WO2023109540A1

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

Info

Publication number: WO2023109540A1
Application number: PCT/CN2022/136451
Authority: WO
Inventors: 闫旭; 陈振华; 刘国标; 蔡绪灿; 尚飞; 杜佩金
Original assignee: 中国医药研究开发中心有限公司
Priority date: 2021-12-17
Filing date: 2022-12-05
Publication date: 2023-06-22
Also published as: CN117677614A

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

Heterocyclic compound with AKT kinase inhibitory activity, preparation method and medical use thereof

technical field

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.

Background technique

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 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 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.

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.

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.

Contents of the invention

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.

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,

in:

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,

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;

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,

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;

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,

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;

^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 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 is 0, 1, 2, 3 or 4;

p is 0, 1 or 2.

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 ;

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,

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.

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.

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.

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,

in:

m is 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 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,

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;

Ring B, L, G, R ² and n are as defined in general formula (I).

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.

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.

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:

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.

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.

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 -.

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,

in,

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).

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,

in,

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).

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:

Wherein 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 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;

Preferably ^R3 is hydrogen.

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,

in,

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;

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 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 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).

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,

in,

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;

t is 0, 1 or 2, preferably 0 or 1, more preferably 0;

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).

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 ;

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, 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.

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,

in,

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;

q is 0, 1 or 2, preferably 0 or 1, more preferably 0;

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 ; Preferably ^R is selected from halogen;

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 is 0, 1 or 2;

R ² and n are as defined in general formula (I).

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,

in,

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;

t is 0, 1 or 2, preferably 0 or 1, more preferably 0;

r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;

s is 0, 1 or 2;

R ² and n are as defined in general formula (I).

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.

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.

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.

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.

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,

in:

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 is 0, 1 or 2;

r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;

s is 0, 1 or 2;

R ² and n are as defined in general formula (I).

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,

in:

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;

r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;

s is 0, 1 or 2;

R ² and n are as defined in general formula (I).

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-.

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 -.

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 -.

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.

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.

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.

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.

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.

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.

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.

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 is 0, 1, 2, preferably 1 or 2, more preferably 2.

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.

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.

Typical compounds of the invention include, but are not limited to, the following compounds:

Stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers thereof, or a mixture thereof or a pharmaceutically acceptable salt thereof.

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:

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;

in:

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, A method for preparing enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

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;

in:

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 , 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.

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 alkaline condition is preferably N,N-diisopropylethylamine;

The acidic condition is preferably hydrochloric acid;

in:

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 alkaline condition is preferably N,N-diisopropylethylamine;

The acidic condition is preferably hydrochloric acid;

in:

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 alkaline condition is preferably N,N-diisopropylethylamine;

The acidic condition is preferably hydrochloric acid;

in:

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 alkaline condition is preferably N,N-diisopropylethylamine;

The acidic condition is preferably hydrochloric acid;

in:

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 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 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.

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 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.

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.

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 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.

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.

Glossary

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

"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.

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.

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.

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.

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.

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:

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:

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:

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.

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.

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:

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:

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:

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:

wait.

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 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:

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.

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:

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 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.

The term "haloalkyl" refers to an alkyl group substituted with one or more halo, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.

The term "alkylthio" refers to -S-(alkyl), wherein alkyl is as defined above.

The term "alkylamino" refers to -NH-(alkyl), -N(alkyl) ₂ -, -NH-(cycloalkyl) or -N-(cycloalkyl) ₂ , wherein alkyl and cycloalkyl is defined as above.

The term "cycloalkyloxy" refers to -O-(cycloalkyl), wherein cycloalkyl is as defined above. Non-limiting examples of cycloalkyloxy include: cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.

The term "cycloalkylthio" refers to -S-(cycloalkyl), wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to -O-(heterocyclyl), wherein heterocyclyl is as defined above.

The term "heterocyclylthio" refers to -S-(heterocyclyl), wherein heterocyclyl is as defined above.

The term "hydroxyl" refers to a -OH group.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" refers to =O.

The term "carboxy" refers to -C(O)OH.

The term "mercapto" refers to -SH.

The term "ester" or "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

The term "acyl" refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

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.

"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.

"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.

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.

"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.

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).

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.

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).

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).

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.

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.

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. 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.

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.

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.

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.

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.

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 synthetic method of compound of the present invention

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.

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:

plan 1

The alkaline condition is preferably N,N-diisopropylethylamine;

The acidic condition is preferably hydrochloric acid.

Compounds of formula IIIDc can be prepared by the following Scheme 2:

Scenario 2

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;

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;

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;

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.

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:

Option 3

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.

in,

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 are as defined in the general formula (IIID).

Description of drawings

Figure 1 is the tumor growth curves in mice of each group in Test Example 4.

Detailed ways

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.

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.

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.

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.

