water (13 mL), THF (25 mL) were added to the reaction flask at room temperature. Cool down to about 5°C in an ice bath, add 30% hydrogen peroxide (533 mg, 4.70 mmol) dropwise, and add (R)-4-((S)-2-((S)-5-benzyl-2-oxo Oxazolidin-3-yl)-1-(4-chlorophenyl)-2-oxoethyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (1.3g, 2.35 mmol), reacted in ice bath for 30 hours. After the reaction, quench the reaction with 12.5wt% sodium sulfite aqueous solution, adjust the pH to 2 with 27.0wt% potassium hydrogensulfate solution, extract the aqueous phase with ethyl acetate, combine the organic phases, concentrate under reduced pressure, and separate (PE:EA=10:1), 90 mg of the target product was obtained as a white solid, which was directly used in the next step with a yield of 9.9%.

LCMS:m/z 366.14[M+H] +。 LCMS: m/z 366.14 [M+H] + .

步骤10：(R)-4-((S)-1-(4-氯苯基)-2-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-氧代乙基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(7j)的制备Step 10: (R)-4-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl Preparation of ester (7j)

于室温，将化合物1k(66.7mg,0.285mmol)、二氯甲烷(5mL)加到反应瓶中，加入N,N-二异丙基乙胺(412mg,3.10mmol)，搅拌5分钟，加入(S)-2-((R)-5-(叔丁氧羰基)-5-氮杂螺[2.4]庚烷-4-基)-2-(4-氯苯基)乙酸(90mg,0.247mmol)，搅拌1分钟，加入HBTU(112mg,0.296mmol)，搅拌反应12小时。反应结束后，减压浓缩，残余物经柱层析色谱法分离纯化(DCM:MeOH＝10:1)，得256mg白色固体状的粗品标题化合物。At room temperature, compound 1k (66.7mg, 0.285mmol) and dichloromethane (5mL) were added to the reaction flask, N,N-diisopropylethylamine (412mg, 3.10mmol) was added, stirred for 5 minutes, and ( S)-2-((R)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-4-yl)-2-(4-chlorophenyl)acetic acid (90mg, 0.247mmol ), stirred for 1 minute, added HBTU (112 mg, 0.296 mmol), and stirred for 12 hours. After the reaction, it was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM:MeOH=10:1) to obtain 256 mg of the crude title compound as a white solid.

LCMS:m/z 582.28[M+H] +。 LCMS: m/z 582.28 [M+H] + .

步骤11：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((R)-5-氮杂螺[2.4]庚烷-4-基)乙-1-酮(7)的制备Step 11: (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-5-azaspiro[2.4]heptane-4-yl)ethan-1-one (7)

于室温，将化合物7j(256mg,粗品)、二氯甲烷(3mL)加入至反应瓶中，冰浴降温至5℃左右，滴加盐酸/二氧六环溶液(0.33mL，1.32mmol)，加毕室温反应10小时。反应结束后直接浓缩，残余物用制备高效液相色谱法分离纯化(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得84mg白色固体标题化合物，两步产率70.8％。At room temperature, compound 7j (256mg, crude product) and dichloromethane (3mL) were added to the reaction flask, cooled to about 5°C in an ice bath, hydrochloric acid/dioxane solution (0.33mL, 1.32mmol) was added dropwise, and Complete reaction at room temperature for 10 hours. Concentrate directly after the reaction, and the residue is separated and purified by preparative high-performance liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), to obtain 84 mg of the title compound as a white solid, 70.8% yield in two steps.

LCMS:m/z 482.22[M+H] +。 LCMS: m/z 482.22 [M+H] + .

1H NMR(400MHz,CDCl3)δ＝8.58(s,1H),7.32(d,J＝8.5,2H),7.25(d,J＝7.4,2H),4.97(s,1H),4.55(s,1H),4.12(d,J＝8.7,2H),3.69(s,3H),3.50(t,J＝23.5,7H),3.26-2.92(m,2H),2.30(s,2H),2.01(s,1H),1.73(dt,J＝12.1,5.9,1H),1.03(d,J＝5.2,3H),0.40(qd,J＝9.6,4.1,2H),0.19(d,J＝37.2,1H),0.07(s,1H)。 1 H NMR (400MHz, CDCl3) δ=8.58(s,1H),7.32(d,J=8.5,2H),7.25(d,J=7.4,2H),4.97(s,1H),4.55(s, 1H), 4.12(d, J=8.7, 2H), 3.69(s, 3H), 3.50(t, J=23.5, 7H), 3.26-2.92(m, 2H), 2.30(s, 2H), 2.01( s,1H),1.73(dt,J=12.1,5.9,1H),1.03(d,J=5.2,3H),0.40(qd,J=9.6,4.1,2H),0.19(d,J=37.2, 1H), 0.07(s, 1H).

实施例8：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并 [d]嘧啶-4-基)哌嗪-1-基)-2-((R)-6-氮杂螺[3.4]辛-5-基)乙-1-酮(8)的制备Example 8: (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta Preparation of alkano[d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-6-azaspiro[3.4]oct-5-yl)ethan-1-one (8)

Figure PCTCN2022136451-appb-000048
Figure PCTCN2022136451-appb-000048

步骤1：环丁烷-1,1-二甲酸二甲酯(8a)的制备Step 1: Preparation of dimethyl cyclobutane-1,1-dicarboxylate (8a)

于室温，将环丁烷-1,1-二甲酸(20.0g，138.85mmol)、甲醇(150mL)、浓盐酸(0.3mL)依次加入至反应瓶中，升温至60℃搅拌过夜。降至室温，减压浓缩，以DCM稀释，有机相用水洗两次，有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝0:1-1:10)，得到标题化合物21.7g，收率：90.7％。At room temperature, cyclobutane-1,1-dicarboxylic acid (20.0 g, 138.85 mmol), methanol (150 mL), and concentrated hydrochloric acid (0.3 mL) were sequentially added to the reaction flask, heated to 60° C. and stirred overnight. Lowered to room temperature, concentrated under reduced pressure, diluted with DCM, the organic phase was washed twice with water, the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: EA/PE=0:1-1: 10) to obtain 21.7 g of the title compound, yield: 90.7%.

LCMS：m/z 173.07.06[M+H] +。 LCMS: m/z 173.07.06 [M+H] + .

步骤2：1-(羟甲基)环丁烷-1-羧酸甲酯(8b)的制备Step 2: Preparation of methyl 1-(hydroxymethyl)cyclobutane-1-carboxylate (8b)

于室温，将环丁烷-1,1-二甲酸二甲酯(15.0g，87.1mmol)和THF(150mL)加入至反应瓶中，分批加入LTBA(55.4g，217.9mmol)，加毕升温至60℃搅拌过夜。降至室温，以10％KHSO 4水溶液淬灭反应，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝0:1-1:10)，得到标题化合物8.6g，收率：68.4％。 At room temperature, dimethyl cyclobutane-1,1-dicarboxylate (15.0g, 87.1mmol) and THF (150mL) were added to the reaction flask, LTBA (55.4g, 217.9mmol) was added in batches, and the temperature was raised after addition Stir overnight at 60 °C. Cool down to room temperature, quench the reaction with 10% KHSO aqueous solution, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase : EA/PE=0:1-1:10), to obtain 8.6 g of the title compound, yield: 68.4%.

LCMS：m/z 145.08[M+H] +。 LCMS: m/z 145.08 [M+H] + .

步骤3：1-((对甲苯磺酰氧基)甲基)环丁烷-1-羧酸甲酯(8c)的制备Step 3: Preparation of methyl 1-((p-toluenesulfonyloxy)methyl)cyclobutane-1-carboxylate (8c)

于室温，将1-(羟甲基)环丁烷-1-羧酸甲酯(7.5g，52.0mmol)、DCM(100mL)、TEA(7.76g，76.8mmol)、DMAP(468mg，3.84mmol)依次加入至反应瓶中，分批加入对甲苯磺酰氯(9.9g，52.0mmol)，室温搅拌过夜。将反应体系倒入冰水中淬灭反应，，水相用DCM萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压 浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝0:1-1:10)，得到标题化合物11.7g，收率：75.4％。Methyl 1-(hydroxymethyl)cyclobutane-1-carboxylate (7.5 g, 52.0 mmol), DCM (100 mL), TEA (7.76 g, 76.8 mmol), DMAP (468 mg, 3.84 mmol) were mixed at room temperature Added to the reaction flask in turn, added p-toluenesulfonyl chloride (9.9 g, 52.0 mmol) in batches, and stirred overnight at room temperature. The reaction system was poured into ice water to quench the reaction, the aqueous phase was extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: EA/PE=0:1-1:10), to obtain 11.7 g of the title compound, yield: 75.4%.

LCMS：m/z 299.09[M+H] +。 LCMS: m/z 299.09 [M+H] + .

步骤4：1-(氰甲基)环丁烷-1-羧酸甲酯(8d)的制备Step 4: Preparation of methyl 1-(cyanomethyl)cyclobutane-1-carboxylate (8d)

于室温，将1-((对甲苯磺酰氧基)甲基)环丁烷-1-羧酸甲酯(11.0g，36.9mmol)和THF(100mL)加入至反应瓶中，滴加TMSCN(10.9g，110.7mmol)和1M TBAF的THF溶液(110.7mL，110.7mmol)，室温搅拌过夜。将反应体系倒入冰水和乙酸乙酯中淬灭反应，水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝0:1-1:10)，得到标题化合物9.6g粗品，直接用于下一步。At room temperature, methyl 1-((p-toluenesulfonyloxy)methyl)cyclobutane-1-carboxylate (11.0 g, 36.9 mmol) and THF (100 mL) were added to the reaction flask, and TMSCN ( 10.9g, 110.7mmol) and 1M TBAF in THF (110.7mL, 110.7mmol), stirred overnight at room temperature. The reaction system was poured into ice water and ethyl acetate to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase: EA/PE=0:1-1:10) yielded 9.6 g of crude product of the title compound, which was directly used in the next step.

LCMS：m/z 154.08[M+H] +。 LCMS: m/z 154.08 [M+H] + .

步骤5：6-氮杂螺[3.4]辛烷-5-酮(8e)的制备Step 5: Preparation of 6-azaspiro[3.4]octan-5-one (8e)

于室温，将1-(氰甲基)环丁烷-1-羧酸甲酯(6.0g，粗品)、THF(80mL)、H 2O(40mL)加入至反应瓶中，加入六水合氯化钴(4.7g，19.6mmol)。冰浴降温至0℃，分批加入硼氢化钠(7.4g，195.9mmol)，加毕，升至室温，搅拌过夜。将反应体系倒入冰水和乙酸乙酯中淬灭反应，水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝0:1-1:1)，得到标题化合物1.0g白色固体，两步收率：34.7％。 At room temperature, add methyl 1-(cyanomethyl)cyclobutane-1-carboxylate (6.0 g, crude product), THF (80 mL), H 2 O (40 mL) into the reaction flask, add chloride hexahydrate Cobalt (4.7 g, 19.6 mmol). The temperature was cooled to 0°C in an ice bath, and sodium borohydride (7.4 g, 195.9 mmol) was added in batches. After the addition was complete, the mixture was raised to room temperature and stirred overnight. The reaction system was poured into ice water and ethyl acetate to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (mobile phase: EA/PE=0:1-1:1) gave the title compound 1.0 g of white solid, two-step yield: 34.7%.

LCMS：m/z 126.08[M+H] +。 LCMS: m/z 126.08 [M+H] + .

步骤6：5-氧代-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(8f)的制备Step 6: Preparation of tert-butyl 5-oxo-6-azaspiro[3.4]octane-6-carboxylate (8f)

于室温，将6-氮杂螺[3.4]辛烷-5-酮(1.0g，8.0mmol)加入二氯甲烷(25mL)中，然后依次加入二碳酸二叔丁酯(3.7g，16.8mmol)、三乙胺(3.4g，33.6mmol)和4-二甲氨基吡啶(68.3mg，0.56mmol)，于室温搅拌2小时。反应液用二氯甲烷萃取，有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：MTBE/DCM＝0:1-1:10)，得标题化合物1.40g，收率：77.7％。At room temperature, 6-azaspiro[3.4]octan-5-one (1.0g, 8.0mmol) was added into dichloromethane (25mL), followed by the addition of di-tert-butyl dicarbonate (3.7g, 16.8mmol) , triethylamine (3.4g, 33.6mmol) and 4-dimethylaminopyridine (68.3mg, 0.56mmol), stirred at room temperature for 2 hours. The reaction solution was extracted with dichloromethane, the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: MTBE/DCM=0:1-1:10) to obtain 1.40 g of the title compound, with a yield of : 77.7%.

LCMS：m/z 170.14[M-55] +。 LCMS: m/z 170.14 [M-55] + .

