Compound and application thereof in preparation of BCL-XL inhibitor

Abstract

The invention discloses a compound and application thereof in preparation of a BCL-XL inhibitor, and belongs to the field of pharmacy. The structure of the compound provided by the invention is as shown in formula I, and the compound can be effectively combined with BCL-XL protein, so that the activity of the BCL-XL protein is further inhibited. The compound can be used for preparing BCL-XL inhibitors and drugs for preventing and / or treating diseases (such as cancers and autoimmune diseases) related to BCL-XL protein activity, and has a wide clinical application prospect. The compound disclosed by the invention has good pharmacological properties, good stability and high patent medicine possibility, and the compound is simple in preparation method, high in yield, low in cost and suitable for industrial production. # imgabs0 #

Description

A compound and its use in preparing BCL-XL inhibitors

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application No. 202210653733.X, filed on June 10, 2022, entitled “A compound and its use in the preparation of BCL-XL inhibitors”, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention belongs to the field of pharmaceuticals, and particularly relates to a compound and its use in preparing a BCL-XL inhibitor. Background Art

[0004] Cancer is a leading threat to human health, with a high incidence and mortality rate. Research has shown that one of the factors contributing to tumorigenesis and drug resistance is overexpression of the BCL-XL gene and protein in human cells, which prevents the body from properly clearing abnormal genes and inhibits cell apoptosis. Previous studies have shown that apoptosis plays a negative regulatory role in tumor development and progression, inhibiting tumor cell proliferation. The ratio of BCL-XL in the heterodimer formed by BAK determines whether a cell survives after receiving apoptotic signals. If BCL-XL expression levels decrease, the effects of the pro-apoptotic gene BAK cannot be balanced, leading to cell apoptosis.

[0005] BCL-XL, a member of the BCL-2 family, is an anti-apoptotic protein overexpressed in a variety of cancer cells and a well-established anti-tumor therapeutic target. Studies have reported that BCL-XL inhibitors have positive therapeutic effects on autoimmune diseases and various cancers, including bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, prostatic lymphocytic leukemia, follicular lymphoma, T-cell or B-cell-derived lymphoid malignancies, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, and spleen cancer. The development of drugs that effectively inhibit the anti-apoptotic activity of BCL-XL proteins would be of great significance for the clinical treatment of autoimmune diseases and various cancers.

[0006] Currently, several BCL-XL inhibitors have been reported, such as A-1155463, A-1331852, etc. Among them, A-1155463 is a highly effective and selective BCL-XL inhibitor that inhibits EC in Molt-4 cells. 50A-1331852 is a selective BCL-XL inhibitor with a Ki value of less than 10 pM. However, in order to meet the large clinical needs, it is important to develop more new BCL-XL inhibitors.

[0007] Summary of the Invention

[0008] The present invention aims to provide a novel compound and the use of the compound in the preparation of BCL-XL inhibitors and drugs for preventing and / or treating diseases related to BCL-XL protein activity.

[0009] The present invention provides a compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, wherein the structure of the compound is shown in Formula I:

[0010] X1, X 2、 Each independently selected from N or CR x ;

[0011] R x are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, -OH, -O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl);

[0012] n1 and n2 are independently selected from 0, 1 or 2;

[0013] R1 is selected from 8-12 membered fused heteroaromatic ring, -NH (6-12 membered fused heteroaromatic ring), Preferably, the 8- to 12-membered fused heteroaromatic ring is

[0014] R 10 Selected from hydrogen, halogen, cyano, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 alkyl);

[0015] R11 Selected from hydrogen, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-C(O)NH(C 1～10 Alkyl), -C 0～2 Alkylene-C(O)N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-O-(C 6～10 aromatic ring), -C 0～2 Alkylene-O-(5-10 membered aromatic heterocycle);

[0016] R 12 Selected from hydrogen, halogen, cyano, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-C(O)NH(C 1～10 Alkyl), -C 0～2 Alkylene-C(O)N(C 1～10 Alkyl)(C 1～10 alkyl);

[0017] Or, R 11 、R 12 Together with the atoms connected to it, they form a 3-10 membered carbon ring, a 3-10 membered heterocyclic ring, a C 6～10 Aromatic ring, 5-10 membered aromatic heterocycle; the carbocyclic ring, heterocyclic ring, aromatic ring, aromatic heterocycle are unsubstituted or replaced by one, two or three independent halogen, oxo, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, -OH, -O(C 1～10alkyl), -NH2, -NH(C 1～10 alkyl) or -N(C 1～10 Alkyl)(C 1～10 alkyl) substituted;

[0018] R 13 Selected from hydrogen, halogen, cyano, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 alkyl);

[0019] R 14 Selected from hydrogen, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 alkyl);

[0020] Or, R 13 、R 14 Together with the atoms it is connected to form C 6～10 Aromatic ring, 5-10 membered aromatic heterocycle;

[0021] R 15 Selected from -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0022] R 16 Selected from hydrogen, halogen, cyano, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-C(O)NH(C 1～10 Alkyl), -C 0～2 Alkylene-C(O)NH(C 6～10 aromatic ring), -C 0～2 Alkylene-NH C(O)(C 1～10 Alkyl), -C 0～2 Alkylene-O-(C 6～10 aromatic ring), -C 0～2 Alkylene-O-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-NHS(O)O(C 1～10 alkyl);

[0023] R 17 Selected from hydrogen, halogen, cyano, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-C(O)NH(C 1～10 Alkyl), -C 0～2 Alkylene-C(O)N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-NHC(O)(C 1～10 Alkyl), -C 0～2 Alkylene-NHS(O)O(C 1～10 alkyl);

[0024] R 16 、R 17 Not simultaneously hydrogen;

[0025] R2 is selected from hydrogen, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 Alkyl); the alkyl group is unsubstituted or substituted by one, two or three independent R 21 replace;

[0026] R 21 Selected from halogen, -OH, -O(C 1～10 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0027] One of A and B is CR 4 R 5 , the other is NR3;

[0028] R 4 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 alkyl;

[0029] R 5 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 alkyl;

[0030] R3 is selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene-C(O)R 31 、-C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is unsubstituted or replaced by one, two or three independent R 32 replace;

[0031] R 31 Selected from hydrogen, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, halogen, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(8-12 membered fused heteroaromatic ring), -C 0～2 Alkylene-(9-12 membered fused aromatic ring); alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is unsubstituted or replaced by one, two or three independent R 32 'replace;

[0032] R 32 and R 32 ' are each independently selected from carboxyl, halogen, cyano, carbonyl, nitro, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, -OH, -O(C 1～10 Alkyl), -O(halogen substituted C 1～6 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-O-(C 6～10 aromatic ring), -C 0～2 Alkylene-O-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(8-12 membered fused heteroaromatic ring), -C 0～2 Alkylene-C(O)OLi, -C 0～2 Alkylene-C(O)OH, -C 0～2 Alkylene-C(O)NHR 33 、-C 0～2 Alkylene-NHC(O)R 33 alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are unsubstituted or replaced by one, two or three independent R 33 'replace;

[0033] R 33 and R 33 ' are each independently selected from hydrogen, carboxyl, halogen, -C 1～10 Alkyl, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 0～2Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-NR 34 R 35 、-C 0～2 Alkylene-NHC(O)R 34 、-C 0～4 Alkylene-C(O)NHR 34 、-C 0～2 Alkylene-NHC(O)OR 34 alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are unsubstituted or replaced by one, two or three independent R 34 'replace;

[0034] R 34 and R 34 ' are each independently selected from hydrogen, halogen, -C 1～10 Alkyl, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-NHC(O)R 35 、-C 0～2 Alkylene-C(O)NHR 35 alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl are unsubstituted or substituted by one, two or three independent R 35 'replace;

[0035] R 33 、R 33 '、R 34 、R 34 The halogens in ' do not contain iodine;

[0036] R 35 and the R 35 ' are each independently selected from hydrogen, halogen, -C 1～10 Alkyl, -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-NHC(O)R 36 、-C 0～2 Alkylene-C(O)NHR 36 、-C 0～2 Alkylene-C(O)OR 36 、-C 0～2 Alkylene-C(O)R 36 alkylene, alkyl, cycloalkyl, heterocycloalkyl are unsubstituted or replaced by one, two or three independent R 36 'replace;

[0037] R 36 and R 36 ' are each independently selected from hydrogen, halogen, -C 1～10 Alkyl, -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl).

[0038] Furthermore, the structure of the compound is shown in Formula IIa, Formula IIb, Formula IIc, Formula IId or Formula IIe:

[0039] wherein R1, R2, and R3 are as described above.

[0040] Furthermore, R 10 Selected from hydrogen, -OH, halogen, -C 1～6 alkyl;

[0041] R 11 Selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene-C(O)NH(C 1～6 Alkyl), -C 0～2 Alkylene-O-(C6 aromatic ring);

[0042] R 12 Selected from hydrogen, halogen, -C 1～6 Alkyl, -C(O)NH(C 1～6 alkyl);

[0043] Or, R 11 、R 12 Together with the atoms connected to it, it forms a 3-6 membered heterocyclic ring or a C6 aromatic ring; the heterocyclic ring or aromatic ring is unsubstituted or replaced by one, two or three independent hydrogens, halogens, hydroxyls, oxos, -C 1～6 Alkyl or halogen substituted C 1～6 Alkyl substitution;

[0044] R 13 Selected from hydrogen, halogen, cyano, -C 1～6 alkyl;

[0045] R 14 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～6 alkyl);

[0046] Or, R 13 、R 14 Together with the atoms to which it is connected, it forms a C6 aromatic ring or a 5- to 6-membered aromatic heterocyclic ring;

[0047] R 15 Selected from -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(C6 aromatic ring), -C 0～2 Alkylene-(5- to 6-membered aromatic heterocycle);

[0048] R 16 Selected from hydrogen, halogen, -C 1～6 Alkyl, -C 0～2 Alkylene-C(O)NH(C6 aromatic ring), -C 0～2 Alkylene-NH C(O)(C 1～6 Alkyl), -C 0～2 Alkylene-NHS(O)O(C 1～6 alkyl);

[0049] R 17 Selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene-C(O)NH(C 1～6 Alkyl), -C 0～2 Alkylene-C(O)N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-NHC(O)(C 1～6 Alkyl), -C 0～2 Alkylene-NHS(O)O(C 1～6 alkyl);

[0050] R 16 、R 17 Not hydrogen at the same time.

[0051] Further, R1 is selected from

[0052] Further, R2 is selected from hydrogen, -OH, -O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl); the alkyl group is unsubstituted or substituted by one, two or three independent R 21 replace;

[0053] R 21 Selected from halogen, -C 0～2 Alkylene-(C6 aromatic ring), -C 0～2 Alkylene-(5- to 6-membered aromatic heterocycle).

[0054] Further, R2 is selected from hydrogen, -OH, Methoxy or

[0055] Further, R3 is selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene-C(O)R 31 、-C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); the alkylene, alkyl, aromatic ring, aromatic heterocycle are unsubstituted or replaced by one, two or three independent R 32 replace;

[0056] R 31 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(8-12 membered fused heteroaromatic ring), -C 0～2 Alkylene-(9-12 membered fused aromatic ring); the alkylene, alkyl, aromatic ring, aromatic heterocycle are unsubstituted or replaced by one, two or three independent R 32 'replace;

[0057] R 32 and R 32 ' are each independently selected from hydrogen, carboxyl, halogen, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 1～6 Alkyl, halogen-substituted C 1～6Alkyl, -OH, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -C 0～2 Alkylene-O-(C 6～10 aromatic ring), -C 0～2 Alkylene-O-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(8-12 membered fused heteroaromatic ring), -C 0～2 Alkylene-C(O)OLi, -C 0～2 Alkylene-C(O)OH, -C 0～2 Alkylene-C(O)NHR 33 、-C 0～2 Alkylene-NHC(O)R 33 The alkylene, alkyl, alkenyl, alkynyl, aromatic ring, aromatic heterocycle is unsubstituted or replaced by one, two or three independent R 33 'replace;

[0058] R 33 and R 33 ' are each independently selected from hydrogen, halogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-NR 34 R 35 、-C 0～2 Alkylene-NHC(O)R 34 、-C 0～4 Alkylene-C(O)NHR 34 、-C 0～2 Alkylene-NHC(O)OR 34 ,; The alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is unsubstituted or replaced by one, two or three independent R 34 'replace;

[0059] R 34 and R 34 ' are each independently selected from hydrogen, halogen, -C 1～6 Alkyl, -C2～6 Alkenyl, -C 2～6 Alkynyl, -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-NHC(O)R 35 、-C 0～2 Alkylene-C(O)NHR 35 The alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is unsubstituted or replaced by one, two or three independent R 35 'replace;

[0060] R 33 、R 34 、R 33 '、R 34 The halogens in ' do not contain iodine;

[0061] R 35 and R 35 ' are each independently selected from hydrogen, halogen, -C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-C(O)OR 36 、-C 0～2 Alkylene-C(O)R 36 ; Alkylene, alkyl, heterocycloalkyl are unsubstituted or replaced by one, two or three independent R 36 'replace;

[0062] R 36 and R 36 ' are each independently selected from hydrogen, halogen, -C 1～6 alkyl.

[0063] Further, R3 is selected from:

[0064] R 32 are independently selected from hydrogen, carboxyl, halogen, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -C 0～2 Alkylene-O-(C 6～10 aromatic ring), -C 0～2Alkylene-O-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(8-12 membered fused heteroaromatic ring), -C 0～2 Alkylene-C(O)OLi, -C 0～2 Alkylene-C(O)OH, -C 0～2 Alkylene-C(O)NHR 33 ; Alkylene, alkyl, alkenyl, alkynyl, aromatic ring, aromatic heterocycle are unsubstituted or replaced by one, two or three independent R 33 'replace;

[0065] R 33 and R 33 ' are each independently selected from hydrogen, halogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-NR 34 R 35 、-C 0～2 Alkylene-NHC(O)R 34 、-C 0～4 Alkylene-C(O)NHR 34 、-C 0～2 Alkylene-NHC(O)OR 34 alkylene, alkyl, alkenyl, alkynyl, heterocycloalkyl, aromatic ring is unsubstituted or replaced by one, two or three independent R 34 'replace;

[0066] R 34 and R 34 ' are each independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkynyl, -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-NHC(O)R 35 alkylene, alkyl, alkynyl, heterocycloalkyl is unsubstituted or substituted by one, two or three independent R 35 'replace;

[0067] R 35 and R 35' are each independently selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-C(O)OR 36 、-C 0～2 Alkylene-C(O)R 36 ; Alkylene, alkyl, heterocycloalkyl are unsubstituted or replaced by one, two or three independent R 36 'Replace; R 36 and R 36 ' are each independently selected from hydrogen, -C 1～6 alkyl.

[0068] Furthermore, R3 is R 32 Selected from carboxyl, -C2 alkenyl, -C 0～2 Alkylene-O-phenyl, -C 0～2 Alkylene-O-benzimidazolyl (such as -2-C 0～2 Alkylene-benzimidazolyl), -C 0～2 Alkylene-C(O)NHR 33 ; Alkylene, alkenyl, phenyl, benzimidazolyl is unsubstituted or substituted by one, two or three independent R 33 'replace;

[0069] R 33 and the R 33 ' are each independently selected from hydrogen, halogen, -C 1～3 Alkyl, -C2 alkynyl, -C 0～2 Alkylene-phenyl, -C 0～2 Alkylene-piperidinyl (such as -4-C 0～2 Alkylene-piperidinyl), -C 0～2 Alkylene-NHC(O)R 34 、-C 0～4 Alkylene-C(O)NHR 34 ; Alkylene, alkyl, alkynyl, phenyl, piperidinyl are unsubstituted or replaced by one, two or three independent R 34 'replace;

[0070] R 34 and the R 34 ' are each independently selected from hydrogen, -C 1～2 Alkyl, -N(C 1～2 Alkyl)(C 1～2 Alkyl), -C 0～2 Alkylene-piperazinyl (such as -4-C 0～2 Alkylene-1-piperazinyl, further such as substituted alkynyl H-4-C 0～2Alkylene-1-piperazinyl); alkylene, alkyl, piperazinyl are unsubstituted or substituted by one, two or three independent R 35 'replace;

[0071] R 35 and the R 35 ' are each independently selected from hydrogen, -C 1～2 Alkyl, -C 0～2 Alkylene-C(O)OR 36 ; The alkyl group is unsubstituted or substituted by one, two or three independent R 36 'Replace; R 36 and R 36 ' are each independently selected from hydrogen, -C 1～4 alkyl.

