WO2023025324A1

WO2023025324A1 - Compound serving as p53 regulator

Info

Publication number: WO2023025324A1
Application number: PCT/CN2022/115635
Authority: WO
Inventors: 张汉承; 王建设; 贾薇; 蔡聪聪
Original assignee: 杭州紫晶医药科技有限公司; 杭州英创医药科技有限公司
Priority date: 2021-08-27
Filing date: 2022-08-29
Publication date: 2023-03-02
Also published as: CN117916230A

Abstract

The present invention provides a compound serving as a p53 regulator, and specifically, the present invention provides a compound having a structure as shown in formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, and a solvate thereof. The compound can be used for treating or preventing diseases or conditions related to the activity or expression level of p53.

Description

Compounds as modulators of p53

technical field

The present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a new type of derivative containing tricyclic heteroaryl, its synthesis method and its use as a p53 regulator in the preparation of medicines for the treatment of tumors and other related diseases in the application.

Background technique

In human tumors, the most common mutation is a mutation in the TP53 gene, which encodes the p53 protein. TP53 mutations are closely related to poor prognosis of various tumors, and germline TP53 mutations can lead to a rare familial cancer-prone disease: Li Fraumeni syndrome. As a tumor suppressor, p53 provides an important barrier to tumor transformation and progression. p53 is very sensitive to cellular stress and coordinates a complex signaling pathway to maintain cellular homeostasis and genome stability. Most of the TP53 mutations are missense mutations, where the codon encoding a certain amino acid becomes the codon encoding another amino acid after base substitution. This mutation usually leads to the inactivation of the tumor suppressor function of the p53 protein and the loss of the function of activating its downstream genes. Some mutations will in turn inhibit the function of the normal p53 protein and play a dominant inhibitory role. In addition, mutated p53 may support tumor progression by promoting adaptive responses to tumor-associated stress. In a growing tumor, cancer cells are exposed to a variety of internal and external stressors. Mutated p53 can sense a variety of cellular stresses and induce cellular adaptive mechanisms to exert cancer-promoting effects.

The p53Y220C mutation is one of the common missense mutation types of p53. This mutation exists in cancer types such as breast cancer, lung cancer, colon cancer, gastric cancer, and head and neck cancer. There are about 100,000 new cancer patients with this mutation every year worldwide. people. Therefore, the development of compounds targeting this mutation to reactivate the function of wild-type p53 is crucial for cancer therapy.

Contents of the invention

The purpose of the present invention is to provide a new class of p53 regulators.

The first aspect of the present invention provides a compound with the structure shown in the following formula (I), or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate :

In formula (I):

Ring A is selected from aryl or heteroaryl;

Ring B is selected from aryl or heteroaryl;

C ring is selected from C _3-8 cycloalkyl or 4- to 12-membered heterocyclyl;

D is selected from a chemical bond, -C≡C-, -CR ^a ═CR ^a -, or a C _3-6 cyclic group;

E is selected from chemical bonds, -(CR ^a R ^a ) _q -, -O-, -NR ^b -, C _3-6 cyclic groups, or 3- to 6-membered heterocyclic groups;

F is selected from a chemical bond, -NR ^b -, -O-, or -(CR ^a R ^a ) _q -;

U is selected from a chemical bond, -NR ^c -, -O-, -NR ^c C(O)R ^c -, -NR ^c C(O)-;

Each R ^a above is independently selected from hydrogen, halogen, C _1-4 alkyl, OR ^b , CN, NR ^b R ^b ; each R ^b and R ^c are independently selected from hydrogen, C _1-4 alkyl, Or C _1-4 haloalkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocyclic group; except for one substituent, the cycloalkyl or heterocyclic group is optionally substituted by =M ; M is selected from O or CR ^e R ^e ; or two R ^b together with the nitrogen atoms connected to them form an optionally substituted 4- to 8-membered ring structure, which may additionally contain 0-1 a heteroatom optionally selected from N, O, S;

R ¹ is selected from hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, C(O)R ^d , or S(O) ₂ R ^d ; said alkyl, cycloalkyl, and heterocyclyl are optionally substituted by one or more groups selected from the group consisting of halogen, CN, OR ^b , SR ^b , NR ^b R ^b ; or the cycloalkyl and heterocyclyl are optionally substituted by =M; M is selected from O or CR ^e R ^e ; each R ^e is independently selected from hydrogen, fluorine, or C _{1 -4} alkyl; the alkyl group in R ^e is optionally substituted by the following substituents: CN, OR ^b , SR ^b , NR ^b R ^b , C(O)OR ^b ; R ^d is selected from C _{1- 4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl; in addition to general substituents, The cycloalkyl or heterocyclic group is optionally substituted by =M; M is selected from O or CR ^e R ^e ; R ^b is defined as above;

Each R ² is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 _haloalkyl , C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _{3 -6} cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR ^b , SR ^b , or NR ^b R ^b ; R ^b is as defined above;

R ³ is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3- to 8-membered Heterocyclyl, aryl, heteroaryl, CN, OR ^b , SR ^b , NR ^b R ^b , C(O)R ^d , C(O)OR ^b , C(O)NR ^b R ^b , C(O) )N(OR ^b )R ^b , NR ^b C(O)R ^d , NR ^b S(O) ₂ R ^d , S(O) ₂ R ^d , S(O)(NR ^b )R ^d , S(O )R ^d , NR ^b S(O) ₂ R ^d , S(O) ₂ NR ^b R ^b , NR ^b S(O) ₂ NR ^b R ^b , P(O)R ^f R ^f , P(O)( NR ^b R ^b )R ^f , or P(O)(OR ^b )R ^f ; the definitions of each R ^b and R ^d are as above; or two R ^b together with the nitrogen atoms connected to them form any substituted 4- to 8-membered ring structure, this ring structure can additionally contain 0-1 heteroatoms optionally selected from N, O, S; said ring structure is optionally substituted by =M; M is selected from O or CR ^e R ^e ; each R ^f is independently selected from C _1-4 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, OR ^b , NR ^b R ^b ; or two R ^f together with the phosphorus atom connected to them form an optionally substituted 4- to 8-membered ring structure, which may additionally contain 0-1 optionally selected from N , a heteroatom of O, S; the alkyl, cycloalkyl, heterocyclic group or ring structure described in R ^f are optionally substituted by the following substituents: hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR ^b , SR ^b , NR ^b R ^b , =0; R ^b is defined as above;

Each R ⁴ is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, hydroxyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkenyl , C _2-4 haloalkenyl, C _{2-4 alkynyl, C 2-4} _haloalkynyl , C _3-6 cycloalkyl, 3- to 8-membered heterocyclyl, C _2-4 alkenyl -O-, C _2-4 haloalkenyl-O-, C _2-4 alkynyl-O-, C _2-4 haloalkynyl-O-, C _3-6 cycloalkyl-O-, 3 - to 8-membered heterocyclyl-O-, CN, SR ^b , NR ^b R ^b , C(O)R ^d , C(O)OR ^b , C(O)NR ^b R ^b ; the alkyl , alkoxy, cycloalkyl, and heterocyclyl are optionally substituted by one or more groups selected from the group consisting of halogen, CN, OR ^b , SR ^b , NR ^b R ^b ; or the cycloalkane Base, heterocyclyl are optionally substituted by =M; M is selected from O or CR ^e R ^e ; each R ^e is independently selected from hydrogen, fluorine, or C _1-4 alkyl; the alkyl group of R ^e optionally substituted by the following substituents: CN, OR ^b , SR ^b , NR ^b R ^b , C(O)OR ^b ; each of R ^b and R ^d is as defined above;

Or R ⁴ and ^R in E and the ring atoms on the F and B rings connected to it together form an optionally substituted 6- to 8-membered ring structure;

Or R ⁴ and R ^b in F and the ring atoms on the B ring to which it is connected together form an optionally substituted 6- to 8-membered ring structure;

R ⁵ is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3- to 8-membered Heterocyclyl, CN, OR ^b , SR ^b , NR ^b R ^b , C(O)R ^d , C(O)OR ^b , C(O)NR ^b R ^b , C(O)NR ^b (OR ^b ) , NR ^b C(O)R ^d , NR ^b S(O) ₂ R ^d , S(O) ₂ R ^d , S(O)(NR ^b )R ^d , S(O)R ^d , NR ^b S( O) ₂ R ^d , S(O) ₂ NR ^b R ^b ; each R ^b is independently selected from hydrogen, C _1-4 alkyl, or C _1-4 haloalkyl; or two R ^b are connected with them The nitrogen atoms together form an optionally substituted 4- to 8-membered ring structure, which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; R ^d is selected from C _{1- 4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3- to 6-membered heterocyclyl; the alkyl in the above R ⁵ , R ^b , R ^d , Cycloalkyl and heterocyclyl are optionally substituted by one or more groups selected from the group consisting of halogen, C _1-4 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocyclyl , CN, OR ^b , SR ^b , NR ^b R ^b ; or the cycloalkyl and heterocyclyl in the above R ⁵ are optionally substituted by C=M; M is selected from O or CR ^e R ^e ; each R ^{e is} each independently selected from hydrogen, fluorine, or C _1-4 alkyl; the alkyl of Re ^e is optionally substituted by the following substituents: CN, OR ^b , SR ^b , NR ^b R ^b , C(O) OR ^b ; each R ^b is as defined above;

Each R ⁶ is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, hydroxyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkane Base, 3- to 6-membered heterocyclyl, CN, SR ^b , NR ^b R ^b ; each R ^b is defined as above; m is selected from 0, 1, 2, 3, or 4;

n is selected from 0, 1, 2, 3, or 4;

p is selected from 0, 1, 2, 3, or 4;

q is selected from 0, 1, 2, or 3;

Wherein, each of the above-mentioned alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups is optionally and independently replaced by 1-3 substituents independently selected from the following group Substitution: halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3- to 8-membered heterocyclyl, Aryl, Heteroaryl, CN, NO2, OR ^b , SR ^b , NR ^b R ^b , C(O)R ^d , C(O)OR ^b , C(O)NR ^b R ^b , NR ^b C(O )R ^d , NR ^b S(O) ₂ R ^d , or S(O) ₂ R ^d , provided that the formed chemical structure is stable and meaningful; wherein each R ^b is independently selected from hydrogen , C _1-4 alkyl, or C _1-4 haloalkyl; or two R ^b together with the nitrogen atoms connected to them form an optionally substituted 4- to 8-membered ring structure, which can be additionally contain 0-1 heteroatoms optionally selected from N, O, S; each R ^d is independently selected from C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl;

Unless otherwise specified, the above-mentioned aryl group is an aromatic group containing 6-12 carbon atoms; the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaromatic group; the ring structure is Single ring, parallel ring, condensed ring or heterocyclic ring, said ring structure may be saturated or partially unsaturated (but not aromatic).

In another preferred example, the ring B is selected from phenyl or 5-7 membered heteroaryl.

In another preferred example, the C ring is selected from C _5-7 cycloalkyl or 5- to 8-membered heterocyclyl.

In another preferred example, R ³ is selected from C(O)NR ^b (OR ^b ), P(O)R ^f R ^f , P(O)(NR ^b R ^b )R ^f , or P(O)( OR ^b ) R ^f ; each R ^f is independently selected from C _1-4 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, OR ^b , NR ^b R ^b ; or two R ^f together with the phosphorus atom connected to them together form a 4- to 8-membered ring structure optionally substituted, this ring structure can additionally contain 0-1 optional selected from N, O , a heteroatom of S; each R ^b is independently selected from hydrogen, C _1-4 alkyl, or C _1-4 haloalkyl; or two R ^b together with the nitrogen atom connected to them form any substituted 4 - to 8-membered ring structure, which may additionally contain 0-1 heteroatoms optionally selected from N, O, S;

Wherein, the alkyl group, cycloalkyl group, heterocyclyl group or ring structure described in R ^f are arbitrarily substituted by a group selected from the following group: hydrogen, halogen, C _1-4 alkyl, C _1-4 Haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR ^b , SR ^b , NR ^b R ^b , =O ; R ^b is as defined above;

or ^R3 is selected from:

Wherein, "—" represents the position where R ³ is connected to other parts of the compound of formula (I); the definition of R ^b is as above.

In another preference, formula (I) is formula (II):

in,

R ¹ is selected from the following groups:

in,

Represent the site where ^R is connected to other parts of the compound of formula (II);

Each _R ² is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, CN, OR ^b , SR ^b , or NR ^b R ^b ; m is selected from 0, 1, or 2; R ^b is as defined above;

R ³ is selected from the following groups:

Wherein, "—" represents the position where R ³ is connected to other parts of the compound of formula (II); R ^b , R ^d , and R ^f are as defined above;

R ⁴ is selected from the following groups:

Wherein, "---" represents the position where R ⁴ is connected to other parts of the compound of formula (II);

fragment

Groups selected from the following groups:

Among them, "*" represents a chiral center;

Represents a fragment

The linking position with other parts of the compound of formula (II); R ⁵ , R ⁶ , R ^e , p are as defined above;

F is selected from -NH-, -NMe-, or -O-.

In another preference, ^R3 is selected from the following groups:

Wherein, "—" represents the position where R is connected to other parts of the compound of ^formula (II); R ^b and R ^f are as defined above;

In another preferred embodiment, the fragment

Groups selected from the following groups:

Among them, "*" represents a chiral center;

Represents a fragment

The points of attachment to other moieties of the compound of formula (II); R ⁵ , R ⁶ , R ^e , p are as defined above.

In another preference, ^R is selected from the following groups:

in,

In another preference, R ⁴ is selected from the following groups:

Wherein, "---" represents the linking position of R ⁴ with other parts of the compound of formula (II).

In another preference, formula (I) is formula (III):

Wherein, each X is independently selected from CH or N, provided that at least two Xs are selected from CH, and the formed structure is stable; wherein the H on one CH is replaced by C(O) in formula (III) NH(OR ^b ) is substituted, H on other CH is optionally substituted by R ⁴ ; R ^b is selected from hydrogen or C _1-4 alkyl;

R ¹ , R ² , m, F, ring C, R ⁵ , R ⁶ , p are as defined above.

In another preference, formula (I) is formula (IV):

Wherein, each X is independently selected from CH or N, provided that at least two Xs are selected from CH, and the formed structure is stable; wherein the H on one CH is replaced by P(O) in formula (IV) ^Rf is substituted with ^Rf , and H on other CHs are optionally substituted with ^R4 ; each ^Rf is independently selected from _C1-4 alkyl, _C3-6 cycloalkyl, 3- to 8-membered heterocycle group, aryl group, heteroaryl group, OR ^b , NR ^b R ^b ; or two R ^f together with the phosphorus atom connected to them form an optionally substituted 4- to 8-membered ring structure, the ring structure May additionally contain 0-1 heteroatoms optionally selected from N, O, S; the alkyl, cycloalkyl, heterocyclyl, or ring structure described in R ^f are optionally substituted by the following substituents: Hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR ^b , SR ^b , NR ^b R ^b , =O;

R ¹ , R ² , m, F, ring C, R ⁴ , R ⁵ , R ⁶ , p, R ^b are as defined above.

In another preference, formula (I) is formula (V):

Wherein, each R ^f is independently selected from C _1-4 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, OR ^b , NR ^b R ^b ; Or two R ^f together with the phosphorus atoms connected to them form an optionally substituted 4- to 8-membered ring structure, and this ring structure can additionally contain 0-1 hetero Atom; the alkyl, cycloalkyl, heterocyclyl, or ring structure described in R ^f is optionally substituted by the following substituents: hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl , C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR ^b , SR ^b , NR ^b R ^b , =O;

R ¹ , R ² , m, R ⁴ , R ⁵ , R ⁶ , p, R ^b are as defined above.

In another preference, in formula (V):

R ¹ is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocyclyl; optionally substituted by one or more groups selected from the following group: halogen, CN, OR ^b , SR ^b , NR ^b R ^b ; or the cycloalkyl and heterocyclyl are optionally substituted by =M; M is selected from O or CR ^e R ^e ; each R ^e is independently selected from hydrogen, fluorine, or C _1-4 alkyl; the alkyl group in the R ^e is optionally substituted by the following substituents: CN, OR ^b , SR ^b , NR ^b R ^b , C(O)OR ^b ;

each R ^is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, CN, OR ^b , SR ^b , or NR ^b R ^b ;

Each R ⁴ is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, hydroxyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkane Base-O-, 3- to 8-membered heterocyclyl-O-; said alkyl, alkoxy, cycloalkyl, heterocyclyl are optionally replaced by one or more groups selected from the following group Substitution: halogen, CN, OR ^b , SR ^b , NR ^b R ^b ;

R ⁵ is selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocyclyl, C(O)R ^d , S(O) ₂ R ^d ; the cycloalkane Base, heterocyclyl are optionally substituted by C=M; M is selected from O or CR ^e R ^e ; each R ^e is independently selected from hydrogen, fluorine, or C _1-4 alkyl;

Each R ⁶ is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, hydroxyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkane Base, 3- to 6-membered heterocyclic group, CN, SR ^b , NR ^b R ^b ; each R ^b is as defined above;

Each R ^b mentioned above is independently selected from hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl; the cycloalkyl is optionally substituted by =M;

Each of the above R ^d is independently selected from C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl , or heteroaryl; the cycloalkyl, heterocyclyl is optionally substituted by =M;

m is selected from 0, 1, 2, or 3;

p is selected from 0, 1, 2, 3, or 4;

In another preference, formula (I) is formula (VI):

T is selected from a chemical bond or -NR ^c -; R ^c is selected from hydrogen or C _1-4 alkyl;

Z is selected from N or CR ^k ; R ^k is selected from hydrogen or C _1-4 alkyl;

Each R ^e is independently selected from hydrogen, fluorine, or C _1-4 alkyl; the alkyl group in the R ^e is optionally substituted by the following substituents: CN, OR ^b , SR ^b , NR ^b R ^b , C(O)OR ^b ;

R ¹ , R ² , m, R ⁴ , R ⁵ , R ⁶ , p, R ^b are as defined above.

In another preference, formula (I) is formula (VIIa) or (VIIb):

Each R ^e is independently selected from hydrogen, fluorine, or C _1-4 alkyl; the alkyl group in the R ^e is optionally substituted by the following substituents: CN, OR ^b , SR ^b , NR ^b R ^b , C(O)OR ^b ; each R ^b is independently selected from hydrogen, C _1-4 alkyl, or C _1-4 haloalkyl;

R ³ is selected from the following groups:

Wherein, "—" represents the position where ^R3 is connected to other parts of the compound of formula (VIIa) or (VIIb);

^Rf is as defined above;

R ¹ , R ² , m, R ⁴ , R ⁶ , p, R ^b , R ^d are as defined above.

In another preference, the compound of formula (I) is selected from the following group:

In the above structural formula, "*" represents a chiral center, which can be optionally R configuration or S configuration, or a mixture of R configuration and S configuration; use

The bonded carbon atom may optionally be in the R or S configuration, or optionally in cis or trans.

The second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated Derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.

The third aspect of the present invention provides a compound as described in the first aspect of the present invention, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate The use of it for the preparation of a pharmaceutical composition for treating a disease, disease or condition related to the p53 Y220C mutation.

In another preferred example, the disease, disease or condition is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, embryonal rhabdomyosarcoma, Granulosa cell tumor of the skin, melanoma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, rectal cancer, bladder cancer, throat cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glioma, ovarian cancer, Head and neck squamous cell carcinoma, cervical cancer, osteosarcoma, esophageal cancer, kidney cancer, skin cancer, gastric cancer, myeloid leukemia, lymphoid leukemia, myelofibrosis, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma , Non-Hodgkin's lymphoma, monocytic leukemia, splenomegaly, polycythemia, eosinophilic leukocytosis syndrome, bone marrow cancer and other solid tumors and blood tumors.

Detailed ways

After long-term and in-depth research, the inventors unexpectedly discovered a class of p53 modulators with novel structures and their preparation methods and applications. The compound of the present invention can be applied to the treatment of various diseases related to the activity of the transcription factor. Based on the above findings, the inventors have accomplished the present invention.

the term

Unless otherwise specified, "or" mentioned herein has the same meaning as "and/or" (referring to "or" and "and").

Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom (chiral center) may optionally be in R configuration or S configuration, or a mixture of R configuration and S configuration.

