WO2023078271A1

WO2023078271A1 - Aromatic compound, preparation method therefor, intermediate thereof, pharmaceutical composition thereof, and use thereof

Info

Publication number: WO2023078271A1
Application number: PCT/CN2022/129103
Authority: WO
Inventors: 杨康敏; 徐文方
Original assignee: 上海旭成医药科技有限公司
Priority date: 2021-11-02
Filing date: 2022-11-01
Publication date: 2023-05-11
Also published as: CN116063243A

Abstract

Disclosed are an aromatic compound, a preparation method therefor, an intermediate thereof, a pharmaceutical composition thereof, and a use thereof, specifically relating to an aromatic compound shown in formula I, a tautomer, stereoisomer, isotope derivative, or pharmaceutically acceptable salt thereof. Also provided are a preparation method therefor, an intermediate thereof, a pharmaceutical composition thereof, and a use thereof. The compound of the present invention has excellent Rad51 inhibitory activity, can effectively inhibit the proliferation of tumor cells, reduce the repair of DNA double-strand breaks in tumor cells, and has good pharmacokinetic characteristics.

Description

Aromatic compound, its preparation method, intermediate, pharmaceutical composition and application

This application claims the priority of Chinese patent application 2021112892194 with a filing date of November 2, 2021. This application cites the full text of the above-mentioned Chinese patent application. This application claims the priority of Chinese patent application 2022103027710 with a filing date of March 24, 2022. This application cites the full text of the above-mentioned Chinese patent application.

technical field

The present invention relates to an aromatic compound and its preparation method, intermediate, pharmaceutical composition and application.

Background technique

Exogenous stimuli such as ultraviolet rays, ionizing radiation, DNA cross-linking agents, hypoxia and other factors can cause cellular DNA damage, of which DNA double-strand breaks (DNA double-strand breaks, DSBs) are the most serious. DNA damage repair methods include non-homologous end joining (NHEJ) and homologous recombination (homologous repair, HR). Among them, homologous recombination uses homologous sequences in sister chromatids as templates to guide repair synthesis and restore chromosome integrity. It is an error-free DNA double-strand break repair mechanism. The repair process of homologous recombination includes single-strand invasion, homologous pairing and strand exchange stages.

Studies have shown that a key step in homologous recombination in eukaryotes lies in a recombinase called Rad51. The Rad51 protein family is encoded by the eukaryotic gene Rad51. The human Rad51 protein is a protein composed of 339 amino acids, with a dense region structure composed of 5 short helices. This dense region is thought to be regulated by amino-terminal phosphorylation and binds to DNA (Cellular and Molecular Life Sciences, 2020, 77, 3–18). In the process of DNA repair, Rad51 protein exerts strand transfer or strand exchange activity, initiates DNA homologous pairing, that is, assembles on single-stranded DNA (ssDNA), and generates helical fibers to search for homologous double-stranded DNA (dsDNA), thereby initially New paired bases are formed between the single-stranded DNA and the complementary strand (Nature Structural & Molecular Biology, 2017, 24, 40–46).

Studies have shown that in breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer and other tumor cells, the expression level of Rad51 protein is increased. The high expression of Rad51 leads to the enhancement of the tumor's ability to repair DNA damage, the enhancement of tumor invasion and metastasis, and the tumor's resistance to radiotherapy and chemotherapy. Rad51 inhibitors alone or in combination with PRAP inhibitors have good clinical therapeutic potential for some tumors. Therefore, the development of new Rad51 inhibitors has gradually become one of the research hotspots of anti-tumor drugs (Pharmacology & Therapeutics, 2020, 208, 107492).

Chinese patent application CN201880072664.5 (WO2019051465) discloses a compound such as the following structure (compound 67A), which is a small molecule inhibitor of Rad51.

Contents of the invention

The object of the present invention is to provide an aromatic compound, its preparation method, intermediate, pharmaceutical composition and application. The aromatic compound of the invention can inhibit Rad51 activity and tumor cell proliferation, and has good pharmacokinetic characteristics.

The present invention provides a compound represented by formula I, its tautomers, stereoisomers, isotopic derivatives or pharmaceutically acceptable salts:

in,

Ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^a is unsubstituted or substituted C _1-6 alkyl, or unsubstituted or substituted C _3-6 monocyclic cycloalkyl; the substituted C _1-6 alkyl and substituted C _3-6 Monocyclic cycloalkyl is substituted by 1, 2, 3 or 4 R ^aa ;

R ^b and R ^c are independently hydrogen, unsubstituted or substituted C _1-6 alkyl, or unsubstituted or substituted C _3-6 monocyclic cycloalkyl; the substituted C _1-6 alkyl and substituted C _3-6 monocyclic cycloalkyl is substituted by 1, 2, 3 or 4 R ^aa ;

R ^aa is independently deuterium or halogen;

Ring Cy ² is unsubstituted or substituted C _3-12 cycloalkyl, or unsubstituted or substituted 3-12 membered heterocycloalkyl; the substituted C _3- ₁₂ cycloalkyl and substituted 3- 12-membered heterocycloalkyl is substituted by 1, 2, 3 or 4 ^R ;

R ^is independently halogen, OH, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy;

X ¹ is -NR ^x1 -, -NR ^x1 C(O)O-, -NR ^x1 C(O)NR ^x1 -, or

^X2 is

When X ³ is connected to the nitrogen atom of ring Cy ² , then X ³ is a single bond; when X ³ is connected to the carbon atom of ring Cy ² , then X ³ is -NR ^x3 -or -O-;

X ⁴ is -NR ^x4 -or -O-;

R ^x1 , R ^x2 , R ^x3 and R ^x4 are independently H or C _1-6 alkyl;

R ¹ is unsubstituted or substituted benzyl, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted C _2-6 alkenyl, unsubstituted or substituted C _3-12 cycloalkane Base, unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted 3-12 membered heterocycloalkyl, or unsubstituted or substituted 5-12 membered heteroaryl; the substituted benzyl group, substituted C _1-6 alkyl, substituted C _2-6 alkenyl, substituted C _3-12 cycloalkyl, substituted C _6-10 aryl, substituted 3-12 membered heterocycloalkyl and Substituted 5-12 membered heteroaryl is substituted by 1, 2, 3 or 4 R ^1a ;

R ^1a is halogen, OH, CN, C _3-6 cycloalkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -NR ^{1a -1} R ^1a-2 , or C _1-6 alkyl substituted by 1, 2, 3 or 4 R ^1a-3 (for example, R ^1a is independently halogen, OH, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy or -NR ^1a-1 R ^1a-2 );

R ^1a-1 and R ^1a-2 are independently H or C _1-6 alkyl;

R ^1a-3 are independently

R ^1a-3-1 is independently C _1-6 alkyl;

R ² is H, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted C _3-12 cycloalkyl, unsubstituted or substituted 5-12 membered heteroaryl or -NR ^{2- 1} R ^2-2 ; the substituted C _1-6 alkyl, substituted C _3-12 cycloalkyl and substituted 5-12 membered heteroaryl are substituted by 1, 2, 3 or 4 R ^2a ;

R ^2-1 and R ^2-2 are independently H, unsubstituted or substituted C _1-6 alkyl; said substituted C _1-6 alkyl is substituted by 1, 2, 3 or 4 R ^2a ;

Or R ^2-1 and R ^2-2 together with the nitrogen atom they are connected to form a 3-7 membered heterocycloalkyl group;

R ^2a is independently OH, C _1-6 alkoxy or C _6-10 aryloxy;

^R3 is H;

R ⁴ is H, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted C _3-6 monocyclic cycloalkyl, or unsubstituted or substituted 3-7 membered heterocycloalkyl; The substituted C _1-6 alkyl, substituted C _3-6 monocyclic cycloalkyl and substituted 3-7 membered heterocycloalkyl are substituted by 1, 2, 3 or 4 R ^4a ;

R ^4a is independently halogen, OH, CN, unsubstituted or substituted C _3-12 cycloalkyl, unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted 3-12 membered heterocycle Alkyl, or unsubstituted or substituted 5-12 membered heteroaryl; said substituted C _3-12 cycloalkyl, substituted C _6-10 aryl, substituted 3-12 membered heterocycloalkyl and Substituted 5-12 membered heteroaryl is substituted by 1, 2, 3 or 4 R ^4a-1 ;

R ^4a-1 is independently halogen, OH, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy;

The heteroatoms or heteroatom groups of the above-mentioned 3-7 membered heterocycloalkyl, 3-12 membered heterocycloalkyl and 5-12 membered heteroaryl are independently N, O, S or C (=O), hetero The number of atoms or heteroatom groups is independently 1, 2, 3 or 4.

In some embodiments, in the definition of R ^a , R ^b and R ^c , the C _1-6 alkyl in the unsubstituted or substituted C _1-6 alkyl can be independently C _1-4 alkyl , such as methyl or ethyl.

In some embodiments, in the definition of R ^a , R ^b and R ^c , the C _3-6 monocyclic cycloalkyl in the unsubstituted or substituted C _3-6 monocyclic cycloalkyl can be independently Cyclopropyl.

In some embodiments, in the definition of R ^a , R ^b and R ^c , the substituted C _1-6 alkyl group can be independently substituted by 1, 2 or 3 R ^aa , for example, 3 R ^aa .

In some embodiments, in the definition of R ^aa , the halogen may independently be F.

In some embodiments, in the definition of ring Cy ² , the unsubstituted or substituted C _3-12 cycloalkyl can be in a cis configuration or a trans configuration.

In some embodiments, in the definition of ring Cy ² , the C _3-12 cycloalkyl in the unsubstituted or substituted C _3-12 cycloalkyl can be a C _3-6 monocyclic cycloalkyl or C _6-12 bridged cycloalkyl, for example

another example

or, where

Can be in cis configuration

or trans configuration

In some embodiments, in the definition of X ¹ , the O atom in -NR ^x1 C(O)O- is attached to R ¹ .

In some embodiments, R ^x1 , R ^x2 , R ^x3 , and R ^x4 can independently be H.

In some embodiments, in the definition of R ¹ , the C _1-6 alkyl group in the unsubstituted or substituted C _1-6 alkyl group may be a C _1-4 alkyl group, such as isopropyl.

In some embodiments, in the definition of R ¹ , the C _6-10 aryl in the unsubstituted or substituted C _6-10 aryl may be phenyl.

In some embodiments, in the definition of ^R , the 3-12 membered heterocycloalkyl in the unsubstituted or substituted 3-12 membered heterocycloalkyl can be a monocyclic 3-7 membered heterocycloalkyl . The heteroatom can be O. The number of heteroatoms may be one.

In some embodiments, in the definition of ^R , the 3-12 membered heterocycloalkyl group in the unsubstituted or substituted 3-12 membered heterocycloalkyl group can be oxetanyl, for example

In some embodiments, in the definition of R ¹ , the 5-12-membered heteroaryl in the unsubstituted or substituted 5-12-membered heteroaryl is a 5-6-membered heteroaryl. Heteroatoms independently can be N or O. The number of heteroatoms may be 1 or 2.

In some embodiments, in the definition of ^R , the 5-12-membered heteroaryl in the unsubstituted or substituted 5-12-membered heteroaryl can be pyrazolyl, imidazolyl, oxazolyl, pyrimidine or pyridazinyl, such as

(also for example

).

In some embodiments, in the definition of R ¹ , the substituted 5-12 membered heteroaryl can be substituted by 1 or 2 R ^1a , for example by 1 or 2 R ^1a substituted, and for example by 1 R ^1a replaced.

In some embodiments, in the definition of ^R , the substituted 5-12 membered heteroaryl can be pyrazolyl or pyridazinyl substituted by 1 or 2 R ^1a , for example

(also for example

another example

).

In some embodiments, in the definition of R ^1a , the C _1-6 alkyl is a C _1-4 alkyl, such as methyl or ethyl.

In some embodiments, in the definition of R ^1a , the C _1-6 haloalkyl is C _1-4 haloalkyl, for example

Or -CF ₃ , and for example -CF ₃ ;

In some embodiments, in the definition of R ^1a , halo is fluoro, chloro, bromo or iodo, eg fluoro.

In some embodiments, in the definition of R ^1a , the C _3-6 cycloalkyl is C _3-4 cycloalkyl, for example

In some embodiments, in the definition of R ^1a-1 and R ^1a-2 , the C _1-6 alkyl is C _1-4 alkyl, such as methyl or ethyl.

In some embodiments, in the definition of R ^1a-3-1 , the C _1-6 alkyl is a C _1-4 alkyl, such as methyl or ethyl.

In some embodiments, in the definition of R ² , the C _1-6 alkyl in the unsubstituted or substituted C _1-6 alkyl can be a C _1-4 alkyl, such as methyl, ethyl or tert-butyl.

In some embodiments, in the _definition of R ² , the C _{3-12 cycloalkyl group in the unsubstituted or substituted C 3-12} _cycloalkyl group can be a C _3-6 monocyclic cycloalkyl group, such as ring Propyl.

In some embodiments, in the definition of R ² , the 5-12-membered heteroaryl in the unsubstituted or substituted 5-12-membered heteroaryl may be a 5-6-membered heteroaryl. The heteroatom can be N. The number of heteroatoms may be four.

In some embodiments, in the definition of ^R , the 5-12 membered heteroaryl in the unsubstituted or substituted 5-12 membered heteroaryl can be tetrazolyl, for example

In some embodiments, in the definition of R ⁴ , the C _1-6 alkyl in the unsubstituted or substituted C _1-6 alkyl may be C _1-4 alkyl, such as isopropyl.

In some embodiments, in the definition of R ⁴ , the 3-7 membered heterocycloalkyl heteroatom in the unsubstituted or substituted 3-7 membered heterocycloalkyl group may be O. The number of heteroatoms may be one.

In some embodiments, in the definition of R ⁴ , the 3-7 membered heterocycloalkyl group in the unsubstituted or substituted 3-7 membered heterocycloalkyl group can be oxetanyl, another example

In one embodiment, in the definition of X ² ,

The N atom in is connected to ^R2 .

In some embodiments, in the definition of X ² ,

The S atom in is connected to ^R2 .

In some embodiments, in the definition of ring Cy ¹ ,

In, R ^a is an unsubstituted or substituted C _1-6 alkyl group, or an unsubstituted C _3-6 monocyclic cycloalkyl group; the substituted C _1-6 alkyl group is replaced by 1, 2, 3 or 4 R ^aa substitution; for example,

for

In some embodiments, in the definition of ring Cy ¹ ,

In, R ^b is C _1-6 alkyl substituted by 1, 2, 3 or 4 halogens; for example,

for

In some embodiments, in the definition of ring Cy ¹ ,

In, R ^c is C _1-6 alkyl substituted by 1, 2, 3 or 4 halogens; for example,

for

In some embodiments, R ^is unsubstituted or substituted C _1-6 alkyl, or unsubstituted C _3-6 monocyclic cycloalkyl; the substituted C _1-6 alkyl is replaced by 1, 2 , 3 or 4 R ^aa substitutions.

In some embodiments, Ra ^is C _1-6 alkyl, C _3-6 monocyclic cycloalkyl, C _1-6 alkyl substituted with 1, 2 or 3 fluoro, or substituted with 1, 2 or 3 deuterium C _1-6 alkyl, such as methyl, ethyl, trifluoromethyl or

In some embodiments, R ^b and R ^c are independently C _1-6 alkyl substituted with 1, 2, 3, or 4 halo.

In some embodiments, Ring ^Cy is unsubstituted C _3-12 cycloalkyl, or unsubstituted 3-12 membered heterocycloalkyl.

In some embodiments, Ring Cy ² is unsubstituted C _3-12 cycloalkyl.

In some embodiments, Ring Cy ² is C _3-8 cycloalkyl.

In some embodiments, Ring ^Cy2 is cyclohexyl or bicyclooctyl.

In some embodiments, X ¹ is -NR ^x1 - or -NR ^x1 C(O)O-.

In some embodiments, R ^x1 , R ^x2 , and R ^x3 are independently H.

In some embodiments, ^X4 is -O-.

In some embodiments, R ^is unsubstituted benzyl, unsubstituted C _1-6 alkyl, unsubstituted C _6-10 aryl, unsubstituted 3-12 membered heterocycloalkyl, or unsubstituted or substituted 5-12 membered heteroaryl; said substituted 5-12 membered heteroaryl is substituted by 1, 2, 3 or 4 R ^1a .

In some embodiments, R ^is unsubstituted C _1-6 alkyl, unsubstituted benzyl, unsubstituted phenyl, unsubstituted 3-6 membered heterocycloalkyl, or unsubstituted or substituted 5- 6-membered heteroaryl (such as pyrazolyl, imidazolyl, pyrimidinyl or pyridazinyl), the substituted 5-6 membered heteroaryl is substituted by 1 or 2 R ^1a .

In some embodiments, R ^1a is halogen, C _3-6 cycloalkyl, C _1-6 alkyl, C _1-6 haloalkyl, or, C _1-6 alkane substituted with 1 or 2 R ^1a-3 base.

In some embodiments, R ^1a is C _1-6 alkyl, C _1-6 alkyl substituted by 1 R ^1a-3 , C _3-6 cycloalkyl or C _1-6 haloalkyl, such as C _{1 -4} alkyl, C _3-4 cycloalkyl, C _1-4 alkyl substituted by 1 R ^1a-3 , or C _1-4 haloalkyl, such as methyl, ethyl,

or -CF ₃ .

In some embodiments, R ^aa is independently deuterium or fluoro.

In some embodiments, R ^1a-3 are independently

In some embodiments, R ² is H, unsubstituted C _1-6 alkyl, unsubstituted C _3-12 cycloalkyl, unsubstituted 5-12 membered heteroaryl, or -NR ^2-1 R ^{2 -2} .

In some embodiments, R ² is preferably H, unsubstituted C _1-6 alkyl, unsubstituted C _3-12 cycloalkyl, or -NR ^2-1 R ^2-2 .

In some embodiments, R ⁴ is unsubstituted C _1-6 alkyl or unsubstituted 3-7 membered heterocycloalkyl.

In some embodiments, R ⁴ is unsubstituted C _1-6 alkyl.

In some embodiments, ring Cy ² is

For example

in

Can be in cis or trans configuration.

In some embodiments, X ^is -NH-, -NHC(O)O-, -NHC(O)NH-, or

In some embodiments, ^X2 is

In some embodiments, ^X3 is -NH-.

In some embodiments, ^R is isopropyl, phenyl, benzyl,

(e.g. isopropyl, phenyl, benzyl,

Another example is isopropyl, phenyl, benzyl,

).

In some embodiments, R ¹ is isopropyl,

In some embodiments, R ² is H, —NH ₂ , —N(CH ₃ ) ₂ , methyl, ethyl, tert-butyl, cyclopropyl, or

For example H, -NH ₂ , -N(CH ₃ ) ₂ , methyl, ethyl, tert-butyl, cyclopropyl or

In some embodiments, R ² is H, —NH ₂ , methyl, ethyl, tert-butyl, cyclopropyl, or

In some embodiments, R ² is -NH ₂ or cyclopropyl.

In some embodiments, R ⁴ is isopropyl or

In some preferred embodiments, -X ² -R ² is

In some embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^a is an unsubstituted or substituted C _1-6 alkyl group, or an unsubstituted C _3-6 monocyclic cycloalkyl group; the substituted C _1-6 alkyl group is replaced by 1, 2, 3 or 4 R ^aa replaced;

R ^b and R ^c are independently C _1-6 alkyl substituted by 1, 2, 3 or 4 halogens;

R ^aa is independently deuterium or halogen;

Ring Cy ² is unsubstituted C _3-12 cycloalkyl;

X ¹ is -NR ^x1 -, -NR ^x1 C(O)O-, -NR ^x1 C(O)NR ^x1 -, or

^X2 is

^X3 is -NR ^x3- ;

^X4 is -O-;

R ^x1 , R ^x2 and R ^x3 are independently H;

R ¹ is unsubstituted benzyl, unsubstituted C _1-6 alkyl, unsubstituted C _6-10 aryl, unsubstituted 3-12 membered heterocycloalkyl, or unsubstituted or substituted 5- 12-membered heteroaryl; the substituted 5-12-membered heteroaryl is substituted by 1, 2, 3 or 4 R ^1a ;

R ^1a is independently C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkyl or C _1-6 haloalkyl substituted by ₁ or 2 R ^1a-3 , such as C _1-6 Alkyl or C _1-6 haloalkyl, also such as C _1-6 alkyl;

R ^1a-3 are independently

R ^1a-3-1 is independently C _1-6 alkyl;

R ² is H, unsubstituted C _1-6 alkyl, unsubstituted C _3-12 cycloalkyl, unsubstituted 5-12 membered heteroaryl or -NR ^2-1 R ^2-2 ;

R ^2-1 and R ^2-2 are independently H or unsubstituted C _1-6 alkyl;

^R3 is H;

R ⁴ is unsubstituted C _1-6 alkyl or unsubstituted 3-7 membered heterocycloalkyl;

The heteroatoms of the above-mentioned 3-7 membered heterocycloalkyl, 3-12 membered heterocycloalkyl and 5-12 membered heteroaryl are independently N, O or S, and the number of heteroatoms is independently 1, 2, 3 or 4.

In some embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^aa is independently deuterium or halogen;

Ring Cy ² is unsubstituted C _3-12 cycloalkyl;

X ¹ is -NR ^x1 -, -NR ^x1 C(O)O-, -NR ^x1 C(O)NR ^x1 -, or

^X2 is

^X3 is -NR ^x3- ;

^X4 is -O-;

R ^x1 , R ^x2 and R ^x3 are independently H;

R ^1a-3 are independently

R ^1a-3-1 is independently C _1-6 alkyl;

R ² is H, unsubstituted C _1-6 alkyl, unsubstituted C _3-12 cycloalkyl or -NR ^2-1 R ^2-2 ;

R ^2-1 and R ^2-2 are independently H or unsubstituted C _1-6 alkyl;

^R3 is H;

In some embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^aa is independently deuterium or halogen;

Ring Cy ² is unsubstituted C _3-12 cycloalkyl;

X ¹ is -NR ^x1 -, -NR ^x1 C(O)O-, -NR ^x1 C(O)NR ^x1 -, or

^X2 is

^X3 is -NR ^x3- ;

^X4 is -O-;

R ^x1 , R ^x2 and R ^x3 are independently H;

R ^1a is independently C _1-6 alkyl or C _1-6 haloalkyl;

R ^2-1 and R ^2-2 are independently H;

^R3 is H;

In some embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^aa is independently deuterium or halogen;

Ring Cy ² is unsubstituted C _3-12 cycloalkyl;

X ¹ is -NR ^x1 -, -NR ^x1 C(O)O-, -NR ^x1 C(O)NR ^x1 -, or

^X2 is

^X3 is -NR ^x3- ;

^X4 is -O-;

R ^x1 , R ^x2 and R ^x3 are independently H;

R ^1a is independently C _1-6 alkyl;

R ^2-1 and R ^2-2 are independently H;

^R3 is H;

The heteroatoms of the above-mentioned 3-7 membered heterocycloalkyl, 3-12 membered heterocycloalkyl and 5-12 membered heteroaryl are independently N, O or S, and the number of heteroatoms is independently 1, 2, 3 or 4;

In some embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^aa is independently deuterium or halogen;

Ring Cy ² is unsubstituted C _3-12 cycloalkyl;

X ¹ is -NR ^x1 -, -NR ^x1 C(O)O- or -NR ^x1 C(O)NR ^x1 -;

^X2 is

^X3 is -NR ^x3- ;

^X4 is -O-;

R ^x1 , R ^x2 and R ^x3 are independently H;

R ¹ is an unsubstituted benzyl group, an unsubstituted C _1-6 alkyl group, an unsubstituted 3-12 membered heterocycloalkyl group, or an unsubstituted or substituted 5-12 membered heteroaryl group; the substituted 5-12 membered heteroaryl is substituted by 1, 2, 3 or 4 R ^1a ;

R ^1a-3 are independently

R ^1a-3-1 is independently C _1-6 alkyl;

R ² is H, unsubstituted C _1-6 alkyl or -NR ^2-1 R ^2-2 ;

R ^2-1 and R ^2-2 are independently H or unsubstituted C _1-6 alkyl;

^R3 is H;

In some preferred embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

^R is C _1-6 alkyl (such as methyl);

^X2 is

R ² is -NR ^2-1 R ^2-2 .

In some preferred embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^a is C _1-6 alkyl;

^X1 is -NH-;

R ¹ is a substituted 5-12 membered heteroaryl group (such as pyrazolyl), and the substituted 5-12 membered heteroaryl group is substituted by 1, 2, 3 or 4 R ^1a ;

R ^1a is independently C _1-6 alkyl (such as methyl) substituted by 1 or 2 R ^1a-3 ;

R ^1a-3 are independently

R ^1a-3-1 is independently C _1-6 alkyl (such as methyl);

^X2 is

R ² is -NR ^2-1 R ^2-2 (eg -NH ₂ ); R ^2-1 and R ^2-2 are independently H, unsubstituted or substituted C _1-6 alkyl.

In some embodiments:

in,

Ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^aa is independently deuterium or halogen;

X ¹ is -NR ^x1 -, -NR ^x1 C(O)O-, -NR ^x1 C(O)NR ^x1 -, or

^X2 is

X ⁴ is -NR ^x4 -or -O-;

R ^x1 , R ^x2 , R ^x3 and R ^x4 are independently H or C _1-6 alkyl;

R ^1a is independently halogen, OH, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy or -NR ^1a-1 R ^1a- ² ;

R ^1a-1 and R ^1a-2 are independently H or C _1-6 alkyl;

R ^2a is independently OH, C _1-6 alkoxy or C _6-10 aryloxy;

^R3 is H;

R ⁴ is H, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted C _3-6 monocyclic cycloalkyl, or unsubstituted or substituted 3-7 membered heterocycloalkyl; The substituted C _1-6 alkyl, substituted C _3-6 monocyclic cycloalkyl or substituted 3-6 membered heterocycloalkyl is substituted by 1, 2, 3 or 4 R ^4a ;

The heteroatoms or heteroatom groups of the above-mentioned 3-7 membered heterocycloalkyl, 3-12 membered heterocycloalkyl and 5-12 membered heteroaryl are independently N, O, S or C (=O), the heteroatom or The number of heteroatom groups is 1, 2, 3 or 4 independently.

In some embodiments, in the definition of R ^a , R ^b and R ^c , the substituted C _1-6 alkyl group can be independently substituted by 3 R ^aa .

In some embodiments, in the definition of R ^a , R ^b and R ^c , the substituted C _1-6 alkyl can be independently -CF ₃ or -CD ₃ .

In some embodiments, in the definitions of R ^a , R ^b and R ^c , the substituted C _3-6 monocyclic cycloalkyl group may be substituted by 3 R ^aa .

another example

or, where

Can be in cis configuration

or trans configuration

In some embodiments, in the definition of X ² ,

The N atom in is connected to ^R2 .

In some embodiments, in the definition of X ² ,

The S atom in is connected to ^R2 .

In some embodiments, R ^x1 , R ^x2 , R ^x3 , and R ^x4 can independently be H.

In some embodiments, in the definition of R ¹ , the substituted 5-12 membered heteroaryl may be substituted by 1 R ^1a .

In some embodiments, in the definition of R ¹ , the substituted 5-12 membered heteroaryl may be substituted by 1 or 2 R ^1a .