步骤7：5-羟基-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(8g)的制备Step 7: Preparation of tert-butyl 5-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (8 g)

于室温，将5-氧代-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(1.0g,3.92mmol)和THF(23.0mL)加入至反应瓶中。降温至-78℃，滴加DIBAL-H(10mL,10.0mmol)，滴毕，-78℃搅拌30分钟。反应结束后，以饱和乙酸钠水溶液(5mL)淬灭反应，升至室温，加入饱和氯化铵水溶液(5mL)和乙酸乙酯(10mL)搅拌10分钟，过滤，水相以乙酸乙酯萃取，合并有机相后，减压浓缩，得865mg黄色油状标题产物，直接用于下一步，产率86.4％。tert-Butyl 5-oxo-6-azaspiro[3.4]octane-6-carboxylate (1.0 g, 3.92 mmol) and THF (23.0 mL) were added to the reaction flask at room temperature. Cool down to -78°C, add DIBAL-H (10 mL, 10.0 mmol) dropwise, and stir at -78°C for 30 minutes. After the reaction was completed, the reaction was quenched with saturated aqueous sodium acetate (5 mL), warmed to room temperature, added saturated aqueous ammonium chloride (5 mL) and ethyl acetate (10 mL) and stirred for 10 minutes, filtered, and the aqueous phase was extracted with ethyl acetate. After combining the organic phases, they were concentrated under reduced pressure to obtain 865 mg of the title product as a yellow oil, which was directly used in the next step with a yield of 86.4%.

LCMS:m/z 228.15[M+H] +。 LCMS: m/z 228.15 [M+H] + .

步骤8：5-甲氧基-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(8h)的制备Step 8: Preparation of tert-butyl 5-methoxy-6-azaspiro[3.4]octane-6-carboxylate (8h)

于室温，将5-羟基-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(822mg,3.62mmol)、甲 醇(20mL)和一水合对甲苯磺酸(36.6mg,0.19mmol)加入至反应瓶中，室温反应2小时。反应结束后，将反应体系倒入饱和碳酸氢钠水溶液中，以乙酸乙酯萃取，合并有机相，减压浓缩后，残余物以二氯甲烷稀释成29wt％溶液，直接用于下一步。At room temperature, tert-butyl 5-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (822mg, 3.62mmol), methanol (20mL) and p-toluenesulfonic acid monohydrate (36.6mg, 0.19mmol ) was added to the reaction flask, and reacted at room temperature for 2 hours. After the reaction, the reaction system was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to obtain a 29 wt% solution, which was directly used in the next step.

LCMS:m/z 242.17[M+H] +。 LCMS: m/z 242.17 [M+H] + .

步骤9：(R)-5-((S)-2-((R)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(8i)的制备Step 9: (R)-5-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (8i)

于室温，将化合物1r(1.7g,5.28mmol)、二氯甲烷(30mL)加入至反应瓶中，降温至-78℃，滴加四氯化钛(1.1g,5.81mmol)，保温30分钟后滴加DIPEA(818mg,6.34mmol)，保温30分钟后滴加5-甲氧基-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯的二氯甲烷溶液，保温30分钟后自然升至室温反应1.5小时。反应结束后，将反应体系倒入水中，水相以二氯甲烷萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(PE:EA＝5:1)，得1.3g黄色固体目标产物，直接用于下一步，产率46.7％。 At room temperature, compound 1r (1.7g, 5.28mmol) and dichloromethane (30mL) were added to the reaction flask, the temperature was lowered to -78°C, titanium tetrachloride (1.1g, 5.81mmol) was added dropwise, and after 30 minutes of insulation DIPEA (818mg, 6.34mmol) was added dropwise, and after 30 minutes of incubation, a dichloromethane solution of tert-butyl 5-methoxy-6-azaspiro[3.4]octane-6-carboxylate was added dropwise, and after 30 minutes of incubation, Naturally rise to room temperature and react for 1.5 hours. After the reaction, the reaction system was poured into water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous Na2SO4 , filtered, the filtrate was concentrated under reduced pressure , and the residue was separated and purified by column chromatography (PE :EA=5:1), 1.3g of the target product as a yellow solid was obtained, which was directly used in the next step with a yield of 46.7%.

LCMS:m/z 539.22[M+H] +。 LCMS: m/z 539.22 [M+H] + .

步骤10：(S)-2-((R)-6-(叔丁氧羰基)-6-氮杂螺[3.4]辛烷-5-基)-2-(4-氯苯基)乙酸(8j)的制备Step 10: (S)-2-((R)-6-(tert-butoxycarbonyl)-6-azaspiro[3.4]octan-5-yl)-2-(4-chlorophenyl)acetic acid ( 8j) Preparation

于室温，将LiOH(247mg,5.88mmol)、水(13mL)、THF(25mL)加入至反应瓶中。冰浴降温至5℃左右，滴加30％双氧水(533mg,4.70mmol)，分批加入(R)-5-((S)-2-((S)-5-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(1.3g,2.41mmol)，冰浴反应30小时。反应结束后，以12.5wt％亚硫酸钠水溶液淬灭反应，27.0wt％硫酸氢钾溶液调节PH为2，水相用乙酸乙酯萃取，合并有机相，减压浓缩后，残余物经柱层析色谱法分离纯化(PE:EA＝10:1)，得90mg白色固体目标产物，直接用于下一步，产率91.5％。LiOH (247 mg, 5.88 mmol), water (13 mL), THF (25 mL) were added to the reaction flask at room temperature. Cool down to about 5°C in an ice bath, add 30% hydrogen peroxide (533 mg, 4.70 mmol) dropwise, and add (R)-5-((S)-2-((S)-5-benzyl-2-oxo Oxazolidin-3-yl)-1-(4-chlorophenyl)-2-oxoethyl)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (1.3g, 2.41 mmol), reacted in ice bath for 30 hours. After the reaction is over, quench the reaction with 12.5wt% sodium sulfite aqueous solution, adjust the pH to 2 with 27.0wt% potassium hydrogensulfate solution, extract the aqueous phase with ethyl acetate, combine the organic phases, concentrate under reduced pressure, and the residue is subjected to column chromatography separation and purification (PE:EA=10:1) to obtain 90 mg of the target product as a white solid, which was directly used in the next step with a yield of 91.5%.

LCMS:m/z 380.16[M+H] +。 LCMS: m/z 380.16 [M+H] + .

步骤11：(R)-5-((S)-1-(4-氯苯基)-2-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-氧代乙基)-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(8k)的制备Step 11: (R)-5-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl Preparation of ester (8k)

于室温，将化合物1k(66.7mg,0.285mmol)、二氯甲烷(5mL)加到反应瓶中，加入N,N-二异丙基乙胺(412mg,3.10mmol)，搅拌5分钟，加入(S)-2-((R)-6-(叔丁氧羰基)-6-氮杂螺[3.4]辛烷-5-基)-2-(4-氯苯基)乙酸(8j)(90mg,0.237mmol)，搅拌1分钟，加入HBTU(112mg,0.296mmol)，搅拌反应12小时。反应结束后，减压浓缩，残余物经柱层析色谱法分离纯化(DCM:MeOH＝10:1)，得256mg白色固体状的粗品标题化合物。At room temperature, compound 1k (66.7mg, 0.285mmol) and dichloromethane (5mL) were added to the reaction flask, N,N-diisopropylethylamine (412mg, 3.10mmol) was added, stirred for 5 minutes, and ( S)-2-((R)-6-(tert-butoxycarbonyl)-6-azaspiro[3.4]octane-5-yl)-2-(4-chlorophenyl)acetic acid (8j) (90mg , 0.237mmol), stirred for 1 minute, added HBTU (112mg, 0.296mmol), stirred and reacted for 12 hours. After the reaction, it was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM:MeOH=10:1) to obtain 256 mg of the crude title compound as a white solid.

LCMS:m/z 596.29[M+H] +。 LCMS: m/z 596.29 [M+H] + .

步骤12：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d] 嘧啶-4-基)哌嗪-1-基)-2-((R)-6-氮杂螺[3.4]辛-5-基)乙-1-酮(8)的制备Step 12: (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-6-azaspiro[3.4]oct-5-yl)ethan-1-one (8)

于室温，将化合物8k(256mg,粗品)、二氯甲烷(3mL)加入至反应瓶中。冰浴降温至5℃左右，滴加盐酸/二氧六环溶液(0.33mL，1.32mmol)，加毕室温反应10小时。反应结束后直接浓缩，残余物用制备搞笑液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得54mg白色固体标题化合物，两步产率46.0％。Compound 8k (256 mg, crude product), dichloromethane (3 mL) were added into the reaction flask at room temperature. Cool down to about 5°C in an ice bath, add hydrochloric acid/dioxane solution (0.33 mL, 1.32 mmol) dropwise, and react at room temperature for 10 hours after addition. Concentrate directly after the reaction, and the residue is separated by preparative liquid chromatography (column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), and 54mg is obtained The title compound as a white solid, 46.0% yield over two steps.

LCMS:m/z 496.24[M+H] +。 LCMS: m/z 496.24 [M+H] + .

1H NMR(400MHz,CDCl3)δ＝8.49(s,1H),7.40(d,J＝8.4,2H),7.34(d,J＝8.6,2H),5.08(t,J＝6.7,1H),4.02(d,J＝8.4,1H),3.74(dd,J＝19.4,10.5,3H),3.69-3.52(m,4H),3.45(s,1H),3.36(d,J＝9.3,1H),3.23(s,1H),2.91(dd,J＝16.0,8.3,2H),2.27-2.00(m,4H),1.97-1.74(m,2H),1.59(dd,J＝14.1,6.3,1H),1.54-1.37(m,2H),1.12(t,J＝11.2,4H)。 1 H NMR (400MHz, CDCl3) δ=8.49(s,1H),7.40(d,J=8.4,2H),7.34(d,J=8.6,2H),5.08(t,J=6.7,1H), 4.02(d,J=8.4,1H), 3.74(dd,J=19.4,10.5,3H), 3.69-3.52(m,4H), 3.45(s,1H), 3.36(d,J=9.3,1H) ,3.23(s,1H),2.91(dd,J=16.0,8.3,2H),2.27-2.00(m,4H),1.97-1.74(m,2H),1.59(dd,J=14.1,6.3,1H ), 1.54-1.37 (m, 2H), 1.12 (t, J = 11.2, 4H).

实施例9：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((S)-5-氮杂螺[2.4]庚-6-基)乙-1-酮(9)的制备Example 9: (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta Preparation of alkano[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-5-azaspiro[2.4]hept-6-yl)ethan-1-one (9)

Figure PCTCN2022136451-appb-000049
Figure PCTCN2022136451-appb-000049

步骤1：2-环丙亚基乙酸甲酯(9a)的制备Step 1: Preparation of methyl 2-cyclopropylidene acetate (9a)

于25℃，将(1-乙氧基环丙氧基)三甲基硅烷(20.0g,114.8mmol)的MeOH(150mL)溶液搅拌1小时，然后减压浓缩。残余物溶于甲苯(500mL)。向上述溶液中加入苯甲酸(7.0g,57.4mmol)。将混合物搅拌加热至90℃，然后于相同的温度下加入乙氧甲酰基亚甲基三苯基膦(40g,114.8mmol)的甲苯(1200mL)溶液。将获得的混合物于90℃搅拌16小时，然后减压浓缩。残余物通过柱层析色谱法纯化(PE:EA＝10:1)，得到标题化合物8.5g，收率：66.4％。A solution of (1-ethoxycyclopropoxy)trimethylsilane (20.0 g, 114.8 mmol) in MeOH (150 mL) was stirred at 25 °C for 1 hour, then concentrated under reduced pressure. The residue was dissolved in toluene (500 mL). Benzoic acid (7.0 g, 57.4 mmol) was added to the above solution. The mixture was stirred and heated to 90° C., then a solution of carbomethoxymethylenetriphenylphosphine (40 g, 114.8 mmol) in toluene (1200 mL) was added at the same temperature. The obtained mixture was stirred at 90°C for 16 hours, then concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=10:1) to obtain 8.5 g of the title compound, yield: 66.4%.

LCMS：m/z 113.05[M+H] +。 LCMS: m/z 113.05 [M+H] + .

步骤2：2-(1-(硝基甲基)环丙基)乙酸甲酯(9b)的制备Step 2: Preparation of methyl 2-(1-(nitromethyl)cyclopropyl)acetate (9b)

于室温，将2-环丙亚基乙酸甲酯(8.5g，75.8mol)加入二甲基亚砜(50mL)中，然后依次加入碳酸铯(12.3g，37.9mol)和硝基甲烷(8.75g，113.7mol)，于80℃搅拌过夜。反应液用冰醋酸(2.04g，0.340mol)淬灭，用甲基叔丁基醚萃取，有机相干燥，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝0:1-1:10)，得到标题化合物3.8g，收率：29.0％。At room temperature, methyl 2-cyclopropylidene acetate (8.5 g, 75.8 mol) was added to dimethyl sulfoxide (50 mL), then cesium carbonate (12.3 g, 37.9 mol) and nitromethane (8.75 g , 113.7mol), stirred overnight at 80°C. The reaction solution was quenched with glacial acetic acid (2.04g, 0.340mol), extracted with methyl tert-butyl ether, the organic phase was dried, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: EA/PE =0:1-1:10), to obtain 3.8g of the title compound, yield: 29.0%.

LCMS：m/z 174.07[M+H] +。 LCMS: m/z 174.07 [M+H] + .

步骤3：5-氮杂螺[2.4]庚烷-6-酮(9c)的制备Step 3: Preparation of 5-azaspiro[2.4]heptan-6-one (9c)

于室温，将2-(1-(硝基甲基)环丙基)乙酸甲酯(3.8g，21.9mmol)加入乙酸乙酯(80mL)中，然后加入Pd/C(1.1g)。于室温，氢气氛围下，搅拌过夜。反应液过滤，有机相减压浓缩，残余物用硅胶层析柱色谱法分离纯化(流动相：MeOH/DCM＝0:1-1:50)，得标题化合物1.5g，收率：62.5％。Methyl 2-(1-(nitromethyl)cyclopropyl)acetate (3.8 g, 21.9 mmol) was added to ethyl acetate (80 mL) followed by Pd/C (1.1 g) at room temperature. Stir overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered, the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: MeOH/DCM=0:1-1:50) to obtain 1.5 g of the title compound, yield: 62.5%.