As used herein, the term "alkyl", by itself or as part of another substituent, refers to a straight chain (i.e., unbranched) or branched chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight chain and branched chain groups . When the alkyl group is defined by the number of carbon atoms (such as C _1-10 ), it means that the said alkyl group contains 1-10 carbon atoms. For example, C _1-8 alkyl refers to an alkyl group containing 1-8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or Similar groups.

As used herein, the term "alkenyl", by itself or as part of another substituent, refers to a straight or branched, carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When the number of carbon atoms (eg C _2- ₈ ) is limited before the alkenyl group, it means that the alkenyl group contains 2-8 carbon atoms. For example, C _2-8 alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups group.

As used herein, the term "alkynyl", alone or as part of another substituent, refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group can be straight or branched, or a combination thereof. When the number of carbon atoms is limited before the alkynyl group (such as C _2-8 alkynyl group), it means that the alkynyl group contains 2-8 carbon atoms. For example, the term " _C2-8 alkynyl" refers to a straight or branched chain alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.

As used herein, the term "cycloalkyl", alone or as part of another substituent, refers to a monocyclic or polycyclic (fused, bridged or spiro) ring system group having a saturated or partially saturated ring . When a cycloalkyl group is preceded by a restriction on the number of carbon atoms (such as C _3- ₁₀ ), it means that the cycloalkyl group contains 3-10 carbon atoms. In some preferred embodiments, the term "C _3-8 cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic alkyl group with 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclo Pentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" means a bicyclic or polycyclic group in which the single rings share a single carbon atom (called a spiro atom), these may contain one or more double bonds, but none of the rings has fully conjugated pi electrons system. "Fused cycloalkyl" means an all-carbon bicyclic or polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more bicyclic bonds, but none of the rings have a fully conjugated π-electron system. "Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system . The atoms contained in the cycloalkyl group are all carbon atoms. The following are some examples of cycloalkyl groups, and the present invention is not limited only to the cycloalkyl groups described below.

Unless stated to the contrary, the following terms used in the specification and claims have the following meanings. "Aryl" refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, eg, phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of connection to the parent must be in a conjugated π-electron system on the carbon atoms in the ring. Aryl groups can be substituted or unsubstituted. The following are some examples of aryl groups, and the present invention is not limited only to the aryl groups described below.

"Heteroaryl" refers to an aromatic monocyclic or polycyclic group containing one to more heteroatoms (optionally selected from nitrogen, oxygen and sulfur), or a heterocyclic group (containing one to more heteroatoms optionally A polycyclic group formed by condensing nitrogen, oxygen and sulfur) with an aryl group, and the connection point is located on the aryl group. Heteroaryl groups can be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited only to the heteroaryl groups described below.

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl. A polycyclic heterocyclic group refers to a heterocyclic group including spiro rings, fused rings and bridged rings. "Spirocyclic heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, with the remaining ring atoms being carbon. "fused ring heterocyclyl" means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none A ring has a fully conjugated pi-electron system, and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. "Bridged heterocyclyl" means a polycyclic heterocyclic group in which any two rings share two atoms not directly connected, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system , and wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If there are both saturated and aromatic rings in the heterocyclic group (for example, the saturated ring and the aromatic ring are fused together), the point of attachment to the parent must be on the saturated ring. Note: When the point of connection to the parent is on the aromatic ring, it is called heteroaryl, not heterocyclic. The following are some examples of heterocyclic groups, and the present invention is not limited only to the following heterocyclic groups.

The "C _3-6 cyclic group" refers to a saturated or partially unsaturated monocyclic or bicyclic cyclic group having 3-6 carbon atoms.

"Heterocyclic group" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group (non-aromatic) in which one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.

"Ring structure" refers to a ring system group having a saturated or partially saturated single ring, bicyclic or polycyclic rings (fused rings, bridged rings or spiro rings) and no heteroatoms in the ring skeleton. The cyclic group may be a monovalent, divalent, trivalent or other valent group, preferably a divalent or trivalent group. When a certain cyclic group is preceded by a restriction on the number of carbon atoms (such as C _3-10 ), it means that the cycloalkyl group contains 3-10 carbon atoms.

As used herein, the term "halogen" refers to F, Cl, Br and I, alone or as part of another substituent.

As used herein, the term "substituted" (with or without "optionally" modified) refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. The specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment. Unless otherwise specified, an optionally substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position. A cyclic substituent, such as a heterocyclyl, may be attached to another ring, such as a cycloalkyl, to form a spirobicyclic ring system, ie, two rings that share a single carbon atom. Those skilled in the art will appreciate that combinations of substituents contemplated by this invention are those that are stable or chemically feasible. The substituents are for example (but not limited to): C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3- to 12-membered heterocyclyl , Aryl, heteroaryl, halogen, hydroxyl, alkoxy, carboxyl (-COOH), C _1-8 aldehyde, C _2-10 acyl, C _2-10 ester, amino.

For the sake of convenience and common understanding, the terms "optional substitution" or "optional substitution" are only applicable to the positions that can be substituted by substituents, excluding those substitutions that cannot be achieved chemically.

As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of a subject (eg, a human) without undue side effects. In some embodiments, a pharmaceutically acceptable salt of a compound of the present invention includes a salt of a compound of the present invention having an acidic group (e.g., potassium salt, sodium salt, magnesium salt, calcium salt) or having a basic Salts (eg, sulfates, hydrochlorides, phosphates, nitrates, carbonates) of compounds of the invention.

use:

The present invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereoisomers, if present), hydrates , the use of a pharmaceutically acceptable carrier or excipient for regulating p53.

The compounds of the present invention are useful as modulators of p53.

The invention is a p53 regulator, which can prevent, alleviate or cure diseases by regulating the activity of p53. The diseases referred to include but are not limited to: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, embryonal rhabdomyosarcoma, granulosa cell tumor of the skin, melanoma, hepatocellular carcinoma , intrahepatic cholangiocarcinoma, rectal cancer, bladder cancer, throat cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, osteosarcoma , esophageal cancer, kidney cancer, skin cancer, gastric cancer, myeloid leukemia, lymphoid leukemia, myelofibrosis, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, monocytes Various solid tumors and blood tumors such as leukemia, splenomegaly, polycythemia, eosinophilic leukocytosis syndrome, and bone marrow cancer.

Compounds of the present invention and deuterated derivatives thereof, as well as pharmaceutically acceptable salts or isomers thereof (if any) or hydrates thereof and/or compositions may be mixed with pharmaceutically acceptable excipients or The carriers are formulated together and the resulting compositions can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases. Compositions can be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injections. Sterile powder, etc. In some embodiments, pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-β-cyclodextrin, β-cyclodextrin (increase), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicate and macromolecular polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic) and lubricants (such as magnesium stearate, glycerin, and talc). In a preferred embodiment, the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders. The amount of the compound or pharmaceutical composition of the present invention administered to the patient is not fixed, and is usually administered in a pharmaceutically effective amount. At the same time, the amount of the compound to be actually administered can be determined by the physician according to the actual situation, including the disease to be treated, the route of administration selected, the actual compound administered, the individual condition of the patient, and the like. Dosage of the compounds of this invention will depend on the particular use for the treatment, the mode of administration, the state of the patient, and the judgment of the physician. The ratio or concentration of the compound of the present invention in the pharmaceutical composition depends on various factors, including dosage, physicochemical properties, route of administration and the like.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions.

Pharmaceutical compositions and methods of administration

Since the compound of the present invention has excellent activity on regulating p53, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and the compound containing the present invention as the main active ingredient The pharmaceutical composition of the invention can be used for treating, preventing and alleviating diseases related to p53 activity or expression.

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. Wherein, "safe and effective dose" refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as

), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.

The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.

Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily The dosage is usually 1-2000 mg, preferably 5-500 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.

The main advantages of the present invention include:

1. A compound as shown in formula I is provided.

2. Provide a p53 Y220C regulator with a novel structure, its preparation and application, the inhibitor can activate the activity of p53 Y220C at very low concentration.

3. A class of pharmaceutical compositions for treating diseases related to p53 Y220C activity is provided.

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.

Some representative compounds of the present invention can be prepared by the following synthetic methods. In the following reaction formulas, the reagents and conditions of each step can be selected from the conventional reagents or conditions of this type of preparation method in the art. In the compound structure of the present invention After the disclosure, the above selection can be made by those skilled in the art based on the knowledge in the art.

General Synthetic Methods of Compounds

abbreviation

Boc ₂ O = di-tert-butyl dicarbonate

Cs ₂ CO ₃ = cesium carbonate

DCM = dichloromethane

DIPEA=N,N-diisopropylamine

DMAP = 4-dimethylaminopyridine

DMF=N,N-Dimethylformamide

DMSO = dimethyl sulfoxide

e.e. = enantiomeric excess percentage

EtOAc or EA = ethyl acetate

HATU=(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)

MgCl ₂ = magnesium chloride

NH ₄ HCO ₃ = ammonium bicarbonate

Pd(OAc) ₂ = palladium(II) acetate

Pd ₂ dba ₃ = tris(dibenzylideneacetone)palladium(0)

PE = petroleum ether

RT = room temperature

TEA = Triethylamine

TFA = trifluoroacetic acid

Some compounds of the present invention can be prepared by the following methods:

plan 1:

Some compounds of formula (II) can be prepared by the following methods.

Compound IIa-1 was prepared by the method in patent WO2021061643. Compound IIa-2 can be prepared by a suitable method. Compound IIa-1 and Compound IIa-2 were metal-catalyzed coupling reaction to obtain compound IIa-3, and then the target compound IIa was obtained through deprotection reaction. Compound 2 and Compound 3 in the present invention were prepared by the method of Scheme 1.

Scenario 2:

The compound of formula (III) can be prepared by the following method.

Compound III-1 was prepared by the method in patent WO2021061643. Compound III-1 is hydrolyzed to obtain compound III-2, and then subjected to condensation to obtain the compound of formula (III).

Option 3:

The compound of formula (V) can be prepared by the following method.

The key step in the synthesis of these compounds is the synthesis of intermediate V-4. There are two methods. When the corresponding dialkylphosphine oxide V-1 is commercially available, it can be coupled with a bromobenzene substituent to obtain V-2 through metal-catalyzed coupling, and V-2 can be reduced to obtain V-4 (route A); When V-1 is not commercially available, V-4 prepared by reacting phosphinate V-3 with Grignard reagent can be used (route B). V-4 was alkylated with bromopropyne and protected by Boc to obtain compound V-5 with a terminal triple bond and different phosphorocarbonyl substitutions. V-5 was coupled with different 2-position OTf substituted indole compounds to obtain V-6. Then carry out Buchward condensation and deprotection with substituted piperidine amino compound to obtain compound V.

Option 4:

The compound of formula (VI) can be prepared by the following method.

Compound VI-1 was prepared by the method in patent WO2021061643, VI-2 was synthesized from tetracyclic carbonyl as raw material, VI-1 and VI-2 were condensed to obtain VI-3, and then deprotected to obtain compound VI.

Option 5:

The compound of formula (VII) can be prepared by the following method.

Compound VII-1 was prepared by the method in patent WO2021061643, and was subjected to Buchward condensation with piperidine derivatives VII-2-a and VII-2-b with exocyclic double bonds to obtain the precursor, and then deprotected to obtain the target Compounds VII-a and VII-b.

Example:

Embodiment 1: the preparation of compound 1

Under nitrogen atmosphere, 5-chloro-2-nitroanisole (100mg, 0.534mmol) was dissolved in DMF (2mL), and K ₃ PO ₄ (125mg, 0.586mmol), Pd(OAc) ₂ (6mg , 0.0026mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (18.4mg, 0.032mmol) and dimethylphosphine oxide (46mg, 0.586mmol), the reaction mixture was heated to Microwave reaction at 150°C for 50 minutes. The reaction solution was cooled to room temperature, added water (5 mL), extracted with ethyl acetate (3×5 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain black liquid compound 1-b (70 mg, yield: 57%). MS (ES ⁺ , m/z): 230.3 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.86(dd, J=8.1, 3.2Hz, 1H), 7.66(dd, J=12.6, 1.0Hz, 1H), 7.17(m 1H), 4.02(s, 3H ), 1.78(s, 3H), 1.76(s, 3H).

Compound 1-b (500 mg, 2.18 mmol) and Pd/C (50 mg) were added into methanol (30 mL), and the reaction mixture was reacted at 25° C. for 4 hours under 1 atmosphere of hydrogen. Methanol (20 mL) was added to dilute the reaction solution, and after filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1-15:1) to obtain black liquid compound 1-c (115 mg, yield 44%). MS (ES ⁺ , m/z): 200.3 [M+H] ⁺ . ¹ H NMR (500 MHz, CD ₃ OD) δ 7.16-7.09 (m, 2H), 6.80 (m, 1H), 3.90 (s, 3H), 1.72 (s, 3H), 1.69 (s, 3H).

Compound 1-c (8 mg, 0.067 mmol) was dissolved in (Boc) ₂ O (1 mL), and the reaction mixture was heated to 80° C. and stirred for three hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain black liquid compound 1-d (3 mg, yield 15%). MS (ES ⁺ , m/z): 300.4 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ8.20(bs, 1H), 7.37(dd, J=12.3, 1.1Hz, 1H), 7.23(s, 1H), 7.09(m, 1H), 3.94(s, 3H), 1.72(s, 3H), 1.69(s, 3H), 1.52(s, 9H).

Compound 1-d (50 mg, 0.167 mmol) was dissolved in DMF (4 mL), and cesium carbonate (162.9 mg, 0.5 mmol) and propargyl bromide (60 mg, 0.5 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Water (5 mL) was added, extracted with ethyl acetate (3×5 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain reddish-brown liquid compound 1-e (50 mg, yield 88.8%). MS (ES ⁺ , m/z): 338.4 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ8.01(s, 1H), 7.42(m, 2H), 7.11(m, 1H), 4.27(bs, 2H), 3.90(s, 3H), 2.17(s, 1H), 1.75(s, 3H), 1.73(s, 3H), 1.35(m, 9H).

Under nitrogen atmosphere, compound 1-e (150mg, 0.44mmol) was dissolved in DMF (3mL) and triethylamine (3mL), and copper iodide (12.56mg, 0.066mmol), (Ph ₃ P) ₂ PdCl ₂ were added (15 mg, 0.022 mmol) and compound 1-f (227 mg, 0.533 mmol, see WO 2021/061643 for synthesis), and the reaction mixture was stirred at room temperature for 2 hours. Water (10 mL) was added, extracted with ethyl acetate (3×10 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain light yellow solid compound 1-g (260 mg, yield 96%). MS (ES ⁺ , m/z): 615.4 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.48(d, J=13.1Hz, 1H), 7.38(s, 1H), 7.33(d, J=7.5Hz, 1H), 7.23(d, J=8.3Hz , 1H), 7.17-7.08(m, 2H), 6.79(s, 1H), 4.64(q, J=8.4Hz, 4H), 3.92(s, 3H), 1.76(s, 3H), 1.73(s, 3H), 1.46 (m, 9H).

Under nitrogen atmosphere, compound 1-g (80 mg, 0.13 mmol) was dissolved in anhydrous 1,4-dioxane, and 2-(dicyclohexylphosphine) 3,6-dimethoxy-2' was added in sequence, 4',6'-triisopropyl-1,1'-biphenyl (8.37mg, 0.0091mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'- Biphenyl (8.5 mg, 0.018 mmol), cesium carbonate (169 mg, 0.52 mmol) and compound 1-h (35 mg, 0.17 mmol). The reaction mixture was warmed up to 100°C and stirred for 16h. Water (10 mL) was added, extracted with ethyl acetate (3×10 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) and then purified by silica gel thin layer chromatography (dichloromethane: methanol = 20: 1) to obtain light yellow solid compound 1-i (6mg , yield 7%). MS (ES ⁺ , m/z): 665.8 [M+H] ⁺ .

Compound 1-i (6 mg, 0.009 mmol) was dissolved in 4M HCl in 1,4-dioxane (3 mL), and stirred at 25°C for 0.5 hour. The reaction solution was concentrated under reduced pressure, NH ₃ /MeOH (0.5mL) was added dropwise to adjust the pH to 8, water (5mL) was added, extracted with ethyl acetate (5mL×3), the organic phase was washed with saturated brine, anhydrous sodium sulfate After drying and filtering, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=15:1). Purification by silica gel thin layer chromatography (dichloromethane:methanol=20:1) gave compound 1 as a light yellow solid (1.6 mg, yield 31.5%). MS (ES ⁺ , m/z): 565.7 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ7.21(m, 1H), 7.17(s, 1H), 7.13(dd, J=11.9, 1.4Hz, 1H), 7.00(t, J=8.0Hz, 1H), 6.84(m, 1H), 6.73(d, J=8.3Hz, 1H), 6.23(d, J=7.9Hz, 1H), 6.04(t, J=6.4Hz, 1H), 5.50(d, J=8.7Hz, 1H), 4.90(q, JH _{, F} =8.8Hz, 2H), 4.80(d, J=50.1Hz, 1H), 4.31(d, J=6.4Hz, 2H), 3.84(s , 3H), 3.61-3.50(m, 1H), 3.02(m, 1H), 2.80(d, J=10.6Hz, 1H), 2.18(s, 3H), 2.07(m, 1H), 2.01(m, 1H), 1.92(m, 1H), 1.69(m, 1H), 1.59(s, 3H), 1.56(s, 3H).

Embodiment 2: the preparation of compound 2

Under nitrogen atmosphere, t-BuOK (168mg, 1.5mmol) was dissolved in DMF (2mL), cooled to -55°C, compound 2-a (213mg, 1mmol) and compound 2-[(difluoromethyl)sulfonate were added in sequence Acyl]-pyridine (61 mg, 0.83 mmol). The reaction mixture was kept at -55°C and stirred for 15 minutes, then saturated aqueous ammonium chloride (0.5 mL) was added, and then 3M aqueous hydrochloric acid (1.3 mL) was added. Water (5 mL) was added, extracted with methyl tert-butyl ether (5 mL×3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain white solid compound 2-b (100 mg, yield 40%). MS (ES ⁺ , m/z): 247.4 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ4.43(s, 1H), 3.52(s, 1H), 2.41(dt, J=15.1, 4.0Hz, 2H), 1.99(dd, J=11.9, 2.8Hz, 2H), 2.00-1.80 (m, 2H), 1.44 (s, 9H), 1.24-1.12 (m, 2H). ¹⁹ F NMR (471 MHz, CDCl ₃ ) δ-97.85 (s).

Compound 2-b (100 mg, 0.4 mmol) was dissolved in 4M HCl in 1,4-dioxane (5 mL), and stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain white solid compound 2-c (73 mg, yield 99%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ8.25(s, 3H), 3.10(s, 1H), 2.40(d, J=14.5Hz, 2H), 2.01(d, J=12.1Hz, 2H) , 1.96-1.84 (m, 2H), 1.42-1.30 (m, 2H).

Compound 2-d (50 mg, 0.08 mmol, see WO 2021/061643 for synthesis), compound 2-c (17.9 mg, 0.096 mmol), cesium carbonate (106 mg, 0.32 mmol), Brettphos Pd G4 (7.3 mg, 0.008 mmol) and 2-bicyclohexylphosphine-2′,6′-diisopropoxybiphenyl (7.3mg, 0.016mmol) was sequentially added to the microwave reaction tube, followed by anhydrous 1,4-dioxane solution (2mL) , reacted at 110° C. for 16 hours under a nitrogen atmosphere. Water (2 mL) and ethyl acetate (3×5 mL) were added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by Prep-TLC (dichloromethane:methanol=15:1). Compound 2-e (40 mg, 72.2%) was obtained as a pale yellow solid. MS (ES ⁺ , m/z): 682.8 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ7.53(d, J=8.0Hz, 1H), 7.32-7.50(m, 2H), 7.15(t, J=8.0Hz, 1H), 6.65(d, J=8.2Hz, 1H), 6.62(s, 1H), 6.31(d, J=7.8Hz, 1H), 4.95-4.36(m, 4H), 3.93(s, 3H), 3.89-3.63(m, 1H ), 3.57-3.44(m, 1H), 3.08(s, 3H), 2.56-2.44(m, 2H), 2.22-2.15(m, 2H), 2.05-1.97(m, 2H), 1.44-1.28(m , 11H).

