Heteroaromatic ring compounds and their use

Abstract

This invention provides heterocyclic compounds having the structure shown in Formula (I), pharmaceutically acceptable salts thereof, or stereoisomers thereof, as well as pharmaceutical compositions and applications thereof. The heterocyclic compounds and their pharmaceutically acceptable salts and isomers provided by this invention can effectively inhibit the activity of RET kinases, including wild-type and various mutant RET kinases, especially G810C and G810R mutant RET kinases, thereby regulating the activation of multiple downstream pathways. These compounds can be used to prepare drugs for the prevention and treatment of various diseases related to abnormal RET kinase expression, such as leukemia and other tumors.

Description

Heterocyclic aromatic compounds and their applications

[0001] This invention claims priority to Chinese Patent Application No. 2024114701392, filed on October 21, 2024, entitled "Heteroaromatic Compounds and Their Applications", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of medicinal chemistry, specifically to a heterocyclic aromatic compound and its applications. Background Technology

[0003] Receptor tyrosine kinase RET (Rearranged during transfection) plays a crucial role in the development of the kidneys and nervous system. RET can activate downstream signaling pathways through gene fusion, point mutations, and overexpression. When abnormally activated, it can act as an oncogene in various malignancies. Specifically, RET fusions that retain the kinase domain are driving factors in cancers such as papillary thyroid carcinoma (PTC) and non-small cell lung cancer (NSCLC); while activating RET mutations are associated with different phenotypes in multiple endocrine neoplasia type 2 (MEN2) and sporadic medullary thyroid carcinoma (MTC). Therefore, RET is an attractive therapeutic target for patients with cancer caused by RET alterations.

[0004] Early multi-kinase inhibitors (MKIs) with RET inhibitor activity, such as cabozantinib and vandetanib, have been explored in clinical trials for RET-driven cancers. However, these MKIs, due to their low targeting specificity, are prone to producing off-target side effects such as hypertension and diarrhea, limiting the tolerable dose for patients. Selpercatinib, a highly selective RET kinase inhibitor developed by Loxo Oncology, was approved by the FDA in May 2020 for the treatment of advanced RET fusion-positive NSCLC and RET mutant / fusion-positive MTC. Another highly selective RET kinase inhibitor, Pralsetinib, developed by Blueprint Medicines, was approved by the FDA in September 2020. In vitro studies have shown that Pralsetinib has significantly better RET selectivity than other multi-target inhibitors, exhibits better tolerability, and only has a slight inhibitory effect on VEGFR-2, making it suitable for the treatment of adult patients with RET fusion-positive NSCLC.

[0005] Despite the high activity and selectivity of Selpercatinib and Pralsetinib against RET, the development of selective inhibitors with novel structures targeting RET gene fusions, overexpression, or key site mutations such as the V804M mutation remains of significant research value. Furthermore, RET G810R, S, and C solvent front mutations have been confirmed as acquired resistance mechanisms in RET patients who have progressed with selective RET inhibitors (Solomon, Benjamin J. et al. J Thorac Oncol. 2020, 15(4), 541-549). Therefore, developing new RET inhibitors to inhibit these mutations is essential and of great research significance. Summary of the Invention

[0006] To address the above problems, this invention provides a new class of heterocyclic aromatic compounds that exhibit excellent inhibitory activity against both wild-type and mutant RET kinases.

[0007] The specific technical solution is as follows:

[0008] In one aspect, the present invention relates to a heterocyclic compound having the structure shown in formula (I) or a pharmaceutically acceptable salt thereof, its stereoisomer, its solvent compound, its prodrug, and its deuterated compound:

[0009] Where n is selected from: 0, 1, 2

[0010] U1 and U2 are independently selected from: -NH-, -CH2-, or one of U1 and U2 is absent, and the other is -NH- or -CH2-;

[0011] Q is selected from: O;

[0012] L1 does not exist or is selected from: -O-, -CONR7-, -NR7CO-, -C(R7)2-NR7-, -C(R7)2-C(R7)2-, -C(R7)=C(R7)-,

[0013] L2 does not exist or is selected from: -CONR7-, -NR7CO-, -C(R7)2-NR7-, -C(R7)2-C(R7)2-, -C(R7)=C(R7)-, L1 and L2 cannot both be absent at the same time;

[0014] Y1, Y2, Y3, Y4 and Y5 are independently selected from: N, C=O, NR1, CR, respectively, and the G ring composed of Y1, Y2, Y3, Y4 and Y5 is an aromatic ring or a heteroaromatic ring;

[0015] X1, X2, X3, X4, X5, and X6 are independently selected from N, NR1, C=O, and CR8, respectively, and the B ring formed by X1, X2, X3, X4, X5, and X6 is an aromatic ring or a heteroaromatic ring;

[0016] Z1, Z2, Z3, and Z4 are independently selected from N, NR1, C=O, O, S, and CR9, respectively, and the A ring formed by Z1, Z2, Z3, and Z4 is an aromatic ring or a heteroaromatic ring;

[0017] V1, V2, and V3 are independently selected from N, O, NR1, and CR1, respectively, and the E ring composed of V1, V2, and V3 is a heteroaromatic ring;

[0018] Each R1 is independently selected from: H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylacyl, or two adjacent R1 substituents linked together to form R. 11 Substituted or unsubstituted 5-8 membered heterocyclic alkyl, heteroaryl, heteroaryl ketone or cycloalkyl groups;

[0019] Each R is independently selected from: H, OH, halogen, R 12 Substituted or unsubstituted C1-C8 alkyl, R 12 Substituted or unsubstituted C1-C8 alkoxy groups, R 12 Substituted or unsubstituted C1-C8 alkylamine groups, R 12 Substituted or unsubstituted C3-C8 cycloalkyl, R 12 Substituted or unsubstituted C3-C8 cycloalkyloxy groups, R 12 Substituted or unsubstituted C3-C8 cycloalkylamine groups, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups: oxygen, cyano, nitro, amino, aminosulfonyl, C1-C8 alkylaminosulfonyl, -C(=O)R 10 Or two adjacent R substituents can be linked together to form R. 11 Substituted or unsubstituted 5-8 membered heterocyclic alkyl, heteroaryl, or cycloalkyl groups; or, R1 substituents on adjacent R and G rings linked together to form R. 11 Substituted or unsubstituted 5-8 membered heterocyclic alkyl, heteroaryl or cycloalkyl groups;

[0020] Each R7 is independently selected from: H, C1-C8 alkyl, halogen-substituted C1-C8 alkyl, and C3-C8 cycloalkyl;

[0021] Each R8 group is independently selected from: H, OH, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamine, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, C3-C8 cycloalkylamine, halogen-substituted C1-C8 alkyl, halogen-substituted C1-C8 alkoxy, halogen-substituted C1-C8 alkylamine, halogen-substituted C3-C8 cycloalkyl, halogen-substituted C3-C8 cycloalkyloxy, halogen-substituted C3-C8 cycloalkylamine, cyano, nitro, amino, aminosulfonyl, -C(=O)R 10 ;

[0022] R9 is selected from: H, halogen, R 12 Substituted or unsubstituted C1-C8 alkyl, R 12 Substituted or unsubstituted C1-C8 alkoxy groups, R 12 Substituted or unsubstituted C1-C8 alkylamine groups, R 12 Substituted or unsubstituted C3-C8 cycloalkyl, R 12 Substituted or unsubstituted C3-C8 cycloalkyloxy, C3-C8 cycloalkylamine carbonyl, C1-C8 alkylamine carbonyl, C1-C8 alkoxy carbonyl, C1-C8 alkylacyl, C1-C8 alkamido, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups, cyano groups, carbamoyl groups, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups -O-, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups -C(=O)-, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups -N(R1)-, R 12 Substituted or unsubstituted 5-8 membered heteroaryl groups;

[0023] Each R 10 Each of the following is independently selected from: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, C3-C8 cycloalkoxy, C3-C8 cycloalkylamino, halogen-substituted C1-C8 alkyl, halogen-substituted C1-C8 alkoxy, halogen-substituted C1-C8 alkylamino, halogen-substituted C3-C8 cycloalkoxy, halogen-substituted C3-C8 cycloalkylamino, hydroxyl, and amino;

[0024] Each R 11 Each of the following is independently selected from: hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, C3-C8 cycloalkoxy, C3-C8 cycloalkylamino, halogen-substituted C1-C8 alkyl, halogen-substituted C1-C8 alkoxy, halogen-substituted C1-C8 alkylamino, halogen-substituted C3-C8 cycloalkoxy, halogen-substituted C3-C8 cycloalkylamino, hydroxyl, and amino;

[0025] Each R 12 Each is independently selected from: hydrogen, halogen, hydroxyl, amino, cyano, C1-C8 alkyl, halogen-substituted C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, C3-C8 cycloalkoxy, C3-C8 cycloalkylamino, 3-8 membered heterocyclic, C3-C8 cycloalkyl, halogen-substituted 3-8 membered heterocyclic, halogen-substituted C3-C8 cycloalkyl, C1-C8 alkyl-substituted 3-8 membered heterocyclic, and C1-C8 alkyl-substituted C3-C8 cycloalkyl.

[0026] In some embodiments of the present invention, ring B is selected from: Wherein, m is selected from: 0, 1, 2, 3, 4; preferably, ring B is selected from: More preferably, the R8 substituent on ring B is located ortho to the -U1(=Q)U2- group.

[0027] In some embodiments of the present invention, ring A is selected from: Where x is selected from: 0, 1, 2, 3, 4.

[0028] In some embodiments of the present invention, ring A is selected from:

[0029] In some embodiments of the present invention, the E ring is selected from: Among them, W1, W2, W3, and W4 are independently selected from: N, O, C=O, NH, and CR, respectively. 11 .

[0030] In some embodiments of the present invention, the E ring is selected from:

[0031] In some embodiments of the present invention, the E ring is selected from: More preferably

[0032] In some embodiments of the present invention, the G ring is selected from:

[0033] Among them, Y2 is selected from: N, CR5;

[0034] Y3 is selected from: N, CR6;

[0035] R2, R3, R4, R5, and R6 are each independently selected from: H, OH, halogen, R 12 Substituted or unsubstituted C1-C8 alkyl, R 12 Substituted or unsubstituted C1-C8 alkoxy groups, R 12Substituted or unsubstituted C1-C8 alkylamine groups, R 12 Substituted or unsubstituted C3-C8 cycloalkyl, R 12 Substituted or unsubstituted C3-C8 cycloalkyloxy groups, R 12 Substituted or unsubstituted C3-C8 cycloalkylamine groups, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups: oxygen, cyano, nitro, amino, aminosulfonyl, C1-C8 alkylaminosulfonyl, -C(=O)R 10 Alternatively, two substituents from R2, R3, R4, R5, and R6 may be linked together to form R. 11 Substituted or unsubstituted 5-8 membered heterocyclic alkyl, heteroaryl or cycloalkyl.

[0036] In some embodiments of the present invention, the G ring is selected from:

[0037] In some embodiments of the present invention, the heterocyclic compound has the structure shown in formula (II) or formula (III):

[0038] In some embodiments of the present invention, the heterocyclic compound has the structure shown in formula (IV), formula (IV-2), or formula (V):

[0039] In some embodiments of the present invention, the heterocyclic compound has the structure shown in formula (VI), formula (VI-1), or (VII):

[0040] In some embodiments of the present invention, the heterocyclic compound has the structure shown in formula (VIII), formula (VIII-2), formula (IX), formula (IX-2), formula (X), or formula (XI):

[0041] In some embodiments of the present invention, the heterocyclic compound has the structure shown in formula (XII), formula (XII-2), formula (XIII), formula (XIII-2), formula (XIV), or formula (XV):

[0042] In some embodiments of the present invention, L1 is selected from: -O-, -CONR7-, -NR7CO-, -C(R7)2-NR7-, -C(R7)2-C(R7)2-, -C(R7)=C(R7)-,

[0043] L2 does not exist;

[0044] Each R7 is independently selected from: H, methyl, ethyl, propyl, and trifluoromethyl.

[0045] In some embodiments of the present invention, L1 is selected from: -O-, -CONH-, -NHCO-, -CH2-NH-, -CH2CH2-, -CH=CH-, More preferably

[0046] In some embodiments of the present invention, U1, U2, and Q are collectively formed.

[0047] In some embodiments of the present invention, R1 on the E ring is selected from: H, methyl, ethyl, propyl; or two adjacent R1 substituents on the E ring are connected to form R. 11 Substituted 5-6 membered heterocyclic alkyl or heteroaryl, wherein R 11 Selected from: hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, hydroxyl, amino; R1 on the E ring is preferably hydrogen.