In some embodiments, in the definition of R ¹ , the substituted 5-12 membered heteroaryl can be pyrazolyl or pyridazinyl substituted by 1 R ^1a , for example

In some embodiments, R ^1a is C _1-6 alkyl or C _1-6 haloalkyl, such as C _1-4 alkyl or C _1-4 haloalkyl, such as methyl, ethyl or -CF ₃ .

In some embodiments, R ^1a is C _1-6 haloalkyl, such as C _1-4 haloalkyl, and for example -CF ₃ .

In some embodiments, R ^1a is C _1-6 alkyl, such as C _1-4 alkyl, and such as methyl or ethyl.

In some embodiments, in the definition of R ² , -NR ^2-1 R ^2-2 may be -NH ₂ or -N(CH ₃ ) ₂ .

In some embodiments, in the definition of R ² , -NR ^2-1 R ^2-2 may be -N(CH ₃ ) ₂ .

In some embodiments, in the definition of R ² , -NR ^2-1 R ^2-2 may be -NH ₂ .

In some embodiments, in the definition of ring Cy ¹ ,

for

In some embodiments, in the definition of ring Cy ¹ ,

In, R ^b is C _1-6 alkyl substituted by 1, 2, 3 or 4 halogens; for example,

for

In some embodiments, in the definition of ring Cy ¹ ,

In, R ^c is C _1-6 alkyl substituted by 1, 2, 3 or 4 halogens; for example,

for

In some embodiments, ring Cy ¹ is

For example

In some embodiments, ring Cy ¹ is

For example

In some embodiments, ring Cy ¹ is

For example

In some embodiments, ring Cy ² is

For example

in

Can be in cis configuration

or trans configuration

In some embodiments, X ^is -NH-, -NHC(O)O-, -NHC(O)NH-, or

In some embodiments, ^X2 is

In some embodiments, ^X3 is ^-NRx3- , eg -NH-.

In some embodiments, ^X4 is -O-.

In some embodiments, ^R is isopropyl, phenyl, benzyl,

In some embodiments, R ² is H, unsubstituted C _1-6 alkyl, unsubstituted C _3-12 cycloalkyl, unsubstituted 5-12 membered heteroaryl, or -NR ^2-1 R ^{2 -2} , such as H, unsubstituted C _1-6 alkyl, unsubstituted C _3-12 cycloalkyl or -NR ^2-1 R ^2-2 .

For example H, _-NH2 , ethyl, tert-butyl or cyclopropyl.

For example H, _-NH2 , -N( _CH3 ) ₂ , ethyl, tert-butyl or cyclopropyl.

In some embodiments, R ² is -N(CH ₃ ) ₂ .

In some embodiments, R ⁴ is unsubstituted C _1-6 alkyl or unsubstituted C _3-6 monocyclic cycloalkyl.

In some embodiments, R ⁴ is isopropyl or

In some embodiments, R ⁴ is isopropyl.

In some embodiments, R ⁴ is

In some embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^aa is independently deuterium or halogen;

Ring Cy ² is unsubstituted C _3-12 cycloalkyl;

X ¹ is -NR ^x1 -, -NR ^x1 C(O)O-, -NR ^x1 C(O)NR ^x1 -, or

^X2 is

^X3 is -NR ^x3- ;

^X4 is -O-;

R ^x1 , R ^x2 and R ^x3 are independently H;

R ^1a is independently C _1-6 alkyl or C _1-6 haloalkyl, such as C _1-6 alkyl; R ² is H, unsubstituted C _1-6 alkyl, unsubstituted C _3-12 ring Alkyl, unsubstituted 5-12 membered heteroaryl or -NR ^2-1 R ^2-2 ;

R ^2-1 and R ^2-2 are independently H;

^R3 is H;

The heteroatoms of the above-mentioned 3-7 membered heterocycloalkyl, 3-12 membered heterocycloalkyl and 5-12 membered heteroaryl are independently N, O or S, and the number of heteroatoms is independently 1, 2, 3 or 4. In some embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^aa is independently deuterium or halogen;

Ring Cy ² is unsubstituted C _3-12 cycloalkyl;

X ¹ is -NR ^x1 -, -NR ^x1 C(O)O-, -NR ^x1 C(O)NR ^x1 -, or

^X2 is

^X3 is -NR ^x3- ;

^X4 is -O-;

R ^x1 , R ^x2 and R ^x3 are independently H;

R ^1a is independently C _1-6 alkyl or C _1-6 haloalkyl, such as C _1-6 alkyl;

R ^2-1 and R ^2-2 are independently H;

^R3 is H;

In some embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^aa is independently deuterium or halogen;

Ring Cy ² is unsubstituted C _3-12 cycloalkyl;

X ¹ is -NR ^x1 -, -NR ^x1 C(O)O- or -NR ^x1 C(O)NR ^x1 -;

^X2 is

^X3 is -NR ^x3- ;

^X4 is -O-;

R ^x1 , R ^x2 and R ^x3 are independently H;

R ^1a is independently C _1-6 alkyl or C _1-6 haloalkyl, such as C _1-6 alkyl;

R ² is H, unsubstituted C _1-6 alkyl or -NR ^2-1 R ^2-2 ;

R ^2-1 and R ^2-2 are independently H;

^R3 is H;

In some preferred embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

^R is C _1-6 alkyl (such as methyl);

^X2 is

R ² is -NR ^2-1 R ^2-2 .

In some preferred embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^a is a substituted C _1-6 alkyl (such as methyl); the substituted C _1-6 alkyl is substituted by 1, 2, 3 or 4 R ^aa ;

R ^aa is independently halogen.

In some preferred embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^a is a substituted C _1-6 alkyl; the substituted C _1-6 alkyl is substituted by 1, 2, 3 or 4 R ^aa ;

R ^aa is independently halogen;

^X2 is

R ² is -NR ^2-1 R ^2-2 .

In some preferred embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^aa is independently halogen;

^X2 is

R ² is C _1-6 alkyl (eg ethyl or tert-butyl).

In some preferred embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^aa is independently halogen;

^X1 is -NR ^x1- ;

R ¹ is an unsubstituted 5-12 membered heteroaryl (such as pyrazolyl);

^X2 is

R ² is C _1-6 alkyl (eg ethyl).

In some preferred embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^aa is independently deuterium or halogen;

^X2 is

R ² is -NR ^2-1 R ^2-2 (eg -NH ₂ ).

In some preferred embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^a is unsubstituted or substituted C _1-6 alkyl; said substituted C _1-6 alkyl is substituted by 1, 2, 3 or 4 R ^aa ;

R ^aa is deuterium;

^X1 is -NR ^x1- ;

R ^1a is independently C _1-6 alkyl;

^X2 is

R ² is C _1-6 alkyl (such as ethyl or tert-butyl); or X ² is

R ² is -NR ^2-1 R ^2-2 (eg -NH ₂ ).

In some preferred embodiments, ring Cy ¹ is

Among them, 1 bit is connected with ring Cy ² ;

R ^a is unsubstituted or substituted C _1-6 alkyl (such as methyl); said substituted C _1-6 alkyl is substituted by 1, 2, 3 or 4 R ^aa ;

R ^aa is independently deuterium or halogen;

X ¹ is -NR ^x1 - or -NR ^x1 C(O)O-;

R ¹ is an unsubstituted C _1-6 alkyl group (such as isopropyl), or an unsubstituted or substituted 5-12 membered heteroaryl group (such as pyrazolyl), and the substituted 5-12 membered heteroaryl group The group is substituted by 1, 2, 3 or 4 R ^1a ;

R ^1a is independently C _1-6 alkyl;

^X2 is

R ² is C _1-6 alkyl (such as ethyl or tert-butyl); or X ² is

R ² is -NR ^2-1 R ^2-2 (eg -NH ₂ ).

In some preferred embodiments, ring Cy ¹ is

-X ² -R ² for

In some preferred embodiments, ring Cy ¹ is

-X ² -R ² for

X ¹ is -NR ^x1 C(O)NR ^x1 -.

In some preferred embodiments, ring Cy ¹ is

-X ² -R ² for

^X1 is -NR ^x1- .

In some preferred embodiments, ring Cy ¹ is

-X ² -R ² for

X ¹ is -NR ^x1 C(O)NR ^x1 -;

R ¹ is benzyl.

In some preferred embodiments, ring Cy ¹ is

-X ² -R ² for

^X1 is -NR ^x1- ;

R ¹ is a 5-12 membered heteroaryl group.

In some embodiments, the compound shown in formula I may have a structure shown in formula A or formula B:

Wherein, the definition of each group is as described in any scheme of the present invention.

In some embodiments, the compound represented by the formula I may have formula A-1, formula A-2, formula A-3, formula A-4, formula A-5, formula A-6, formula A-7 , the structure shown in formula A-8, formula A-9 or formula B-1:

In some embodiments, the compound represented by formula I may have formula A-10, formula A-11, formula A-12, formula A-13, formula A-14, formula A-15, formula A-16 , the structure shown in formula A-17 or formula B-2:

In some embodiments, the compound shown in Formula I may have a structure shown in Formula C:

In some embodiments, the compound represented by formula I may have a structure represented by formula C-1, formula C-2, formula C-3, formula C-4 or formula C-5:

In some embodiments, the compound represented by the formula I may have a structure represented by formula C-6, formula C-7 or formula C-8:

In some embodiments, the compound shown in formula I may have a structure shown in formula C-9 or formula C-10:

In some embodiments, the compound shown in Formula I may have a structure shown in Formula D:

In some embodiments, the compound represented by the formula I may have a structure represented by the formula D-1, the formula D-2 or the formula D-3:

In some embodiments, the compound represented by the formula I may have a structure represented by the formula D-4:

In some embodiments, the compound shown in Formula I may have a structure shown in Formula E:

In some embodiments, the compound shown in formula I may have a structure shown in formula E-1, formula E-2 or formula E-3:

In some embodiments, the compound shown in the formula I can have the structure shown in the formula E-4:

In any of the above formulas, in the definition of ring Cy ² , the unsubstituted or substituted C _3-12 cycloalkyl group can be in a cis configuration or a trans configuration. For example, in the definition of ring Cy ² , the C _3-12 cycloalkyl in the unsubstituted or substituted C _3-12 cycloalkyl can be a C _3-6 monocyclic cycloalkyl, for example

another example

in

Can be in cis configuration

or trans configuration

In some embodiments, the compound represented by the formula I can have any of the following structures:

On the other hand, the present invention also provides a preparation method of the compound shown in the above formula I, which is any one of the following methods:

Method a: the compound shown in formula Ia and the compound shown in formula I-a1 or formula I-a2 (for example in ethylene glycol dimethyl ether and water, in the presence of tetrakistriphenylphosphine palladium and potassium fluoride; Or, dioxane and water, in the presence of Pd(dppf) _Cl2 and sodium bicarbonate; or, dioxane and water, in the presence of Pd( _PPh3 ) ₄ and potassium carbonate; or, dioxane ring and water, in the presence of tetrakistriphenylphosphine palladium and potassium fluoride) through the reaction shown below, the compound shown in formula I is obtained,

Among them, ring Cy ¹ is

Ring Cy ^1a is

The definitions of the remaining groups are as described in any scheme of the present invention;

Method b: the compound shown in formula I-b and the compound shown in formula I-b1 (for example, in tetrahydrofuran, in the presence of sodium carbonate; or, in tetrahydrofuran, in the presence of sodium bicarbonate; or, in dichloromethane, carbonic acid In the presence of sodium) through the reaction shown below, the compound shown in formula I is obtained,

Wherein, X ³ is -NH-, and the definitions of other groups are as described in any scheme of the present invention;

Method c: the compound shown in formula I-c and the compound shown in formula I-c1 (for example, in 2-methyltetrahydrofuran or methanol) are reacted as follows to obtain the compound shown in formula I,

Among them, X ¹ is -NR ^x1 C(O)NR ^x1 -, -X ^1c R ^1c is

or ^X1 for

X ^1c R ^1c is

Method d: the compound shown in formula I-d (for example, in methanol, in the presence of catalyst Pd/C) is reacted as shown below to obtain the compound shown in formula I,

Among them, ring Cy ² is

Method e: the compound shown in formula I-e (for example, in the presence of trifluoroacetic acid) is deprotected to obtain the compound shown in formula I through the reaction shown below,

where ^R1 is

Method f: the compound shown in formula I-f1 and the compound shown in formula I-f2 (for example in dioxane, in Pd(dppf)Cl ₂ and potassium acetate exist; Or ethylene glycol dimethyl ether and water , in the presence of tetrakistriphenylphosphine palladium and potassium fluoride) through the reaction shown below, the compound shown in formula I is obtained,

Among them, ring Cy ¹ is

Ring Cy ² is

Method g: the compound shown in formula I-g is reacted as shown below to obtain the compound shown in formula I,

Wherein, R ⁴ is isopropyl, X ⁴ is -O-, and the definitions of the rest of the groups are as described in any scheme of the present invention;

Method h: the compound shown in formula I-h (for example in the presence of trifluoroacetic acid) is reacted as shown below to obtain the compound shown in formula I,

where -X ² -R ² is

The definitions of the remaining groups are as described in any scheme of the present invention.

Method i: the compound shown in formula I-i is reacted as shown below to obtain the compound shown in formula I,

Wherein, Hal is a halogen (such as Br), X ¹ is -NH-, R ¹ is an unsubstituted or substituted 5-12 membered heteroaryl group, and the definitions of the remaining groups are as described in any scheme of the present invention;

Method j: the compound shown in formula I-j obtains the compound shown in formula I through the following reactions (such as in the presence of acetonitrile and sodium iodide),

where ^R1 is

Method e-1: the compound represented by formula I-e1 (for example, in the presence of trifluoroacetic acid) is deprotected to obtain the compound represented by formula I through the following reaction,

Wherein, R ¹ is an unsubstituted or substituted 5-12 membered heteroaryl group, R ^1e is a divalent group corresponding to R ¹ , and the definitions of the remaining groups are as described in any scheme of the present invention;

Method e-2: In a solvent (such as dichloromethane), the compound shown in formula I-e2 (for example, in the presence of trifluoroacetic acid) is deprotected to obtain the compound shown in formula I through the following reaction,

Wherein, R ¹ is an unsubstituted or substituted 5-12 membered heteroaryl group, R ^1e is a divalent group corresponding to R ¹ , and -X ² -R ² is

On the other hand, the present invention also provides a compound represented by formula I-a, I-b, I-c, I-d, I-e, I-f1, I-g, I-h, I-i, I-e1, I-e2 or I-f2,

In some embodiments, the compound represented by the formula I-a, I-b, I-c, I-d, I-e, I-f1, I-g, I-h, I-e1 or I-i is any of the following structures:

In some embodiments, the compound represented by the formula I-a, I-b, I-c, I-d, I-e, I-f1, I-g, I-h, I-e1, I-e2, or I-i is any of the following structures:

On the other hand, the present invention also provides a pharmaceutical composition, which comprises (i) the compound represented by the above formula I, or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable a salt; and (ii) a pharmaceutically acceptable carrier.

On the other hand, the present invention also provides a compound represented by the above formula I, or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt as a medicine.

On the other hand, the present invention also provides a compound represented by the above formula I, or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt or the above pharmaceutical composition in the preparation of therapeutic Or the application in medicines for preventing diseases related to Rad51.

On the other hand, the present invention also provides a method for treating diseases related to Rad51, which includes applying the compound shown in the above formula I to a subject in need of this treatment (preferably, applying A therapeutically effective amount of the compound represented by the above formula I), or its tautomers, stereoisomers, isotope derivatives or pharmaceutically acceptable salts, or the above pharmaceutical composition. In some embodiments, the Rad51-associated disease may be cancer, autoimmune disease, immunodeficiency disease or neurodegenerative disease.

In some embodiments, the cancer may be multiple myeloma, lymphoma (e.g., non-Hodgkin's lymphoma, follicle center lymphoma, mantle cell lymphoma), sarcoma, breast cancer (e.g., triple negative breast tumors) , head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, or B-cell malignancies.

Definition

Unless otherwise stated, the terms used in this application have the following definitions, and the definitions of terms not involved in the following are as commonly understood by those skilled in the art to which the present invention belongs.

In this application, the term "tautomer" refers to functional group isomers produced by rapid movement of one atom in two positions in a molecule. For example, acetone and 1-propen-2-ol can be interconverted by the rapid movement of hydrogen atoms on the oxygen and on the α-carbon.

In the present application, the term "stereoisomer" refers to isomers caused by atoms or atomic groups connected to each other in the same sequence but with different spatial arrangements, such as cis-trans isomers (such as Z-isomers, E-isomers, etc. isomers), optical isomers (eg, enantiomers, diastereomers), atropisomers, and the like. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution through bond formation (chemical combination, etc.) or salt formation (physical combination, etc.) with other chiral compounds. Optical isomers include enantiomers and diastereomers. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

In this application, the term "cis-trans isomers" refers to the isomers produced by the atoms (or groups) on both sides of the double bond or ring system due to their different positions relative to the reference plane. In the cis-isomers The atoms (or groups) are located on the same side of the double bond or ring system, and the atoms (or groups) are located on different sides of the double bond or ring system in trans isomers. For example, the following formulas 1-1 and 1-2 can be used interchangeably, indicating that the compound exists in the form of cis isomers; the following formulas 1-3 and 1-4 can be used interchangeably, indicating that the compound exists in the form of trans isomers body form exists.

In this application, the term "isotopic derivative" means that one or more atoms in a compound are replaced by one or more atoms with specific atomic mass or mass number. Examples of isotopes that can be incorporated into compounds include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O , ¹⁸ F, ³⁵ S and ³⁶ Cl). Isotopically-labeled compounds can generally be prepared according to the methods described herein by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent. Typical examples of isotopic derivatives include deuterated compounds.

In the present application, the term "pharmaceutically acceptable salt" refers to a salt prepared from a compound with a relatively non-toxic, pharmaceutically acceptable acid or base. When compounds contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base either in neat solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. A salt. When the compound contains relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.

In this application, the term "halogen" means fluorine, chlorine, bromine or iodine.

In this application, the term "hydroxyl" means -OH.

In the present application, the term "benzyl" means _-CH2 -benzene.

In the present application, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group having a certain number of carbon atoms. C _1-6 alkyl refers to an alkyl group having 1-6 (eg 1, 2, 3, 4, 5, 6) carbon atoms, including C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl , n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2, 2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3- Dimethylbutyl etc.

In the present application, the term "haloalkyl" refers to an alkyl group in which one or more (such as 1, 2, 3, 4 or 5) hydrogen atoms are replaced by halogen, wherein the definition of alkyl group is as above. Specific examples include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, Difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.

As used herein, the term "alkoxy" refers to the group -OR ^x , wherein R ^x is alkyl as defined above.

In the present application, the term "haloalkoxy" refers to an alkoxy group in which one or more (such as 1, 2, 3, 4 or 5) hydrogen atoms are replaced by halogen, wherein the definition of alkoxy group is as above. Specific examples include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.

In the present application, the term "alkenyl" refers to an unsaturated alkyl compound containing a carbon-carbon double bond in the molecule, wherein the definition of alkyl is as above.

In the present application, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon group, including, for example, monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl. The term "C _3-12 cycloalkyl" refers to a cycloalkyl group having 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) ring carbon atoms, including C _{3-12 -6} monocyclic cycloalkyl, C _6-12 spirocycloalkyl, C _6-12 fused cycloalkyl and C _6-12 bridged cycloalkyl.

In this application, the term "C _3-6 monocyclic cycloalkyl" refers to a saturated monocyclic cyclic hydrocarbon group with 3 to 6 ring carbon atoms, including C ₃ , C ₄ , C ₅ or C ₆ monocyclic cycloalkane base. Specific examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

In the present application, the term "spirocycloalkyl" refers to a polycyclic cyclic hydrocarbon group formed by sharing one carbon atom (called a spiro atom) between two or more monocyclic rings. According to the number of spiro atoms shared between rings, spirocycloalkyl groups can be divided into single spirocycloalkyl, double spirocycloalkyl and polyspirocycloalkyl.

In the present application, the term "fused cycloalkyl" refers to a polycyclic cyclic hydrocarbon group formed by two or more monocyclic rings sharing a pair of adjacent carbon atoms. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups.

In the present application, the term "bridged cycloalkyl" refers to a polycyclic cyclic hydrocarbon group formed by sharing two carbon atoms that are not directly connected between two or more monocyclic rings. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. The term "C _6-12 bridged cycloalkyl" refers to a polycyclic cyclic hydrocarbon group having 6 to 12 ring carbon atoms, wherein any two rings share two carbon atoms that are not directly connected.

In this application, unless otherwise specified in the specification, a heterocycloalkyl group may be monocyclic ("monocyclic heterocycloalkyl"), or a bicyclic, tricyclic or multicyclic ring system, It may include fused (merged rings), bridged (bridged rings) or spiro (spiro ring) ring systems (such as bicyclic ring systems (“bicyclic heterocycloalkyl”). Heterocycloalkylbicyclic Ring systems may include one or more heteroatoms in one or both rings and be saturated.

In the present application, the "x-y members" in the cyclic group described herein means that the number of atoms on the ring is x-y. For example, cyclopropyl is 3-membered, tetrahydropyrrolyl is 5-membered, and piperidinyl is 6-membered.

In this application, the term "substituted by" means that any one or more hydrogen atoms on a specific atom are replaced by substituents, including deuterium and hydrogen variants, as long as the valence of the specific atom is Normal and substituted compounds are stable.

In general, the term "substituted by" means that one or more hydrogen atoms in a given structure have been replaced by a particular substituent. Further, when the group is substituted by one or more substituents, the substituents are independent of each other, that is, the one or more substituents can be different from each other, or can be identical. Unless otherwise indicated, a substituent may substitute at each substitutable position of the substituent. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently.

When a substituent is listed without specifying the atom through which it is bonded to a compound included in a general chemical formula but not specifically mentioned, such a substituent may be bonded through any atom thereof. Combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

When a substituent is not clearly indicated in the enumerated group, this group only means unsubstituted. For example, when there is no limitation of "unsubstituted or substituted" before "C ₁ -C ₄ alkyl", it only refers to "C ₁ -C ₄ alkyl" itself or "unsubstituted C ₁ -C ₄ alkyl".

In various sections of the invention linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited for that group are to be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable recites "cycloalkyl" or "heterocycloalkyl," it is understood that the "cycloalkyl" or "heterocycloalkane "group" represents a linked "cycloalkylene group" or "heterocycloalkylene group", respectively.

As used herein, the terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" refer to a specific segment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities embedded or attached to molecules.

In this application, the term "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content.

It should be understood that as used in this application, a singular form such as "a" includes plural referents unless otherwise specified. In addition, the term "comprising" is an open definition rather than a closed one, that is, it includes the content specified in the present invention, but does not exclude other content.

In addition, it should be noted that, unless otherwise clearly stated, the description method "...independently" used in this application should be interpreted in a broad sense, which means that the described individuals are independent of each other and can be independent are the same or different specific groups. In more detail, the description "...independently" can mean that in different groups, the specific options expressed by the same symbols do not affect each other; it can also mean that in the same group, the same symbols The specific options expressed between them do not affect each other.

Those skilled in the art can understand that, according to the practice used in this field, the application describes the structural formula used in the group

means that the corresponding group is connected with other fragments and groups in the compound through this site.

In this application, the term "treatment" refers to therapeutic therapy. In relation to a specific condition, treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.

As used herein, the term "therapeutically effective amount" refers to an amount of a compound sufficient to effectively treat or prevent a disease or condition described herein when administered to a patient. A "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by those skilled in the art. Depending on the dosage form and the severity of the disease, the dosage may exceed this range.

The pharmaceutical composition can be formulated into various types of administration unit dosage forms according to the therapeutic purpose.

The compounds of the present invention can be clinically administered in conventional ways.

In the present application, the term "subject" refers to any animal that is about to or has received the administration of the compound or composition, preferably a mammal, and most preferably a human. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being most preferred.

Unless otherwise specified, this application adopts traditional methods of mass spectrometry and elemental analysis, and the steps and conditions can refer to the conventional operating steps and conditions in the art.

Unless otherwise indicated, this application employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.

On the basis of conforming to common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are commercially available or obtained by conventional methods.

The positive progress effect of the present invention is that: the compound of the present invention has excellent Rad51 inhibitory activity, can effectively inhibit the proliferation of related tumor cells; has good pharmacokinetic characteristics (such as half-life, T _max , C _max , relative exposure), predicts It has a better in vivo efficacy or safety window. The compound of the present invention is superior to the control compound in at least one aspect of activity, pharmacokinetic properties (such as half-life, T _max , C _max , relative bioavailability) and the like.

Detailed ways

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

Embodiment 1: the synthesis of compound I-1

Step 1: Synthesis of Intermediate 1-2

Compound 1-1 (19.99g, 82.2mmol) was placed in a 250mL single-necked bottle and dissolved with acetonitrile (100mL); HATU (37.51g, 98.6mmol) and DIEA (31.87g, 246.6mmol) were added to the above reaction system The reaction system was stirred at 25° C. for 30 minutes; solid ammonium chloride (8.79 g, 164.4 mmol) was added to the reaction solution in batches; the reaction system was stirred at 25° C. for 2 hours. TLC (PE:EtOAc=1:1) monitored the complete consumption of the starting material, and at the same time, the product was formed (the Rf value of the starting material was 0.05, and the Rf value of the product was 0.27). The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 1-2 as a crude white solid (17 g, crude).

LCMS (ESI): m/z C ₁₂ H ₂₃ N ₂ O ₃ ⁺ [M+H] ⁺ = 243.14, found [M-(t-Bu) + H] ⁺ = 187.2.

Step 2: Synthesis of Intermediates 1-3

Intermediate 1-2 (17g, 70.2mmol) was dissolved in a 500mL single-necked bottle, and dissolved with 2-methyltetrahydrofuran (100mL), and Lawson's reagent (cas number 19172-47-5, 15.61g, 38.6mmol) and sodium carbonate (7.44g, 70.2mmol); the reaction solution was stirred at 80°C for 5 hours. Water (100 mL) was added to the system, and extracted with ethyl acetate (200 mL*3); the organic phases were combined, dried, and filtered. The resulting filtrate was evaporated to dryness under reduced pressure to obtain Intermediate 1-3 as a crude white solid (16 g, crude).

LCMS (ESI): m/z C ₁₂ H ₂₃ N ₂ O ₂ S ⁺ [M+H] ⁺ = 259.14, found [M-(t-Bu) + H] ⁺ = 202.6.

Step 3: Synthesis of Intermediates 1-4

In a 500mL three-neck flask, add intermediate 1-3 (16g, 62mmol), dissolve with ethanol (200mL); add 2-bromo-1,1-diethoxyethane (24.4g, 124mmol ), the monohydrate of toluenesulfonic acid (5.89g, 31mmol); the reaction solution was stirred at 80°C for 12 hours; TLC (PE:EtOAc=1:1) monitored that the raw material was consumed completely, and simultaneously the product was generated (raw material Rf value 0.4, the Rf value of the product is 0.06). The reaction system was filtered, and the resulting filtrate was evaporated to dryness under reduced pressure to obtain Intermediate 1-4 as a crude white solid (13 g, crude).

LCMS (ESI): m/z C ₉ H ₁₅ N ₂ S ⁺ [M+H] ⁺ = 183.09, found [M+H] ⁺ = 182.8.