Compound 2-e (20 mg, 0.029 mmol) was dissolved in 4M HCl in 1,4-dioxane (2 mL), and stirred at 25° C. for 0.5 hour. The completion of the reaction was monitored by TLC, and the reaction solution was concentrated under reduced pressure. The hydrochloride salt of Compound 2 (16 mg, 85.7%) was obtained as a light yellow solid after lyophilization. MS (ES ⁺ , m/z): 582.7 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ7.39 (dd, J=8.4, 1.9Hz, 1H), 7.26 (d, J=1.9Hz, 1H), 7.23-7.16 (m, 1H), 7.16- 7.12(m, 1H), 6.90(d, J=8.4Hz, 1H), 6.82-6.43(m, 2H), 5.09-5.01(m, 2H), 4.38(s, 2H), 4.32(s, 1H) , 3.90(s, 3H), 3.82(m, 2H), 3.39(s, 1H), 3.10(s, 3H), 2.44-2.39(m, 2H), 2.05-1.99(m, 2H), 1.98-1.89 (m, 2H), 1.47-1.38 (m, 2H).

Embodiment 3: the preparation of compound 3

Under a nitrogen atmosphere, sodium hydride (60%, 48mg, 1.2mmol) was dispersed in THF (3mL), cooled to -78°C, and the compound triethyl phosphoroacetate (250mg, 1.2mmol) was slowly added dropwise. Warm to room temperature and stir for 0.5 hours. The reaction mixture was cooled to zero, compound 3-a (213mg, 1mmol) was added, stirred at room temperature for 2 hours, saturated aqueous sodium bicarbonate (5mL), extracted with ethyl acetate (5mLx3), and the organic phase was washed with saturated brine. Dry over sodium sulfate, filter and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1). Compound 3-b (260 mg, yield 92%) was obtained as a white solid. ¹ H NMR (500MHz, CDCl ₃ ) δ5.62(s, 1H), 4.45(s, 1H), 4.13(m, 2H), 3.68(s, 1H), 3.62(d, J=14.1Hz, 1H) , 2.27(dd, J=18.7, 14.7Hz, 2H), 2.17(dd, J=22.0, 9.3Hz, 1H), 2.07(t, J=11.8Hz, 2H), 1.43(s, 9H), 1.35- 1.28 (m, 2H), 1.25 (d, J = 7.1 Hz, 3H).

Under nitrogen atmosphere, compound 3-b (347mg, 1.225mmol) was dissolved in anhydrous tetrahydrofuran (5mL), cooled to -78°C, diisobutylaluminum hydride (2.55mL, 2.55mmol) was slowly added dropwise, and the addition was completed , the reaction mixture was kept at -78°C and stirred for 1 hour. The reaction solution was warmed to zero, and water (0.15mL), 15% aqueous sodium hydroxide solution (0.15mL), and water (0.3mL) were added dropwise in sequence, and the reaction mixture was warmed to room temperature and stirred for 15 minutes, and an appropriate amount of anhydrous sodium sulfate was added, and stirred After 15 minutes, it was filtered and the filtrate was concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain compound 3-c (250 mg, 85%). ¹ H NMR (500MHz, CDCl ₃ ) δ5.40(t, J=7.0Hz, 1H), 4.43(s, 1H), 4.14(d, J=3.0Hz, 2H), 3.62(s, 1H), 2.60 -2.51(m, 1H), 2.23(m, 1H), 2.14(t, J=12.7Hz, 1H), 2.06-1.97(m, 2H), 1.97-1.89(m, 1H), 1.44(s, 9H ), 1.24-1.19 (m, 2H).

Compound 3-c (242mg, 1.0mmol) was dissolved in dichloromethane (8mL), diisopropylethylamine (390mg, 3mmol) and methanesulfonyl chloride (173mg, 1.5mmol) were added dropwise under ice-cooling, and the reaction The solution was warmed to room temperature and stirred for 2 hours. Saturated brine was added to the reaction solution, extracted with dichloromethane (20mL x 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the obtained crude compound 3-d (319mg) was directly used in the next step reaction.

Compound 3-d (319 mg, 1.0 mmol), sodium iodide (15 mg, 0.1 mmol), dimethylamine (1.0 M in THF, 5.5 mL, 5.5 mmol) were dissolved in acetonitrile (6 mL). The reaction mixture was heated and stirred at 60°C in a sealed tube for 3 hours. The reaction mixture was concentrated under reduced pressure, separated and purified by silica gel column chromatography (dichloromethane:methanol=15:1) to obtain compound 3-e (200 mg, 75%) as a white solid. MS (ES ⁺ , m/z): 269.5 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ6.79(d, J=7.7Hz, 1H), 5.27(t, J=7.7Hz, 1H), 3.64(d, J=7.7Hz, 2H), 2.65 (s, 6H), 2.59(d, J=14.3Hz, 1H), 2.25(d, J=13.6Hz, 1H), 2.10(t, J=12.5Hz, 1H), 1.88(t, J=13.2Hz , 1H), 1.82 (d, J=8.8Hz, 2H), 1.37 (s, 10H), 1.27-1.16 (m, 2H).

Compound 3-e (20 mg, 0.074 mmol) was dissolved in 4M HCl in 1,4-dioxane (3 mL), and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and freeze-dried to obtain white solid compound 3-f (10 mg, yield 66%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ10.81(s, 1H), δ8.31(s, 3H), 5.34(t, J=7.7Hz, 1H), 3.66(d, J=5.2Hz, 2H), 3.56(s, 1H), 3.24-3.12(m, 1H), 2.69(m, 1H), 2.65(s, 6H), 2.32(m, 1H), 2.14(m, 1H), 2.04(m , 2H), 1.95-1.85 (m, 1H), 1.50-1.34 (m, 2H).

Under nitrogen atmosphere, compound 2-d (15 mg, 0.024 mmol), compound 3-f (6 mg, 0.029 mmol), cesium carbonate (31.8 mg, 0.097 mmol), Brettphos Pd G4 (2.2 mg, 0.0024 mmol), 2- Dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (2.2mg, 0.0048mmol) and 1,4-dioxane solution (1mL) in a sealed tube at 110°C React for 16 hours. After the reaction solution was cooled, water (2 mL) was added, extracted with ethyl acetate (3x5 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:methanol=15:1) to obtain light yellow solid compound 3-g (8 mg, 46.7%). MS (ES ⁺ , m/z): 703.8 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ7.58(s, 1H), 7.53(s, 2H), 7.09(s, 1H), 7.03(t, J=8.0Hz, 1H), 6.70(d, J=8.4Hz, 1H), 6.22(d, J=7.9Hz, 1H), 5.50(d, J=8.0Hz, 1H), 5.20(t, J=7.2Hz, 1H), 4.93-4.83(m, 2H), 4.80-4.50(m, 2H), 3.92(s, 3H), 3.62-3.51(m, 1H), 3.27(s, 3H), 3.01-2.88(m, 2H), 2.32-2.12(m, 8H), 2.10-2.03 (m, 2H), 1.96-1.88 (m, 1H), 1.46-1.24 (m, 12H).

Compound 3-g (8 mg, 0.011 mmol) was dissolved in dichloromethane (0.5 mL), and 4M hydrochloric acid in 1,4-dioxane (0.1 mL, 0.4 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated, and the pH was adjusted to >7 with methanolic ammonia solution. Separation and purification by preparative thin-layer chromatography (dichloromethane:methanol=15:1) gave brown solid compound 3 (1.3 mg, 19%). MS (ES ⁺ , m/z): 603.7 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ8.26(s, 1H), 7.39(dd, J=8.3, 1.8Hz, 1H), 7.25(d, J=1.8Hz, 1H), 7.08(s, 1H), 7.01(t, J=8.0Hz, 1H), 6.89(d, J=8.4Hz, 1H), 6.68(d, J=8.2Hz, 1H), 6.50(t, J=6.2Hz, 1H) , 6.20(d, J=7.9Hz, 1H), 5.48(d, J=8.0Hz, 1H), 5.19(t, J=7.0Hz, 1H), 4.93(q, J=9.0Hz, 2H), 4.36 (d, J=6.2Hz, 2H), 3.90(s, 3H), 3.10(s, 3H), 2.87(d, J=7.1Hz, 2H), 2.15(s, 6H), 2.05-1.95(m, 4H), 1.94-1.86 (m, 2H), 1.34-1.27 (m, 2H).

Embodiment 4: the preparation of compound 4

Compound 4-a (171 mg, 1 mmol) was dissolved in DMF (2.5 mL), and NaSMe (140 mg, 2 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. The completion of the reaction was monitored by TLC, the reaction solution was added with water (5 mL), extracted with MTBE (5 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain yellow solid compound 4-b (150 mg, yield 75%). MS (ES ⁺ , m/z): 200.3 [M+H] ⁺ . ¹ H NMR (500MHz, MeOD) δ7.83 (d, J=8.6Hz, 1H), 7.04 (d, J=1.8Hz, 1H), 6.91 (dd, J=8.6, 1.9Hz, 1H), 3.96( s, 3H), 2.57 (s, 3H).

Compound 4-b (40 mg, 0.2 mmol) was dissolved in methanol (3 mL), and a solution of NaIO ₄ (35 mg, 0.16 mmol) in water (1 mL) was added. The reaction mixture was stirred at 25°C for 16 hours. The completion of the reaction was monitored by TLC. The reaction solution was added with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2) to obtain compound 4-c (25 mg, yield 58%) as a yellow solid. MS (ES ⁺ , m/z): 216.3 [M+H] ⁺ . ¹ H NMR (500MHz, MeOD) δ7.97 (d, J=8.3Hz, 1H), 7.62 (d, J=1.6Hz, 1H), 7.37 (dd, J=8.3, 1.7Hz, 1H), 4.04( s, 3H), 2.87 (s, 3H).

Under nitrogen atmosphere, compound 4-c (30mg, 0.14mmol) was dissolved in dichloromethane (2mL), MgO (23mg, 0.56mmol) was added, after stirring for two minutes, trifluoroacetamide (32mg, 0.28mmol) was added successively , PhI(OAc) ₂ (68 mg, 0.21 mmol), Rh ₂ (OAc) ₄ (1.6 mg, 0.035 mmol). The reaction mixture was stirred at 25°C for 16 hours. The completion of the reaction was monitored by TLC. The reaction solution was added with water (5 mL), extracted with dichloromethane (5 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1). Compound 4-d (24 mg, yield 52%) was obtained as a yellow solid. MS (ES ⁺ , m/z): 327 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.99 (d, J=8.4Hz, 1H), 7.72 (d, J=1.8Hz, 1H), 7.61 (dd, J=8.4, 1.8Hz, 1H), 4.07 (s,3H), 3.49(s,3H).

Under hydrogen atmosphere, compound 4-d (30 mg, 0.1 mmol) was dissolved in methanol (10 mL), and Pd/C (5 mg) was added. The reaction mixture was stirred at 25°C for 4 hours. The completion of the reaction was monitored by TLC, and methanol (2 mL) was added to dilute the reaction solution. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1). Compound 4-e (20 mg, yield 67%) was obtained as a gray solid. MS (ES ⁺ , m/z): 297.3 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.39 (dd, J=8.4, 2.1Hz, 1H), 7.25 (d, J=2.1Hz, 1H), 6.74 (d, J=8.4Hz, 1H), 4.54 (s, 2H), 3.90 (s, 3H), 3.40 (s, 3H).

Compound 4-e (150 mg, 0.5 mmol) was dissolved in (Boc) ₂ O (2 mL), and the reaction mixture was heated to 90° C. and stirred for 16 hours. The completion of the reaction was monitored by TLC, cooled to room temperature, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1). Compound 4-f (160 mg, yield 81%) was obtained as a white solid. MS (ES ⁺ , m/z): 397.4 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ8.38 (d, J=8.7Hz, 1H), 7.54 (dd, J=8.7, 2.1Hz, 1H), 7.40 (d, J=2.1Hz, 1H), 7.34 (s, 1H), 3.97 (s, 3H), 3.43 (s, 3H), 1.53 (s, 9H).

Compound 4-f (600mg, 1.5mmol) was dissolved in DMF (20mL), and cesium carbonate (975mg, 3mmol) and propyne bromide (360mg, 3mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The completion of the reaction was monitored by TLC. Water (20 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1). Compound 4-g (420 mg, yield 82.8%) was obtained as a colorless liquid. MS (ES ⁺ , m/z): 339.5 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.63-7.57(m, 1H), 7.54(t, J=2.2Hz, 1H), 7.46(bs, 1H), 7.29(d, J=8.1Hz, 1H) , 4.29 (bs, 2H), 3.90 (m, 3H), 3.11 (m, 3H), 2.18 (t, J=2.3Hz, 1H), 1.42 (s, 9H).

Compound 4-g (280 mg, 0.83 mmol) was dissolved in (Boc) ₂ O (3 mL), and the reaction mixture was heated to 90° C. and stirred for 16 hours. The completion of the reaction was monitored by TLC, cooled to room temperature, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1). Compound 4-i (350 mg, yield 94%) was obtained as a white solid. MS (ES ⁺ , m/z): 439.5 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.57-7.53(m, 1H), 7.49(d, J=1.7Hz, 1H), 7.32(d, J=8.2Hz, 1H), 4.32(bs, 2H) , 3.91(s, 3H), 3.25(s, 3H), 2.18(t, J=2.3Hz, 1H), 1.40(s, 9H), 1.39(s, 9H).

Under nitrogen atmosphere, compound 4-i (200 mg, 0.456 mmol) was dissolved in DMF (3 mL) and triethylamine (3 mL), and CuI (13 mg, 0.68 mmol), (Ph ₃ P) ₂ PdCl ₂ (16 mg, 0.023 mmol), compound 1-f (240 mg, 0.563 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The completion of the reaction was monitored by TLC. Water (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2). Compound 4-J (250 mg, yield 71.5%) was obtained as a pale yellow solid. MS (ES ⁺ , m/z): 716.7 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.54-7.49(m, 3H), 7.33(d, J=7.8Hz, 1H), 7.23(d, J=8.4Hz, 1H), 7.14(t, J= 7.9Hz, 1H), 6.79(s, 1H), 5.04-4.37(m, 4H), 3.92(d, J=11.7Hz, 3H), 3.25(d, J=8.4Hz, 3H), 1.43-1.36( m, 18H).

Under nitrogen atmosphere, compound 4-J (50 mg, 0.07 mmol) was dissolved in anhydrous dioxane, and Brettphos (4.5 mg, 0.0049 mmol), Ruphos (4.5 mg, 0.0098 mmol), cesium carbonate (91 mg, 0.28 mmol), compound 1-h (17 mg, 0.085 mmol). The reaction mixture was warmed up to 100°C and stirred for 16h. The completion of the reaction was monitored by TLC. Water (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1). Purify again by silica gel thin layer chromatography (dichloromethane:methanol=20:1) to obtain light yellow solid compound 4-k (15 mg, yield 28%). MS (ES ⁺ , m/z): 766.9 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.59-7.44(m, 3H), 7.14(t, J=8.0Hz, 1H), 6.71-6.69(m, 2H), 6.29(d, J=7.7Hz, 1H), 4.87(d, J=48.6Hz, 1H), 4.64-4.56(m, 4H), 4.19(s, 1H), 3.93(s, 3H), 3.61-3.56(m, 1H), 3.33-3.26 (m, 1H), 3.23(s, 3H), 2.99(m, 1H), 2.40(s, 3H), 2.32-2.23(m, 1H), 2.12-1.90(m, 3H), 1.38(s, 18H) ).

Compound 4-k (15 mg, 0.019 mmol) was dissolved in 4M HCl/dioxane (2 mL), stirred at 25°C for 1 h. The completion of the reaction was monitored by TLC, the reaction solution was concentrated under reduced pressure, NH ₃ /MeOH (0.5 mL) was added dropwise to adjust the pH to 8, water (5 mL) was added, extracted with ethyl acetate (5 mL x 3), the organic phase was washed with saturated brine, Dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=15:1). Purified by silica gel thin-layer chromatography (dichloromethane:methanol=15:1), and freeze-dried to obtain light yellow solid compound 4 (8 mg, yield 72.1%). MS (ES ⁺ , m/z): 566.6 [M+H] ⁺ . ¹ HNMR (500MHz, DMSO-d ₆ ) δ7.42(dd, J=8.3, 2.0Hz, 1H), 7.30(d, J=2.0Hz, 1H), 7.19(s, 1H), 7.01(t, J =8.0Hz, 1H), 6.87(d, J=8.4Hz, 1H), 6.74(d, J=8.2Hz, 1H), 6.33(t, J=6.3Hz, 1H), 6.24(d, J=7.8 Hz, 1H), 5.52(d, J=8.7Hz, 1H), 4.93(q, J=9.2Hz, 2H), 4.82(d, J=49.3Hz, 1H), 4.35(d, J=6.3Hz, 2H), 3.88(s, 3H), 3.82(bs, 1H), 3.60-3.51(m, 1H), 3.05(m, 1H), 2.99(s, 3H), 2.82(d, J=10.8Hz, 1H ), 2.20(s, 3H), 2.11(m, 1H), 1.95-1.91(m, 2H), 1.70(d, J=12.6Hz, 1H).

Embodiment 5: the preparation of compound 5

Cyclopropanol (200mg, 3.42mmol) was dissolved in tetrahydrofuran (10mL), sodium hydride (140mg, 3.42mmol) was added in portions at 0°C, stirred at 0°C for 30 minutes, and then compound 5-a (500mg, 2.28mmol) of THF solution, TLC monitoring the completion of the reaction. The reaction was quenched with ice water, extracted with ethyl acetate (3 x 10 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 5-b (450 mg, 76.7%) as a yellow solid. ¹ HNMR (500MHz, CDCl ₃ ) δ8.02 (d, J=1.8Hz, 1H), 7.92 (d, J=8.3Hz, 1H), 7.62 (dd, J=8.3, 1.8Hz, 1H), 4.00- 3.97 (m, 1H), 3.12 (s, 3H), 0.97-0.92 (m, 4H).

Under a nitrogen atmosphere, compound 5-b (450 mg, 1.75 mmol) was dissolved in ethyl acetate (20 mL), and Pd/C (100 mg) was added to replace the nitrogen in the bottle with hydrogen. The reaction mixture was stirred at 25°C for 4 hours. The completion of the reaction was monitored by TLC, and diatomaceous earth and ethyl acetate were added for filtration. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound 5-c (350 mg, 88.1%) as a gray solid. MS (ES ⁺ , m/z): 228.3 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.61 (d, J=2.1Hz, 1H), 7.39 (dd, J=8.2, 2.0Hz, 1H), 6.73 (d, J=8.2Hz, 1H), 4.25 (s, 2H), 3.85-3.81 (m, 1H), 3.03 (s, 3H), 0.90-0.82 (m, 2H), 0.84-0.77 (m, 2H).

Under nitrogen atmosphere, compound 5-c (320mg, 1.47mmol) was dissolved in anhydrous tetrahydrofuran (5mL), and di-tert-butyl dicarbonate (642mg, 2.94mmol) and DMAP (180mg, 1.47mmol) were added sequentially. The reaction mixture was stirred at 70°C for 4 hours. The completion of the reaction was monitored by LCMS. After the reaction mixture was cooled, water (5 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound 5-d (520 mg, 86.4%) as a white solid. MS (ES ⁺ , m/z): 428.4 [M+H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ7.81(d, J=2.0Hz, 1H), 7.54(dd, J=8.1, 2.0Hz, 1H), 7.29(d, J=8.1Hz, 1H), 3.85( m, 1H), 3.08 (s, 3H), 1.41 (s, 18H), 0.88-0.84 (m, 2H), 0.80-0.75 (m, 2H).

Compound 5-d (320 mg, 0.75 mmol) was dissolved in methanol solution (30 mL), then anhydrous potassium carbonate (518 mg, 3.75 mmol) was added, and stirred overnight at room temperature. LCMS detected that the reaction was complete. The methanol solution was distilled under reduced pressure, water (10 mL) and ethyl acetate (3 x 20 mL) were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 5-e (230 mg, 93.9%) as a colorless oil. MS (ES ⁺ , m/z): 272.3 [M-(t-Bu)+H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ8.30(d, J=8.6Hz, 1H), 7.71(d, J=2.1Hz, 1H), 7.55(dd, J=8.5, 2.0Hz, 1H), 7.13( s, 1H), 3.88-3.83 (m, 1H), 3.05 (s, 3H), 1.53 (s, 9H), 0.94-0.89 (m, 2H), 0.88-0.85 (m, 2H).