[0072] Or further, R3 is R 32 Each independently selected from hydrogen, phenyl; the phenyl is unsubstituted or substituted by one, two or three independent R 33 'replace;

[0073] R 33 'Selected from hydrogen, halogen, -C 1～6 Alkyl, -C 2～6 Alkynyl, -C 0～2 Alkylene-piperidinyl (such as -4-C 0～2 Alkylene-piperidinyl), -C 0～2 Alkylene-NHC(O)R 34 、-C 0～4 Alkylene-C(O)NHR 34 、-C 0～2 Alkylene-NHC(O)OR 34 alkylene, alkyl, alkynyl, piperidinyl are unsubstituted or replaced by one, two or three independent R 34 'replace;

[0074] R 34 and the R 34 ' are each independently selected from hydrogen, -C 1～2 Alkyl, piperazinyl, -N(C 1～2 Alkyl)(C 1～2 alkyl); alkyl, piperazinyl is unsubstituted or substituted by one, two or three independent R 35 'Substitution, such as replacing the H on the alkynyl with the nitrogen at position 1 of the piperazinyl, or replacing the H on the alkyl with the nitrogen at position 1 of the piperazinyl;

[0075] R 35 'Selected from hydrogen, -C 0～2 Alkylene-C(O)R 36 , such as replacing the -C on the nitrogen at position 4 of piperazinyl0～2 Alkylene-C(O)R 36 The alkylene group is unsubstituted or substituted by one, two or three independent R 36 'Replace; R 36 and the R 36 ' are each independently selected from hydrogen, -C 1～2 alkyl.

[0076] Further, R3 is selected from:

[0077] Further, R3 is selected from:

[0078] Furthermore, the structure of the compound is shown in Formula III:

[0079] Among them, R 31 , R2 is as described above. Preferably, R2 is selected from hydrogen,

[0080] Furthermore, R 31 Selected from:

[0081] Furthermore, R 31 Selected from:

[0082] Furthermore, the structure of the compound is selected from:

[0083] The present invention also provides a pharmaceutical composition comprising any one of the above-mentioned compounds, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug and a pharmaceutically acceptable excipient, wherein any one of the above-mentioned compounds, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug is an active ingredient.

[0084] The present invention also provides the use of the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, or its pharmaceutical composition in the preparation of a BCL-XL inhibitor.

[0085] Furthermore, BCL-XL inhibitors are capable of binding to BCL-XL proteins.

[0086] Furthermore, BCL-XL inhibitors are drugs for preventing and / or treating diseases related to BCL-XL protein activity.

[0087] Furthermore, the disease associated with BCL-XL protein activity is an autoimmune disease, bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, follicular lymphoma, lymphoid malignancies of T cell or B cell origin, melanoma, myeloma, oral cancer, ovarian cancer, leukemia, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer; the leukemia is preferably chronic lymphocytic leukemia, lymphoblastic leukemia or myeloid leukemia.

[0088] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0089] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0090] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0091] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1～6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms.

[0092] "Alkyl" refers to a saturated hydrocarbon chain having the specified number of member atoms. For example, C 1～6Alkyl refers to an alkyl group having 1 to 6 member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl groups may also be part of other groups, such as C1-C6 alkoxy.

[0093] "Alkenyl" refers to an unsaturated hydrocarbon chain having at least one carbon-carbon double bond. For example, C1-6 alkenyl refers to an alkenyl group having 1 to 6 carbon atoms. Alkenyl groups can be straight or branched. Representative branched alkenyl groups have one, two or three branches. Alkenyl groups may be optionally substituted with one or more substituents as defined herein. 1～6 Alkenyl groups include ethenyl, propenyl (n-propenyl and isopropenyl), butenyl (n-butenyl, isobutenyl and t-butenyl), pentenyl (n-pentenyl, isopentenyl and neopentenyl) and hexenyl.

[0094] "Alkynyl" refers to an unsaturated hydrocarbon chain having at least one carbon-carbon triple bond. For example, C 1～6 Alkynyl refers to an alkynyl group having 1 to 6 carbon atoms. An alkynyl group can be straight or branched. Representative branched alkynyl groups have one, two, or three branches. An alkynyl group can be optionally substituted with one or more substituents as defined herein. 1～6 Alkynyl groups include ethynyl, propynyl (n-propynyl and isopropynyl), butynyl (n-butynyl, isobutynyl and tert-butynyl), pentynyl (n-pentynyl, isopentenyl and neopentynyl) and hexynyl.

[0095] "Cycloalkyl", "carbocycle" refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged and spirocyclic systems). For polycyclic systems with aromatic and non-aromatic rings without ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8,-tetrahydronaphthalene-5-yl) is used when the point of attachment is at a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, etc. Two such bicycloalkyl polycyclic structures are exemplified and named below: Biscyclohexyl and Biscyclohexyl.

[0096] "Halogen" is fluorine, chlorine, bromine or iodine.

[0097] "Halogen-substituted alkyl" means that the hydrogen atoms in the alkyl group may be substituted by one or more halogen atoms. 1～6 The alkyl group refers to an alkyl group containing 1 to 6 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms.

[0098] "Heterocycle" and "heterocycloalkyl" refer to saturated or non-aromatic unsaturated rings containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0099] "Aryl" and "aryl ring" are used interchangeably and refer to an all-carbon ring having a conjugated π electron system.

[0100] "Aromatic heterocycle" refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0101] "Fused aromatic ring" refers to an aromatic unsaturated fused polycyclic ring. For example

[0102] "Fused heteroaromatic ring" refers to an aromatic unsaturated fused polycyclic ring containing at least one heteroatom, for example: an 8-12 membered fused heteroaromatic ring. The 8-12 membered fused heteroaromatic ring can be a fused ring of a 6-membered heteroaromatic ring and a C5 aliphatic ring, a fused ring of a 6-membered heteroaromatic ring and a 5-membered heteroaromatic ring, a fused ring of a 6-membered heteroaromatic ring and a 5-membered heteroaromatic ring, a fused ring of a C6 aromatic ring and a 5-membered heteroaromatic ring, a fused ring of a 6-membered heteroaromatic ring and a 5-membered heteroaromatic ring, a fused ring of a 6-membered heteroaromatic ring and a 5-membered heteroaromatic ring, a fused ring of a 6-membered heteroaromatic ring and a 6-membered heteroaromatic ring, etc.

[0103] "Stereoisomers" include enantiomers and diastereomers;

[0104] "Tautomers" generally refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0105] "Polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) that has a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one polymorph to dominate.

[0106] A "solvate" is a mixture formed by dissolving a compound in a solvent.

[0107] "N-oxides", also known as amine oxides, are a class of organic compounds with the general formula R3N+-O- (also written as R3N=O or R3N→O).

[0108] An "isotope-labeled compound" is a molecule or group in which one or more atoms are replaced by their isotope atoms, such as hydrogen atoms replaced by deuterium atoms, where the proportion of deuterium atoms is greater than the abundance of deuterium in nature; or 12C replaced by 13C.

[0109] "Metabolites" refer to substances produced by chemical structure transformation of drug molecules under the action of the body after they are absorbed by the body.

[0110] "Prodrug" refers to a compound that is obtained by chemically modifying a drug and is inactive or has low activity in vitro, but releases active drugs through enzymatic or non-enzymatic conversion in the body to exert its pharmacological effect.

[0111] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0112] The terms "salts" and "pharmaceutically acceptable salts" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compounds. They can also be obtained by mixing the above-mentioned compounds, or their stereoisomers, with a suitable amount of acid or base (e.g., an equivalent amount). These salts may be precipitated in solution and collected by filtration, or recovered after evaporation of the solvent, or obtained by freeze-drying after reaction in an aqueous medium.

[0113] The pharmaceutically acceptable excipients described in the present invention include pharmaceutically acceptable excipients, carriers, adjuvants, vehicles or any combination thereof.

[0114] In certain embodiments, one or more compounds of the present invention may be used in combination with one another. Compounds of the present invention may also be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0115] The compounds provided by the present invention can effectively bind to the BCL-XL protein, thereby further inhibiting its activity. The compounds of the present invention can be used to prepare BCL-XL inhibitors and drugs for preventing and / or treating diseases associated with BCL-XL protein activity (e.g., cancer, autoimmune diseases, etc.), and have broad prospects for clinical application.

[0116] The compound of the present invention has good pharmacological properties, good stability and high drugability, and the preparation method of the compound is simple, high in yield and low in cost, and is suitable for industrial production.

[0117] The term "prevention" includes suppressing and delaying the onset of a disease, and includes not only prevention before the development of a disease but also prevention of recurrence of a disease after treatment.

[0118] The terms "treat," "treat," "treat," and "treating" mean to reverse, alleviate, or eliminate the progression of the disorder or condition to which such terms apply, or one or more symptoms of such disorder or condition.

[0119] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0120] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0121] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased as commercially available products.

[0122] Unless otherwise specified, reactions were conducted under a nitrogen atmosphere. Unless otherwise specified, solutions in the examples are aqueous solutions. Unless otherwise specified, reactions were conducted at room temperature. Room temperature is the most suitable reaction temperature, ranging from 20°C to 30°C. Unless otherwise specified, M is moles per liter.

[0123] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using a (Brμker AvanceIII 400 and Brμker Avance 600) nuclear magnetic spectrometer, with the solvents being deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (Methol-d4), and the internal standard being tetramethylsilane (TMS). LC-MS measurements were performed using a Shimadzu LC-MS2020 (ESI) liquid chromatography-mass spectrometer. HPLC measurements were performed using a Shimadzu high-pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium pressure preparative chromatography) was performed using a Gilson GX-281 reverse phase preparative chromatograph. Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0124] The reagents described in the examples are abbreviated as follows: Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium; Pd(OAc)3: palladium acetate; Pd2(dba)3: tris(dibenzylideneacetone)dichloride; XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; S-Phos: 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; DIPEA: N,N-diisopropylethylamine; H ATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HOBt: 1-hydroxybenzotriazole; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMAP: 4-dimethylaminopyridine; TCDI: N,N'-thiocarbonyldiimidazole; LiHMDS: lithium bis(trimethylsilyl)amide; DMF: N,N-dimethylformamide; THF: tetrahydrofuran; DMSO: N,N-dimethyl sulfoxide; KOAc: potassium acetate; MIBK: methyl isobutyl ketone.

[0125] Example 1, Synthesis of Compound A1 of Series A of the Present Invention:

[0126] Step 1, synthesis of compound A-2

[0127] Compound A-1 (304.00 mg, 999.44 μmol), methylamine hydrochloride (80.98 mg, 1.20 mmol), sodium carbonate (317.82 mg, 3.00 mmol) and tetrahydrofuran / water (4 mL / 2 mL) were added to a 50 mL reaction flask. The mixture was stirred at room temperature until the reaction was complete, and then water was added to quench the reaction (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (10 mL) and ethyl acetate (3 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound A-2 (132.00 mg, 441.81 μmol, 44.21% yield). LCMS: C 13 H 20 ClN4O2, (ESI)[M+H]: 299.13.

[0128] Step 2, synthesis of compound A-3

[0129] Under nitrogen, compound A-2 (132.00 mg, 441.81 μmol), compound 1 (91.18 mg, 530.18 μmol), potassium carbonate (182.91 mg, 1.33 mmol), 1,4-dioxane and water (4 mL / 1 mL), and Pd(dppf)Cl2 (6.44 mg, 0.25 mol%) were added to a 50 mL reaction vial in sequence. The reaction system was sealed and stirred at 80°C for 2 hours before quenching the reaction (monitored by LC-MS). The mixture was extracted with saturated sodium chloride solution (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated and separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 1:100 to 1:5. The solvent was removed by concentration under reduced pressure to obtain compound A-3 (96.00 mg, 245.85 μmol, 55.65% yield). LCMS: C 22 H 26 N5O2, (ESI) [M+H]: 392.2.

[0130] Step 3, Synthesis of Compound A-4

[0131] Compound A-3 (96.00 mg, 245.85 μmol) was dissolved in dichloromethane (2 mL) in a 50 mL reaction flask, and trifluoroacetic acid (1 mL) was then added dropwise. The mixture was stirred at room temperature for 3 hours, and the solvent was removed by concentration under reduced pressure to obtain compound A-4 (crude product). LCMS: C 17 H 18 N5, (ESI) [M+H]: 292.2.

[0132] Step 4, Synthesis of Compound A1

[0133] Compound 2 (28.00 mg, 122.68 μmol), DIPEA (47.56 mg, 368.03 μmol, 64.10 μL), HATU (46.62 mg, 122.68 μmol) and DMF (2 mL) were added to a 50 mL reaction flask in sequence. After the reaction system temperature dropped to 0°C, compound A-4 (crude product) was added. The reaction was stirred in an ice bath for 2 hours and then quenched (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain A1 (20.00 mg, 39.75 μmol, 32.41% yield, 99.7% purity). LC-MS: C 31 H 28 N5O2, [M+H] + 502.2; Detection value: 502.2. 1 H NMR (400MHz, DMSO-d6) δ9.82-9.11(m,2H),8.16-7.99(m,2H),7.97-7.80(m,2H),7.55(q,J=8.0Hz,4H),7.32(t,J=8.0Hz,2H),7. 04(d,J=8.2Hz,2H),6.96(t,J=7.2Hz,1H),5.18(s,2H),4.71–4.51(m,2H),3.97–3.65(m,2H),3.07(d,J=4.4Hz,3H),2.56(s,2H).

[0134] According to the synthetic route of compound A1, compounds A2 and A3 can be obtained by replacing the raw material methylamine hydrochloride used in the first step with the raw materials listed in Table 1.

[0135] Table 1. Compounds A2 and A3

[0136] According to the synthetic route of compound A1, compounds A4 to A12 can be obtained by replacing compound 1 with the raw materials listed in Table 2.

[0137] Table 2. Compounds A4 to A12

[0138] According to the synthetic route of compound A1, compounds A13 to A19 can be obtained by replacing compound 2 with the raw materials listed in Table 3.

[0139] Table 3. Compounds A13 to A19

[0140] The synthesis method of series A-compound A20 of the present invention:

[0141] Step 1, synthesis of compound A-5

[0142] Compound A-4 (80.00 mg, 274.58 μmol), TCDI (58.72 mg, 329.50 μmol) and DMF (5 mL) were added to a 50 mL reaction flask in sequence. After stirring for 10 minutes, triethylamine (111.14 mg, 1.10 mmol, 153.19 μL) was added. The reaction was kept at room temperature for 1 hour and then quenched (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (20.0 mL) and dichloromethane (3×15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain compound A-5 (crude product). LCMS: C 21 H 20 N7S, (ESI) [M+H]: 402.2.