Step 4: Synthesis of Intermediates 1-5

In a 250mL three-neck flask, add intermediate 1-4 (10.5g, 58mmol), and dissolve it with 150mL of ethanol; add di-tert-butyl dicarbonate (63.4g, 290mmol) to the above reaction system; The mixture was stirred at low temperature for 2 hours; TLC (PE:EtOAc=1:1) monitored the complete consumption of the starting material and the formation of the product at the same time. The reaction solution was diluted with 100 mL of water, and extracted with ethyl acetate (150 mL*3); the organic phases were combined, dried, and filtered; the obtained filtrate was evaporated to dryness under reduced pressure to obtain a brownish-yellow solid. The solid was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-95%) to obtain intermediate 1-5 as a pure white solid (8.0 g, yield: 49%).

LCMS (ESI): m/z C ₁₄ H ₂₃ N ₂ O ₂ S ⁺ [M+H] ⁺ = 283.14, found [M+H] ⁺ = 283.1.

Step 5: Synthesis of Intermediates 1-6

In a 250 mL three-neck flask, intermediate 1-5 (4.0 g, 14.2 mmol) was added, the reactant was dissolved with 40 mL of DMF, and NBS (3.78 g, 21.2 mmol) was added. The reaction system was stirred at 20° C. for 2 hours; TLC (PE:EtOAc=1:3) monitored the complete consumption of raw materials and the formation of products; the reaction solution was diluted with 100 mL of water and extracted with ethyl acetate (150 mL*3). The combined organic phases were dried and filtered; the resulting filtrate was evaporated to dryness under reduced pressure to obtain a brownish-yellow solid. The solid was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-40%) to obtain intermediate 1-6 (3.2 g, yield: 62%) as a white solid.

LCMS ( _ESI ): m/z _{C14H22BrN2O2S} ⁺ [M+H] ⁺ = 361.05/ _363.05 , found [M+ _H ] ⁺ = 360.7/362.7.

Step 6: Synthesis of Intermediates 1-7

In a 250mL three-neck flask, add intermediate 1-6 (3.2g, 8.86mmol), and dissolve it with 40mL of dichloromethane; add trifluoroacetic acid (1.01g, 8.86mmol) to the reaction system; Stir for 2 hours; TLC (PE:EtOAc=1:3) monitors the complete consumption of starting material and simultaneous formation of product. The reaction liquid was directly evaporated to dryness under reduced pressure to obtain Intermediate 1-7 as light yellow oil (2.2 g, yield: 95%).

LCMS (ESI): m/z _C9H14BrN2S ⁺ [M+H] ⁺ = 261.05/ _263.05 , found [M+H _] ⁺ = 260.7/262.7.

Step 7: Synthesis of Intermediates 1-8

Intermediate 1-7 (2.2g, 8.42mmol) was dissolved in 30mL of dichloromethane in a 100mL one-necked flask, and sodium carbonate (8.93g, 84.2mmol) and isopropyl chloroformate (3.10g, 25.3 mmol); the reaction system was stirred at 20°C for 2 hours; the reaction was diluted with 20 mL of water, and extracted with ethyl acetate (30 mL*3); the organic phases were combined, dried and filtered. The resulting filtrate was evaporated to dryness under reduced pressure to obtain Intermediate 1-8 (2.1 g, yield 72%) as a crude white solid.

LCMS ( _ESI ): m/z _{C13H19SN2O2Br} ⁺ [M+H] ⁺ = 347.04/ _349.04 , found [M+H _] ⁺ = 346.6/348.6.

Step 8: Synthesis of Intermediates 1-9

In a 25mL one-mouth bottle, add intermediate 1-8 (200mg, 0.58mmol), compound 1-8A (356mg, 0.86mmol); the reactant was dissolved in 5mL of dioxane and 1mL of water, and added Pd (dppf)Cl ₂ (42mg, 0.058mmol), potassium carbonate (239mg, 1.73mmol); after the reaction system was stirred at 110°C for 1 hour, the reaction solution was evaporated to dryness to obtain a brown-black solid. The solid residue was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-70%) to obtain Intermediate 1-9 (60 mg) as a white solid.

LCMS (ESI): m _/ z _C25H37N4O6S2 ⁺ , calculated _for [M+H _] ⁺ = _553.21 , found = 553.1. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.27(d, J=2.3Hz, 1H), 7.75-7.62(m, 2H), 7.44-7.34(m, 1H), 5.05-4.92(m, 1H), 4.86-4.77(m,1H),3.54-3.40(m,1H),3.00(tt,J=3.5,12.0Hz,1H),2.92(q,J=7.2Hz,2H),2.30-2.20(m, 2H), 2.08(br d, J＝10.1Hz, 2H), 1.79-1.63(m, 2H), 1.50-1.37(m, 2H), 1.33(d, J＝6.2Hz, 6H), 1.24-1.21( m,6H), 1.09-1.03(m,3H).

Step 9: Synthesis of Intermediates 1-10

In a 25mL one-mouth bottle, add intermediate 1-9 (50mg, 90μmol) and dissolve it with 3mL of DMF; add NBS (48mg, 270μmol) to the above solution; diluted with water. The reaction solution was extracted with ethyl acetate (30 mL*3); the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered; the filtrate was evaporated to dryness to obtain a brown solid. The solid was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-70%) to obtain Intermediate 1-10 as a white solid (35 mg, yield: 61%).

LCMS (ESI): m/z C ₂₅ H ₃₆ ^BrN ₄ O ₆ S ₂ ⁺ [M+H] ⁺ calcd = 631.12/633.12, found = 631.1/633.1.1 H NMR (400MHz, CD ₃ OD) δppm 8.26(d, J=2.3Hz, 1H), 7.76-7.63(m, 1H), 7.38-7.24(m, 1H), 5.00(spt, J=6.2Hz, 1H), 4.84-4.75(m, 1H) ,3.44(tt,J＝4.1,11.6Hz,1H),3.02-2.89(m,3H),2.29-2.16(m,2H),2.11-2.03(m,2H),1.76-1.60(m,2H) , 1.47-1.37 (m, 2H), 1.32 (d, J=6.3Hz, 6H), 1.23 (dd, J=3.0, 6.7Hz, 6H), 1.12-1.07 (m, 3H).

Step 10: Synthesis of Compound I-1

In a 10mL single-necked bottle, add intermediate 1-10 (35mg, 55μmol), dissolve with 4mL of dioxane and 1mL of water; in the above reaction system, add methylboronic acid (5mg, 83μmol), Pd( dppf) Cl ₂ (4 mg, 5.5 μmol) and sodium bicarbonate (9 mg, 110 μmol); after the reaction was stirred at 110° C. for 1 hour, the solvent was evaporated under reduced pressure to obtain a black solid. The solid was separated and purified by a reverse-phase column to obtain compound I-1 as a white solid (10 mg, yield 31%, purity 98.6%).

LCMS (ESI): m/z C ₂₆ H ₃₉ N ₄ O ₆ S ₂ ⁺ [M+H] ⁺ calcd = 567.23, found = 567.1.1 H NMR (400MHz, CD ₃ OD) δppm 8.25(d ^, J＝2.3Hz, 1H), 7.67(dd, J＝2.3, 8.3Hz, 1H), 7.28(d, J＝8.3Hz, 1H), 5.00(td, J＝6.2, 12.5Hz, 1H), 4.81( br s,1H),3.44(br t,J=12.0Hz,1H),2.97-2.86(m,3H),2.21(br d,J=12.5Hz,2H),2.14(s,3H),2.06( br d, J = 10.4Hz, 2H), 1.72-1.60 (m, 2H), 1.46-1.36 (m, 2H), 1.32 (d, J = 6.3Hz, 6H), 1.27-1.20 (m, 9H).

Embodiment 2: the synthesis of compound 1-2

Step 1: Synthesis of Intermediate 2-2

In a 100mL three-neck flask, add compound 2-1 (1.0g, 3.87mmol), and dissolve it with 20mL of ethanol; add calcium carbonate (1.16g, 11.6mmol) and 1-chloropropane-2-one to the above solution in turn (950mg, 10.3mmol); the reaction system was stirred at 70°C for 12 hours. LCMS monitored that the reaction was complete, and the reaction solution was concentrated to obtain a solid residue, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 60%) to obtain Intermediate 2-2 as a white solid (900mg, yield : 78%).

¹ H NMR (400MHz, CD ₃ Cl) δppm 6.73(d, J=0.7Hz, 1H), 3.49(br s, 1H), 2.93(tt, J=3.4, 12.1Hz, 1H), 2.42(s, 3H ), 2.24-2.08 (m, 5H), 1.74-1.56 (m, 4H), 1.46-1.44 (m, 9H).

Step 2: Synthesis of Intermediate 2-3

In a 150mL single-necked bottle, add intermediate 2-2 (900mg, 3.04mmol) and NBS (540mg, 3.04mmol), and dissolve with 10mL of DMF; the reaction system was stirred at 20°C for 2 hours; after the disappearance of the raw materials, the reaction The solution was diluted with 100 mL of water, and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to obtain a brown oil. After silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-40%), Intermediate 2-3 was obtained as a white solid (700 mg, yield: 61%).

LCMS (ESI): m/z Calcd. for C ₁₅ H ₂₄ BrN ₂ O ₂ S ⁺ [M+H] ⁺ = 375.1/377.1, found = 375.0/377.1. ¹ H NMR (400MHz, CD ₃ Cl) δppm 3.49 (br s,1H),2.85(tt,J＝3.4,12.1Hz,1H),2.36(s,3H),2.20-2.10(m,4H),1.66-1.54(m,4H),1.45(s, 9H).

Step 3: Synthesis of Intermediates 2-4

In a 50mL three-neck flask, add compound 2-3A (180mg, 409μmol), intermediate 2-3 (150mg, 400μmol), tetrakistriphenylphosphine palladium (39mg, 34umol) and potassium fluoride (150mg, 2.58mmol) ; Dissolve the mixture with 8 mL of dioxane and 2 mL of water. The reaction system was replaced with nitrogen three times, and heated to 110° C. under nitrogen atmosphere, and stirred for 1 hour. TLC (PE:EtOAc=1:1) monitored the completion of the raw material reaction and the formation of the main product. The reaction solution was concentrated under reduced pressure to a solid residue, and intermediate 2-4 was obtained as a colorless oil (160 mg, purity: 99 %).

LCMS (ESI): m/z _calcd _{for C29H45N4O6S2} ₊ ^[ M+H _] ⁺ = 609.3, _found = 609.3.

Step 4: Synthesis of Intermediates 2-5

In a 10 mL one-necked bottle, intermediate 2-4 (160 mg, 263 μmol) was added and dissolved with 4 mL of dichloromethane. Trifluoroacetic acid (4 mL) was added dropwise to the above reaction solution. After the dropwise addition was completed, the system was stirred at 20° C. for 20 minutes. The reaction solution was concentrated under reduced pressure to obtain Intermediate 2-5 as a crude yellow oil (140 mg).

LCMS ( _ESI ): m/z _Calcd _{for C24H37N4O4S2} ₊ ^[ M+H _] ⁺ = 509.2, found = 509.2.

Step 5: Synthesis of Compound I-2

In a 50mL single-necked bottle, add intermediate 2-5 (140mg, 275μmol), and dissolve it with 8mL of tetrahydrofuran; add 4M aqueous sodium bicarbonate solution (4M, 2mL) to the above reaction system, and then add isopropyl chloroformate Ester (50 mg, 413 μmol); the reaction system was stirred at 20° C. for 20 minutes. TLC (PE:EtOAc=1:1) monitored the complete reaction; the reaction solution was diluted with 20 mL of water, and extracted with ethyl acetate (10 mL*3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered , the filtrate was evaporated to dryness under reduced pressure to obtain an oily substance, and compound I-2 was obtained as a white solid (100mg, yield: 61% , purity: 100%).

LCMS (ESI): m/z C ₂₈ H ₄₃ N ₄ O ₆ S ₂ ⁺ [M+H] ⁺ calcd = 595.3, found = 595.3. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.34(d, J＝2.1Hz, 1H), 7.65(dd, J＝2.1, 8.3Hz, 1H), 7.25(d, J＝8.3Hz, 1H), 5.12-4.99(m, 1H), 4.82-4.81(m, 1H ),3.51-3.39(m,1H),2.94(br t,J=12.0Hz,1H),2.21(br d,J=12.3Hz,2H),2.16(s,3H),2.06(br d,J =10.8Hz,2H),1.74-1.59(m,2H),1.45-1.37(m,2H),1.32(d,J=6.2Hz,6H),1.22(br d,J=6.1Hz,6H), 1.20(s,9H).

Embodiment 3: the synthesis of compound 1-3

In a 10mL single-mouth bottle, put trideuteromethylboronic acid (29mg, 475μmol) and the aforementioned intermediate 1-10 (60mg, 95μmol), and dissolve it with 4mL of dioxane and 1mL of water; add Potassium carbonate (39 mg, 285 μmol) and Pd(PPh ₃ ) ₄ (11 mg, 9.5 μmol); the reaction system was stirred at 110° C. for 1.6 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid, and compound I-3 was prepared by a reverse-phase column as a white solid (10 mg, yield: 18%, purity: 100%).

LCMS (ESI): m/z C ₂₆ H ₃₆ D ₃ N ₄ O ₆ S ₂ ⁺ [M+H] ⁺ calcd = 570.25, found = 570.3. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.28 ( d,J=2.3Hz,1H),7.70(dd,J=2.3,8.3Hz,1H),7.33(d,J=8.3Hz,1H),5.06-4.94(m,1H),4.84-4.80(m ,1H),3.55-3.41(m,1H),3.14-3.02(m,1H),2.95(q,J=7.3Hz,2H),2.24(br d,J=12.8Hz,2H),2.13-2.04 (m,2H),1.80-1.63(m,2H),1.51-1.37(m,2H),1.33(d,J=6.3Hz,6H),1.23(br d,J=6.0Hz,6H),1.11 (t,J=7.3Hz,3H).

Embodiment 4: the synthesis of compound 1-4

Step 1: Synthesis of Intermediate 4-2

Add compound 4-1 (15 mg, 26 μmol) into a 10 mL single-necked bottle (refer to WO2020257752 for the synthesis method), and dissolve it with 1 mL of DMF; add NBS (18 mg, 103 μmol) to the above reaction solution, and stir the reaction solution at 20°C for 17 Hour. After the raw materials are completely consumed, the reaction system is diluted with 4mL of ethyl acetate and 4mL of water; the organic phase is separated, the aqueous phase is extracted with ethyl acetate (4mL*2), the organic phase is combined, and washed with saturated brine (1mLx2) , dried over anhydrous sodium sulfate, filtered _, and the filtrate was evaporated to dryness under reduced pressure. Yield: 73%, purity: 96%).

LCMS (ESI): m/z C ₂₇ H ₄₀ BrN ₄ O ₆ S ₂ ⁺ [M+H] ⁺ calcd = 659.2/ ^661.2 , found = 659.2/661.2.1 H NMR (400MHz, CD ₃ OD) δppm 8.36(d,J=2.3Hz,1H),7.70(dd,J=2.2,8.4Hz,1H),7.33(d,J=8.3Hz,1H),5.07-5.02(m,1H),4.85-4.83 (m,1H),3.51-3.41(m,1H),3.03-2.94(m,1H),2.25(br d,J=11.9Hz,2H),2.09(br d,J=10.1Hz,2H), 1.76-1.64 (m, 2H), 1.48-1.39 (m, 2H), 1.34 (d, J=6.2Hz, 6H), 1.27-1.19 (m, 15H).

Step 2: Synthesis of Compound I-4

In a 5mL single-necked bottle, add trideuteriomethylboronic acid pinacol ester (66mg, 454μmol) (refer to US2020/95239 for the synthesis method) and intermediate 4-2 (10mg, 15μmol); Phenylphosphine palladium (2mg, 1.5μmol) and potassium fluoride (4mg, 76μmol), and the mixture was dissolved with 0.5mL of dioxane and 0.2mL of water; after the reaction system was stirred at 100°C for 17 hours, the pressure was reduced Evaporate to dryness to obtain a residue. The residue was prepared by reverse-phase column to obtain compound I-4 as a white solid (4 mg, yield: 46%, purity: 99%).

LCMS (ESI): m/z C ₂₈ H ₄₀ D ₃ N ₄ O ₆ S ₂ ⁺ [M+H] ⁺ calcd = 598.3, found = 598.9. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.39 ( d,J=2.0Hz,1H),7.69(dd,J=2.0,8.3Hz,1H),7.31(d,J=8.2Hz,1H),5.03(br s,1H),4.86-4.84(m, 1H),3.54-3.43(m,1H),3.07(br s,1H),2.26(br d,J=13.0Hz,2H),2.10(br d,J=10.6Hz,2H),1.80-1.66( m, 2H), 1.51-1.39 (m, 2H), 1.34 (d, J=6.3Hz, 6H), 1.29-1.21 (m, 15H).

Embodiment 5: the synthesis of compound 1-5

Step 1: Synthesis of Intermediate 5-2

In a 100mL single-necked bottle, add raw material 5-1 (1.0g, 3.87mmol) and 3-chloro-1,1,1-trifluoropropane-2-one (850mg, 5.81mmol); reactant with 20mL of ethanol After dissolution, calcium carbonate (775 mg, 7.74 mmol) was added; the system was stirred at 70° C. for 12 hours; LCMS monitored the formation of product. TLC (developer EtOAc monitors that the reaction of the raw materials is complete, and new spots are generated. The reaction solution is diluted with 100mL of water, and extracted with ethyl acetate (80mL*3); after the organic phases are combined, they are washed with saturated brine, anhydrous sodium sulfate Dry and filter. The filtrate was evaporated to dryness under reduced pressure to obtain a brown solid; the solid was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 60%) to obtain intermediate 5-2 as a white solid (800mg , yield: 56%). LCMS (ESI): m/z C ₁₅ H ₂₄ SN ₂ F ₃ O ₃ ⁺ [M+H] ⁺ calculated value = 369.2, found value [M-(t-Bu) + H ] ⁺ ＝313.0.

Step 2: Synthesis of Intermediate 5-3

In a 50mL single-necked bottle, add intermediate 5-2 (300mg, 0.81mmol), and dissolve with 5mL of dichloromethane; add trifluoroacetic acid (5mL) to the above reaction solution; the reaction system is stirred at 25°C for 10 minutes; the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was dissolved in 10 mL of tetrahydrofuran, and 2M aqueous sodium carbonate solution (1.6 mL, 3.26 mmol) was added; the reaction system was stirred at 20°C and isopropyl chloroformate (196 mg, 1.6 mmol) was added dropwise; the dropwise addition was completed, and the system was Stir at 20°C for 1 hour, add 30 mL of ethyl acetate and 30 mL of water to dilute. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL*2). After the organic phases were combined, they were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to a residue under reduced pressure and subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-60%) to obtain intermediate 5-3 as a yellow oil (310 mg crude product).

LCMS ( _ESI ): m/z _Calcd _for _{C14H22F3N2O3S} ⁺ [M+H] ⁺ = 355.1, _found = 355.0.

Step 3: Synthesis of Intermediate 5-4

In a 50mL single-necked bottle, add intermediate 5-3 (280mg, 790μmol), and dissolve with 3mL of dichloromethane; add thionyl chloride (141mg, 1.18mmol) and pyridine (125mg, 1.58mmol) to the above reaction solution ); the reaction system was stirred at 30° C. for 2 hours. After diluting the reaction solution with 30 mL of ethyl acetate, slowly pour it into 50 mL of 0.5 M hydrochloric acid aqueous solution; after the organic phase was separated, it was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain Intermediate 5-4 as a colorless oil (230 mg, yield: 86%).

LCMS (ESI): m/z Calcd. for C ₁₄ H ₂₀ F ₃ N ₂ O ₂ S ⁺ [M+H] ⁺ = 337.1, found = 337.3. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.04(d ,J=0.8Hz,1H),4.88-4.78(m,1H),3.53-3.42(m,1H),3.04(tt,J=3.6,12.1Hz,1H),2.28-2.19(m,2H), 2.15-2.04 (m, 2H), 1.69 (dq, J = 3.2, 12.9Hz, 2H), 1.50-1.35 (m, 2H), 1.24 (br d, J = 6.2Hz, 6H).

Step 4: Synthesis of Intermediate 5-5

In a 50mL three-neck flask, put intermediate 5-4 (200mg, 595μmol), and dissolve it with 10mL of tetrahydrofuran; cool the reaction solution under an ice bath; add LDA (2M, 1.19mL) dropwise to the system under stirring, dropwise After the addition, the mixture was stirred for 20 minutes; CBr ₄ (789 mg, 2.38 mmol) was added to the above reaction solution; the system was slowly raised to room temperature with stirring, and continued to stir for 20 minutes. After the raw materials have reacted completely, the reaction solution is diluted with 10 mL of ethyl acetate and 10 mL of water; the organic phase is separated, and the aqueous phase is extracted with ethyl acetate (10 mL*2); Dry over sodium sulfate and filter. The filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 20%) to obtain intermediate 5-5 as a white solid (107mg, purity: 89%) .

LCMS ( _ESI ): m/z calcd for _{C14H19N2O2SBrF3} ⁺ [M+H] ⁺ ₌ 415.0 _/ 417.0, found ₌ 414.9/417.1.

Step 5: Synthesis of Compound I-5

Intermediate 5-5 (50mg, 120μmol) and Intermediate 1-8A (50mg, 120μmol) were placed in a 10mL microwave reaction tube, and 1mL of water and 4mL of ethylene glycol dimethyl ether were added successively; Tetrakistriphenylphosphine palladium (14 mg, 12 μmol) and potassium fluoride (21 mg, 361 μmol) were added to the mixture; the reaction system was replaced with nitrogen, sealed; and reacted under microwave conditions at 110° C. for 2 hours. The reaction solution was concentrated under reduced pressure to a brown residue, which was separated and purified by reverse-phase column to obtain compound I-5 as a white solid (10 mg, purity: 98%).

LCMS (ESI): m/z C ₂₆ H ₃₆ F ₃ N ₄ O ₆ S ₂ ⁺ [M+H] ⁺ calculated value = 621.20, found value 621.1. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.26 (d ,J=2.3Hz,1H),7.66(dd,J=2.3,8.5Hz,1H),7.39-7.27(m,1H),5.02-4.97(m,1H),4.87-4.80(m,1H), 3.52-3.40(m,1H),3.07-2.88(m,3H),2.31-2.20(m,2H),2.14-2.04(m,2H),1.78-1.63(m,2H),1.48-1.36(m , 2H), 1.33 (d, J=6.2Hz, 6H), 1.23 (br d, J=6.2Hz, 6H), 1.16-1.05 (m, 3H).

Embodiment 6: the synthesis of compound 1-6

Intermediate 5-5 (50 mg, 120 μmol) and Intermediate 2-3A (53 mg, 120 μmol) were placed in a 15 mL microwave tube, and dissolved with 4 mL of ethylene glycol dimethyl ether and 1 mL of water; Tetrakistriphenylphosphine palladium (14 mg, 12 μmol) and potassium fluoride (21 mg, 361 μmol) were added sequentially; the reaction system was replaced with nitrogen, sealed, and stirred at 110° C. for 2 hours under microwave conditions. Then the reaction solution was concentrated under reduced pressure to a brown solid; Compound I-6 was isolated as a white solid (10 mg, yield: 13%, purity: 99%) by reverse-phase column preparation.

LCMS ( _ESI ): m/z calcd for _{C28H40F3N4O6S2} ⁺ [ _M +H] ₊ ⁼ 649.23, found ₌ _649.1 . ¹ H NMR (400MHz, CD ₃ OD) δppm 8.37 (d, J = 2.3Hz, 1H), 7.62 (dd, J = 2.3, 8.4Hz, 1H), 7.28 (d, J = 8.3Hz, 1H), 5.04 -4.97(m,1H),4.86-4.77(m,1H),3.54-3.37(m,1H),3.00(tt,J＝3.6,12.0Hz,1H),2.25(br d,J＝11.6Hz, 2H), 2.11-2.01(m, 2H), 1.78-1.61(m, 2H), 1.41(dq, J=3.3, 12.6Hz, 2H), 1.32(d, J=6.2Hz, 6H), 1.26-1.20 (m,15H).

Embodiment 7: the synthesis of compound 1-7

Step 1: Synthesis of intermediate 7-2

In a 25mL single-necked bottle, add intermediate 2-1 (258mg, 1.00mmol), and dissolve with 5mL of ethanol; add calcium carbonate (300mg, 3.00mmol) and compound (7-1A) (326mg, 2.00mmol) to the above solution mmol); the reaction system was stirred at 80° C. for 30 minutes; the reaction solution was concentrated under reduced pressure to a residue, and the intermediate 7- 2, as a white solid (270 mg, yield: 84%, purity: 100%).

LCMS (ESI): m/z C ₁₇ H ₂₇ N ₂ O ₂ S ⁺ [M+H] ⁺ calcd = 323.2, found = 323.3. ¹ H NMR (400MHz, CD ₃ Cl) δppm 6.67(s, 1H ),4.43(br s,1H),3.49(br d,J=13.1Hz,1H),3.04-2.85(m,1H),2.17(br t,J=15.7Hz,4H),2.10-1.99(m ,1H), 1.69-1.56(m,3H), 1.47(s,10H), 1.37-1.18(m,2H), 0.97-0.82(m,4H).

Step 2: Synthesis of intermediate 7-3

Intermediate 7-2 (200mg, 620μmol) was placed in a 10mL single-necked bottle, dissolved with 2mL of DMF, and NBS (144mg, 806μmol) was added; the reaction system was stirred at 20°C for 20 minutes; Add 10 mL of water and 10 mL of ethyl acetate to the system; separate the organic phase, and extract the aqueous phase with ethyl acetate (10 mL*2); combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure to obtain an oil, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-20%) to obtain intermediate 7-3 as a white solid (220 mg, yield: 88%, Purity: 99%).

LCMS (ESI): m/z C ₁₇ H ₂₆ N ₂ O ₂ SBr ⁺ [M+H] ⁺ calcd = 401.1/403.1, found = 401.0/403.0. ¹ H NMR (400MHz, CD ₃ Cl) δppm 4.45 -4.22(m,1H),3.40(br s,1H),2.89-2.66(m,1H),2.04(br d,J＝11.1Hz,4H),1.99-1.93(m,1H),1.53(br s, 2H), 1.45 (br d, J = 10.5Hz, 2H), 1.37 (s, 9H), 1.07-1.06 (m, 1H), 0.92-0.85 (m, 4H).

Step 3: Synthesis of Intermediate 7-4

In a 10mL one-mouth bottle, add intermediates 7-3 (41mg, 102μmol) and 1-8A (42mg, 102μmol), and dissolve with 2mL of dioxane and 0.2mL of water; Phenylphosphine palladium (6 mg, 5.1 μmol) and potassium fluoride (30 mg, 511 μmol); the reaction system was stirred at 120° C. for 1 hour; the reaction solution was concentrated to a solid residue, and subjected to silica gel column chromatography (mobile phase: ethyl acetate/ Petroleum ether, gradient 0%-60%) to obtain intermediate 7-4 as a colorless oil (25 mg, yield: 40%).

LCMS (ESI) _: m _{/z calcd for C29H43N4O6S2} ₊ ^[ M+H _] ⁺ = _607.3 , found = 607.1.