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 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 10μm 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.

Column chromatography generally uses Qingdao Marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

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.

Unless otherwise specified in the examples, 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. Unless otherwise specified in the examples, 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.

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.

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.

Compounds of the invention are prepared according to the exemplary procedures provided herein and variations thereof known to those skilled in the art.

Example

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)

Step 1: Preparation of (R)-methyl 3-(4,6-dichloropyrimidin-5-yl)butanoate (1a)

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] ⁺ .

Step 2: (R)-tert-butyl 4-(6-chloro-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate Preparation of (1b)

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] ⁺ .

Step 3: Preparation of (R)-3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloropyrimidin-5-yl)butanoic acid (1c)

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] ⁺ .

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)

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] ⁺ .

Step 5: (R)-5-(4-(Benzyloxy)-4-oxobutan-2-yl)-6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine- Preparation of isopropyl 4-carboxylate (1e)

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] ⁺ .

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)

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] ⁺ .

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)

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] ⁺ .

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)

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] ⁺ .

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)

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] ⁺ .

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)

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] ⁺ .

Step 11: (5R,7R)-5-Methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride Preparation of (1k)

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] ⁺ .

Step 12: Preparation of methyl 2-cyclopentylene acetate (1l)

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] ⁺ .

Step 13: Preparation of methyl 2-(1-(nitromethyl)cyclopentyl)acetate (1m)

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] ⁺ .

Step 14: Preparation of 2-azaspiro[4.4]nonan-3-one (1n)

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] ⁺ .

Step 15: Preparation of tert-butyl 3-oxo-2-azaspiro[4.4]nonane-2-carboxylate (1o)

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] ⁺ .

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 ).

Step 16: Preparation of tert-butyl 3-hydroxy-2-azaspiro[4.4]nonane-2-carboxylate (1p)

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] ⁺ .

Step 17: Preparation of tert-butyl 3-methoxy-2-azaspiro[4.4]nonane-2-carboxylate (1q)

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] ⁺ .

Step 18: Preparation of (R)-4-benzyl-3-(2-(4-chlorophenyl)acetyl)oxazolidin-2-one (1r)

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] ⁺ .

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)

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] ⁺ .

Step 20: (S)-2-((S)-2-(tert-butoxycarbonyl)-2-azaspiro[4.4]non-3-yl)-2-(4-chlorophenyl)acetic acid (1t ) preparation

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] ⁺ .

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)

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] ⁺ .

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)

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] ⁺ .

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).

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

Step 1: Preparation of (E)-methyl 2-(dihydrofuran-3(2H)-ylidene)acetate (2a)

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%.

Step 2: Preparation of methyl 2-(3-(nitromethyl)tetrahydrofuran-3-yl)acetate (2b)

(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%.

Step 3: Preparation of 2-oxa-7-azaspiro[4.4]nonan-8-one (2c)

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%.

Step 4: Preparation of tert-butyl 8-oxo-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate (2d)

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] ⁺ .

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).

Step 5: Preparation of tert-butyl 8-hydroxy-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate (2e)

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] ⁺ .

Step 6: Preparation of tert-butyl 8-methoxy-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate (2f)

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] ⁺ .

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)

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] ⁺ .

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)

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] ⁺ .

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)

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] ⁺ .

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

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] ⁺ .

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).

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

Step 1: Preparation of tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (3a)

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] ⁺ .

Step 2: Preparation of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (3b)

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] ⁺ .

Step 3: Preparation of tert-butyl 2-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (3c)

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] ⁺ .

Step 4: Preparation of tert-butyl 2-methoxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (3d)

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] ⁺ .

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)

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] ⁺ .

Step 6: (2S)-2-((2S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-2-yl)-2-(4-chlorophenyl) Preparation of acetic acid (3f)

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] ⁺ .

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)

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] ⁺ .

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

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] ⁺ .

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).

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)

Step 1: Preparation of 4-azaspiro[2.4]heptan-5-one (4a)

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] ⁺ .

Step 2: Preparation of tert-butyl 5-oxo-4-azaspiro[2.4]heptane-4-carboxylate (4b)

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] ⁺ .

Step 3: Preparation of tert-butyl 5-hydroxy-4-azaspiro[2.4]heptane-4-carboxylate (4c)

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] ⁺ .

Step 4: Preparation of tert-butyl 5-methoxy-4-azaspiro[2.4]heptane-4-carboxylate (4d)

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] ⁺ .

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)

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] ⁺ .

Step 6: (S)-2-((S)-4-(tert-butoxycarbonyl)-4-azaspiro[2.4]heptan-5-yl)-2-(4-chlorophenyl)acetic acid ( 4f) Preparation

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] ⁺ .

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)

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] ⁺ .

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)

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] ⁺ .

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).