[0143] Step 2, Synthesis of Compound A-6

[0144] Compound A-5 (crude) and methylamino alcohol solution (7N, 1 mL) were added to a 50 mL reaction bottle, and the mixture was reacted at room temperature overnight and then quenched (LCMS monitoring). The excess methylamino alcohol solution was removed by concentration under reduced pressure to obtain compound A-6 (crude). LCMS: C 18 H 19 N6S, (ESI) [M+H]: 351.1.

[0145] Step 3. Synthesis of Compound A20

[0146] Compound A-6 (crude), compound 3 (38.11 mg, 228.28 μmol) and ethanol (2 mL) were added to a 50 mL reaction flask and the reaction was maintained at 50°C for approximately 2 hours until the reaction was complete (LC-MS monitoring). The reaction solution was concentrated under reduced pressure and purified by MPLC to obtain compound A20 (27.00 mg, 64.52 μmol, 28.26% yield, 92.0% purity). LC-MS: C 21 H 19N6O2S, [M+H] + 419.1; Detection value: 419.2. 1 H NMR (400MHz, DMSO-d6) δ13.17 (s, 1H), 9.81 (dd, J = 9.3, 2.1Hz, 1H), 9.19 (dd, J=15.5,2.1Hz,1H),8.17(d,J=8.2Hz,1H),8.08(d,J=8.5Hz,1H),7.84-7.79 (m,1H),7.74-7.58(m,3H),7.22-7.16(m,1H),4.89(s,1H),4.57(s,1H),4.0 8(s,1H),3.87(t,J=5.8Hz,1H),3.07(d,J=4.4Hz,3H),2.65(t,J=5.8Hz,2H).

[0147] According to the synthetic route of compound A20, compound A21 can be obtained by replacing compound A-4 with the raw materials listed in Table 4.

[0148] Table 4. Compound A21

[0149] The synthesis method of series A-compound A22 of the present invention:

[0150] Step 1, Synthesis of Compound A-7

[0151] Under nitrogen, compound A-4 (20.00 mg, 68.65 μmol), compound 4 (11.85 mg, 68.65 μmol), BINAP (42.74 mg, 68.65 μmol), cesium carbonate (22.36 mg, 68.65 μmol), 1,4-dioxane, water (4 mL / 1 mL), and Pd(OAc)2 (15.41 mg, 0.25 mol%) were added to a 50 mL reaction vial in the order described. The reaction system was sealed and stirred at 100°C for 2 hours before quenching the reaction (monitored by LC-MS). The mixture was extracted with saturated sodium chloride solution (10 mL) and ethyl acetate (3 × 10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated and separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 1:100 to 1:5. After concentration under reduced pressure to remove the solvent, compound A-7 (25.00 mg, 58.49 μmol, 85.20% yield) was obtained. LCMS: C 23 H 22 N7O2, (ESI) [M+H]: 428.2.

[0152] Step 2, Synthesis of Compound A22

[0153] Compound A-7 (25.00 mg, 58.49 μmol), lithium hydroxide (560.25 μg, 23.39 μmol), methanol (2 mL), and water (2 mL) were added sequentially to a 50 mL reaction flask. The reaction was stirred at room temperature for 5 hours and then quenched (LC-MS monitoring). The pH of the system was adjusted to 6-7 with 1N hydrochloric acid solution. The reaction solution was concentrated and purified by MPLC to obtain compound A22 (5.00 mg, 12.09 μmol, 51.70% yield, 95.0% purity). LC-MS: C 22 H 20 N7O2, [M+H] + 414.2; Detection value: 414.3. 1 H NMR (400MHz, DMSO-d6) δ9.81 (d, J = 2.4Hz, 1H), 9.79 (s, 1H), 8.69 (d, J=4.8Hz,1H),8.34–8.28(m,2H),8.03(t,J=8.0Hz,1H),7.84(t,J=5.6Hz,1H),7. 18(d,J=4.8Hz,1H),5.08(s,2H),4.18(t,J=5.6Hz,2H),3.12(s,3H),2.72(s,2H).

[0154] According to the synthetic route of compound A22, compounds A23 to A25 can be obtained by replacing compound 4 with the raw materials listed in Table 5.

[0155] Table 5. Compounds A23 to A25

[0156] The synthesis method of series A-compound A26 of the present invention:

[0157] Step 1, Synthesis of Compound A-9

[0158] Compound A-8 (500.00 mg, 1.64 mmol), methylamine hydrochloride (61.26 mg, 1.97 mmol), triethylamine (499.01 mg, 4.93 mmol, 687.82 μL), and acetonitrile (10 mL) were added to a 50 mL reaction flask. After reacting at 80°C for 2 hours, the reaction was quenched with water (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (10 mL) and ethyl acetate (3 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound A-9 (490.00 mg, 1.64 mmol, 99.77% yield). LCMS: C 13 H 20 ClN4O2, (ESI)[M+H]: 299.2.

[0159] Step 2, Synthesis of Compound A-10

[0160] Under nitrogen, compound A-9 (490.00 mg, 1.64 mmol), compound 1 (91.18 mg, 530.18 μmol), potassium carbonate (182.91 mg, 1.33 mmol), 1,4-dioxane and water (4 mL / 1 mL), and Pd(dppf)Cl2 (6.44 mg, 0.25 mol%) were added to a 50 mL reaction vial in sequence. The reaction system was sealed and stirred at 80°C for 2 hours before quenching the reaction (monitored by LC-MS). The mixture was extracted with saturated sodium chloride solution (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 1:100 to 1:5. The solvent was removed by concentration under reduced pressure to obtain compound A-10 (96.00 mg, 245.85 μmol, 55.65% yield). LCMS (ESI): C 22 H 26 N5O2, [M+H]: 392.2.

[0161] Step 3, Synthesis of Compound A-11

[0162] Compound A-10 (96.00 mg, 245.85 μmol) was dissolved in dichloromethane (2 mL) in a 50 mL reaction flask, and trifluoroacetic acid (1 mL) was then added dropwise. The mixture was stirred at room temperature for 3 hours, and the solvent was removed by concentration under reduced pressure to obtain compound A-11 (crude product). LCMS: C 17 H 18 N5, (ESI) [M+H]: 292.2.

[0163] Step 4, Synthesis of Compound A-12

[0164] Compound A-11 (crude), compound 5 (24.38 mg, 137.29 μmol), triethylamine (41.68 mg, 411.88 μmol, 57.45 μL), and DMSO (5 mL) were added to a 50 mL reaction flask. The mixture was stirred at 80°C for 2 hours and then quenched with water (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (25 mL) and ethyl acetate (3 x 25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound A-12 (35.00 mg, 80.93 μmol, 58.94% yield). LCMS: C 22 H 21 N6O2S, (ESI) [M+H]: 433.1.

[0165] Step 5. Synthesis of Compound A26

[0166] Compound A-12 (35.00 mg, 80.93 μmol), lithium hydroxide (560.25 μg, 23.39 μmol), methanol (2 mL), and water (2 mL) were added sequentially to a 50 mL reaction flask. The reaction was stirred at room temperature for 5 hours and then quenched (LC-MS monitoring). The pH of the system was adjusted to 6-7 with 1N hydrochloric acid solution. The reaction solution was concentrated and purified by MPLC to obtain compound A26 (10.80 mg, 25.81 μmol, 31.89% yield, 98.0% purity). LC-MS: C 21 H 19 N6O2S, [M+H] + 419.1; Detection value: 419.1. 1 H NMR (400MHz, DMSO-d6) δ9.77(d,J=2.1Hz,1H),9.56(s,1H),8.60(s,1H),8.27(d,J=8.4Hz,1H),8.22(d,J=8.4Hz,1H ),7.99(t,J=7.7Hz,1H),7.86(s,1H),7.80(t,J=7.6Hz,1H),4.48(s,2H),3.96(t,J=5.8Hz,2H),3.17-3.14(m,5H).

[0167] According to the synthetic route of compound A26, compound A27 can be obtained by replacing compound 5 with the raw materials listed in Table 6.

[0168] Table 6. Compound A27

[0169] Example 2: Synthesis of Series B Compounds B1 and B2 of the present invention:

[0170] Step 1, Synthesis of Compound B-1

[0171] Compound A-1 (400.00 mg, 1.32 mmol), sodium ethoxide (71.01 mg, 1.32 mmol) and methanol (5 mL) were added sequentially to a 50 mL reaction flask. After stirring at room temperature for 0.5 hours, water was added to quench the reaction (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (25 mL) and ethyl acetate (3 x 25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain compound B-1 (crude product). LCMS: C 13 H 19 ClN3O3, (ESI)[M+H]: 300.1.

[0172] Step 2, Synthesis of Compound B-2

[0173] Under nitrogen, compound B-1 (crude), compound 1 (219.28 mg, 1.27 mmol), hydrated lithium hydroxide (191.59 mg, 8.00 mmol), Pd(OAc)2 (2.85 mg, 0.25 mol%), S-Phos (10.40 mg, 25.35 μmol), 1,4-dioxane, and water (8 mL / 2 mL) were added sequentially to a microwave reaction tube. The reaction system was sealed and stirred at 110°C for 1 hour before quenching the reaction (monitored by LC-MS). The mixture was extracted with saturated sodium chloride solution (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 1:100 to 1:5. After concentration under reduced pressure to remove the solvent, compound B-2 (140.00 mg, 369.96 μmol, 29.18% yield) was obtained. LCMS: C 22 H 25 N4O3, (ESI) [M+H]: 393.2.

[0174] Step 3, Synthesis of Compound B-3

[0175] Compound B-2 (140.00 mg, 369.96 μmol) was dissolved in dichloromethane (4 mL) in a 50 mL reaction flask, and TFA (1 mL) was then added dropwise. The mixture was stirred at room temperature for 0.5 hours, and the solvent was removed by concentration under reduced pressure to obtain compound B-3 (crude product). LCMS: C17 H 17 N4O, (ESI) [M+H]: 293.1.

[0176] Step 4, Synthesis of Compound B1

[0177] Compound 2 (91.30 mg, 400.00 μmol), DIPEA (129.24 mg, 1.00 mmol, 174.18 μL), HATU (182.40 mg, 480.00 μmol), and DMF (4 mL) were added to a 50 mL reaction flask in sequence. After the reaction system temperature dropped to 0°C, compound B-3 (crude product) was added. The reaction was stirred in an ice bath for 1.5 hours before quenching (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound B1 (28.40 mg, 52.55 μmol, 13.14% yield, 93.0% purity). LC-MS: C 31 H 27 N4O3, [M+H] + 503.2; Detection value: 503.2. 1 H NMR(400MHz, Methanol-d4)δ9.88-9.78(m,1H),9.63-9.53(m,1H),8.27-8.16(m,2H),8.02(s,1H),7.84(s,1H),7.61-7.53(m,4H),7.37-7.24(m,2 H),7.01-6.96(m,2H),6.95-6.92(m,1H),5.16(s,2H),4.86(s,1H),4.72( s,1H),4.19(s,3H),4.07-4.01(m,1H),3.75(s,1H),2.80(s,2H).Purity>90%.

[0178] Step 5, Synthesis of Compound B-4

[0179] Under nitrogen, compound B-1 (crude), compound 1 (219.28 mg, 1.27 mmol), hydrated lithium hydroxide (191.59 mg, 8.00 mmol), Pd(OAc)2 (2.85 mg, 0.25 mol%), S-Phos (10.40 mg, 25.35 μmol), 1,4-dioxane, and water (8 mL / 2 mL) were added sequentially to a microwave reaction tube. The reaction system was sealed and stirred at 110°C for 1 hour before quenching the reaction (monitored by LC-MS). The mixture was extracted with saturated sodium chloride solution (20.0 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated and separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 1:100 to 1:5. After concentration under reduced pressure to remove the solvent, compound B-4 (140.29 mg, 369.96 μmol, 29.18% yield) was obtained. LCMS: C 21 H 23 N4O3, (ESI) [M+H]: 379.2.

[0180] Step 6, Synthesis of Compound B-5

[0181] Compound B-4 (140.29 mg, 369.96 μmol) was dissolved in dichloromethane (4 mL) in a 50 mL reaction flask, and TFA (1 mL) was then added dropwise. The mixture was stirred at room temperature for 0.5 hours, and the solvent was removed by concentration under reduced pressure to obtain compound B-5 (crude product). LCMS: C 16 H 15 N4O, (ESI) [M+H]: 279.1.

[0182] Step 7. Synthesis of Compound B2

[0183] Compound 2 (91.30 mg, 0.4 mmol), EDCI (91.68 mg, 480.00 μmol), HOBt (64.86 mg, 480.00 μmol), DIPEA (62.04 mg, 480.00 μmol), and DMF (4 mL) were added sequentially to a 50 mL reaction flask. After the reaction system cooled to 0°C, compound B-5 (crude product) was added. The reaction was stirred on ice for 1 hour before quenching (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (10 mL) and ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound B2 (2.60 mg, 5.24 μmol, 1.31% yield, 98.5% purity). LC-MS: C 30 H25 N4O3, [M+H] + 489.2; Detection value: 489.4. 1 H NMR (400MHz, DMSO-d6) δ13.06(s,1H),9.53-9.42(m,1H),9.11-9.05(m,1H),8.10(s,2H),7.89(s,1H),7.72(s,1H),7.55(q,J=8.0Hz,4H) ,7.31(t,J=8.0Hz,2H),7.04(d,J=8.0Hz,2H),7.03-6.96(m,1H),5.18(s,2H),4.67-4.47(m,2H),3.75-3.15(m,2H),2.50(s,2H). Purity>95%.

[0184] Example 3, Synthesis of Series C Compound C1 of the Present Invention:

[0185] Step 1. Synthesis of Compound C-1

[0186] Compound A-1 (250.00 mg, 821.90 μmol), ammonium hydroxide (4.11 mmol), zinc powder (6.58 mmol), and ethanol (2 mL) were added sequentially to a 50 mL reaction flask. The mixture was heated to 80°C and refluxed for 4 hours (monitored by LC-MS). The zinc powder was removed by filtration and washed with methanol (2×20 mL). The filtrate was collected and concentrated under reduced pressure to remove the solvent. After purification by MPLC, compound C-1 (175.00 mg, 648.80 μmol, 78.94% yield) was obtained. LCMS: C 12 H 17 ClN3O2, (ESI)[M+H]: 270.1.

[0187] Step 2, Synthesis of Compound C-2

[0188] Under nitrogen, compound C-1 (175.00 mg, 648.80 μmol), compound 1 (134.67 mg, 778.57 μmol), potassium carbonate (224.18 mg, 1.62 mmol), 1,4-dioxane and water (4 mL / 1 mL), and Pd(dppf)Cl2 (2.46 mg, 0.25 mol%) were added to a 50 mL reaction vial in sequence. The reaction system was sealed and stirred at 80°C for 2 hours before quenching the reaction (monitored by LC-MS). The mixture was extracted with saturated sodium chloride solution (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 1:100 to 1:5. After concentration under reduced pressure to remove the solvent, compound C-2 (235.00 mg, 648.41 μmol, 99.94% yield) was obtained. LCMS: C 21 H 23 N4O2, (ESI) [M+H]: 363.2.

[0189] Step 3, Synthesis of Compound C-3

[0190] Compound C-2 (235.00 mg, 648.41 μmol) was dissolved in dichloromethane (4 mL) in a 50 mL reaction flask, and trifluoroacetic acid (1 mL) was then added dropwise. The mixture was stirred at room temperature for 0.5 hours, and the solvent was removed by concentration under reduced pressure to obtain compound C-3 (crude product). LCMS: C 16 H 15 N4, (ESI) [M+H]: 263.1.