Step 4: Synthesis of Compound I-7

Put intermediate 7-4 (30mg, 49μmol) into a 10mL one-mouth bottle, and dissolve it with 3mL of dichloromethane, and stir and drop trifluoroacetic acid (9.89mmol) into the reaction solution at 20°C; after the dropwise addition, The reaction system was stirred at 20°C for 10 minutes; the residue was obtained after concentration. The residue was dissolved with 3 mL of tetrahydrofuran while adding aqueous sodium carbonate (1M, 494 μL). While stirring the reaction system, isopropyl chloroformate (12 mg, 99 μmol) was added dropwise. After the dropwise addition was completed, the system was stirred at 20° C. for 1 hour. After the raw materials reacted completely, 30 mL of water and 30 mL of ethyl acetate were added to the reaction solution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to an oily substance, and was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-60%) to obtain a light yellow solid crude product (35mg, purity: 80%), and further reverse phase Compound I-7 was obtained by column separation and purification as a white solid (20 mg, yield: 67%, purity: 98.3%).

LCMS (ESI): m/z C ₂₈ H ₄₁ S ₂ N ₄ O ₆ ⁺ [M+H] ⁺ calcd = 593.2, found = 593.6. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.28(d, J＝2.3Hz, 1H), 7.70(dd, J＝2.3, 8.3Hz, 1H), 7.36(d, J＝8.3Hz, 1H), 5.05-4.96(m, 1H), 4.85-4.83(m, 1H ),3.51-3.39(m,1H),3.33(td,J＝1.6,3.3Hz,3H),2.87(br s,1H),2.23-2.15(m,2H),2.10-2.02(m,2H) ,1.70-1.59(m,3H),1.45-1.37(m,1H),1.34(d,J=6.2Hz,6H),1.24(br d,J=6.2Hz,6H),1.10(t,J= 7.3Hz, 3H), 0.90 (br s, 2H), 0.79 (dd, J=2.5, 8.3Hz, 2H).

Embodiment 8～9: the synthesis of compound 1-8 and compound 1-9

Step 1: Synthesis of intermediate 8-2

In a 500mL three-neck flask, add raw material 8-1 (5.0g, 23.4mmol), dissolve it with 100mL of tetrahydrofuran; protect the system with nitrogen, and add LiHMDS (1M, 41mL) dropwise at -78°C; , N-phenylbis(trifluoromethanesulfonyl)imide (8-1A) (8.38g, 23.4mmol) was dissolved in 10mL of tetrahydrofuran solution, and the solution was added dropwise to the above reaction under nitrogen protection system, while keeping the system at -78°C and stirring for 1 hour; the system was slowly raised to 15°C, and continued to stir for 16 hours. After the reaction was complete, it was quenched with 80 mL of saturated ammonium chloride solution; the aqueous phase was extracted with ethyl acetate (50 mL*2); the organic phases were combined, dried with anhydrous sodium sulfate, filtered and evaporated to dryness to obtain an oily substance. The residue was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-20%) to obtain intermediate 8-2 as a white solid (4.9 g, yield: 61%).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 6.90 (br d, J=7.5Hz, 1H), 5.76 (br s, 1H), 3.45 (br s, 1H), 2.43-2.26 (m, 3H), 2.10-1.97 (m, 1H), 1.83 (br d, J=9.0Hz, 1H), 1.66-1.51 (m, 1H), 1.35 (s, 9H).

Step 2: Synthesis of Intermediate 8-3

Intermediate 8-2 (2.0g, 5.79mmol) and bis-linked pinacol borate (2.94g, 11.58mmol) were placed in a 100mL three-necked flask, and the system was dissolved with 30mL of dioxane; in the solution Pd(dppf)Cl ₂ (424mg, 579μmol) and potassium acetate (11.58mmol) were added; under the protection of nitrogen, the reaction was heated to 100°C and stirred for 2 hours. The reaction solution was directly evaporated to dryness under reduced pressure to obtain a brown-black solid residue; the residue was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 30%) to obtain intermediate 8-3 as a colorless oil (1.5 g, yield: 80%).

¹ H NMR (400MHz, CD ₃ Cl) δppm 6.39 (br t, J = 3.6Hz, 1H), 4.45 (br s, 1H), 3.83-3.63 (m, 1H), 2.41 (br d, J = 18.4Hz ,1H),2.15(br dd,J＝2.3,4.8Hz,2H),1.92-1.74(m,2H),1.55(br s,1H),1.53(br s,1H),1.48-1.40(m, 1H), 1.37(s, 9H), 1.19(s, 12H).

Step 3: Synthesis of Intermediate 8-4

In a 100mL three-necked flask, add 2,5-dibromo-1,3,4-thiadiazole 8-3A (589mg, 2.41mmol), intermediate 8-3 (779mg, 2.41mmol); Ethylene glycol dimethyl ether and 3mL of water were dissolved, and Pd(PPh ₃ ) ₄ (107mg, 93μmol) and sodium bicarbonate (468mg, 5.57mmol) were added sequentially; the system was stirred and reacted at 80°C for 2 hours; TLC monitoring A product is produced. Add 30mL of ethyl acetate and 30mL of water to the reaction system; separate the organic phase, and extract the aqueous phase with ethyl acetate (10mL*2); combine the organic phases, wash with saturated brine (10mL*2), anhydrous sulfuric acid Dry over sodium, filter, and evaporate the filtrate to dryness under reduced pressure to obtain a residue. The residue was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 40%) to obtain intermediate 8-4 as light yellow oil (210mg, yield: 22%, purity: 93% ).

LCMS (ESI): m/z C ₁₃ H ₁₉ BrN ₃ O ₂ S [M+H] ⁺ calcd = 360.03/362.03, found = 360.03/362.02. ¹ H NMR (400MHz, CD ₃ Cl) δppm 6.39 ( br s,1H),4.52(br s,1H),3.81(br s,1H),2.76-2.67(m,1H),2.65-2.55(m,2H),2.16-2.03(m,1H),2.02 -1.95(m,1H),1.73-1.61(m,1H),1.38(s,9H).

Step 4: Synthesis of Intermediate 8-5

In a 100 mL three-neck flask, add intermediate 8-4 (60 mg, 167 μmol) and compound 2-3A (200 μmol) (see WO2020/186006 for the synthesis method); the reactant is dissolved in 5 mL of dioxane and 1 mL of water; Pd(dppf)Cl ₂ (12 mg, 17 μmol) and potassium carbonate (69 mg, 500 μmol) were sequentially added to the above system; the reaction was stirred at 100° C. under nitrogen protection for 17 hours. The reaction solution was evaporated to dryness under reduced pressure, and silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-80%) gave Intermediate 8-5 as a yellow oil (95 mg).

LCMS (ESI): m/z Calcd. for C ₂₇ H ₄₀ N ₅ O ₆ S ₂ ⁺ [M+H] ⁺ = 594.24, found [M-(t-Bu) + H] ⁺ = 538.2.

Step 5: Synthesis of Intermediate 8-6

Intermediate 8-5 (82mg) was placed in a 50mL single-necked bottle and dissolved with 20mL of dichloromethane; trifluoroacetic acid (5.39g, 47.3mmol) was added dropwise to the system; the reaction was stirred at 20°C for 0.5 hours . The solvent was distilled off from the reaction liquid directly under reduced pressure to obtain Intermediate 8-6 as a colorless oil (62 mg, crude product).

LCMS (ESI): m/z Calcd _. for _C22H32N5O4S2 ⁺ [M+H _] ⁺ = _494.19 , found [M-(t-Bu)+ _H ] ⁺ = 438.1

Step 6: Synthesis of Intermediate 8-7

Intermediate 8-6 (62mg, 126μmol) was dissolved in 10mL of tetrahydrofuran in a 100mL one-necked bottle; aqueous sodium carbonate solution (0.5M, 913μL) was added to the system, and isopropyl chloroformate (56mg , 456 μmol); the reaction system was stirred at 20° C. for 1 hour; TLC (PE/EtOAc=1/1) monitored that the raw materials were completely consumed, and the main product was formed. Add 10 mL of ethyl acetate and 10 mL of water to the system; separate the organic phase, and extract the aqueous phase with ethyl acetate (10 mL*2); combine the organic phases, wash with saturated brine (10 mL*2), and dry over anhydrous sodium sulfate , filtered; the filtrate was evaporated to dryness under reduced pressure to obtain a residue. The residue was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 50%) to obtain intermediate 8-7 as a colorless oil (53 mg, yield: 55%, purity 75%) .

LCMS ( _ESI ): m/z _Calcd for _C26H38N5O6S2 ⁺ [M+H _] ⁺ = _580.23 , found = 580.2.

Step 7: Synthesis of Compound I-8 and Compounds I-8 and I-9

Intermediate 8-7 (53 mg, 69 μmol, purity 75%) was dissolved in 10 mL of methanol; under nitrogen protection, 10% Pd/C (50 mg) was added to the solution; the hydrogen replacement reaction system was performed three times, and the reaction was carried out in a hydrogen atmosphere (15Psi) and stirred at 20°C for 1 hour; the reaction solution was filtered through celite, and the filtrate was evaporated to dryness under reduced pressure, and purified by reverse-phase column preparation to obtain a mixture of compounds I-8 and I-9 (24 mg).

The mixture was further separated by chiral column SFC. Chiral analysis conditions: DAICEL CHIRALPAK AS-3 (specification 150mm*4.6mm, particle size 3μm), elution phase is CO ₂ (A): ethanol containing 0.05% diethylamine (B), gradient 0-5 minutes ( A/B=95/5 to 60/40), 5-5.5 minutes (A/B=60/40 to 95/5), 5.5-7 minutes (A/B=95/5); flow rate 2.5mL per minute ; Compound I-8, retention time: 3.053 minutes; Compound I-9, retention time: 3.458 minutes.

Chiral preparation conditions: chiral column DAICEL CHIRALPAK AS (specification 250mm*30mm, particle size 10μm); elution phase: ethanol containing 0.1% ammonia: carbon dioxide = 75%: 25%.

Compound I-8, the former peak, was obtained as a white solid (5 mg, yield: 13%, purity 95.7%).

LCMS ( _ESI ) _: m/z _Calcd . for _C26H40N5O6S2 ⁺ [M+H] ⁺ = _582.23 , found [M+H] ⁺ = 582.3. ¹ H NMR (400MHz, CD ₃ OD )δppm 8.34(d,J=2.2Hz,1H),7.78(dd,J=2.0,8.4Hz,1H),7.63(br t,J=7.8Hz,1H),5.07-4.94(m,1H), 4.83-4.76(m,1H),3.79-3.65(m,1H),3.39-3.32(m,1H),2.12-1.97(m,4H),1.78(q,J＝5.4Hz,4H),1.31( d, J=6.2Hz, 6H), 1.24(s, 9H), 1.21(d, J=6.2Hz, 6H).

Compound I-9 was obtained, the latter peak, as a white solid (6 mg, yield: 15%, purity: 96.9%).

LCMS ( _ESI ): m/z _Calcd . for _C26H40N5O6S2 ⁺ [M+H] ⁺ = _582.23 , found [M+H] ⁺ = _582.3 . ¹ H NMR (400MHz, CD ₃ OD )δppm 8.34(d, J=2.2Hz, 1H), 7.78(dd, J=2.1, 8.5Hz, 1H), 7.61(d, J=8.6Hz, 1H), 4.99(td, J=6.3, 12.4Hz ,1H),4.82-4.80(m,1H),3.51-3.39(m,1H),3.23-3.13(m,1H),2.26(br d,J＝12.3Hz,2H),2.07(br d,J ＝10.6Hz, 2H), 1.81-1.70(m, 2H), 1.47-1.40(m, 2H), 1.30(d, J＝6.2Hz, 6H), 1.25-1.20(m, 15H).

Embodiment 10～11: the synthesis of compound I-10 and compound I-11

Step 1: Synthesis of Intermediate 10-2

Dissolve compound 10-1 (100 mg, 278 μmol) and 1-8A (172 mg, 416 μmol) in 5 mL of dioxane and 1 mL of water; add Pd(dppf)Cl ₂ (278 μmol) and K ₂ in turn to the reaction system CO ₃ (77mg, 555μmol); the reaction system was replaced with nitrogen three times, and stirred at 105°C for 15 hours under the protection of nitrogen; after that, the reaction solution was distilled off the solvent under reduced pressure to obtain a brown residue. The residue was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 40%-50%) to obtain intermediate 10-2 as a light brown solid (60 mg, yield: 38%).

LCMS (ESI) _: m _/ z _C25H36N5O6S2 ⁺ , calculated for [M+H _] ⁺ = _566.2 , found = 566.25.

Step 2: Synthesis of Intermediate 10-3

Intermediate 10-2 (60 mg, 106 μmol) was dissolved in 5 mL of methanol; under nitrogen protection, 10% Pd/C (63 mg, 53 μmol) was added to the solution. The reaction system was replaced by hydrogen three times, and the reaction was stirred in a hydrogen atmosphere (15Psi) at 20°C for 1 hour; the reaction solution was filtered with diatomaceous earth, and the filtrate was evaporated to dryness under reduced pressure to obtain intermediate 10-3 as a crude yellow oil (47mg , yield: 78%).

LCMS (ESI) _: m _{/z C25H38N5O6S2} ₊ ^, calcd for [M+H _] ⁺ ₌ 568.2, found = 568.2.

Step 3: Synthesis of intermediate 10-4

Intermediate 10-3 (47 mg, 82.4 μmol) was dissolved in a 25 mL one-necked flask with 4 mL of dichloromethane; 1 mL of trifluoroacetic acid was added with stirring; the reaction was stirred at 20° C. for 1 hour; TLC (PE:EtOAc= 4:1, the Rf value of the product is 0.37) monitoring the consumption of raw materials is complete, there is product generation. The reaction solution was evaporated to dryness under reduced pressure to obtain Intermediate 10-4 as a crude white solid (50 mg).

LCMS (ESI) _: m _/ z _C20H30N5O4S2 ⁺ , calculated for [M+H _] ⁺ = _468.2 , found = 468.1.

Step 4: Synthesis of Compounds I-10 and I-11

Intermediate 10-4 (50 mg) was dissolved in a 50 mL single-necked bottle with 5 mL of tetrahydrofuran; sodium carbonate (6 mg, 53 μmol) and 1 mL of water were added to the system; isopropyl chloroformate ( 131mg, 1.07mmol); the reaction system was stirred at 20°C for 0.5 hours; TLC (PE/EtOAc=1/1) monitored that the starting material was completely consumed, and the main product was formed. After the reaction solution was filtered, it was evaporated to dryness under reduced pressure to obtain a residue; the residue was purified by reverse-phase column preparation to obtain a mixture of compounds I-10 and I-11 (40 mg).

The mixture was further separated by chiral column SFC. Chiral analysis conditions: DAICEL CHIRALPAK AS-3 (specification 150mm*4.6mm, particle size 3μm), elution phase is CO ₂ (A): ethanol containing 0.05% diethylamine (B), gradient 0-4.5 minutes ( A/B=95/5 to 60/40), 4.5-6 minutes (A/B=95/5); flow rate was 2.5 mL per minute. The retention time of compound I-10 was 3.057 minutes, and the retention time of compound I-11 was 3.493 minutes.

Compound I-10 was obtained as the former peak as a white solid (12 mg, yield: 20%, purity 98%).

LCMS (ESI): m/z C ₂₄ H ₃₆ N ₅ O ₆ S ₂ ⁺ [M+H] ⁺ = 554.2, measured [M+H] ⁺ = 554.2. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.19 (d,J=2.3Hz,1H),7.74(dd,J=2.1,8.5Hz,1H),7.55(d,J=8.5Hz,1H),4.96-4.87(m,1H),4.72(br s ,1H),3.69-3.58(m,1H),3.33-3.24(m,1H),2.94(q,J＝7.3Hz,2H),2.02-1.90(m,4H),1.74-1.67(m,4H ), 1.23 (d, J=6.2Hz, 6H), 1.13 (d, J=6.2Hz, 6H), 1.03 (t, J=7.3Hz, 3H).

Compound I-11 was obtained as the back peak, white solid (15 mg, yield: 25%, purity 100%).

Embodiment 12: the synthesis of compound I-12

Step 1: Synthesis of intermediate 12-2

Compound 12-1 (300mg, 833μmol) was dissolved in 10mL of dichloromethane in a 50mL single-necked bottle; trifluoroacetic acid (949mg, 8.33mmol) was added dropwise to the above reaction solution; the reaction system was stirred at 20°C for 2 hours ; TLC (PE:EtOAc=3:1) monitors that the reaction of raw materials is complete, and the main product is generated. The reaction solution was concentrated under reduced pressure to obtain Intermediate 12-2 as a colorless oil (280 mg, crude product).

LCMS (ESI): m/z _calcd for _C8H11BrN3S ⁺ [M+H] ⁺ = 259.99/261.99, found = 260.1 _/ 262.1.

Step 2: Synthesis of intermediate 12-3.

Intermediate 12-2 (190 mg, 730 μmol) was dissolved in 10 mL of dichloromethane in a 25 mL one-necked bottle; sodium carbonate (774 mg, 7.30 mmol) was added to the system, and isopropyl chloroformate ( 269mg, 2.19mmol); the reaction system was stirred at 20°C for 2 hours. The reaction solution was diluted with 20 mL of water and extracted with ethyl acetate (30 mL*3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain intermediate 12-3. As a crude white solid (200 mg, yield: 79%).

LCMS (ESI) _: m/z _calcd for _{C12H17BrN3O2S} ⁺ [M+H] ⁺ = _346.01 /348.01, found = 346.1/348.0.

Step 3: Synthesis of Intermediate 12-4

In a 15mL microwave reaction tube, put intermediate 12-3 (150mg, 433μmol), 12-3A (283mg, 866μmol), tetrakistriphenylphosphine palladium (50mg, 43.3μmol), potassium phosphate (276mg, 1.30mmol ); the reactants were dissolved with 4 mL of dioxane and 1 mL of water; the reaction system was sealed after being replaced with nitrogen, and reacted by microwave at 110° C. for 2 hours. The reaction solution was evaporated to dryness under reduced pressure to obtain a brown solid residue, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 60%) to obtain intermediate 12-4 as a yellow oil (110 mg, yield : 55%).

LCMS (ESI): m _/ z _{calcd for C20H27N5O4S2} ₊ ^[ M+H _] ⁺ = _466.15 , found = 466.1.

Step 4: Synthesis of Intermediate 12-5

Dissolve intermediate 12-4 (100 mg, 215 μmol) in 5 mL of methanol; under nitrogen atmosphere, add 10% Pd/C (215 μmol) to the above reaction solution; the reaction system is replaced by hydrogen three times, then stirred at 20°C 2 hours; the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to a brown residue. Chiral analysis SFC (Agilent 1260, DAD detector; Daicel chiralpack AS-3 (150mm*4.6mm, particle size 3μm); mobile phase A: CO ₂ ; B: Ethanol (0.05% DEA), gradient 5%-40% B, 0-4.5min; 5% B, 4.5-6.0min), there are two isomers in the product (the retention times are 4.159min and 4.632min, respectively). After chiral preparation (Daicel chiralpack AS (250mm*30mm, particle size 10μm), ethanol/CO ₂ containing 0.1% ammonia water), intermediate 12-5 was obtained as a white solid (70mg, retention time 4.632min, yield: 67%, purity 96%).

LCMS (ESI): m/z C ₂₀ H ₃₀ N ₅ O ₄ S ₂ ⁺ .[M+H] ⁺ calcd. = 468.17, found = 468.1; ¹ H NMR (400MHz, CD ₃ OD) δppm 7.46-7.35 (m,2H),6.88(dd,J=2.3,8.4Hz,1H),4.85-4.80(m,1H),3.53-3.40(m,1H),3.16(tt,J=3.5,12.0Hz,1H ),3.01(q,J=7.2Hz,2H),2.26(br d,J=12.3Hz,2H),2.15-2.01(m,2H),1.74(dq,J=2.9,12.8Hz,2H), 1.43(dq,J＝3.2,12.6Hz,2H),1.07–1.28(m,9H).

Step 5: Synthesis of Intermediate 12-6

Intermediate 12-5 (20mg, 43μmol) was dissolved in 3mL of 2-methyltetrahydrofuran; at 0°C, potassium carbonate (12mg, 86μmol) and p-nitrophenol chloroformate (55.6μmol ); the reaction system was stirred at 20° C. for 12 hours. TLC (PE:EtOAc=1:1) monitored the completion of the reaction, and the reaction solution was concentrated under reduced pressure to obtain Intermediate 12-6 as a crude yellow solid (23 mg).

LCMS ( _{ESI): m/z calcd for C27H32S2N6O8} ₊ _[ _M ⁺ H] ⁺ = _633.2 , found = 633.2.

Step 6: Synthesis of Compound I-12

In a 15mL single-necked bottle, add intermediate 12-6 (23mg, 36μmol) and dissolve it with 2mL of 2-methyltetrahydrofuran; add benzylamine (4mg, 36μmol) to the above reaction solution; stir the reaction at 20°C for 12 hours Afterwards, dilute with 10mL of water, and extract with ethyl acetate (5mL*3). After the organic phases are combined, they are washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a brown solid, which is separated and purified by a reverse-phase column to obtain Compound I-12, as a pale yellow solid (10 mg, yield: 45%, purity: 99.2%).

LCMS (ESI): m/z C ₂₈ H ₃₆ ^N ₆ O ₅ S ₂ ⁺ [M+H] ⁺ calcd = 601.22, found = 601.1.1 H NMR (400MHz, CD ₃ OD) δppm 8.23(d, J＝2.1Hz, 1H), 7.82(dd, J＝2.3, 8.5Hz, 1H), 7.62(d, J＝8.3Hz, 1H), 7.37-7.31(m, 4H), 7.29-7.23(m, 1H ),4.83(br d,J=6.0Hz,1H),4.42(s,2H),3.54-3.42(m,1H),3.19(tt,J=3.4,12.1Hz,1H),3.03(q,J ＝7.3Hz, 2H), 2.28(br d, J=12.0Hz, 2H), 2.09(br d, J=10.4Hz, 2H), 1.83-1.68(m, 2H), 1.51-1.37(m, 2H) ,1.23(br d,J=6.1Hz,6H),1.13(t,J=7.3Hz,3H).

Embodiment 13: the synthesis of compound I-13

Step 1: Synthesis of Intermediate 13-2

Intermediate 12-5 (10 mg, 21.4 μmol) was dissolved in 2 mL of methanol, and 3,4-dimethoxycyclobutene-3-ene-1,2-dione (25.7 μmol) was added; the reaction system After stirring at 20°C for 48 hours, it was concentrated under reduced pressure to obtain Intermediate 13-2 as a crude white solid (11 mg).

LCMS (ESI) _: m _/ z _{calcd for C25H32N5O7S2} ₊ ^[ M+H _] ⁺ = 578.17, found = 578.1.

Step 2: Synthesis of Compound I-13

Intermediate 13-2 (11 mg, 19 μmol) was dissolved in 5 mL of methanol, and aniline (18 mg, 190 μmol) was added simultaneously; the resulting reaction system was stirred at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a yellow solid, which was separated by a reverse-phase column to obtain compound I-13 as a white solid (3 mg, yield: 22%, purity: 89%).

LCMS (ESI): m/z C ₃₀ H ₃₆ N ₆ O ₆ S ₂ ⁺ [M+H] ⁺ calcd = 639.21, found = 639.2. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.21-8.15 ( m,1H),7.93(br d,J=7.7Hz,1H),7.70(d,J=8.2Hz,1H),7.51(br d,J=8.2Hz,2H),7.38(t,J=7.9 Hz, 2H), 7.18-7.10(m, 1H), 4.84-4.79(m, 1H), 3.48(br t, J=11.7Hz, 1H), 3.19(br t, J=12.1Hz, 1H), 3.08 (q,J=7.2Hz,2H),2.28(br d,J=12.8Hz,2H),2.09(br d,J=11.1Hz,2H),1.82-1.68(m,2H),1.51-1.38( m, 2H), 1.23 (br d, J = 6.1 Hz, 6H), 1.17-1.06 (m, 3H).

Embodiment 14: the synthesis of compound I-14

Step 1: Synthesis of Intermediate 14-6

In a 250mL single-necked bottle, add compound 14-5 (1.00g, 4.64mmol), and dissolve it with 50mL of dichloromethane; add triethylamine (940mg, 9.29mmol) and methanesulfonic anhydride (6.04mmol) to the reaction system ; The reaction system was stirred at 0°C for 0.5 hours. TLC monitors that the starting material is consumed completely, and the main product is formed. The reaction solution was concentrated under reduced pressure to an oil, and silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 30%) gave intermediate 14-6 as a white solid (1.1 g, yield: 81 %).

¹ H NMR (400MHz, CD ₃ Cl) δPPM 4.86(br s,1H),4.60-4.37(m,1H),3.50(br s,1H),2.99(s,3H),2.11-1.96(m,2H ), 1.89-1.77(m,2H), 1.75-1.66(m,2H), 1.61-1.51(m,2H), 1.42(s,9H).

Step 2: Synthesis of Intermediate 14-2A

In a 50 mL single-necked bottle, intermediate 14-6 (200 mg, 682 μmol) was added and dissolved with 6 mL of DMF; sodium azide (171 mg, 2.64 mmol) was added to the above solution, and stirred at 80° C. for 5 hours. TLC (PE:EtOAc=3:1) the reaction was complete, the reaction system was quenched with 30 mL of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried, and concentrated to obtain a yellow oil; the oil was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 36%) to obtain Intermediate 14-2A as a yellow solid (105 mg , yield: 64%).

¹ H NMR (400MHz, CD ₃ Cl) δppm 4.39(br s,1H),3.45(br s,1H),3.29(tt,J=4.0,11.3Hz,1H),2.13-1.99(m,4H), 1.53-1.39(m,11H),1.26-1.15(m,2H).

Step 3: Synthesis of intermediate 14-2

In a 15 mL microwave reaction tube, add alkynyl(trimethyl)silane 1A (538 mg, 5.48 mmol), intermediate 14-1 (100 mg, 274 μmol), triethylamine (554 mg, 5.48 mmol), Pd(dppf) Cl ₂ (20 mg, 27.4 μmol) and cuprous iodide (26 mg, 137 μmol); the reactant was dissolved in 4 mL of acetonitrile; the system was replaced with nitrogen three times, and the reaction vial was sealed and microwaved at 100°C for 12 hours. The reaction solution was evaporated to dryness to obtain a residue, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 30%-40%) to obtain Intermediate 14-2 as a brown oil (100 mg, purity 93%).

LCMS (ESI): m/z _Calcd _{for C17H27N2O4SSi} ₊ ^[ M+H] ⁺ = _383.1 , found = 383.1.

Step 4: Synthesis of intermediate 14-3

In a 25mL single-necked flask, intermediates 14-2A (100mg, 416μmol) and 14-2 (167mg, 437μmol) were added; 5mL of tert-butanol and 1mL of water were added to the reaction mixture, and sodium ascorbate (83mg, 416μmol ) and copper sulfate pentahydrate (52 mg, 208 μmol); the reaction system was stirred at 60° C. for 2 hours. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-40%) to obtain intermediate 14-3 as a white solid (90mg, yield: 38% , purity: 96%).

LCMS (ESI ₎ : m/z _{Calcd for C25H39N6O6S} ₊ _[ ^M +H] ⁺ = 551.2, found = 551.2.