Compound 5-e (230 mg, 0.7 mmol) was dissolved in anhydrous DMF (5 mL) under nitrogen atmosphere, and cesium carbonate (682 mg, 2.1 mmol) and propyne bromide (250 mg, 2.1 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 3 h. The completion of the reaction was monitored by LCMS. Water (5 mL) and ethyl acetate (3 x 10 mL) were added to the reaction solution for extraction. The organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1). Compound 5-f (250 mg, 97.3%) was obtained as a yellow solid. MS (ES ⁺ , m/z): 310.3 [M-(t-Bu)+H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ7.81(d, J=1.9Hz, 1H), 7.54(dd, J=8.2, 2.0Hz, 1H), 7.45(s, 1H), 4.24(s, 2H), 3.84 (s, 1H), 3.09 (s, 3H), 2.17 (s, 1H), 1.41 (s, 9H), 0.88-0.85 (m, 2H), 0.81-0.78 (m, 2H).

Compound 5-f (100mg, 0.27mmol), compound 1-f (128mg, 0.3mmol), cuprous iodide (10mg, 0.05mmol), bis(triphenylphosphine)palladium dichloride (10mg , 0.014mmol) was dissolved in DMF (2mL) and triethylamine (1mL), the mixture was stirred at room temperature for 1 hour, LCMS monitored the completion of the reaction, and the reaction solution was extracted with water (3mL) and ethyl acetate (3 x 5mL) , the organic phase was washed three times with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1). Compound 5-g (95 mg, 54.8%) was obtained as a yellow solid. LCMS (ES, m/z): MS (ES ⁺ , m/z): 585.4, 587.4 [M-(t-Bu)+H] ⁺ . ¹ HNMR (500MHz, DMSO-d6) δ7.85-7.82(m, 1H), 7.64(d, J=8.3Hz, 1H), 7.56(s, 2H), 7.37(d, J=7.5Hz, 1H) , 7.26-7.20(m, 1H), 6.77(s, 1H), 5.09(d, J=9.2Hz, 2H), 4.62(s, 2H), 4.06(s, 1H), 3.27(s, 3H), 1.37(s, 9H), 0.85(m, 2H), 0.67(m, 2H).

Compound 5-g (40mg, 0.062mmol), compound 1-h (16mg, 0.074mmol), cesium carbonate (60mg, 0.186mmol), Brettphos (4mg, 0.004mmol), Ruphos (4mg, 0.08mmol) were sequentially added to the microwave The tube was then added with anhydrous dioxane solution (2 mL), and a long needle was used to penetrate the solution into the solution and stir for 10 minutes with nitrogen gas, and then the microwave tube was sealed. The reaction mixture was stirred at 110°C for 16 hours. LCMS monitored the completion of the reaction. Add water (2mL) and ethyl acetate (3 x 5mL) for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, which was separated and purified by silica gel column chromatography (dichloromethane: methanol =20:1). Compound 5-h (10 mg, 23.1%) was obtained as a yellow solid. MS (ES ⁺ , m/z): 693.8 [M+H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ7.84(s, 1H), 7.54(d, J=7.8Hz, 1H), 7.44(s, 1H), 7.14(t, J=8.0Hz, 1H), 6.74- 6.66(m, 2H), 6.29(d, J=7.8Hz, 1H), 4.85(d, J=48.9Hz, 1H), 4.60-4.54(m, 4H), 3.85(s, 1H), 3.56(dd , J=28.4, 11.6Hz, 1H), 3.29-3.20(m, 1H), 3.08(s, 3H), 2.97(d, J=12.0Hz, 1H), 2.35(s, 3H), 2.28-2.13( m, 2H), 1.94-1.88 (m, 2H), 1.37 (s, 9H), 0.87-0.86 (m, 2H), 0.84-0.76 (m, 2H).

Compound 5-h (10 mg, 0.014 mmol) was dissolved in hydrogen chloride dioxane solution, stirred at room temperature for 1 hour, and the reaction was completed by LCMS monitoring. The reaction solution was concentrated, ethyl acetate and triethylamine were added, and compound 5 (3 mg, 35.1%) was obtained by Prep-TLC separation. MS (ES ⁺ , m/z): 593.7 [M+H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ7.62(d, J=2.0Hz, 1H), 7.53(dd, J=8.4, 2.0Hz, 1H), 7.14(t, J=8.0Hz, 1H), 6.80( d, J=8.4Hz, 1H), 6.76(s, 1H), 6.70(d, J=8.2Hz, 1H), 6.29(d, J=7.7Hz, 1H), 5.02(t, J=6.3Hz, 1H), 4.89(d, J=46.7Hz, 2H), 4.59(q, JH _{, F} =8.5Hz, 2H), 4.32(d, J=6.3Hz, 2H), 3.88-3.81(m, 1H) , 3.66-3.61(m, 1H), 3.31-3.28(m, 1H), 3.04(s, 3H), 2.44(s, 3H), 3.03-3.01(m, 1H), 2.08-1.97(m, 4H) , 0.89-0.85 (m, 2H), 0.84-0.80 (m, 2H).

Embodiment 6: the preparation of compound 6

Under nitrogen atmosphere, compound 6-a (507mg, 6.84mmol) was dissolved in THF (20mL), NaH (280mg, 6.84mmol) was added, stirred in an ice-water bath for ten minutes, and oxetan-3-ol (1g, 4.56mmol) was added. The reaction mixture was stirred at room temperature for sixteen hours. The completion of the reaction was monitored by TLC. Water (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1). Compound 6-b (1 g, yield 80%) was obtained as a white solid. MS (ES ⁺ , m/z): 274 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.99 (d, J=8.3Hz, 1H), 7.66 (dd, J=8.3, 1.7Hz, 1H), 7.20 (d, J=1.6Hz, 1H), 5.45 -5.39 (m, 1H), 5.07-5.02 (m, 2H), 4.83 (m, 2H), 3.09 (s, 3H).

Under hydrogen atmosphere, compound 6-b (30 mg, 0.109 mmol) was dissolved in methanol (5 mL), and Pd/C (10 mg) was added. The reaction mixture was stirred at 25°C for 4 hours. The completion of the reaction was monitored by TLC, and methanol (10 mL) was added to dilute the reaction solution. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1). Compound 6-c (22 mg, yield 74%) was obtained as a white solid. MS (ES ⁺ , m/z): 244 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.40(dd, J=8.3, 1.9Hz, 1H), 6.83(d, J=1.8Hz, 1H), 6.78(m, 1H), 5.32-5.25(m, 1H), 5.03 (m, 2H), 4.76 (m, 2H), 4.44 (s, 2H), 2.99 (s, 3H).

Compound 6-c (350 mg, 1.44 mmol) was dissolved in (Boc)2O (10 mL), and the reaction mixture was heated to 80° C. and stirred for three hours. The completion of the reaction was monitored by TLC, cooled to room temperature, and purified by wet loading silica gel column chromatography (petroleum ether: ethyl acetate = 1:1). Compound 6-d (300 mg, yield 61%) was obtained as a white solid. MS (ES ⁺ , m/z): 344 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.99 (d, J=7.8Hz, 1H), 7.48 (d, J=2.1Hz, 1H), 7.44 (dd, J=8.7, 2.2Hz, 1H), 4.33 -4.27 (m, 1H), 4.16 (m, 1H), 3.88-3.80 (m, 2H), 3.59 (m, 1H), 3.03 (s, 3H), 1.55 (s, 9H).

Compound 6-d (270mg, 0.786mmol) was dissolved in DMF (5mL), and cesium carbonate (770mg, 2.36mmol) and propyne bromide (290mg, 2.36mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The completion of the reaction was monitored by TLC. Water (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1). Compound 6-e (100 mg, yield 33%) was obtained as a pale yellow solid. MS (ES ⁺ , m/z): 326 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ8.01 (d, J=8.8Hz, 1H), 7.48 (d, J=2.3Hz, 1H), 7.44 (dd, J=8.7, 2.3Hz, 1H), 4.37 (m, 1H), 4.24(t, J=1.9Hz, 2H), 4.20(m, 1H), 3.80(m, 1H), 3.73(m, 1H), 3.54(m, 1H), 3.02(s, 3H), 2.48(t, J=2.4Hz, 1H), 1.56(s, 9H).

Compound 6-e (95mg, 0.25mmol), compound 1-f (128mg, 0.3mmol), cuprous iodide (9.5mg, 0.05mmol), bis(triphenylphosphine)palladium dichloride were mixed under nitrogen atmosphere (9mg, 0.013mmol) was dissolved in DMF (2mL) and triethylamine (2mL), the mixture was stirred at room temperature for 2 hours, LCMS monitored the completion of the reaction, the reaction solution was extracted with water (3mL) and ethyl acetate (3x10mL) , the organic phase was washed three times with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1). Compound 6-f (130 mg, 79.4%) was obtained as a yellow solid. MS (ES, m/z): 601.3, 603.3 [M-tBu+H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ7.49(d, J=2.3Hz, 1H), 7.44(dd, J=8.7, 2.2Hz, 1H), 7.35(d, J=7.6Hz, 1H), 7.26( s, 2H), 7.18(t, J=7.9Hz, 1H), 6.91(s, 1H), 4.77(q, J=8.4Hz, 2H), 4.56(d, J=1.6Hz, 2H), 4.40( m, 1H), 4.24(m, 1H), 3.88(m, 1H), 3.81(m, 1H), 3.55(m, 1H), 3.00(s, 3H), 1.54(s, 9H).

Compound 6-f (115mg, 0.175mmol), compound 1-h (43mg, 0.21mmol), cesium carbonate (228mg, 0.7mmol), Brettphos (11.3mg, 0.012mmol), Ruphos (11.4mg, 0.024mmol) were added sequentially into the microwave tube, then add anhydrous dioxane solution (2mL), use a long needle to penetrate into the solution and stir with nitrogen for 10 minutes, and then seal the microwave tube. The reaction mixture was stirred at 110°C for 16 hours. LCMS monitored the completion of the reaction. Add water (2mL), extract with ethyl acetate (3x10mL), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product, which is separated and purified by silica gel column chromatography (dichloromethane:methanol=20 : 1). Compound 6-g (34 mg, 27.4%) was obtained as a yellow solid. MS (ES, m/z): 709.8 [M+H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ8.02(d, J=8.7Hz, 1H), 7.50(d, J=2.2Hz, 1H), 7.44(dd, J=8.8, 2.2Hz, 1H), 7.17( t, J=8.0Hz, 1H), 6.83(s, 1H), 6.73(d, J=8.3Hz, 1H), 6.31(d, J=7.7Hz, 1H), 4.86(d, J=49.1Hz, 1H), 4.72(q, J=8.5Hz, 2H), 4.55(s, 2H), 4.42-4.38(m, 1H), 4.23(d, J=13.7Hz, 1H), 3.88(m, 1H), 3.81(m, 1H), 3.63-3.51(m, 2H), 3.30-3.21(m, 1H), 3.01(s, 3H), 2.35(s, 3H), 2.28-2.12(m, 2H), 2.02- 1.87 (m, 2H), 1.54 (s, 9H).

Compound 6-g (10 mg, 0.014 mmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.5 mL) was added dropwise, stirred at room temperature for 1 hour, and the reaction was completed by LCMS monitoring. Ammonia-methanol solution was added dropwise to adjust the pH of the reaction solution to 8. After concentration, Compound 6 (3 mg, 35.1%) was obtained by Prep-TLC separation. MS (ES, m/z): 609.7 [M+H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ7.37(S, 1H), 7.33(d, J=8.4Hz, 1H), 7.17(t, J=8.0Hz, 1H), 6.83(s, 1H), 6.73( d, J=8.3Hz, 1H), 6.63(d, J=8.3Hz, 1H), 6.31(d, J=7.7Hz, 1H), 4.87(d, J=49.1Hz, 1H), 4.70(q, J=8.5Hz, 2H), 4.55(s, 2H), 4.36-4.34(m, 2H), 4.24(bs, 1H), 3.87(m, 1H), 3.80(m, 1H), 3.64-3.55(m , 1H), 3.52(d, J=12.0Hz, 1H), 3.40(m, 1H), 3.26(t, J=11.2Hz, 1H), 2.97(s, 3H), 2.36(s, 3H), 2.33 -2.23(m, 1H), 2.18(t, J=11.4Hz, 1H), 2.05-2.03(m, 1H), 1.93(q, J=12.1Hz, 1H).

Embodiment 7: the preparation of compound 7

Compound 7-a (2.53 g, 13.96 mmol, 1.0 eq) was dissolved in (Boc) ₂ O (30 mL), and stirred at 110° C. for 3 hours. The completion of the reaction was monitored by TLC, separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain white solid compound 7-b-1/7-b-2 (4.74g), which was directly used in the next reaction.

Compound 7-b-1/7-b-2 (3.74g, 1.0eq), K ₂ CO ₃ (3.86g, 27.92mmol, 2.0eq) was dissolved in methanol (30mL), and reacted at 41°C for 16h. Extracted with DCM, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Separation and purification by column chromatography (petroleum ether: ethyl acetate = 10:1) gave compound 7-c (3.74 g, 95%). LC-MS (ES ⁺ , m/z): 282.1 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ8.16(d, J=8.4Hz, 1H) 7.67(dd, J=8.5, 1.5Hz, 1H), 7.52(d, J=1.5Hz, 1H), 7.26( s, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 1.35 (s, 9H).

Compound 7-c (2.74g, 9.74mmol, 1.0eq), _Cs2CO3 ( _9.52g , 29.22mmol, 3.0eq), 3-propyne (3.48g, 29.22mmol. 3.0eq) were dissolved in DMF ( 50 mL), stirred at room temperature for 2 h. The completion of the reaction was monitored by TLC, extracted with water/MTBE, spin-dried, separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 7-d (2.89 g, 93%) as a white solid. LC-MS (ES ⁺ , m/z): 319.2 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl3) δ7.63(dd, J=8.0, 1.55Hz, 1H), 7.58(s, 1H), 7.33(s, 1H), 4.27(s, 2H), 3.91(s, 3H ), 3.87(s, 3H), 2.15(s, 1H), 1.38(s, 9H).

Compound 7-d (400mg, 1.25mmol, 1.0eq), 1-f (640mg, 1.50mmol, 1.2eq), CuI (36mg, 0.188mmol, 0.15eq), (PPh ₃ ) ₂ PdCl ₂ (44mg, 0.063 mmol, 0.05eq) was dissolved in a mixed solvent of triethylamine (10 mL) and DMF (5 mL), and reacted at room temperature for 16 h under a nitrogen atmosphere. The completion of the reaction was monitored by TLC, spin-dried with triethylamine, extracted with water/MTBE, separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 7-e (398 mg, 54%) as a yellow solid. LC-MS (ES ⁺ , m/z): 539.4541.3 [M+H-56] ⁺ . ¹ H NMR (500MHz, CDCl3) δ7.66(d, J=8.1Hz, 1H), 7.63(s, 1H), 7.34-7.29(m, 2H), 7.22(d, J=8.2Hz, 1H), 7.14(t, J=7.9Hz, 1H), 6.78(s, 1H), 4.73(bs, 2H), 4.60(q, J=8.5Hz, 2H), 3.93(s, 3H), 3.91(s, 3H ), 1.39(s, 9H).

Compound 7-e (300mg, 0.504mmol, 1.0eq), 1-h (205mg, 0.68mmol, 1.3eq), Cs ₂ CO ₃ (654mg, 2.02mmol, 4eq), BrettPhos (44mg, 0.063mmol, 0.05eq ), RuPhos (33mg, 0.07mmol, 0.14eq) was dissolved in dioxane (5mL) and reacted at 110°C for 16h under nitrogen atmosphere. The completion of the reaction was monitored by TLC, extracted with water/MTBE and spin-dried, separated and purified by column chromatography (DCM:MeOH=50:1) to obtain compound 7-f (210 mg, 64%) as a yellow solid. LC-MS (ES ⁺ , m/z): 647.6 [M+H] ⁺ . used directly in the next reaction.

Compound 7-f (100 mg, 0.155 mmol, 1.0 eq) was dissolved in methanol (10 mL), and LiOH (H ₂ O compound) (32 mg, 0.77 mmol, 5.0 eq) was added. The reaction was stirred at 45°C for 16 hours. The completion of the reaction was monitored by TLC, methanol was spin-dried, and purified by a C-18 column to obtain compound 7-g (48 mg, 48%) as a yellow solid. LC-MS (ES ⁺ , m/z): 633.3 [M-Li+2H] ⁺ .

Compound 7-g (10.2mg, 0.016mmol, 1.0eq) was dissolved in DMF (2mL), and HATU (25mg, 0.080mmol, 5eq), methoxyamine hydrochloride (7mg, 0.080mmol, 5eq), DIPEA ( 21mg, 0.16mmol, 110eq), react at room temperature for 16h. After the TLC reaction was completed, THF was extracted, the organic phase was dried, filtered, concentrated under reduced pressure, separated and purified by PTLC (DCM:MeOH=20:1), and a yellow solid 7-h (6.3 mg, 60%) was obtained.

Under nitrogen atmosphere, 7-h (6.2 mg, 00094 mmol, 1.0 eq) was stirred in DCM (1 mL) and TFA (1 mL), and reacted for 30 min. LC-MS monitored the completion of the reaction, and the reaction solution was spin-dried. NH ₃ /MeOH (5 mL) was free, separated and purified by PTLC (DCM:MeOH=15:1), and a yellow solid 7 (2.6 mg, 49%) was obtained. LC-MS (ES ⁺ , m/z): 562.5 [M+ H] ⁺ . ¹ H NMR (500MHz, CDCl3) δ8.57(s, 1H), 7.32(s, 1H), 7.24(d, J=8.6Hz, 1H), 7.14(t, J=8.0Hz, 1H), 6.75( s, 1H), 6.70(t, J=8.3Hz, 2H), 6.29(d, J=7.7Hz, 1H), 5.00(m, 1H), 4.86(d, J=48.5Hz, 1H), 4.57( q, J=8.5Hz, 2H), 4.32(d, J=6.1Hz, 2H), 4.18(m, 1H), 3.82(s, 3H), 3.88(s, 3H).3.57(m, 1H), 3.28(t, J=11.0Hz, 1H), 3.00(d, J=10.0Hz, 1H), 2.39(s, 3H), 1.91-2.07(m, 3H).

Embodiment 8: the preparation of compound 8

Compound 7-g (33mg, 0.052mmol, 1.0eq) was dissolved in DMF (2mL), HATU (80mg, 0.258mmol, 5eq), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine ( 30mg, 0.258mmol, 5eq), DIPEA (67mg, 0.52mmol, 10eq) were reacted at room temperature for 16h. After the TLC reaction was completed, THF was extracted, the organic phase was dried, filtered, concentrated under reduced pressure, separated and purified by PTLC (DCM:MeOH=20:1), and a yellow solid 8-a (27mg, 71%) was obtained. LC-MS (ES ⁺ , m/z): 732.4 [M+H] ⁺ .

Under nitrogen atmosphere, 8-a (27mg, 0.0368mmol 1.0eq) was stirred in DCM (5mL) and TFA (2mL) and reacted for 30min. The completion of the reaction was monitored by LC-MS, and the reaction solution was spin-dried. NH ₃ /MeOH (5 mL) was free, separated and purified by PTLC (DCM:MeOH=15:1), and 8 was obtained as a yellow solid (3.0 mg, 14%). LC-MS (ES ⁺ , m/z): 548.30 [M+H] ⁺ .

Embodiment 9: the preparation of compound 9

Under nitrogen atmosphere, compound 9-a (232 mg, 1 mmol) was dissolved in DMF (3.5 mL), and K ₃ PO ₄ (255 mg, 1.2 mmol), Pd(OAc) 2 (12 mg, 0.05 mmol), Xantphos (58 mg , 0.1 mmol), POEt ₂ (160 mg, 1.5 mmol), and the reaction mixture was heated to 150° C. and microwaved for fifty minutes. The completion of the reaction was monitored by TLC. The reaction solution was cooled to room temperature, added with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=15:1). Black liquid compound 9-b (200 mg, yield 77.8%) was obtained. MS (ES ⁺ , m/z): 258.4 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.86 (dd, J=8.1, 3.1Hz, 1H), 7.64 (d, J=11.5Hz, 1H), 7.10 (dd, J=13.0, 4.6Hz, 1H) , 4.03(s, 3H), 2.11-1.98(m, 2H), 1.92-1.81(m, 2H), 1.15(t, J=7.7Hz, 3H), 1.11(t, J=7.7Hz, 3H).