LCMS：m/z 112.07[M+H] +。 LCMS: m/z 112.07 [M+H] + .

步骤4：6-氧代-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(9d)的制备Step 4: Preparation of tert-butyl 6-oxo-5-azaspiro[2.4]heptane-5-carboxylate (9d)

于室温，将5-氮杂螺[2.4]庚烷-6-酮(1.5g，13.5mmol)加入二氯甲烷(50mL)中，然后依次加入二碳酸二叔丁酯(4.4g，20.2mmol)、三乙胺(4.1g，40.5mmol)和4-二甲氨基吡啶(82mg，0.675mmol)。于室温搅拌2小时。反应液用二氯甲烷萃取，有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：MTBE/DCM＝0:1-1:10)，得标题化合物1.4g，收率：49.1％。At room temperature, 5-azaspiro[2.4]heptan-6-one (1.5g, 13.5mmol) was added into dichloromethane (50mL), followed by di-tert-butyl dicarbonate (4.4g, 20.2mmol) , triethylamine (4.1 g, 40.5 mmol) and 4-dimethylaminopyridine (82 mg, 0.675 mmol). Stir at room temperature for 2 hours. The reaction solution was extracted with dichloromethane, the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: MTBE/DCM=0:1-1:10) to obtain 1.4 g of the title compound. The yield was : 49.1%.

LCMS：m/z 156.12[M-55] +。 LCMS: m/z 156.12 [M-55] + .

步骤5：6-羟基-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(9e)的制备Step 5: Preparation of tert-butyl 6-hydroxy-5-azaspiro[2.4]heptane-5-carboxylate (9e)

于室温，将6-氧代-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(1.4g,6.63mmol)和THF(30mL)加入至反应瓶中。降温至-78℃，滴加DIBAL-H(10mL,10.0mmol)，滴毕，-78℃搅拌30分钟。反应结束后，以饱和乙酸钠水溶液(5mL)淬灭反应，升至室温，加入饱和氯化铵水溶液(5mL)和乙酸乙酯(10mL)搅拌10分钟，过滤，水相以乙酸乙酯萃取，合并有机相后，减压浓缩，得1.27g黄色油状标题产物，直接用于下一步，产率90.0％。tert-Butyl 6-oxo-5-azaspiro[2.4]heptane-5-carboxylate (1.4 g, 6.63 mmol) and THF (30 mL) were added to the reaction flask at room temperature. Cool down to -78°C, add DIBAL-H (10 mL, 10.0 mmol) dropwise, and stir at -78°C for 30 minutes. After the reaction was completed, the reaction was quenched with saturated aqueous sodium acetate (5 mL), warmed to room temperature, added saturated aqueous ammonium chloride (5 mL) and ethyl acetate (10 mL) and stirred for 10 minutes, filtered, and the aqueous phase was extracted with ethyl acetate. After combining the organic phases, they were concentrated under reduced pressure to obtain 1.27 g of the title product as a yellow oil, which was directly used in the next step with a yield of 90.0%.

LCMS:m/z 214.14[M+H] +。 LCMS: m/z 214.14 [M+H] + .

步骤6：6-甲氧基-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(9f)的制备Step 6: Preparation of tert-butyl 6-methoxy-5-azaspiro[2.4]heptane-5-carboxylate (9f)

于室温，将6-羟基-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(1.27g,5.95mmol)、甲醇(20mL)和一水合对甲苯磺酸(52.0mg,0.270mmol)加入至反应瓶中，室温反应2小时。反应结束后将反应体系倒入饱和碳酸氢钠水溶液中，以乙酸乙酯萃取，合并有机相，减压浓缩后，残余物以二氯甲烷稀释成29wt％溶液，直接用于下一步。At room temperature, tert-butyl 6-hydroxy-5-azaspiro[2.4]heptane-5-carboxylate (1.27g, 5.95mmol), methanol (20mL) and p-toluenesulfonic acid monohydrate (52.0mg, 0.270 mmol) was added to the reaction flask, and reacted at room temperature for 2 hours. After the reaction, the reaction system was poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to obtain a 29 wt% solution, which was directly used in the next step.

LCMS:m/z 228.15[M+H] +。 LCMS: m/z 228.15 [M+H] + .

步骤7：(S)-6-((S)-2-((R)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(9g)的制备Step 7: (S)-6-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (9g)

于室温，将化合物1r(1.86g,5.64mmol)、二氯甲烷(30mL)加入至反应瓶中，降温至-78℃，滴加四氯化钛(1.18g,6.23mmol)，保温30分钟后滴加DIPEA(878mg,6.79mmol)，保温30分钟后滴加6-甲氧基-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯的二氯甲烷溶液，保温30分钟后自然升至室温反应1.5小时。反应结束后将反应体系倒入水中，水相以二氯甲烷萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(PE:EA＝5:1)，得1.76g黄色油状的目标产物，直接用于下一步，产率59.6％。 At room temperature, compound 1r (1.86g, 5.64mmol) and dichloromethane (30mL) were added to the reaction flask, the temperature was lowered to -78°C, titanium tetrachloride (1.18g, 6.23mmol) was added dropwise, and after 30 minutes of insulation DIPEA (878mg, 6.79mmol) was added dropwise, and after 30 minutes of incubation, a dichloromethane solution of tert-butyl 6-methoxy-5-azaspiro[2.4]heptane-5-carboxylate was added dropwise, and after 30 minutes of incubation, Naturally rise to room temperature and react for 1.5 hours. After the reaction, the reaction system was poured into water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE: EA=5:1), 1.76g of the target product in the form of yellow oil was obtained, which was directly used in the next step with a yield of 59.6%.

LCMS:m/z 525.21[M+H] +。 LCMS: m/z 525.21 [M+H] + .

步骤8：(S)-2-((S)-5-(叔丁氧羰基)-5-氮杂螺[2.4]庚烷-6-基)-2-(4-氯苯基)乙酸(9h)的制备Step 8: (S)-2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptan-6-yl)-2-(4-chlorophenyl)acetic acid ( 9h) Preparation

于室温，将LiOH(1.40g,33.5mmol)、水(20mL)和THF(40mL)加入至反应瓶中。冰浴降温至5℃左右，滴加30％双氧水(569mg,5.0mmol)，分批加入(S)-6-((S)-2-((R)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(1.76g,3.35mmol)，冰浴反应30小时。反应结束后以12.5wt％亚硫酸钠水溶液淬灭反应，27.0wt％硫酸氢钾溶液调节PH为2，水相用乙酸乙酯萃取，合并有机相，减压浓缩，残余物经柱层析色谱法分离纯化(PE:EA＝10:1)，得896mg黄色油状的目标产物，直接用于下一步，产率73.1％。LiOH (1.40 g, 33.5 mmol), water (20 mL) and THF (40 mL) were added to the reaction flask at room temperature. Cool down to about 5°C in an ice bath, add 30% hydrogen peroxide (569 mg, 5.0 mmol) dropwise, and add (S)-6-((S)-2-((R)-4-benzyl-2-oxo Oxazolidin-3-yl)-1-(4-chlorophenyl)-2-oxoethyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (1.76g, 3.35 mmol), reacted in ice bath for 30 hours. After the reaction was finished, quench the reaction with 12.5wt% sodium sulfite aqueous solution, adjust the pH to 2 with 27.0wt% potassium hydrogensulfate solution, extract the aqueous phase with ethyl acetate, combine the organic phases, concentrate under reduced pressure, and the residue was separated by column chromatography After purification (PE:EA=10:1), 896 mg of the target product was obtained as a yellow oil, which was directly used in the next step with a yield of 73.1%.

LCMS:m/z 366.14[M+H] +。 LCMS: m/z 366.14 [M+H] + .

步骤9：(S)-6-((S)-1-(4-氯苯基)-2-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-氧代乙基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(9i)的制备Step 9: (S)-6-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl Preparation of ester (9i)

于室温，将化合物1k(200mg,0.854mmol)、二氯甲烷(5mL)加到反应瓶中，加入N,N-二异丙基乙胺(412mg,3.10mmol)，搅拌5分钟，加入(S)-2-((S)-5-(叔丁氧羰基)-5-氮杂螺[2.4]庚烷-6-基)-2-(4-氯苯基)乙酸(105mg,0.287mmol)，搅拌1分钟，加入HBTU(204mg,0.540mmol)，搅拌反应12小时。反应结束后，减压浓缩，残余物经柱层析色谱法分离纯化(DCM:MeOH＝10:1)，得230mg白色固体状的粗品标题化合物。At room temperature, compound 1k (200mg, 0.854mmol) and dichloromethane (5mL) were added to the reaction flask, N,N-diisopropylethylamine (412mg, 3.10mmol) was added, stirred for 5 minutes, and (S )-2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-yl)-2-(4-chlorophenyl)acetic acid (105mg, 0.287mmol) , stirred for 1 minute, added HBTU (204 mg, 0.540 mmol), and stirred for 12 hours. After the reaction, it was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM:MeOH=10:1) to obtain 230 mg of the crude title compound as a white solid.

LCMS:m/z 582.28[M+H] +。 LCMS: m/z 582.28 [M+H] + .

步骤10：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((S)-5-氮杂螺[2.4]庚-6-基)乙-1-酮(9)的制备Step 10: (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-5-azaspiro[2.4]hept-6-yl)ethan-1-one (9)

于室温，将化合物9i(230mg,粗品)、二氯甲烷(3mL)加入至反应瓶中。冰浴降温至5℃左右，滴加盐酸/二氧六环溶液(0.33mL，1.32mmol)，加毕室温反应10小时。反应结束后直接浓缩，残余物用制备搞笑液相色谱法分离纯化(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得49mg白色固体标题化合物，两步产率35.4％。Compound 9i (230 mg, crude product), dichloromethane (3 mL) were added into the reaction flask at room temperature. Cool down to about 5°C in an ice bath, add hydrochloric acid/dioxane solution (0.33 mL, 1.32 mmol) dropwise, and react at room temperature for 10 hours after addition. Concentrate directly after the reaction, and the residue is separated and purified by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), to obtain 49 mg of the title compound as a white solid, 35.4% yield over two steps.

LCMS:m/z 482.22[M+H] +。 LCMS: m/z 482.22 [M+H] + .

1H NMR(400MHz,CDCl3)δ＝8.63-8.31(m,1H),7.31(d,J＝8.4,2H),7.26(s,2H),5.06(s,1H),3.79(ddd,J＝59.9,38.7,34.0,6H),3.43(s,4H),3.25-2.85(m,3H),2.30-1.98(m,2H),1.76(d,J＝29.7,1H),1.24(t,J＝7.0,1H),1.14(dd,J＝14.1,10.6,4H),0.72-0.39(m,3H)。 1 H NMR (400MHz, CDCl3) δ = 8.63-8.31 (m, 1H), 7.31 (d, J = 8.4, 2H), 7.26 (s, 2H), 5.06 (s, 1H), 3.79 (ddd, J = 59.9,38.7,34.0,6H),3.43(s,4H),3.25-2.85(m,3H),2.30-1.98(m,2H),1.76(d,J=29.7,1H),1.24(t,J = 7.0, 1H), 1.14 (dd, J = 14.1, 10.6, 4H), 0.72-0.39 (m, 3H).

实施例10：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((S)-6-氮杂螺[3.4]辛-7-基)乙-1-酮(10)的制备Example 10: (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta Preparation of alkano[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-6-azaspiro[3.4]oct-7-yl)ethan-1-one (10)

Figure PCTCN2022136451-appb-000050
Figure PCTCN2022136451-appb-000050

Figure PCTCN2022136451-appb-000051
Figure PCTCN2022136451-appb-000051

步骤1：2-环丁亚基乙酸甲酯(10a)的制备Step 1: Preparation of methyl 2-cyclobutylidene acetate (10a)

将2-(二乙氧基磷酰基)乙酸甲酯(8.97g，42.7mmol)溶于无水四氢呋喃(80mL)中，于冰浴条件下，分批缓慢加入氢化钠(2.28g，57.0mmol)，于室温反应1小时。然后加入环丁酮(2.0g,28.5mmol)并于室温搅拌4小时。将反应液减压浓缩，残余物用乙酸乙酯和水萃取，有机相干燥，并减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝0:1-1:10)，得到油状标题化合物2.6g，收率：72.2％。Dissolve methyl 2-(diethoxyphosphoryl)acetate (8.97g, 42.7mmol) in anhydrous tetrahydrofuran (80mL), and slowly add sodium hydride (2.28g, 57.0mmol) in batches under ice-bath conditions , reacted at room temperature for 1 hour. Cyclobutanone (2.0 g, 28.5 mmol) was then added and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was extracted with ethyl acetate and water, the organic phase was dried, and concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (mobile phase: EA/PE=0:1-1 : 10), to obtain 2.6g of the oily title compound, yield: 72.2%.

LCMS：m/z 127.07[M+H] +。 LCMS: m/z 127.07 [M+H] + .