Step 5: Synthesis of intermediate 14-4

Intermediate 14-3 (80 mg, 145 μmol) was dissolved in 4 mL of dichloromethane in a 25 mL one-necked flask; 1 mL of trifluoroacetic acid was added with stirring; the reaction was stirred at 20° C. for 1 hour. TLC (PE:EtOAc=4:1) monitored the complete consumption of starting materials and formation of products. The reaction solution was evaporated to dryness under reduced pressure to obtain Intermediate 14-4 as a crude yellow oil (80 mg).

LCMS (ESI): m/z _{Calcd for C20H31N6O4S} ₊ _[ ^M +H] ⁺ = _451.21 , found = 451.3.

Step 6: Synthesis of Compound I-14

Intermediate 14-4 (80 mg, 178 μmol) was dissolved in a 10 mL one-necked flask with 2 mL of tetrahydrofuran; sodium carbonate (53.5 μmol) and 0.5 mL of water were added to the system. Isopropyl chloroformate (218mg, 1.78mmol) was added under stirring at 20°C; the reaction system was stirred at 20°C for 0.5 hours. TLC (PE/EtOAc=1/1) monitored that the starting material was completely consumed and the main product was formed. After the reaction solution was filtered, it was evaporated to dryness under reduced pressure to obtain a residue. The residue was purified by reverse-phase column preparation to obtain compound I-14 as a white solid (68 mg, yield: 68%, purity 95.6%).

LCMS (ESI): m/z C ₂₄ H ₃₇ N ₆ O ₆ S ⁺ [M+H] ⁺ calcd = 537.3, found = 537.3. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.12-7.99 (m ,2H),7.56(dd,J=2.1,8.3Hz,1H),7.39(d,J=8.3Hz,1H),4.86-4.76(m,1H),4.64(br s,1H),4.40-4.31 (m,1H),3.35(tt,J=4.0,11.6Hz,1H),2.79(q,J=7.3Hz,2H),2.11(br d,J=12.2Hz,2H),2.02-1.76(m , 4H), 1.39-1.23 (m, 2H), 1.14 (d, J = 6.2Hz, 6H), 1.05 (br d, J = 6.1Hz, 6H), 0.91 (t, J = 7.2Hz, 3H).

Embodiment 15: the synthesis of compound I-15

Step 1: Synthesis of Intermediate 15-2

In a 500mL single-necked bottle, add compound 15-1 (7.0g, 23.3mmol), and dissolve it with 100mL of dichloromethane; add dimethylaminopyridine (285mg, 2.33mmol) and cyclopropylamine (3.99 g, 70 mmol); the reaction system was stirred at 20°C for 6 hours. TLC monitors that the reaction of raw materials is complete, and the main product is formed. The reaction solution was diluted with 50 mL of water, extracted with ethyl acetate (80 mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a brown solid residue. After silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-46%), intermediate 15-2 was obtained as a yellow solid (5.7 g, yield: 76%).

LCMS ( _ESI ): m/z _Calcd . for _C9H10BrN2O4S ⁺ [M+H] ⁺ ₌ 320.95/322.95, found = 320.9/322.9.

Step 2: Synthesis of Intermediate 15-3

In a 250mL three-neck flask, put intermediate 15-2 (5.0g, 15.6mmol), and dissolve it with 50mL of ethanol and 10mL of water; add ammonium chloride (6.66g, 125mmol) and iron powder to the system in turn (6.96g, 125mmol); the reaction system was stirred at 80°C for 1 hour. After the reaction was complete, filter, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 30%) to obtain intermediate 15-3 as a yellow solid ( 3.0 g, yield: 66%).

LCMS (ESI): m/z C ₉ H ₁₂ BrN ₂ O ₂ S ⁺ [M+H] ⁺ calcd = 290.0/292.0, found = 290.0/291.9. ¹ H NMR (400MHz, CD ₃ Cl) δppm 7.51 (d,J=3.0Hz,1H),7.44(d,J=8.5Hz,1H),6.70(dd,J=2.9,8.5Hz,1H),5.51(s,1H),4.15-3.77(m, 2H), 2.19 (dtt, J=1.8, 3.5, 6.8Hz, 1H), 0.73-0.66 (m, 2H), 0.61-0.55 (m, 2H).

Step 3: Synthesis of intermediate 15-4

In a 100mL single-necked bottle, put intermediate 15-3 (3.0g, 10.3mmol), and dissolve it with 10mL of dichloromethane; add sodium carbonate (10.92g, 103mmol) to the above solution; react under stirring at 20°C , dropwise added isopropyl chloroformate (3.79g, 30.9mmol); the reaction system was stirred at 20°C for 2 hours, diluted with 20mL of water, and extracted with dichloromethane (10mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure to obtain a white solid residue, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 46%) to obtain intermediate 15-4 as a white solid (2.2 g, yield: 57%).

LCMS ( _ESI ): m/z _Calcd . for _{C13H18BrN2O4S} ⁺ [M+H] ⁺ ₌ 377.01/379.01, found = 377.0/379.0.

Step 4: Synthesis of Intermediate 15-5

In a 25mL three-neck flask, put intermediate 15-4 (300mg, 795μmol) and ethynyl (trimethyl)silane (234mg, 2.39mmol), and dissolve it with 10mL of dioxane; Pd(dppf)Cl ₂ (29mg, 40μmol), cuprous iodide (15mg, 80μmol), triethylamine (241mg, 2.39mmol); the reaction system was stirred at 110°C for 8 hours, then concentrated under reduced pressure to a brown residue , the residue was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-50%) to obtain intermediate 15-5 as a yellow oil (200 mg, yield: 64%).

LCMS (ESI): m _/ z _calcd for _{C18H27N2O4SSi} ⁺ [M+H] ⁺ = _395.14 , found = 395.1.

Step 5: Synthesis of Intermediate 15-6

Intermediate 15-5 (190 mg, 482 μmol), sodium ascorbate (95 mg, 482 μmol), copper sulfate pentahydrate (60 mg, 241 μmol), N-(4-azidodicyclohexyl) tert-butyl carbamate (intermediate 14 -2A) (173 mg, 722 μmol) was placed in a 25 mL three-necked flask, and dissolved by adding 5 mL of tert-butanol and 1 mL of water. After the reaction system was stirred at 110°C for 8 hours, the reaction solution was concentrated to a brown solid residue, and the residue was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 50%) to obtain intermediate 15- 6, as a yellow oil (80 mg, yield: 30%).

LCMS (ESI): m _/ z calcd for _C26H38N6O6S ⁺ [M+H] ⁺ = _563.26 , _found = 563.1.

Step 6: Synthesis of intermediate 15-7

Intermediate 15-6 (40mg, 71μmol) was placed in a 20mL single-necked bottle, and 5mL of dichloromethane was added to dissolve it; to the above reaction solution, trifluoroacetic acid (8mg, 71μmol) was slowly added dropwise; after the dropwise addition, The reaction system was stirred at 20°C for 2 hours. TLC (PE:EtOAc=3:1) monitored the completion of the raw material reaction and the formation of product. After the reaction solution was concentrated, Intermediate 15-7 was obtained as a crude colorless oil (25 mg, yield: 76%).

LCMS (ESI): m _/ z calcd _for _C21H31N6O4S ⁺ [M+H] ⁺ = _463.20 , found = 463.1.

Step 7: Synthesis of Compound I-15

Intermediate 15-7 (25mg, 54μmol) was placed in a 50mL single-necked bottle, and 10mL of dichloromethane was added to dissolve it; sodium carbonate (17mg, 162μmol) was added to the above system, and isochloroformic acid was added dropwise under stirring. Propyl ester (20mg, 162μmol); the reaction system was stirred at 20°C for 2 hours, then quenched with 20mL of water; the system was extracted with dichloromethane (30mL*3); after the organic phases were combined, they were washed with saturated brine, anhydrous Dry over sodium sulfate, filter and distill off the solvent under reduced pressure to obtain a white solid residue, and obtain compound I-15 as a white solid ( 20 mg, yield: 66%, purity 97%).

LCMS (ESI): m/z C ₂₅ H ₃₇ N ₆ O ₆ S ⁺ [M+H] ⁺ calculated value = 549.24, found value = 549.1. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.31-8.22 (m ,2H),7.78(dd,J=2.0,8.5Hz,1H),7.58(d,J=8.5Hz,1H),5.03-4.97(m,1H),4.86-4.79(m,1H),4.54( tt,J=3.9,11.9Hz,1H),3.52(tt,J=4.0,11.6Hz,1H),2.34-2.22(m,3H),2.17-1.93(m,4H),1.56-1.43(m, 2H), 1.32 (d, J=6.2Hz, 6H), 1.27-1.18 (m, 6H), 0.56-0.46 (m, 4H).

Embodiment 16～17: the synthesis of compound I-16 and compound I-17

Step 1: Synthesis of Intermediate 16-2

Compound 16-1 (400mg, 908μmol) was placed in a 50mL single-necked bottle, and 10mL of methanol was added; after the reactant was dissolved, cuprous oxide (26mg, 182μmol) and 30% ammonia water (2.28g, 19.5mmol, Concentration: 30%); the reaction system was stirred at 25° C. for 2 hours. TLC (PE:EtOAc=1:1) monitored the complete reaction of raw materials, and the formation of new products. The reaction solution was concentrated to a solid residue and subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-50%) to obtain Intermediate 16-2 as a yellow oil (210 mg).

LCMS (ESI): m/z C ₁₄ H ₂₃ N ₃ NaO ₄ S ⁺ , [M+Na] ⁺ calcd. = 352.0, found = 352.3.

Step 2: Synthesis of Intermediate 16-2A

In a 50 mL single-necked bottle, compound 16-5 (500 mg, 2.34 mmol) and compound 16-5A (312 mg, 2.34 mmol) were added; the reactant was dissolved in 5 mL of methanol; the system was stirred at 25° C. for 20 minutes. TLC (PE:EtOAc=5:1) monitored the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the intermediate 16-2A was obtained by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-25%), As a yellow oil (360 mg, yield: 46%).

LCMS (ESI): m/z _Calcd _for _C17H35N2O4 ⁺ , [M+H] ⁺ = 331.3, _found = 331.0.

Step 3: Synthesis of Intermediate 16-3

Intermediate 16-2 (200mg) was dissolved in 8mL of tetrahydrofuran, and at 0°C, potassium carbonate (3eq.) and p-nitrophenol carbonate (1.2eq.) were added successively; the reaction system was stirred at 0°C 20 minutes. A tetrahydrofuran (5 mL) solution of Intermediate 16-2A (1.5 eq.) was slowly added dropwise to the above reaction solution; the system was stirred at 20° C. for 1 hour. TLC (PE:EtOAc=3:1) monitored the complete consumption of raw materials and the formation of new products. The reaction solution was concentrated to a residue under reduced pressure, and the intermediate 16-3 was obtained as a yellow solid (220 mg) through silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-100%).

LCMS (ESI) _: m/z _Calcd _for _C30H50N5O8S ⁺ , [M+H] ⁺ = 640.3, found = 640.7.

Step 4: Synthesis of intermediate 16-4

Intermediate 16-3 (220 mg, 344 μmol) was placed in a 25 mL one-necked bottle and dissolved with 4 mL of dichloromethane; at 20° C., 4 mL of trifluoroacetic acid was slowly added dropwise to the above system. After the addition was complete, the reaction was stirred at 20°C for 20 minutes. The completion of the reaction was monitored by TLC, and the reaction solution was evaporated to dryness under reduced pressure to obtain Intermediate 16-4 as a yellow oil (170 mg).

LCMS (ESI): m/z _Calcd _{for C23H36N5O5S} ₊ ^[ M+H] ⁺ = _494.2 , found = 494.2.

Step 5: Synthesis of Compounds I-16 and I-17

Put the intermediate 16-4 (150mg, 304μmol) into a 100mL single-necked bottle, and dissolve it with 8mL of tetrahydrofuran; add 2.5mL of sodium carbonate aqueous solution (4M) to the solution; Isopropyl chloroformate (1.56 g, 12.7 mmol); after the dropwise addition, the system was stirred at 25° C. for 20 minutes. TLC (PE:EtOAc=1:1) monitored the completion of the reaction, and the reaction solution was diluted with 30 mL of water, and extracted with ethyl acetate (20 mL*2). After the organic phases were combined, they were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain a solid residue, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 50% ) to give a mixture of compounds I-16 and I-17 as a white solid (85 mg).

The mixture was further separated by chiral column SFC. Chiral analysis conditions: DAICEL CHIRALPAK AS-3 (size 150mm*4.6mm, particle size 3μm), elution phase is CO ₂ (A): ethanol containing 0.05% diethylamine (B), gradient 0-2 minutes ( A/B=95/5 to 60/40), 2-3.2 minutes (A/B=60/40), 3.2-4 minutes (A/B=95/5). The flow rate was 4 mL per minute. Compound I-16 retention time: 1.155 minutes, compound I-17 retention time: 1.392 minutes.

Chiral column SFC separation and preparation conditions: chiral column DAICEL CHIRALPAK AS (specification 250mm*30mm, particle size 10μm); elution phase: ethanol containing 0.1% ammonia: carbon dioxide = 70%: 30%.

Compound I-16, as the front peak, was a white solid (24 mg, yield: 13%, purity: 95.2%).

LCMS (ESI): m/z C ₂₇ H ₄₂ N ₅ O ₇ S ⁺ , calculated for [M+H] ⁺ = 580.3, found = 580.2. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.32(d, J＝2.5Hz, 1H), 7.71(dd, J＝2.5, 8.6Hz, 1H), 7.31(d, J＝8.6Hz, 1H), 6.76(d, J＝3.0 Hz, 1H), 6.56(d, J＝3.1Hz,1H),5.03-4.96(m,2H),4.06-3.94(m,1H),3.84(br s,1H),1.96-1.85(m,4H),1.82-1.68(m,4H ), 1.32 (d, J=6.2Hz, 6H), 1.28-1.23 (m, 15H).

Compound I-17, the latter peak, white solid (27 mg, yield: 15%, purity: 97.3%).

LCMS (ESI): m/z C ₂₇ H ₄₂ N ₅ O ₇ S ⁺ , calculated for [M+H] ⁺ = 580.3, found = 580.2. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.32(d, J＝2.5Hz, 1H), 7.71(dd, J＝2.5, 8.6Hz, 1H), 7.31(d, J＝8.6Hz, 1H), 6.71(d, J＝3.1Hz, 1H), 6.56(d, J＝3.1Hz,1H),5.03-4.97(m,2H),4.02-3.91(m,1H),3.51-3.40(m,1H),2.10-1.94(m,4H),1.83-1.70(m, 2H), 1.48-1.38 (m, 2H), 1.32 (d, J=6.2Hz, 6H), 1.28-1.19 (m, 15H).

Embodiment 18: Synthesis of Compound I-18

In a 50 mL single-necked bottle, compound I-2 (10 mg, 16.8 μmol) and TFA (2 mL) were added, and the reaction system was stirred at 25° C. for 15 minutes; the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase chromatography to obtain compound I-18 as a white solid (8 mg, purity 95.7%).

LCMS (ESI): m/z calculated for C ₂₄ H ₃₅ N ₄ O ₆ S ₂ ⁺ , [M+H] ⁺ = 539.2, found 539.1. ¹ H NMR (400MHz, CD ₃ OD) δppm 9.65(s, 1H), 8.32(d, J=2.1Hz, 1H), 7.70(dd, J=2.1, 8.3Hz, 1H), 7.38-7.24(m, 1H), 5.10-5.01(m, 1H), 4.85-4.81 (m,1H),3.47(tt,J=3.9,11.6Hz,1H),3.01(tt,J=3.4,12.1Hz,1H),2.28-2.21(m,2H),2.20-2.16(m,3H ),2.13-2.05(m,2H),1.70(dq,J＝3.0,12.8Hz,2H),1.49-1.39(m,2H),1.34(d,J＝6.2Hz,6H),1.24(br d , J=6.2Hz, 6H).

Embodiment 19: Synthesis of Compound I-19

Put compound I-6 (11 mg, 16.8 μmol) into a 10 mL single-necked bottle, and dissolve it with 2 mL of TFA; the reaction system was stirred at 30° C. for 0.2 hours. The reaction solution was evaporated to dryness under reduced pressure to an oily substance, and compound I-19 was prepared by a reverse-phase column as a white solid (7 mg, yield: 68%, purity: 99%).

LCMS (ESI): m/z calculated for C ₂₄ H ₃₂ N ₄ O ₆ S ₂ F ₃ ⁺ , [M+H] ⁺ = 593.2, found 593.1. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.32 ( d,J=2.3Hz,1H),7.68(dd,J=2.3,8.3Hz,1H),7.32(d,J=8.5Hz,1H),5.01(dt,J=6.3,12.5Hz,1H), 4.83(br s,1H),3.47(tt,J＝3.9,11.6Hz,1H),3.02(tt,J＝3.5,12.1Hz,1H),2.32-2.23(m,2H),2.13-2.05(m ,2H),1.71(dq,J=2.9,12.9Hz,2H),1.49-1.39(m,2H),1.34(d,J=6.3Hz,6H),1.24(br d,J=6.2Hz,6H ).

Embodiment 20: the synthesis of compound 1-20

Step 1: Synthesis of Intermediate 20-1

Intermediates 5-5 (350mg, 843μmol) and 12-3A (220mg, 647μmol) were placed in a 10mL microwave reaction tube, and 1mL of water and 5mL of ethylene glycol dimethyl ether were added sequentially; in the above reaction mixture 1,1'-di-tert-butylphosphinoferrocenepalladium dichloride (55 mg, 84.3 μmol) and potassium fluoride (244 mg, 4.21 mmol) were added to the reaction system, which was replaced with nitrogen and then sealed. And react under microwave conditions at 130° C. for 3 hours. The reaction solution was concentrated under reduced pressure to a brown residue, and intermediate 20-1 was obtained as a white solid (25mg, purity: 98.4% ).

LCMS (ESI): m/z calculated for C ₂₂ H ₃₀ N ₄ S ₂ O ₄ F ₃ ⁺ , [M+H] ⁺ = 535.2, found 535.0.

Step 2: Synthesis of Intermediate 20-2

Intermediate 20-1 (20 mg, 37.4 μmol), 3-bromo-1-tetrahydropyran-2-ylpyrazole (9 mg, 37.4 μmol), cesium carbonate (12 mg, 37.4 μmol), Pd ₂ (dba) ₃ (3mg, 3.74μmol) and XPhos (18mg, 37.4μmol) were placed in a 10mL single-necked bottle; dissolved with 2mL of dioxane; the reaction system was replaced with nitrogen for 3 times, and stirred at 120°C under nitrogen protection for 24 Hour. The reaction solution was evaporated to dryness under reduced pressure to obtain an oily residue, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 50%) to obtain intermediate 20-2 as a white solid (18 mg, purity 95 %). LCMS (ESI): m/z calculated for C ₃₀ H ₄₀ O ₅ N ₆ S ₂ F ₃ ⁺ , [M+H] ⁺ = 685.2, found 685.0.

Step 3: Synthesis of Compound I-20

Intermediate 20-2 (14mg) was placed in a 10mL single-necked bottle, and 3mL of trifluoroacetic acid was added; the reaction system was stirred at 40°C for 2 hours; after the reaction solution was concentrated, compound I-20 was isolated by reverse phase column preparation , as a white solid (7 mg, purity: 90%).

LCMS (ESI): m/z calculated for C ₂₅ H ₃₂ N ₆ S ₂ O ₄ F ₃ ⁺ , [M+H] ⁺ = 601.2, found 601.1.1 H NMR (400MHz, CD ₃ OD) δ = ^7.98 (br s,1H),7.59(d,J=2.4Hz,1H),7.42(br d,J=7.6Hz,1H),7.21(d,J=8.3Hz,1H),6.04(d,J= 2.1Hz, 1H), 4.85(br s, 1H), 3.54-3.41(m, 1H), 3.06-2.84(m, 3H), 2.30-2.21(m, 2H), 2.09(br d, J＝10.5Hz ,2H),1.76-1.66(m,2H),1.49-1.37(m,2H),1.24(br d,J=6.1Hz,6H),1.11(t,J=7.2Hz,3H).

Embodiment 21: the synthesis of compound I-21

Step 1: Synthesis of intermediate 21-1

In a 25mL single-necked bottle, add raw material 5-1 (500mg, 1.94mmol), and dissolve it with 5mL of ethanol; add calcium carbonate (581mg, 5.81mmol) and 1-bromobutan-2-one ( 584mg, 3.87mmol); the reaction system was stirred at 80°C for 0.4 hours. The reaction solution was concentrated under reduced pressure to a residue, and the intermediate 21-1 was obtained as a white solid (570mg, yield: 95% , purity: 99%).

LCMS (ESI): m/z calculated for C ₁₆ H ₂₇ N ₂ O ₂ S ⁺ .[M+H] ⁺ = 311.18, found [M+H] ⁺ = 311.1.

Step 2: Synthesis of intermediate 21-2

Intermediate 21-1 (500mg, 1.61mmol) was placed in a 10mL single-necked bottle, dissolved with 2mL of DMF, and NBS (373mg, 2.09mmol) was added; the reaction system was stirred at 20°C for 0.2 hours; after the raw materials disappeared , Add 10 mL of water and 10 mL of ethyl acetate to the system. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL*2); the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain an oil, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 20%) to obtain intermediate 21-2 as a white solid (600 mg, yield: 96%, Purity: 99%).

LCMS (ESI): m/z calculated for C ₁₆ H ₂₆ BrN ₂ O ₂ S ⁺ .[M+H] ⁺ = 389.09/391.09, found [M+H] ⁺ = 389.0/391.1.

Step 3: Synthesis of intermediate 21-3

Intermediate 21-2 (1.79g, 4.62mmol) was placed in a 50mL single-necked bottle; and dissolved with 10mL of dichloromethane; trifluoroacetic acid (7.70g, 67.5mmol) was added to the above reaction solution; the reaction system was Stir at 25°C for 10 minutes; the reaction solution is concentrated under reduced pressure to obtain a residue. The residue was dissolved in 20 mL of THF, and aqueous sodium bicarbonate solution (2M, 3.08 mL) was added to the system; while the reaction was stirred at 20°C, isopropyl chloroformate (1.69 g, 13.9 mmol) was added, and the reaction system continued to stir for 4 hours ; Add 30mL of water and 30mL of ethyl acetate to the system. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20mL*2); after the organic phases were combined, they were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain an oil, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 20%) to obtain intermediate 21-3 as a white solid (480 mg, yield: 27%, Purity: 99%).

LCMS (ESI): m/z calculated for C ₁₅ H ₂₄ BrN ₂ O ₂ S ⁺ .[M+H] ⁺ = 374.07/376.06, found [M+H] ⁺ = 374.03/376.06.

Step 4: Synthesis of Compound I-21

Intermediate 21-3 (50 mg, 133 μmol) and Intermediate 2-3A (59 mg, 133 μmol) were placed in a 10 mL single-necked bottle, and 2 mL of ethylene glycol dimethyl ether, tetrakistriphenylphosphine palladium (8 mg , 6.66 μmol) and potassium fluoride (39 mg, 666 μmol); the reaction system was replaced with nitrogen, and reacted at 90° C. for 15 hours. The reaction solution was concentrated under reduced pressure to a brown residue, and compound I-21 was obtained as a white solid (12 mg, yield: 15%, purity: 98.5%) by reverse-phase column separation and purification.

LCMS (ESI): m/z calculated for C ₂₉ H ₄₅ N ₄ O ₆ S ₂ ⁺ , [M+H] ⁺ = 609.28, found 609.2. ¹ H NMR (400MHz, CD ₃ OD) δppm ¹ H NMR ( 400MHz, METHANOL-d4) δppm 8.37 (d, J = 2.0Hz, 1H), 7.65 (dd, J = 2.0, 8.3Hz, 1H), 7.27 (d, J = 8.3Hz, 1H), 5.05-4.99 (m ,1H),4.86-4.82(m,1H),3.50-3.46(m,1H),2.98(br t,J=3.3Hz,1H),2.61(q,J=7.5Hz,2H),2.22(br t,J=11.9Hz,2H),2.08(br d,J=10.5Hz,2H),1.72-1.62(m,2H),1.49-1.37(m,2H),1.34(d,J=6.3Hz, 6H),1.26-1.21(m,15H),1.19-1.15(m,3H).

Embodiment 22: the synthesis of compound I-22

Referring to the synthetic routes of Example 12 and Example 20, the corresponding raw materials were replaced with 5-amino-N-(tert-butyl)-2-(4,4,5,5-tetramethyl-1,3,2-di Oxybenzaldehyde-2-yl)benzenesulfonamide and intermediate 5-5 were used as starting materials to prepare compound I-22 as a white solid.

LCMS (ESI): m/z calculated value C ₃₂ H ₄₁ F ₃ N ₅ O ₅ S ₂ ⁺ .[M+H] ⁺ = 696.25, found value [M+H] ⁺ = 696.2. ¹ H NMR (400MHz, CD ₃ OD)δppm 8.19(d,J=2.3Hz,1H),7.51(dd,J=2.3,8.4Hz,1H),7.28-7.20(m,4H),7.18-7.12(m,2H),4.70 (m,1H),4.32(s,2H),3.43-3.29(m,1H),2.89(tt,J=3.6,12.1Hz,1H),2.15(br d,J=11.8Hz,2H),2.03 -1.92(m,2H),1.67-1.52(m,2H),1.37-1.25(m,2H),1.15-1.10(m,15H).

Embodiment 23: Synthesis of compound 1-23

Referring to the synthetic route of Example 20, the corresponding raw materials were replaced with 5-amino-N-(tert-butyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde- 2-yl)benzenesulfonamide and 2-bromo-1H-imidazole were used as raw materials to prepare compound I-23 as a white solid.

LCMS (ESI): m/z calculated for C ₂₇ H ₃₆ F ₃ N ₆ O ₄ S ₂ ⁺ .[M+H] ⁺ = 629.22, found [M+H] ⁺ = 629.3.

Embodiment 24: Synthesis of Compound I-24

Referring to the synthetic route of Example 20, the corresponding raw materials were replaced with 5-amino-N-(tert-butyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde- 2-yl)benzenesulfonamide and 2-bromooxazole were used as raw materials to prepare compound I-24 as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δppm 8.38 (d, J = 2.2Hz, 1H), 7.63 (dd, J = 2.2, 8.3Hz, 1H), 7.42 (s, 1H) 7.36 (d, J = 8.2 Hz,1H),7.05(s,1H),4.80-4.70(m,1H),3.55-3.40(m,1H),3.05-2.88(m,1H),2.37-2.16(m,2H),2.15- 2.05(m,2H),1.80-1.64(m,2H),1.53-1.32(m,2H),1.33-1.21(m,15H).

Embodiment 25: the synthesis of compound 1-25

With reference to the synthetic routes of Example 1 and Example 5, the corresponding raw materials were replaced with 5-amino-N-(tert-butyl)-2-(4,4,5,5-tetramethyl-1,3,2-di Oxybenzaldehyde-2-yl)benzenesulfonamide and oxetan-3-ol were used as raw materials to prepare compound I-25 as a white solid.