Under hydrogen atmosphere, compound 9-b (1.3 g, 5.054 mmol) was dissolved in methanol (50 mL), and Pd/C (300 mg) was added. The reaction mixture was stirred at 25°C for 4 hours. The completion of the reaction was monitored by TLC, and methanol (20 mL) was added to dilute the reaction solution. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1-15:1). Compound 9-c (1.1 g, yield 96%) was obtained as a black liquid. MS (ES ⁺ , m/z): 228.44 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.17(d, J=11.4Hz, 1H), 6.94-6.88(m, 1H), 6.72(dd, J=7.8, 3.3Hz, 1H), 4.41-3.95( m, 2H), 3.87(s, 3H), 1.97-1.85(m, 2H), 1.85-1.74(m, 2H), 1.09(t, J=7.9Hz, 3H), 1.06(t, J=7.8Hz , 3H).

Compound 9-c (1.1 g, 4.84 mmol) was dissolved in (Boc) ₂ O (10 mL), and the reaction mixture was heated to 80° C. and stirred for three hours. The completion of the reaction was monitored by TLC, cooled to room temperature, and wet-loaded to silica gel column chromatography for separation and purification (dichloromethane:methanol=20:1). Compound D (1.5 g, yield 95%) was obtained as a black liquid. MS (ES ⁺ , m/z): 328.45 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ8.19(d, J=6.0Hz, 1H), 7.35(d, J=11.4Hz, 1H), 7.23(s, 1H), 7.02(t, J=9.3Hz , 1H), 3.93(s, 3H), 1.95(m, 2H), 1.84(m, 2H), 1.51(s, 9H), 1.11(t, J=7.8Hz, 3H), 1.08(t, J= 8.0Hz, 3H).

Compound 9-d (1.2g, 3.65mmol) was dissolved in DMF (20mL), and cesium carbonate (3.6g, 10.97mmol) and propyne bromide (1.4g, 10.97mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The completion of the reaction was monitored by TLC. Water (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1). Compound 9-e (1.3 g, yield 97%) was obtained as a pale yellow solid. MS (ES ⁺ , m/z): 366.46 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.40(d, J=11.4Hz, 1H), 7.36(s, 1H), 7.08-7.00(m, 1H), 4.25(bs, 2H), 3.88(s, 3H), 2.17(s, 1H), 1.99(m, 2H), 1.87(m, 2H), 1.56-1.20(m, 9H), 1.13(t, J=8.0Hz, 3H), 1.09(d, J = 7.6Hz, 3H).

Under nitrogen atmosphere, compound 9-e (50 mg, 0.137 mmol) was dissolved in DMF (1 mL) and triethylamine (2 mL), and CuI (4 mg, 0.02 mmol), (Ph ₃ P) ₂ PdCl ₂ (5 mg, 0.0068 mmol), compound 1-f (70 mg, 0.164 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The completion of the reaction was monitored by TLC. Water (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=25:1). Compound 9-f (60 mg, yield 68%) was obtained as a pale yellow solid. MS (ES ⁺ , m/z): 641.6 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.46 (dd, J=7.6, 4.4Hz, 1H), 7.36 (d, J=8.0Hz, 1H), 7.32 (d, J=7.7Hz, 1H), 7.23 (d, J=8.2Hz, 1H), 7.14(t, J=7.9Hz, 1H), 7.05(t, J=9.0Hz, 1H), 6.78(s, 1H), 4.66(m, 4H), 3.92 (s, 3H), 2.00(m, 2H), 1.93-1.84(m, 2H), 1.34(m, 9H), 1.13(t, J=8.1Hz, 3H), 1.10(t, J=7.9Hz, 3H).

Under nitrogen atmosphere, compound 9-f (100mg, 0.156mmol) was dissolved in anhydrous dioxane, and Brettphos (10mg, 0.011mmol), Ruphos (10mg, 0.02184mmol), cesium carbonate (202mg, 0.624mmol) were added successively , compound 1-h (45 mg, 0.202 mmol). The reaction mixture was warmed up to 100°C and stirred for 16h. The completion of the reaction was monitored by TLC. Water (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=15:1). Purification by silica gel thin layer chromatography (dichloromethane:methanol=15:1) gave compound 9-g (25 mg, yield 23%) as a pale yellow solid. MS (ES ⁺ , m/z): 693.6 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.46(d, J=9.0Hz, 1H), 7.36(s, 1H), 7.14(t, J=8.0Hz, 1H), 7.09-7.00(m, 1H) , 6.69(m, 2H), 6.29(d, J=7.7Hz, 1H), 4.84(d, J=49.0Hz, 1H), 4.61(m, 4H), 4.19(bs, 1H), 3.92(s, 3H), 3.55(m, 1H), 3.24(t, J=10.6Hz, 1H), 2.95(d, J=11.0Hz, 1H), 2.33(s, 3H), 2.32-2.20(m, 1H), 2.15(t, J=11.6Hz, 1H), 2.06-1.86(m, 6H), 1.58-1.31(m, 9H), 1.16-1.12(m, 3H), 1.12-1.07(m, 3H).

Compound 9-g (10 mg, 0.0144 mmol) was dissolved in DCM/TFA (1 mL/1 mL), stirred at 25° C. for 1 h. The completion of the reaction was monitored by TLC, the reaction solution was concentrated under reduced pressure, NH ₃ /MeOH (0.5 mL) was added dropwise to adjust the pH to 8, water (5 mL) was added, extracted with ethyl acetate (5 mL x 3), the organic phase was washed with saturated brine, Dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=12:1). Purified by silica gel thin-layer chromatography (dichloromethane:methanol=12:1), and freeze-dried to obtain light yellow solid compound 9 (5 mg, yield 59%). MS (ES ⁺ , m/z): 593.6 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.23(d, J=11.4Hz, 1H), 7.13(t, J=8.0Hz, 1H), 7.10-7.04(m, 1H), 6.82(dd, J= 8.0, 3.1Hz, 1H), 6.76(s, 1H), 6.68(d, J=8.2Hz, 1H), 6.29(d, J=7.8Hz, 1H), 4.93(t, J=6.1Hz, 1H) , 4.85(d, J=49.0Hz, 1H), 4.57(dd, J=17.1, 8.6Hz, 2H), 4.32(d, J=6.2Hz, 2H), 4.19(s, 1H), 3.93(s, 3H), 3.53(m, 1H), 3.25(m, 1H), 2.95(m, 1H), 2.36(s, 3H), 2.24-1.78(m, 8H), 1.14(t, J=8.0Hz, 3H ), 1.10 (d, J=7.7Hz, 3H).

Embodiment 10: the preparation of compound 10

Compound 10-a (3.90 g, 26.32 mmol, 1.0 eq) was dissolved in (Boc) ₂ O (40 mL), and stirred at 100° C. for 48 hours. The completion of the reaction was monitored by TLC, and separation and purification by column chromatography (petroleum ether: ethyl acetate = 30:1) gave white solid compound 10-b (5.38 g, 83%). LC-MS (ES ⁺ , m/z): 249.3[M+H] ⁺

Compound 10-b (4.07 g, 16.39 mmol, 1.0 eq), NaN ₃ (5.33 g, 81.96 mmol, 5.0 eq), NH ₄ Cl (4.38 g, 81.96 mmol, 5.0 eq) were dissolved in DMF (50 mL), Reaction at 120°C for 16h. TLC monitored the completion of the reaction, diluted with water, adjusted the pH to 1 with 1M HCl, extracted with THF, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Separation and purification by column chromatography (DCM:THF=5:1) gave compound 10-c (3.86 g, 81%). LC-MS (ES ⁺ , m/z): 292.4[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO) δ8.23 (s, 1H), 7.98 (d, J=8.3Hz, 1H), 7.64 (s, 1H), 7.61 (d, J=8.4Hz, 1H), 3.92 (s, 3H), 1.48 (s, 9H).

Compound 10-c (720mg, 2.56mmol, 1.0eq), DHP (323mg, 3.8mmol, 1.5eq), PPTS (65mg, 0.256mmol, 0.1eq) were dissolved in THF (15mL) and reacted at room temperature for 16h. The reaction was monitored by TLC and concentrated. Separation and purification by column chromatography (PE:EA=5:1) gave compound 10-d (800 mg, 83%) as a colorless liquid. LC-MS (ES ⁺ , m/z): 376.2[M+H] ⁺ ; ¹ H NMR (500MHz, CDCl ₃ ), δ8.20(s, 1H), 7.80 (dd, J=8.4, 1.25Hz, 1H), 7.67(d, J=1.3Hz, 1H), 7.22(s, 1H), 6.03(dd, J=8.0, 2.45Hz, 1H), 4.05(m, 1H), 3.97(s, 3H), 3.83 (m, 1H), 2.51 (m, 1H), 2.18 (m, 2H), 1.71-1.83 (m, 3H), 1.54 (s, 9H).

Compound 10-d (400 mg, 1.06 mmol, 1.0 eq), Cs ₂ CO ₃ (1.0 g, 3.2 mmol, 3.0 eq), 3-bromopropyne (380 mg, 3.2 mmol, 3.0 eq) were dissolved in DMF (5 mL) , stirred at room temperature for 16h. The completion of the reaction was monitored by TLC, extracted with water/MTBE and spin-dried, separated and purified by column chromatography (PE:EA=5:1) to obtain compound 10-e (400 mg, 91%) as a colorless liquid. LC-MS (ES ⁺ , m/z): 430.2[M+H] ⁺ ; ¹ H NMR (500MHz, CDCl ₃ ) δ7.78(d, J=8.0Hz, 1H), 7.74(s, 1H), 7.37(s, 1H), 6.05(dd, J=7.8, 2.6Hz, 1H), 4.04(m, 1H), 3.92(s, 3H), 3.83(m, 1H), 4.3(bs, 2H) 2.51( m, 1H), 2.18 (m, 3H), 1.71-1.83 (m, 3H), 1.54 (s, 2H) 1.34 (s, 7H).

Compound 10-e (80mg, 0.188mmol, 1.0eq), 1-f (124mg, 0.288mmol, 1.2eq), CuI (6mg, 0.029mmol, 0.15eq), (PPh ₃ ) ₂ PdCl ₂ (7mg, 0.010 mmol, 0.05eq) was dissolved in a mixed solvent of triethylamine (2mL) and DMF (1mL), and reacted at room temperature under a nitrogen atmosphere for 16h. TLC monitored the completion of the reaction, spin-dried triethylamine, extracted with water/MTBE, spin-dried, separated and purified by Prep-TLC (petroleum ether: ethyl acetate = 2:1) to obtain yellow solid compound 10-f (42mg, 32%) LC -MS (ES ⁺ , m/z): 689.5[M+H] ⁺ , 691.6[M+H+2] ⁺ ; 1H NMR (500MHz, CDCl3) δ7.80 (d, J=8.0Hz, 1H), 7.39(t, J=7.8Hz, 1H), 7.27-7.33(m, 2H), 7.22(d, J=8.2Hz, 1H), 7.13(t, J=7.9Hz, 1H), 6.79(s, 1H )6.07(dd, J=7.7, 2.4Hz, 1H), 4.23-5.19(s, 2H), 4.61(q, J=8.5Hz, 2H), 4.04(m, 1H), 3.94(s, 3H), 3.83 (m, 1H), 2.52(m, 1H), 2.19(m, 3H), 1.71-1.82(m, 3H), 1.34(s, 9H)

Compound 10-f (69mg, 0.10mmol, 1.0eq), 1-h (27mg, 0.13mmol, 1.3eq), Cs ₂ CO ₃ (130mg, 0.40mmol, 4eq), BrettPhos (7mg, 0.007mmol, 0.07eq ), RuPhos (7mg, 0.014mmol, 0.14eq) was dissolved in dioxane (2mL) and reacted at 110°C for 16h under nitrogen atmosphere. The completion of the reaction was monitored by TLC, extracted with water/MTBE and spin-dried, separated and purified by column chromatography (DCM:MeOH=50:1) to obtain a yellow solid compound (30 mg), and the yellow solid compound 10-g (3 mg, 3%). LC-MS (ES ⁺ , m/z): 741.6 [M+H] ⁺ .

Under nitrogen atmosphere, 10-g (3 mg, 0.0041 mmol, 1.0 eq) was stirred in DCM (2 mL) and TFA (1 mL), and reacted for 30 min. The completion of the reaction was monitored by LC-MS, and the reaction solution was spin-dried. NH ₃ /MeOH (5 mL) was free and separated and purified by Prep-TLC (DCM:MeOH=10:1) to obtain 10 (1.0 mg, 44%) as a yellow solid. LC-MS (ES ⁺ , m/z): 557.5 [M+H] ⁺ .

Embodiment 11: Preparation of compound 11

Compound 11-a (4.86 g, 27.58 mmol) and difluoromethyl (2- A solution of pyridyl)sulfone (4.44g, 22.98mmol) in DMF (15mL) was stirred at -45°C for 60 minutes. Add 15ml of saturated ammonium chloride and 15ml of 3M hydrochloric acid dropwise, then slowly rise to room temperature, and react for 16h, extract with water (60mL) and MTBE (3x50mL), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, and filter ,concentrate. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain colorless liquid compound 11-b, 2.98g, yield 62%, LC-MS (ES ⁺ , m/z): 211.35 [M+H] ⁺ .

Under nitrogen atmosphere at -78°C, compound 11-b (2.98g, 14.3mmol) was dissolved in DCM (50mL), then boron tribromide (7.15g, 28.54mmol) was added and stirred at -78°C for 30min. Quench with saturated sodium bicarbonate solution (5 mL). The aqueous phase was extracted with DCM, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The residue was purified by column chromatography to remove benzyl bromide, and compound 11-c was dissolved in THF and used directly in the next step.

Under nitrogen atmosphere and ice bath at 0°C, compound 11-c (198 mg, 1.65 mmol) in anhydrous THF (25 mL) was added dropwise to a suspension of sodium hydride (1.14 g, 28.54 mmol) in anhydrous THF (25 mL) solution, and the mixture was stirred at 0°C for 30 minutes. A solution of TsCl (3.26 g, 17.12 mmol) in anhydrous THF (5 mL) was added dropwise, and the mixture was raised to 25° C. and stirred overnight. The reaction was quenched with water (100 mL), extracted with ethyl acetate (3x50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate=20:1) to obtain white solid compound 11-d, 2.53g, yield 65% (two steps), LC-MS (ES ⁺ , m/z ): 275.53 [M+H] ⁺ .

Under a nitrogen atmosphere and an ice bath at 0 °C, sodium hydride (696 mg, 17.40 mmol) was added batchwise to a suspension of compound 11-e (3.58 g, 15.82 mmol) in anhydrous HMPA (70 mL), and the mixture was stirred at 0 °C 30 minutes. 11-d (5.20 g, 18.98 mmol) was added, and the mixture was raised to 78° C. and stirred for 16 h. The reaction was quenched with water (100 mL), extracted with ethyl acetate (3×100 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain light yellow solid compound 11-f, 513 mg, yield 9.9%. LC-MS (ES ⁺ , m/z): 327.93, 330.08 [M+H] ⁺ .

Under nitrogen atmosphere, compound 11-f (513mg, 1.56mmol) was dissolved in THF (15mL), then TiCl4 (890mg, 4.69mmol), Zn powder (612mg, 9.36mmol) were added, and stirred at reflux for 2h at 70°C. Quenched with 1M HCl solution (50 mL). The aqueous phase was extracted with MTBE (3x30mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a light yellow Solid compound 11-g, 371 mg, yield 76%. LC-MS (ES ⁺ , m/z): 314.08, 315.91 [M+H] ⁺ .

To a solution of 11-g (423 mg, 1.34 mmol) in anhydrous THF (10 mL) was added dropwise compound KHMDS (2.7 mL, 2.69 mmol) at -78°C under nitrogen atmosphere, and the mixture was stirred at -78°C for 45 minutes. A solution of N-phenylbis(trifluoromethanesulfonyl)imide (961 mg, 2.69 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise, and the mixture was stirred at -78°C for 1 h. The reaction was quenched with water (20 mL), extracted with ethyl acetate (3x20 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain white solid compound 11-h, 518mg, yield 86%, ¹ H NMR (500MHz, CDCl ₃ ), δ7.50(d , J=8.4Hz, 1H), 7.39(d, J=7.8Hz, 1H), 7.18(t, J=8.2, 7.9Hz, 1H), 6.42(s, 1H), 5.06(m, 1H), 3.55 (m, 2H), 3.33 (m, 2H).

Under nitrogen atmosphere, compound 11-h (134 mg, 0.30 mmol) was dissolved in DMF (2 mL) and triethylamine (2 mL), and CuI (12 mg, 0.06 mmol), (Ph ₃ P) ₂ PdCl ₂ (11 mg, 0.015 mmol), compound 11-i (122 mg, 0.36 mmol, see WO 2021/061643 for synthesis), and the reaction mixture was stirred at room temperature for 2 hours. The completion of the reaction was monitored by TLC. Water (20 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1-3:1). Compound 11-j (140 mg, yield 73%) was obtained as an off-white solid. LC-MS (ES ⁺ , m/z): 636.71 [M+H] ⁺ .

Under nitrogen atmosphere, compound 11-j (64mg, 0.10mmol) was dissolved in anhydrous dioxane, and Brettphos (10mg, 0.01mmol), Ruphos (10mg, 0.02mmol), cesium carbonate (130mg, 0.40mmol) were added successively ), compound 1-h (27 mg, 0.13 mmol). The reaction mixture was warmed up to 100°C, stirred for 16 h, TLC monitored the completion of the reaction, added water (10 mL), extracted with ethyl acetate (10 mL x 3), washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, and filtered the filtrate under reduced pressure Concentration gave the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=15:1). Purification by silica gel thin layer chromatography (dichloromethane:methanol=20:1) gave light yellow solid compound 11-k (34 mg, yield 50%). LC-MS (ES ⁺ , m/z): 687.84 [M+H] ⁺ .

Under nitrogen atmosphere, compound 11-k (34 mg, 0.50 mmol) was dissolved in DCM (10 mL) and TFA (1 mL), stirred at 25° C. for 2 hours. The reaction solution was spin-dried, and after freeing NH ₃ /MeOH, PTLC separation and purification (dichloromethane:methanol=25:1) gave off-white solid compound 11 (6.0 mg, yield 21%). LC-MS (ES ⁺ , m/z): 587.83 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.53(dd, J=1.8, 8.3Hz, 1H), 7.28(d, J=1.8Hz, 1H), 7.10(t, J=8.3Hz, 1H), 6.85 (d, J=8.4Hz, 1H), 6.81(d, J=8.4Hz, 1H), 6.72(s, 1H), 6.26(d, J=7.7Hz, 1H), 5.20(m, 1H), 5.14 (t, J=6.0Hz, 1H), 4.84(d, _{JH, F} =48.9Hz, 1H), 4.35(d, J=6.1Hz, 2H), 4.17(bs, 1H), 3.94(s, 3H ), 3.62(m, 2H), 3.55(m, 1H), 3.23(m, 1H), 3.15(m, 2H), 3.03(s, 3H), 2.94(d, J=11Hz 1H), 2.34(s , 3H), 2.22(m, 1H), 2.58(m, 2H), 2.14(m, 1H), 2.02(m, 1H), 1.90(m, 1H),

Embodiment 12: the preparation of compound 12

Under a nitrogen atmosphere, 12-a (19.7g, 91mmol) was dissolved in tetrahydrofuran (25mL), and added dropwise to a tetrahydrofuran solution (75mL) containing magnesium chips (5g, 208mmol), stirred at room temperature for 2h, and then poured into the reaction solution Add diethyl phosphate (6.4g, 46mmol) in tetrahydrofuran (20mL), continue stirring at room temperature for 1h, add potassium carbonate aqueous solution (30g potassium carbonate dissolved in 50mL water) to the reaction solution to form a large amount of white precipitate, filter The precipitate was washed with ethanol, and the filtrate was collected and concentrated, then added dichloromethane, and dried over anhydrous magnesium sulfate. After concentrated by filtration, it was distilled under reduced pressure (160°C) to obtain a colorless transparent liquid 12-b (900 mg, yield 18.6%). LCMS (ES, m/z) = 105.1 [M+1]. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.44 (d, J=458.6 Hz, 1H), 2.02-1.99 (m, 2H), 1.82-1.71 (m, 6H).