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)

Step 1: Preparation of tert-butyl 1-oxo-2-azaspiro[4.5]decane-2-carboxylate (5a)

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] ⁺ .

Step 2: Preparation of tert-butyl 1-hydroxy-2-azaspiro[4.5]decane-2-carboxylate (5b)

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] ⁺ .

Step 3: Preparation of tert-butyl 1-methoxy-2-azaspiro[4.5]decane-2-carboxylate (5c)

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] ⁺ .

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)

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] ⁺ .

Step 5: (S)-2-((R)-2-(tert-butoxycarbonyl)-2-azaspiro[4.5]dec-1-yl)-2-(4-chlorophenyl)acetic acid (5e ) preparation

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] ⁺ .

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)

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] ⁺ .

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)

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] ⁺ .

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).

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)

Step 1: Preparation of methyl 1-(cyanomethyl)cyclopentane-1-carboxylate (6a)

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] ⁺ .

Step 2: Preparation of 2-azaspiro[4,4]nonan-1-one (6b)

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] ⁺ .

Step 3: Preparation of tert-butyl 1-oxo-2-azaspiro[4.4]nonan-2-carboxylate (6c)

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] ⁺ .

Step 4: Preparation of tert-butyl 1-hydroxy-2-azaspiro[4.4]nonan-2-carboxylate (6d)

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] ⁺ .

Step 5: Preparation of tert-butyl 1-methoxy-2-azaspiro[4.4]nonan-2-carboxylate (6e)

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] ⁺ .

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)

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] ⁺ .

Step 7: (S)-2-((R)-2-(tert-butoxycarbonyl)-2-azaspiro[4.4]non-1-yl)-2-(4-chlorophenyl)acetic acid (6g ) preparation

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] ⁺ .

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)

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] ⁺ .

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)

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] ⁺ .

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).

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)

Step 1: Preparation of methyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (7a)

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] ⁺ .

Step 2: Preparation of methyl 1-((p-toluenesulfonyloxy)methyl)cyclopropane-1-carboxylate (7b)

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] ⁺ .

Step 3: Preparation of methyl 1-(cyanomethyl)cyclopropane-1-carboxylate (7c)

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] ⁺ .

Step 4: Preparation of 5-azaspiro[2.4]heptan-4-one (7d)

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] ⁺ .

Step 5: Preparation of tert-butyl 4-oxo-5-azaspiro[2.4]heptane-5-carboxylate (7e)

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] ⁺ .

Step 6: Preparation of tert-butyl 4-hydroxy-5-azaspiro[2.4]heptane-5-carboxylate (7f)

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] ⁺ .

Step 7: Preparation of tert-butyl 4-methoxy-5-azaspiro[2.4]heptane-5-carboxylate (7 g)

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] ⁺ .

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)

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] ⁺ .

Step 9: (S)-2-((R)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptan-4-yl)-2-(4-chlorophenyl)acetic acid ( 7i) Preparation

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] ⁺ .

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)

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] ⁺ .

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)

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] ⁺ .

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).

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)

Step 1: Preparation of dimethyl cyclobutane-1,1-dicarboxylate (8a)

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] ⁺ .

Step 2: Preparation of methyl 1-(hydroxymethyl)cyclobutane-1-carboxylate (8b)

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] ⁺ .

Step 3: Preparation of methyl 1-((p-toluenesulfonyloxy)methyl)cyclobutane-1-carboxylate (8c)

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] ⁺ .

Step 4: Preparation of methyl 1-(cyanomethyl)cyclobutane-1-carboxylate (8d)

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] ⁺ .

Step 5: Preparation of 6-azaspiro[3.4]octan-5-one (8e)

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] ⁺ .

Step 6: Preparation of tert-butyl 5-oxo-6-azaspiro[3.4]octane-6-carboxylate (8f)

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] ⁺ .

Step 7: Preparation of tert-butyl 5-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (8 g)

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] ⁺ .

Step 8: Preparation of tert-butyl 5-methoxy-6-azaspiro[3.4]octane-6-carboxylate (8h)

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] ⁺ .

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)

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] ⁺ .

Step 10: (S)-2-((R)-6-(tert-butoxycarbonyl)-6-azaspiro[3.4]octan-5-yl)-2-(4-chlorophenyl)acetic acid ( 8j) Preparation

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] ⁺ .

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)

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] ⁺ .

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)

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] ⁺ .

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).

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)

Step 1: Preparation of methyl 2-cyclopropylidene acetate (9a)

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] ⁺ .

Step 2: Preparation of methyl 2-(1-(nitromethyl)cyclopropyl)acetate (9b)

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] ⁺ .

Step 3: Preparation of 5-azaspiro[2.4]heptan-6-one (9c)

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] ⁺ .

Step 4: Preparation of tert-butyl 6-oxo-5-azaspiro[2.4]heptane-5-carboxylate (9d)

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] ⁺ .