LCMS (ESI): m/z calculated value C ₂₈ H ₃₈ F ₃ N ₄ O ₇ S ₂ ⁺ .[M+H] ⁺ = 663.21, found value [M+H] ⁺ = 663.3. ¹ H NMR (400MHz, CD ₃ OD)δppm 8.39(d,J=2.1Hz,1H),7.63(dd,J=2.3,8.3Hz,1H),7.30(d,J=8.3Hz,1H),5.38(quin,J=5.7 Hz,1H),5.02(td,J=6.2,12.5Hz,1H),4.90(br s,2H),4.65-4.59(m,2H),3.54-3.41(m,1H), 3.03(tt,J =3.5,12.0Hz,1H),2.28(br d,J=12.2Hz,2H),2.10(br d,J=11.0Hz,2H),1.79-1.64(m,2H),1.52-1.41(m, 2H), 1.34(d, J=6.3Hz, 6H), 1.24(s, 9H).

Embodiment 26: Synthesis of Compound I-26

With reference to the synthetic routes of Examples 12 and 20, replace the corresponding raw materials with 5-amino-N-(tert-butyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxobenzene Formaldehyde-2-yl)benzenesulfonamide, intermediate 5-5 and oxetan-3-ol were used as raw materials to prepare compound I-26 as a white solid.

LCMS (ESI): m/z calculated value C ₂₈ H ₃₈ F ₃ N ₄ O ₇ S ₂ ⁺ .[M+H] ⁺ = 663.21, found value [M+H] ⁺ = 663.3. ¹ H NMR (400MHz, CD ₃ OD)δppm 8.38(d,J=1.8Hz,1H),7.65(dd,J=2.1,8.3Hz,1H),7.33(d,J=8.3Hz,1H),5.54(quin,J=5.6 Hz,1H),4.99-4.95(m,2H),4.84(br d,J=5.8Hz,1H),4.72(dd,J=5.3,7.3Hz,2H),3.47(ddd,J=3.9,7.7 ,11.4Hz,1H),3.10-2.95(m,1H),2.27(br d,J=12.4Hz,2H),2.09(br d,J=10.4Hz,2H),1.78-1.66(m,2H) ,1.49-1.38(m,2H),1.29-1.21(m,15H).

Example 27: Synthesis of Compound 1-27

Referring to the synthetic route of Example 20, the corresponding raw materials were replaced with 5-amino-N-(tert-butyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde- 2-yl)benzenesulfonamide, intermediate 5-5 and 2-chloropyrimidine were used as raw materials to prepare compound I-27 as a white solid.

LCMS (ESI): m/z calculated value C ₂₈ H ₃₆ F ₃ N ₆ O ₄ S ₂ ⁺ .[M+H] ⁺ = 641.22, measured value [M+H] ⁺ = 641.1. ¹ H NMR (400MHz, CD ₃ OD)δppm 8.83-8.75(m,1H),8.53(d,J=4.8Hz,2H),7.96-7.80(m,1H),7.31(d,J=8.5Hz,1H),6.92(t ,J=4.8Hz,1H),4.85-4.81(m,1H),3.52-3.42(m,1H),3.02(tt,J=3.5,12.1Hz,1H),2.27(br d,J=11.9Hz ,2H),2.15-2.04(m,2H),1.80-1.65(m,2H),1.50-1.36(m,2H),1.31-1.20(m,15H).

Example 28: Synthesis of Compound I-28

Referring to the synthetic route of Example 20, the corresponding raw materials were replaced with 5-amino-N-(tert-butyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde- 2-base) benzenesulfonamide, intermediate 5-5 and 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole are raw materials to prepare compound I-28, which is white solid.

LCMS (ESI): m/z calculated value C ₂₇ H ₃₆ F ₃ N ₆ O ₄ S ₂ ⁺ .[M+H] ⁺ = 629.22, found value [M+H] ⁺ = 629.3. ¹ H NMR (400MHz, CD ₃ OD)δppm 8.06(br s,1H),7.59(d,J=2.4Hz,1H),7.40(br d,J=7.6Hz,1H),7.25-7.14(m,1H),6.04(d ,J=2.1Hz,1H),4.86-4.81(m,1H),4.61(br s,1H),3.54-3.41(m,H),3.00(tt,J=3.5,12.1Hz,1H),2.32 -2.22(m,2H),2.14-2.04(m,2H),1.70(dq,J=2.9,12.8Hz,2H),1.52-1.36(m,2H),1.30-1.23(m,15H).

Embodiment 29: Synthesis of Compound I-29

Referring to the synthetic route of Example 19, the corresponding raw materials were replaced, and compound I-29 was prepared from I-28 as a white solid.

LCMS (ESI): m/z calculated value C ₂₃ H ₂₈ F ₃ N ₆ O ₄ S ₂ ⁺ .[M+H] ⁺ = 573.16, found value [M+H] ⁺ = 573.1. ¹ H NMR (400MHz, CD ₃ OD)δppm 7.91(br s,1H),7.47(d,J=2.4Hz,1H),7.28(br d,J=7.0Hz,1H),7.11-7.04(m,1H),6.69-6.64 (m,1H),6.67(br d,J=7.7Hz,1H),5.93(d,J=2.3Hz,1H),4.74-4.66(m,1H),3.43-3.28(m,1H),2.87 (tt,J=3.5,12.0Hz,1H),2.18-2.09(m,2H),2.00-1.94(m,2H),1.57(dq,J=2.9,12.8Hz,2H),1.29(dq,J =3.1,12.6Hz,2H),1.12(br d,J=6.2Hz,6H).

Example 30: Synthesis of Compound 1-30

Referring to the synthetic route of Example 20, the corresponding raw materials were replaced with 5-amino-N-(tert-butyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde- 2-yl)benzenesulfonamide, intermediate 5-5 and 3-chloro-6-ethylpyridazine were used as raw materials to obtain compound I-30 as a white solid.

LCMS (ESI): m/z calculated value C ₃₀ H ₄₀ F ₃ N ₆ O ₄ S ₂ ⁺ .[M+H] ⁺ = 669.2, found value [M+H] ⁺ = 669.2. ¹ H NMR (400MHz, CD ₃ OD)δppm 8.60-8.51(m,1H),7.91(dd,J=2.3,8.4Hz,1H),7.39(d,J=9.2Hz,1H),7.20(d,J=8.5Hz,1H ), 7.10(d, J=9.1Hz, 1H), 4.75-4.71(m, 1H), 3.41-3.31(m, 1H), 2.90(tt, J=3.4Hz, 12.1Hz, 1H), 2.79(q ,J=7.6Hz,2H),2.16(br d,J=12.5Hz,2H),2.02-1.94(m,2H),1.59(q,J=12.8Hz,2H),1.38-1.28(m,2H ), 1.23(t, J=7.6Hz, 3H), 1.51-1.10(m, 15H).

Example 31-32: Synthesis of Compound 1-31 and Compound 1-32

Step 1: Synthesis of Intermediate 31-2

Compound 31-1 (100 mg, 213 μmol) was placed in a 10 mL single-necked bottle, dissolved in 2 mL of dioxane, and cesium carbonate (139 mg, 428 μmol), 3-bromo-1-tetrahydropyran-2 -ylpyrazole (98 mg, 427 μmol), Pd ₂ (dba) ₃ (19 mg, 21 μmol), Xphos (15.29 mg, 32.08 μmol). The reaction system was replaced with nitrogen for 3 times, and stirred and reacted for 17 hours under the protection of nitrogen at 110°C. The reaction solution was evaporated to dryness under reduced pressure to obtain an oily residue, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 60%) to obtain intermediate 31-2 as a yellow oil (110 mg, 178 μmol , Yield: 84%). LCMS (ESI): m/z calculated for C ₂₈ H ₄₀ N ₇ O ₅ S ₂ ⁺ .[M+H] ⁺ = 618.25, found [M+H] ⁺ = 618.3.

Step 2: Synthesis of Compound 1-31 and Compound 1-32

Compound 31-2 (100 mg, 161.87 μmol) was placed in a 10 mL one-necked bottle, dissolved with 2 mL of dichloromethane, and 1.2 mL of trifluoroacetic acid (1.85 g, 16.19 mmol) was added dropwise. After the dropwise addition, the reaction system was stirred at 50° C. for 2 hours. TLC monitors that the starting material is consumed completely, and the main product is formed. After the reaction solution was evaporated to dryness under reduced pressure, silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-90%) was used to obtain a mixture of compounds I-31 and I-32 (40.2 mg).

The mixture was further separated by chiral SFC, chiral analysis conditions: instrument Agilent 126 with DAD detector, chiral column CHIRAL PAK AD-3 (specification: 150mm*4.6mm, particle size 3μm), elution phase is CO ₂ ( A): containing 0.05% ethylenediamine in ethanol (B), isocratic (A/B=60/40); flow rate 2.5 mL per minute; compound I-31, retention time: 5.605 minutes; compound I-32, retention Time: 7.736 minutes. Chiral preparation conditions: chiral column DAICEL CHIRALPAK AD (specification 250mm*30mm, particle size 10μm); elution phase: ethanol containing 0.1% ammonia water; carbon dioxide = 50%: 50%.

Compound I-31, the former peak, was obtained as a white solid (18.8 mg, yield: 21%, purity: 95%).

LCMS (ESI): m/z calculated for C ₂₃ H ₃₂ N ₇ O ₄ S ₂ ⁺ .[M+H] ⁺ = 534.20, found [M+H] ⁺ = 534.0. ¹ H NMR (400MHz, CD ₃ OD)δppm 7.91(br s,1H),7.52-7.38(m,3H),5.93(d,J=2.3Hz,1H),4.72-4.67(m,1H),3.43-3.32(m,1H), 3.05-2.96(m,1H),2.93(q,J＝7.3Hz,2H),2.20-2.11(m,2H),2.02-1.94(m,2H),1.65-1.61(m,2H),1.34- 1.33(m,2H),1.13-1.11(m,6H),1.03(t,J＝7.3Hz,3H).

Compound I-32 was obtained, the latter peak, as a white solid (4.4 mg, yield: 5%, purity: 92%).

LCMS (ESI): m/z calculated for C ₂₃ H ₃₂ N ₇ O ₄ S ₂ ⁺ .[M+H] ⁺ = 534.20, found [M+H] ⁺ = 534.0. ¹ H NMR (400MHz, CD ₃ OD)δppm 7.91(br s,1H),7.52-7.40(m,3H),5.93(d,J=2.1Hz,1H),4.72(m,1H),3.63(br t,J=4.8Hz,1H ),3.28-3.22(m,1H),2.94(q,J=7.3Hz,2H),2.00-1.90(m,4H),1.69(q,J=5.4Hz,4H),1.12(d,J= 6.2Hz, 5H), 1.14-1.09(m, 1H), 1.04(t, J=7.3Hz, 3H).

Example 33: Synthesis of Compound 1-33

Compound 1-4 (100 mg, 167 μmol) was dissolved with 2 mL of trifluoroacetic acid. The reaction system was stirred at 60°C for 1 hour. LCMS monitored the reaction to be complete. The residue after the reaction solution was evaporated to dryness under reduced pressure was dissolved in 5 mL of methanol, and 2 mL of saturated aqueous sodium bicarbonate solution was added. The reaction system was concentrated under reduced pressure to obtain a crude solid, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 100%) to obtain compound I-33 as a white solid (72.4mg, yield: 80% ). LCMS (ESI): m/z calculated value C ₂₄ H ₃₂ D ₃ N ₄ O ₆ S ₂ ⁺ .[M+H] ⁺ = 542.22, measured value [M+H] ⁺ = 542.1. ¹ H NMR (400MHz, CD ₃ OD)δppm 8.31(d,J=2.3Hz,1H),7.69(dd,J=2.3,8.3Hz,1H),7.29(d,J=8.3Hz,1H),5.07-4.97(m,1H ),4.87-4.82(m,1H),3.49-3.43(m,1H),2.98-2.95(m,1H),2.23(br d,J=12.5Hz,2H),2.08(br dd,J=3.0 ,13.5Hz,2H),1.70-1.67(m,2H),1.47-1.38(m,2H),1.34(d,J=6.2Hz,6H),1.24(br d,J=6.2Hz,6H).

Example 34: Synthesis of Compound 1-34

Step 1: Synthesis of intermediate 34-1

Compound I-4 (54 mg, 90.3 μmol) was dissolved with 5 mL of ethanol, and aqueous NaOH (2.5M, 108 μL) was added. The reaction system was stirred at 110°C for 2 hours. TLC and LCMS monitored that the starting material was completely consumed and the main product was formed. 30 mL of ethyl acetate and 30 mL of water were added to the reaction system. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL*2). After the organic phases were combined, they were washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under reduced pressure, and compound 34-1 was obtained as a white solid (40 mg, yield: 87%) through silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-90%). LCMS (ESI): m/z calculated for C ₂₄ H ₃₄ D ₃ N ₄ O ₄ S ₂ ⁺ .[M+H] ⁺ =512.24, found [M+H] ⁺ =512.3.

Step 2: Synthesis of compound I-34

Compound 34-1 (20 mg, 39 μmol) was dissolved in 0.2 mL of dioxane, and Cs ₂ CO ₃ (25.47 mg, 78.17 μmol), 5-bromo-1-methylpyrazole (31.46 mg , 195 μmol), Xphos (2.79 mg, 5.86 μmol), Pd ₂ (dba) ₃ (3.58 mg, 3.91 μmol). The reaction system was stirred at 110°C for 17 hours. The reaction solution was evaporated to dryness under reduced pressure to obtain an oily residue, which was separated by reverse phase column chromatography (column model: Welch Xtimate C18, specification 150*30mm, particle size 5um; elution phase: [A: water (NH ₃ H ₂ O +NH ₄ HCO ₃ ); B: acetonitrile]; B%: 48%-78%, 7 minutes), to obtain compound I-34 as a white solid (7.2 mg, yield: 31.13%). LCMS ( _ESI ): m/ _z calculated for _{C28H38D3N6O4S2} ⁺ . [M+H] ₊ ⁼ 592.28, _found [M ₊ H] ⁺ = 592.1. ¹ H NMR (400MHz, CD ₃ OD) δppm 7.59(d, J=2.5Hz, 1H), 7.50(d, J=2.0Hz, 1H), 7.20(d, J=8.3Hz, 1H), 7.05(dd ,J=2.5,8.3Hz,1H),6.16(d,J=2.0Hz,1H),4.85(br dd,J=6.6,13.0Hz,1H),3.75(s,3H),3.48-3.44(m ,1H),2.98-2.92(m,1H),2.27-2.18(m,2H),2.08(br dd,J=2.8,12.8Hz,2H),1.69-1.65(z,2H),1.47-1.36( m,2H),1.24(br d,J=6.2Hz,6H),1.19(s,9H).

Example 35: Synthesis of Compound 1-35

Referring to the synthesis method of I-34, using intermediate 34-1 and 3-bromo-1-methyl-1H-pyrazole as raw materials, compound I-35 was prepared as a white solid (7.2mg, yield: 30% ). LCMS ( _ESI ): m/ _z calculated for _{C28H38D3N6O4S2} ⁺ . [M+H] ₊ ⁼ 592.28, _found [ _M +H] ⁺ = 592.1. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.07(d, J=2.5Hz, 1H), 7.52-7.36(m, 2H), 7.15(d, J=8.3Hz, 1H), 5.94(d, J= 2.3Hz, 1H), 4.88-4.79(m, 1H), 3.84(s, 3H), 3.47-3.43(m, 1H), 3.03-2.88(m, 1H), 2.22(br d, J=12.2Hz, 2H), 2.08(br dd, J＝3.1, 13.2Hz, 2H), 1.69-1.65(m, J＝3.0, 12.9Hz, 2H), 1.50-1.35(m, 2H), 1.26-1.20(m, 15H ).

Example 36: Synthesis of Compound 1-36

Referring to the synthetic route of Example 20 to replace the corresponding raw materials, intermediate 5-5 and isopropyl (3-(N,N-dimethylsulfamoyl)-4-(4,4,5,5-tetramethyl 1,3,2-Dioxybenzaldehyde-2-yl)phenyl)carbamate as raw material to prepare compound I-36 as a white solid. LCMS (ESI): m/z calculated value C ₂₆ H ₃₆ F ₃ N ₄ O ₆ S ₂ ⁺ .[M+H] ⁺ = 621.20, found value [M+H] ⁺ = 621.2. ¹ H NMR (400MHz, CDCl ₃ )δppm 8.02(d, J=2.3Hz,1H),7.80(br d,J=8.5Hz,1H),7.35(d,J=8.3Hz,1H),6.83(s,1H),5.10- 5.04(m,1H),4.99-4.87(m,1H),4.49(br d,J＝4.3Hz,1H),3.68-3.45(m,1H),3.04-2.98(m,1H),2.61(s ,6H),2.34-2.12(m,4H),1.80-1.64(m,2H),1.40-1.18(m,14H).

Example 37: Synthesis of Compound 1-37

Step 1: Synthesis of Intermediate 37-2

Compound 37-1 (300 mg, 1.86 mmol) was dissolved in 5 mL of toluene, and p-toluenesulfonic acid monohydrate (35.44 mg, 186 μmol) and 3,4-dihydro-2H-pyran (157 mg, 1.86 mmol, 170 μL). The reaction system was stirred at 100°C for 2 hours. LCMS monitored that the reaction was complete and the main product was formed. The reaction solution was evaporated to dryness under reduced pressure to obtain an oily residue, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 30%) to obtain compound 37-2 as a white solid (120mg, yield: 26 %). LCMS (ESI): m/ ^z calculated for C ₉ H ₁₄ BrN ₂ O ⁺ .[M+H] ⁺ =245.03,247.03, found [M+H] ⁺ =245.2,247.2.1 H NMR (400MHz, CD ₃ Cl)δppm 6.08(s,1H),5.23(dd,J＝2.6,9.8Hz,1H),4.12-3.92(m,1H),3.71-3.53(m,1H),2.55-2.40(m,1H ),2.34(s,3H),2.19-2.07(m,1H),2.00-1.89(m,1H),1.78-1.59(m,3H).

Step 2: Synthesis of intermediate 37-3

Compound 37-2 (134 mg, 547 μmol) was dissolved in 4 mL of dioxane, and cesium carbonate (89 mg, 274 μmol), Xphos (9.78 mg, 20.5 μmol), Pd ₂ (dba) ₃ (12.5 mg, 13.7 μmol) and compound 34-1 (70mg, 137μmol). The reaction system was stirred at 110°C for 17 hours. LCMS monitors that the starting material is completely consumed and the main product is formed. The reaction solution was evaporated to dryness under reduced pressure to obtain an oily residue, which was subjected to silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0%-70%) to obtain compound 37-3 as a white solid (90 mg). _LCMS ( _ESI ): m/z calcd. _for _{C33H46D3N6O5S2} ⁺ . [M+H] ⁺ = 676.34, found _[ M+ _H ] ⁺ = 676.3.

Step 3: Synthesis of Compound I-37

Compound 37-3 (10 mg, 14.8 μmol) was dissolved with 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction system was stirred at 40°C for 2 hours. LCMS monitored complete consumption of starting material. The reaction solution was evaporated to dryness under reduced pressure to obtain a solid residue, which was separated by reverse phase column chromatography to obtain compound I-37 as a white solid (4 mg, yield: 46%), LCMS (ESI): m/z calculated value C ₂₈ H ₃₈ D ₃ N ₆ O ₄ S ₂ ⁺ .[M+H] ⁺ = 592.28, found [M+H] ⁺ = 592.1. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.00(br s,1H),7.40(br d,J=7.6Hz,1H),7.14(d,J=8.3Hz,1H),5.80(s,1H) ,4.87-4.79(m,1H),3.49-3.43(m,1H),2.98-2.95(m,1H),2.30(s,3H),2.22(br d,J=12.2Hz,2H),2.11- 2.04(m,2H),1.69-1.65(m,2H),1.48-1.37(m,2H),1.27-1.21(m,15H).

Example 38: Synthesis of Compound 1-38

Compound 37-3 (80 mg, 118 μmol) was dissolved with 10 mL of trifluoroacetic acid. The reaction system was stirred at 60°C for 2 hours. LCMS monitored complete consumption of starting material. The reaction solution was evaporated to dryness under reduced pressure to obtain a solid residue, which was separated by reverse phase column chromatography to obtain compound I-38 as a white solid (37 mg, yield: 58%). LCMS (ESI): m/z calcd _. for _{C24H30D3N6O4S2} ⁺ .[M+H] ⁺ ₌ _536.22 , _found [M ₊ H] ⁺ = 536.1. ¹ H NMR (400MHz, CD ₃ OD) δppm 7.99(br s,1H),7.39(br d,J=8.8Hz,1H),7.16(br d,J=8.3Hz,1H),5.81(s,1H ),4.84-4.79(m,1H),3.46-3.43(m,1H),2.97-2.91(m,1H),2.30(s,3H),2.22(br d,J＝13.1Hz,2H),2.07 (br d,J=13.3Hz,2H),1.69-1.66(m,2H),1.47-1.35(m,2H),1.24(br d,J=6.0Hz,6H).

Example 39: Synthesis of Compound 1-39

Referring to the synthetic route of Example 37, the corresponding raw materials were replaced, and 3-bromo-5-(trifluoromethyl)-1H pyrazole was used as the raw material to prepare compound 39-2 as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm 7.19(s,1H),6.54(s,1H),6.57-6.47(m,1H),6.57-6.47(m,1H),5.46(dd,J=2.7, 9.7Hz,1H),4.05-3.92(m,1H),3.70-3.55(m,1H),2.46-2.29(m,1H),2.15-2.01(m,1H),1.94-1.82(m,1H) ,1.73-1.47(m,3H). Compound I-39 was prepared from compound 39-2 and compound 34-1 as a white solid. LCMS ( _ESI ₎ : m/ _z _calculated for _{C28H35D3F3N6O4S2} ⁺ . [M+H] ₊ ⁼ 646.25, found _[ M+H] ⁺ = 646.1. ¹ H NMR (400MHz, CD ₃ OD) δppm 7.75(br s,1H),7.22-7.06(m,2H),6.28(s,1H),4.78-4.71(m,1H),3.45-3.30(m, 1H),2.94-2.77(m,1H),2.12(br d,J=12.3Hz,2H),1.98(br d,J=10.3Hz,2H),1.59-1.57(m,2H),1.40-1.28 (m,2H),1.17-1.07(m,15H).

Example 40: Synthesis of Compound 1-40

Refer to the synthetic route of Example 38 to replace the corresponding raw materials, and use 39-3 as the raw material to prepare compound I-40 as a white solid. LCMS ( _ESI ₎ _: m/z _calculated for _{C24H27D3F3N6O4S2} ⁺ . [M+H] ₊ ⁼ 590.19, found [ _M +H] ⁺ = 590.1. ¹ H NMR (400MHz, CD ₃ OD) δppm 7.85(s,1H),7.36-7.20(m,2H),6.40(s,1H),4.88-4.80(m,1H),3.50-3.46(m,J =3.9,11.7Hz,1H),2.98-2.92(m,1H),2.23(br d,J=12.6Hz,2H),2.12-2.03(m,2H),1.70-1.66(m,2H),1.43 -1.40(m,2H),1.24(br d,J＝6.2Hz,6H).

Example 41: Synthesis of Compound I-41

Referring to the synthetic route of Example 37, the corresponding raw materials were replaced, and 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole was used as the raw material to prepare compound I-41 as a white solid. LCMS ( _ESI ): m/ _z calculated for _{C27H36D3N6O4S2} ⁺ . [M+H] ⁺ = 578.27, found _[ _M ₊ H] ⁺ = 578.1. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.10-7.90(m,1H),7.65-7.49(m,1H),7.44-7.33(m,1H),7.19-7.07(m,1H),6.03-5.95 (m,1H),5.00-4.92(m,1H),3.42(br s,1H),2.96-2.94(m,1H),2.22-2.16(m,2H),2.06-2.02(m,2H), 1.69-1.65(m,2H),1.36-1.30(m,2H),1.24-1.13(m,15H).

Example 42: Synthesis of Compound I-42

Refer to the synthetic route of Example 38 to replace the corresponding raw materials, and use 41-2 as the raw material to prepare compound I-42 as a white solid. LCMS (ESI): m/ _z calculated for _{C23H28D3N6O4S2} ⁺ . [M+H] ⁺ ₌ _522.20 , found [ _M + _H ] ⁺ = 522.1. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.02 (d, J = 2.4Hz, 1H), 7.58 (d, J = 2.4Hz, 1H), 7.41 (dd, J = 2.5, 8.3Hz, 1H), 7.25 -7.11(m,1H),6.03(d,J＝2.4Hz,1H),4.87-4.77(m,1H),3.50-3.39(m,1H),3.04-2.91(m,1H),2.22(br d,J=11.7Hz,2H),2.07(br d,J=9.9Hz,2H),1.76-1.60(m,2H),1.45-1.42(m,2H),1.23(br d,J=6.1Hz ,6H).

Example 43: Synthesis of Compound I-43

Refer to the synthetic route of Example 33 to replace the corresponding raw materials, and use I-35 as the raw material to prepare compound I-43 as a white solid. LCMS (ESI) _: m/ _z calcd. for _{C24H30D3N6O4S2} ⁺ . [M+H] ⁺ = _536.22 , _found [M+H] ⁺ = _536.3 . ¹ H NMR (400MHz, CD ₃ OD) δppm 8.04(d, J=2.3Hz, 1H), 7.53-7.42(m, 2H), 7.17(d, J=8.3Hz, 1H), 5.96(d, J= 2.3Hz, 1H), 4.86-4.79(m, 1H), 3.83(s, 3H), 3.54-3.39(m, 1H), 2.97-2.93(m, 1H), 2.22(br d, J=12.3Hz, 2H), 2.12-2.03(m, 2H), 1.73-1.60(m, 2H), 1.48-1.34(m, 2H), 1.24(br d, J=6.0Hz, 6H).

Example 44: Synthesis of Compound I-44

Refer to the synthetic route of Example 34 to replace the corresponding raw materials, and use I-3 and 3-bromo-1-methyl-1H-pyrazole as raw materials to prepare compound I-44 as a white solid. LCMS (ESI): m/z calcd. _for _{C26H34D3N6O4S2} ₊ ^. [M+H] ⁺ = _564.25 , _found [M+H] ⁺ = 564.1. ¹ H NMR (400MHz, CD ₃ Cl) δppm 7.81 (d, J = 2.5Hz, 1H), 7.45 (dd, J = 2.5, 8.3Hz, 1H), 7.31 (d, J = 2.3Hz, 1H), 7.21 (d,J=8.3Hz,1H),6.31(s,1H),6.02(d,J=2.3Hz,1H),5.00–4.88(m,1H),4.51-4.49(m,1H),3.94- 3.85(m,4H),3.00-2.84(m,3H),2.31-2.14(m,4H),1.76-1.66(m,2H),1.37-1.28(m,2H),1.25(br d,J= 6.2Hz, 6H), 1.08(t, J=7.3Hz, 3H).

Example 45: Synthesis of Compound I-45

Refer to the synthesis routes of Example 33 and Example 34 to replace the corresponding raw materials, and use I-2 and 3-bromo-1-methyl-1H-pyrazole as raw materials to prepare compound I-45 as a white solid. LCMS (ESI): m _{/z calcd. for C24H33N6O4S2} ₊ _. ^[ M+H _] ⁺ = _533.20 , found [M+H] ⁺ = 533.2. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.04(d, J=2.5Hz, 1H), 7.54-7.40(m, 2H), 7.17(d, J=8.3Hz, 1H), 5.96(d, J= 2.3Hz, 1H), 4.87-4.79(m, 1H), 3.83(s, 3H), 3.53-3.41(m, 1H), 3.04-2.87(m, 1H), 2.23(br d, J＝11.5Hz, 2H),2.17(s,3H),2.09-2.06(m,2H),1.74-1.61(m,2H),1.48-1.38(m,2H),1.25(br d,J＝6.0Hz,6H).