Under nitrogen atmosphere, compound 12-b (156mg, 1.5mmol), 5-bromo-2-nitroanisole (232mg, 1mml), potassium phosphate (233mg, 1.1mmol), palladium acetate (11.2mg, 0.05mmol) , Xantphos (35mg, 0.06mmol) was added into DMF (3mL), heated to 90°C and stirred for 16h. The completion of the reaction was monitored by LCMS, cooled to room temperature, extracted with water (5 mL) and ethyl acetate (3×10 mL), the organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=30:1) to obtain yellow oil 12-c (150 mg, yield 58.8%). LCMS (ES, m/z) = 256.1 [M+1], ¹ H NMR (500 MHz, CDCl3) δ7.88 (dd, J = 8.1, 3.2 Hz, 1H), 7.71 (dd, J = 12.3, 1.4 Hz , 1H), 7.13(ddd, J=10.4, 8.1, 1.4Hz, 1H), 4.04(s, 3H), 2.31-2.19(m, 2H), 2.17-2.09(m, 2H), 2.04-1.96(m , 4H).

Under a nitrogen atmosphere, compound 12-c (150 mg, 0.588 mmol) was dissolved in ethyl acetate (20 mL), and palladium on carbon (50 mg) was added to replace the nitrogen in the bottle with hydrogen. The reaction mixture was stirred at 25°C for 4 hours. The completion of the reaction was monitored by LCMS, and diatomaceous earth and ethyl acetate were added for filtration. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 30: 1) to obtain light yellow solid compound 12-d (130 mg, 98.5%), LCMS (ES, m/z) = 226.1 [M+1] , ¹ H NMR (500MHz, CDCl3) δ7.26 (dd, J=12.0, 1.6Hz, 1H), 6.97 (ddd, J=11.4, 7.9, 1.5Hz, 1H), 6.74 (dd, J=7.9, 3.4 Hz, 1H), 4.12 (s, 2H), 3.91 (s, 3H), 2.22-2.09 (m, 2H), 2.08-1.86 (m, 6H).

Under nitrogen atmosphere, compound 12-d (130 mg, 0.578 mmol) was dissolved in methanol (2 mL), and di-tert-butyl dicarbonate (3 mL) was added. The reaction mixture was stirred at 70°C for 16 hours. The completion of the reaction was monitored by LCMS. After the reaction mixture was cooled, water (10 mL) was added and extracted with ethyl acetate (20 mLx3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=40:1) to obtain yellow oil 12-e (180mg, 95.8%), LCMS (ES, m/z)=326.1[M+1], ¹ H NMR (500MHz, CDCl ₃ ) δ8.20(d, J=6.4Hz, 1H), 7.42(dd, J=12.0, 1.6Hz, 1H), 7.24(s, 1H), 7.08-7.02(m, 1H), 3.94(s, 3H), 2.23-2.11(m, 2H), 2.10-1.88(m, 6H), 1.53(s, 9H).

Compound 12-e (180 mg, 0.554 mmol) was dissolved in anhydrous DMF (5 mL) under nitrogen atmosphere, cesium carbonate (541 mg, 1.62 mmol) and propyne bromide (193 mg, 1.62 mmol) were added sequentially. The reaction mixture was stirred at 30 °C for 2 h. The completion of the reaction was monitored by LCMS. Water (5 mL) and ethyl acetate (3×10 mL) were added to the reaction solution for extraction. The organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=40:1). Compound 12-f (180 mg, yield 89.5%) was obtained as a yellow solid. LCMS (ES, m/z) = 364.1 [M+1], ¹ HNMR (500MHz, CDCl ₃ ) δ7.48 (d, J = 12.2Hz, 1H), 7.38 (s, 1H), 7.12-7.04 (m , 1H), 4.28(s, 2H), 3.90(s, 3H), 2.27-2.14(m, 3H), 2.13-1.87(m, 6H), 1.34(s, 9H).

Compound 12-f (100mg, 0.275mmol), compound 1f (142mg, 0.33mmol), cuprous iodide (10mg, 0.055mmol), bis(triphenylphosphine)palladium dichloride (10mg, 0.014 mmol) was dissolved in DMF (2mL) and triethylamine (3mL), the mixture was stirred at room temperature for 2 hours, LCMS monitored the completion of the reaction, the reaction solution was extracted with water (10mL) and ethyl acetate (3x20mL), and the organic phase was extracted with Wash with saturated brine three times, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a crude product, which is separated and purified by silica gel column chromatography (dichloromethane:methanol=40:1). 12-g (120 mg, yield 68.2%) of yellow oil was obtained. LCMS (ES, m/z) = 638.9, 640.9 [M+1], ¹ H NMR (500 MHz, CDCl ₃ ) δ7.52 (d, J = 12.3 Hz, 1H), 7.42-7.31 (m, 2H), 7.23(d, J=8.3Hz, 1H), 7.17-7.12(m, 1H), 7.11-7.05(m, 1H), 6.79(s, 1H), 4.91-4.43(m, 4H), 3.92(s, 3H), 2.25-2.14 (m, 2H), 2.14-1.89 (m, 6H), 1.37 (s, 9H).

Compound 12-g (60mg, 0.094mmol), compound 1-h (27mg, 0.132mmol), cesium carbonate (122mg, 0.376mmol), BrettphosPd G4 (6mg, 0.0066mmol), Ruphos (6mg, 0.0132mmol) were added sequentially into a microwave tube, then anhydrous dioxane solution (2 mL) was added, stirred under nitrogen for 10 min, and then the microwave tube was sealed. The reaction mixture was stirred at 100°C for 16 hours. LCMS monitored the completion of the reaction. Water (5 mL) and ethyl acetate (3x10 mL) were added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: methanol = 20 : 1). Compound 12-h (20 mg, 30.86%) was obtained as a yellow solid. LCMS (ES, m/z) = 691.1 [M+1], ¹ H NMR (500 MHz, CDCl ₃ ) δ7.58-7.49 (m, 1H), 7.46-7.32 (m, 1H), 7.14 (t, J =8.0Hz, 1H), 7.11-7.04(m, 1H), 6.76-6.66(m, 2H), 6.29(d, J=7.8Hz, 1H), 4.85(d, J=49.1Hz, 1H), 4.75 -4.44(m, 4H), 4.20(s, 1H), 3.92(s, 3H), 3.62-3.50(m, 1H), 3.24(t, J=11.6Hz, 1H), 2.99-2.91(m, 1H ), 2.35(s, 3H), 2.28-2.06(m, 6H), 2.04-1.87(m, 6H), 1.37(s, 9H).

Compound 12-h (10 mg, 0.0145 mmol) was dissolved in dichloromethane solution (1 mL), trifluoroacetic acid (0.4 mL) was added, the reaction was stirred at room temperature for 30 minutes, and the reaction was completed by LCMS monitoring. The reaction solution was concentrated, ammonia methanol solution was added to adjust the reaction solution to pH=8, and then compound 12 (2.8 mg, 42.8%) was obtained by Prep-TLC (dichloromethane:methanol=15:1) separation. LCMS (ES, m/z) = 591.2 [M+1], ¹ H NMR (500 MHz, CDCl ₃ ) δ7.31-7.27 (m, 1H), 7.16-7.08 (m, 2H), 6.82 (dd, J =8.0, 3.2Hz, 1H), 6.76(s, 1H), 6.68(d, J=8.3Hz, 1H), 6.29(d, J=7.7Hz, 1H), 4.95(t, J=6.3Hz, 1H ), 4.85(d, J=49.0Hz, 1H), 4.57(q, J=8.5Hz, 2H), 4.32(d, J=6.3Hz, 2H), 4.19(s, 1H), 3.93(s, 3H ), 3.61-3.50(m, 1H), 3.29-3.21(m, 1H), 2.99-2.92(m, 1H), 2.35(s, 3H), 2.26-2.10(m, 4H), 2.09-1.85(m , 8H).

Embodiment 13: Preparation of compound 13

Compound 13-a (1g, 4.31mmol), methyldiethoxyphosphine (0.88g, 6.46mmol), palladium acetate (96.8mg, 0.43mmol), Xantphos (249.2mg, 0.43mmol) and potassium phosphate (1.37 g, 6.46mol) into the microwave tube in turn, and then add anhydrous DMF solution (3 mL), use a long needle to penetrate into the solution and stir for 10 minutes with nitrogen gas, and then seal the microwave tube. The reaction mixture was subjected to microwave reaction at 150° C. for 2 hours. TLC monitored the completion of the reaction. The above operation was repeated 5 times, the combined reaction solution was added with water (40 mL), extracted with ethyl acetate (3 x 50 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1-0:100). Red liquid compound 13-b (2.5 g, yield 44.7%) was obtained. LC-MS (ES ⁺ , m/z): 260.2[M+H] ⁺ ; ¹ H NMR (500MHz, CDCl ₃ ) δ7.88(dd, J=8.1, 3.6Hz), 7.63(d, J=12.9 Hz), 7.35(dd, J=10.6, 8.6Hz), 4.14-4.08(m, 1H), 4.03(s, 3H), 3.91-3.81(m, 1H), 1.69(s, 3H), 1.32(t , J=7.1Hz, 3H).

Compound 13-b (900 mg, 3.47 mmol) was dissolved in ethyl acetate (20 mL) under hydrogen atmosphere, and Pd/C (90 mg) was added. The reaction mixture was stirred at 25°C for 3 hours. The completion of the reaction was monitored by TLC, and ethyl acetate (20 mL) was added to dilute the reaction solution. After filtration, the filtrate was concentrated under reduced pressure to obtain yellow compound 13-c (700 mg, yield 87.9%). LC-MS (ES ⁺ , m/z): 230.1 [M+H] ⁺ .

Under nitrogen atmosphere, compound 13-c (700 mg, 3.05 mmol) was dissolved in (Boc) ₂ O (4 mL), and stirred at 80° C. for 16 hours. The completion of the reaction was monitored by TLC, cooled to room temperature, and purified by wet loading silica gel column chromatography (petroleum ether: ethyl acetate = 2:1-0:100). Compound 13-d (700 mg, yield 76.6%) was obtained as light yellow liquid. LC-MS (ES ⁺ , m/z): 430.4 [M+H] ⁺ .

Compound 13-d (700 mg, 1.63 mmol) was dissolved in absolute ethanol (10 mL), and anhydrous potassium carbonate (1.12 g, 8.15 mmol) was added. The reaction mixture was stirred at 78°C for 8 hours. TLC monitored the completion of the reaction. Water (30 mL) was added and extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1-0:100). Compound 13-e (350 mg, yield 65.2%) was obtained as a pale yellow liquid. LC-MS (ES ⁺ , m/z): 330.3[M+H] ⁺ ; ¹ H NMR (500MHz, CDCl ₃ ) δ7.34 (d, J=12.6Hz, 1H), 7.30-7.27 (m, 1H ), 7.25-7.22(m, 1H), 4.39(s, 1H), 4.13-4.00(m, 1H), 3.94(s, 3H), 3.87-3.73(m, 1H), 1.65(d, J=14.5 Hz, 3H), 1.46(s, 9H), 1.40(t, J=9.1Hz, 3H).

Compound 13-e (350 mg, 1.06 mmol) was dissolved in DMF (3 mL), and cesium carbonate (1.04 g, 3.19 mmol) and propyne bromide (379.4 mg, 3.19 mmol) were added. The reaction mixture was stirred at 80°C for 16 hours. The completion of the reaction was monitored by TLC. Water (15 mL) was added and extracted with ethyl acetate (3 x 15 mL). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1-0:100). Compound 13-f (290 mg, yield 74.2%) was obtained as light yellow liquid. LC-MS (ES ⁺ , m/z): 368.3[M+H] ⁺ ; ¹ H NMR (500MHz, CDCl ₃ ) δ7.38-7.30 (m, 2H), 7.24-7.20 (m, 1H), 4.30 -4.13(m, 1H), 4.08-3.98(m, 2H), 3.82(s, 3H), 3.80-3.75(m, 1H), 2.11(t, J=2.5Hz, 1H), 1.62(d, J =14.5Hz, 3H), 1.31-1.18(m, 12H).

Under nitrogen atmosphere, compound 13-f (290mg, 0.79mmol) was dissolved in DMF (4mL) and triethylamine (2mL), CuI (22.5mg, 0.12mmol), Pd(PPh ₃ ) ₂ Cl ₂ (27.7mg , 0.04mmol), compound 1f (437.3mg, 1.03mmol), and the reaction mixture was stirred at room temperature for 2 hours. TLC monitored the completion of the reaction, added water (15 mL), extracted with ethyl acetate (3 x 20 mL), washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1-0:100) to obtain light yellow solid compound 13-g (370 mg, yield 72.8%). LC-MS (ES ⁺ , m/z): 643.4[M+H] ⁺ , 645.5[M+2+H]; ¹ H NMR (500MHz, CDCl ₃ ) δ7.49-7.40 (m, 1H), 7.39 -7.31(m, 2H), 7.31-7.28(m, 1H), 7.23(d, J=8.4Hz, 1H), 7.15(t, J=7.9Hz, 1H), 6.79(s, 1H), 4.95- 4.43(m, 2H), 4.65(q, J=8.1Hz, 2H), 4.09-4.02(m, 1H), 3.91(s, 3H), 3.89-3.75(m, 1H), 1.68(d, J= 14.5Hz, 3H), 1.45-1.34(m, 9H), 1.28(t, J=6.9Hz, 3H).

Under nitrogen atmosphere, compound 13-g (370 mg, 0.57 mmol) was dissolved in anhydrous dioxane (4 mL), and Brettphos Pd G4 (52.9 mg, 0.058 mmol), Ruphos (53.6 mg, 0.115 mmol), carbonic acid Cesium (750 mg, 2.30 mmol), compound 1h (153.3 mg, 0.75 mmol). The reaction mixture was warmed up to 100°C and stirred for 16h. TLC monitored the completion of the reaction, added water (10 mL), extracted with ethyl acetate (3 x 15 mL), washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=15:1). Compound 13-h (150 mg, yield 37.5%) was obtained as a pale yellow solid. LC-MS (ES ⁺ , m/z): 695.5[M+H] ⁺ ; ¹ H NMR (500MHz, CDCl ₃ ) δ7.48-7.34 (m, 2H), 7.14(t, J=8.0Hz, 1H ), 6.72(s, 1H), 6.70(d, J=8.5Hz, 1H), 6.29(d, J=7.7Hz, 1H), 4.85(d, J=48.9Hz, 1H), 4.60(q, J =8.5Hz, 2H), 4.77-4.27(m, 2H), 4.26-4.11(m, 1H), 4.11-4.02(m, 1H), 3.91(s, 3H), 3.88-3.78(m, 1H), 3.56(dd, J=29.1, 11.6Hz, 1H), 3.24(t, J=11.5Hz, 1H), 2.95(d, J=11.5Hz, 1H), 2.34(s, 3H), 2.26-2.20(m , 1H), 2.15(t, J=11.8Hz, 1H), 2.05-1.99(m, 2H), 1.96-1.89(m, 1H), 1.67(d, J=15.0Hz, 3H), 1.41-1.20( m, 12H).

Compound 13-h (5 mg, 0.007 mmol) was dissolved in DCM (1 mL), and trifluoroacetic acid (0.25 mL) was added. Stir at 25°C for 3h. The completion of the reaction was monitored by TLC, the reaction solution was concentrated under reduced pressure, NH ₃ /MeOH (0.5 mL) was added dropwise to adjust the pH value to 8, water (3 mL) was added, extracted with ethyl acetate (3 x 5 mL), the organic phase was washed with saturated brine, Dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel thin-layer chromatography (dichloromethane:methanol=10:1), and freeze-dried to obtain light yellow solid compound 13 (2 mg, yield, 46.7%). LC-MS (ES ⁺ , m/z): 595.4[M+H] ⁺ ; ¹ H NMR (500MHz, CD ₃ CN) δ7.22 (ddd, J=12.1, 8.1, 1.6Hz, 1H), 7.07- 6.99(m, 2H), 6.81(dd, J=8.1, 3.6Hz, 1H), 6.77(s, 1H), 6.65(d, J=8.3Hz, 1H), 6.23(d, J=7.7Hz, 1H ), 5.30(t, J=6.6Hz, 1H), 4.75(d, J=49.1Hz, 1H), 4.66(q, J=8.9Hz, 2H), 4.47(d, J=9.2Hz, 1H), 4.26(d, J=6.5Hz, 2H), 3.86-3.81(m, 1H), 3.81(s, 3H), 3.79-3.62(m, 1H), 3.59-3.45(m, 1H), 3.05(t, J=11.5Hz, 1H), 2.81(d, J=11.6Hz, 1H), 2.19(s, 3H), 1.82-1.77(m, 1H), 1.47(d, J=14.5Hz, 3H), 1.14( t, J=7.1Hz, 3H).

Embodiment 14: the preparation of compound 14

Under nitrogen atmosphere, cyclopropylmagnesium bromide (0.5M, 18 mL, 9 mmol) was added to a solution of compound 14-a (260 mg, 1.13 mmol) in THF (5 mL). The reaction mixture was stirred at 70°C for 16 hours. The reaction solution was cooled to room temperature, quenched by adding saturated ammonium chloride solution (5 mL), and extracted with ethyl acetate (3x30 mL). The combined organic phases were washed with saturated brine (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain yellow oily compound 14-b (240 mg, yield 93.9%). LCMS (ES, m/z): 226.1 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.21-7.17(m, 1H), 7.09-7.03(m, 1H), 6.73(dd, J=7.8, 3.4Hz, 1H), 4.13(s, 2H), 3.89 (s, 3H), 1.68 (d, J=12.9Hz, 3H), 1.01-0.74 (m, 5H).

Under nitrogen atmosphere, compound 14-b (180 mg, 0.799 mmol) was dissolved in methanol (2 mL), and di-tert-butyl dicarbonate (4 mL) was added. The reaction mixture was stirred at 70°C for 16 hours. The completion of the reaction was monitored by LCMS. After the reaction mixture was cooled, water (10 mL) was added and extracted with ethyl acetate (20 mLx3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=40:1) to obtain yellow oil 14-c (160 mg, 61.6%). LCMS (ES, m/z): 326.1 [M+1], ¹ H NMR (500 MHz, CDCl ₃ ) δ8.19 (d, J=8.1 Hz, 1H), 7.35-7.30 (m, 1H), 7.23 (s, 1H), 7.20-7.15 (m, 1H), 3.93 (s, 3H), 1.71 (d, J=12.9Hz, 3H), 1.52 (s, 9H), 1.03-0.80 (m, 5H).

Compound 14-c (160mg, 0.49mmol) was dissolved in anhydrous DMF (3mL) under a nitrogen atmosphere, cesium carbonate (479mg, 1.47mmol) and propyne bromide (175mg, 1.47mmol) were added successively, and the reaction mixture was Stir at 30°C for 2 h, LCMS monitored the completion of the reaction, added water (5 mL) to the reaction solution, extracted with ethyl acetate (3x10 mL), washed the organic phase three times with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=40:1) to obtain yellow solid compound 14-d (150 mg, yield 83.9%). LCMS (ES, m/z): 364.1 [M+1], ¹ H NMR (500 MHz, CDCl ₃ ) δ7.47-7.31 (m, 2H), 7.24-7.17 (m, 1H), 4.27 (s, 2H ), 3.89 (s, 3H), 2.19-2.15 (m, 1H), 1.74 (d, J=12.6Hz, 3H), 1.34 (s, 9H), 1.05-0.79 (m, 5H).