[0048] In some embodiments of the present invention, each R8 is independently selected from: H, OH, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamine, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylamine, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkylamine, halogen-substituted C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyloxy, halogen-substituted C3-C6 cycloalkylamine, cyano, nitro, amino, aminosulfonyl, -C(=O)R 10 ;

[0049] Each R in R8 10 Each of the following is independently selected from: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, C3-C6 cycloalkoxy, C3-C6 cycloalkylamino, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkylamino, halogen-substituted C3-C6 cycloalkoxy, halogen-substituted C3-C6 cycloalkylamino, hydroxyl, and amino;

[0050] The halogen is either chlorine or fluorine.

[0051] In some embodiments of the present invention, each R8 is independently selected from: H, OH, fluorine, chlorine, bromine, trifluoromethyl, methoxy, ethoxy, methyl, ethyl.

[0052] In some embodiments of the present invention, each R8 is independently selected from: H, OH, halogen, C1-C3 alkyl.

[0053] In some embodiments of the present invention, each R8 is independently selected from: H, OH, fluorine, chlorine, methyl, ethyl.

[0054] In some embodiments of the present invention, R is selected from: H, OH, halogen, R 12 Substituted or unsubstituted C1-C3 alkyl groups, R 12 Substituted or unsubstituted C1-C3 alkoxy groups, R 12 Substituted or unsubstituted C1-C3 alkylamine groups, R 12 Substituted or unsubstituted C3-C6 cycloalkyl, R 12 Substituted or unsubstituted C3-C6 cycloalkyloxy groups, R 12 Substituted or unsubstituted C3-C6 cycloalkylamine groups, R 12 Substituted or unsubstituted 3-6 membered heterocyclic groups, R 12 Substituted or unsubstituted 3-6 membered heterocyclic groups: oxy, cyano, nitro, amino, aminosulfonyl, C1-C3 alkylaminosulfonyl, -C(=O)R 10 Or two adjacent R substituents can be linked together to form R. 11 Substituted or unsubstituted 5-6 membered heterocyclic alkyl, heteroaryl, or cycloalkyl groups; or, R1 substituents on adjacent R and G rings linked together to form R. 11 Substituted or unsubstituted 5-6 membered heterocyclic alkyl, heteroaryl, or cycloalkyl groups;

[0055] Each R in R 10 Each of the following is independently selected from: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, C3-C6 cycloalkoxy, C3-C6 cycloalkylamino, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkylamino, halogen-substituted C3-C6 cycloalkoxy, halogen-substituted C3-C6 cycloalkylamino, hydroxyl, and amino;

[0056] Each R in R 12 Each of the following is independently selected from: hydrogen, fluorine, chlorine, hydroxyl, amino, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, C3-C6 cycloalkoxy, C3-C6 cycloalkylamino, 3-6 membered heterocyclic, C3-C6 cycloalkyl, halogen-substituted 3-6 membered heterocyclic, halogen-substituted C3-C6 cycloalkyl, C1-C3 alkyl-substituted 3-6 membered heterocyclic, and C1-C3 alkyl-substituted C3-C6 cycloalkyl.

[0057] In some embodiments of the present invention, R is selected from: H, methyl, ethyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, oxacyclobutoxy, hydroxyl, fluorine, chlorine, cyano, trifluoromethyl, trifluoromethoxy, methylaminocarbonyl, aminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, methoxycarbonyl, carboxyl, ethoxycarbonyl, Dimethylamino, methylamino, amino, hydroxymethyl, methylaminosulfonyl, aminosulfonyl; or, two adjacent R substituents linked together to form or Or, adjacent R and R1 substituents may be linked together to form...

[0058] In some embodiments of the present invention, R2, R3, R4, R5, and R6 are each independently selected from: H, OH, halogens, R... 12 Substituted or unsubstituted C1-C3 alkyl groups, R 12 Substituted or unsubstituted C1-C3 alkoxy groups, R 12 Substituted or unsubstituted C1-C3 alkylamine groups, R 12 Substituted or unsubstituted C3-C6 cycloalkyl, R 12 Substituted or unsubstituted C3-C6 cycloalkyloxy groups, R 12 Substituted or unsubstituted C3-C6 cycloalkylamine groups, R 12 Substituted or unsubstituted 3-6 membered heterocyclic groups, R 12 Substituted or unsubstituted 3-6 membered heterocyclic groups: oxy, cyano, nitro, amino, aminosulfonyl, C1-C3 alkylaminosulfonyl, -C(=O)R 10 Alternatively, two adjacent substituents from R2, R3, R4, R5, and R6 may connect to form R. 11 Substituted or unsubstituted 5-6 membered heterocyclic alkyl, heteroaryl, or cycloalkyl groups;

[0059] Each of R2, R3, R4, R5, and R6 10 Each of the following is independently selected from: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, C3-C6 cycloalkoxy, C3-C6 cycloalkylamino, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkylamino, halogen-substituted C3-C6 cycloalkoxy, halogen-substituted C3-C6 cycloalkylamino, hydroxyl, and amino;

[0060] Each of R2, R3, R4, R5, and R6 12Each of the following is independently selected from: hydrogen, fluorine, chlorine, hydroxyl, amino, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, C3-C6 cycloalkoxy, C3-C6 cycloalkylamino, 3-6 membered heterocyclic, C3-C6 cycloalkyl, halogen-substituted 3-6 membered heterocyclic, halogen-substituted C3-C6 cycloalkyl, C1-C3 alkyl-substituted 3-6 membered heterocyclic, and C1-C3 alkyl-substituted C3-C6 cycloalkyl.

[0061] In some embodiments of the present invention, R2, R3, R4, R5, and R6 are independently selected from: H, methyl, ethyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, oxacyclobutoxy, hydroxyl, fluorine, chlorine, cyano, trifluoromethyl, trifluoromethoxy, methylaminocarbonyl, aminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, methoxycarbonyl, carboxyl, ethoxycarbonyl, etc. Dimethylamino, methylamino, amino, hydroxymethyl, methylaminosulfonyl, aminosulfonyl; or, two adjacent substituents from R2, R3, R4, R5, and R6 linked together to form or

[0062] In some embodiments of the present invention, R2 is selected from: H, methoxy, fluorine, cyano, methylaminocarbonyl, ethylaminocarbonyl, methoxycarbonyl, aminocarbonyl, trifluoromethyl;

[0063] Both R3 and R4 are H; or R3 is hydrogen and R4 is fluorine or methoxy.

[0064] R5 is selected from: H, methoxy group;

[0065] R6 is selected from: H, methoxy, methylaminocarbonyl, ethylaminocarbonyl, cyclopropylaminocarbonyl, trifluoromethyl,

[0066] Or R6 and R2 are connected to form

[0067] In some embodiments of the present invention, Y3 is CR6.

[0068] In some embodiments of the present invention, Y2 is N, Y3 is CR6; R2 is methoxy or fluorine, and R6 is H or methoxy.

[0069] In some embodiments of the present invention, Y2 is CH, Y3 is CR6; R2 is hydrogen, methylaminocarbonyl, cyano, or methoxy, and R6 is H, methoxy, methylaminocarbonyl, ethylaminocarbonyl, cyclopropylaminocarbonyl, or... Or R6 and R2 are connected to form

[0070] In some embodiments of the present invention, the G ring is selected from:

[0071] In some embodiments of the present invention, G is selected from:

[0072] In some embodiments of the present invention, L is... G is selected from:

[0073] In some embodiments of the present invention, H, halogen, R 12 Substituted or unsubstituted C1-C4 alkyl groups, R 12 Substituted or unsubstituted C1-C3 alkoxy groups, R 12 Substituted or unsubstituted C1-C4 alkylamine groups, R 12 Substituted or unsubstituted C3-C6 cycloalkyl, R 12 Substituted or unsubstituted C3-C6 cycloalkyloxy, C3-C6 cycloalkylamine carbonyl, C1-C3 alkylamine carbonyl, C1-C3 alkoxy carbonyl, C1-C3 alkylacyl, C1-C3 alkamido, R 12 Substituted or unsubstituted 5-6 membered heterocyclic groups, cyano, carbamoyl, R 12 Substituted or unsubstituted 5-6 membered heterocyclic groups -O-, R 12 Substituted or unsubstituted 5-6 membered heterocyclic groups -C(=O)-, R 12 Substituted or unsubstituted 5-6 membered heterocyclic groups -N(R1)-, R 12 Substituted or unsubstituted 5-6 membered heteroaryl groups;

[0074] Each R 12 Each is independently selected from: hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkyl-substituted 5-6 membered heterocyclic group, 5-6 membered heterocyclic group, methylamino, and dimethylamino.

[0075] In some embodiments of the present invention, each R9 is independently selected from: hydrogen, methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, fluorine, chlorine, cyano, trifluoromethoxy, methylaminocarbonyl, methoxycarbonyl, acetamido, carbamoyl, formyl, methyl-substituted cyclopropyl, trifluoromethyl-substituted n-propyl, etc.

[0076] In some embodiments of the present invention, ring A is selected from:

[0077] In some embodiments of the present invention, L is... Ring A is selected from:

[0078] In some embodiments of the present invention, L is... Ring A is selected from:

[0079] Optimal

[0080] In some embodiments of the present invention, the heterocyclic compound has the structure shown in formula (A) or formula (B):

[0081] Among them, one of X1 and X2 is N, and the other is CH; R9 is selected from

[0082] The present invention also provides applications of the above-mentioned compounds, including the following technical solutions.

[0083] The use of the heterocyclic aromatic compounds or their pharmaceutically acceptable salts, stereoisomers, solvent compounds, prodrugs, and deuterated compounds described in this invention in the preparation of RET kinase inhibitors.

[0084] The use of the heterocyclic compounds or their pharmaceutically acceptable salts, stereoisomers, solvent compounds, prodrugs, and deuterated compounds described in this invention in the preparation of medicaments for the prevention and / or treatment of diseases associated with abnormal RET kinase expression.

[0085] In some embodiments of the present invention, the RET kinase is a wild-type RET kinase, a RET kinase carrying the V804M mutation, a RET kinase carrying the G810C mutation, and / or a RET kinase carrying the G810R mutation.

[0086] In some embodiments of the present invention, the disease associated with abnormal RET kinase expression is a tumor.

[0087] In some embodiments of the present invention, the tumor is: leukemia, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, gastric cancer, histiocytic lymphoma, nasopharyngeal carcinoma. Preferably, the tumor is chronic myeloid leukemia, gastric cancer, or lung adenocarcinoma.

[0088] Thirdly, the present invention also provides a pharmaceutical composition for the prevention and / or treatment of tumors, prepared from an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient includes the heterocyclic aromatic compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, solvent compounds, prodrugs, and deuterated compounds.

[0089] In a fourth aspect, the present invention provides a method for preventing and / or treating tumors, comprising: administering to a patient a safe and effective amount of the heterocyclic compound of the present invention or a pharmaceutically acceptable salt thereof, its stereoisomer, its solvent compound, its prodrug, or its deuterated compound; or administering to a patient a safe and effective amount of the pharmaceutical composition of the present invention for preventing and / or treating tumors.

[0090] In some embodiments of the present invention, the tumor is a tumor associated with abnormal RET kinase expression.

[0091] In some embodiments of the present invention, the RET kinase is a wild-type RET kinase, a RET kinase carrying the V804M mutation, a RET kinase carrying the G810C mutation, and / or a RET kinase carrying the G810R mutation.

[0092] In some embodiments of the present invention, the tumor is leukemia, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, gastric cancer, histiocytic lymphoma, or nasopharyngeal carcinoma. Preferably, the tumor is chronic myeloid leukemia, gastric cancer, or lung adenocarcinoma.