Step 5: Preparation of tert-butyl 6-hydroxy-5-azaspiro[2.4]heptane-5-carboxylate (9e)

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] ⁺ .

Step 6: Preparation of tert-butyl 6-methoxy-5-azaspiro[2.4]heptane-5-carboxylate (9f)

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] ⁺ .

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)

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] ⁺ .

Step 8: (S)-2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptan-6-yl)-2-(4-chlorophenyl)acetic acid ( 9h) Preparation

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] ⁺ .

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)

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] ⁺ .

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)

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] ⁺ .

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).

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)

Step 1: Preparation of methyl 2-cyclobutylidene acetate (10a)

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] ⁺ .

Step 2: Preparation of methyl 2-(1-(nitromethyl)cyclobutyl)acetate (10b)

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] ⁺ .

Step 3: Preparation of 6-azaspiro[3.4]octan-7-one (10c)

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] ⁺ .

Step 4: Preparation of tert-butyl 7-oxo-6-azaspiro[3.4]octane-6-carboxylate (10d)

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] ⁺ .

Step 5: Preparation of tert-butyl 7-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (10e)

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] ⁺ .

Step 6: Preparation of tert-butyl 7-methoxy-6-azaspiro[3.4]octane-6-carboxylate (10f)

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] ⁺ .

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)

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] ⁺ .

Step 8: (S)-2-((S)-6-(tert-butoxycarbonyl)-6-azaspiro[3.4]octan-7-yl)-2-(4-chlorophenyl)acetic acid ( 10h) Preparation

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] ⁺ .

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)

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] ⁺ .

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)

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] ⁺ .

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).

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)

Step 1: Preparation of methyl 2-(4-chlorophenyl)-3-hydroxypropionate (11a)

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] ⁺ .

Step 2: Preparation of methyl 2-(4-chlorophenyl)acrylate (11b)

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] ⁺ .

Step 3: Preparation of methyl 2-(4-chlorophenyl)-3-(3-nitrooxetan-3-yl)propanoate (11c)

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] ⁺ .

Step 4: Preparation of 2-(4-chlorophenyl)-3-(3-nitrooxetan-3-yl)propanoic acid (11d)

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] ⁺ .

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).

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)

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] ⁺ .

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)

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] ⁺ .

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).

biological test

Test Example 1: Inhibitory activity of compounds of the present invention on AKT1/AKT2/AKT3 kinases

In the experiment, the HTRF method was used to detect the inhibition of the activity of the compound on AKT kinase.

experiment method

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).

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.

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.

Table 1 The compounds of the present invention inhibit the _IC50 values of AKT1, AKT2 and AKT3 kinases

Conclusion: It can be seen from Table 1 that the compound of the present invention has significant inhibitory effect on AKT1/2/3 kinase.

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 (PTEN loss) 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 ^™ 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.

The IC ₅₀ values of the compounds of the present invention for the inhibition of LNCaP cells are shown in Table 2 below.

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

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.

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.

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.

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 x dose _iv )/(AUC _iv x dose _po ) x 100%.

The pharmacokinetic parameters of the compounds of the present invention on mice are shown in Table 3 below.

The pharmacokinetic parameter of table 3 compound mice of the present invention

Conclusion: As can be seen from Table 3, the compounds of the present invention have good pharmacokinetic properties.

Test Example 4: Pharmacodynamic experiments of compounds of the present invention on mouse prostate cancer model

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%.

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.

Table 4 The tumor volume and tumor growth inhibition rate of animals after treatment for 21 days

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

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,

in:

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 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 , hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple groups substituted; or,

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;

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,

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;

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,

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;

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 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 is 0, 1, 2, 3 or 4;

p is 0, 1 or 2.
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 ;

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,

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.
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,

in:

m is 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 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,

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;

Ring B, L, G, R 2 , n are as defined in claim 1.
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.
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.
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,

in,

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;

Rings B, G, R2 and n are as defined in claim 1.
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,

in,

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;

Rings B, G, R2 and n are as defined in claim 1.
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:

Wherein 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 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;

Preferably R3 is hydrogen.
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,

in,

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 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 is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;

G, R2 and n are as defined in claim 1.
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,

in,

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 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 is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;

G, R2 and n are as defined in claim 1.
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 ;

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, 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.
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,

in,

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 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 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 ; Preferably 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 is 0, 1 or 2;

R 2 and n are as defined in claim 1.
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,

in,

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 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 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 ; Preferably 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 is 0, 1 or 2;

R 2 and n are as defined in claim 1.
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 is 0, 1, 2, preferably 1 or 2, more preferably 2.
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:
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:

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;

in:

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 claim 9 .
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:

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 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;

in:

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 claim 10 .
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.
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.
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.