步骤2：2-(1-(硝基甲基)环丁基)乙酸甲酯(10b)的制备Step 2: Preparation of methyl 2-(1-(nitromethyl)cyclobutyl)acetate (10b)

于室温，将2-环丁亚基乙酸甲酯(2.6g，20.6mmol)加入二甲基亚砜(50mL)中，然后依次加入碳酸铯(3.35g，10.3mmol)和硝基甲烷(7.33g，1.19mol)，于80℃搅拌过夜。反应液用冰醋酸(2.04g，0.340mol)淬灭，用甲基叔丁基醚萃取，有机相干燥，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝0:1-1:10)，得到标题化合物1.4g，收率：36.3％。At room temperature, methyl 2-cyclobutylidene acetate (2.6 g, 20.6 mmol) was added to dimethyl sulfoxide (50 mL), then cesium carbonate (3.35 g, 10.3 mmol) and nitromethane (7.33 g, 1.19 mol), stirred overnight at 80°C. The reaction solution was quenched with glacial acetic acid (2.04g, 0.340mol), extracted with methyl tert-butyl ether, the organic phase was dried, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: EA/PE =0:1-1:10), the title compound was obtained 1.4g, yield: 36.3%.

LCMS：m/z 188.08[M+H] +。 LCMS: m/z 188.08 [M+H] + .

步骤3：6-氮杂螺[3.4]辛烷-7-酮(10c)的制备Step 3: Preparation of 6-azaspiro[3.4]octan-7-one (10c)

于室温，将2-(1-(硝基甲基)环丁基)乙酸甲酯(1.4g，7.48mmol)加入乙酸乙酯(50mL)中，然后加入Pd/C催化剂(420mg)。于室温，氢气氛围下，搅拌过夜。反应液过滤，有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：MeOH/DCM＝0:1-1:50)，得标题化合物1.1g粗品直接用于下一步。Methyl 2-(1-(nitromethyl)cyclobutyl)acetate (1.4 g, 7.48 mmol) was added to ethyl acetate (50 mL) at room temperature, followed by Pd/C catalyst (420 mg). Stir overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered, the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: MeOH/DCM=0:1-1:50) to obtain 1.1 g of the crude product of the title compound, which was directly used in the next step.

LCMS：m/z 126.08[M+H] +。 LCMS: m/z 126.08 [M+H] + .

步骤4：7-氧代-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(10d)的制备Step 4: Preparation of tert-butyl 7-oxo-6-azaspiro[3.4]octane-6-carboxylate (10d)

于室温，将6-氮杂螺[3.4]辛烷-7-酮(1.1g，8.79mmol)加入二氯甲烷(50mL)中，然后依次加入二碳酸二叔丁酯(2.88g，13.2mmol)、三乙胺(TEA)(2.67g，26.4mmol)和4-二甲氨基吡啶(DMAP)(53.7mg，0.44mmol)，于室温搅拌2小时。反应液用二氯甲烷萃取，有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：MTBE/DCM＝0:1-1:10)，得标题化合物1.2g，收率：60.3％。At room temperature, 6-azaspiro[3.4]octan-7-one (1.1g, 8.79mmol) was added into dichloromethane (50mL), followed by di-tert-butyl dicarbonate (2.88g, 13.2mmol) , triethylamine (TEA) (2.67g, 26.4mmol) and 4-dimethylaminopyridine (DMAP) (53.7mg, 0.44mmol), stirred at room temperature for 2 hours. The reaction solution was extracted with dichloromethane, the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: MTBE/DCM=0:1-1:10) to obtain 1.2 g of the title compound, with a yield of : 60.3%.

LCMS：m/z 170.14[M-55] +。 LCMS: m/z 170.14 [M-55] + .

步骤5：7-羟基-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(10e)的制备Step 5: Preparation of tert-butyl 7-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (10e)

于室温，将7-氧代-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(1.2g,5.33mmol)和THF(24mL)加入至反应瓶中。降温至-78℃，滴加DIBAL-H(10mL,10.0mmol)，滴毕，-78℃搅拌30分钟。反应结束后，以饱和乙酸钠水溶液(5mL)淬灭反应，升至室温，加入饱和氯化铵水溶液(5mL)和乙酸乙酯(10mL)搅拌10分钟，过滤，水相以乙酸乙酯萃取，合并有机相后，减压浓缩，得1.11g黄色油状标题产物，直接用于下一步，产率91.7％。tert-butyl 7-oxo-6-azaspiro[3.4]octane-6-carboxylate (1.2 g, 5.33 mmol) and THF (24 mL) were added to the reaction flask at room temperature. Cool down to -78°C, add DIBAL-H (10 mL, 10.0 mmol) dropwise, and stir at -78°C for 30 minutes. After the reaction was completed, the reaction was quenched with saturated aqueous sodium acetate (5 mL), warmed to room temperature, added saturated aqueous ammonium chloride (5 mL) and ethyl acetate (10 mL) and stirred for 10 minutes, filtered, and the aqueous phase was extracted with ethyl acetate. After combining the organic phases, they were concentrated under reduced pressure to obtain 1.11 g of the title product as a yellow oil, which was directly used in the next step with a yield of 91.7%.

LCMS:m/z 228.15[M+H] +。 LCMS: m/z 228.15 [M+H] + .

步骤6：7-甲氧基-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(10f)的制备Step 6: Preparation of tert-butyl 7-methoxy-6-azaspiro[3.4]octane-6-carboxylate (10f)

于室温，将7-羟基-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(1.11g,4.89mmol)、甲醇(20mL)和一水合对甲苯磺酸(52.0mg,0.270mmol)加入至反应瓶中，室温反应2小时。反应结束后，将反应体系倒入饱和碳酸氢钠水溶液中，以乙酸乙酯萃取，合并有机相，减压浓缩后，残余物以二氯甲烷稀释成29wt％溶液，直接用于下一步。At room temperature, tert-butyl 7-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (1.11g, 4.89mmol), methanol (20mL) and p-toluenesulfonic acid monohydrate (52.0mg, 0.270 mmol) was added to the reaction flask, and reacted at room temperature for 2 hours. After the reaction, the reaction system was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to obtain a 29 wt% solution, which was directly used in the next step.

LCMS:m/z 242.17[M+H] +。 LCMS: m/z 242.17 [M+H] + .

步骤7：(S)-7-((S)-2-((R)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(10g)的制备Step 7: (S)-7-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (10g)

于室温，将化合物1r(1.86g,5.64mmol)、二氯甲烷(30mL)加入至反应瓶中。降温至-78℃，滴加四氯化钛(1.18g,6.23mmol)，保温30分钟后滴加DIPEA(878mg,6.79mmol)，保温30分钟后滴加7-甲氧基-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯的二氯甲烷溶液，保温30分钟后自然升至室温反应1.5小时。反应结束后，将反应体系倒入水中，水相以二氯甲烷萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(PE:EA＝5:1)，得1.5g黄色油状的目标产物，直接用于下一步，产率57.0％。 Compound 1r (1.86 g, 5.64 mmol), dichloromethane (30 mL) were added into the reaction flask at room temperature. Cool down to -78°C, add titanium tetrachloride (1.18g, 6.23mmol) dropwise, add DIPEA (878mg, 6.79mmol) dropwise after 30 minutes of insulation, and add 7-methoxy-6-aza The dichloromethane solution of spiro[3.4]octane-6-carboxylic acid tert-butyl ester was incubated for 30 minutes and then naturally raised to room temperature for 1.5 hours of reaction. After the reaction, the reaction system was poured into water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous Na2SO4 , filtered, the filtrate was concentrated under reduced pressure , and the residue was separated and purified by column chromatography (PE :EA=5:1), 1.5g of the target product in the form of yellow oil was obtained, which was directly used in the next step with a yield of 57.0%.

LCMS:m/z 539.22[M+H] +。 LCMS: m/z 539.22 [M+H] + .

步骤8：(S)-2-((S)-6-(叔丁氧羰基)-6-氮杂螺[3.4]辛烷-7-基)-2-(4-氯苯基)乙酸(10h)的制备Step 8: (S)-2-((S)-6-(tert-butoxycarbonyl)-6-azaspiro[3.4]octan-7-yl)-2-(4-chlorophenyl)acetic acid ( 10h) Preparation

于室温，将LiOH(175mg,4.18mmol)、水(20mL)、THF(40mL)加入至反应瓶中。冰浴降温至5℃左右，滴加30％双氧水(472mg,4.16mmol)，分批加 入(S)-7-((S)-2-((S)-4-苄基-2-氧代噁唑烷-3-基)-1-(4-氯苯基)-2-氧代乙基)-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(1.5g,2.78mmol)，冰浴反应30小时。反应结束后，以12.5wt％亚硫酸钠水溶液淬灭反应，27.0wt％硫酸氢钾溶液调节PH为2，水相用乙酸乙酯萃取，合并有机相，减压浓缩后，残余物经柱层析色谱法分离(PE:EA＝10:1)，得777mg黄色油状的目标产物，直接用于下一步，产率73.5％。LiOH (175 mg, 4.18 mmol), water (20 mL), THF (40 mL) were added to the reaction flask at room temperature. Cool down to about 5°C in an ice bath, add 30% hydrogen peroxide (472 mg, 4.16 mmol) dropwise, and add (S)-7-((S)-2-((S)-4-benzyl-2-oxo Oxazolidin-3-yl)-1-(4-chlorophenyl)-2-oxoethyl)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (1.5g, 2.78 mmol), reacted in ice bath for 30 hours. After the reaction is over, quench the reaction with 12.5wt% sodium sulfite aqueous solution, adjust the pH to 2 with 27.0wt% potassium hydrogensulfate solution, extract the aqueous phase with ethyl acetate, combine the organic phases, concentrate under reduced pressure, and the residue is subjected to column chromatography (PE:EA=10:1) to obtain 777 mg of the target product as a yellow oil, which was directly used in the next step with a yield of 73.5%.

LCMS:m/z 380.16[M+H] +。 LCMS: m/z 380.16 [M+H] + .

步骤9：(S)-7-((S)-1-(4-氯苯基)-2-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-氧代乙基)-6-氮杂螺[3.4]辛烷-6-羧酸叔丁酯(10i)的制备Step 9: (S)-7-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl Preparation of ester (10i)

于室温，将化合物1k(200mg,0.854mmol)、二氯甲烷(5mL)加到反应瓶中，加入N,N-二异丙基乙胺(412mg,3.19mmol)，搅拌5分钟，加入(S)-2-((S)-6-(叔丁氧羰基)-6-氮杂螺[3.4]辛烷-7-基)-2-(4-氯苯基)乙酸(200mg,0.527mmol)，搅拌1分钟，加入HBTU(204mg,0.540mmol)，搅拌反应12小时。反应结束后，减压浓缩，残余物经柱层析色谱法分离纯化(DCM:MeOH＝10:1)，得256mg白色固体状的粗品标题化合物。At room temperature, compound 1k (200mg, 0.854mmol) and dichloromethane (5mL) were added to the reaction flask, N,N-diisopropylethylamine (412mg, 3.19mmol) was added, stirred for 5 minutes, and (S )-2-((S)-6-(tert-butoxycarbonyl)-6-azaspiro[3.4]octane-7-yl)-2-(4-chlorophenyl)acetic acid (200mg, 0.527mmol) , stirred for 1 minute, added HBTU (204 mg, 0.540 mmol), and stirred for 12 hours. After the reaction, it was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM:MeOH=10:1) to obtain 256 mg of the crude title compound as a white solid.

LCMS:m/z 596.29[M+H] +。 LCMS: m/z 596.29 [M+H] + .

步骤10：(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-2-((S)-6-氮杂螺[3.4]辛-7-基)乙-1-酮(10)的制备Step 10: (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-6-azaspiro[3.4]oct-7-yl)ethan-1-one (10)

于室温，将化合物10i(256mg,粗品)、二氯甲烷(3mL)加入至反应瓶中。冰浴降温至5℃左右，滴加盐酸/二氧六环溶液(0.33mL，1.32mmol)，加毕室温反应10小时。反应结束后直接浓缩，残余物用制备高效液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得46mg白色固体标题化合物，两步产率17.6％。Compound 10i (256 mg, crude), dichloromethane (3 mL) were added to the reaction flask at room temperature. Cool down to about 5°C in an ice bath, add hydrochloric acid/dioxane solution (0.33 mL, 1.32 mmol) dropwise, and react at room temperature for 10 hours after addition. Concentrate directly after the reaction, and the residue is separated by preparative high-performance liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%) to obtain 46mg The title compound as a white solid, 17.6% yield over two steps.

LCMS:m/z 496.24[M+H] +。 LCMS: m/z 496.24 [M+H] + .

1H NMR(400MHz,CDCl3)δ＝8.45(s,1H),7.33(d,J＝8.5,2H),7.23(d,J＝8.4,2H),5.05(s,1H),3.87(s,4H),3.72(dd,J＝14.0,7.0,1H),3.50(dd,J＝60.9,24.6,6H),3.05(t,J＝15.1,3H),2.31–1.85(m,5H),1.81(d,J＝16.7,3H),1.55(s,2H),1.24(t,J＝7.0,1H),1.09(d,J＝4.9,3H)。 1 H NMR (400MHz, CDCl3) δ=8.45(s,1H),7.33(d,J=8.5,2H),7.23(d,J=8.4,2H),5.05(s,1H),3.87(s, 4H), 3.72(dd, J=14.0, 7.0, 1H), 3.50(dd, J=60.9, 24.6, 6H), 3.05(t, J=15.1, 3H), 2.31–1.85(m, 5H), 1.81 (d, J = 16.7, 3H), 1.55 (s, 2H), 1.24 (t, J = 7.0, 1H), 1.09 (d, J = 4.9, 3H).