[0093] Based on the above technical solution, the present invention has the following beneficial effects:

[0094] The heterocyclic compounds and their pharmaceutically acceptable salts and isomers provided by this invention can effectively inhibit the activity of RET kinases, including wild-type and various mutant RET kinases, especially G810C and G810R mutant RET kinases, thereby regulating the activation of multiple downstream pathways. They can be used to prepare drugs for the prevention and treatment of various diseases related to abnormal RET kinase expression, such as leukemia and other tumors. Attached Figure Description

[0095] Figure 1 shows the test results of compound CQ1373 on cell apoptosis and cell cycle arrest. Detailed Implementation

[0096] In the compounds of this invention, when any variable (e.g., R8, etc.) appears more than once in any component, the definition of each occurrence is independent of the definition of each subsequent occurrence. Similarly, combinations of substituents and variables are permitted, provided such combinations stabilize the compound. A line drawn from a substituent into the ring system indicates that the bond referred to can be attached to any substituted ring atom. If the ring system is polycyclic, it means that such a bond is attached only to any suitable carbon atom of a neighboring ring. It is to be understood that those skilled in the art can select the substituents and substitution patterns of the compounds of this invention to provide chemically stable compounds that can be readily synthesized from readily available starting materials using techniques in the art and the methods described below. If a substituent is itself substituted by more than one group, it should be understood that these groups can be on the same carbon atom or different carbon atoms, as long as the structure is stable. The phrase "optionally substituted by one or more substituents" is considered equivalent to the phrase "optionally substituted by at least one substituent," and in this case, the preferred embodiment will have 0-3 substituents.

[0097] As used herein, the term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" includes groups with 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight or branched chain. Specifically, "C1-C6 alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The term "alkoxy" refers to a group having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc. The term "heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent in which one or more ring atoms are selected from heteroatoms of N, O, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon atoms. Examples include: morpholinyl, piperidinyl, piperazine, pyrrolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazine, dihydropyridinyl, dihydropyrimidinyl, dihydropyrroleyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophene, dihydrotriazolyl, dihydroazacyclobutane, tetrahydrofuranyl, tetrahydrothiophene, etc., and their N-oxides. The connection of heterocyclic substituents can be achieved through carbon atoms or through heteroatoms. The term "heteroaryl" or "heteroary ring" refers to an aromatic ring containing one or more heteroatoms selected from O, N, or S. Heteroaryl groups within the scope of this invention include, but are not limited to: quinolinyl, pyrazolyl, pyrroleyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, and pyridazinyl. They can also be understood as ketone compounds, for example: "Hyperaryl" is also understood to include any N-oxide derivative of a heteroaryl group containing nitrogen. The connection of heterocyclic substituents can be achieved through carbon atoms or through heteroatoms.

[0098] As will be understood by those skilled in the art, the term “halo” or “halogen” as used herein refers to chlorine, fluorine, bromine, and iodine.

[0099] Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic alkyl substituents may be unsubstituted or substituted. For example, C1-C6 alkyl groups may be substituted by one, two, or three substituents selected from OH, halogens, alkoxy groups, dialkylamino groups, or heterocyclic groups such as morpholino, piperidinyl, etc.

[0100] This invention includes the free forms of compounds of formulas (I)-(XV), as well as their pharmaceutically acceptable salts and stereoisomers. Some specific exemplary compounds described herein are protonated salts of amine compounds. The term "free form" refers to an amine compound in its non-salt form. Pharmaceutically acceptable salts include not only exemplary salts of the specific compounds described herein, but also typical pharmaceutically acceptable salts of the free forms of all compounds of formulas (I)-(XV). The free forms of specific salts of said compounds can be separated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous solution of a base, such as dilute aqueous solution of NaOH, potassium carbonate, dilute ammonia, or sodium bicarbonate. The free forms may differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention, such acid salts and base salts are otherwise pharmaceutically equivalent to their respective free forms.

[0101] Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing either a basic or acidic moiety using conventional chemical methods. Typically, salts of basic compounds are prepared by ion-exchange chromatography or by reacting a free base with a stoichiometric or excess amount of the desired salt form of an inorganic or organic acid in a suitable solvent or a combination of solvents. Similarly, salts of acidic compounds are formed by reacting with a suitable inorganic or organic base.

[0102] Therefore, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting an alkaline compound of the present invention with an inorganic or organic acid. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc., and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pyric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethylsulfonic acid, trifluoroacetic acid, etc.

[0103] If the compounds of this invention are acidic, then a suitable "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali, including inorganic and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary, and tertiary amines, wherein substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, guanidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, aminobutanetriol, etc.

[0104] Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci. '1977: 66: 1–19, describe in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

[0105] Since the deprotonated acidic portion of the compound, such as the carboxyl group, can be anionic under physiological conditions, and this charge can then be balanced by the protonated or alkylated basic portion, such as the tetravalent nitrogen atom, which carries a cation, it should be noted that the compounds of the present invention are potential internal salts or zwitterions.

[0106] The pharmaceutical composition or method for the prevention and / or treatment of tumors provided by this invention comprises (administered to a patient or subject) an active ingredient (i.e., the heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound as described in this invention) and pharmaceutically acceptable excipients within a safe and effective range, and administers them to the patient or subject. When administering the drug, a safe and effective amount of the active ingredient is given to the mammal (such as a human) requiring treatment, wherein the dose administered is a pharmaceutically considered effective dose. Of course, the specific dose should also consider factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise.

[0107] "Safe and effective dose" means that the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.

[0108] "Pharmaceutical acceptable excipients" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity.

[0109] "Compatibility" here refers to the ability of the components in the composition to interact with and blend with the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients.

[0110] Pharmaceutically acceptable examples of carriers or excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as...). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0111] There are no particular limitations on the administration of the active ingredients or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0112] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0113] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components:

[0114] (a) Fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol and silica;

[0115] (b) Adhesives, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

[0116] (c) Moisturizers, such as glycerin;

[0117] (d) Disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginate, certain complex silicates, and sodium carbonate;

[0118] (e) Slow solvents, such as paraffin;

[0119] (f) Absorption accelerators, such as quaternary ammonium compounds;

[0120] (g) Wetting agents, such as cetyl alcohol and glyceryl monostearate;

[0121] (h) Adsorbents, such as kaolin; and

[0122] (i) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain a buffer.

[0123] The solid dosage form can also be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient from this composition can be delayed in a portion of the digestive tract. Examples of suitable encapsulating components are polymers and waxes.

[0124] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. Besides these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0125] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0126] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0127] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Unless otherwise stated, percentages and parts are by weight. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar with the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0128] In this invention, the compound number consists of letters and numbers. The hyphens "-" between the letters and numbers are optional. The same compound is referred to by the same combination of letters and numbers, regardless of whether there is a hyphen in the middle. For example, "CQ1280" and "CQ-1280" refer to the same compound.

[0129] All reagents used in the following examples are commercially available.

[0130] Example 1: Preparation of compound CQ1280

[0131] Preparation of compound 1c:

[0132] Carbon tetrabromide (6.6 g, 20 mmol) and triphenylphosphine (10.5 g, 40 mmol) were dissolved in 100 mL of dichloromethane and cooled to 0 °C. Compound 1a (1.5 g, 10 mmol) was then slowly added. After the addition was complete, the mixture was allowed to react at room temperature overnight. After the reaction was complete, the mixture was evaporated to dryness, then slurried with petroleum ether, filtered, and the filtrate was collected and evaporated to dryness to obtain crude product 1b, which can be used directly in the next step without further purification.

[0133] The product obtained in the previous step was dissolved in 20 mL of N,N-dimethylformamide, cooled to 0 °C, and diethyl phosphite (3.9 mL, 30 mmol) and triethylamine (4.2 mL, 30 mmol) were added. The mixture was then moved to room temperature and reacted for 3 hours. After the starting material was exhausted, water was added, and the mixture was extracted with ethyl acetate. The organic phase was stirred with silica gel and separated by column chromatography to obtain 1.78 g of product 1c. The two-step yield was 78%.

[0134] 1 H NMR (400MHz, CDCl3) δ8.20(d,J=8.8Hz,2H),7.45(d,J=8.8Hz,2H),7.18(d,J=14.0Hz,1H),7.03(d,J=14.0Hz,1H).

[0135] Preparation of compound 1e:

[0136] Compound 1c (344 mg, 1.5 mmol), compound 1d (629 mg, 2.25 mmol), potassium carbonate (622 mg, 4.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (55 mg, 0.075 mmol) were mixed and, under argon protection, 6 mL of dioxane / water (5:1, v / v) was added. The mixture was then moved to 100 °C and reacted overnight. After the starting material was exhausted, water was added, and the mixture was extracted with ethyl acetate. The organic phase was stirred with silica gel and separated by column chromatography to obtain 320 mg of product 1e, with a yield of 71%.

[0137] 1H NMR (400MHz, CDCl3) δ8.23(d,J=8.8Hz,2H),7.61(d,J=8.8Hz,2H),7.53(d,J=1.6Hz,1H),7.31(d,J=16.4Hz,1H),7.08(d,J=16.4Hz,1H),6.60 (d,J=1.6Hz,1H),5.54(dd,J=9.2,2.8Hz,1H),4.01-4.10(m,1H),3.68-3.79(m,1H),2.37-2.50(m,1H),1.99-2.21(m,2H),1.68-1.78(m,3H).

[0138] Preparation of compound 1f:

[0139] Compound 1e (300 mg, 1 mmol) was dissolved in 3 mL of N,N-dimethylformamide, followed by the addition of N-iodosuccinimide (338 mg, 1.5 mmol) and p-toluenesulfonic acid (34 mg, 0.2 mmol). The reaction was carried out at room temperature for 8 hours. After the starting material was exhausted, the reaction was quenched with saturated sodium thiosulfate solution, extracted with ethyl acetate, washed with water, and the organic phase was mixed with silica gel. The mixture was then separated by column chromatography to obtain 350 mg of product 1f, with a yield of 82%.

[0140] 1 H NMR (400MHz, CDCl3) δ8.25(d,J=8.8Hz,2H),7.66(d,J=8.8Hz,2H),7.59(s,1H),7.46(d,J=16.8Hz,1H),7.19(d,J=16.8Hz,1H),5.47(d d,J=9.2,2.8Hz,1H),4.00-4.13(m,1H),3.63-3.79(m,1H),2.38-2.57(m,1H),2.10-2.21(m,1H),1.91-2.08(m,1H),1.61-1.83(m,3H).

[0141] Preparation of compound 1h:

[0142] Compound 1f (330 mg, 0.77 mmol), compound 1g (175 mg, 1.15 mmol), potassium carbonate (318 mg, 2.38 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (28 mg, 0.038 mmol) were mixed and, under argon protection, 3 mL of dioxane / water (5:1, v / v) was added. The mixture was then moved to 100 °C and reacted overnight. After the starting material was exhausted, water was added, and the mixture was extracted with ethyl acetate. The organic phase was stirred with silica gel and separated by column chromatography to obtain 306 mg of product in 1 h, with a yield of 98%.

[0143] 1 H NMR (400MHz, CDCl3) δ8.15-8.27(m,3H),7.59-7.67(m,2H),7.53(d,J=8.8Hz ,2H),7.20(d,J=16.4Hz,1H),6.98(d,J=16.4Hz,1H),6.79(d,J=8.4Hz,1H),5 .46(dd,J=9.6,2.8Hz,1H),4.11-4.19(m,1H),3.96(s,3H),3.69-3.79(m,1H) ,2.48-2.67(m,1H),2.13-2.24(m,1H),1.96-2.09(m,1H),1.62-1.85(m,3H).

[0144] Preparation of compound CQ-1280:

[0145] Compound 1h (300 mg, 0.74 mmol) was dissolved in 6 mL of dichloromethane, and then 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 3 hours. The solvent was evaporated to dryness, and the solution was neutralized with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was then dissolved in 10 mL of ethanol / water (4:1, v / v), and reduced iron powder (246 mg, 4.4 mmol) and ammonium chloride (321 mg, 6 mmol) were added. The mixture was then reacted at 80 °C for 3 hours. After the starting material was exhausted, the mixture was filtered through diatomaceous earth. The filtrate was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain 1 L of crude product. No further purification was required in this step, and the product was used directly in the next step.

[0146] The crude product 1L obtained in the previous step was dissolved in 3 mL of N,N-dimethylformamide, and then compound 1j (350 mg, 1.1 mmol), triethylamine (0.42 mL, 2.2 mmol) and 4-dimethylaminopyridine (12 mg, 0.07 mmol) were added. The mixture was then moved to 80 °C and reacted overnight. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The organic phase was stirred with silica gel and separated by column chromatography to obtain 103 mg of product CQ-1280. The two-step yield was 26%.

[0147] 1 H NMR (400MHz, DMSO) δ13.27&13.04(2s,1H),9.68(s,1H),8.96&8.92(2s,1H),8.17-8.33(m,1H),7.67- 7.98(m,2H),7.40-7.54(m,4H),7.20(d,J=16.4Hz,1H),6.87-7.05(m,3H),3.89(s,3H),1.56(s,6H).