Example 46: Synthesis of Compound I-46

Refer to the synthesis routes of Example 33 and Example 34 to replace the corresponding raw materials, and use I-2 and 3-bromo-1,5-dimethyl-1H-pyrazole as raw materials to prepare compound I-46 as a white solid. LCMS (ESI): m/z calcd. _for _C25H35N6O4S2 ⁺ . [M+H _] ⁺ = _547.22 , found _[ M+H] ⁺ = 547.3. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.00 (d, J = 2.4Hz, 1H), 7.42 (dd, J = 2.5, 8.3Hz, 1H), 7.16 (d, J = 8.3Hz, 1H), 5.79 (s,1H),4.84(br d,J=6.1Hz,1H),3.72(s,3H),3.53-3.41(m,1H),2.97-2.91(m,1H),2.29(s,3H) ,2.23-2.20(m,2H),2.16(s,3H),2.08-2.05(m,2H),1.70-1.66(m,2H),1.43-1.39(m,2H),1.25-1.21(m, 6H)

Example 47: Synthesis of Compound I-47

Referring to the synthesis routes of Example 33 and Example 34, replacing the corresponding raw materials, using I-2 and 4-bromo-1-methyl-1H-pyrazole as raw materials, prepared compound I-47 as a white solid. LCMS (ESI): m _{/z calcd. for C24H33N6O4S2} ₊ _. ^[ M+H _] ⁺ = _533.20 , found [M+H] ⁺ = 533.1.

¹ H NMR (400MHz, CD ₃ OD) δppm 7.63(s, 1H), 7.53(d, J=2.5Hz, 1H), 7.43(s, 1H), 7.10(d, J=8.3Hz, 1H), 6.96 (dd,J=2.5,8.3Hz,1H),4.83-4.79(m,1H),3.88(s,3H),3.46-3.41(m,1H),2.96-2.89(m,1H),2.23-2.16 (m,2H),2.14(s,3H),2.08-2.02(m,2H),1.66-1.62(m,2H),1.40-1.36(m,2H),1.22(br d,J＝6.2Hz, 6H).

Example 48: Synthesis of Compound I-48

Referring to the synthetic route of Example 37 and Example 38, replace the corresponding raw materials, and use 51-1 and 3-bromo-1-(2-tetrahydropyranyl)-1H-pyrazole as raw materials to prepare compound I-48 , as a white solid. LCMS (ESI): m/z calcd. _for _C23H31N6O4S2 ⁺ .[M+H _] ⁺ = _519.2 , found _[ M+H] ⁺ = 519.2.

H NMR (400MHz, CD ₃ OD): 8.01 (d, J = 2.4Hz, 1H), 7.56 (d, J = 2.4Hz, 1H), 7.40 (dd, J = 2.5, 8.3Hz, 1H), 7.15 ( d,J=8.3Hz,1H),6.03(d,J=2.4Hz,1H),4.84-4.77(m,1H),3.47-3.43(m,1H),2.93-2.89(m,1H),2.21 -2.14(m,2H),2.15(s,3H),2.10-1.97(m,2H),1.75-1.58(m,2H),1.41-13.7(m,2H),1.22(br d,J=6.2 Hz, 6H).

Example 49: Synthesis of Compound I-49

Referring to the synthetic routes of Example 33 and Example 34, replacing the corresponding raw materials, using I-2 and 4-bromo-1-cyclopropyl-1H-pyrazole as raw materials, prepared compound I-49 as a white solid. LCMS ( _ESI ): m/z calcd. _for _C26H35N6O4S2 ⁺ .[M+H] ⁺ = _559.2 , found _[ M+H] ⁺ = 559.2.

¹ H NMR (400MHz, CD ₃ OD) δppm 7.70(s, 1H), 7.53(d, J=2.5Hz, 1H), 7.43(s, 1H), 7.13-7.07(m, 1H), 6.96(dd, J＝2.5,8.3Hz,1H),4.84-4.78(m,1H),3.65-3.62(m,1H),3.44-3.40(m,1H),2.97-2.83(m,1H),2.21-2.18( m,2H),2.13(s,3H),2.05-2.03(m,2H),1.67-1.64(m,2H),1.47-1.31(m,2H),1.22(br d,J＝6.2Hz,6H ),1.15-1.00(m,4H).

Example 50: Synthesis of Compound 1-50

Referring to the synthetic route of Example 33 and Example 34, replace the corresponding raw materials, and use I-2 and 4-bromo-1-(difluoromethyl)-1H pyrazole as raw materials to prepare compound I-50 as a white solid . LCMS ₍ _ESI ): m/z calcd _. for _{C24H31F2N6O4S2} ⁺ . [M+H] ⁺ = 569.2, found [ _M +H _] ⁺ = 569.2. ¹ H NMR (400MHz, CD ₃ OD) δppm 8.03(s, 1H), 7.72(s, 1H), 7.61(d, J=2.5Hz, 1H), 7.58-7.24(m, 1H), 7.17(d, J＝8.3Hz, 1H), 7.06(dd, J＝2.6, 8.3Hz, 1H), 4.84-4.83(m, 1H), 3.53-3.38(m, 1H), 3.01-2.84(m, 1H), 2.21 -2.16(m,2H),2.14(s,3H),2.10-2.01(m,2H),1.72-1.58(m,2H),1.41-1.38(m,2H),1.23-1.21(br d,J = 6.2Hz, 6H).

Example 51: Synthesis of Compound I-51

Step 1: Synthesis of Intermediate 51-2:

With reference to the synthesis method of Example 34, using I-2 as a raw material, intermediate 51-1 was prepared. Intermediate 51-1 (339.36 mg, 667.11 μmol) was dissolved in 10 mL of acetonitrile, and isoamyl nitrite ( 117.22mg, 1.00mmol) and copper bromide (149.0mg, 667.11μmol). The reaction system was stirred at 20°C for 2 hours. LCMS monitored the disappearance of starting material and the formation of product. 20 mL of ethyl acetate and 20 mL of water were added to the reaction system. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL*2). After the organic phases were combined, they were washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under reduced pressure, and intermediate 51-2 was obtained as a white solid (280 mg, yield: 73.30%) through silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 39%). _LCMS (ESI) _: m/z calcd. for _{C24H35BrN3O4S2} ⁺ . [M+H] ⁺ = 572.1 _, 574.1 found [ _M +H] ⁺ = 572.2, 574.2.

Step 2: Synthesis of intermediate 51-3:

Intermediate 51-2 (250 mg, 436.62 μmol) and 1-(trifluoromethyl) pyrazol-3-amine (98.95 mg, 654.93 μmol) were dissolved in 5 mL of dioxane, and potassium carbonate (181.03 mg, 1.31 mmol), BrettPhos Pd G3 (39.58 mg, 43.66 μmol). The reaction system was evacuated, replaced with nitrogen three times, and then stirred at 110° C. for 12 hours. LCMS monitors that the main product is formed, and some raw materials remain. The reaction solution was filtered, and 10 mL of ethyl acetate and 10 mL of water were added to the filtrate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (5 mL*2). After the organic phases were combined, they were washed successively with saturated ammonium chloride solution (10 mL*2) and saturated brine (8 mL*2). After drying over anhydrous sodium sulfate, it was filtered. The filtrate was evaporated to dryness under reduced pressure, and intermediate 51-3 was obtained as a white solid (130 mg, yield: 46.32%) through silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether, gradient 0% to 31%). LCMS ( _ESI ): m/z calculated _for : _{C28H38F3N6O4S2} ⁺ . [M+H _] ₊ ⁼ 643.2 found _[ M+H] ⁺ = 643.2.

Step 3: Synthesis of Compound I-51:

Intermediate 51-3 (130 mg, 202.25 μmol) was dissolved in 5 mL of trifluoroacetic acid, and the reaction system was stirred at 60° C. for 2 hours. LCMS monitors that the reaction is complete and the main product is formed. The reaction solution was evaporated to dryness under reduced pressure, and the residue was subjected to reverse-phase column chromatography to prepare compound I-51 as a white solid (83 mg, yield: 69.94%). LCMS ( _ESI ): m/z _calculated _for : _{C24H30F3N6O4S2} ₊ ^. [M+H] ⁺ = 587.2 found [M ₊ H] ⁺ = 587.0.

¹ H NMR (400MHz, CD ₃ OD) δppm 8.21(d, J=2.4Hz, 1H), 7.97(d, J=3.0Hz, 1H), 7.89-7.83(m, 1H), 7.28-7.23(m, 1H), 6.19(d, J=2.9Hz, 1H), 4.87-4.84(m, 1H), 3.46-3.42(m, 1H), 2.95-2.91(m, 1H), 2.21-2.16(m, 2H), 2.15 (s, 3H), 2.07-2.04 (m, 2H), 1.74-1.58 (m, 2H), 1.48-1.32 (m, 2H), 1.22 (br d, J = 6.2Hz, 6H).

Example 52: Synthesis of Compound I-52

Referring to the synthetic routes of Example 33 and Example 34, replacing the corresponding raw materials, using I-2 and 3-bromo-1-cyclopropyl-1H-pyrazole as raw materials, prepared compound I-52 as a white solid. LCMS (ESI): m/z calcd. _for _C26H35N6O4S2 ⁺ .[M+H _] ⁺ = _559.2 , found _[ M+H] ⁺ = 559.0.

¹ H NMR (400MHz, CD ₃ OD) δppm 8.04 (d, J = 2.5Hz, 1H), 7.53 (d, J = 2.4Hz, 1H), 7.45 (dd, J = 2.4, 8.4Hz, 1H), 7.16 (d,J=8.3Hz,1H),5.92(d,J=2.4Hz,1H),4.81-4.78(m,1H),3.56-3.52(m,1H),3.50-3.38(m,1H), 3.03-2.87(m,1H),2.22-2.20(m,2H),2.15(s,3H),2.06-2.04(m,2H),1.72-1.59(m,2H),1.41-1.39(m,2H ), 1.22 (br d, J = 6.1 Hz, 6H), 1.11-1.05 (m, 2H), 1.02-0.94 (m, 2H).

Example 53: Synthesis of Compound I-53

Referring to the synthetic routes of Example 33 and Example 34, replacing the corresponding raw materials, using I-2 and 3-bromo-1-ethyl-1H-pyrazole as raw materials, prepared compound I-53 as a white solid. LCMS (ESI): m/z calcd. _for _C25H35N6O4S2 ⁺ . [M+H _] ⁺ = _547.2 , found _[ M+H] ⁺ = 547.6.

¹ H NMR (400MHz, CD ₃ OD) δppm 8.05 (d, J = 2.5Hz, 1H), 7.51 (d, J = 2.3Hz, 1H), 7.44 (dd, J = 2.4, 8.4Hz, 1H), 7.15 (d,J=8.3Hz,1H),5.95(d,J=2.4Hz,1H),4.83-4.81(m,1H),4.13-4.07(m,2H),3.50-3.40(m,1H), 2.96-2.92(m,1H),2.26-2.18(m,2H),2.15(s,3H),2.072.04(m,2H),1.66-1.62(m,2H),1.46(t,J＝7.3 Hz, 3H), 1.43-1.34 (m, 2H), 1.23 (br d, J = 6.2Hz, 6H).

Example 54: Synthesis of Compound I-54

Referring to the synthetic route of Example 33 and Example 34, replace the corresponding raw materials, and use I-2 and 3-bromo-1-(2-fluoroethyl)-1H pyrazole as raw materials to prepare compound I-54, which is white solid. LCMS (ESI): m/z calcd. for _{C25H34FN6O4S2} ⁺ . [M+H _] ⁺ = _565.2 , _found _[ M+H] ⁺ = 565.6.

¹ H NMR (400MHz, CD ₃ OD) δppm 8.16 (d, J = 2.4Hz, 1H), 7.55 (d, J = 2.4Hz, 1H), 7.50 (dd, J = 2.4, 8.3Hz, 1H), 7.18 (d,J=8.3Hz,1H),5.97(d,J=2.4Hz,1H),4.84-4.81(m,2H),4.72-4.69(m,1H),4.42-4.38(m,1H), 4.34-4.32(m,1H),3.51-3.40(m,1H),2.97-2.93(m,1H),2.28-2.19(m,2H),2.17(s,3H),2.08-2.05(m,2H ), 1.69-1.65 (m, 2H), 1.42-1.39 (m, 2H), 1.24 (br d, J = 6.2Hz, 6H).

Example 55: Synthesis of Compound I-55

Referring to the synthetic routes of Example 33 and Example 34, replace the corresponding raw materials, and use I-2 and 3-bromo-1-(2,2,2-trifluoroethyl)-1H pyrazole as raw materials to prepare compound I -55, as a white solid. LCMS ( _ESI ): m/ _z calcd. for _{C25H32F3N6O4S2} ⁺ . [M+H] ⁺ ₌ 601.2, _found [M+ _H ] ⁺ = 601.2.

¹ H NMR (400MHz, CD ₃ OD) δppm 8.14(d, J=2.4Hz, 1H), 7.68-7.56(m, 2H), 7.18(d, J=8.3Hz, 1H), 6.03(d, J= 2.5Hz,1H),4.85-4.79(m,3H),3.51-3.39(m,1H),3.01-2.87(m,1H),2.22-2.19(m,2H),2.16(s,3H),2.07 -2.05 (m, 2H), 1.71-1.61 (m, 2H), 1.41-1.38 (m, 2H), 1.23 (br d, J=6.2Hz, 6H).

Example 56: Synthesis of Compound 1-56

Compound 1-48 (300 mg, 578.42 μmol) was dissolved in 10 mL of acetonitrile, and sodium iodide (86.70 mg, 578.42 μmol) and methyl chloromethyl carbonate (360.13 mg, 2.89 mmol) were added sequentially. The reaction system was stirred at 60°C for 16 hours. TLC (ethyl acetate:petroleum ether=1:1) monitored that the reaction of raw materials was complete, and the main product was formed. The reaction solution was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was subjected to reverse phase column chromatography (column model: Phenomenex C18 specification 80*40mm particle diameter 3um; elution phase: ([A phase: water (0.225% formic acid)-B Phase: Acetonitrile]; B% 40%-70%, 7min) Compound I-56 was prepared as a white solid (105 mg, yield: 29.92%). LCMS (ESI): m/z calculated value C ₂₆ H ₃₅ N ₆ O ₇ S ₂ ⁺ .[M+H] ⁺ ＝607.2, measured value [M+H] ⁺ ＝607.0. ¹ H NMR (400MHz, CD ₃ OD) δppm7.72 (d, J＝2.4Hz, 1H) ,7.62(d,J=1.9Hz,1H),7.24-7.19(m,1H),7.18-7.10(m,1H),6.24(d,J=1.9Hz,1H),6.05(s,2H), 4.82-4.80(m,1H),3.78(s,3H),3.44-3.40(m,1H),2.95-2.92(m,1H),2.26-2.17(m,2H),2.15(s,3H), 2.06-2.03 (m, 2H), 1.67-1.63 (m, 2H), 1.40-1.37 (m, 2H), 1.22 (br d, J = 6.2Hz, 6H).

Example 57: Synthesis of Compound 1-57

Referring to the synthetic route of Example 34, replacing the corresponding raw materials, using I-2 and 3-bromo-1-cyclopropyl-1H-pyrazole as raw materials, compound I-57 was prepared as a white solid. LCMS (ESI): _m /z _calcd . for _C30H43N6O4S2 ⁺ .[M+H _] ⁺ = 615.3, found _[ M+H] ⁺ = 615.3.

Biological Test Example 1: Inhibition of Daudi Cell Proliferation by Compounds

The initial screening process was to identify compounds that potently inhibit RAD51 through the synthetic lethal effect between cellular AID expression and RAD51. Cells with high AID expression have more DNA double-strand break damage and rely on the repair ability of RAD51 to repair DNA. Therefore, their survival depends on RAD51. By inhibiting the expression of RAD51 in such cells, significant cytotoxicity can be produced. In the biological screening activity test, Daudi cells with high AID expression were used to screen out compounds with high RAD51 inhibitory activity.

1. Materials and supplies

In addition to Daudi cells, plastic products and consumables required for this experiment include: cell culture medium, DMSO, fetal bovine serum FBS,

Chemiluminescent cell detection reagent, 96-well flat-bottom white-walled cell culture plate, 1.5mL Epi tube, 200μL pipette tip, etc.; the equipment required for this experiment includes: Envision 2104 Multilabel Reader microplate reader, SANYO carbon dioxide incubator, XDS-1B Inverted microscope, Vi-Cell XR cell viability counter, Eppendorf pipette, etc.

2. Operating procedure

All steps were performed in a sterile environment inside a biosafety cabinet, and a cell killing assay was established in the Daudi cell line. Firstly, cells in the exponential phase were collected and viable cells were counted, and each cell suspension was adjusted to an appropriate concentration with the corresponding medium, so that 90 μL of cell suspension was added to each well of a 96-well flat-bottom culture plate, and the number of cells seeded was 2000 cells/well. Take another 96-well plate, use DMSO to dissolve the test substance as the storage solution, and dilute it in equal proportions to make 10-fold working solutions with different concentrations; prepare 10-fold solvent control solution with pure DMSO.

Using a multi-channel pipette, add 10 times the compound working solution or 10 μL of the control solution to the 96-well plate inoculated with Daudi cells; each compound has three replicate wells at each concentration, and some compounds can be repeatedly detected. After adding the drugs, the culture plate was placed in a 37°C, 5% CO ₂ incubator for 3 days. On day 4, 100 μL of new medium corresponding to the compound concentration was added to the wells inoculated with cells (including solvent wells). Continue to culture the plate in a 37°C, 5% CO ₂ incubator until day 7, and read the plate with CTG. CTG assay was performed to detect cell viability as follows. The 96-well plate was equilibrated at room temperature for about 30 minutes, and 80 μl of CTG solution was added to each well. Mix with a shaker for 2 minutes to lyse the cells, and place at room temperature for 20 minutes to stabilize the fluorescent signal. Fluorescent signal values were measured with an Envision 2104 plate reader.

Percent cell death and _IC50 values were calculated comparing cell viability of compound-treated wells to control solvent wells by fluorescence signal value calculation. Subtract the medium well value from each well value in the same column, then divide this value by the solvent control cell value to obtain the normalized relative light unit value (i value). According to the RLU value, calculate the IC ₅₀ value, and take the average value of multiple tests. By calculating the IC ₅₀ value for Duadi cells, the sensitivity of the compound to the synthetic lethality of RAD51 and AID was investigated.

The test results are shown in Table 1 and Table 2 below.

In Table 1, A means: IC ₅₀ ≤0.05 μM; B means: 0.05 μM<IC ₅₀ ≤0.5 μM; C means: 0.5 μM<IC ₅₀ ≤5 μM; D means: IC ₅₀ >5 μM.

Table 1

Table 2

Biological Test Example 2: Rat Pharmacokinetic Test

According to the blood drug concentration in SD rats after oral administration of the compound at 0-24h, the pharmacokinetic parameters such as in vivo exposure, half-life and bioavailability were calculated.

1. Materials and supplies

The main reagents and consumables used are: DMSO, PEG400, Vitamin E TPGS, gavage needles and blood collection needles, EDTA-K 2 anticoagulant blood vessels, 96-well plates, acetonitrile, etc.

The main experimental instruments used are: 4°C constant temperature high-speed centrifuge, -80°C refrigerator, AB 5500LC-MS/MS.

2. Operating procedure

In vivo administration test:

The experimental animals were grouped and numbered, 3 animals in each group, and the test compound was administered orally by gavage. The dosage is 5mg/kg.

Plasma sample collection:

At 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after oral administration, 0.2 mL of blood was collected from the jugular vein and placed in an EDTA-K 2 anticoagulant test tube. Whole blood samples were centrifuged at 12,000 rpm for 3 minutes (4°C), separated from plasma within 1 hour, and stored below -70°C for testing.

Plasma sample analysis:

After the plasma sample was melted on wet ice, 30 μL of the sample was taken in a 96-well plate, and 200 μL of glacial acetonitrile containing IS (100 nM tolbutamide) was added to precipitate, vortexed and mixed for 10 minutes, and the sample was centrifuged at 5000 rpm for 5 minutes (4 ℃); take 100 μL of the sample supernatant into a 96-well liquid mass sampling plate, dilute with 100 μL of pure water, vortex and mix well, and inject into LC-MS/MS for analysis.

The concentration results of different animal tests at each time point were summarized, and the average values were used to calculate T _max (h) and C _max . T _1/2 , AUC _0-t and other parameters were calculated using a non-compartmental model.

The test results are shown in Table 3 below.

table 3

Under the test conditions, under the same dosage, compounds I-5 and I-6 have longer half-life and higher relative exposure.

Claims

A compound represented by formula I, its tautomers, stereoisomers, isotopic derivatives or pharmaceutically acceptable salts:

in,

Ring Cy 1 is

Among them, 1 bit is connected with ring Cy 2 ;

R a is unsubstituted or substituted C 1-6 alkyl, or unsubstituted or substituted C 3-6 monocyclic cycloalkyl; the substituted C 1-6 alkyl and substituted C 3-6 Monocyclic cycloalkyl is substituted by 1, 2, 3 or 4 R aa ;

R b and R c are independently hydrogen, unsubstituted or substituted C 1-6 alkyl, or unsubstituted or substituted C 3-6 monocyclic cycloalkyl; the substituted C 1-6 alkyl and substituted C 3-6 monocyclic cycloalkyl is substituted by 1, 2, 3 or 4 R aa ;

R aa is independently deuterium or halogen;

Ring Cy 2 is unsubstituted or substituted C 3-12 cycloalkyl, or unsubstituted or substituted 3-12 membered heterocycloalkyl; the substituted C 3- 12 cycloalkyl and substituted 3- 12-membered heterocycloalkyl is substituted by 1, 2, 3 or 4 R ;

R is independently halogen, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

X 1 is -NR x1 -, -NR x1 C(O)O-, -NR x1 C(O)NR x1 -, or

X2 is

When X 3 is connected to the nitrogen atom of ring Cy 2 , then X 3 is a single bond; when X 3 is connected to the carbon atom of ring Cy 2 , then X 3 is -NR x3 -or -O-;

X 4 is -NR x4 -or -O-;

R x1 , R x2 , R x3 and R x4 are independently H or C 1-6 alkyl;

R 1 is unsubstituted or substituted benzyl, unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 2-6 alkenyl, unsubstituted or substituted C 3-12 cycloalkane Base, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 3-12 membered heterocycloalkyl, or unsubstituted or substituted 5-12 membered heteroaryl; the substituted benzyl group, substituted C 1-6 alkyl, substituted C 2-6 alkenyl, substituted C 3-12 cycloalkyl, substituted C 6-10 aryl, substituted 3-12 membered heterocycloalkyl and Substituted 5-12 membered heteroaryl is substituted by 1, 2, 3 or 4 R 1a ;

R 1a is halogen, OH, CN, C 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -NR 1a -1 R 1a-2 , or C 1-6 alkyl substituted by 1, 2, 3 or 4 R 1a-3 (for example, R 1a is independently halogen, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or -NR 1a-1 R 1a-2 );

R 1a-1 and R 1a-2 are independently H or C 1-6 alkyl;

R 1a-3 are independently

R 1a-3-1 is independently C 1-6 alkyl;

R 2 is H, unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 3-12 cycloalkyl, unsubstituted or substituted 5-12 membered heteroaryl or -NR 2- 1 R 2-2 ; the substituted C 1-6 alkyl, substituted C 3-12 cycloalkyl and substituted 5-12 membered heteroaryl are substituted by 1, 2, 3 or 4 R 2a ;

R 2-1 and R 2-2 are independently H, unsubstituted or substituted C 1-6 alkyl; said substituted C 1-6 alkyl is substituted by 1, 2, 3 or 4 R 2a ;

Or R 2-1 and R 2-2 together with the nitrogen atom they are connected to form a 3-7 membered heterocycloalkyl group;

R 2a is independently OH, C 1-6 alkoxy or C 6-10 aryloxy;

R3 is H;

R 4 is H, unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 3-6 monocyclic cycloalkyl, or unsubstituted or substituted 3-7 membered heterocycloalkyl; The substituted C 1-6 alkyl, substituted C 3-6 monocyclic cycloalkyl and substituted 3-7 membered heterocycloalkyl are substituted by 1, 2, 3 or 4 R 4a ;

R 4a is independently halogen, OH, CN, unsubstituted or substituted C 3-12 cycloalkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 3-12 membered heterocycle Alkyl, or unsubstituted or substituted 5-12 membered heteroaryl; said substituted C 3-12 cycloalkyl, substituted C 6-10 aryl, substituted 3-12 membered heterocycloalkyl and Substituted 5-12 membered heteroaryl is substituted by 1, 2, 3 or 4 R 4a-1 ;

R 4a-1 is independently halogen, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

The heteroatoms or heteroatom groups of the above-mentioned 3-7 membered heterocycloalkyl, 3-12 membered heterocycloalkyl and 5-12 membered heteroaryl are independently N, O, S or C (=O), hetero The number of atoms or heteroatom groups is independently 1, 2, 3 or 4.
The compound shown in formula I as claimed in claim 1, its tautomer, stereoisomer, isotopic derivative or pharmaceutically acceptable salt, it is characterized in that, in the compound shown in described formula I Each group definition satisfies one or more of the following conditions:

(1) In the definition of R a , R b and R c , the C 1-6 alkyl in the unsubstituted or substituted C 1-6 alkyl is independently a C 1-4 alkyl, such as methyl or ethyl;

(2) In the definition of R a , R b and R c , the C 3-6 monocyclic cycloalkyl in the unsubstituted or substituted C 3-6 monocyclic cycloalkyl is independently cyclopropyl;

(3) In the definition of R a , R b and R c , the substituted C 1-6 alkyl group is independently substituted by 1, 2 or 3 R aa , for example, 3 R aa ;

(4) In the definition of R aa , the halogen is independently F;

(5) In the definition of ring Cy 2 , the unsubstituted or substituted C 3-12 cycloalkyl is in cis configuration or trans configuration;

(6) In the definition of ring Cy 2 , the C 3-12 cycloalkyl in the unsubstituted or substituted C 3-12 cycloalkyl is a C 3-6 monocyclic cycloalkyl or a C 6-12 bridge Cycloalkyl, such as
another example

(7) In the definition of X 1 , the O atom in -NR x1 C(O)O- is connected to R 1 ;

(8) R x1 , R x2 , R x3 and R x4 are independently H;

(9) In the definition of R , the C 1-6 alkyl in the unsubstituted or substituted C 1-6 alkyl is a C 1-4 alkyl, such as isopropyl;

(10) In the definition of R , the C 6-10 aryl in the unsubstituted or substituted C 6-10 aryl is phenyl;

(11) In the definition of R 1 , the 3-12 membered heterocycloalkyl group in the unsubstituted or substituted 3-12 membered heterocycloalkyl group is a 3-7 membered monocyclic heterocycloalkyl group;

(12) In the definition of R 1 , the heteroatom of the 3-12 membered heterocycloalkyl group in the unsubstituted or substituted 3-12 membered heterocycloalkyl group is O;

(13) In the definition of R 1 , the number of heteroatoms in the 3-12 membered heterocycloalkyl group in the unsubstituted or substituted 3-12 membered heterocycloalkyl group is 1;