实施例11：3-(3-氨基氧杂环丁烷-3-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮(11)的制备Example 11: 3-(3-aminooxetan-3-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxyl-5-methanol Preparation of yl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one (11)

Figure PCTCN2022136451-appb-000052
Figure PCTCN2022136451-appb-000052

步骤1：2-(4-氯苯基)-3-羟基丙酸甲酯(11a)的制备Step 1: Preparation of methyl 2-(4-chlorophenyl)-3-hydroxypropionate (11a)

于室温，向干燥的250mL三口烧瓶中依次加入2-(4-氯苯基)乙酸甲酯(10.0g，54.2mmol)、二甲基亚砜(60mL)、多聚甲醛(1.71g，56.9mmol)和甲醇钠(142mg，2.62mmol)。于室温搅拌反应2小时，将反应液倒入冰水中，用稀盐酸(1N)调节pH至中性，乙酸乙酯(200mL)萃取，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经柱层析色谱法分离纯化(流动相：PE/EA＝10:1)，得浅黄色油状标题化合物8.50g，收率：73.7％。At room temperature, add 2-(4-chlorophenyl)methyl acetate (10.0g, 54.2mmol), dimethyl sulfoxide (60mL), paraformaldehyde (1.71g, 56.9mmol ) and sodium methoxide (142 mg, 2.62 mmol). Stir the reaction at room temperature for 2 hours, pour the reaction solution into ice water, adjust the pH to neutral with dilute hydrochloric acid (1N), extract with ethyl acetate (200 mL), wash with water and saturated brine successively, dry over anhydrous sodium sulfate, and filter , the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: PE/EA=10:1) to obtain 8.50 g of the title compound as light yellow oil, yield: 73.7%.

LCMS:m/z 215.0[M+H] +。 LCMS: m/z 215.0 [M+H] + .

步骤2：2-(4-氯苯基)丙烯酸甲酯(11b)的制备Step 2: Preparation of methyl 2-(4-chlorophenyl)acrylate (11b)

于室温，将2-(4-氯苯基)-3-羟基丙酸甲酯(8.50g，39.7mmol)加入到干燥的250mL单口烧瓶中，加入二氯甲烷(80mL)和三乙胺(10.0g，99.3mmol)。在氮气氛下，降温至0℃，缓慢滴入甲磺酰氯(1.45g，10.6mmol)，搅拌2小时。反应液用稀盐酸(1N)调节pH至7，二氯甲烷萃取，依次用碳酸氢钠溶液、饱和食盐水和水洗涤，干燥，过滤，滤液减压浓缩，残余物经柱层析色谱法分离纯化(流动相：PE/EA＝10:1)，得浅黄色固体状标题化合物5.00g，收率：64.3％。At room temperature, 2-(4-chlorophenyl)-3-hydroxypropionic acid methyl ester (8.50g, 39.7mmol) was added into a dry 250mL one-necked flask, and dichloromethane (80mL) and triethylamine (10.0 g, 99.3 mmol). Under a nitrogen atmosphere, the temperature was lowered to 0°C, methanesulfonyl chloride (1.45 g, 10.6 mmol) was slowly added dropwise, and stirred for 2 hours. The reaction solution was adjusted to pH 7 with dilute hydrochloric acid (1N), extracted with dichloromethane, washed successively with sodium bicarbonate solution, saturated brine and water, dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography After purification (mobile phase: PE/EA=10:1), 5.00 g of the title compound was obtained as a light yellow solid, yield: 64.3%.

LCMS:m/z 196.9[M+H] +。 LCMS: m/z 196.9 [M+H] + .

步骤3：2-(4-氯苯基)-3-(3-硝基氧杂环丁烷-3-基)丙酸甲酯(11c)的制备Step 3: Preparation of methyl 2-(4-chlorophenyl)-3-(3-nitrooxetan-3-yl)propanoate (11c)

于室温，将2-(4-氯苯基)丙烯酸甲酯(0.700g，3.57mmol)加入到100mL单口瓶中，加入乙腈(10mL)和3-硝基氧杂环丁烷(432mg，4.21mmol)。降温至0℃，加入DBU(639mg，4.21mmol)。氮气氛围下，于室温反应18小时，反应液减压浓缩，残余物通过柱层析色谱法分离纯化(流动相：PE/EA＝5:1)，得白色固体状标题化合物390mg，收率37.3％。At room temperature, 2-(4-chlorophenyl)methyl acrylate (0.700g, 3.57mmol) was added to a 100mL one-necked flask, and acetonitrile (10mL) and 3-nitrooxetane (432mg, 4.21mmol ). Cool down to 0°C and add DBU (639 mg, 4.21 mmol). Under nitrogen atmosphere, reacted at room temperature for 18 hours, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: PE/EA=5:1) to obtain 390 mg of the title compound as a white solid, with a yield of 37.3 %.

LCMS:m/z 300.0[M+H] +。 LCMS: m/z 300.0 [M+H] + .

步骤4：2-(4-氯苯基)-3-(3-硝基氧杂环丁烷-3-基)丙酸(11d)的制备Step 4: Preparation of 2-(4-chlorophenyl)-3-(3-nitrooxetan-3-yl)propanoic acid (11d)

于室温，向干燥的100mL单口烧瓶中依次加入2-(4-氯苯基)-3-(3-硝基氧杂环丁-3-基)丙酸甲酯(300.0mg，1.00mmol)、乙醇(5mL)、氢氧化锂(210.0mg，5.00mmol)、四氢呋喃(5mL)和水(5mL)。室温搅拌2小时，减压浓缩除去溶剂，2M盐酸调节pH为5～6，减压浓缩，残余物用制备高效液相色谱法分离(色谱柱型号：Gemini-C18 150*21.2mm，5μm，流动相：乙腈/水0.1％TFA，梯度：30％-60％)，得类白色固体状标题化合物172.3mg，收率60.5％。At room temperature, add 2-(4-chlorophenyl)-3-(3-nitrooxetan-3-yl)methyl propanoate (300.0mg, 1.00mmol) successively to a dry 100mL single-necked flask, Ethanol (5 mL), lithium hydroxide (210.0 mg, 5.00 mmol), tetrahydrofuran (5 mL) and water (5 mL). Stir at room temperature for 2 hours, concentrate under reduced pressure to remove the solvent, adjust the pH to 5-6 with 2M hydrochloric acid, concentrate under reduced pressure, and separate the residue by preparative high-performance liquid chromatography (column model: Gemini-C18 150*21.2mm, 5 μm, flow Phase: acetonitrile/water 0.1% TFA, gradient: 30%-60%) to obtain 172.3 mg of the title compound as an off-white solid, yield 60.5%.

LCMS:m/z 286.0[M+H] +。 LCMS: m/z 286.0 [M+H] + .

1H NMR(400MHz,CDCl3)δ7.36(s,1H),7.34(s,1H),7.23(s,1H),7.21(s,1H),5.01(d,J＝8.0Hz,1H),4.81-4.71(m,1H),4.15(d,J＝8.0Hz,1H),3.55-3.51(m,1H),3.08-3.03(m,1H),2.76-2.70(m,1H)。 1 H NMR (400MHz, CDCl3) δ7.36(s,1H),7.34(s,1H),7.23(s,1H),7.21(s,1H),5.01(d,J=8.0Hz,1H), 4.81-4.71 (m, 1H), 4.15 (d, J=8.0Hz, 1H), 3.55-3.51 (m, 1H), 3.08-3.03 (m, 1H), 2.76-2.70 (m, 1H).

步骤5：2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)-3-(3-硝基氧杂环丁烷-3-基)丙-1-酮(11e)的制备Step 5: 2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d] Preparation of pyrimidin-4-yl)piperazin-1-yl)-3-(3-nitrooxetan-3-yl)propan-1-one (11e)

于室温，将化合物1k(270mg粗品)、二氯甲烷(6mL)、DIPEA(1.04g,8.07mmol)加入至反应瓶中，室温反应30分钟。加入2-(4-氯苯基)-3-(3-硝基氧杂环丁烷-3-基)丙酸(230.5mg,0.807mmol)和HBTU(367mg,0.968mmol)，室温反应10小时。反应结束后，以饱和碳酸氢钠水溶液淬灭反应，水相以二氯甲烷萃取，合并有机相，无水Na 2SO 4干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法分离纯化(DCM:MeOH＝5:1)，得589mg淡黄色油状粗品，直接用于下一步。 At room temperature, compound 1k (270 mg crude product), dichloromethane (6 mL), and DIPEA (1.04 g, 8.07 mmol) were added into the reaction flask, and reacted at room temperature for 30 minutes. Add 2-(4-chlorophenyl)-3-(3-nitrooxetan-3-yl)propionic acid (230.5mg, 0.807mmol) and HBTU (367mg, 0.968mmol) and react at room temperature for 10 hours . After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous Na2SO4 , filtered, the filtrate was concentrated under reduced pressure , and the residue was separated by column chromatography Purification (DCM:MeOH=5:1) yielded 589 mg of crude product as pale yellow oil, which was directly used in the next step.

LCMS:m/z 502.18[M+H] +。 LCMS: m/z 502.18 [M+H] + .

步骤6：3-(3-氨基氧杂环丁烷-3-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊烷并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮(11)的制备Step 6: 3-(3-Aminoxetan-3-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl Preparation of -6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one (11)

于室温，将化合物11e(589mg粗品)、甲醇(6mL)、1M盐酸(11.7mL)加入至反应瓶中，分批加入锌粉(172mg,2.69mmol)，室温搅拌过夜。反应结束后直接浓缩，残余物用制备高效液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得22mg白色固体标题化合物，产率5.7％。Compound 11e (589mg crude product), methanol (6mL), 1M hydrochloric acid (11.7mL) were added to the reaction flask at room temperature, zinc powder (172mg, 2.69mmol) was added in batches, and stirred overnight at room temperature. Concentrate directly after the reaction, and the residue is separated by preparative high-performance liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%) to obtain 22mg The title compound as a white solid, 5.7% yield.

LCMS:m/z 472.2[M+H] +。 LCMS: m/z 472.2 [M+H] + .

1H NMR(400MHz,CDCl3)δ8.46(dd,J＝23.3,6.7Hz,1H),7.45-7.27(m,3H),7.21(dd,J＝19.6,8.6Hz,1H),5.08(t,J＝7.1Hz,1H),4.52(dd,J＝6.2,1.6Hz,1H),4.34(d,J＝6.2Hz,1H),4.18(d,J＝3.0Hz,1H),4.08-3.93(m,1H),3.92-3.74(m,2H), 3.74-3.31(m,7H),3.31-3.12(m,1H),3.06(s,1H),2.82-2.58(m,2H),2.32-1.97(m,4H),1.11(dt,J＝11.7,6.6Hz,3H)。1H NMR (400MHz, CDCl3) δ8.46(dd, J＝23.3, 6.7Hz, 1H), 7.45-7.27(m, 3H), 7.21(dd, J＝19.6, 8.6Hz, 1H), 5.08(t, J＝7.1Hz, 1H), 4.52(dd, J＝6.2, 1.6Hz, 1H), 4.34(d, J＝6.2Hz, 1H), 4.18(d, J＝3.0Hz, 1H), 4.08-3.93( m,1H),3.92-3.74(m,2H), 3.74-3.31(m,7H),3.31-3.12(m,1H),3.06(s,1H),2.82-2.58(m,2H),2.32- 1.97 (m, 4H), 1.11 (dt, J=11.7, 6.6Hz, 3H).

生物学测试biological test

试验例1：本发明化合物对AKT1/AKT2/AKT3激酶的抑制活性Test Example 1: Inhibitory activity of compounds of the present invention on AKT1/AKT2/AKT3 kinases

实验采用HTRF方法检测化合物对AKT激酶的活性抑制。In the experiment, the HTRF method was used to detect the inhibition of the activity of the compound on AKT kinase.

试验方法experiment method

材料和试剂：AKT1、AKT2、AKT3均购自Thermo公司，货号分别为P2999、PV3184和PV3185。HTRF KinEASE-STK S3试剂盒来自Cisbio，货号62ST3PEB。其他试剂：ATP溶液(Sigma，R0441)，MgCl 2(Sigma，7786-30-3)，DMSO(Sigma，D2650-100ML)，Ipatasertib(MCE，HY-15186)。 Materials and reagents: AKT1, AKT2, and AKT3 were purchased from Thermo Company, and the article numbers were P2999, PV3184, and PV3185, respectively. The HTRF KinEASE-STK S3 kit was from Cisbio, Cat. No. 62ST3PEB. Other reagents: ATP solution (Sigma, R0441), MgCl 2 (Sigma, 7786-30-3), DMSO (Sigma, D2650-100ML), Ipatasertib (MCE, HY-15186).