[0148] Example 2: Preparation of compound CQ-1291

[0149] Preparation of compound 2b:

[0150] Compound 2a (1.5 g, 7.74 mmol), p-nitrophenylacetylene (2.2 g, 15.48 mmol), triethylamine (0.75 mL, 0.54 mmol), cuprous iodide (147.4 mg, 0.774 mmol), and tetraphenylphosphine palladium (447.2 mg, 0.387 mmol) were mixed under argon protection, and then 80 mL of tetrahydrofuran was added. The mixture was then moved to 60 °C and reacted overnight. After the reaction was completed, the mixture was stirred and separated by column chromatography to obtain 1.65 g of compound 2b, with a yield of 100%.

[0151] 1 H NMR (400MHz, DMSO) δ13.35(s,1H),8.26(d,J=8.4Hz,2H),7.88(s,1H),7.81(d,J=8.4Hz,2H),6.63(s,1H).

[0152] Preparation of compound 2c:

[0153] Compound 2b (1.65 g, 7.74 mmol) was dissolved in 80 mL of N,N-dimethylformamide and cooled to 0 °C. Then, N-iodosuccinimide (2.6 g, 11.6 mmol) was added. After the addition was complete, the mixture was allowed to react at room temperature overnight. When the starting material was exhausted, the reaction was quenched with saturated sodium thiosulfate solution, extracted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give 2.52 g of compound 2c, with a yield of 96%.

[0154] 1 H NMR (400MHz, DMSO) δ13.69 (s, 1H), 8.29 (d, J = 8.0Hz, 2H), 8.11 (s, 1H), 7.82 (d, J = 8.0Hz, 2H).

[0155] Preparation of compound 2d:

[0156] Compound 2c (2.52 g, 7.43 mmol) was dissolved in 70 mL of N-methylpyrrolidone, and potassium carbonate (1.43 g, 10.4 mmol) and di-tert-butyl dicarbonate (2.1 mL, 8.92 mmol) were added. The reaction was carried out at room temperature. After the starting material was exhausted, water was added, and the mixture was extracted with ethyl acetate. The organic phase was stirred with silica gel and separated by column chromatography to give 2.67 g of compound 2d, with a yield of 82%.

[0157] 1H NMR (400MHz, CDCl3) δ8.24(d,J=8.4Hz,2H),8.19(s,1H),7.74(d,J=8.8Hz,2H),1.66(s,9H).

[0158] Preparation of compound 2e:

[0159] Compound 2d (1.32 g, 3.14 mmol), compound 7 (624 mg, 4.08 mmol), potassium carbonate (1.08 g, 7.85 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (230 mg, 0.314 mmol) were mixed under argon protection, and then 32 mL of dioxane / water (5:1, v / v) was added. The mixture was then moved to 100 °C and reacted overnight. After the starting material was exhausted, the mixture was diluted with water, extracted with ethyl acetate, and the organic phase was stirred with silica gel. The mixture was separated by column chromatography to obtain 233 mg of compound 2e, with a yield of 23%.

[0160] 1 H NMR(400MHz,DMSO)δ13.58(s,1H),8.59(s,1H),8.25-8.35(m,3H),8.11(dd, J=8.4,2.4Hz,1H),7.82(d,J=8.4Hz,2H),6.94(d,J=8.8Hz,1H),3.88(s,3H).

[0161] Preparation of compound 2f:

[0162] Compound 2e (230 mg, 0.72 mmol), reduced iron powder (243 mg, 4.35 mmol), and ammonium chloride (233 mg, 4.35 mmol) were mixed and 10 mL of ethanol / water (4:1, v / v) was added. The mixture was then moved to 80 °C and reacted overnight. After the starting material was exhausted, the mixture was filtered. The filtrate was extracted with water and ethyl acetate. The organic phase was stirred with silica gel and separated by column chromatography to obtain 138 mg of compound 2f, with a yield of 66%.

[0163] 1 H NMR(400MHz,DMSO)δ13.46&13.23(2s,1H),8.60(s,1H),8.20&8.11(2s,1H),8.06&7.95(2s,1H) ,7.14-7.28(m,2H),6.90(d,J=8.4Hz,1H),6.51-6.62(m,2H),5.69&5.59(2s,2H),3.86(s,3H).

[0164] Preparation of compound CQ-1291:

[0165] Compound 2f (102 mg, 0.35 mmol), compound 1j (166 mg, 0.53 mmol), triethylamine (0.15 mL, 1.06 mmol), and 4-dimethylaminopyridine (4.5 mg, 0.035 mmol) were mixed, and 4 mL of N,N-dimethylformamide was added. The mixture was then heated to 80 °C and reacted for 24 hours. After dilution with water and extraction with ethyl acetate, the organic phase was stirred with silica gel and separated by column chromatography to obtain 66 mg of compound CQ-1291, with a yield of 37%.

[0166] 1 H NMR(400MHz,DMSO)δ13.36&13.62(2s,1H),9.75(s,1H),9.01-9.26(m,1H),8.60(s,1H) ),7.93-8.37(m,2H),7.43-7.64(m,4H),6.88-7.02(m,2H),3.87(s,3H),1.56(s,6H).

[0167] Example 3: Preparation of compound CQ1331

[0168] Preparation of compound 3a:

[0169] Compound 1h (222 mg, 0.55 mmol) was dissolved in 10 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. After reacting for 3 hours, the mixture was evaporated to dryness, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, dissolved in 10 mL of methanol, and 40 mg of palladium on carbon was added. The mixture was then heated to 60 °C and reacted overnight. After the starting material was exhausted, the mixture was filtered and evaporated to dryness to give 96 mg of compound 3a, with a yield of 60%.

[0170] 1 H NMR (400MHz, DMSO) δ12.74(s,1H),8.15(s,1H),7.54-7.78(m,2H),6.74-6.92(m,3H),6.44(d ,J=8.0Hz,2H),5.58(s,2H),3.85(s,3H),2.83-2.94(m,2H),2.66-2.76(m,2H),2.63(s,3H).

[0171] Preparation of compound CQ-1331:

[0172] Compound 3a (96 mg, 0.33 mmol), compound 1j (154 mg, 0.49 mmol), triethylamine (0.1 mL, 0.98 mmol), and 4-dimethylaminopyridine (4 mg, 0.033 mmol) were mixed, and 3 mL of N,N-dimethylformamide was added. The mixture was then heated to 80 °C and reacted for 24 hours. After dilution with water and extraction with ethyl acetate, the organic phase was stirred with silica gel and separated by column chromatography to obtain 83 mg of compound CQ-1331, with a yield of 49%.

[0173] 1 H NMR (400MHz, DMSO) δ12.79&12.68(2s,1H),9.60(s,1H),8.73(s,1H),8.11-8.20(m,1H),7.57-7.88(m,2H),7.33(d ,J=8.0Hz,2H),7.03-7.13(m,2H),6.89(s,1H),6.84(d,J=8.4Hz,1H),3.86(s,3H),2.77-3.05(m,4H),1.55(s,6H).

[0174] Example 4: Preparation of compound CQ1293

[0175] The synthesis route and method are similar to those in Example 1.

[0176] 1 H NMR (400MHz, DMSO) δ13.35&13.14(2s,1H),9.68(s,1H),8.88-9.03(m,1H),8.20-8.31(m,2H),8.09&7.83(2s, 1H),7.39-7.54(m,5H),7.22(d,J=16.0Hz,1H),7.05(d,J=16.0Hz,1H),6.90(s,1H),3.88(s,3H),1.55(s,6H).

[0177] Example 5: Preparation of compound CQ1294

[0178] The synthesis route and method are similar to those in Example 1.

[0179] 1H NMR (400MHz, DMSO) δ13.33&13.09(2s,1H),9.68(s,1H),8.84-9.03(m,1H),8.00(s,1H),7.89(d,J=7.6Hz,1H),8.07&7.79(2s,1H),7.75(d, J=7.6Hz,1H),7.56-7.64(m,1H),7.41-7.55(m,4H),7.23(d,J=16.4Hz,1H),7.00(d,J=16.4Hz,1H),6.90(s,1H),3.87(s,3H),1.55(s,6H).

[0180] Example 6: Preparation of compound CQ1307

[0181] The synthesis route and method are similar to those in Example 1.

[0182] 1 H NMR (400MHz, DMSO) δ13.30&13.08(2s,1H),9.68(s,1H),8.96(s,1H),8.50(d,J=3.6Hz,1H),7.92(s,1H),7.70-7.86(m,2H),7.60(d ,J=7.6Hz,1H),7.41-7.56(m,5H),7.24(d,J=16.4Hz,1H),7.03(d,J=16.4Hz,1H),6.91(s,1H),2.81(d,J=4.4Hz,3H),1.55(s,6H).

[0183] Example 7: Preparation of compound CQ1308

[0184] The synthesis route and method are similar to those in Example 1.

[0185] 1 H NMR (400MHz, DMSO) δ13.39&13.09(2s,1H),9.69(s,1H),8.85-9.09(m,1H),7.84-8.22(m,2H),7.38-7.6 3(m,4H),7.23(d,J=16.4Hz,1H),7.01-7.15(m,2H),6.91(s,1H),6.87(s,1H),3.87(s,3H),1.55(s,6H).

[0186] Example 8: Preparation of compound CQ1309

[0187] The synthesis route and method are similar to those in Example 1.

[0188] 1 H NMR (400MHz, DMSO) δ13.42&13.20(2s,1H),9.68(s,1H),8.89-9.10(m,1H),8.58(s,1H),8.50(d,J=2.4Hz,1H), 7.77-8.21(m,2H),7.40-7.61(m,4H),7.24(d,J=16.4Hz,1H),7.08(d,J=16.4Hz,1H),6.90(s,1H),1.55(s,6H).

[0189] Example 9: Preparation of compound CQ1327

[0190] The synthesis route and method are similar to those in Example 1.

[0191] 1 H NMR(400MHz,DMSO)δ13.39(s,1H),9.68(s,1H),8.84-9.19(m,3H),8.28(s,1H),7.98(s,1H),7.44- 7.54(m,4H),7.24(d,J=16.4Hz,1H),7.05(d,J=16.4Hz,1H),6.90(s,1H),3.91(s,3H),1.55(s,6H).

[0192] Example 10: Preparation of compound CQ1328

[0193] The synthesis route and method are similar to those in Example 1.

[0194] 1 H NMR (400MHz, DMSO) δ13.41&13.19(2s,1H),9.69(s,1H),8.97(s,1H),8.90(d,J=2.0Hz,1H),8.80(s,1H),8.64-8.75(m,1H),8.22(t,J=2.0Hz, 1H), δ8.22&8.13(2s,1H),7.38-7.60(m,4H),7.24(d,J=16.4Hz,1H),7 .05(d,J=16.4Hz,1H),6.90(s,1H),2.83(d,J=4.4Hz,3H),1.55(s,6H).

[0195] Example 11: Preparation of compound CQ1329

[0196] The synthesis route and method are similar to those in Example 1.

[0197] 1 H NMR(400MHz,DMSO)δ13.26&13.03(2s,1H),9.68(s,1H),8.95(s,1H),7.69-8.01(m,3H),7.39-7.58(m,4H),7 .32(d,J=8.8Hz,1H),7.20(d,J=16.4Hz,1H),6.99(d,J=16.4Hz,1H),6.90(s,1H),3.95(s,3H),1.55(s,6H).

[0198] Example 12: Preparation of compound CQ1330

[0199] The synthesis route and method are similar to those in Example 1.

[0200] 1 H NMR(400MHz,DMSO)δ13.10(s,1H),9.64(s,1H),8.97(s,1H),7.71(s,1H),7.41-7.52(m,4H ),7.18(d,J=16.4Hz,1H),6.93-7.03(m,3H),6.86-6.93(m,2H),6.04(s,2H),1.55(s,6H).

[0201] Example 13: Preparation of compound CQ1334

[0202] The synthesis route and method are similar to those in Example 1.

[0203] 1 H NMR(400MHz,DMSO)δ13.22&13.00(2s,1H),9.70(s,1H),8.98(s,1H),δ7.95&7.72(2s,1H),7.42-7.56(m,4H),7.20(d,J =16.4Hz,1H),7.03(d,J=16.0Hz,1H),6.90(s,1H),6.57(d,J=2.0Hz,2H),6.41-6.51(m,1H),3.77(s,6H),1.55(s,6H).

[0204] Example 14: Preparation of compound CQ1335

[0205] The synthesis route and method are similar to those in Example 1.