[0191] Step 4, Synthesis of Compound C1

[0192] Compound 2 (170.00 mg, 648.09 μmol), EDCI (246.27 mg, 1.30 mmol), and piperidine solution (1 mL) were added sequentially to a 50 mL reaction flask. After the reaction system temperature dropped to 0°C, compound C-3 (crude product) was added. The reaction was stirred in an ice bath for 1 hour, then quenched. Extraction was completed with saturated sodium chloride solution (20 mL) and dichloromethane (3 × 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The organic phases were purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound C1 (10.00 mg, 20.32 μmol, 3.13% yield, 96.0% purity). LC-MS: C 30 H 25 N4O2, [M+H] + 473.2; Detection value: 473.1. 1H NMR(400MHz,Chloroform-d)δ8.69(s,1H),8.25(s,1H),7.99(s,1H),7.81(t,J=8..0Hz,1H),7.63(t,J=8..0Hz,1H),7.58 -7.52(m,5H),7.34-7.30(m,2H),7.01-6.98(m,3H),5.14(s,2H),5.09-4.78(m,2H),4.10-3.73(m,2H),3.03-3.01(m,2H).

[0193] According to the synthetic route of compound C1, compounds C2 to C10 can be obtained by replacing compound 2 with the raw materials listed in Table 7.

[0194] Table 7. Compounds C2 to C10

[0195] The synthesis method of series C compound C11 of the present invention:

[0196] Step 1. Synthesis of Compound C-5

[0197] To a 50 mL reaction flask, compound C-4 (400 mg, 1.32 mmol), ammonium hydroxide (4.11 mmol), zinc powder (3.95 mmol), and ethanol (5 mL) were added sequentially. The mixture was heated to 80°C and refluxed for 3 hours (monitored by LC-MS). The zinc powder was removed by filtration and washed with methanol (2 × 20 mL). The filtrate was collected and concentrated under reduced pressure. The concentrate was dissolved in a mixture of 6N hydrochloric acid and ethyl acetate (10 mL). The reaction was stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure to obtain compound C-5 (crude product). LCMS: C7H9ClN3, (ESI) [M+H]: 170.0.

[0198] Step 2, Synthesis of Compound C-6

[0199] Compound 2 (150.00 mg, 657.19 μmol), DIPEA (254.81 mg, 1.97 mmol, 343.41 μL), HATU (274.71 mg, 722.91 μmol) and DMF (5 mL) were added to a 50 mL reaction flask in sequence. After the reaction system temperature dropped to 0°C, compound C-5 (crude product) was added. The reaction was stirred for 1 hour under ice bath conditions and then quenched (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound C-6 (210.00 mg, 552.87 μmol, 84.13% yield). LCMS: C 21 H 19 ClN3O2, (ESI)[M+H]: 380.1.

[0200] Step 3. Synthesis of Compound C11

[0201] Compound C-6 (50.00 mg, 131.63 μmol), compound 6 (12.52 mg, 131.63 μmol), sodium hydroxide (15.80 mg, 394.90 μmol), and DMSO (5 mL) were added to a 50 mL reaction flask. The mixture was stirred at 120°C for 2 hours and then quenched with water (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (25 mL) and ethyl acetate (3 x 25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The organic phases were purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound C11 (30.00 mg, 61.71 μmol, 46.88% yield, 90.2% purity). LC-MS: C 22 H 23 N4O4S,[M+H] + 439.1; Detection value: 439.1. 1 H NMR (400MHz, DMSO-d6) δ8.19-7.93(m,1H),7.56(d,J=7.8Hz,2H),7.48(d,J=7.8Hz,2H),7.32(t,J=7.8Hz,2 H),7.04(d,J=8.2Hz,2H),6.97(t,J=7.4Hz,1H),5.16(s,2H),4.62-4.44(m,2H),3.60(s,2H),2.94(s,3H), 2.72(s,2H).

[0202] According to the synthetic route of compound 11, compounds C12 and C13 can be obtained by replacing compound 6 with the raw materials listed in Table 8.

[0203] Table 8. Compounds C12 and C13

[0204] The synthesis method of the series C compound C14 of the present invention:

[0205] Step 1. Synthesis of Compound C-8

[0206] Compound C-7 (300.00 mg, 1.12 mmol) was dissolved in dichloromethane (8 mL) in a 50 mL reaction flask, and trifluoroacetic acid (1.5 mL) was then added dropwise. The mixture was stirred at room temperature for 0.5 hours, and the solvent was removed by concentration under reduced pressure to obtain compound C-8 (crude product). LCMS: C8H 10 ClN2, (ESI) [M+H]: 169.0.

[0207] Step 2, Synthesis of Compound C-9

[0208] Compound 2 (228.00 mg, 998.94 μmol), DIPEA (322.76 mg, 2.50 mmol, 434.99 μL), HATU (455.51 mg, 1.20 mmol) and dichloromethane (10 mL) were added to a 50 mL reaction flask in sequence. After the reaction system temperature dropped to 0°C, compound C-8 (crude product) was added. The reaction was stirred for 12 hours under ice bath conditions and then quenched (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound C-9 (300.00 mg, 791.87 μmol, 79.27% ​​yield). LCMS: C 22 H 20 ClN2O2, (ESI)[M+H]: 379.1.

[0209] Step 4. Synthesis of Compound C14

[0210] Under nitrogen, compound C-9 (300.00 mg, 791.87 μmol), compound 7 (59.47 mg, 395.93 μmol), cesium carbonate (258.15 mg, 791.87 μmol), Xantphos (76.36 mg, 131.98 μmol), Pd2(dba)3 (48.34 mg, 52.79 μmol), 1,4-dioxane, and water (4 mL / 1 mL) were added sequentially to a microwave reaction tube. The reaction system was sealed and microwaved at 150°C for 1 hour before quenching the reaction (monitored by LC-MS). Extraction was completed with saturated sodium chloride solution (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 1:100 to 1:5. The solvent was removed by concentration under reduced pressure to obtain compound C14 (46.50 mg, 94.40 μmol, 35.76% yield, 96.6% purity). LC-MS: C 29 H 25 N4O2S,[M+H] + 493.2; detection value: 439.1. 1 H NMR(400MHz, DMSO-d6)δ7.89(d,J=7.7Hz,1H),7.62-7.55(m,6H),7.37-7.30(m,3H),7.19(t,J=7.5Hz,1H ),7.04(d,J=8.1Hz,3H),6.96(t,J=7.3Hz,1H),5.18(s,2H),4.74-4.57(m,2H),3.70(s,3H),3.01(s,2H).

[0211] Example 4, Synthesis Method of Series D of the Present Invention:

[0212] Step 1, synthesis of compound D1

[0213] Compound 8 (40.00 mg, 129.30 μmol), EDCI (74.48 mg, 387.90 μmol), and piperidine solution (5 mL) were added sequentially to a 50 mL reaction flask. After the reaction system cooled to 0°C, compound A-4 (39.56 mg, 135.77 μmol) was added. The reaction was stirred on ice for 0.5 hours and then quenched. Extraction was completed with saturated sodium chloride solution (20 mL) and dichloromethane (3 × 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The organic phases were purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound D1 (25.20 mg, 42.43 μmol, 32.81% yield, 98.1% purity). LC-MS: C 36 H 35 N6O2, [M+H] + 583.3; Detection value: 583.3. 1 H NMR (400MHz, Methanol-d4) δ9.78(s,1H),9.52(s,1H),8.28-8.20(m,2H),8.04(t,J=4.0Hz,1H),7.86(s,1H),7.62-7.55(m,4H),7.48(d,J=8.4Hz,2H ),7.05(d,J=8.4Hz,2H),5.21(s,2H),4.86(s,1H),4.70(s,1H),4.28(s,2 H),4.12-4.09(m,1H),3.85(s,1H),3.25(s,3H),3.00(s,6H),2.66(s,2H). .

[0214] According to the synthetic route of compound D1, compounds D2 to D6 can be obtained by replacing compound 8 with the raw materials listed in Table 9.

[0215] Table 9. Compounds D2 to D6

[0216] Example 5, Synthesis of Series E Compound E1 of the Present Invention:

[0217] Step 1. Synthesis of Compound E-2

[0218] Compound E-1 (260.14 mg, 999.44 μmol), methylamine hydrochloride (80.98 mg, 1.20 mmol), sodium carbonate (317.82 mg, 3.00 mmol), and tetrahydrofuran / water (4 mL / 2 mL) were added to a 50 mL reaction flask. The mixture was stirred at room temperature until the reaction was complete, after which water was added to quench the reaction (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (10 mL) and ethyl acetate (3 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound E-2 (113.64 mg, 441.81 μmol, 44.21% yield). LCMS: C 12 H 18 ClN4O2, (ESI)[M+H]: 285.1.

[0219] Step 2, Synthesis of Compound E-3

[0220] Under nitrogen, compound E-2 (113.64 mg, 441.81 μmol), compound 1 (91.18 mg, 530.18 μmol), potassium carbonate (182.91 mg, 1.33 mmol), 1,4-dioxane and water (4 mL / 1 mL), and Pd(dppf)Cl2 (6.44 mg, 0.25 mol%) were added sequentially to a 50 mL reaction vial. The reaction system was sealed and stirred at 80°C for 2 hours before quenching the reaction (monitored by LC-MS). The mixture was extracted with saturated sodium chloride solution (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 1:100 to 1:5. The solvent was removed by concentration under reduced pressure to obtain compound E-3 (92.41 mg, 245.85 μmol, 55.65% yield). LCMS (ESI): C 21 H 24 N5O2, [M+H]: 378.2.

[0221] Step 3, Synthesis of Compound E-4

[0222] Compound E-3 (92.41 mg, 245.85 μmol) was dissolved in dichloromethane (2 mL) in a 50 mL reaction flask, and trifluoroacetic acid (1 mL) was then added dropwise. The mixture was stirred at room temperature for 1 hour, and the solvent was removed by concentration under reduced pressure to obtain compound E-4 (crude product). LCMS: C 16 H 16 N5, (ESI) [M+H]: 278.1.

[0223] Step 4, Synthesis of Compound E-5

[0224] Compound E-4 (crude), TCDI (42.41 mg, 237.99 μmol), and DMF (5 mL) were added to a 50 mL reaction flask in sequence. After stirring for 10 minutes, triethylamine (60.21 mg, 594.97 μmol, 82.98 μL) was added. The reaction was maintained at room temperature for 1 hour and then quenched (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (20 mL) and dichloromethane (3 × 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain compound E-5 (crude). LCMS: C 20 H 18 N7S, (ESI) [M+H]: 388.1.

[0225] Step 5, Synthesis of Compound E-6

[0226] Compound E-5 (crude) and methylamino alcohol solution (7N, 1 mL) were added to a 50 mL reaction bottle, and the mixture was reacted at room temperature overnight and then quenched (LCMS monitoring). The excess methylamino alcohol solution was removed by concentration under reduced pressure to obtain compound E-6 (crude). LCMS: C 17 H 17 N6S, (ESI) [M+H]: 337.1.

[0227] Step 6. Synthesis of Compound E1

[0228] Compound E-6 (crude), compound 3 (67.28 mg, 0.2 mmol) and ethanol (2 mL) were added to a 50 mL reaction flask and the reaction was maintained at 50°C for approximately 2 hours until the reaction was complete (LC-MS monitoring). The reaction solution was concentrated under reduced pressure and purified by MPLC to obtain compound E1 (7.50 mg, 18.43 μmol, 9.22% yield, 99.4% purity). LC-MS: C 20 H 17 N6O2S, [M+H]+405.1; detected value: 405.0. 1 H NMR (400MHz, Methanol-d4) δ9.73(s,1H),9.43(s,1H),8.10(d,J=2.0Hz,1H),8.01(d,J=7 .2Hz,1H),7.92(s,1H),7.74(s,1H),7.22(s,1H),4.44(s,2H),4.23(s,2H),3.16(s,3H).

[0229] According to the synthetic route of compound E1, compound E2 can be obtained by replacing compound 3 with the raw materials listed in Table 10.

[0230] Table 10. Compound E2

[0231] The synthesis method of the series E compound E3 of the present invention:

[0232] Step 1. Synthesis of compound E-8

[0233] Under nitrogen, compound E-3 (42.50 mg, 153.25 μmol), compound 9 (33.11 mg, 153.25 μmol), BINAP (12.06 mg, 30.65 μmol), cesium carbonate (151.18 mg, 459.75 μmol), and Pd2(dba)3 (15.41 mg, 0.25 mol%) dissolved in 10 mL of MIBK were added sequentially to a 50 mL reaction vial. The reaction system was sealed and microwave-treated at 110°C for 2 hours before quenching (monitored by LC-MS). The mixture was extracted with saturated sodium chloride solution (10 mL) and ethyl acetate (3×10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 1:100 to 1:5. The solvent was removed by concentration under reduced pressure to obtain compound E-8 (24.11 mg, 58.49 μmol, 85.20% yield). LCMS: C 23 H 21 N6O2, (ESI) [M+H]: 413.2.

[0234] Step 2, Synthesis of Compound E3

[0235] Compound E-8 (24.11 mg, 58.49 μmol), lithium hydroxide (560.25 μg, 23.39 μmol), methanol (2 mL), and water (2 mL) were added sequentially to a 50 mL reaction flask. The reaction was stirred at room temperature for 5 hours and then quenched (LC-MS monitoring). The pH of the system was adjusted to 6-7 with 1N hydrochloric acid solution. The reaction solution was concentrated and purified by MPLC to obtain compound E3 (5.00 mg, 12.55 μmol, 10.35% yield, 98.1% purity). LC-MS: C 22 H 19 N6O2, [M+H]+399.2; detected value: 399.3. 1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 9.28 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.76-7.67 (m, 3H), 7.33 (d, J = 7.2 Hz, 1H), 4.68-4.64 (m, 4H), 3.09 (d, J = 4.2 Hz, 3H). Purity > 95%.

[0236] According to the synthetic route of compound E3, compounds E4 and E5 can be obtained by replacing compound 9 with the raw materials listed in Table 11.

[0237] Table 11. Compounds E4 and E5

[0238] The synthesis method of the series E compound E6 of the present invention:

[0239] Step 1. Synthesis of compound E-9

[0240] In a 50 mL reaction flask, E-2 (113.64 mg, 441.81 μmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1.5 mL) was added dropwise. The mixture was stirred at room temperature for 0.5 hours, and the solvent was removed by concentration under reduced pressure to obtain compound E-9 (crude product). LCMS: C7H 10 ClN4, (ESI) [M+H]: 185.1.

[0241] Step 2, Synthesis of Compound E-10

[0242] Compound E-9 (crude), compound 10 (79.91 mg, 0.51 mmol), NaBH3CN (32.05 mg, 0.51 mmol), acetic acid (0.5 mL) and methanol (5 mL) were added to a 50 mL reaction flask in sequence. The mixture was stirred at room temperature for 2 hours and then quenched (LC-MS monitoring). The solvent was evaporated to dryness, purified by MPLC, and concentrated under reduced pressure to remove the solvent to obtain compound E-10 (142.16 mg, 0.46 mmol, 90.02% yield). LCMS: C 13 H 14 C l2 N5, (ESI) [M+H]: 310.1.