实验过程：首先将5×激酶缓冲液进行稀释，配制1×实验工作液，MgCl 2和DTT终浓度分别为5mM和1mM。化合物稀释按照27倍比稀释法，从最高浓度点稀释共4个浓度点，并转移到Echo板中(Labcyte，LP0200)。用Echo将化合物转移到384孔板(Greiner，784075)，使化合物变成3倍比稀释矩阵，11个浓度点。加5ul 2×激酶(终浓度AKT1：0.02ng/ul；AKT2：0.03ng/ul；AKT3：0.01ng/ul)到384孔板中，1000rpm,离心30秒，室温孵育15分钟。加5ul 2×STK-Sub3-biotin底物和ATP(终浓度AKT1：150uM；AKT2：250uM；AKT3：100uM)的工作液到384孔板中，1000rpm,离心30秒，室温孵育75分钟。加10ul检测液到384孔板中，1000rpm,离心30秒，室温孵育30分钟。Envision酶标仪(PerkinElmer)检测665/615荧光信号值。使用XL-Fit软件进行数据分析，通过非线性拟合得出化合物IC 50。 Experimental process: first dilute 5×kinase buffer solution to prepare 1×experimental working solution, and the final concentrations of MgCl 2 and DTT are 5mM and 1mM respectively. The compound was diluted to 4 concentration points from the highest concentration point according to the 27-fold dilution method, and transferred to the Echo plate (Labcyte, LP0200). Compounds were transferred to a 384-well plate (Greiner, 784075) with Echo, making the compounds into a 3-fold ratio dilution matrix with 11 concentration points. Add 5ul 2× kinase (final concentration AKT1: 0.02ng/ul; AKT2: 0.03ng/ul; AKT3: 0.01ng/ul) to a 384-well plate, centrifuge at 1000rpm for 30 seconds, and incubate at room temperature for 15 minutes. Add 5ul 2×STK-Sub3-biotin substrate and ATP (final concentration AKT1: 150uM; AKT2: 250uM; AKT3: 100uM) working solution to a 384-well plate, centrifuge at 1000rpm for 30 seconds, and incubate at room temperature for 75 minutes. Add 10ul detection solution to the 384-well plate, centrifuge at 1000rpm for 30 seconds, and incubate at room temperature for 30 minutes. Envision microplate reader (PerkinElmer) detects 665/615 fluorescence signal value. XL-Fit software was used for data analysis, and compound IC 50 was obtained by nonlinear fitting.

本发明化合物对AKT1、AKT2和AKT3激酶抑制的IC 50值如下表1所示。 The IC50 values of the compounds of the present invention for the inhibition of AKT1, AKT2 and AKT3 kinases are shown in Table 1 below.

表1本发明化合物对AKT1、AKT2和AKT3激酶抑制的IC 50值 Table 1 The compounds of the present invention inhibit the IC50 values of AKT1, AKT2 and AKT3 kinases

Figure PCTCN2022136451-appb-000053
Figure PCTCN2022136451-appb-000053

结论：从表1可以看出，本发明化合物对AKT1/2/3激酶具有显著抑制作用。Conclusion: It can be seen from Table 1 that the compound of the present invention has significant inhibitory effect on AKT1/2/3 kinase.

试验例2：本发明化合物前列腺癌细胞抑制作用Test Example 2: Inhibitory effect of compounds of the present invention on prostate cancer cells

采用CTG方法检测本发明化合物对前列腺癌Lncap细胞(PTEN缺失)的抑制水平。The inhibitory level of the compound of the present invention on prostate cancer Lncap cells (PTEN loss) was detected by CTG method.

LNCaP细胞(ATCC，CRL-1740)培养于RPMI-1640培养基(Gibco，C11875500BT)中，添加10％FBS(Gibco，10099141)和双抗(1％的青霉素和链霉素，Gibco公司，15140122)。待细胞生长至70～80％的汇合度，使用胰酶替代物Tryple TM express酶(Invitrogen，12604021)消化8分钟。用添加10％FBS的RPMI-1640培养液制备细胞悬液，计数，调整细胞密度为1.25×10 4/ml。将细胞悬液加入384孔板中，每孔40μl，即LNCaP细胞500个/孔。化合物配制：化合物从10mM起始，在100％的DMSO中3倍连续稀释，10个浓度梯度。然后用含10％FBS的培养基进行中间稀释，取1μl的化合物到199μl的培养基中，稀释200倍。实验起始浓度为10μM，取经过培养基中间稀释的化合物10μl，加入384孔板的细胞中，2个复孔，共50μl的反应体系中，DMSO终浓度为0.1％。37℃，5％CO 2培养箱中培养96小时。然后将384孔板取出，室温平衡30分钟，每孔加入20μl Cell Titer-Glo(Promega，Cat.No.：G7572)，振荡混匀，室温孵育10分钟。多功能酶标仪(Biotek，型号Cytation 3)读取发光值。采用GraphPad prism 8.0软件进行非线性拟合，计算化合物对细胞增殖抑制的IC 50值。 LNCaP cells (ATCC, CRL-1740) were cultured in RPMI-1640 medium (Gibco, C11875500BT), adding 10% FBS (Gibco, 10099141) and double antibodies (1% penicillin and streptomycin, Gibco, 15140122) . After the cells grew to a confluence of 70-80%, they were digested with trypsin substitute Tryple ™ express enzyme (Invitrogen, 12604021) for 8 minutes. Cell suspension was prepared with RPMI-1640 culture medium supplemented with 10% FBS, counted, and the cell density was adjusted to 1.25×10 4 /ml. The cell suspension was added to a 384-well plate, 40 μl per well, that is, 500 LNCaP cells per well. Compound preparation: starting from 10 mM, the compound was serially diluted 3 times in 100% DMSO with 10 concentration gradients. Then intermediate dilution was performed with medium containing 10% FBS, and 1 μl of the compound was added to 199 μl of medium, and diluted 200 times. The initial concentration of the experiment was 10 μM, and 10 μl of the compound diluted in the middle of the medium was added to the cells of the 384-well plate, 2 duplicate wells, a total of 50 μl of the reaction system, and the final concentration of DMSO was 0.1%. Incubate in a 37°C, 5% CO 2 incubator for 96 hours. Then the 384-well plate was taken out, equilibrated at room temperature for 30 minutes, 20 μl Cell Titer-Glo (Promega, Cat. No.: G7572) was added to each well, vortexed to mix, and incubated at room temperature for 10 minutes. The luminescence value was read with a multifunctional microplate reader (Biotek, model Cytation 3). GraphPad prism 8.0 software was used for nonlinear fitting, and the IC 50 value of the compound on cell proliferation inhibition was calculated.

本发明化合物对LNCaP细胞抑制的IC 50值如下表2所示。 The IC 50 values of the compounds of the present invention for the inhibition of LNCaP cells are shown in Table 2 below.

表2本发明化合物对LNCaP细胞抑制的IC 50值 Table 2 The compounds of the present invention inhibit the IC50 value of LNCaP cells

化合物编号Compound number IC 50(nM) IC 50 (nM) 11 76.1576.15 22 86.9486.94 33 27.4827.48 44 32.2332.23 55 42.8042.80 66 57.0057.00 77 33.0033.00 88 70.0070.00 99 66.0066.00 1010 115.0115.0 1111 500.00500.00

结论：从表2可以看出，本发明化合物对人前列腺癌LNCaP细胞的增殖具有显著抑制作用。Conclusion: It can be seen from Table 2 that the compound of the present invention has a significant inhibitory effect on the proliferation of human prostate cancer LNCaP cells.

试验例3：本发明化合物的小鼠药代动力学实验Test example 3: mouse pharmacokinetic experiment of the compound of the present invention

实验动物选用7-8周龄雄性ICR小鼠，购自北京维通利华实验动物技术有限公司，饲养于SPF环境，温度20～26℃，每日温差不超过4℃，相对湿度40～70％RH， 每日12h/12h交替照明。实验动物经过3-5天的适应期，其中口服给药动物于实验前1天禁食过夜(>12h)，不禁水。The experimental animals were male ICR mice aged 7-8 weeks, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and raised in an SPF environment with a temperature of 20-26°C, a daily temperature difference of no more than 4°C, and a relative humidity of 40-70°C. %RH, 12h/12h alternate lighting every day. The experimental animals went through an adaptation period of 3-5 days, and the animals administered orally were fasted overnight (>12h) one day before the experiment, without water.

每个待测化合物分为iv(静脉给药)和po(灌胃)组(n＝6)，剂量设为iv 1mg/kg、p.o 10mg/kg。溶媒：静脉组为20％HP-β-CD，灌胃组为Tween80：PEG400：水＝1：9：90(v/v/v)。化合物溶液配制流程如下：先用DMSO溶解化合物，配成10mg/mL的储液；取100μL储液，用20％的HP-β-CD定容至5mL，得到浓度为0.2mg/mL的静脉给药溶液；取100μL的储液，加入溶媒定容至5mL，涡旋，使分散均匀，得到化合物浓度为1mg/mL的灌胃给药溶液。Each compound to be tested was divided into iv (intravenous administration) and po (gastric administration) groups (n=6), and the dosage was set as iv 1mg/kg, p.o 10mg/kg. Vehicle: 20% HP-β-CD for the intravenous group, and Tween80:PEG400:water for the intragastric administration group=1:9:90 (v/v/v). The compound solution preparation process is as follows: dissolve the compound in DMSO first, and prepare a 10 mg/mL stock solution; take 100 μL of the stock solution, dilute it to 5 mL with 20% HP-β-CD, and obtain a concentration of 0.2 mg/mL for intravenous administration. Drug solution; take 100 μL of the stock solution, add solvent to make it up to 5 mL, vortex to disperse evenly, and obtain an intragastric administration solution with a compound concentration of 1 mg/mL.

给药前称量体重，通过眼静脉丛采血方式，采集0.1mL血样加入肝素钠抗凝管中，防止凝血。每个受试化合物6只静脉给药，6只口服给药，并于给药后2h给予食物。样品采集时间点为，灌胃组：给药前及给药后15min、30min、1h、2h、4h、8h；静脉组：给药前及给药后5min、15min、30min、1h、2h、4h、8h。动物采血分成2部分分别进行，采用交叉时间点采血，同1只小鼠最多设5个采血点。在取血60min内，用Sorvall ST 8R高速低温离心机以3000rpm离心10min，取上层血浆，冻存到-20℃冰箱内，备用。使用LC-MS/MS的分析方法检测样品中化合物浓度。采用MAS Studio(V1.3.1stable)软件计算并得到化合物在小鼠体内的血药浓度-时间曲线，以及主要的PK参数：AUC 0-t、C max、T max、T 1/2和F％。 Body weight was weighed before administration, and 0.1mL blood samples were collected through the ophthalmic venous plexus and added to heparin sodium anticoagulant tubes to prevent coagulation. Each test compound was administered intravenously to 6 rats, and 6 rats were given oral administration, and food was given 2 hours after administration. The sample collection time points are: gavage group: before administration and 15min, 30min, 1h, 2h, 4h, 8h after administration; intravenous group: before administration and after administration 5min, 15min, 30min, 1h, 2h, 4h , 8h. Animal blood collection was divided into two parts, and cross-time point blood collection was adopted, and a maximum of 5 blood collection points were set for one mouse. Within 60 minutes of blood collection, centrifuge at 3,000 rpm for 10 minutes with a Sorvall ST 8R high-speed low-temperature centrifuge, take the upper layer of plasma, and store it in a -20°C refrigerator for later use. The concentration of the compound in the sample was detected by the analytical method of LC-MS/MS. Use MAS Studio (V1.3.1stable) software to calculate and obtain the blood drug concentration-time curve of the compound in mice, as well as the main PK parameters: AUC 0-t , C max , T max , T 1/2 and F% .

F％＝(AUC po×剂量 iv)/(AUC iv×剂量 po)×100％。 F% = (AUC po x dose iv )/(AUC iv x dose po ) x 100%.

本发明化合物对小鼠的药代动力学参数如下表3所示。The pharmacokinetic parameters of the compounds of the present invention on mice are shown in Table 3 below.

表3本发明化合物小鼠的药代动力学参数The pharmacokinetic parameter of table 3 compound mice of the present invention

Figure PCTCN2022136451-appb-000054
Figure PCTCN2022136451-appb-000054

结论：从表3可以看出，本发明化合物具有良好的药代动力学性质。Conclusion: As can be seen from Table 3, the compounds of the present invention have good pharmacokinetic properties.