[0206] 1 H NMR(400MHz,DMSO)δ13.31&13.10(2s,1H),9.68(s,1H),8.96(s,1H),8.14(s,1H),7.79-8.09(m,2H),7.40- 7.57(m,4H),7.23(d,J=15.6Hz,1H),7.04-7.17(m,3H),6.90(s,1H),3.94(s,3H),2.82(s,3H),1.55(s,6H).

[0207] Example 15: Preparation of compound CQ1355

[0208] The synthesis route and method are similar to those in Example 1.

[0209] 1 H NMR (400MHz, DMSO) δ13.22&12.97(2s,1H),10.75(s,1H),9.67(s,1H),8.95(s,1H),7.63&7.86(2s,1H) ,7.40-7.57(m,4H),7.21(d,J=16.4Hz,1H),6.93-7.07(m,4H),6.90(s,1H),4.59(s,2H),1.55(s,6H).

[0210] Example 16: Preparation of compound CQ1362

[0211] The synthesis route and method are similar to those in Example 1.

[0212] 1 H NMR(400MHz,DMSO)δ13.47&13.26(2s,1H),9.71(s,1H),9.01(s,1H),8.88-8.98(m,2H),8.40(s,1H),8.18& 7.91(2s,1H),7.41-7.62(m,4H),7.24(d,J=16.0Hz,1H),7.10(d,J=16.4Hz,1H),6.90(s,1H),1.55(s,6H).

[0213] Example 17: Preparation of compound CQ-1372

[0214] Preparation of compound 17c:

[0215] Compound 17a (5 g, 52 mmol) was dissolved in 50 mL of N,N-dimethylformamide, and N-iodosuccinimide (14 g, 62 mmol) and p-toluenesulfonic acid (4.47 g, 26 mmol) were added. The mixture was reacted overnight at room temperature. After the starting material was exhausted, the reaction was quenched with saturated sodium thiosulfate solution, diluted with water, allowed to stand, and filtered. The filter cake was dried to obtain the crude product compound 17b, which was used directly in the next step.

[0216] The crude product obtained in the previous step was dissolved in 70 mL of tetrahydrofuran, followed by the addition of dihydropyran (8.7 g, 104 mmol) and p-toluenesulfonic acid (17.8 g, 104 mmol). The mixture was reacted overnight at room temperature, then extracted with water and ethyl acetate, washed with saturated sodium bicarbonate solution, and the organic phase was stirred with silica gel. The mixture was then separated by column chromatography to obtain 6 g of compound 17c. The two-step yield was 38%.

[0217] 1 H NMR (400MHz, CDCl3) δ9.95(s,1H),7.79(s,1H),5.37-5.54(m,1H),3.98-4.09(m,1H),3.65-3.78(m,1H),1.95-2.16(m,3H),1.63-1.70(m,4H).

[0218] Preparation of compound 17e:

[0219] Compound 17d (4 g, 23.3 mmol) was dissolved in 80 mL of dichloroethane, followed by the addition of N-bromosuccinimide (4.1 g, 23.3 mmol) and azobisisobutyronitrile (383 mg, 2.3 mmol). The reaction was heated to 80 °C and carried out overnight. The reaction was then quenched with saturated sodium thiosulfate solution, diluted with water, extracted with dichloromethane, and the organic phase was stirred with silica gel. The mixture was then separated by column chromatography to yield 3.6 g of compound 17e, with a yield of 61%.

[0220] 1 H NMR (400MHz, CDCl3) δ8.27 (d, J = 2.4Hz, 1H), 8.12 (dd, J = 8.4, 2.0Hz, 1H), 7.64 (d, J = 8.4Hz, 1H), 4.60 (s, 2H).

[0221] Preparation of compound 17f:

[0222] Compound 17e (3.5 g, 14.2 mmol) was dissolved in 20 mL of toluene, and then triphenylphosphine (3.9 g, 15 mmol) was added. The mixture was moved to 110 °C and reacted overnight. The solution was then evaporated to dryness, and then slurried with petroleum ether / ethyl acetate (3:1, v / v). The mixture was filtered, and the filter cake was dried to give 6.6 g of compound 17f, with a yield of 91%.

[0223] 1 H NMR (400MHz, CDCl3) δ7.92-8.08 (m, 3H), 7.58-7.89 (m, 15H), 5.90 (d, J = 15.2Hz, 2H).

[0224] Preparation of 17g of compound:

[0225] Compound 17f (1.33 g, 2.6 mmol) and potassium tert-butoxide (291 mg, 2.6 mmol) were mixed, and 5 mL of anhydrous tetrahydrofuran was injected under argon protection. The mixture was stirred at room temperature for 30 minutes, followed by the addition of compound 20 (400 mg, 1.3 mmol). The mixture was reacted overnight at room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was stirred with silica gel. The mixture was then separated by column chromatography to obtain 260 mg of compound 17f, with a yield of 44%.

[0226] 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),8.15(d,J=8.8Hz,1H),7.95(d,J=16.8Hz,1H),7.87(d,J=8.4Hz,1H),7.75(s,1H),7 .17(d,J=16.4Hz,1H),5.37-5.49(m,1H),4.06-4.16(m,1H),3.66-3.80(m,1H),2.00-2.17(m,3H),1.66-1.82(m,3H).

[0227] Preparation of compound 17i:

[0228] Compound 17 g (260 mg, 0.57 mmol), compound 17 h (160 mg, 0.68 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21 mg, 0.028 mmol) and potassium carbonate (236 mg, 1.71 mmol) were mixed under argon protection, and then 6 mL of dioxane / water (5:1, v / v) was added. The mixture was reacted overnight at 100 °C, diluted with water, extracted with ethyl acetate, and the organic phase was stirred with silica gel. The mixture was then separated by column chromatography to obtain 200 mg of compound 17 i, with a yield of 79%.

[0229] 1H NMR (400MHz, CDCl3) δ8.29-8.35(m,2H),8.27(d,J=2.0Hz,1H),8.09(dd,J=8.8,2.0Hz,1H),7.68-7.80(m,3H),7.23-7.26(m,1H),7 .21(d,J=16.4Hz,1H),5.46-5.52(m,1H),4.13-4.20(m,1H),3.91(s,3H),3.75-3.84(m,1H),2.07-2.24(m,3H),1.68-1.84(m,3H).

[0230] Preparation of compound 17j:

[0231] Compound 17i (200 mg, 0.45 mmol), iron powder (127 mg, 2.26 mmol), and ammonium chloride (193 mg, 3.6 mol) were dissolved in 5 mL of ethanol / water (4:1 v / v). After reacting at 80 °C for 4 hours, the mixture was filtered, the filtrate was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The solution was concentrated to give 180 mg of compound 17j, with a yield of 97%.

[0232] 1 H NMR (400MHz, CDCl3) δ8.23-8.32(m,2H),7.70(s,1H),7.58(d,J=16.4Hz,1H),7.40(d,J=8.4Hz,1H),7.24-7.26(m,1H),6.87(d,J=16.0 Hz,1H),6.67(s,1H),6.49-6.58(m,1H),5.39-5.47(m,1H),4.09-4.15(m,1H),3.64-3.92(m,6H),2.05-2.21(m,3H),1.67-1.81(m,3H).

[0233] Preparation of compound 17k:

[0234] Compound 17j (180 mg, 0.43 mmol), compound 1j (212 mg, 0.68 mmol), triethylamine (0.19 mL, 1.35 mmol), and 4-dimethylaminopyridine (27 mg, 0.22 mmol) were dissolved in 2 mL of N,N-dimethylformamide. The mixture was reacted overnight at 80 °C, diluted with water, extracted with ethyl acetate, and the organic phase was stirred with silica gel. The mixture was then separated by column chromatography to obtain 98 mg of compound 17k, with a yield of 36%.

[0235] 1H NMR(400MHz, CDCl3)δ9.11(s,1H),8.51(s,1H),8.24-8.38(m,2H),7.68-7.79 (m,2H),7.59(d,J=16.0Hz,1H),7.49(d,J=8.0Hz,1H),7.23-7.28(m,2H),6.9 8(d,J=15.6Hz,1H),6.38(s,1H),5.42-5.54(m,1H),4.14-4.24(m,1H),3.89( s,3H),3.73-3.84(m,1H),2.09-2.27(m,3H),1.69-1.88(m,3H),1.60(s,6H).

[0236] Preparation of compound CQ-1372:

[0237] Compound 17k (98 mg, 0.15 mmol) was dissolved in 2 mL of dichloromethane, and then 2 mL of trifluoroacetic acid was added. After reacting at room temperature for 3 hours, the solution was evaporated to dryness, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was mixed with silica gel and separated by column chromatography to obtain 35 mg of compound CQ-1372, with a yield of 43%.

[0238] 1 H NMR (400MHz, DMSO) δ13.53&13.21(2s,1H),9.81(s,1H),9.12(s,1H),8.21-8.32(m,2H),7.73-8.14(m,3H),7.52 (d,J=16.4Hz,1H),7.43(s,1H),7.31(d,J=7.6Hz,1H),7.04-7.18(m,1H),6.92(s,1H),3.88(s,3H),1.56(s,6H).

[0239] Example 18: Preparation of compound CQ1373

[0240] The synthesis route and method are similar to those in Example 17.

[0241] 1H NMR (400MHz, DMSO) δ13.39&13.19(2s,1H),10.43(s,1H),8.70&8.67(2s,1H),8.26-8.33(m,1H),8.24(d,J=2.8Hz,1H),8.12-8.23(m,1 H),8.11&7.85(2s,1H)7.70-7.77(m,1H),7.53(d,J=8.8Hz,1H),7.42(s,1H),7.11-7.27(m,2H),6.89(s,1H),3.89(s,3H),1.56(s,6H).

[0242] Example 19: Preparation of compound CQ1366

[0243] The synthesis route and method are similar to those in Example 17.

[0244] 1 H NMR(400MHz,DMSO)δ13.40&13.20(2s,1H),10.01(s,1H),8.89(s,1H),7.7 4-8.44(m,4H),7.06-7.65(m,5H),6.90(s,1H),3.88(s,3H),1.55(s,6H).

[0245] Example 20: Preparation of compound CQ1371

[0246] The synthesis route and method are similar to those in Example 17.

[0247] 1 H NMR (400MHz, DMSO) δ13.60&13.22(2s,1H),9.86&9.84(2s,1H),9.27&9.23(2s,1H),8.20-8.30(m,2H),7.81- 8.13(m,3H),7.55-7.65(m,1H),7.36-7.53(m,2H),7.05-7.23(m,1H),6.94(s,1H),3.87(s,3H),1.56(s,6H).

[0248] Example 21: Preparation of compound CQ1368

[0249] The synthesis route and method are similar to those in Example 17.

[0250] 1H NMR (400MHz, DMSO) δ13.34&13.09(2s,1H),9.70(s,1H),9.01&8.97(2s,1H),8.27(s,1H),8.23(s,1H),8.08&7.81(2s,1H), 7.51(d,J=8.4Hz,1H),7.28-7.47(m,3H),7.09(d,J=16.4Hz,1H),6.87-6.99(m,2H),3.88(s,3H),3.84(s,3H),1.56(s,6H).

[0251] Example 22: Preparation of compound CQ1369

[0252] The synthesis route and method are similar to those in Example 17.

[0253] 1 H NMR (400MHz, DMSO) δ13.47&13.20(m,1H),9.80(s,1H),9.16&9.12(2s,1H),8.28(s,1H),8.24(d,J=2.4Hz,1H),8.11&7.84(2s,1H),7.63-7.74( m,1H),7.47-7.59(m,1H),7.42(s,1H),7.27-7.38(m,1H),7.18(d,J=8. 4Hz, 1H), 7.12 (d, J = 17.2Hz, 1H), 6.91 (s, 1H), 3.89 (s, 3H), 1.56 (s, 6H).

[0254] Example 23: Preparation of compound CQ1363

[0255] The synthesis route and method are similar to those in Example 17.

[0256] 1 H NMR(400MHz,DMSO)δ13.36&13.16(2s,1H),10.26(s,1H),8.71(s,1H),7.78-8.36(m,4H ),7.43(s,1H),7.01-7.32(m,4H),6.90(s,1H),3.93(s,3H),3.88(s,3H),1.55(s,6H).

[0257] Example 24: Preparation of compound CQ1364

[0258] The synthesis route and method are similar to those in Example 17.