[0243] Step 3. Synthesis of Compound E6

[0244] Under nitrogen, compound E-10 (47.00 mg, 151.52 μmol), compound 11 (31.97 mg, 151.52 μmol), potassium carbonate (41.82 mg, 303.05 μmol), and Pd(dppf)Cl2 (5.55 mg, 0.25 mol%) were added sequentially to a 50 mL reaction vial. The reaction system was sealed and stirred at 80°C for 8 hours before quenching (LC-MS monitoring). Extraction was completed with saturated sodium chloride solution (20 mL) and ethyl acetate (3 x 25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The product was separated by column chromatography using a volume ratio of petroleum ether to ethyl acetate of 1:100 to 1:5. The solvent was removed by concentration under reduced pressure to obtain compound E6 (6.90 mg, 15.74 μmol, 10.39% yield, 99.9% purity). LC-MS: C 22 H 23 ClFN6O, [M+H] + 441.1; Detection value: 441.3. 1 H NMR (400MHz, Methanol-d4) δ8.56(d,J=2.4Hz,1H),8.40–-8.37(m,1H),8.29(dd,J=6.0,2.4Hz,1H),7.88(dd,J=4.0,2.4H z, 1H), 7.74 (d, J = 2.0Hz, 1H), 7.49 (t, J = 8.0Hz, 1H), 7.39-738 (m, 2H), 5.56 (s, 2H), 3.32 (s, 3H), 3.17 (s, 3H), 3.05 (s, 3H). Purity >95%.

[0245] According to the synthetic route of compound E6, compounds E7 to E9 and E11 can be obtained by replacing compound 11 with the raw materials listed in Table 12.

[0246] Table 12. Compounds E7, E8, E9, and E11

[0247] Example 6, Synthesis of Series F Compound F6 of the Present Invention:

[0248] Step 1. Synthesis of Compound F-9

[0249] Compound 2 (100.00 mg, 438.13 μmol), DIPEA (141.56 mg, 1.10 mmol, 190.78 μL), HATU (183.14 mg, 481.94 μmol) and DCM (2 mL) were added to a 50 mL reaction bottle in sequence. After the reaction system temperature dropped to 0°C, compound 15 (92.92 mg, 438.13 μmol) was added. The reaction was stirred in an ice bath for 0.5 hours and then quenched (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated and purified by MPLC. The solvent was removed by concentration under reduced pressure to obtain compound F-9 (182.00 mg, 430.96 μmol, 98.36% yield). LCMS: C 23 H 21 BrNO2, (ESI) [M+H]: 422.1.

[0250] Step 2, Synthesis of Compound F-10

[0251] Under nitrogen, compound F-9 (182.00 mg, 430.96 μmol), bis(pinacolato)diboron (240.76 mg, 948.11 μmol), potassium acetate (105.74 mg, 1.08 mmol), 1,4-dioxane and water (4 mL / 1 mL), and Pd(dppf)Cl2 (31.98 mg, 0.25 mol%) were added to a 50 mL reaction vial. The reaction system was sealed and stirred at 100°C for 1 hour before quenching (monitored by LC-MS). The mixture was extracted with saturated sodium chloride solution (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 1:100 to 1:5. The solvent was removed by concentration under reduced pressure to obtain compound F-10 (202.00 mg, 430.36 μmol, 99.86% yield). LCMS: C 29 H 33 BNO4, (ESI) [M+H]: 470.2.

[0252] Step 3. Synthesis of Compound F6

[0253] Under nitrogen, to a 50 mL reaction vial were added compound F-10 (202.00 mg, 430.36 μmol), compound 16 (126.02 mg, 516.43 μmol), potassium carbonate (148.70 mg, 1.08 mmol), and Pd(dppf)Cl2 (31.93 mg, 0.25 mol%) dissolved in a mixture of 1,4-dioxane (3 mL) and water (1 mL). The reaction was sealed and stirred at 80°C for 1 hour before quenching (monitored by LC-MS). Extraction was completed with saturated sodium chloride solution (20 mL) and ethyl acetate (3 x 20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and separated by column chromatography using a volume ratio of petroleum ether to ethyl acetate of 1:100 to 1:5 as the eluent. The solvent was removed by concentration under reduced pressure to obtain compound F6 (25.00 mg, 54.40 μmol, 12.64% yield, 97.7% purity). LC-MS: C 30 H 26 N3O2, [M+H]+460.2; detected value: 460.2. 1 H NMR(400MHz,Chloroform-d)δ8.23(s,2H),7.78-7.72(m,2H),7.60-7.57(m,2H),7.53-7.51(m,2H),7.35-7 .26(m,4H),7.05-6.92(m,4H),5.16(s,2H),4.03(s,1H),3.98-3.87(m,2H),3.73(s,1H),3.05-2.96(m,2H). Purity >95%.

[0254] Example 7, Synthesis of Series A Compound 1A of the Present Invention:

[0255] Step 1, synthesis of compound A-2

[0256] Compound A-1 (304.00 mg, 999.44 μmol), methylamine hydrochloride (80.98 mg, 1.20 mmol), sodium carbonate (317.82 mg, 3.00 mmol), and tetrahydrofuran / water (4 mL / 2 mL) were added to a 50 mL reaction flask. The mixture was stirred at room temperature until the reaction was complete, after which water was added to quench the reaction (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (10 mL) and ethyl acetate (3 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The organic phases were purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound A-2 (132.00 mg, 441.81 μmol, 44.21% yield). The obtained compound was characterized: MS (ESI) m / z = 299.1 (M+1). +

[0257] Step 2, synthesis of compound A-3

[0258] Under nitrogen, compound A-2 (132.00 mg, 441.81 μmol), compound 1 (91.18 mg, 530.18 μmol), potassium carbonate (182.91 mg, 1.33 mmol), 1,4-dioxane and water (4 mL / 1 mL), and Pd(dppf)Cl2 (6.44 mg, 0.25 mol%) were added to a 50 mL reaction vial in sequence. The reaction system was sealed and stirred at 80°C for 2 hours before quenching the reaction (monitored by LC-MS). The mixture was extracted with saturated sodium chloride solution (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 1:100 to 1:5. The solvent was removed by concentration under reduced pressure to obtain compound A-3 (96.00 mg, 245.85 μmol, 55.65% yield). The obtained compound was characterized: MS (ESI) m / z = 392.2 (M+1) +

[0259] Step 3, Synthesis of Compound A-4

[0260] Compound A-3 (96.00 mg, 245.85 μmol) was dissolved in dichloromethane (2 mL) in a 50 mL reaction flask, and trifluoroacetic acid (1 mL) was then added dropwise. The mixture was stirred at room temperature for 3 hours, and the solvent was removed by concentration under reduced pressure to obtain compound A-4 (crude product). The obtained compound was characterized: MS (ESI) m / z = 292.2 (M+1) + .

[0261] Step 4, Synthesis of Compound 7-5

[0262] To a 10 mL reaction flask, DCM (2 mL), compound 2-a (191 mg, 1.00 mmol), EDCI (229 mg, 1.20 mmol), and pyridine (159 mg, 2.00 mmol, 161 uL) were added sequentially. After the reaction system temperature dropped to 0°C, compound A-4 (292 mg, 1.00 mmol) was added. The reaction was stirred in an ice bath for 0.5 hours, then quenched. The product was purified by MPLC and concentrated under reduced pressure to remove the solvent, yielding compound 7-5 (199 mg, 457.1 μmol, 45.71% yield). The obtained compound was characterized: MS (ESI) m / z = 464.1 (M+1). + .

[0263] Step 5.1. Synthesis of compound 3-a

[0264] Step 5.1.1. Synthesis of compound 3-a-2

[0265] Under nitrogen, 10 mL of THF, compound 3-a-1 (392 mg, 2.00 mmol), and iodomethane (709.84 mg, 5.00 mmol) were added to a 50 mL flask. After cooling to 0°C, sodium hydride (119.96 mg, 5.00 mmol) was added. The reaction was warmed to room temperature and stirred at room temperature for 3 hours. After LCMS analysis showed that the reaction was complete, water was added to quench the reaction. Saturated NaCl solution (20.0 mL) and ethyl acetate (3×20 mL) were used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain compound 3-a-2 (380 mg, 1.70 mmol, 84.80% yield). The obtained compound was characterized: MS (ESI) m / z = 224.0 (M+1) + .

[0266] Step 5.1.2. Synthesis of compound 3-a-3

[0267] To a 50 mL flask, add compound 3-a-2 (380 mg, 1.70 mmol), 20 mL of anhydrous ethanol, and nickel dichloride hexahydrate (403.03 mg, 1.70 mmol). Cool to 0°C and add sodium borohydride (320.76 mg, 8.48 mmol). Warm the reaction to room temperature and stir at room temperature for 1 hour. After LCMS analysis shows the reaction is complete, add 5 mL of 1N HCl solution, followed by 1N NaOH solution to adjust the pH to 10. The resulting mixture is filtered to obtain a filtrate containing compound 3-a-3, which is used directly in the next reaction.

[0268] The obtained compound was characterized: MS (ESI) m / z = 228.0 (M+1) + .

[0269] Step 5.1.3. Synthesis of compound 3-a-4

[0270] To the filtrate containing compound 3-a-3 obtained in the previous step was added di-tert-butyl dicarbonate (370.60 mg, 1.70 mmol). The resulting mixture was stirred at room temperature for 1 hour. After LCMS analysis showed that the reaction was complete, extraction was completed with ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness, followed by column chromatography to obtain compound 3-a-4 (500 mg, crude product). The obtained compound was characterized: MS (ESI) m / z=328.1 (M+1) + .

[0271] Step 5.1.4. Synthesis of compound 3-a

[0272] Under nitrogen, compound 3-a-4 (500 mg, crude), pinacol diboronate (676.92 mg, 2.67 mmol), KCO (294.29 mg, 2.13 mmol), 1,4-dioxane (10 mL), and Pd(dppf)Cl (38.97 mg, 53.31 μmol) were added sequentially to a 50 mL reaction vial. The reaction was stirred at 90°C for 2 hours under nitrogen and then quenched (LC-MS monitoring). Extraction was completed with saturated NaCl solution (20.0 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The product was separated by column chromatography using a 30:1 volume ratio of petroleum ether to ethyl acetate eluent. The solvent was removed by concentration under reduced pressure to afford compound 3-a (143 mg, 381.02 μmol, 35.73% yield). The obtained compound was characterized: MS (ESI) m / z = 376.3 (M+1) + .

[0273] Step 5.2. Synthesis of Compound 1A

[0274] Under nitrogen, compound 3-a (48.50 mg, 129.23 μmol), compound 7-5 (50 mg, 107.69 μmol), K2CO3 (29.72 mg, 215.38 μmol), 1,4-dioxane and water (4 mL / 1 mL), and Pd(dppf)Cl2 (15.74 mg, 21.54 μmol) were added sequentially to a 50 mL reaction vial. The reaction system was sealed and stirred at 110°C for 1 hour before quenching (LC-MS monitoring). Extraction was completed with saturated NaCl solution (20.0 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The organic phases were separated by MPLC and concentrated under reduced pressure to remove the solvent to afford compound 1A (30 mg, 43.81 μmol, 40.68% yield, 92.4% purity). The obtained compound was characterized: MS (ESI) m / z = 633.4 (M+1) + .

[0275] 1 H NMR (400MHz, DMSO-d6) δ9.74-9.71(m,1H),9.36-9.31(m,1H),8.28(t,J=4.8Hz,1H), 8.26(t,J=4.8Hz,1H),7.98(d,J=7.2Hz,1H),7.82-7.71(m,3H),7.47(d,J=7.2Hz,2H),7.15(s,1H),5.17(s,1 H),4.84(s,1H),4.27(s,1H),4.03(s,1H),3.14(s,5H),2.72-2.66(m,2H),1.33(d,J=6.8Hz,9H),1.25(s,6H).

[0276] Example 8, Synthesis of Series A Compound 2A of the Present Invention:

[0277] Compound 1A (30 mg, 43.81 μmol) was dissolved in a mixture of 6N HCl and ethyl acetate (5 mL) in a 50 mL reaction flask. The mixture was stirred at room temperature for 0.5 hours. The solvent was then concentrated under reduced pressure to yield compound 2A (24 mg, 37.95 μmol, 80.05% yield, 90% purity). The obtained compound was characterized by MS (ESI) m / z = 533.5 (M+1). +

[0278] Example 9, Synthesis of Series A Compound 3A of the Present Invention:

[0279] Compound 2A (20 mg, 37.55 μmol), DMF (1 mL), N,N-diisopropylethylamine (9.71 mg, 75.10 μmol, 13.08 uL), and acetic anhydride (3.83 mg, 37.55 μmol) were added sequentially to a 10 mL flask at room temperature. After stirring at room temperature for 1 hour, LC-MS indicated the reaction was complete. The solvent was evaporated, and the mixture was separated and purified by MPLC. After removal of the solvent by concentration under reduced pressure, compound 3A (2.5 mg, 4.29 μmol, 11.41% yield, 98.5% purity) was obtained. The obtained compound was characterized: MS (ESI) m / z = 575.3 (M+1). + . 1 H NMR(400MHz, Methanol–d4)δ9.77-9.75(m,1H),9.49-9.48(m,1H),8.27(t,J=4.8 Hz,1H),8.20(t,J=4.8Hz,1H),8.05(t,J=7.2Hz,1H),7.86(s,1H),7.69(d,J=8.0 Hz,2H),7.51(d,J=8.0Hz,2H),7.02(s,1H),5.30(s,1H),5.08(s,1H),4.39(s,1H ),4.21(s,1H),3.41(s,2H),3.34(s,2H),3.26(s,3H),1.88(s,3H),1.35(s,6H).

[0280] Example 10: Synthesis of Series A Compounds 4A, 5A, and 6A of the present invention:

[0281] According to the synthetic route 1A, compounds 4A, 5A, and 6A can be obtained by replacing the raw material 3-a used in the first step reaction with the raw materials listed in Table 13.

[0282] Table 13. Compounds 4A-6A

[0283] Synthesis of compound 3-b

[0284] Step 1, Synthesis of Compound 3-b-2

[0285] Compound 3-b-1 (1 g, 3.62 mmol) and 15 mL of THF were added to a dry 50 mL flask at room temperature. After cooling to 0°C, sodium hydride (260 mg, 14.49 mmol) was added. After stirring at 0°C for one hour, iodomethane (220 g, 14.49 mmol) was added and the temperature was gradually raised to room temperature. When LCMS showed that the reaction was complete, water was added to quench the reaction. Extraction was completed with ethyl acetate (3 × 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 1.1 g of crude product 3-b-2, which was directly used in the next reaction. The obtained compound was characterized: MS (ESI) m / z = 305.0 (M+1) + .

[0286] Step 2, Synthesis of Compound 3-b-3

[0287] Compound 3-b-2 (1.1 g, crude), sodium hydroxide (104.23 mg, 2.48 mmol), methanol (5 mL), and water (5 mL) were added sequentially to a 50 mL reaction flask. The mixture was stirred at 60°C for 12 hours before quenching the reaction (LC-MS monitoring). The pH of the system was adjusted to 4 with 1N hydrochloric acid solution. The reaction solution was concentrated to obtain compound 3-b-3 (150.00 mg, crude), which was used directly in the next reaction. The obtained compound was characterized: MS (ESI) m / z = 291.0 (M+1) + .

[0288] Step 3, Synthesis of Compound 3-b-4

[0289] To a 50 mL reaction flask were added compound 3-b-3 (1 g, 3.62 mmol), DIPEA (300.47 mg, 2.32 mmol, 404.94 uL), HATU (353.38 mg, 929.95 μmol) and DMF (15 mL) in sequence. After the reaction system temperature dropped to 0°C, methylamine hydrochloride (135.00 mg, 774.96 μmol) was added. The reaction was stirred in an ice bath for 1 hour and then quenched (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (20.0 mL) and ethyl acetate (3×20.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated and purified by MPLC. The solvent was removed by concentration under reduced pressure to give compound 3-b-4 (230.00 mg, 495.14 μmol, yield 63.89%). The obtained compound was characterized: MS (ESI) m / z = 304.0 (M+1) + .