试验例4：本发明化合物对小鼠前列腺癌模型的药效学实验Test Example 4: Pharmacodynamic experiments of compounds of the present invention on mouse prostate cancer model

实验用雄性4-5周龄的nu/nu裸鼠，购自北京维通利华实验动物技术有限公司，饲养于SPF环境，经过4-5天的适应性饲养，用于构建肿瘤模型。培养人前列腺癌细胞PC-3(ATCC，CRL-1435；培养液F12K+10％FBS)，离心收集细胞，用生理盐水制备细胞悬液，按1：1比例与基质胶(Corning，货号354234)混匀， 用预冷的注射器，接种在裸鼠右前肢皮下，每只动物接种体积100μL，接种1×10 8细胞。接种2周后，肿瘤体积生长至约100mm 3，将动物随机分为5组(n＝6)，分组如下：对照组(溶媒：3％DMSO+97％(20％HP-β-CD))，化合物3低剂量组(25mg/kg，QD)，化合物3高剂量组(50mg/kg，QD)，化合物4低剂量组(25mg/kg，QD)，化合物4高剂量组(50mg/kg，QD)，从分组当天(day 0)开始至day20，连续灌胃给药21天。治疗期间，每周秤重2次，测量肿瘤2次。用电子游标卡尺测量肿瘤最大直径L，最短直径W，根据公式V＝L×W 2/2，计算肿瘤体积V；依据公式1-T/C％计算肿瘤生长抑制率(Tumor growth inhibition，TGI)，其中T是治疗组平均肿瘤体积(tumor volume,TV)，C是对照组平均肿瘤体积；相对肿瘤增殖率T/C％＝TRTV/CRTV×100％(Relative tumor volume，RTV：根据测量结果计算出相对肿瘤体积，RTV＝Vt/V0；其中V0为分笼给药时测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积；TRTV，治疗组RTV；CRTV，溶媒对照组RTV)。给药结束后，实验动物安乐死，剥离瘤体秤重，计算瘤重抑瘤率：(对照组平均瘤重-给药组平均瘤重)/对照组平均瘤重×100％。 Male nu/nu nude mice aged 4-5 weeks were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and were raised in SPF environment. After 4-5 days of adaptive feeding, they were used to construct tumor models. Cultivate human prostate cancer cell PC-3 (ATCC, CRL-1435; culture medium F12K+10% FBS), collect cells by centrifugation, prepare cell suspension with normal saline, mix with matrigel (Corning, Cat. No. 354234) at a ratio of 1:1 Mix well, and use a pre-cooled syringe to inoculate subcutaneously on the right forelimb of nude mice, with an inoculation volume of 100 μL for each animal, and inoculate 1×10 8 cells. Two weeks after inoculation, the tumor volume grew to about 100 mm 3 , and the animals were randomly divided into 5 groups (n=6), grouped as follows: control group (vehicle: 3% DMSO+97% (20% HP-β-CD)) , compound 3 low dose group (25mg/kg, QD), compound 3 high dose group (50mg/kg, QD), compound 4 low dose group (25mg/kg, QD), compound 4 high dose group (50mg/kg, QD), from the day of grouping (day 0) to day 20, continuous intragastric administration for 21 days. During the treatment period, the weight was weighed twice a week, and the tumor was measured twice. The largest diameter L and the shortest diameter W of the tumor were measured with an electronic vernier caliper, and the tumor volume V was calculated according to the formula V=L×W 2 /2; the tumor growth inhibition rate (Tumor growth inhibition, TGI) was calculated according to the formula 1-T/C%, Where T is the average tumor volume (tumor volume, TV) of the treatment group, C is the average tumor volume of the control group; the relative tumor proliferation rate T/C%=TRTV/CRTV×100% (Relative tumor volume, RTV: calculated according to the measurement results Relative tumor volume, RTV=Vt/V0; where V0 is the tumor volume measured during administration in separate cages, and Vt is the tumor volume at each measurement; TRTV, RTV of the treatment group; CRTV, RTV of the vehicle control group). After the administration, the experimental animals were euthanized, the tumors were stripped off and weighed, and the tumor weight inhibition rate was calculated: (average tumor weight in the control group−average tumor weight in the administration group)/average tumor weight in the control group×100%.

实验结果见表4和图1，表4为治疗21天后动物的肿瘤体积及肿瘤增殖抑制率，图1为各组小鼠中的肿瘤生长曲线。The experimental results are shown in Table 4 and Figure 1. Table 4 shows the tumor volume and tumor growth inhibition rate of the animals after 21 days of treatment, and Figure 1 shows the tumor growth curves in the mice of each group.

表4治疗21天后动物的肿瘤体积及肿瘤增殖抑制率Table 4 The tumor volume and tumor growth inhibition rate of animals after treatment for 21 days

Figure PCTCN2022136451-appb-000055
Figure PCTCN2022136451-appb-000055

结论：从表4和图1可以看出，本发明化合物能显著抑制小鼠前列腺癌皮下瘤的生长，具有良好的抗肿瘤活性。Conclusion: It can be seen from Table 4 and Figure 1 that the compound of the present invention can significantly inhibit the growth of subcutaneous tumors of prostate cancer in mice, and has good antitumor activity.

Claims (20)