[0259] 1 H NMR(400MHz,DMSO)δ13.37&13.16(2s,1H),10.07(s,1H),7.70-8.52(m,5H),7.28-7 .56(m,3H),6.97-7.28(m,2H),6.88(s,1H),3.88(s,3H),2.26(s,3H),1.55(s,6H).

[0260] Example 25: Preparation of compound CQ1365

[0261] The synthesis route and method are similar to those in Example 17.

[0262] 1 H NMR (400MHz, DMSO) δ13.44&13.14(2s,1H),9.68(s,1H),8.86(s,1H),8.28(s,1H),8.23(d,J=1.6Hz,1H),8.08 &7.83(2s,1H),7.22-7.65(m,5H),6.96(d,J=16.4Hz,1H),6.91(s,1H),3.88(s,3H),2.37(s,3H),1.55(s,6H).

[0263] Example 26: Preparation of compound CQ1374

[0264] Preparation of compounds 26b and 26c:

[0265] Compound 26a (3.1 g, 6.6 mmol) and potassium tert-butoxide (739 mg, 6.6 mmol) were mixed, and 10 mL of anhydrous tetrahydrofuran was injected under argon protection. The mixture was stirred at room temperature for 30 minutes, followed by the addition of compound 20 (1 g, 3.3 mmol). The mixture was reacted overnight at room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was stirred with silica gel. The mixture was then separated by column chromatography to obtain 360 mg of compound 26b (26% yield) and 700 mg of compound 26c (51% yield).

[0266] 26b: 1 H NMR (400MHz, CDCl3) δ8.10(d,J=8.0Hz,2H),7.60-7.77(m,3H),6.71(d,J=12.8Hz,1H),6.56(d,J=12 .4Hz,1H),5.32(s,1H),3.93-4.03(m,1H),3.58-3.73(m,1H),1.87-2.02(m,3H),1.60-1.67(m,3H).

[0267] 26c: 1 H NMR (400MHz, CDCl3) δ8.21(d,J=7.6Hz,2H),7.70(s,1H),7.64(d,J=8.0Hz,2H),7.54(d,J=16.4Hz,1H),7.12(d,J=1 6.0Hz,1H),5.33-5.44(m,1H),4.08(d,J=11.6Hz,1H),3.71(t,J=9.6Hz,1H),1.96-2.13(m,3H),1.63-1.78(m,3H).

[0268] Preparation of compound 26e:

[0269] Compound 26b (350 mg, 0.83 mmol), compound 17h (235 mg, 1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (30 mg, 0.04 mmol) and potassium carbonate (343 mg, 2.49 mmol) were mixed under argon protection, and then 6 mL of dioxane / water (5:1, v / v) was added. The mixture was reacted overnight at 100 °C, diluted with water, extracted with ethyl acetate, and evaporated to dryness to obtain crude product 26d. No purification was required, and it was used directly in the next step.

[0270] The compound 26d obtained in the previous step, iron powder (232 mg, 4.15 mmol) and ammonium chloride (355 mg, 6.64 mol) were dissolved in 5 mL of ethanol / water (4:1 v / v). After reacting at 80 °C for 4 hours, the mixture was filtered, the filtrate was diluted with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give 210 mg of compound 26e, with a two-step yield of 67%.

[0271] 1 H NMR (400MHz, CDCl3) δ8.21(s,1H),8.10(s,1H),7.79(s,1H),7.28(s,1H),7.18(s,1H),7.11(d,J=8.0Hz,2H),6.63(d,J=12.0Hz,1H),6.43 (d,J=8.4Hz,2H),6.38(d,J=12.4Hz,1H),5.39-5.49(s,1H),4.09-4.16(m,1H),3.69-3.81(m,4H),1.397-2.24(m,5H),1.56-1.73(s,3H).

[0272] Preparation of compound 26f:

[0273] Compound 26e (200 mg, 0.53 mmol), compound 1j (250 mg, 0.8 mmol), triethylamine (0.22 mL, 1.59 mmol), and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were dissolved in 2 mL of N,N-dimethylformamide and reacted overnight at 80 °C. The mixture was then diluted with water, extracted with ethyl acetate, and the organic phase was stirred with silica gel. The mixture was separated by column chromatography to obtain 150 mg of compound 26f, with a yield of 47%.

[0274] 1 H NMR(400MHz, CDCl3)δ9.07(s,1H),8.24(s,1H),7.99-8.20(m,2H),7.81(s,1H),7.22(s,1H),7.01-7.19(m,4H),6.67(d,J=12.8Hz,1H),6.63 (s,1H),6.48(d,J=12.4Hz,1H),5.32-5.42(m,1H),3.94-4.05(m,1H), 3.81(s,3H),3.56-3.68(m,1H),1.96-2.12(m,3H),1.49-1.68(m,9H).

[0275] Preparation of compound CQ-1374:

[0276] Compound 26f (150 mg, 0.25 mmol) was dissolved in 2 mL of dichloromethane, and then 2 mL of trifluoroacetic acid was added. After reacting at room temperature for 3 hours, the solution was evaporated to dryness, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was mixed with silica gel and separated by column chromatography to obtain 100 mg of compound CQ-1374, with a yield of 78%.

[0277] 1 H NMR (400MHz, DMSO) δ13.15&12.95(2s,1H),9.65(s,1H),8.84&8.81(2s,1H),7.94-8.36(m,3H),7. 22-7.40(m,4H),7.00(d,J=7.6Hz,1H),6.87(s,1H),6.49-6.85(m,2H),3.79(s,3H),1.55(s,6H).

[0278] Example 27: Preparation of compound CQ1380

[0279] Preparation of compound 27a: The synthesis method is the same as that of compound 26d in Example 26.

[0280] 1H NMR (400MHz, CDCl3) δ8.28(s,1H),8.24(s,1H),8.19(d,J=7.6Hz,2H),7.66(s,1H),7.53(d,J=8.0Hz,2H),7.16-7.25(m,2H),6.98(d,J =16.4Hz,1H),5.46(d,J=9.2Hz,1H),4.14(d,J=10.8Hz,1H),3.83(s,3H),3.74(t,J=10.4Hz,1H),1.98-2.27(m,3H),1.59-1.83(m,3H).

[0281] Preparation of compound 27b: The synthesis method is the same as that of compound 1i in Example 1.

[0282] 1 H NMR (400MHz, DMSO) δ13.07(s,1H),8.27(s,1H),8.21(s,1H),7.85(s,1H),7.39(s,1H),7.23(d,J=7.2H z,2H),7.11(d,J=16.0Hz,1H),6.81(d,J=16.4Hz,1H),6.56(d,J=7.6Hz,2H),5.38(s,2H),3.87(s,3H).

[0283] Preparation of compound 27d:

[0284] Compound 27c (1 g, 10.19 mmol) was dissolved in 30 mL of tetrahydrofuran, potassium carbonate (2.1 g, 15.3 mmol) was added, followed by dropwise addition of phenyl chloroformate (1.9 g, 12.2 mmol). The mixture was reacted overnight at room temperature, diluted with water, extracted with ethyl acetate, and the solvent was evaporated. The mixture was then slurried with petroleum ether, filtered, and the filter cake was dried to give 1.9 g of compound 27d, with a yield of 85%.

[0285] 1 H NMR (400MHz, CDCl3) δ9.21 (s, 1H), 7.12-7.53 (m, 5H), 6.59 (s, 1H), 2.40 (s, 3H).

[0286] Preparation of compound CQ-1380: The synthesis method is the same as that of compound 1.

[0287] 1H NMR(400MHz,DMSO)δ13.36&13.14(2s,1H),9.46&9.45(2s,1H),8.95&8.90(2s 1H),8.28(s,1H),8.23(d,J=2.0Hz,1H),8.09&7.83(2s,1H),7.35-7.60(m,5H),7 .22(d,J=16.4Hz,1H),6.99-7.12(m,1H),6.54(s,1H),3.88(s,3H),2.36(s,3H).

[0288] Example 28: Preparation of compound CQ1381

[0289] The synthesis route and method are similar to those in Example 27.

[0290] 1 H NMR (400MHz, DMSO) δ13.36&13.14(2s,1H),9.62(s,1H),8.98&8.93(2s,1H),8.74(s,1H),8.28(s,1H),8.23(s,1H) ,8.09&7.83(2s,1H),7.35-7.61(m,5H),7.23(d,J=16.4Hz,1H),7.05(d,J=16.4Hz,1H),6.85(s,1H),3.88(s,3H).

[0291] Example 29: Preparation of compound CQ1382

[0292] The synthesis route and method are similar to those in Example 27.

[0293] 1 H NMR (400MHz, DMSO) δ13.33(s,1H),10.31(s,1H),9.33(s,1H),8.28(s,1H),8.23(s,1H),7.91(s,1H),7.34-7.58( m,5H),7.23(d,J=16.8Hz,1H),7.05(d,J=16.8Hz,1H),5.81(s,1H),3.88(s,3H),1.37(s,3H),0.80-0.98(m,4H).

[0294] Example 30: Preparation of compound CQ1333

[0295] The synthesis route and method are similar to those in Example 27.

[0296] 1 H NMR (400MHz, DMSO) δ13.13&13.35(2s,1H),9.52(s,1H),8.84-9.06(m,1H),8.28(s,1H),8.23(d,J=2.8Hz,1H),7.83&8 .09(2s,1H),7.39-7.55(m,5H),7.22(d,J=16.4Hz,1H),7.04(d,J=16.4Hz,1H),6.51(s,1H),3.88(s,3H),1.29(s,9H).

[0297] Example 31: Preparation of compound CQ1383

[0298] The synthesis route and method are similar to those in Example 27.

[0299] 1 H NMR (400MHz, DMSO) δ13.34&13.13(2s,1H),9.04(s,1H),8.98(s,1H),8.29(s,1H),8.23(s,1H),8.08&7.83(2s, 1H),7.94(s,1H),7.28-7.61(m,7H),7.23(d,J=16.4Hz,1H),7.04(d,J=16.4Hz,1H),3.89(s,3H),2.38(s,3H).

[0300] Example 32: Preparation of compound CQ1306

[0301] Preparation of compound 32b: The synthesis method is the same as that of compound 1e in Example 1.

[0302] 1 H NMR (400MHz, CDCl3) δ8.23(d,J=8.0Hz,2H),7.62(d,J=8.4Hz,2H),7.48(s,1 H),7.12(d,J=16.0Hz,1H),7.06(d,J=16.4Hz,1H),6.56(s,1H),3.99(s,3H).

[0303] Preparation of compound 32c: The synthesis method is the same as that of compound 1f in Example 1.

[0304] 1H NMR (400MHz, CDCl3) δ8.26(d,J=8.8Hz,2H),7.66(d,J=8.8Hz,2H),7.54(s,1H),7.47(d,J=16.8Hz,1H),7.05(d,J=16.4Hz,1H),4.03(s,3H).

[0305] Preparation of compound 32d: The synthesis method is the same as that of compound 1h in Example 1.

[0306] 1 H NMR (400MHz, CDCl3) δ8.31 (s, 1H), 8.28 (s, 1H), 8.23 ​​(d, J = 8.4Hz, 2H), 7.62 (s, 1H), 7.56 (d, J = 8. 4Hz,2H),7.25(s,1H),7.15(d,J=16.8Hz,1H),6.92(d,J=16.4Hz,1H),4.09(s,3H),3.89(s,3H).

[0307] Preparation of compound 32e: The synthesis method is the same as that of compound 17j in Example 17.

[0308] 1 H NMR(400MHz, CDCl3)δ8.32(s,1H),8.19(s,1H),7.57(s,1H),7.26(s,1H),7.21 (d,J=8.0Hz,2H),6.70-6.75(m,2H),6.62(d,J=8.4Hz,2H),3.70-4.03(m,8H).

[0309] Preparation of compound CQ-1306: The synthesis method is the same as that of compound 17k in Example 17.

[0310] 1 H NMR (400MHz, CDCl3) δ9.15(s,1H),8.86(s,1H),8.33(d,J=1.2Hz,1H),8.22(d,J=2.8Hz,1H),7.59(s,1H),7.49(d,J=8.4Hz,2H),7.38( d,J=8.4Hz,2H),7.26-7.28(m,1H),6.89(d,J=16.8Hz,1H),6.80(d,J=16.8Hz,1H),6.34(s,1H),4.01(s,3H),3.83(s,3H),1.58(s,6H).

[0311] Example 33: Preparation of compound CQ1305

[0312] The synthesis route and method are similar to those in Example 32.