Compound 14-d (100 mg, 0.275 mmol), 1f (176 mg, 0.412 mmol), cuprous iodide (10 mg, 0.055 mmol), bis(triphenylphosphine) palladium dichloride (10 mg, 0.014 mmol) was dissolved in DMF (2mL) and triethylamine (2mL), the mixture was stirred at room temperature for 2 hours, LCMS monitored the completion of the reaction, the reaction solution was added water (10mL), extracted with ethyl acetate (3x20mL), the organic phase Washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane:methanol=40:1). The yellow oil 14-e (60 mg, yield 34.1%) was obtained. LCMS (ES, m/z): 639.1, [M+1], ¹ HNMR (500 MHz, CDCl ₃ ) δ7.50-7.35 (m, 2H), 7.34-7.31 (m, 1H), 7.25-7.18 (m , 2H), 7.17-7.12(m, 1H), 6.79(s, 1H), 4.77-4.51(m, 4H), 3.92(s, 3H), 1.75(d, J=12.7Hz, 3H), 1.37( s, 9H), 1.06-0.86 (m, 5H).

Compound 14-e (55mg, 0.086mmol), compound 1h (26mg, 0.129mmol), cesium carbonate (112mg, 0.344mmol), BrettphosPd G4 (8mg, 0.009mmol), Ruphos (8mg, 0.018mmol) were sequentially added to the microwave Anhydrous dioxane solution (3 mL) was then added into the tube, followed by stirring with nitrogen gas for 10 minutes, then the microwave tube was sealed, and the reaction mixture was stirred at 100° C. for 16 hours. LCMS monitored the completion of the reaction. Add water (5mL), extract with ethyl acetate (3x10mL), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product, which is separated and purified by silica gel column chromatography (dichloromethane:methanol= 20:1), to obtain yellow solid compound 14-f (20 mg, 33.7%). LCMS (ES, m/z): 691.3 [M+1]. ¹ H NMR (500MHz, CDCl ₃ ) δ7.46-7.32(m, 2H), 7.23-7.17(m, 1H), 7.14(t, J=8.0Hz, 1H), 6.75-6.66(m, 2H), 6.29(d, J=7.7Hz, 1H), 4.85(d, J=49.7Hz, 1H), 4.73-4.41(m, 4H), 4.20(s, 1H), 3.91(s, 3H), 3.62-3.47 (m, 1H), 3.29-3.20(m, 1H), 2.99-2.91(m, 1H), 2.34(s, 3H), 2.25-2.19(m, 1H), 2.15(t, J=11.8Hz, 1H ), 2.06-2.02 (m, 1H), 1.96-1.88 (m, 1H), 1.74 (d, J=12.7Hz, 4H), 1.36 (s, 9H), 1.06-0.89 (m, 5H).

Compound 14-f (10mg, 0.015mmol) was dissolved in dichloromethane solution (1mL), trifluoroacetic acid (0.5mL) was added, the reaction was stirred at room temperature for 1 hour, LCMS monitored the completion of the reaction, the reaction solution was concentrated, and ammonia methanol solution was added The pH of the reaction solution was adjusted to 8, and compound 14 (2 mg, 23.4%) was obtained by separation by preparative TLC (dichloromethane:methanol=15:1). LCMS (ES, m/z): 591.3 [M+1]. ¹ HNMR (500MHz, CDCl ₃ ) δ7.25-7.18(m, 2H), 7.13(t, J=8.0Hz, 1H), 6.82(dd, J=8.0, 3.3Hz, 1H), 6.76(s, 1H ), 6.68(d, J=8.3Hz, 1H), 6.29(d, J=7.7Hz, 1H), 4.94(t, J=6.3Hz, 1H), 4.84(d, J=49.1Hz, 1H), 4.56(q, J=8.5Hz, 2H), 4.32(d, J=6.3Hz, 2H), 4.20(br, 1H), 3.92(s, 3H), 3.62-3.49(m, 1H), 3.24(t , J=10.7Hz, 1H), 2.99-2.91(m, 1H), 2.34(s, 3H), 2.31-2.20(m, 1H), 2.15(t, J=9.6Hz, 1H), 2.06-1.99( m, 1H), 1.95-1.85(m, 1H), 1.71(d, J=12.9Hz, 3H), 1.02-0.91(m, 2H), 0.91-0.85(m, 2H), 0.84-0.76(m, 1H).

Embodiment 15: Preparation of compound 15

Under a nitrogen atmosphere, potassium tert-butoxide (0.99g, 8.7mmol) was dissolved in DMF (10mL), cooled to -45°C, and a solution of compound 15-a (1g, 5.39mmol) in DMF (5mL) and two A solution of fluoromethyl(2-pyridyl)sulfone (0.87 g, 4.5 mmol) in DMF (5 mL) was slowly raised to room temperature and stirred overnight. The completion of the reaction was monitored by TLC, and saturated aqueous ammonium chloride (10 mL) was added, followed by 3M aqueous hydrochloric acid (3 mL) and stirred at room temperature for one hour. Ethyl acetate (10mL x 3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1). Compound 15-b (300 mg, yield 25.4%) was obtained as a white solid. MS (ES ⁺ , m/z): 220.1 [M+H] ⁺ .

Compound 15-b (7 mg, 0.031 mmol) was dissolved in DCM (1 mL), and 4M hydrochloric acid 1,4-dioxane solution (1 mL) was added. The reaction was stirred at room temperature for 1 h. The starting material disappeared by TLC, and concentrated to obtain yellow liquid compound 15-c (3.8 mg, yield 100%). MS (ES ⁺ , m/z): 120.1 [M+H] ⁺ .

Compound 7-g (10 mg, 0.0156 mmol) was dissolved in DCM (1 mL), compound 15-c (3.8 mg, 0.031 mmol), DIPEA (8 mg, 0.0624 mmol), HATU (8.9 mg, 0.0234 mmol) were added, and the reaction was mixed The solution was stirred at room temperature for two hours. The completion of the reaction was monitored by TLC, water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=18:1). Compound 15-d (7 mg, yield 61%) was obtained as a yellow solid. MS (ES ⁺ , m/z): 734.3 [M+H] ⁺ .

Compound 15-d (7 mg, 0.0095 mmol) was dissolved in DCM (2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction was stirred at room temperature for 1 h. The TLC raw material disappeared, concentrated to obtain the crude product, added ammonia methanol to adjust the pH to weakly alkaline, purified by silica gel thin layer chromatography (dichloromethane:methanol=18:1), and freeze-dried to obtain white solid compound 15 (2.9mg, yield 48%). MS (ES ⁺ , m/z): 634.3 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.37(d, J=1.8Hz, 1H), 7.25-7.21(m, 1H), 7.14(t, J=8.0Hz, 1H), 6.81-6.60(m, 3H), 6.29(d, J=7.7Hz, 1H), 6.24(d, J=7.4Hz, 1H), 4.95(t, J=6.4Hz, 1H), 4.84(d, J=49.1Hz, 1H) , 4.68(q, J=7.5Hz, 1H), 4.56(q, J=8.5Hz, 2H), 4.33(d, J=6.3Hz, 2H), 4.19(s, 1H), 3.92(s, 3H) , 3.60(m, 1H), 3.28(m, 1H), 3.23-3.13(m, 2H), 3.00(s, 1H), 2.74-2.63(m, 2H), 2.38(s, 3H), 2.22(t , J=7.6Hz, 1H), 1.95(m, 3H).

Embodiment 16: Preparation of compound 16

Compound 16-a (2g, 10.8mmol) was dissolved in acetonitrile (100mL), triphenylphosphine (14g, 54mmol) was added, the reaction solution was cooled to 0°C, carbon tetrabromide (8.9g, 27mmol) was added in batches, The reaction mixture was raised to room temperature and reacted for 16 hours. TLC monitored the completion of the reaction, filtered, collected the filtrate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1). Compound 16-b (350 mg, yield 9.5%) was obtained as a white solid. MS (ES ⁺ , m/z): 339.8 [M+H] ⁺ .

Compound 16-b (30mg, 0.088mmol) was dissolved in acetonitrile (2mL), di-tert-butyl dicarbonate (40mg, 0.176mmol), triethylamine (18mg, 0.176mmol), 4-dimethylaminopyridine (2.15 mg, 0.0176mmol). The reaction mixture was stirred at room temperature for sixteen hours. The completion of the reaction was monitored by TLC, water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel thin layer chromatography (petroleum ether: ethyl acetate = 10:1). Compound 16-c (20 mg, yield 51.5%) was obtained as a white solid. MS (ES ⁺ , m/z): 440 [M+H] ⁺ .

Under nitrogen atmosphere, copper iodide (425mg, 2.27mmol) was dispersed in anhydrous tetrahydrofuran (2.2mL), and methyllithium in tetrahydrofuran (1.5M, 1.8mL) was added dropwise at 0°C. A solution of compound 16-c (100 mg, 0.227 mmol) in tetrahydrofuran (2.6 mL) was added. The reaction mixture was stirred at room temperature for sixteen hours. The completion of the reaction was monitored by TLC, and saturated aqueous ammonium chloride (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel thin layer chromatography (petroleum ether: ethyl acetate = 10:1). Compound 16-d (25 mg, yield 35.4%) was obtained as a colorless transparent liquid. MS (ES ⁺ , m/z): 312.2 [M+H] ⁺ .

Compound 16-d (10 mg, 0.032 mmol) was dissolved in DCM (1 mL), and trifluoroacetic acid (54 mg, 0.48 mmol) was added. The reaction was stirred at room temperature for 1 h. The starting material disappeared on TLC, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain compound 16-e (3 mg, yield 84%) as a colorless liquid. MS (ES ⁺ , m/z): 112.1 [M+H] ⁺ .

Compound 7-f (30 mg, 0.046 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (0.3 mL) was added. The reaction was stirred at room temperature for 1 h. The TLC raw material disappeared, concentrated under reduced pressure to obtain the crude product, added ammonia methanol to adjust the pH to weakly alkaline, and purified by silica gel thin layer chromatography (dichloromethane: methanol = 30: 1) to obtain yellow solid compound 16-g (8 mg, yield 32%). MS (ES ⁺ , m/z): 547.3 [M+H] ⁺ .

Compound 16-g (25mg, 0.046mmol) was dissolved in methanol (3mL), lithium hydroxide hydrate (10mg, 0.232mmol) was added, and the reaction mixture was heated to 50°C and stirred for sixteen hours. The raw material disappeared on TLC, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel thin layer chromatography (dichloromethane:methanol=10:1) to obtain compound 16-h as a yellow solid (10 mg, yield 41%). MS (ES ⁺ , m/z): 533.2 [M+H] ⁺ .

Compound 16-h (11mg, 0.02mmol) was dissolved in DMF (1.5mL), compound 16-e (5mg, 0.04mmol), DIPEA (10.32mg, 0.08mmol), HATU (11mg, 0.03mmol) were added, and the reaction was mixed The solution was stirred at room temperature for two hours. The completion of the reaction was monitored by TLC, water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=18:1). Compound 16 (4.1 mg, yield 32.7%) was obtained as a yellow solid after lyophilization. MS (ES ⁺ , m/z): 626.3 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.41-7.36(m, 1H), 7.26-7.20(m, 1H), 7.13(t, J=8.0Hz, 1H), 6.75(s, 1H), 6.72( d, J=8.2Hz, 1H), 6.68(d, J=8.3Hz, 1H), 6.28(d, J=7.7Hz, 1H), 6.23(d, J=7.1Hz, 1H), 4.98-4.90( m, 1H), 4.84(d, J=49.3Hz, 1H), 4.60-4.47(m, 3H), 4.32(d, J=5.5Hz, 2H), 4.27-4.10(m, 1H), 3.91(s , 3H), 3.56(m, 1H), 3.25(t, J=11.4Hz, 1H), 3.19-3.07(m, 2H), 2.96(d, J=11.8Hz, 1H), 2.59-2.50(m, 2H), 2.35(s, 3H), 2.24-2.19(m, 1H), 2.15(d, J=15.1Hz, 1H), 2.07-2.02(m, 1H), 1.96-1.89(m, 1H), 1.54 (s, 6H).

Embodiment 17: the preparation of compound 17

Compound 7-g (10 mg, 0.0156 mmol) and 17-a (5.3 mg, 0.0312 mmol) were dissolved in N, N-methylformamide (1 mL), and 2-(7-azobenzotriazole )-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.9mg, 0.0234mmol) and N,N-diisopropylethylamine (8.1mg, 0.0628mmol). The reaction mixture was stirred at room temperature for 2 h, LCMS monitored the completion of the reaction, the reaction solution was cooled to room temperature, added water (10 mL), extracted with ethyl acetate (3 x 15 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative chromatography on a silica gel plate (dichloromethane:methanol=18:1). Compound 17-b (7 mg, yield 59.7%) was obtained as a pale yellow solid. LC-MS (ES ⁺ , m/z): 748.4[M+H] ⁺ ; ¹ H NMR (500MHz, CDCl ₃ ) δ7.40-7.26 (m, 1H), 7.13(t, J=8.0Hz, 1H ), 7.05-6.98(m, 1H), 6.96-6.90(m, 1H), 6.75-6.65(m, 2H), 6.28(d, J=7.7Hz, 1H), 4.84(d, J=49.0Hz, 1H), 4.75-4.31(m, 4H), 3.86(s, 3H), 3.80-3.68(m, 2H), 3.60-3.52(m, 1H), 3.47-3.33(m, 2H), 3.24(t, J=11.4Hz, 1H), 3.02-2.86(m, 2H), 2.34(s, 3H), 2.32-2.27(m, 2H), 2.24-2.20(m, 1H), 2.18-2.12(m, 2H) , 2.05-2.00 (m, 2H), 1.95-1.90 (m, 1H), 1.31 (d, J=57.8Hz, 9H).

Compound 17-b (6 mg, 0.008 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.25 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The completion of the reaction was monitored by LCMS, and the reaction solution was diluted with dichloromethane, adjusted to pH=8 with a methanol solution of ammonia, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative chromatography on a silica gel plate (DCM:MeOH=18:1). Compound 17 (3.1 mg, yield 59.6%) was obtained as a pale yellow solid. LC-MS (ES ⁺ , m/z): 648.4[M+H] ⁺ ; ¹ H NMR (500MHz, CDCl ₃ ) δ7.14 (t, J=8.0Hz, 1H), 7.00 (dd, J=8.0 , 1.8Hz, 1H), 6.98-6.95(m, 1H), 6.75(s, 1H), 6.73(d, J=8.0Hz, 1H), 6.69(d, J=8.3Hz, 1H), 6.29(d , J=7.7Hz, 1H), 4.99-4.72(m, 2H), 4.59(q, J=8.5Hz, 2H), 4.31(s, 2H), 3.82-3.40(m, 6H), 3.62(s, 6H), 3.27(t, J=11.5Hz, 1H), 2.99(d, J=11.6Hz, 1H), 2.38(s, 3H), 2.28-2.18(m, 5H), 2.09-2.00(m, 2H), 1.96-1.92 (m, 1H).

Embodiment 18: Preparation of compound 18

Under nitrogen atmosphere, take a microwave tube and add 11-d (1.53g, 5.58mmol), 4-tert-butoxycarbonylaminopiperidine (1.68g, 8.37mmol) and DIPEA (3.61g, 27.9mmol) in anhydrous DMF (25mL ), and the mixture was stirred at 110°C for 48h. The reaction was quenched with water (100 mL), extracted with ethyl acetate (3 x 50 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate=10:1-2:1) to obtain white solid compound 18-a, 280 mg, yield 17%. LC-MS (ES ⁺ , m/z): 303.23 [M+H] ⁺ .

Compound 18-a (280 mg, 0.926 mmol) was dissolved in 4M HCl in 1,4-dioxane (15 mL) under nitrogen atmosphere, and stirred at 25° C. for 1 hour. The reaction solution was diluted with EA (20 mL), and filtered to obtain white solid 18-b, 215 mg, yield 84%. LC-MS (ES ⁺ , m/z): 203.1 [M+H] ⁺ .

Under nitrogen atmosphere, compound 18-b (105 mg, 0.280 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL), and 2-(dicyclohexylphosphine)-3,6-dimethoxy -2',4',6'-triisopropyl-1,1'-biphenyl (20mg, 0.020mmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1, 1'-biphenyl 20 mg, 0.04 mmol), cesium carbonate (459 mg, 1.41 mmol) and compound 7-f (167 mg, 0.337 mmol). The reaction mixture was warmed up to 100°C and stirred for 16h. Water (10 mL) was added, extracted with ethyl acetate (3x10 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=30:1) to obtain light yellow solid compound 18-c (153 mg, yield 76%). LC-MS (ES ⁺ , m/z): 717.7 [M+H] ⁺ .

Under nitrogen atmosphere, compound 18-c (153mg, 0.213mmol) was dissolved in 5mL of methanol and 1mL of water mixed solvent, LiOH·H2O (45mg, 1.07mmol) was added, and the reaction mixture was stirred at room temperature for 16h. The crude product was subjected to C-18 Separation and purification by silica gel column chromatography gave off-white solid compound 18-d (128 mg, yield 85%). LC-MS (ES ⁺ , m/z): 709.9 [M+H] ⁺ .

Under nitrogen atmosphere, compound 18-d (58mg, 0.818mmol) was dissolved in 5mL DMF solvent, and methylamine hydrochloride (11mg, 0.164mmol), HATU (62mg, 0.164mmol), DIPEA (42mg, 0.327mmol) were added , The reaction mixture was stirred at room temperature for 16 h. Add water (20 mL), extract with MTBE (3x10 mL), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=30:1) to obtain light yellow solid compound 18-e (53 mg, yield 91%). LC-MS (ES ⁺ , m/z): 716.8 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.47(s, 1H), 7.18(dd, J=1.6, 8.0Hz, 1H), 7.13(t, J=8.0Hz, 1H), 6.65(d, J= 7.8Hz, 1H), 6.64(s, 1H), 6.29(d, J=7.8Hz, 1H), 6.11(s, 1H), 5.02-4.10(s, 2H), 4.55(q, JH, F=8.6 Hz, 2H), 3.90(s, 3H), 3.48(m, 1H), 3.03(d, J=4.9Hz, 3H), 2.88(m, 1H), 2.83(m, 2H), 2.75(m, 2H ), 2.59(m, 2H), 2.15(m, 2H), 2.02(m, 2H), 1.35(s, 9H), 1.31(m, 2H).

Under nitrogen atmosphere, compound 18-e (53 mg, 074 mmol) was dissolved in DCM (10 mL) and TFA (1 mL), stirred at 25°C for 2 hours. After the reaction liquid was spin-dried, it was dissociated with NH ₃ /MeOH, and separated and purified by PTLC (dichloromethane:methanol=25:1) to obtain compound 18 as an off-white solid (35.6 mg, yield 78.1%). LC-MS (ES ⁺ , m/z): 616.8 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ7.38 (d, J=1.5Hz, 1H), 7.24 (dd, J=1.5, 8.2Hz, 1H), 7.13 (t, J=8.0Hz, 1H), 6.72 (d, J=8.2Hz, 1H), 6.68(s, 1H), 6.64(d, J=8.2Hz, 1H), 6.29(d, J=7.8Hz, 1H), 6.03(d, J=4.1Hz , 1H), 4.90(t, J=6.3Hz, 1H), 4.56(q, JH _{, F} =8.6Hz, 2H), 4.31(d, J=6.3Hz, 2H), 3.92(s, 3H), 3.47(m, 1H), 3.00(d, J=4.9Hz, 3H), 2.87(m, 1H), 2.83(m, 2H), 2.75(m, 2H), 2.58(m, 2H), 2.14(m , 2H), 2.02(m, 2H), 1.53(m, 2H).

Example 19: In vitro p53 Y220C and DNA binding activity test.

The HTRF method was used to detect the activation of p53 Y220C protein activity by the compound. Compounds were dissolved in DMSO to make 10 mM stock solutions and further diluted to 100 μM. Transfer 60 μL of the compound to a 384-well plate, and perform serial dilution according to the multiple of 1:4, with a total of 10 concentrations. Use the Echo to transfer 0.1 μL of the diluted compound to a 384-well plate, and duplicate each compound. Add 2.5 μL of p53 Y220C protein solution to the 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate for 10 min. Add 2.5 μL MAb-Anti-His-Tb working solution, and incubate at 30°C for 60 min. Add 5 μL of Streptavidin-d2&dsDNA to initiate the reaction, and incubate at 30°C for 60 min. Fluorescence values at 665nM/620nM were read using BMG. Calculate according to the following formula: activation rate (% activator) = 100*(ave Low control-ave cpd well)/(ave Low control-ave High control). Among them, ave High control is the average reading value of wild-type p53 wells added with equal concentration of DMSO, ave cpd well is the average reading value of compound wells, and ave Low control is the average reading value of p53 Y220C wells added with equal concentration of DMSO. EC ₅₀ is used to represent the concentration required for the compound to restore p53 Y220C DNA-binding function to 50% of the wild type. The EC ₅₀ value of each compound was analyzed by the nonlinear regression method of XLFit 5.5.0 software, and the formula was: Y=Bottom+(Top-Bottom)/(1+10^((LogEC ₅₀ -X)*HillSlope)). The activity data of representative compounds to activate p53 Y220C protein and DNA binding are shown in Table 1.