[0290] Step 4, Synthesis of Compound 3-b

[0291] Under nitrogen, compound 3-b-4 (303.14 mg, 1 mmol), pinacol diboronate (634.85 mg, 2.50 mmol), K2CO3 (276.00 mg, 2.00 mmol), 1,4-dioxane (10 mL), and Pd(dppf)Cl2 (73.10 mg, 100.00 μmol) were added sequentially to a 50 mL reaction flask. The reaction system was sealed and stirred at 90°C for 5 hours (monitored by LC-MS). The resulting mixture was separated by MPLC and concentrated under reduced pressure to remove the solvent, yielding compound 3-b (20 mg, 65.96 μmol, 6.60% yield). The resulting compound was characterized: MS (ESI) m / z = 304.2 (M+1). + .

[0292] Synthesis of compound 3-c

[0293] Step 1. Synthesis of compound 3-c-2

[0294] To a 50 mL reaction flask were added compound 3-b-3 (1 g, crude, 3.45 mmol), DIPEA (1.34 mg, 10.34 mmol, 1.80 mL), HATU (1.44 g, 3.79 mmol), and anhydrous DCM (15 mL). After the reaction system cooled to 0°C, compound 3-c-1 (642.03 mg, 3.45 mmol) was added. The reaction was stirred in an ice bath for 1 hour before quenching (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (20.0 mL) and ethyl acetate (3 × 20.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The organic phases were purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound 3-c-2 (1.3 g, crude). The obtained compound was characterized: MS (ESI) m / z = 459.1 (M+1). +

[0295] Step 2, Synthesis of Compound 3-c-3

[0296] Compound 3-c-2 (1.3 g, crude) and 9-BBN (10 mL) were added to a 50 mL reaction flask and dissolved in THF (20 mL). The mixture was heated to 60°C under nitrogen and stirred for 5 hours (LC-MS monitoring), followed by quenching with 20 mL of water. The mixture was extracted with ethyl acetate (3 × 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent, yielding compound 3-c-3 (300 mg, 675.15 μmol, 23.80% yield). The obtained compound was characterized: MS (ESI) m / z = 459.1 (M+1). +

[0297] Step 3, Synthesis of Compound 3-c-4

[0298] Under nitrogen, compound 3-c-3 (335.49 mg, 755.00 μmol), pinacol diboronate (230.07 mg, 906.01 μmol), KOAc (369.95 mg, 3.78 mmol), 1,4-dioxane, water (4 mL / 1 mL), and Pd(dppf)Cl2 (55.27 mg, 75.50 μmol) were added sequentially to a 50 mL reaction vial. The reaction system was sealed and stirred at 100°C for 2 hours before quenching (LC-MS monitoring). Extraction was completed with saturated NaCl solution (20.0 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The product was separated by MPLC and concentrated under reduced pressure to afford compound 3-c-4 (100 mg, 290.45 μmol, 38.47% yield). The obtained compound was characterized: MS (ESI) m / z = 445.3 (M+1) +

[0299] Step 4, Synthesis of Compound 3-c

[0300] In a 50 mL reaction flask, compound 3-c-4 (100 mg, 290.45 μmol) was dissolved in a mixture of 6N HCl and ethyl acetate (10 mL). The mixture was stirred at room temperature for 0.5 hours. The solvent was then concentrated under reduced pressure to obtain compound 3-c (90 mg, the crude product was used directly in the next reaction). The obtained compound was characterized: MS (ESI) m / z = 345.3 (M+1) +

[0301] Synthesis of compound 3-d

[0302] Step 1. Synthesis of compound 3-d-2

[0303] To a 100 mL flask, add compound 3-d-1 (252 mg, 1.52 mmol), DCM (20 mL), and 3 drops of DMF (catalytic amount). Cool the mixture to 0°C and add oxalyl chloride (964.59 mg, 7.6 mmol). Allow the reaction to slowly warm to room temperature. After 1 hour at room temperature, evaporate the solvent to yield crude product 3-d-2 (300 mg) which was used directly in the next reaction.

[0304] Step 2, Synthesis of Compound 3-d

[0305] To the crude product 3-d-2 obtained in the previous step were added DCM (10 mL), DIPEA (500 mg, 4.56 mmol), and methylamine hydrochloride (103 mg, 1.52 mmol). The reaction was allowed to react at room temperature for 1 hour before being stopped (LC-MS monitoring). Extraction was completed with saturated NaCl solution (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to give compound 3-d (223 mg, 82% yield). The obtained compound was characterized: MS (ESI) m / z = 179.1 (M+1) +

[0306] Example 11: Synthesis of Series A Compound 1A of the Present Invention

[0307] According to the synthetic route of compound 7-5 in the synthetic route of compound 1A (i.e., steps 1 to 4), compounds 7A, 8A, 9A, and 10A can be obtained by replacing the raw material 2-a used in the reaction with the raw materials listed in Table 14.

[0308] Table 14. Compounds 7A-10A

[0309] Synthesis of compound 2-d

[0310] Step 1. Synthesis of compound 2-d-2

[0311] Synthesis steps: To compound 2-d-1 (500 mg, 2.62 mmol) dissolved in 10 mL of anhydrous methanol was added dropwise thionyl chloride (622.94 mg, 5.24 mmol, 379.84 uL) at 0°C. The reaction was heated to 50°C and stirred for 1.5 hours. LC-MS indicated the reaction was complete. The reaction was cooled to room temperature, then cooled in an ice bath and quenched with water. The reaction mixture was filtered, and the filtrate was concentrated and evaporated to dryness. Purification by MPLC afforded compound 2-d-2. The resulting compound was characterized: MS (ESI) m / z = 206.0 (M+1). +

[0312] Step 2, Synthesis of Compound 2-d

[0313] Under nitrogen, compound 2-d-2 (50 mg, 243.89 μmol), compound 2-d-3 (52.11 mg, 292.67 μmol), K2CO3 (100.97 mg, 731.67 μmol), 1,4-dioxane (5 mL), and Pd(dppf)Cl2 (8.92 mg, 12.19 μmol) were added sequentially to a 25 mL reaction vial. The reaction system was sealed and stirred at 100°C overnight before quenching (LC-MS monitoring). Extraction was completed with saturated NaCl solution (20.0 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The organic phases were separated by MPLC and concentrated under reduced pressure to remove the solvent to afford compound 2-d (20 mg, 81.87 μmol, 33.57% yield). The obtained compound was characterized: MS (ESI) m / z = 245.1 (M+1) +

[0314] Synthesis of compound 2-e

[0315] Under nitrogen protection, compound 2-e-1 (265 mg, 992.22 μmol), compound 2-e-2 (123.73 mg, 1.49 mmol), piperidine (168.97 mg, 1.98 mmol), DMF (4 mL), CuI (1.78 mg, 9.36 μmol), and Pd(dppf)Cl2 (69.55 mg, 99.22 μmol) were added sequentially to a 50 mL microwave reaction tube. The reaction system was sealed and heated with stirring at 110°C for 1 hour before the reaction was stopped (LC-MS monitoring). The solvent was evaporated and the product 2-e (20 mg, 74.27 μmol, 7.48% yield) was isolated and purified by MPLC. The obtained compound was characterized: MS (ESI) m / z = 270.1 (M+1) +

[0316] Example 12, Synthesis of Series B Compound 1B of the Present Invention:

[0317] Step 1. Synthesis of compound 12-2

[0318] Under nitrogen, compound 2-e-1 (114 mg, 427 μmol), compound 12-1 (145 mg, 470 μmol), K2CO3 (138 mg, 177 μmol), 5 mL of 1,4-dioxane, and Pd(dppf)Cl2 (18 mg, 24.2 μmol) were added sequentially to a 25 mL reaction vial. The reaction system was sealed and stirred at 80°C overnight before quenching the reaction (LC-MS monitoring). Extraction was completed with saturated NaCl solution (20.0 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined and dried over anhydrous sodium sulfate, the solvent was evaporated, and the mixture was separated by MPLC. After removal of the solvent, the solvent was concentrated under reduced pressure to obtain compound 12-2 (100 mg, 270 μmol, 63.42% yield). The obtained compound was characterized: MS (ESI) m / z = 370.2 (M+1) +

[0319] Step 2, Synthesis of Compound 12-3

[0320] To a 50 mL reaction flask, compound 12-2 (100 mg, 270 μmol), methanol (5.0 mL), and palladium on carbon (10 mg) were added sequentially. The reaction system was replaced with hydrogen, maintaining a hydrogen atmosphere at 1 atmosphere, and stirred at room temperature for 3 hours (LC-MS monitoring). The palladium on carbon was removed by filtration, washed with methanol (2 × 20 mL), and the filtrate was collected and concentrated under reduced pressure to remove the solvent to give compound 12-3 (100 mg, crude product). LCMS (ESI) [M+H]: 372.2.

[0321] Step 3, Synthesis of Compound 12-4

[0322] To a 10 mL reaction flask, DCM (2 mL), compound A-4 (25 mg, 130 μmol), EDCI (30 mg, 156 μmol), and pyridine (21 mg, 260 μmol, 25 μL) were added sequentially. After the reaction system temperature dropped to 0°C, compound 12-3 (50 mg, 130 μmol) was added. The reaction was stirred in an ice bath for 0.5 hours, then quenched. The product was purified by MPLC and concentrated under reduced pressure to remove the solvent, yielding compound 12-4 (32 mg, 496 μmol, 38.14% yield). The obtained compound was characterized: MS (ESI) m / z = 645.3 (M+1).+ .

[0323] Step 4. Synthesis of Compound 1B

[0324] In a 25 mL reaction flask, compound 12-4 (32 mg, 496 μmol) was dissolved in dichloromethane (4.0 mL), followed by the dropwise addition of TFA (1.5 mL). The reaction was stirred at room temperature for 0.5 hours, and the solvent was removed by concentration under reduced pressure to obtain compound 1B (24.5 mg, 450 μmol, 90.73% yield, 99.9% purity). The obtained compound was characterized: MS (ESI) m / z = 545.3 (M+1) + . 1 H NMR (400MHz, Methanol-d4) δ9.80 (s, 1H), 9.51-9.47 (m, 1H), 8.28-8.21 (m, 2H), 8.05-7.72 (m, 5H), 7.39 (d, J = 9.6Hz, 3H), 5.27 (s, 1H), 4.95(s,1H),4.38-4.14(m,2H),3.54(s,1H),3.51(s,1H),3.16(s,2H),2.98(s,2H),2.67(s,1H),2.13-2.10(m,2H),1.98-1.92(m,2H).

[0325] According to the synthetic route of compound 7-5, compounds 2B to 3B can be obtained by replacing compound 2-a with the raw materials listed in Table 15.

[0326] Table 15. Compounds 2B to 3B

[0327] Example 13: Synthesis of Series C Compound 1C of the Present Invention

[0328] Step 1. Synthesis of Compound C-1

[0329] Compound A-1 (400 mg, 1.32 mmol), concentrated aqueous ammonia (447 mg, 6.58 mmol), zinc powder (673.30 mg, 10.52 mmol), and anhydrous ethanol (5 mL) were added to a 50 mL flask. The reaction was stopped after stirring at 80°C for 1 hour (LC-MS monitoring). The reaction mixture was filtered, and the filtrate was collected and the solvent was evaporated to dryness to obtain crude compound C-1 (355 mg). The obtained compound was characterized: MS (ESI) m / z = 270.1 (M+1) +

[0330] Step 2, Synthesis of Compound C-2

[0331] Under nitrogen protection, compound C-1 (355 mg, 1.32 mmol), compound 1 (273.19 mg, 1.58 mmol), K2CO3 (544.88 mg, 3.95 mmol), 1,4-dioxane and water (4 mL / 1 mL) and Pd(dppf)Cl2 (10 mg, 1.32 mmol) were added to a 50 mL reaction bottle in sequence. The reaction system was sealed and stirred at 80°C for 2 hours before stopping the reaction (LC-MS monitoring). The filtrate was filtered through celite, concentrated, and the solvent was evaporated to dryness. The product was separated and purified by preparative HPLC, and the solvent was removed by concentration under reduced pressure to obtain compound C-2 (200 mg, 551.84 μmol, 41.93% yield). The obtained compound was characterized: MS (ESI) m / z = 363.2 (M+1) +

[0332] Step 3, synthesis of compound C-3

[0333] In a 50 mL reaction flask, compound C-2 (150 mg, 413.88 μmol) was dissolved in a mixture of 6N HCl and ethyl acetate (2 mL). The mixture was stirred at room temperature for 0.5 hours and then concentrated under reduced pressure to remove the solvent to obtain compound C-3 (109 mg, crude product). The obtained compound was characterized by MS (ESI) m / z = 263.1 (M+1). +

[0334] Step 4, synthesis of compound 13-4

[0335] To a 10 mL reaction flask, DCM (2 mL), compound 2-a (132 mg, 691.16 μmol), EDCI (158.41 mg, 829.39 μmol), and pyridine (109.34 mg, 1.38 mmol, 111.36 μL) were added sequentially. After the reaction system cooled to 0°C, compound C-3 (181.30 mg, 691.16 μmol) was added. The reaction was stirred in an ice bath for 0.5 hours, then quenched. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent, yielding compound 13-4 (150 mg, 344.61 μmol, 49.86% yield). The resulting compound was characterized: MS (ESI) m / z = 435.1 (M+1). +

[0336] Step 5, synthesis of compound 1C

[0337] Under nitrogen, compound 2-d-3 (22.50 mg, 126.36 μmol), compound 13-4 (50 mg, 114.87 μmol), K2CO3 (47.56 mg, 344.61 μmol), 1,4-dioxane, water (4 mL / 1 mL), and Pd(dppf)Cl2 (5 mg, 114.87 μmol) were added sequentially to a 50 mL reaction vial. The reaction system was sealed and microwave-treated at 110°C for 2 hours before quenching (LC-MS monitoring). Extraction was completed with saturated NaCl solution (20.0 mL) and ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The organic phases were separated by MPLC and concentrated under reduced pressure to remove the solvent to afford compound 1C (13.9 mg, 26.03 μmol, 22.66% yield, 91.5% purity). The obtained compound was characterized: MS (ESI) m / z = 489.2 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ13.73(s,1H),9.84-9.79(m,1H),9.30-9.25(m,1H),8.84(s,1H),8.22(d,J=4.0Hz,1H),8.10(s,1H),7.84(s,1H),7.73(t ,J=7.6Hz,2H),7.63(t,J=8.8Hz,2H),7.06(s,1H),5.46(s,1H),4.98(s, 1H), 4.35 (s, 1H), 4.01 (s, 1H), 3.05-2.98 (m, 2H), 1.34 (t, J = 5.6Hz, 9H).

[0338] Example 14, Synthesis of Series C Compound 2C of the Present Invention:

[0339] According to the synthetic route of compound 1c above, compound 2c can be obtained by replacing compound 2-a with the raw materials listed in Table 16.

[0340] Table 16. Compound 2C

[0341] Synthesis of compound 2-f

[0342] Under nitrogen, compound 2-a (50 mg, 261.80 μmol), compound 2-f-1 (33.06 mg, 261.80 μmol), Cs2CO3 (170.17 mg, 523.61 μmol), MeOH (0.2 mL), H2O (2 mL), DMA (0.2 mL), CuI (2.49 mg, 13.09 μmol), and Pd(dppf)Cl2 (9.19 mg, 13.09 μmol) were added sequentially to a 5 mL microwave reaction tube. The reaction system was sealed and stirred in a microwave at 100°C for 2 hours before stopping the reaction (monitored by LC-MS). The organic phase was separated and concentrated, and then purified by preparative HPLC to obtain product 2-f (10 mg, 60.92 μmol, 23.27% yield). The obtained compound was characterized: MS (ESI) m / z = 241.1 (M+1).