[0313] 1 H NMR (400MHz, CDCl3) δ9.00(s,1H),8.71(s,1H),8.29(d,J=1.6Hz,1H),8.27(d,J=2.8Hz,1H),7.48(s,1H),7.45(d,J=8.8Hz,2H),7.42( d,J=8.8Hz,2H),7.31(d,J=16.0Hz,1H),7.20-7.25(m,1H),6.97(d,J=16.0Hz,1H),6.33(s,1H),3.98(s,3H),3.88(s,3H),1.58(s,6H).

[0314] Example 34: Preparation of compound CQ-1238

[0315] Preparation of compound 34c:

[0316] Compound 34a (5 g, 39.6 mmol) was dissolved in 40 mL of N,N-dimethylformamide, and then compound 34b (5.47 mL, 43.6 mmol) was added dropwise. The mixture was reacted overnight at room temperature, then water was added and the mixture was filtered. The filter cake was dried to give 5.7 g of compound 34c, with a yield of 65%.

[0317] Preparation of compound 34d:

[0318] Compound 34c (2 g, 9.52 mmol) was dissolved in 30 mL of N,N-dimethylformamide, and NIS (3.2 g, 14.3 mmol) was slowly added. The mixture was reacted overnight at room temperature, filtered with water, and the filter cake was dried to give 450 mg of compound 34d, with a yield of 14%.

[0319] Preparation of 34g of compound:

[0320] Compound 34e (1 g, 4.5 mmol), compound 34f (1.26 g, 6.75 mmol), potassium carbonate (1.72 g, 13.5 mmol), and potassium iodide (1.12 g, 6.75 mmol) were mixed, and 10 mL of N,N-dimethylformamide was added. The mixture was reacted overnight at 80 °C, extracted with water and ethyl acetate, and the organic phase was stirred with silica gel. The mixture was separated by column chromatography to obtain 1 g of compound 34, with a yield of 66%.

[0321] Preparation of compound 34h:

[0322] Compound 34d (526 mg, 1.57 mmol), compound 34g (1 g, 3.1 mmol), potassium carbonate (651 mg, 4.71 mmol), and dppfPdCl2 (58 mg, 0.08 mmol) were mixed under argon protection, and then 6 mL of dioxane / water (5:1, v / v) was added. The mixture was reacted overnight at 100 °C, and then extracted with water and ethyl acetate. The organic phase was then separated by silica gel, stirred, and column chromatography to obtain 300 mg of compound 34 h, with a yield of 45%.

[0323] Preparation of compound 34k:

[0324] Compound 34h (5500 mg, 1.17 mmol) was dissolved in 10 mL of ethanol, and then lithium hydroxide hydrate (147 mg, 3.51 mmol) and 5 mL of water were added. After reacting at room temperature for 6 hours, the mixture was evaporated to dryness. Compound 34j (291 mg, 1.4 mmol), DIPEA (0.31 mL, 1.76 mmol), HATU (669 mg, 1.76 mmol) and 5 mL of N,N-dimethylformamide were added. The mixture was reacted at room temperature overnight, extracted with water and ethyl acetate, and the organic phase was separated by silica gel and column chromatography to obtain 450 mg of compound 34k. The two-step yield was 65%.

[0325] Preparation of compound CQ-1238:

[0326] Compound 34k (118 mg, 0.2 mmol) was dissolved in 2 mL of dichloromethane, and then 2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours, evaporated to dryness, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate, and evaporated to dryness. Compound 1j (96 mg, 0.3 mmol), triethylamine (85 μL, 0.6 mmol), DMAP (2 mg, 0.02 mmol), and 1 mL of N,N-dimethylformamide were added to the crude product. The mixture was reacted overnight at 80 °C, extracted with water and ethyl acetate, and the organic phase was separated by silica gel. The mixture was stirred and column chromatography to obtain 96 mg of compound CQ-1238. The two-step yield was 68%.

[0327] Example 35: Preparation of compound CQ1237

[0328] The synthesis route and method are similar to those in Example 34.

[0329] Example 36: Preparation of compound CQ1239

[0330] The synthesis route and method are similar to those in Example 34.

[0331] Example 37: Preparation of compound CQ1240

[0332] The synthesis route and method are similar to those in Example 34.

[0333] Example 38: Preparation of compound CQ1241

[0334] The synthesis route and method are similar to those in Example 34.

[0335] Example 39: Preparation of compound CQ-1250

[0336] Preparation of compound 39b:

[0337] Compound 34d (0.94 g, 2.7 mmol), compound 39a (0.62 g, 4 mmol), potassium carbonate (1.12 g, 8.1 mmol), and dppfPdCl2 (99 mg, 0.135 mmol) were mixed under argon protection, and then 12 mL of dioxane / water (5:1, v / v) was added. The mixture was reacted overnight at 100 °C, and then extracted with water and ethyl acetate. The organic phase was then separated by silica gel, stirred, and column chromatography to obtain 687 mg of compound 39b, with a yield of 77%.

[0338] Preparation of compound 39c:

[0339] Compound 39b (540 mg, 1.64 mmol) was dissolved in 12 mL of THF / MeOH (5:1, v / v), sodium borohydride (374 mg, 9.84 mmol) was added at 0 °C, and the mixture was then moved to 50 °C and reacted overnight. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was stirred with silica gel. The mixture was then separated by column chromatography to obtain 370 mg of compound 39c, with a yield of 79%.

[0340] Preparation of compound 39d:

[0341] Compound 39c (336 mg, 1.17 mmol) was dissolved in 10 mL of DMF, and manganese dioxide (2 g, 23.4 mmol) was added. The mixture was reacted overnight at 60 °C. After the reaction was complete, the mixture was filtered with diatomaceous earth. The filtrate was then filtered with water and the filter cake was dried to give 211 mg of compound 39d, with a yield of 63%.

[0342] Preparation of compound 39e:

[0343] Compound 26a (0.33 g, 0.7 mmol) and potassium tert-butoxide (78 mg, 0.7 mmol) were mixed, and 2 mL of anhydrous tetrahydrofuran was injected under argon protection. The mixture was stirred at room temperature for 30 minutes, followed by the addition of compound 39d (0.1 g, 0.35 mmol). The mixture was reacted overnight at room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was stirred with silica gel. The mixture was then separated by column chromatography to obtain 98 mg of compound 39e, with a yield of 69%.

[0344] Preparation of compound 39f:

[0345] Compound 39e (93 mg, 0.23 mmol), iron powder (64 mg, 1.15 mmol), and ammonium chloride (98 mg, 1.84 mol) were dissolved in 5 mL of a mixed solvent of ethanol / water (4:1, v / v). After reacting at 80 °C for 4 hours, the mixture was filtered, the filtrate was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The solution was concentrated to give 76 mg of compound 39f, with a yield of 88%.

[0346] Preparation of compound CQ-1250:

[0347] Compound 39f (60 mg, 0.16 mmol) was dissolved in 2 mL of LDM, and compound 1j (78 mg, 0.25 mmol), triethylamine (67 μL, 0.48 mmol), and DMAP (2 mg, 0.016 mmol) were added. The mixture was reacted overnight at 70 °C, then extracted with water and ethyl acetate. The organic phase was then separated by silica gel chromatography with stirring to obtain 57 mg of compound CQ-1250, in 60% yield.

[0348] Example 40: Preparation of compound CQ1243

[0349] The synthesis route and method are similar to those in Example 39.

[0350] Example 41: Preparation of compound CQ-1336

[0351] Preparation of compound 41c:

[0352] Compound 41a (532 mg, 1.91 mmol), compound 41b (300 mg, 1.6 mmol), dppfPdCl2 (58 mg, 0.08 mmol), and potassium carbonate (663 mg, 4.8 mmol) were mixed and reacted overnight at 100 °C under argon protection. After the reaction was complete, water and ethyl acetate were added for extraction. The organic phase was stirred with silica gel and separated by column chromatography to obtain 300 mg of compound 41c, with a yield of 72%.

[0353] 1H NMR(400MHz,Chloroform-d)δ8.30-8.40(m,2H),7.63(d,J=1.6Hz,1H),7.42(dd,J=2.8,2.0Hz,1H),6.40(d,J=2.0Hz,1H),5.16(dd,J=10.0,2.4Hz,1 H),4.07-4.18(m,1H),3.90(s,3H),3.57-3.66(m,1H),2.51-2.63(m,1H),2 .02-2.14(m,1H),1.84-1.93(m,1H),1.69-1.79(m,1H),1.49-1.60(m,2H).

[0354] Preparation of compound 41d:

[0355] Compound 41c (300 mg, 1.16 mmol) was dissolved in 10 mL of LDM, and then NIS (313 mg, 1.39 mmol) and p-toluenesulfonic acid (10 mg, 0.06 mmol) were added. After reacting overnight at room temperature, water and ethyl acetate were added for extraction. The organic phase was mixed with silica gel and separated by column chromatography to obtain 150 mg of compound 41d, with a yield of 34%.

[0356] 1 H NMR (400MHz, Chloroform-d) δ8.42(d,J=2.8Hz,1H),8.33(d,J=1.6Hz,1H),7.67(s,1H),7.38(dd,J=2.8,1.6Hz,1H),5.07(dd,J=10.4,2. 4Hz,1H),4.04-4.10(m,1H),3.91(s,3H),3.47-3.56(m,1H),2.42-2.59(m,1H),2.05-2.09(m,1H),1.69-1.91(m,2H),1.43-1.61(m,2H).

[0357] Preparation of compound 41f:

[0358] Compound 41d (260 mg, 0.67 mmol), compound 41e (78 mg, 0.67 mmol), triethylamine (0.6 mL, 4 mmol), cuprous iodide (13 mg, 0.067 mmol), and tetraphenylphosphine palladium (39 mg, 0.033 mmol) were mixed and subjected to argon protection. 5 mL of tetrahydrofuran was added, and the mixture was reacted overnight at 60 °C. The mixture was then separated by column chromatography to obtain 130 mg of compound 41f, with a yield of 56%.

[0359] Preparation of compound CQ1336:

[0360] Compound 41f (125 mg, 0.33 mmol), compound 1j (157 mg, 0.5 mmol), triethylamine (0.14 mL, 1 mmol), and DMAP (4 mg, 0.033 mmol) were dissolved in 3 mL of LDM. The mixture was heated to 80 °C and reacted overnight. The mixture was extracted with water and ethyl acetate, and the organic phase was evaporated to dryness. Then, 3 mL of dichloromethane and 3 mL of trifluoroacetic acid were added, and the mixture was reacted at room temperature for 2 hours. The solvent was evaporated to dryness, and the mixture was neutralized with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was mixed with silica gel and separated by column chromatography to obtain 48 mg of compound CQ1336. The two-step yield was 27%.

[0361] 1 H NMR(400MHz,DMSO-d6)δ13.48&13.78(2s,1H),9.75(s,1H),9.04(s,1H),8.82&8.88(2s,1H),8.29-8.39(m,1H) ,8.27(s,1H),7.96(s,1H),7.53(d,J=8.8Hz,2H),7.45(d,J=8.0Hz,2H),6.91(s,1H),3.87(s,3H),1.56(s,6H).

[0362] Example 42: Preparation of compound CQ1349

[0363] The synthesis route and method are similar to those in Example 41.

[0364] 1 H NMR(400MHz,Chloroform-d)δ9.12(s,1H),8.83(s,1H),8.37-8.44(m,2H),7.73(s,1H),7. 41-7.51(m,3H),7.35(d,J=8.0Hz,2H),6.29(s,1H),3.93(s,3H),3.90(s,3H),1.58(s,6H).

[0365] Example 43: Preparation of compound CQ1350

[0366] The synthesis route and method are similar to those in Example 41.

[0367] 1H NMR(400MHz,DMSO-d6)δ13.43&13.73(2s,1H),9.75(s,1H),9.05(s,1H),7.64-8.29(m,5H),7.52(d ,J=8.4Hz,2H),7.47(d,J=8.0Hz,2H),6.90(s,1H),3.90(s,3H),2.81(d,J=4.4Hz,3H),1.55(s,6H).

[0368] Example 44: Preparation of compound CQ1351

[0369] The synthesis route and method are similar to those in Example 41.

[0370] 1 H NMR(400MHz,DMSO-d6)δ13.18&13.45(2s,1H),9.74(s,1H),9.03(s,1H),7.56-8.19(m,3H),7.51(d,J =8.4Hz,2H),7.45(d,J=8.0Hz,2H),7.10(s,1H),6.90(s,1H),3.80(s,3H),3.78(s,3H),1.55(s,6H).