一种通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，A compound represented by general formula (I) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022136451-appb-100001
Figure PCTCN2022136451-appb-100001
 其中：in: 环A选自C 3-C 12环烷基、3至14元杂环基、C 6-C 14芳基和6至14元杂芳基；其中所述C 3-C 12环烷基、3至14元杂芳基、C 6-C 14芳基和6至14元杂芳基各自独立地任选被一个或多个R 1所取代； Ring A is selected from C 3 -C 12 cycloalkyl, 3 to 14 membered heterocyclic group, C 6 -C 14 aryl and 6 to 14 membered heteroaryl; wherein the C 3 -C 12 cycloalkyl, 3 to 14-membered heteroaryl, C 6 -C 14 aryl, and 6 to 14-membered heteroaryl are each independently optionally substituted by one or more R 1 ; L为键或-CH 2-； L is a bond or -CH 2 -; 环B选自包含1-2个氮原子的5至8元饱和杂环基；所述杂环基任选被一个或多个R 3所取代； Ring B is selected from 5 to 8 membered saturated heterocyclic groups containing 1-2 nitrogen atoms; the heterocyclic group is optionally substituted by one or more R 3 ; G选自氢、苯基、5-6元杂芳基，其中所述苯基、5-6元杂芳基任选被一个或多个R 4所取代； G is selected from hydrogen, phenyl, 5-6 membered heteroaryl, wherein the phenyl, 5-6 membered heteroaryl is optionally substituted by one or more R 4 ; 每个R 1各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团所取代；或者， Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl, heteroaryl, said alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano , hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple groups substituted; or, 任意两个R 1与他们连接的原子一起形成环烷基、杂环基、芳基和杂芳基，所述环烷基、杂环基、芳基和杂芳基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代； Any two R together with the atoms to which they are attached form cycloalkyl, heterocyclyl, aryl and heteroaryl which are optionally selected from the group consisting of halogen, heterocyclyl, aryl and heteroaryl Amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl One or more groups of radicals and heteroaryls are substituted; 每个R 2各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团所取代；或 者， Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl, heteroaryl, said alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano , hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple groups substituted; or, 任意两个R 2与他们连接的原子一起形成环烷基、杂环基、芳基和杂芳基，所述环烷基、杂环基、芳基和杂芳基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代； Any two R 2 together with the atoms to which they are attached form cycloalkyl, heterocyclyl, aryl and heteroaryl, which are optionally selected from the group consisting of halogen, heterocyclyl, aryl and heteroaryl Amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl One or more groups of radicals and heteroaryls are substituted; 每个R 3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团所取代；或者， Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl, heteroaryl, said alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano , hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple groups substituted; or, 任意两个R 3与他们连接的原子一起形成环烷基、杂环基、芳基和杂芳基，所述环烷基、杂环基、芳基和杂芳基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代； Any two R 3 together with the atoms to which they are attached form cycloalkyl, heterocyclyl, aryl and heteroaryl, which are optionally selected from the group consisting of halogen, heterocyclyl, aryl and heteroaryl Amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl One or more groups of radicals and heteroaryls are substituted; 每个R 4各自独立地选自氢、卤素、硝基、氰基、羟基、巯基、烷基、烯基、炔基、-S(O) pR a、-NR aR b、-OR a、-C(O)R a、-C(O)NR aR b、-S(O) pNR aR b、环烷基、杂环基、芳基、杂芳基，所述烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团所取代； Each R is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, -S(O) p R a , -NR a R b , -OR a , -C(O)R a , -C(O)NR a R b , -S(O) p NR a R b , cycloalkyl, heterocyclyl, aryl, heteroaryl, the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl , alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more groups; R a和R b各自独立地选自氢、卤素、羟基、巯基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，所述烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团所取代；或者， R a and R b are each independently selected from hydrogen, halogen, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy One or more groups of radical, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or, R a和R b他们连接的氮原子一起形成含氮杂环基，所述含氮杂环基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代； R a and R b and their connected nitrogen atoms together form a nitrogen-containing heterocyclic group, and the nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, Ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more groups; n为0、1、2、3或4；n is 0, 1, 2, 3 or 4; p为0、1或2。p is 0, 1 or 2. 根据权利要求1所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环A选自C 3-C 12环烷基和3至14元杂环基，优选3至14元杂环基， 更优选3至6元单环杂环基、6至11元双环杂环基，进一步优选6至10元稠杂环基、6至10元螺杂环基；所述环烷基或杂环基各自独立地任选被一个或多个R 1所取代； The compound represented by the general formula (I) according to claim 1 or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereoisomers or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from C 3 -C 12 cycloalkyl and 3 to 14 membered heterocyclic groups, preferably 3 to 14 membered heterocyclic groups, more preferably 3 to 14 membered heterocyclic groups 6-membered monocyclic heterocyclic group, 6-11 membered bicyclic heterocyclic group, more preferably 6-10 membered condensed heterocyclic group, 6-10 membered spiro heterocyclic group; each of the cycloalkyl or heterocyclic group is independently any is selected to be replaced by one or more R 1 ; 每个R 1各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代；或者， Each R 1 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclic group, C 6 -C 10 aryl group, 5 to 10-membered heteroaryl group substituted by one or more groups; or, 任意两个R 1与他们连接的原子一起形成环烷基、杂环基、芳基和杂芳基，所述环烷基、杂环基、芳基和杂芳基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基的一个或多个基团取代。 Any two R together with the atoms to which they are attached form cycloalkyl, heterocyclyl, aryl and heteroaryl which are optionally selected from the group consisting of halogen, heterocyclyl, aryl and heteroaryl Amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 -C 10 aryl and 5 to 10 membered One or more groups of heteroaryl are substituted. 根据权利要求1或2所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to claim 1 or 2 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (II) or their stereoisomers, tautomers, mesomers, racemates, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
Figure PCTCN2022136451-appb-100002
Figure PCTCN2022136451-appb-100002
 其中：in: m为0、1、2、3或4；m is 0, 1, 2, 3 or 4; 每个R 1各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5 至10元杂芳基的一个或多个基团所取代；或者， Each R 1 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 -C 10 aryl, 5 to 10-membered heteroaryl by one or more groups; or, 任意两个R 1与他们连接的原子一起形成环烷基、杂环基、芳基和杂芳基，所述环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基的一个或多个基团取代； Any two R together with the atoms to which they are attached form cycloalkyl, heterocyclyl, aryl and heteroaryl which are optionally further selected from the group consisting of halogen , amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 - C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, C 6 -C 10 aryl Substituted with one or more groups of 5 to 10 membered heteroaryl; 环B、L、G、R 2、n如权利要求1所定义。 Ring B, L, G, R 2 , n are as defined in claim 1. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中任意两个R 1与他们连接的原子一起形成C 3-C 6环烷基或3至6元杂环基，所述C 3-C 6环烷基或3至6元杂环基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基的一个或多个基团取代。 The compound represented by the general formula (I) according to any one of claims 1 to 3 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein any two R 1 form a C 3 -C 6 cycloalkyl group or a 3 to 6-membered heterocyclic group together with the atoms they are connected to, The C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, One or more groups of C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl and 5 to 10 membered heteroaryl are substituted. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中L为键。The compound represented by the general formula (I) according to any one of claims 1 to 4 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers , a diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III-1)、通式(III-2)或通式(III-3)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to any one of claims 1 to 5 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III-1), general formula (III-2) or general formula (III-3) or Stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
Figure PCTCN2022136451-appb-100003
Figure PCTCN2022136451-appb-100003
 其中，in, X 1和X 2各自独立地选自-CH 2-、-O-、-NH-； X 1 and X 2 are each independently selected from -CH 2 -, -O-, -NH-; n 1为0或1； n 1 is 0 or 1; n 2为0、1或2； n2 is 0, 1 or 2; 每个R c各自独立地选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基； Each R c is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group; q为0、1或2，优选0或1，更优选0；q is 0, 1 or 2, preferably 0 or 1, more preferably 0; 环B、G、R 2和n如权利要求1所定义。 Rings B, G, R2 and n are as defined in claim 1. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IV-1)或(IV-2)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to any one of claims 1 to 5 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IV-1) or (IV-2) or its stereoisomers, tautomers body, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022136451-appb-100004
Figure PCTCN2022136451-appb-100004
 其中，in, 环E 1为C 3-C 6环烷基或3至6元杂环基； Ring E 1 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group; 环E 2为C 3-C 6环烷基或3至6元杂环基； Ring E 2 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group; 每个R e各自独立地选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基； Each R e is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group; t为0、1或2，优选0或1，更优选0；t is 0, 1 or 2, preferably 0 or 1, more preferably 0; 环B、G、R 2和n如权利要求1所定义。 Rings B, G, R2 and n are as defined in claim 1. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中环B为包含1-2个氮原子的6至8元饱和杂环基；环B优选自 以下基团：The compound represented by the general formula (I) according to any one of claims 1 to 7 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is a 6-8 membered saturated heterocyclic group containing 1-2 nitrogen atoms; ring B is preferably selected from the following groups:
Figure PCTCN2022136451-appb-100005
Figure PCTCN2022136451-appb-100005
 其中单波线表示连接至羰基的位置，双波线表示连接至嘧啶的位置；Wherein the single wave line represents the position connected to the carbonyl, and the double wave line represents the position connected to the pyrimidine; 环B任选被一个或多个R 3所取代； Ring B is optionally substituted by one or more R3 ; 每个R 3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代； Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 Substituted by one or more groups from 6-membered heterocyclic group, C 6 -C 10 aryl group, 5- to 10-membered heteroaryl group; 优选R 3为氢。 Preferably R3 is hydrogen. 根据权利要求1至6或8中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IIIA)、通式(IIIB)或通式(IIIC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to any one of claims 1 to 6 or 8 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers isomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIIA), general formula (IIIB) or general formula (IIIC) or a stereoisomer thereof isomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
Figure PCTCN2022136451-appb-100006
Figure PCTCN2022136451-appb-100006
 其中，in, X 1和X 2各自独立地选自-CH 2-、-O-、-NH-； X 1 and X 2 are each independently selected from -CH 2 -, -O-, -NH-; n 1为0或1； n 1 is 0 or 1; n 2为0、1或2； n2 is 0, 1 or 2; 每个R c各自独立地选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基； Each R c is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group; q为0、1或2，优选0或1，更优选0；q is 0, 1 or 2, preferably 0 or 1, more preferably 0; 每个R 3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代；优选R 3为氢； Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclic group, C 6 -C 10 aryl group, 5 to 10-membered heteroaryl group substituted by one or more groups; preferably R 3 is hydrogen; r为0、1、2、3或4，优选0、1或2，更优选0或1；r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1; G、R 2和n如权利要求1所定义。 G, R2 and n are as defined in claim 1. 根据权利要求1至5或7至8中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IVA)或(IVB)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，According to the compound represented by the general formula (I) described in any one of claims 1 to 5 or 7 to 8, or its stereoisomers, tautomers, mesomers, racemates, para Enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (IVA) or (IVB) or stereoisomers, tautomers thereof body, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022136451-appb-100007
Figure PCTCN2022136451-appb-100007
 其中，in, 环E 1为C 3-C 6环烷基或3至6元杂环基； Ring E 1 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group; 环E 2为C 3-C 6环烷基或3至6元杂环基； Ring E 2 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group; 每个R e各自独立地选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6 烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基； Each R e is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group; t为0、1或2，优选0或1，更优选0；t is 0, 1 or 2, preferably 0 or 1, more preferably 0; 每个R 3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代；优选R 3为氢； Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclic group, C 6 -C 10 aryl group, 5 to 10-membered heteroaryl group substituted by one or more groups; preferably R 3 is hydrogen; r为0、1、2、3或4，优选0、1或2，更优选0或1；r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1; G、R 2和n如权利要求1所定义。 G, R2 and n are as defined in claim 1. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中G选自苯基，所述苯基任选被任选被一个或多个R 4所取代； The compound represented by the general formula (I) according to any one of claims 1 to 10 or its stereoisomers, tautomers, mesomers, racemates, enantiomers , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is selected from phenyl, which is optionally substituted by one or more R 4 ; 每个R 4各自独立地选自卤素、氰基、羟基、巯基、C 1-C 6烷基、-NR aR b、-OR a，所述C 1-C 6烷基任选被卤素取代； Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ; R a和R b各自独立地选自氢和C 1-C 6烷基；或者， R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or, R a和R b他们连接的氮原子一起形成含5-6元氮杂环基，所述5-6元含氮杂环基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代。 R a and R b , the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replaced. 根据权利要求1至6或8至9或11中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IIID)、通式(IIIE)或通式(IIIF)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，According to the compound represented by the general formula (I) described in any one of claims 1 to 6 or 8 to 9 or 11 or its stereoisomers, tautomers, mesomers, racemates , enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIID), general formula (IIIE) or general formula (IIIF) or Stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
Figure PCTCN2022136451-appb-100008
Figure PCTCN2022136451-appb-100008
 其中，in, X 1和X 2各自独立地选自-CH 2-、-O-、-NH-； X 1 and X 2 are each independently selected from -CH 2 -, -O-, -NH-; n 1为0或1； n 1 is 0 or 1; n 2为0、1或2； n2 is 0, 1 or 2; 每个R c各自独立地选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基； Each R c is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group; q为0、1或2，优选0或1，更优选0；q is 0, 1 or 2, preferably 0 or 1, more preferably 0; 每个R 3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代；优选R 3为氢； Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclic group, C 6 -C 10 aryl group, 5 to 10-membered heteroaryl group substituted by one or more groups; preferably R 3 is hydrogen; r为0、1、2、3或4，优选0、1或2，更优选0或1；r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1; 每个R 4各自独立地选自卤素、氰基、羟基、巯基、C 1-C 6烷基、-NR aR b、-OR a，所述C 1-C 6烷基任选被卤素取代；优选R 4选自卤素； Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ; Preferably R is selected from halogen; R a和R b各自独立地选自氢和C 1-C 6烷基；或者， R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or, R a和R b他们连接的氮原子一起形成含5-6元氮杂环基，所述5-6元含氮杂环基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代； R a and R b , the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replacement; s为0、1或2；s is 0, 1 or 2; R 2和n如权利要求1所定义。 R 2 and n are as defined in claim 1. 根据权利要求1至5或7至8或10-11中任一项所述的通式(I)所示的化合物 或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IVC)或(IVD)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，According to the compound represented by the general formula (I) described in any one of claims 1 to 5 or 7 to 8 or 10-11 or its stereoisomers, tautomers, mesomers, racemates Rotary body, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IVC) or (IVD) or a stereoisomer thereof, Tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
Figure PCTCN2022136451-appb-100009
Figure PCTCN2022136451-appb-100009
 其中，in, 环E 1为C 3-C 6环烷基或3至6元杂环基； Ring E 1 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group; 环E 2为C 3-C 6环烷基或3至6元杂环基； Ring E 2 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group; 每个R e各自独立地选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基烯基、C 2-C 6烯基炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基和5至10元杂芳基； Each R e is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group; t为0、1或2，优选0或1，更优选0；t is 0, 1 or 2, preferably 0 or 1, more preferably 0; 每个R 3各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、3至6元杂环基、C 6-C 10芳基、5至10元杂芳基的一个或多个基团所取代；优选R 3为氢； Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclic group, C 6 -C 10 aryl group, 5 to 10-membered heteroaryl group substituted by one or more groups; preferably R 3 is hydrogen; r为0、1、2、3或4，优选0、1或2，更优选0或1；r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1; 每个R 4各自独立地选自卤素、氰基、羟基、巯基、C 1-C 6烷基、-NR aR b、-OR a，所述C 1-C 6烷基任选被卤素取代；优选R 4选自卤素； Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ; Preferably R is selected from halogen; R a和R b各自独立地选自氢和C 1-C 6烷基；或者， R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or, R a和R b他们连接的氮原子一起形成含5-6元氮杂环基，所述5-6元含氮杂环基任选被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代； R a and R b , the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replacement; s为0、1或2；s is 0, 1 or 2; R 2和n如权利要求1所定义。 R 2 and n are as defined in claim 1. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中每个R 2各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团所取代；优选每个R 2各自独立地选自氢、羟基和C 1-C 6烷基； The compound represented by the general formula (I) according to any one of claims 1 to 13 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy C 2 -C 6 alkenyl, C 2 -C 6 alkynyl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 One or more groups of haloalkyl, C 1 -C 6 haloalkoxy are substituted; preferably each R 2 is independently selected from hydrogen, hydroxyl and C 1 -C 6 alkyl; n为0、1、2，优选1或2，更优选2。n is 0, 1, 2, preferably 1 or 2, more preferably 2. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其选自：The compound represented by the general formula (I) according to any one of claims 1 to 14 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure PCTCN2022136451-appb-100010
Figure PCTCN2022136451-appb-100010
 一种通式(IIIA)或通式(IIIB)或通式(IIIC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：A compound represented by general formula (IIIA) or general formula (IIIB) or general formula (IIIC) or its stereoisomer, tautomer, mesomer, racemate, enantiomer The preparation method of body, diastereoisomer, or its mixture form, or its pharmaceutically acceptable salt, it comprises the following steps:
Figure PCTCN2022136451-appb-100011
Figure PCTCN2022136451-appb-100011
 式IIIAa的化合物与式IIIAc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IIIAb的化合物；式IIIAb的化合物在酸性条件下脱除保护基得到通式(IIIA)所示的化合物；The compound of the formula IIIAa and the compound of the formula IIIAc obtain the compound of the formula IIIAb in the presence of a catalyst under alkaline conditions; compound;
Figure PCTCN2022136451-appb-100012
Figure PCTCN2022136451-appb-100012
 式IIIAa的化合物与式IIIBc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IIIBb的化合物；式IIIBb的化合物在酸性条件下脱除保护基得到通式(IIIB)所示的化合物；The compound of formula IIIAa and the compound of formula IIIBc obtain the compound of formula IIIBb in the presence of catalyst coupling reaction under basic conditions; compound;
Figure PCTCN2022136451-appb-100013
Figure PCTCN2022136451-appb-100013
 式IIIAa的化合物与式IIICc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IIICb的化合物；式IIICb的化合物在酸性条件下脱除保护基得到通式(IIIC)所示的化合物；The compound of formula IIIAa and the compound of formula IIICc obtain the compound of formula IIICb in the presence of catalyst coupling reaction under basic conditions; compound; 其中：in: 所述催化剂优选苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐；The catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate; 所述碱性条件优选N,N-二异丙基乙胺；The alkaline condition is preferably N,N-diisopropylethylamine; 所述酸性条件优选盐酸；The acidic condition is preferably hydrochloric acid; R x为氨基保护基，优选Boc； R x is an amino protecting group, preferably Boc; G、R 2、R 3、X 1、X 2、R c、n、n 1、n 2、q、r如权利要求9所定义。 G, R 2 , R 3 , X 1 , X 2 , R c , n, n 1 , n 2 , q, r are as defined in claim 9 . 一种通式(IVA)或通式(IVB)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：A compound represented by general formula (IVA) or general formula (IVB) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers The preparation method of a conformer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:
Figure PCTCN2022136451-appb-100014
Figure PCTCN2022136451-appb-100014
 式IIIAa的化合物与式IVAc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IVAb的化合物；式IVAb的化合物在酸性条件下脱除保护基得到通式(IVA)所示的化合物；The compound of the formula IIIAa and the compound of the formula IVAc obtain the compound of the formula IVAb in the presence of the catalyst in the presence of a catalyst under alkaline conditions; the compound of the formula IVAb removes the protecting group under acidic conditions to obtain compound;
Figure PCTCN2022136451-appb-100015
Figure PCTCN2022136451-appb-100015
 式IIIAa的化合物与式IVBc的化合物在碱性条件下在催化剂的存在下发生偶联反应得到式IVBb的化合物；式IVBb的化合物在酸性条件下脱除保护基得到通式(IVB)所示的化合物；The compound of the formula IIIAa and the compound of the formula IVBc obtain the compound of the formula IVBb in the presence of a catalyst under alkaline conditions in the coupling reaction; the compound of the formula IVBb removes the protecting group under acidic conditions and obtains compound; 其中：in: 所述催化剂优选苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐；The catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate; 所述碱性条件优选N,N-二异丙基乙胺；The alkaline condition is preferably N,N-diisopropylethylamine; 所述酸性条件优选盐酸；The acidic condition is preferably hydrochloric acid; R x为氨基保护基，优选Boc； R x is an amino protecting group, preferably Boc; 环E 1、G、R 2、R 3、R e、n、r、t如权利要求10所定义。 Ring E 1 , G, R 2 , R 3 , Re , n, r, t are as defined in claim 10 . 一种药物组合物，所述药物组合物含有根据权利要求1至15中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition, which contains the compound represented by the general formula (I) according to any one of claims 1 to 15 or its stereoisomers, tautomers, meso body, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients agent. 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求18所述的药物组合物在制备用于抑制AKT1/2/3的药物中的用途。The compound represented by the general formula (I) according to any one of claims 1 to 15 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18 in the preparation of a medicament for inhibiting AKT1/2/3. 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求18所述的药物组合物在制备用于治疗和/或预防与AKT1/2/3激酶活性相关的疾病的药物中的用途，所述疾病优选癌症，特别是与以AKT1/2/3的扩增或过表达为特征的癌症，所述癌症优选卵巢癌、乳腺癌、前列腺癌、神经胶质瘤、胶质细胞瘤、胃癌、输卵管癌、肺癌、腹膜肿瘤、黑色素瘤、脑癌、食管癌、肝癌、胰腺癌、结直癌、肺癌、肾癌、宫颈癌、皮肤癌、神经母细胞瘤、肉瘤、骨癌、子宫癌、子宫内膜癌、头颈肿瘤、多发性骨髓瘤、淋巴瘤、非霍奇金淋巴瘤、非小细胞肺癌、真性红细胞增多症、白血病、甲状腺肿瘤、膀胱癌和胆囊癌，特别优选卵巢癌、乳腺癌和前列腺癌。The compound represented by the general formula (I) according to any one of claims 1 to 15 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 is used in the preparation for the treatment and/or prevention of diseases associated with AKT1/2/3 kinase activity The purposes in the medicine of said disease preferably cancer, especially the cancer that is characterized by the amplification or overexpression of AKT1/2/3, said cancer is preferably ovarian cancer, breast cancer, prostate cancer, glioma, Glioma, gastric cancer, fallopian tube cancer, lung cancer, peritoneal tumor, melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer, skin cancer, neuroblastoma, sarcoma , bone cancer, uterine cancer, endometrial cancer, head and neck cancer, multiple myeloma, lymphoma, non-Hodgkin's lymphoma, non-small cell lung cancer, polycythemia vera, leukemia, thyroid tumors, bladder cancer, and gallbladder cancer , ovarian cancer, breast cancer and prostate cancer are particularly preferred.
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