[0343] Example 15, Synthesis of Series C Compound 3C of the Present Invention:

[0344] Step 1. Synthesis of compound C3-2

[0345] Under nitrogen protection, compound 2-e-1 (50 mg, 187.21 μmol), compound C3-1 (41.99 mg, 187.21 μmol), Cs2CO3 ((121.69 mg, 374.42 μmol), MeOH (0.2 mL), H2O (2 mL), DMA (0.2 mL), CuI (1.78 mg, 9.36 μmol) and Pd(dppf)Cl2 (6.57 mg, 9.36 μmol) were added to a 5 mL microwave reaction tube in sequence. The reaction system was sealed and stirred at 100 ° C for 2 hours before stopping the reaction (LC-MS monitoring). The organic phase was separated and concentrated, and the product C3-2 (7 mg, 17.05 μmol, 9.11% yield) was separated and purified by preparative HPLC. The obtained compound was characterized: MS (ESI) m / z = 411.2 (M+1)

[0346] Step 2, Synthesis of Compound C3-3

[0347] To a 10 mL reaction vial were added compound C3-2 (7 mg, 17.05 μmol), EDCI (3.91 mg, 20.46 μmol), DCM (1 mL), and pyridine (2.70 mg, 34.11 μmol, 2.75 μL) in sequence. After the reaction system cooled to 0°C, compound C-3 (4.47 mg, 17.05 μmol) was added. The temperature was slowly raised to room temperature and stirred for one hour before the reaction was terminated (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (5 mL) and dichloromethane (3 × 5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by preparative HPLC and concentrated under reduced pressure to remove the solvent, yielding compound C3-3 (6.00 mg, 9.16 μmol, 53.73% yield). The resulting compound was characterized: MS (ESI) m / z = 655.3 (M+1).

[0348] Step 3, Synthesis of Compound C3-4

[0349] 2 mL of 6N HCl in ethyl acetate was added to compound C3-3 and stirred at room temperature for 30 min until the reaction was complete (LC-MS detection). The solvent was evaporated to dryness, and the resulting compound C3-4 (6.00 mg, crude product) was used directly in the next reaction. The obtained compound was characterized: MS (ESI) m / z = 555.3 (M+1) +

[0350] Step 4. Synthesis of Compound 3C

[0351] To a 10 mL reaction vial were added compound C3-4 (6 mg, crude), DCM (1 mL), and acetic anhydride (1.21 mg, 11.90 μmol). The mixture was stirred at room temperature for 0.5 h before terminating the reaction (monitored by LC-MS). The solvent was evaporated to dryness, and the mixture was purified by preparative HPLC and concentrated under reduced pressure to remove the solvent, yielding compound 3C (2.00 mg, 3.14 μmol, 29.00% yield, 93.6% purity). The resulting compound was characterized by MS (ESI) m / z = 597.3 (M+1). 1H NMR(400MHz,DMSO-d6)δ13.89(s,1H),9.84-9.79(m,1H),9.30-9.26(m,1H),8.85(s,1 H),8.22(d,J=7.6Hz,1H),8.10(s,1H),7.98-7.84(m,3H),7.70(t,J=3.6Hz,1H),7.55- 7.53(m,2H),7.17(s,1H),5.42(s,1H),4.98(s,1H),4.31(s,1H),4.14(t,J=3.2Hz,1H ),4.03(s,2H),3.95(s,2H),3.05(s,2H),2.98(s,2H),2.88-2.76(m,4H),2.00(s,3H).

[0352] Example 16, Synthesis of Series D Compound 1D of the Present Invention:

[0353] Step 1, synthesis of compound D1-2

[0354] Under nitrogen, a 50 mL reaction flask was charged with compound D1-1 (590 mg, 1.97 mmol), compound 1 (340.47 mg, 1.97 mmol), LiOH (94.27 mg, 3.94 mmol), 1,4-dioxane, water (12 mL / 3 mL), S-Phos (80.70 mg, 196.83 μmol), and Pd(OAc)2 (44.09 mg, 196.83 μmol). The reaction was stirred at 140°C for 2 hours and then quenched (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (20.0 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to yield the crude product, compound D1-2 (600.00 mg). The obtained compound was characterized: MS (ESI) m / z = 393.2 (M+1).

[0355] Step 2, synthesis of compound D1-3

[0356] In a 50 mL reaction flask, compound D1-2 (600.00 mg, crude product, 1.53 mmol) was dissolved in a mixture of 6N HCl and ethyl acetate (10 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure to obtain the crude product, compound D1-3, which was used directly in the next reaction. The obtained compound was characterized: MS (ESI) m / z = 293.2 (M+1) + .

[0357] Step 3, Synthesis of Compound D1-4

[0358] Compound 2-a (287.45 mg, 1.51 mmol), DIPEA (583.58 mg, 4.52 mmol, 786.50 μL), HATU (629.14 mg, 1.66 mmol), and DMF (10 mL) were added to a 50 mL reaction flask. After the reaction system cooled to 0°C, compound D1-3 (440.00 mg, 1.51 mmol) was added. The reaction was stirred in an ice bath for 0.5 hours before quenching (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (20 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The organic phases were purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound D1-4 (400.00 mg, crude product). The obtained compound was characterized: MS (ESI) m / z = 465.1 (M+1). + .

[0359] Step 4. Synthesis of Compound 1D

[0360] Under nitrogen, compound D1-4 (130 mg, 279.39 μmol), compound 2-d-3 (49.74 mg, 279.39 μmol), K2CO3 (96.39 mg, 698.47 μmol), 1,4-dioxane and water (4 mL / 1 mL), and Pd(dppf)Cl2 (20.45 mg, 27.94 μmol) were added sequentially to a 50 mL reaction vial. The reaction system was sealed and stirred at 100°C for 2 hours before quenching (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (20.0 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to afford compound 1D (30.00 mg, 57.38 μmol, 20.54% yield, 99.2% purity). The obtained compound was characterized: MS (ESI) m / z = 519.3 (M+1) + . 1 H NMR(400MHz,DMSO-d6)δ13.73(s,1H),9.81(s,1H),9.25(s,1H),8.19-8.09(m,2H),7.84-7.7 2(m,4H),7.49(s,2H),7.03(s,1H),5.34(s,2H),4.88(s,2H),4.26-4.16(m,5H),1.30(s,9H).

[0361] Example 17, Synthesis of Series E Compound 1E of the Present Invention:

[0362] Step 1. Synthesis of Compound E1-2

[0363] Under nitrogen, compound D1-1 (268.00 mg, 997.25 μmol), compound E1-1 (224.68 mg, 1.50 mmol), Cs2CO3 (975.31 mg, 2.99 mmol), 1,4-dioxane (5 mL), XantPhos (288.50 mg, 498.63 μmol), and Pd2(dba)3 (182.64 mg, 199.45 μmol) were added sequentially to a dry microwave reaction tube. The reaction system was sealed and microwave-heated at 150°C for 1 hour before quenching. The mixture was extracted with saturated NaCl solution (20.0 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by MPLC and concentrated under reduced pressure to afford compound E1-2 (300.00 mg, 784.36 μmol, 78.65% yield). The obtained compound was characterized: MS (ESI) m / z = 414.2 (M+1) +

[0364] Step 2, Synthesis of Compound E1-3

[0365] Compound E1-2 (300 mg, 784.36 μmol) was dissolved in a mixed solution of 6N HCl and ethyl acetate (10 mL) in a 50 mL reaction flask, stirred at room temperature for 1 hour, and concentrated under reduced pressure to remove the solvent to obtain the crude product Compound E1-3, which was directly used in the next reaction.

[0366] Step 3, Synthesis of Compound E1

[0367] To a 50 mL reaction flask, compound 2-d (20 mg, 81.87 μmol), EDCI (47.08 mg, 245.61 μmol), and pyridine (2 mL) were added sequentially. After the reaction system cooled to 0°C, compound E1-3 (23.12 mg, 81.87 μmol) was added. The reaction was stirred at room temperature for 0.5 hours, then quenched with 1 mL of water. The product was purified by MPLC and concentrated under reduced pressure to remove the solvent, yielding compound 1E (9.10 mg, 17.89 μmol, 21.85% yield, 99.1% purity). The resulting compound was characterized: MS (ESI) m / z = 509.4 (M+1).+ . 1 H NMR (400MHz, DMSO-d6) δ11.53(s,1H),7.90(d,J=7.7Hz,1H),7.75-7.60(m,4H),7.49(d,J=8.0Hz,2H),7.36(t,J=7.6H z,1H),7.20(dd,J=7.5,5.9Hz,1H),7.05(s,2H),5.11-4.77(m,2H),4.23-4.01(m,2H),3.09-3.02(m,3H),1.31(s,9H).

[0368] Example 18, Synthesis of Compound 1F of the Present Invention:

[0369] Step 1, synthesis of compound A-2

[0370] Compound A-1 (304.00 mg, 999.44 μmol), methylamine hydrochloride (80.98 mg, 1.20 mmol), sodium carbonate (317.82 mg, 3.00 mmol), and tetrahydrofuran / water (4 mL / 2 mL) were added to a 50 mL reaction flask. The mixture was stirred at room temperature until the reaction was complete, and then water was added to quench the reaction (LC-MS monitoring). The mixture was extracted with saturated sodium chloride solution (10 mL) and ethyl acetate (3 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound A-2 (132.00 mg, 441.81 μmol, 44.21% yield). LCMS: C 13 H 20 ClN4O2, (ESI)[M+H]: 299.1.

[0371] Step 2, synthesis of compound A-3

[0372] Under nitrogen, compound A-2 (132.00 mg, 441.81 μmol), compound 1 (91.18 mg, 530.18 μmol), potassium carbonate (182.91 mg, 1.33 mmol), 1,4-dioxane and water (4 mL / 1 mL), and Pd(dppf)Cl2 (6.44 mg, 0.25 mol%) were added to a 50 mL reaction vial in sequence. The reaction system was sealed and stirred at 80°C for 2 hours before quenching the reaction (monitored by LC-MS). The mixture was extracted with saturated sodium chloride solution (20 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 1:100 to 1:5. After concentration under reduced pressure to remove the solvent, compound A-3 (96.00 mg, 245.85 μmol, 55.65% yield) was obtained. LCMS: C 22 H 26 N5O2, (ESI) [M+H]: 392.2.

[0373] Step 3, Synthesis of Compound A-4

[0374] Compound A-3 (96.00 mg, 245.85 μmol) was dissolved in dichloromethane (2 mL) in a 50 mL reaction flask, and trifluoroacetic acid (1 mL) was then added dropwise. The mixture was stirred at room temperature for 3 hours, and the solvent was removed by concentration under reduced pressure to obtain compound A-4 (crude product). LCMS: C 17 H 18 N5, (ESI) [M+H]: 292.2.

[0375] Step 4. Synthesis of Compound 1F

[0376] Compound 18-2 (10 mg, 40.79 μmol), EDCI (7.79 mg, 40.79 μmol), and pyridine (0.5 mL) were added sequentially to a 3 mL reaction vial. After the reaction system temperature dropped to 0°C, compound A-4 (12 mg, 41.19 μmol) was added. The reaction was stirred in an ice bath for 0.5 hours and then quenched. The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound 1F (10 mg, 19.29 μmol, 47.28% yield). LC-MS: C 31 H 28 N5O2, [M+H] + 519.2; Detection value: 519.3. 1H NMR (400MHz, DMSO-d6) δ11.99(s,1H),9.74(s,1H),9.26(s,1H),8.21(d,J=4.0Hz,1H),8.11(d,J=4.0Hz,1H),7.88(t,J=7.6Hz,1H),7.71(t, J=7.6Hz,2H),7.52(t,J=8.8Hz,2H),7.20(d,J=8.4Hz,1H),7.05(s,1H),4.91–4.83(m,2H),4.38(s,2H),3.10(d,J=4.0Hz,3H),2.65(s,2H).

[0377] The beneficial effects of the present invention are demonstrated by the following test examples.

[0378] Experimental Example 1: BCL-XL surface plasmon resonance (SPR) binding experiment

[0379] 1. Test method

[0380] Prepare running buffer: Protein fixation buffer has the same composition as running buffer A, with 10 mM NaH2PO4, 40 mM Na2HPO4, 150 mM NaCl, 0.03% Tween 20, and a pH of 7.4. Running buffer B has 10 mM NaH2OP4, 40 mM Na2HOP4, 150 mM NaCl, 0.03% Tween 20, and 5.00% DMSO, and a pH of 7.4. After preparation, filter the running buffer through a 0.22 μm filter.

[0381] BCL-XL protein immobilization: BCL-XL was immobilized on an NTA chip via His-capture and amino-coupling using protein immobilization buffer. The NTA chip surface was washed with 50 mM NaOH and 350 mM EDTA for 60 seconds each at a flow rate of 60.0 μL / min. The chip was then activated with 10 mM NiCl2 for 1100 seconds and then with a 1:1 mixture of EDC (75.00 mg / mL) and NHS (11.50 mg / mL) for 650 seconds at a flow rate of 10.0 μL / min. BCL-XL (0.04 mg / mL) was then injected at 4.0 μL / min for 850 seconds. After BCL-XL injection, a 1:1 volume ratio mixture of EDC (75.00 mg / mL) and NHS (11.50 mg / mL) was cross-linked at 10.0 μL / min for 200 seconds. Finally, the chip surface was blocked with 1 M ethanolamine (pH 8.5) at 6.0 μL / min for 7 minutes. The final immobilized BCL-XL concentration was 4690.00 RU.

[0382] Compound Dilution: Dilute the test compound with 100% DMSO to 100x the desired final concentration. Mix thoroughly, pipette 4.0 μL into 396 μL of Running Buffer A, and centrifuge at 15,000 rpm for 5 minutes to obtain a 1X compound solution containing 1% DMSO for subsequent dilutions. Serially dilute the test compound 2-fold starting at 50 μM for 9 concentrations (add 200 μL of compound solution to 200 μL of Running Buffer B for 2-fold dilutions, 10 concentration steps, including one zero concentration (using Running Buffer B instead), starting at 50 μM). Transfer the diluted compound to a 96-well plate for sample injection.

[0383] Run Procedure: The experiment was performed at 25°C using running buffer B at a flow rate of 30.0 μL / min. After equilibration with eight injections of running buffer B, the compounds were injected sequentially from the lowest to the highest concentration, with association and dissociation times of 120 seconds. The syringe was rinsed with 50% DMSO after each injection. Solvent variability caused by DMSO was corrected using 0.50%, 0.75%, 1.00%, 1.25%, and 1.50% DMSO.

[0384] 2. Test results

[0385] The response values ​​of the compound binding to the BCL-XL protein were analyzed after deducting the reference channel and 0 concentration, and the affinity Kd was fitted using the steady state affinity model (1:1 binding model) using Biacore T200 Evaluation Software.

[0386] The prepared compounds were subjected to SPR detection according to the above method. The test results are shown in Table 17.

[0387] Table 17. Binding response values ​​of compounds to BCL-XL

[0388] Note: + is used in the table to indicate the range of Kd values. The specific information is as follows:

[0389] +: 10μM-100μM;

[0390] ++:1μM-10μM;

[0391] +++:0.1μM-1μM;

[0392] ++++: <0.1 μM;

[0393] -:>100μM.

[0394] The experimental results show that the compounds of the present invention can effectively bind to the BCL-XL protein, thereby further inhibiting the activity of the BCL-XL protein. The compounds of the present invention can be used to prepare BCL-XL inhibitors and drugs for preventing and / or treating diseases related to BCL-XL protein activity.