(14) In the definition of R 1 , the 5-12-membered heteroaryl in the unsubstituted or substituted 5-12-membered heteroaryl is a 5-6-membered heteroaryl;

(15) In the definition of R 1 , the heteroatoms of the 5-12-membered heteroaryl in the unsubstituted or substituted 5-12-membered heteroaryl are independently N or O;

(16) In the definition of R 1 , the number of heteroatoms in the 5-12 membered heteroaryl group in the unsubstituted or substituted 5-12 membered heteroaryl group is 1 or 2;

(17) In the definition of R 1 , the substituted 5-12 membered heteroaryl group is substituted by 1 or 2 R 1a , for example substituted by 1 or 2 R 1a , and for example substituted by 1 R 1a ;

(18) In the definition of R 1a , the C 1-6 alkyl group is a C 1-4 alkyl group, such as methyl or ethyl;

(19) In the definition of R 1a , the C 1-6 haloalkyl is a C 1-4 haloalkyl, for example
Or -CF 3 , and for example -CF 3 ;

(20) In the definition of R 1a , halogen is fluorine, chlorine, bromine or iodine, such as fluorine;

(21) In the definition of R 1a , the C 3-6 cycloalkyl is a C 3-4 cycloalkyl, for example

(22) In the definition of R 1a-1 and R 1a-2 , the C 1-6 alkyl group is a C 1-4 alkyl group, such as methyl or ethyl;

(23) In the definition of R 1a-3-1 , the C 1-6 alkyl group is a C 1-4 alkyl group, such as methyl or ethyl;

(24) In the definition of R 2 , the C 1-6 alkyl in the unsubstituted or substituted C 1-6 alkyl is a C 1-4 alkyl, such as methyl, ethyl, tert-butyl;

(25) In the definition of R 2 , the C 3-12 cycloalkyl group in the unsubstituted or substituted C 3-12 cycloalkyl group is a C 3-6 monocyclic cycloalkyl group, such as cyclopropyl;

(26) In the definition of R 2 , the 5-12-membered heteroaryl in the unsubstituted or substituted 5-12-membered heteroaryl is a 5-6-membered heteroaryl;

(27) In the definition of R 2 , the heteroatom of the 5-12 membered heteroaryl in the unsubstituted or substituted 5-12 membered heteroaryl is N;

(28) In the definition of R 2 , the number of heteroatoms in the 5-12 membered heteroaryl group in the unsubstituted or substituted 5-12 membered heteroaryl group is 4;

(29) In the definition of R 2 , -NR 2-1 R 2-2 is -NH 2 or -N(CH 3 ) 2 , for example -NR 2-1 R 2-2 is -NH 2 ;

(30) In the definition of R 4 , the C 1-6 alkyl group in the unsubstituted or substituted C 1-6 alkyl group is a C 1-4 alkyl group, such as isopropyl;

(31) In the definition of R 4 , the 3-7 membered heterocycloalkyl group in the unsubstituted or substituted 3-7 membered heterocycloalkyl group is a 3-7 membered monocyclic heterocycloalkyl group;

(32) In the definition of R 4 , the heteroatom of the 3-7 membered heterocycloalkyl group in the unsubstituted or substituted 3-7 membered heterocycloalkyl group is O;

(33) In the definition of R 4 , the number of heteroatoms in the 3-7 membered heterocycloalkyl group in the unsubstituted or substituted 3-7 membered heterocycloalkyl group is 1;

(34) In the definition of X2 ,
The N atom in is connected to R2 ;

(35) In the definition of X2 ,
The S atom in is connected to R2 .
The compound shown in formula I as claimed in claim 2, its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt, is characterized in that, in the compound shown in described formula I Each group definition satisfies one or more of the following conditions:

(1) In the definition of R a , R b and R c , the substituted C 1-6 alkyl is independently -CF 3 or -CD 3 ;

(2) In the definition of ring Cy 2 ,
is in the cis or trans configuration;

(3) In the definition of R 1 , the 3-12 membered heterocycloalkyl group in the unsubstituted or substituted 3-12 membered heterocycloalkyl group is oxetanyl, for example

(4) In the definition of R 1 , the 5-12 membered heteroaryl in the unsubstituted or substituted 5-12 membered heteroaryl is pyrazolyl, imidazolyl, oxazolyl, pyrimidinyl or pyridazine base, for example

(also for example

);

(5) In the definition of R 1 , the substituted 5-12 membered heteroaryl is pyrazolyl or pyridazinyl substituted by 1 or 2 R 1a , for example

(also for example
another example
);

( 6 ) In the definition of R, the 5-12 membered heteroaryl in the unsubstituted or substituted 5-12 membered heteroaryl is tetrazolyl, for example

(7) In the definition of R 4 , the 3-7 membered heterocycloalkyl group in the unsubstituted or substituted 3-7 membered heterocycloalkyl group is oxetanyl, for example
The compound shown in formula I as claimed in any one of claims 1-3, its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt, it is characterized in that, said formula I The definition of each group in the compound shown meets one or more of the following conditions:

(1) In the definition of ring Cy 1 ,
In, R a is an unsubstituted or substituted C 1-6 alkyl group, or an unsubstituted C 3-6 monocyclic cycloalkyl group; the substituted C 1-6 alkyl group is replaced by 1, 2, 3 or 4 R aa substitution; for example,
for

(2) In the definition of ring Cy 1 ,
In, R b is C 1-6 alkyl substituted by 1, 2, 3 or 4 halogens; for example,
for

(3) In the definition of ring Cy 1 ,
In, R c is C 1-6 alkyl substituted by 1, 2, 3 or 4 halogens; for example,
for
The compound shown in formula I as claimed in any one of claims 1-3, its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt, it is characterized in that, said formula I The definition of each group in the compound shown meets one or more of the following conditions:

(1) R a is an unsubstituted or substituted C 1-6 alkyl group, or an unsubstituted C 3-6 monocyclic cycloalkyl group; the substituted C 1-6 alkyl group is replaced by 1, 2, 3 or 4 R aa are substituted; R a is preferably C 1-6 alkyl, C 3-6 monocyclic cycloalkyl, C 1-6 alkyl substituted by 1, 2 or 3 fluorine or 1, 2 or 3 Deuterium-substituted C 1-6 alkyl, such as methyl, ethyl, cyclopropyl, trifluoromethyl or

(2) R b and R c are independently C 1-6 alkyl substituted by 1, 2, 3 or 4 halogens;

(3) Ring Cy 2 is unsubstituted C 3-12 cycloalkyl, or unsubstituted 3-12 membered heterocycloalkyl; ring Cy 2 is preferably unsubstituted C 3- 12 cycloalkyl; for example, C 3-8 cycloalkyl, also such as cyclohexyl or bicyclooctyl;

(4) X 1 is -NR x1 - or -NR x1 C(O)O-;

(5) R x1 , R x2 and R x3 are independently H;

(6) X4 is -O-;

(7) R 1 is unsubstituted benzyl, unsubstituted C 1-6 alkyl, unsubstituted C 6-10 aryl, unsubstituted 3-12 membered heterocycloalkyl, or unsubstituted or substituted 5-12 membered heteroaryl; said substituted 5-12 membered heteroaryl is substituted by 1, 2, 3 or 4 R 1a ; R 1 is preferably unsubstituted C 1-6 alkyl, unsubstituted Benzyl, unsubstituted phenyl, unsubstituted 3-6 membered heterocycloalkyl or unsubstituted or substituted 5-6 membered heteroaryl (such as pyrazolyl, imidazolyl, pyrimidinyl or pyridazinyl), The substituted 5-6 membered heteroaryl is substituted by 1 or 2 R 1a ;

(8) R 1a is independently halogen, C 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkyl substituted by 1 or 2 R 1a-3 ; R 1a is independently preferably C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl or C 1-6 alkyl substituted by 1 or 2 R 1a-3 ; for example trifluoromethane group, methyl, cyclopropyl, difluoromethyl, ethyl, monofluoroethyl, trifluoroethyl or
Substituted C 1-6 alkyl;

(9) R 1a-3 is independently

(10) R aa is independently deuterium or fluorine;

(11) R 2 is H, unsubstituted C 1-6 alkyl, unsubstituted C 3-12 cycloalkyl, unsubstituted 5-12 membered heteroaryl or -NR 2-1 R 2- 2 ; R 2 is preferably H, unsubstituted C 1-6 alkyl, unsubstituted C 3-12 cycloalkyl or -NR 2-1 R 2-2 ;

(12) R 4 is unsubstituted C 1-6 alkyl or unsubstituted 3-7 membered heterocycloalkyl, R 4 is preferably unsubstituted C 1-6 alkyl.
The compound shown in formula I as claimed in claim 1, its tautomer, stereoisomer, isotopic derivative or pharmaceutically acceptable salt, it is characterized in that, in the compound shown in described formula I Each group definition satisfies one or more of the following conditions:

(1) Ring Cy 2 is
For example
in
Can be in cis or trans configuration;

(2) X 1 is -NH-, -NHC(O)O-, -NHC(O)NH- or

(3) X 2 is

(4) X3 is -NH-;

(5) R 1 is isopropyl, phenyl, benzyl,

(e.g. isopropyl, phenyl, benzyl,

Another example is isopropyl, phenyl, benzyl,

);

(6) R 2 is H, -NH 2 , -N(CH 3 ) 2 , methyl, ethyl, tert-butyl, cyclopropyl or
(such as H, -NH 2 , methyl, ethyl, tert-butyl, cyclopropyl or
);

(7) R 4 is isopropyl or

(8) X 4 is -O-;

(9)-X 2 -R 2 is
The compound shown in formula I as claimed in claim 1, its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt, is characterized in that, the compound shown in described formula I satisfies Either of the following options:

Scenario 1: Ring Cy 1 is

Among them, 1 bit is connected with ring Cy 2 ;

R a is an unsubstituted or substituted C 1-6 alkyl group, or an unsubstituted C 3-6 monocyclic cycloalkyl group; the substituted C 1-6 alkyl group is replaced by 1, 2, 3 or 4 R aa replaced;

R b and R c are independently C 1-6 alkyl substituted by 1, 2, 3 or 4 halogens;

R aa is independently deuterium or halogen;

Ring Cy 2 is unsubstituted C 3-12 cycloalkyl;

X 1 is -NR x1 -, -NR x1 C(O)O-, -NR x1 C(O)NR x1 -, or

X2 is

X3 is -NR x3- ;

X4 is -O-;

R x1 , R x2 and R x3 are independently H;

R 1 is unsubstituted benzyl, unsubstituted C 1-6 alkyl, unsubstituted C 6-10 aryl, unsubstituted 3-12 membered heterocycloalkyl, or unsubstituted or substituted 5- 12-membered heteroaryl; the substituted 5-12-membered heteroaryl is substituted by 1, 2, 3 or 4 R 1a ;

R 1a is independently C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl or C 1-6 haloalkyl substituted by 1 or 2 R 1a-3 , such as C 1-6 Alkyl or C 1-6 haloalkyl, also such as C 1-6 alkyl;

R 1a-3 are independently

R 1a-3-1 is independently C 1-6 alkyl;

R 2 is H, unsubstituted C 1-6 alkyl, unsubstituted C 3-12 cycloalkyl, unsubstituted 5-12 membered heteroaryl or -NR 2-1 R 2-2 ;

R 2-1 and R 2-2 are independently H or unsubstituted C 1-6 alkyl;

R3 is H;

R 4 is unsubstituted C 1-6 alkyl or unsubstituted 3-7 membered heterocycloalkyl;

The heteroatoms of the above-mentioned 3-7 membered heterocycloalkyl, 3-12 membered heterocycloalkyl and 5-12 membered heteroaryl are independently N, O or S, and the number of heteroatoms is independently 1, 2, 3 or 4;

Scheme 2: Ring Cy 1 is
Among them, 1 bit is connected with ring Cy 2 ;

R a is an unsubstituted or substituted C 1-6 alkyl group, or an unsubstituted C 3-6 monocyclic cycloalkyl group; the substituted C 1-6 alkyl group is replaced by 1, 2, 3 or 4 R aa replaced;

R aa is independently deuterium or halogen;

Ring Cy 2 is unsubstituted C 3-12 cycloalkyl;

X 1 is -NR x1 -, -NR x1 C(O)O-, -NR x1 C(O)NR x1 -, or

X2 is

X3 is -NR x3- ;

X4 is -O-;

R x1 , R x2 and R x3 are independently H;

R 1 is unsubstituted benzyl, unsubstituted C 1-6 alkyl, unsubstituted C 6-10 aryl, unsubstituted 3-12 membered heterocycloalkyl, or unsubstituted or substituted 5- 12-membered heteroaryl; the substituted 5-12-membered heteroaryl is substituted by 1, 2, 3 or 4 R 1a ;

R 1a is independently C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl or C 1-6 haloalkyl substituted by 1 or 2 R 1a-3 , such as C 1-6 Alkyl or C 1-6 haloalkyl, also such as C 1-6 alkyl;

R 1a-3 are independently

R 1a-3-1 is independently C 1-6 alkyl;

R 2 is H, unsubstituted C 1-6 alkyl, unsubstituted C 3-12 cycloalkyl or -NR 2-1 R 2-2 ;

R 2-1 and R 2-2 are independently H or unsubstituted C 1-6 alkyl (eg R 2-1 and R 2-2 are independently H);

R3 is H;

R 4 is unsubstituted C 1-6 alkyl or unsubstituted 3-7 membered heterocycloalkyl;

The heteroatoms of the above-mentioned 3-7 membered heterocycloalkyl, 3-12 membered heterocycloalkyl and 5-12 membered heteroaryl are independently N, O or S, and the number of heteroatoms is independently 1, 2, 3 or 4;

Scheme 3: Ring Cy 1 is
Among them, 1 bit is connected with ring Cy 2 ;

R a is an unsubstituted or substituted C 1-6 alkyl group, or an unsubstituted C 3-6 monocyclic cycloalkyl group; the substituted C 1-6 alkyl group is replaced by 1, 2, 3 or 4 R aa replaced;

R aa is independently deuterium or halogen;

Ring Cy 2 is unsubstituted C 3-12 cycloalkyl;

X 1 is -NR x1 -, -NR x1 C(O)O-, -NR x1 C(O)NR x1 -, or

X2 is

X3 is -NR x3- ;

X4 is -O-;

R x1 , R x2 and R x3 are independently H;

R 1 is unsubstituted benzyl, unsubstituted C 1-6 alkyl, unsubstituted C 6-10 aryl, unsubstituted 3-12 membered heterocycloalkyl, or unsubstituted or substituted 5- 12-membered heteroaryl; the substituted 5-12-membered heteroaryl is substituted by 1, 2, 3 or 4 R 1a ;

R 1a is independently C 1-6 alkyl or C 1-6 haloalkyl;

R 2 is H, unsubstituted C 1-6 alkyl, unsubstituted C 3-12 cycloalkyl or -NR 2-1 R 2-2 ;

R 2-1 and R 2-2 are independently H;

R3 is H;

R 4 is unsubstituted C 1-6 alkyl or unsubstituted 3-7 membered heterocycloalkyl;

The heteroatoms of the above-mentioned 3-7 membered heterocycloalkyl, 3-12 membered heterocycloalkyl and 5-12 membered heteroaryl are independently N, O or S, and the number of heteroatoms is independently 1, 2, 3 or 4;

Scheme 4: Ring Cy 1 is
Among them, 1 bit is connected with ring Cy 2 ;

R a is an unsubstituted or substituted C 1-6 alkyl group, or an unsubstituted C 3-6 monocyclic cycloalkyl group; the substituted C 1-6 alkyl group is replaced by 1, 2, 3 or 4 R aa replaced;

R aa is independently deuterium or halogen;

Ring Cy 2 is unsubstituted C 3-12 cycloalkyl;

X 1 is -NR x1 -, -NR x1 C(O)O-, -NR x1 C(O)NR x1 -, or

X2 is

X3 is -NR x3- ;

X4 is -O-;

R x1 , R x2 and R x3 are independently H;

R 1 is unsubstituted benzyl, unsubstituted C 1-6 alkyl, unsubstituted C 6-10 aryl, unsubstituted 3-12 membered heterocycloalkyl, or unsubstituted or substituted 5- 12-membered heteroaryl; the substituted 5-12-membered heteroaryl is substituted by 1, 2, 3 or 4 R 1a ;

R 1a is independently C 1-6 alkyl;

R 2 is H, unsubstituted C 1-6 alkyl, unsubstituted C 3-12 cycloalkyl or -NR 2-1 R 2-2 ;

R 2-1 and R 2-2 are independently H;

R3 is H;

R 4 is unsubstituted C 1-6 alkyl or unsubstituted 3-7 membered heterocycloalkyl;

The heteroatoms of the above-mentioned 3-7 membered heterocycloalkyl, 3-12 membered heterocycloalkyl and 5-12 membered heteroaryl are independently N, O or S, and the number of heteroatoms is independently 1, 2, 3 or 4;

Scheme 5: Ring Cy 1 is
Among them, 1 bit is connected with ring Cy 2 ;

R a is an unsubstituted or substituted C 1-6 alkyl group, or an unsubstituted C 3-6 monocyclic cycloalkyl group; the substituted C 1-6 alkyl group is replaced by 1, 2, 3 or 4 R aa replaced;

R aa is independently deuterium or halogen;

Ring Cy 2 is unsubstituted C 3-12 cycloalkyl;

X 1 is -NR x1 -, -NR x1 C(O)O- or -NR x1 C(O)NR x1 -;

X2 is

X3 is -NR x3- ;

X4 is -O-;

R x1 , R x2 and R x3 are independently H;

R 1 is an unsubstituted benzyl group, an unsubstituted C 1-6 alkyl group, an unsubstituted 3-12 membered heterocycloalkyl group, or an unsubstituted or substituted 5-12 membered heteroaryl group; the substituted 5-12 membered heteroaryl is substituted by 1, 2, 3 or 4 R 1a ;

R 1a is independently C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl or C 1-6 haloalkyl substituted by 1 or 2 R 1a-3 , such as C 1-6 Alkyl or C 1-6 haloalkyl, also such as C 1-6 alkyl;

R 1a-3 are independently

R 1a-3-1 is independently C 1-6 alkyl;

R 2 is H, unsubstituted C 1-6 alkyl or -NR 2-1 R 2-2 ;

R 2-1 and R 2-2 are independently H or unsubstituted C 1-6 alkyl;

R3 is H;

R 4 is unsubstituted C 1-6 alkyl or unsubstituted 3-7 membered heterocycloalkyl;

The heteroatoms of the above-mentioned 3-7 membered heterocycloalkyl, 3-12 membered heterocycloalkyl and 5-12 membered heteroaryl are independently N, O or S, and the number of heteroatoms is independently 1, 2, 3 or 4;

Scheme 6: Ring Cy 1 is
Among them, 1 bit is connected with ring Cy 2 ;

R a is C 1-6 alkyl;

X1 is -NH-;

R 1 is a substituted 5-12 membered heteroaryl group (such as pyrazolyl), and the substituted 5-12 membered heteroaryl group is substituted by 1, 2, 3 or 4 R 1a ;

R 1a is independently C 1-6 alkyl (such as methyl) substituted by 1 or 2 R 1a-3 ;

R 1a-3 are independently

R 1a-3-1 is independently C 1-6 alkyl (such as methyl);

X2 is
R 2 is -NR 2-1 R 2-2 (eg -NH 2 ); R 2-1 and R 2-2 are independently H, unsubstituted or substituted C 1-6 alkyl.
The compound shown in formula I as claimed in claim 1, its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt, is characterized in that, the compound shown in described formula I has Formula A, Formula A-1, Formula A-2, Formula A-3, Formula A-4, Formula A-5, Formula A-6, Formula A-7, Formula A-8, Formula A-9, Formula A -10, formula A-11, formula A-12, formula A-13, formula A-14, formula A-15, formula A-16, formula A-17, formula B, formula B-1, formula B-2 , Formula C, Formula C-1, Formula C-2, Formula C-3, Formula C-4, Formula C-5, Formula C-6, Formula C-7, Formula C-8, Formula C-9, Formula C-10, formula D, formula D-1, formula D-2, formula D-3, formula D-4, formula E, formula E-1, formula E-2, formula E-3, formula E-4 The structure shown:

Wherein, R 1 , R 2 , R 4 , R a , ring Cy 2 , X 1 , X 2 , X 3 and X 4 are as defined in any one of claims 1 to 7.
The compound represented by formula I as claimed in claim 1, its tautomer, stereoisomer, isotopic derivative or pharmaceutically acceptable salt, is characterized in that, the compound represented by formula I is Either of the following structures:
A preparation method of a compound shown in formula I as described in any one of claims 1-9, characterized in that it is any one of the following methods:

Method a: a compound shown in formula Ia and a compound shown in formula I-a1 or formula I-a2 (for example, in ethylene glycol dimethyl ether and water, in the presence of tetrakistriphenylphosphine palladium and potassium fluoride; or , dioxane and water in the presence of Pd(dppf)Cl 2 and sodium bicarbonate; or, dioxane and water in the presence of Pd(PPh 3 ) 4 and potassium carbonate; or, dioxane and water, in the presence of tetrakistriphenylphosphine palladium and potassium fluoride) through the reaction shown below, the compound shown in formula I is obtained,

Among them, ring Cy 1 is
Ring Cy 1a is
The definitions of R a , R 1 , R 2 , R 3 , R 4 , ring Cy 2 , X 1 , X 2 , X 3 and X 4 are as described in any one of claims 1 to 9;

Method b: the compound shown in formula I-b and the compound shown in formula I-b1 (for example, in tetrahydrofuran, in the presence of sodium carbonate; or in tetrahydrofuran, in the presence of sodium bicarbonate; or, in dichloromethane, in the presence of sodium carbonate In the presence of) through the reaction shown below, the compound shown in formula I is obtained,

Wherein, X 3 is -NH-, R 1 , R 2 , R 3 , R 4 , ring Cy 1 , ring Cy 2 , X 1 , X 2 and X 4 are as defined in any one of claims 1 to 9 stated;

Method c: the compound shown in formula I-c and the compound shown in formula I-c1 (for example, in 2-methyltetrahydrofuran or methanol) are reacted as follows to obtain the compound shown in formula I,

Among them, X 1 is -NR x1 C(O)NR x1 -, -X 1c R 1c is
or X1 for
-X 1c R 1c is
R x1 , R 1 , R 2 , R 3 , R 4 , ring Cy 1 , ring Cy 2 , X 1 , X 2 , X 3 and X 4 are as defined in any one of claims 1 to 9;

Method d: the compound shown in formula I-d (for example in methanol, in the presence of catalyst Pd/C) undergoes the reaction shown below to obtain the compound shown in formula I,

Among them, ring Cy 2 is
R 1 , R 2 , R 3 , R 4 , ring Cy 1 , X 1 , X 2 , X 3 and X 4 are as defined in any one of claims 1 to 9;

Method e: the compound shown in formula I-e (for example, in the presence of trifluoroacetic acid) is deprotected to obtain the compound shown in formula I through the reaction shown below,

where R1 is
R 2 , R 3 , R 4 , ring Cy 1 , ring Cy 2 , X 1 , X 2 , X 3 and X 4 are as defined in any one of claims 1 to 9;

Method f: the compound shown in formula I-f1 and the compound shown in formula I-f2 (for example in dioxane, in Pd(dppf)Cl 2 and potassium acetate exist; Or ethylene glycol dimethyl ether and water , in the presence of tetrakistriphenylphosphine palladium and potassium fluoride) through the reaction shown below, the compound shown in formula I is obtained,

Among them, ring Cy 1 is
Ring Cy 2 is
R a , R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 and X 4 are as defined in any one of claims 1 to 9;

Method g: the compound shown in formula I-g is reacted as shown below to obtain the compound shown in formula I,

Wherein, R 4 is isopropyl, X 4 is -O-, R 1 , R 2 , R 3 , ring Cy 1 , ring Cy 2 , X 1 , X 2 and X 3 are as defined in claims 1 to 9 any of the above;

Method h: the compound shown in formula I-h (for example in the presence of trifluoroacetic acid) is reacted as shown below to obtain the compound shown in formula I,

where -X 2 -R 2 is
R 1 , R 3 , R 4 , ring Cy 1 , ring Cy 2 , X 1 , X 3 and X 4 are as defined in any one of claims 1 to 9;

Method e-1: the compound represented by formula I-e1 (for example, in the presence of trifluoroacetic acid) is deprotected to obtain the compound represented by formula I through the following reaction,

Wherein, R 1 is an unsubstituted or substituted 5-12 membered heteroaryl group, R 1e is a divalent group corresponding to R 1 , R 2 , R 3 , R 4 , ring Cy 1 , ring Cy 2 , X 1 , X 2 , X 3 and X 4 are as defined in any one of claims 1 to 9;

Method e-2: In a solvent, the compound shown in formula I-e2 (for example, in the presence of trifluoroacetic acid) undergoes the reaction shown below to deprotect the compound shown in formula I,

Wherein, R 1 is an unsubstituted or substituted 5-12 membered heteroaryl group, R 1e is a divalent group corresponding to R 1 , and -X 2 -R 2 is
R 3 , R 4 , ring Cy 1 , ring Cy 2 , X 1 , X 3 and X 4 are as defined in any one of claims 1 to 9;

Method i: the compound shown in formula I-i is reacted as shown below to obtain the compound shown in formula I,

Wherein, Hal is halogen, X 1 is -NH-, R 1 is unsubstituted or substituted 5-12 membered heteroaryl, R 2 , R 3 , R 4 , ring Cy 1 , ring Cy 2 , X 2 , The definition of X 3 and X 4 is as described in any one of claims 1 to 9;

Method j: the compound shown in formula I-j is reacted as shown below (for example in the presence of acetonitrile and sodium iodide), to obtain the compound shown in formula I,

where R1 is
X 1 is -NH-, R 2 , R 3 , R 4 , R 1a-3-1 , ring Cy 1 , ring Cy 2 , X 2 , X 3 and X 4 are as defined in any one of claims 1 to 9 item described.
A compound shown in formula I-a, I-b, I-c, I-d, I-e, I-e1, I-e2, I-f1, I-f2, I-g, I-h, or I-i,

Wherein, the definitions of R a , R 1 , R 2 , R 3 , R 4 , ring Cy 1 , ring Cy 2 , X 1 , X 2 , X 3 and X 4 are as described in any one of claims 1 to 9, Ring Cy 1a , -X 1c R 1c and R 1e are as defined in claim 10.
The compound according to claim 11, wherein the compound is any of the following structures:
A pharmaceutical composition, characterized in that it comprises (i) a compound represented by formula I as claimed in any one of claims 1 to 9, its tautomers, stereoisomers, and isotopic derivatives or a pharmaceutically acceptable salt; and (ii) a pharmaceutically acceptable carrier.
A compound shown in formula I as described in any one of claims 1 to 9, its tautomers, stereoisomers, isotopic derivatives or pharmaceutically acceptable salts or claimed in claim 13 The application of the pharmaceutical composition in the preparation of medicines for the treatment or prevention of Rad51-related diseases;

Preferably, the Rad51-related disease is cancer, autoimmune disease, immunodeficiency disease or neurodegenerative disease;

Preferably, the cancer is multiple myeloma, lymphoma (e.g. non-Hodgkin's lymphoma, follicle center lymphoma, mantle cell lymphoma), sarcoma, breast cancer (e.g. triple negative breast tumors), head and neck cancer, Lung, ovarian, pancreatic, colorectal, prostate, or B-cell malignancies.