Table 1: In vitro activity of compounds on p53 Y220C and DNA binding

Note: A<100nM;100nM≤B<500nM;500nM≤C<1000nM. The positive drug Ref-A has an EC ₅₀ value in the range of 60-120nM under the test conditions.

Example 20: Inhibition of compound on proliferation of p53 Y220C mutated liver cancer cell line Huh7.

Huh7 cells in good growth state were selected and digested with trypsin. Add fresh medium, mix well, and centrifuge at 800rpm for 3 minutes. According to the seed plate density of 2000 Huh7 cells per well, they were seeded in 96-well plates and cultured overnight in a 37°C incubator. The next day, the culture plate was taken out, and the compound was diluted in a five-fold gradient for administration. Among them, the blank control wells only added normal medium, no cells, and no DMSO; the DMSO wells contained cells and contained 0.5% DMSO. The 96-well plate was placed in a 37°C incubator for 144 hours.

Place the cell culture plate at room temperature to equilibrate for 30 minutes; add 100 μL of CellTiter Glo detection reagent to each well, and mix on a vibrating plate machine for 2 minutes to induce cell lysis; place the 96-well plate at room temperature for 10 minutes to stabilize the luminescent signal; Paste the white base film on the bottom of the culture plate, use Enspire to detect the chemiluminescence value and calculate according to the following formula: inhibition rate (%)=(1-(compound reading-blank control reading)/(DMSO control reading-blank control reading))× 100%. The IC ₅₀ value of each compound was analyzed by nonlinear regression method of XLFit software. The activity data of representative compounds in inhibiting cell proliferation are shown in Table 2.

Table 2: Inhibitory activity of compounds on Huh7 cell proliferation

化合物compound	Huh7 IC ₅₀ Huh7 IC ₅₀
Ref-ARef-A	BB
11	BB
44	CC
55	CC
66	DD.
77	CC
88	CC
99	AA
1212	BB
1414	BB
1515	CC
1616	DD.
1818	DD.

Note: A<500nM; 500nM≤B<1000nM; 1000nM≤C<5000nM; 5000nM≤D<10000nM.

The chemical structure of compound Ref-A is as follows:

Example 21: Pharmacokinetic studies in rats

Instrument: XEVO TQ-S liquid-mass spectrometer produced by Waters, all measurement data were collected and processed by Masslynx V4.1 software, and Microsoft Excel was used to calculate and process data. The pharmacokinetic parameters were calculated by the statistical moment method with WinNonLin 8.0 software. Mainly including kinetic parameters Tmax, T _1/2 , Cmax, AUC _0-24h and so on. Chromatographic column: ACQUITY UPLC BEH C18 (2.1mm×50mm, 1.7μm); column temperature 40°C; mobile phase A is water (0.1% formic acid), mobile phase B is acetonitrile, the flow rate is 0.350 ml/min, using gradient elution , the elution gradient is 0.50min: 10%B; 1.50min: 90%B; 2.50min: 90%B; 2.51min: 10%B; 3.50min: stop. Injection volume: 1 μL.

Animals: 3 SD male rats, with a weight range of 200-220g, were used after being raised in the laboratory of the Experimental Animal Center for 2 days after purchase, fasted for 12 hours before administration and within 4 hours after administration, and free to drink water during the test. After the rats were gavaged, blood samples were collected within a predetermined period of time.

Vehicle: 0.4% ethanol + 0.4% Tween 80 + 99.2% (0.5% methylcellulose M450). Preparation of solution for intragastric administration: Precisely weigh the compound, add it to the solvent, sonicate at room temperature for 5 minutes to completely dissolve the drug, and prepare a 0.3 mg/ml medicinal solution.

Drug samples: generally take multiple samples with similar structures (the difference in molecular weight is more than 2 units), weigh them accurately, and administer them together (cassette PK). This allows multiple compounds to be screened simultaneously and their oral absorption rates compared. Pharmacokinetics of drug samples in rats were also studied using single administration.

Blood was collected from the orbit at 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours after intragastric administration. Take 50 μL of plasma sample, add 200 μL of acetonitrile (containing internal standard verapamil 2ng/mL), vortex for 3 min, centrifuge at 20000 rcf, 4 °C for 10 min, and take the supernatant for LC-MS/MS analysis.

Accurately weigh the compound to prepare different concentrations, conduct quantitative analysis on the mass spectrometer, so as to establish a standard curve, and then test the concentration of the compound in the above plasma to obtain the concentration of the compound at different time points. All the measurement data are collected and processed by relevant software, and the pharmacokinetic parameters are calculated by statistical moment method (mainly including kinetic parameters Tmax, T _1/2 , Cmax, AUC _0-24h , etc.).

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

A compound of the structure shown in the following formula (I), or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates:

In formula (I):

Ring A is selected from aryl or heteroaryl;

Ring B is selected from aryl or heteroaryl;

C ring is selected from C 3-8 cycloalkyl or 4- to 12-membered heterocyclyl;

D is selected from a chemical bond, -C≡C-, -CR a ═CR a -, or a C 3-6 cyclic group;

E is selected from chemical bonds, -(CR a R a ) q -, -O-, -NR b -, C 3-6 cyclic groups, or 3- to 6-membered heterocyclic groups;

F is selected from a chemical bond, -NR b -, -O-, or -(CR a R a ) q -;

U is selected from a chemical bond, -NR c -, -O-, -NR c C(O)R c -, -NR c C(O)-;

Each R a above is independently selected from hydrogen, halogen, C 1-4 alkyl, OR b , CN, NR b R b ; each R b and R c are independently selected from hydrogen, C 1-4 alkyl, Or C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl; in addition to general substituents, the cycloalkyl or heterocyclyl is optionally substituted by =M; M is selected from O or CR e R e ; or two R b together with the nitrogen atoms connected to them form an optionally substituted 4- to 8-membered ring structure, which may additionally contain 0-1 A heteroatom optionally selected from N, O, S;

R 1 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, C(O)R d , or S(O) 2 R d ; said alkyl, cycloalkyl, and heterocyclyl are optionally substituted by one or more groups selected from the group consisting of halogen, CN, OR b , SR b , NR b R b ; or the cycloalkyl and heterocyclyl are optionally substituted by =M; M is selected from O or CR e R e ; each R e is independently selected from hydrogen, fluorine, or C 1 -4 alkyl; the alkyl group in R e is optionally substituted by the following substituents: CN, OR b , SR b , NR b R b , C(O)OR b ; R d is selected from C 1- 4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl; in addition to general substituents, The cycloalkyl or heterocyclic group is optionally substituted by =M; M is selected from O or CR e R e ; R b is defined as above;

Each R 2 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3 -6 cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR b , SR b , or NR b R b ; R b is as defined above;

R 3 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 8-membered Heterocyclyl, aryl, heteroaryl, CN, OR b , SR b , NR b R b , C(O)R d , C(O)OR b , C(O)NR b R b , C(O) )N(OR b )R b , NR b C(O)R d , NR b S(O) 2 R d , S(O) 2 R d , S(O)(NR b )R d , S(O )R d , NR b S(O) 2 R d , S(O) 2 NR b R b , NR b S(O) 2 NR b R b , P(O)R f R f , P(O)( NR b R b )R f , or P(O)(OR b )R f ; the definitions of each R b and R d are as above; or two R b together with the nitrogen atoms connected to them form any substituted 4- to 8-membered ring structure, this ring structure can additionally contain 0-1 heteroatoms optionally selected from N, O, S; said ring structure is optionally substituted by =M; M is selected from O or CR e R e ; each R f is independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, OR b , NR b R b ; or two R f together with the phosphorus atom connected to them form an optionally substituted 4- to 8-membered ring structure, this ring structure can additionally contain 0-1 optional from N , a heteroatom of O, S; the alkyl, cycloalkyl, heterocyclic group or ring structure described in R f are optionally substituted by the following substituents: hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR b , SR b , NR b R b , =0; R b is defined as above;

Each R 4 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl , C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, C 2-4 alkenyl -O-, C 2-4 haloalkenyl-O-, C 2-4 alkynyl-O-, C 2-4 haloalkynyl-O-, C 3-6 cycloalkyl-O-, 3 - to 8-membered heterocyclyl-O-, CN, SR b , NR b R b , C(O)R d , C(O)OR b , C(O)NR b R b ; the alkyl , alkoxy, cycloalkyl, and heterocyclyl are optionally substituted by one or more groups selected from the group consisting of halogen, CN, OR b , SR b , NR b R b ; or the cycloalkane Base, heterocyclyl are optionally substituted by =M; M is selected from O or CR e R e ; each R e is independently selected from hydrogen, fluorine, or C 1-4 alkyl; the alkyl group of R e optionally substituted by the following substituents: CN, OR b , SR b , NR b R b , C(O)OR b ; each of R b and R d is as defined above;

Or R 4 and R in E and the ring atoms on the F and B rings connected to it together form an optionally substituted 6- to 8-membered ring structure;

Or R 4 and R b in F and the ring atoms on the B ring to which it is connected together form an optionally substituted 6- to 8-membered ring structure;

R 5 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 8-membered Heterocyclyl, CN, OR b , SR b , NR b R b , C(O)R d , C(O)OR b , C(O)NR b R b , C(O)NR b (OR b ) , NR b C(O)R d , NR b S(O) 2 R d , S(O) 2 R d , S(O)(NR b )R d , S(O)R d , NR b S( O) 2 R d , S(O) 2 NR b R b ; each R b is independently selected from hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl; or two R b are connected with them The nitrogen atoms together form an optionally substituted 4- to 8-membered ring structure, which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; R d is selected from C 1- 4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl; the alkyl in the above R 5 , R b , R d , Cycloalkyl and heterocyclyl are optionally substituted by one or more groups selected from the group consisting of halogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl , CN, OR b , SR b , NR b R b ; or the cycloalkyl and heterocyclyl in the above R 5 are optionally substituted by C=M; M is selected from O or CR e R e ; each R e is each independently selected from hydrogen, fluorine, or C 1-4 alkyl; the alkyl of Re e is optionally substituted by the following substituents: CN, OR b , SR b , NR b R b , C(O) OR b ; each R b is as defined above;

Each R 6 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkane Base, 3- to 6-membered heterocyclyl, CN, SR b , NR b R b ; each R b is defined as above; m is selected from 0, 1, 2, 3, or 4;

n is selected from 0, 1, 2, 3, or 4;

p is selected from 0, 1, 2, 3, or 4;

q is selected from 0, 1, 2, or 3;

Wherein, each of the above-mentioned alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups is optionally and independently replaced by 1-3 substituents independently selected from the following group Substitution: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8 - membered heterocyclyl, Aryl, Heteroaryl, CN, NO 2 , OR b , SR b , NR b R b , C(O)R d , C(O)OR b , C(O)NR b R b , NR b C( O)R d , NR b S(O) 2 R d , or S(O) 2 R d , provided that the formed chemical structure is stable and meaningful; wherein each R b is independently selected from Hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl; or two R b together with the nitrogen atom connected to them form an optionally substituted 4- to 8-membered ring structure, the ring structure Can additionally contain 0-1 heteroatoms optionally selected from N, O, S; each R d is independently selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl;

Unless otherwise specified, the above-mentioned aryl group is an aromatic group containing 6-12 carbon atoms; the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaromatic group; the ring structure is Single ring, parallel ring, condensed ring or heterocyclic ring, said ring structure may be saturated or partially unsaturated (but not aromatic).
The compound of claim 1, wherein,

R 3 is selected from C(O)NR b (OR b ), P(O)R f R f , P(O)(NR b R b )R f , or P(O)(OR b )R f ; each R f is independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, OR b , NR b R b ; or two R f together with the phosphorus atoms connected to them form a 4- to 8-membered ring structure optionally substituted, and this ring structure may additionally contain 0-1 heteroatoms optionally selected from N, O, S; each Each R b is independently selected from hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl; or two R b together with the nitrogen atom connected to them form an optionally substituted 4- to 8-membered ring A ring structure, which may additionally contain 0-1 heteroatoms optionally selected from N, O, and S;

Wherein, the alkyl group, cycloalkyl group, heterocyclyl group or ring structure described in R f are arbitrarily substituted by a group selected from the following group: hydrogen, halogen, C 1-4 alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR b , SR b , NR b R b , =O ; R b is as defined above;

or R3 is selected from:
in,
Represents the linking position of R 3 to other moieties of the compound of formula (I); R b is as defined above.
The compound of claim 1, wherein formula (I) is formula (II):

in,

R 1 is selected from the following groups:

in,
Represent the site where R is connected to other parts of the compound of formula (II);

Each R is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, CN, OR b , SR b , or NR b R b ; m is selected from 0, 1, or 2; R b is as defined in claim 1;

R 3 is selected from the following groups:

in,
Represents the site where R 3 is connected to other parts of the compound of formula (II); the definitions of R b , R d , and R f are as described in claim 2;

R 4 is selected from the following groups:

in,
Represent the site where R is connected to other parts of the compound of formula (II);

fragment
Groups selected from the following groups:

Among them, "*" represents a chiral center;

Represents a fragment
The site connected to other parts of the compound of formula (II); the definitions of R 5 , R 6 , R e , p are as described in claim 1;

F is selected from -NH-, -NMe-, or -O-.
compound as claimed in claim 3, is characterized in that,

R 3 is selected from the following groups:

in,
Represents the site where R 3 is connected to other parts of the compound of formula (II); the definitions of R b and R f are as described in claim 2.
compound as claimed in claim 3, is characterized in that,

fragment
Groups selected from the following groups:

Among them, "*" represents a chiral center;

Represents a fragment
The positions connected with other parts of the compound of formula (II); the definitions of R 5 , R 6 , R e , p are as described in claim 1.
compound as claimed in claim 3, is characterized in that,

R 1 is selected from the following groups:

in,
represents the point of attachment of R 1 to the rest of the compound of formula (II).
compound as claimed in claim 3, is characterized in that,

R 4 is selected from the following groups:

in,
Indicates the point of attachment of R4 to the rest of the compound of formula (II).
The compound of claim 1, wherein formula (I) is formula (III):

Wherein, each X is independently selected from CH or N, provided that at least two Xs are selected from CH, and the formed structure is stable; wherein the H on one CH is replaced by C(O) in formula (III) NH(OR b ) is substituted, H on other CH is optionally substituted by R 4 ; R b is selected from hydrogen or C 1-4 alkyl;

The definitions of R 1 , R 2 , m, F, ring C, R 5 , R 6 and p are as described in claim 1.
The compound of claim 1, wherein formula (I) is formula (IV):

Wherein, each X is independently selected from CH or N, provided that at least two Xs are selected from CH, and the formed structure is stable; wherein the H on one CH is replaced by P(O) in formula (IV) Rf is substituted with Rf , and H on other CHs are optionally substituted with R4 ; each Rf is independently selected from C1-4 alkyl, C3-6 cycloalkyl, 3- to 8-membered heterocycle group, aryl group, heteroaryl group, OR b , NR b R b ; or two R f together with the phosphorus atom connected to them form an optionally substituted 4- to 8-membered ring structure, the ring structure May additionally contain 0-1 heteroatoms optionally selected from N, O, S; the alkyl, cycloalkyl, heterocyclyl, or ring structure described in R f are optionally substituted by the following substituents: Hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR b , SR b , NR b R b , =O;

The definitions of R 1 , R 2 , m, F, ring C, R 4 , R 5 , R 6 , p, and R b are as described in claim 1.
The compound of claim 1, wherein formula (I) is formula (V):

Wherein, each R f is independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, OR b , NR b R b ; Or two R f together with the phosphorus atoms connected to them form an optionally substituted 4- to 8-membered ring structure, and this ring structure can additionally contain 0-1 hetero Atom; the alkyl, cycloalkyl, heterocyclyl, or ring structure described in R f is optionally substituted by the following substituents: hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR b , SR b , NR b R b , =O;

The definitions of R 1 , R 2 , m, R 4 , R 5 , R 6 , p, and R b are as described in claim 1.
The compound of claim 10, wherein in formula (V):

R 1 is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl; optionally substituted by one or more groups selected from the following group: halogen, CN, OR b , SR b , NR b R b ; or the cycloalkyl and heterocyclyl are optionally substituted by =M; M is selected from O or CR e R e ; each R e is independently selected from hydrogen, fluorine, or C 1-4 alkyl; the alkyl group in the R e is optionally substituted by the following substituents: CN, OR b , SR b , NR b R b , C(O)OR b ;

each R is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, OR b , SR b , or NR b R b ;

Each R 4 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkane Base-O-, 3- to 8-membered heterocyclyl-O-; said alkyl, alkoxy, cycloalkyl, heterocyclyl are optionally replaced by one or more groups selected from the following group Substitution: halogen, CN, OR b , SR b , NR b R b ;

R 5 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, C(O)R d , S(O) 2 R d ; the cycloalkane Base, heterocyclyl are optionally substituted by C=M; M is selected from O or CR e R e ; each R e is independently selected from hydrogen, fluorine, or C 1-4 alkyl;

Each R 6 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkane Base, 3- to 6-membered heterocyclic group, CN, SR b , NR b R b ; each R b is as defined above;

Each R b mentioned above is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl; the cycloalkyl is optionally substituted by =M;

Each of the above R d is independently selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl , or heteroaryl; the cycloalkyl, heterocyclyl is optionally substituted by =M;

m is selected from 0, 1, 2, or 3;

p is selected from 0, 1, 2, 3, or 4.
The compound of claim 1, wherein formula (I) is formula (VI):

T is selected from a chemical bond or -NR c -; R c is selected from hydrogen or C 1-4 alkyl;

Z is selected from N or CR k ; R k is selected from hydrogen or C 1-4 alkyl;

Each R e is independently selected from hydrogen, fluorine, or C 1-4 alkyl; the alkyl group in the R e is optionally substituted by the following substituents: CN, OR b , SR b , NR b R b , C(O)OR b ;

The definitions of R 1 , R 2 , m, R 4 , R 5 , R 6 , p, and R b are as described in claim 11.
The compound of claim 1, wherein formula (I) is formula (VIIa) or (VIIb):

Each R e is independently selected from hydrogen, fluorine, or C 1-4 alkyl; the alkyl group in the R e is optionally substituted by the following substituents: CN, OR b , SR b , NR b R b , C(O)OR b ; each R b is independently selected from hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl;

R 3 is selected from the following groups:

in,
Represents the site where R is connected to other moieties of the compound of formula (VIIa) or (VIIb);

The definition of R f is as described in claim 10;

The definitions of R 1 , R 2 , m, R 4 , R 6 , p, R b , and R d are as described in claim 11.
The compound of claim 1, wherein the compound of formula (I) is selected from the group consisting of:

In the above structural formula, "*" represents a chiral center, which can be optionally R configuration or S configuration, or a mixture of R configuration and S configuration; use
The bonded carbon atom may optionally be in the R or S configuration, or optionally in cis or trans.
A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1 to 14, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, Solvates, and pharmaceutically acceptable carriers.
A compound according to any one of claims 1 to 14, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, is characterized in that the use For the preparation of a pharmaceutical composition for treating diseases, disorders or conditions related to p53 activity or expression.
The use according to claim 16, wherein the disease, disease or condition is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer , embryonal rhabdomyosarcoma, cutaneous granulosa cell tumor, melanoma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, rectal cancer, bladder cancer, throat cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glial Cytoma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, osteosarcoma, esophageal cancer, kidney cancer, skin cancer, gastric cancer, myeloid leukemia, lymphoid leukemia, myelofibrosis, B cell lymphoma, T cell lymphoma , Hodgkin's lymphoma, non-Hodgkin's lymphoma, monocytic leukemia, splenomegaly, polycythemia, eosinophilia syndrome multiple, bone marrow cancer and other solid tumors and blood tumors.