[0395] In summary, the compounds provided by the present invention can effectively bind to the BCL-XL protein, thereby further inhibiting the activity of the BCL-XL protein. The compounds of the present invention can be used to prepare BCL-XL inhibitors, as well as drugs for preventing and / or treating diseases associated with BCL-XL protein activity (e.g., cancer, autoimmune diseases, etc.), and have broad prospects for clinical application. The compounds of the present invention have favorable pharmacological properties, good stability, and a high potential for drug development. Furthermore, the compounds are simple to prepare, with high yields and low costs, making them suitable for industrial production.

[0396] Although the specific embodiments of the present invention have been described in detail, those skilled in the art will understand that various modifications and substitutions can be made to those details based on all the teachings disclosed, and these changes are all within the scope of protection of the present invention. The full scope of the present invention is given by the appended claims and any equivalents thereof.

Claims

1. A compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, characterized in that: The structure of the compound is shown in Formula I: X1 and X2 are independently selected from N or CR x ; R x are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, -OH, -O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl); Said n1 and n2 are independently selected from 0, 1 or 2; The R1 is selected from 8-12 membered fused heteroaromatic ring, -NH (6-12 membered fused heteroaromatic ring), Preferably, the 8-12 membered fused heteroaromatic ring is R 10 Selected from hydrogen, halogen, cyano, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 alkyl); R 11 Selected from hydrogen, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-C(O)NH(C 1～10 Alkyl), -C 0～2 Alkylene-C(O)N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-O-(C 6～10 aromatic ring), -C 0～2 Alkylene-O-(5-10 membered aromatic heterocycle); R 12 Selected from hydrogen, halogen, cyano, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-C(O)NH(C 1～10 Alkyl), -C 0～2 Alkylene-C(O)N(C 1～10 Alkyl)(C 1～10 alkyl); Or, R 11 、R 12 Together with the atoms connected to it, they form a 3-10 membered carbon ring, a 3-10 membered heterocyclic ring, a C 6～10 Aromatic ring, 5 to 10 The carbocyclic ring, heterocyclic ring, aromatic ring, aromatic heterocyclic ring are unsubstituted or replaced by one, two or three independent halogen, oxo, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 alkyl) or -N(C 1～10 Alkyl)(C 1～10 alkyl) substituted; The R 13 Selected from hydrogen, halogen, cyano, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 alkyl); R 14 Selected from hydrogen, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 alkyl); Or, R 13 、R 14 Together with the atoms it is connected to form C 6～10 Aromatic ring, 5-10 membered aromatic heterocycle; The R 15 Selected from -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); The R 16 Selected from hydrogen, halogen, cyano, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-C(O)NH(C 1～10 Alkyl), -C 0～2 Alkylene-C(O)NH(C 6～10 aromatic ring), -C 0～2 Alkylene-NHC(O)(C 1～10 Alkyl), -C 0～2 Alkylene-O-(C 6～10 aromatic ring), -C 0～2 Alkylene-O-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-NHS(O)O(C 1～10 alkyl); R 17 Selected from hydrogen, halogen, cyano, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-C(O)NH(C 1～10 Alkyl), -C 0～2 Alkylene-C(O)N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-NHC(O)(C 1～10 Alkyl), -C 0～2 Alkylene-NHS(O)O(C 1～10 alkyl); R 16 、R 17 Not simultaneously hydrogen; The R2 is selected from hydrogen, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 Alkyl); the alkyl group is unsubstituted or substituted by one, two or three independent R 21 replace; The R 21 Selected from halogen, -OH, -O(C 1～10 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); One of A and B is CR 4 R 5 , the other is NR3; R 4 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 alkyl; R 5 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 alkyl; R3 is selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-C(O)R 31 、-C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is unsubstituted or replaced by one, Two or three independent R 32 replace; The R 31 Selected from hydrogen, -C 1～10 Alkyl, halogen-substituted C 1～10 Alkyl, halogen, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(8-12 membered fused heteroaromatic ring), -C 0～2 Alkylene-(9-12 membered fused aromatic ring); the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is unsubstituted or replaced by one, two or three independent R 32’ replace; The R 32 and the R 32’ Each independently selected from carboxyl, halogen, cyano, carbonyl, nitro, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -OH, -O(C 1～10 Alkyl), -O(halogen substituted C 1～6 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-O-(C 6～10 aromatic ring), -C 0～2 Alkylene-O-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(8-12 membered fused heteroaromatic ring), -C 0～2 Alkylene-C(O)OLi, -C 0～2 Alkylene-C(O)OH, -C 0～2 Alkylene-C(O)NHR 33 、-C 0～2 Alkylene-NHC(O)R 33 The alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is unsubstituted or replaced by one, two or three independent R 33’ replace; The R 33 and the R 33’ are independently selected from hydrogen, carboxyl, halogen, -C 1～10 Alkyl, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-NR 34 R 35 、-C 0～2 Alkylene-NHC(O)R 34 、-C 0～4 Alkylene-C(O)NHR 34 、-C 0～2 Alkylene-NHC(O)OR 34 The alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is unsubstituted or replaced by one, two or three independent R 34’ replace; The R 34 and the R 34’ are each independently selected from hydrogen, halogen, -C 1～10 Alkyl, -C 2～10 Alkenyl, -C 2～10 Alkynyl, -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-NHC(O)R 35 、-C 0～2 Alkylene-C(O)NHR 35 The alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is unsubstituted or replaced by one, two or three independent R 35’ replace; The R 35 and the R 35’ are each independently selected from hydrogen, halogen, -C 1～10 Alkyl, -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-NHC(O)R 36 、-C 0～2 Alkylene-C(O)NHR 36 、-C 0～2 Alkylene-C(O)OR 36 、-C 0～2 Alkylene-C(O)R 36 The alkylene, alkyl, cycloalkyl, heterocycloalkyl is unsubstituted or replaced by one, two or three independent R 36’ replace; The R 36 and the R 36’ are each independently selected from hydrogen, halogen, -C 1～10 Alkyl, -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl).

2. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The structure of the compound is shown in Formula IIa, Formula IIb, Formula IIc, Formula IId or Formula IIe: Wherein, R1, R2, and R3 are as described in claim 1.

3. The compound according to any one of claims 1 to 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, characterized in that: The R 10 Selected from hydrogen, -OH, halogen, -C 1～6 alkyl; R 11 Selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene-C(O)NH(C 1～6 Alkyl), -C 0～2 Alkylene-O-(C6 aromatic ring); R 12 Selected from hydrogen, halogen, -C 1～6 Alkyl, -C(O)NH(C 1～6 alkyl); Or, R 11 、R 12 Together with the atoms connected thereto, a 3-6 membered heterocyclic ring or a C6 aromatic ring is formed; the heterocyclic ring or aromatic ring is unsubstituted or substituted by one, two or three independent halogens, hydroxyls, oxo, -C 1～6 Alkyl or halogen substituted C 1～6 Alkyl substitution; The R 13 Selected from hydrogen, halogen, cyano, -C 1～6 alkyl; R 14 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～6 alkyl); Or, R 13 、R 14 Together with the atoms to which it is connected, it forms a C6 aromatic ring or a 5- to 6-membered aromatic heterocyclic ring; The R 15 Selected from -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(C6 aromatic ring), -C 0～2 Alkylene-(5- to 6-membered aromatic heterocycle); The R 16 Selected from hydrogen, halogen, -C 1～6 Alkyl, -C 0～2 Alkylene-C(O)NH(C6 aromatic ring), -C 0～2 Alkylene-NHC(O)(C 1～6 Alkyl), -C 0～2 Alkylene-NHS(O)O(C 1～6 alkyl); R 17 Selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene-C(O)NH(C 1～6 Alkyl), -C 0～2 Alkylene-C(O)N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-NHC(O)(C 1～6 Alkyl), -C 0～2 Alkylene-NHS(O)O(C 1～6 alkyl); R 16 、R 17 Not hydrogen at the same time.

4. The compound according to claim 3, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The R1 is selected from 5. The compound according to any one of claims 1 to 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, characterized in that: The R2 is selected from hydrogen, -OH, -O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl); the alkyl group is unsubstituted or substituted by one, two or three independent R 21 replace; The R 21 Selected from halogen, -C 0～2 Alkylene-(C6 aromatic ring), -C 0～2 Alkylene-(5- to 6-membered aromatic heterocycle).

6. The compound according to claim 5, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The R2 is selected from hydrogen, -OH, Methoxy or 7. The compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, characterized in that: Said R3 is selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene-C(O)R 31 、-C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); the alkylene, alkyl, aromatic ring, aromatic heterocycle are unsubstituted or replaced by one, two or three independent R 32 replace; The R 31 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(8-12 membered fused heteroaromatic ring), -C 0～2 Alkylene-(9-12 membered fused aromatic ring); the alkylene, alkyl, aromatic ring, aromatic heterocycle are unsubstituted or replaced by one, two or three independent R 32’ replace; The R 32 and the R 32’ Each independently selected from carboxyl, halogen, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -OH, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -C 0～2 Alkylene-O-(C 6～10 aromatic ring), -C 0～2 Alkylene-O-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(8-12 membered fused heteroaromatic ring), -C 0～2 Alkylene-C(O)OLi, -C 0～2 Alkylene-C(O)OH, -C 0～2 Alkylene-C(O)NHR 33 、-C 0～2 Alkylene-NHC(O)R 33 The alkylene, alkyl, alkenyl, alkynyl, aromatic ring, aromatic heterocycle is unsubstituted or replaced by one, two or three independent R 33’ replace; The R 33 and the R 33’ are each independently selected from hydrogen, halogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-NR 34 R 35 、-C 0～2 Alkylene-NHC(O)R 34 、-C 0～4 Alkylene-C(O)NHR 34 、-C 0～2 Alkylene-NHC(O)OR 34 The alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is unsubstituted or replaced by one, two or three independent R 34’ replace; The R 34 and the R 34’ are each independently selected from hydrogen, halogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-NHC(O)R 35 、-C 0～2 Alkylene-C(O)NHR 35 The alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is unsubstituted or replaced by one, two or three independent R 35’ replace; The R 35 and the R 35’ are each independently selected from hydrogen, halogen, -C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-C(O)OR 36 、-C 0～2 Alkylene-C(O)R 36 The alkylene, alkyl, heterocycloalkyl group is unsubstituted or replaced by one, two or three independent R 36’ replace; The R 36 and the R 36’ are each independently selected from hydrogen, halogen, -C 1～6 alkyl.

8. The compound according to claim 7, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The R3 is selected from: The R 32 are independently selected from hydrogen, carboxyl, halogen, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -C 0～2 Alkylene-O-(C 6～10 aromatic ring), -C 0～2 Alkylene-O-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-(8-12 membered fused heteroaromatic ring), -C 0～2 Alkylene-C(O)OLi, -C 0～2 Alkylene-C(O)OH, -C 0～2 Alkylene-C(O)NHR 33 The alkylene, alkyl, alkenyl, alkynyl, aromatic ring, aromatic heterocycle is unsubstituted or replaced by one, two or three independent R 33’ replace; The R 33 and the R 33’ are each independently selected from hydrogen, halogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(C 6～10 aromatic ring), -C 0～2 Alkylene-NR 34 R 35 、-C 0～2 Alkylene-NHC(O)R 34 、-C 0～4 Alkylene-C(O)NHR 34 、-C 0～2 Alkylene-NHC(O)OR 34 The alkylene, alkyl, alkenyl, alkynyl, heterocycloalkyl, aromatic ring is unsubstituted or replaced by one, two or three independent R 34’ replace; The R 34 and the R 34’ are each independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkynyl, -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-NHC(O)R 35 The alkylene, alkyl, alkynyl, heterocycloalkyl group is unsubstituted or replaced by one, two or three independent R 35’ replace; The R 35 and the R 35’ are each independently selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-C(O)OR 36 、-C 0～2 Alkylene-C(O)R 36 The alkylene, alkyl, heterocycloalkyl group is unsubstituted or replaced by one, two or three independent R 36’ Substituted; said R 36 and the R 36’ are each independently selected from hydrogen, -C 1～6 alkyl; Preferably, said R3 is The R 32 Selected from carboxyl, -C2 alkenyl, -C 0～2 Alkylene-O-phenyl, -C 0～2 Alkylene-benzimidazolyl, -C 0～2 Alkylene-C(O)NHR 33 The alkylene, alkenyl, phenyl, benzimidazolyl is unsubstituted or replaced by one, two or three independent R 33’ replace; The R 33 and the R 33’ are each independently selected from hydrogen, halogen, -C 1～3 Alkyl, -C2 alkynyl, -C 0～2 Alkylene-phenyl, -C 0～2 Alkylene-piperidinyl, -C 0～2 Alkylene-NHC(O)R 34 、-C 0～4 Alkylene-C(O)NHR 34 The alkylene, alkyl, alkynyl, phenyl, piperidinyl is unsubstituted or substituted by one, two or three independent R 34’ replace; The R 34 and the R 34’ are each independently selected from hydrogen, -C 1～2 Alkyl, -N(C 1～2 Alkyl)(C 1～2 Alkyl), -C 0～2 Alkylene-piperazinyl; the alkylene, alkyl, piperazinyl is unsubstituted or substituted by one, two or three independent R 35’ replace; The R 35’ Selected from hydrogen, -C 1～2 Alkyl, -C 0～2 Alkylene-C(O)OR 36 The alkyl group is unsubstituted or substituted by one, two or three independent R 36’ Substituted; said R 36 and the R 36’ Selected from hydrogen, -C 1～4 alkyl; Or preferably, said R3 is The R 32 Selected from hydrogen, phenyl; the phenyl is unsubstituted or substituted by one, two or three independent R 33’ replace; The R 33’ Selected from hydrogen, halogen, -C 1～6 Alkyl, -C 2～6 Alkynyl, -C 0～2 Alkylene-piperidinyl, -C 0～2 Alkylene-NHC(O)R 34 、-C 0～4 Alkylene-C(O)NHR 34 、-C 0～2 Alkylene-NHC(O)OR 34 The alkylene, alkyl, alkynyl, piperidinyl is unsubstituted or replaced by one, two or three independent R 34’ replace; The R 34 and the R 34’ are each independently selected from hydrogen, -C 1～2 Alkyl, piperazinyl, -N(C 1～2 Alkyl)(C 1～2 Alkyl); the alkyl group, the piperazinyl group are unsubstituted or replaced by one, two or three independent R 35’ replace; The R 35’ Selected from hydrogen, -C 0～2 Alkylene-C(O)R 36 The alkylene group is unsubstituted or substituted by one, two or three independent R 36’ Substituted; said R 36 and the R 36’ are each independently selected from hydrogen, -C 1～2 alkyl.

9. The compound according to claim 8, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The R3 is selected from: Preferably, said R3 is selected from:

10. The compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, characterized in that: The structure of the compound is shown in Formula III: Preferably, R2 is selected from hydrogen, 11. The compound according to claim 10, or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: The R 31 Selected from: Preferably, the R 31 Selected from:

12. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The structure of the compound is selected from:

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, and a pharmaceutically acceptable excipient.

14. Use of the compound according to any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, or the pharmaceutical composition according to claim 13 in the preparation of a BCL-XL inhibitor.

15. The pharmaceutical use according to claim 14, characterized in that: The BCL-XL inhibitor is capable of binding to the BCL-XL protein.

16. The pharmaceutical use according to claim 14 or 15, characterized in that: The BCL-XL inhibitor is a drug for preventing and / or treating diseases related to BCL-XL protein activity.

17. The pharmaceutical use according to claim 16, characterized in that: The disease associated with BCL-XL protein activity is an autoimmune disease, bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, follicular lymphoma, lymphoid malignancies of T cell or B cell origin, melanoma, myeloma, oral cancer, ovarian cancer, leukemia, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer; the leukemia is preferably chronic lymphocytic leukemia, progenitor lymphocytic leukemia or granulocytic leukemia.

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