[0371] Example 45: Preparation of compound CQ1352

[0372] The synthesis route and method are similar to those in Example 41.

[0373] 1 H NMR(400MHz,DMSO-d6)δ13.30&13.60(2s,1H),9.75(s,1H),9.03(s,1H),7.58-8.20(m,3H),7.5 2(d,J=8.0Hz,2H),7.30-7.48(m,3H),6.92-7.06(m,1H),6.90(s,1H),3.79(s,3H),1.56(s,6H).

[0374] Example 46: Preparation of compound CQ1354

[0375] The synthesis route and method are similar to those in Example 41.

[0376] 1H NMR (400MHz, DMSO-d6) δ13.44&13.74(2s,1H),9.74(s,1H),9.03(s,1H),8.59(s,1H),7.76-8. 28(m,4H),7.53(d,J=8.0Hz,2H),7.47(d,J=8.0Hz,2H),6.91(s,1H),4.47(s,2H),1.56(s,6H).

[0377] Example 47: Preparation of compound CQ1367

[0378] The synthesis route and method are similar to those in Example 41.

[0379] 1 H NMR(400MHz,DMSO-d6)δ13.69(s,1H),9.76(s,1H),9.48(s,1H),88.98-9.10(m,2H),8.81( s,1H),8.32(s,1H),7.54(d,J=7.6Hz,2H),7.47(d,J=7.2Hz,2H),6.91(s,1H),1.56(s,6H).

[0380] Example 48: Preparation of compound CQ1370

[0381] The synthesis route and method are similar to those in Example 41.

[0382] 1 H NMR(400MHz,DMSO-d6)δ13.67(s,1H),9.78(s,1H),9.51(s,1H),9.07(s,1H),9.01(s,1H),8.7 7(s,1H),8.28(s,1H),7.54(d,J=8.4Hz,2H),7.44(d,J=8.0Hz,2H),6.91(s,1H),1.56(s,6H).

[0383] Example 49: Preparation of compound CQ1289

[0384] Preparation of compound 49b:

[0385] Compound 49a (5 g, 42.3 mmol) was added to 85 mL of tetrahydrofuran, and sodium hydride (60%, 2.2 g, 55.1 mmol) was slowly added at 0 °C. The mixture was stirred for 15 minutes, and then benzenesulfonyl chloride (6 mL, 46.6 mmol) was added. The mixture was then allowed to react at room temperature. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was stirred with silica gel. The mixture was then passed through a column to obtain 10 g of compound 49b, with a yield of 91%.

[0386] 1 H NMR (400MHz, CDCl3) δ8.37-8.49(m,1H),8.18(d,J=7.6Hz,2H),7.79-7.87(m,1H),7.71(d,J=4.0 Hz,1H),7.51-7.58(m,1H),7.42-7.50(m,2H),7.16(dd,J=7.6,4.8Hz,1H),6.58(d,J=4.0Hz,1H).

[0387] Preparation of compound 49c:

[0388] Compound 49b (5 g, 19.4 mmol) was dissolved in 100 mL of dry tetrahydrofuran. Under argon protection, the mixture was stirred at -78 °C for 15 min. A 2 M lithium diisopropylamine solution in tetrahydrofuran / n-heptane (15 mL, 29.1 mmol) was slowly added dropwise. After the addition was complete, the mixture was moved to -30 °C and reacted for 3 h. Dry N,N-dimethylamide (3.8 mL, 48. mmol) was added dropwise, and the reaction was continued at -30 °C. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer was stirred with silica gel and column chromatography to obtain 4.6 g of compound 49c, with a yield of 83%.

[0389] 1 H NMR (400MHz, CDCl3) δ10.63 (s, 1H), 8.58-8.66 (m, 1H), 8.17 (d, J = 7.6Hz, 2H), 7.94- 8.01(m,1H),7.56-7.63(m,1H),7.45-7.52(m,2H),7.40(s,1H),7.26-7.30(m,1H).

[0390] Preparation of compound 49d:

[0391] Compound 49c (4.6 g, 16 mmol) was dissolved in 160 mL of methanol under argon protection and stirred at room temperature. 10 mL of an aqueous solution of 3.6 g of potassium hydroxide was added dropwise. After the addition was complete, the reaction was continued at room temperature. After the reaction was completed, a saturated sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, mixed with silica gel, and passed through a column to obtain 1.1 g of compound 49d, with a yield of 48%.

[0392] 1 H NMR (400MHz, CDCl3) δ12.37(s,1H),9.96(s,1H),8.71-8.86(m,1H),8.08-8.20(m,1H),7.21-7.26(m,2H).

[0393] Preparation of compound 49e:

[0394] Compound 49d (449 mg, 3.07 mmol) was dissolved in 9 mL of N,N-dimethylamide. 6 mL of N,N-dimethylamide solution containing 780 mg, 3.07 mmol of iodine was added at 0 °C. The mixture was then allowed to react at room temperature. After the reaction was complete, the reaction was quenched with saturated sodium thiosulfate aqueous solution. The mixture was extracted with ethyl acetate, and the organic layer was stirred with silica gel and passed through a column to obtain 676 mg of compound 49e, with a yield of 80%.

[0395] 1 H NMR (400MHz, DMSO) δ12.97 (s, 1H), 9.83 (s, 1H), 8.52 (d, J = 4.4Hz, 1H), 7.96 (d, J = 8.0Hz, 1H), 7.24-7.32 (m, 1H).

[0396] Preparation of 49g of compound:

[0397] Compound 49e (676 mg, 2.48 mmol), compound 49f (494 mg, 3.23 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (91 mg, 0.13 mmol), potassium carbonate (1 g, 7.45 mmol), and 25 mL of a 5:1 mixture of 1,4-dioxane / water were mixed and reacted under argon protection at 80 °C. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The organic phase was stirred with silica gel and column chromatography was performed to obtain 49 g of compound 472 mg, with a yield of 75%.

[0398] 1 H NMR (400MHz, DMSO) δ12.69(s,1H),9.85(s,1H),8.54(d,J=4.4Hz,1H),8.47(s,1H),8.17(d, J=8.0Hz,1H),8.05(d,J=8.8Hz,1H),7.21-7.27(m,1H),7.01(d,J=8.4Hz,1H),3.94(s,3H).

[0399] Preparation of compound 49h:

[0400] Compound 26a (579 mg, 1.2 mmol), potassium tert-butoxide (136 mg, 1.2 mmol), and 10 mL of tetrahydrofuran were mixed and stirred at room temperature for 30 minutes under argon protection. Then, 10 mL of a tetrahydrofuran solution containing 49 g (153.3 mg, 0.6 mmol) of compound 26a was added, and the mixture was heated to 70 °C. After the reaction was complete, the mixture was extracted with ethyl acetate and water, and the organic layer was evaporated to dryness. The mixture was then stirred with 10 mL of petroleum ether:dichloromethane (2:1), filtered, and the filter cake was dried to give 213 mg of compound 49 h, with a yield of 95%.

[0401] 1 H NMR (400MHz, DMSO) δ12.31(s,1H),8.30-8.37(m,2H),8.21(d,J=8.4Hz,2H),7.87-7.95(m,2H),7.77(d,J=8.4 Hz,2H),7.60(d,J=16.4Hz,1H),7.35(d,J=16.4Hz,1H),7.09-7.16(m,1H),7.01(d,J=8.4Hz,1H),3.94(s,3H).

[0402] Preparation of compound 49i:

[0403] Compound 49h (262 mg, 0.7 mmol), iron powder (236 mg, 4.2 mmol), ammonium chloride (301 mg, 5.6 mmol), and 7 mL of 80% ethanol aqueous solution were mixed and reacted at 80 °C. After the reaction was completed, the mixture was filtered while hot, the filter cake was washed with water and ethyl acetate, extracted and separated, the organic phase was mixed with silica gel, and the mixture was passed through a column to obtain 224 mg of compound 49i, with a yield of 93%.

[0404] 1 H NMR (400MHz, DMSO) δ12.00(s,1H),8.27(d,J=2.0Hz,1H),8.21(d,J=3.6Hz,1H),7.78-7.88(m,2H),7.34(d,J=16.4Hz,1H),7.19(d ,J=8.4Hz,2H),7.02-7.10(m,1H),6.98(d,J=8.4Hz,1H),6.81(d,J=16.4Hz,1H),6.56(d,J=8.4Hz,2H),5.41(s,2H),3.93(s,3H).

[0405] Preparation of compound CQ1289:

[0406] Compound 49i (100 mg, 0.29 mmol), compound 1j (129 mg, 0.41 mmol), and 4-dimethylaminopyridine (3.3 mg, 0.027 mmol) were dissolved in 2 mL of N,N-dimethylamide, and triethylamine (82 mg, 0.87 mmol) was added. The mixture was reacted overnight at 60 °C. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The organic phase was stirred with silica gel and separated by column chromatography to obtain 118 mg of compound CQ1289, with a yield of 72%.

[0407] 1 H NMR (400MHz, DMSO) δ12.14(s,1H),9.66(s,1H),8.96(s,1H),8.30(d,J=1.6Hz,1H),8.26(d,J=4.0Hz,1H),7.87(d,J=6.8Hz,2H ),7.41-7.54(m,5H),7.07-7.12(m,1H),7.03(d,J=16.4Hz,1H),7.00(d,J=8.4Hz,1H),6.91(s,1H),3.94(s,3H),1.56(s,6H).

[0408] Example 50: Preparation of compound CQ1290

[0409] Preparation of compound 50b:

[0410] Compound 50a (124 mg, 0.36 mmol), 10% palladium on carbon (10 mg, 0.094 mmol), palladium hydroxide on carbon (10 mg, 0.071 mmol), and 4 mL of methanol were mixed, purged with hydrogen, and reacted at 60 °C. After the reaction was complete, the mixture was filtered, and the filtrate was mixed with silica gel and separated by column chromatography to obtain 100 mg of compound 50b, with a yield of 80%.

[0411] 1 H NMR (400MHz, DMSO) δ11.82(s,1H),8.18(d,J=4.8Hz,1H),8.11(d,J=2.0Hz,1H),7.78(d,J=7.6Hz,1H),7.58-7.66(m,1H),7.01-7.07(m, 1H),6.88(d,J=8.8Hz,1H),6.79(d,J=8.4Hz,2H),6.44(d,J=8.4Hz,2H),4.82(s,2H),3.89(s,3H),2.91-3.01(m,2H),2.80-2.89(m,2H).

[0412] Preparation of compound CQ1290:

[0413] Compound 50b (100 mg, 0.29 mmol), compound 1j (139 mg, 0.44 mmol), and 4-dimethylaminopyridine (3.5 mg, 0.028 mmol) were dissolved in 3 mL of N,N-dimethylamide. Triethylamine (86.5 mg, 0.86 mmol) was added, and the mixture was reacted overnight at 70 °C. After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium chloride aqueous solution. The organic phase was stirred with silica gel and separated by column chromatography to obtain 112 mg of compound CQ1290, with a yield of 68%.

[0414] 1 H NMR (400MHz, DMSO) δ11.86(s,1H),9.60(s,1H),8.72(s,1H),8.15(d,J=30.8Hz,2H),7.77(s,1H),7. 61(s,1H),7.31(s,2H),7.05(s,3H),6.88(s,2H),3.89(s,3H),3.01(d,J=13.6Hz,4H),1.54(s,6H).

[0415] Example 51: Preparation of compound CQ1292

[0416] Preparation of compound 51b:

[0417] Compound 51a (150 mg, 0.72 mmol), compound 1j (340 mg, 1.08 mmol), and 4-dimethylaminopyridine (9 mg, 0.072 mmol) were dissolved in 7 mL of N,N-dimethylamide. Triethylamine (218.5 mg, 2.16 mmol) was added, and the mixture was reacted overnight at 70 °C. After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium chloride aqueous solution. The organic phase was stirred with silica gel and separated by column chromatography to obtain 305 mg of compound 51b, with a yield of 98%.

[0418] 1 H NMR (400MHz, CDCl3) δ8.78(s,1H),8.55(s,1H),7.37(d,J=8.8Hz,2H),7.31(d,J=8.8Hz,2H),6.50(s,1H),6.31(s,1H),1.64(s,6H),1.52(s,9H).

[0419] Preparation of compound 51c:

[0420] Compound 51b (302 mg, 0.71 mmol) was dissolved in 5 mL of dichloromethane and 5 mL of trifluoroacetic acid. The mixture was stirred at room temperature and reacted. After the reaction was completed, the mixture was evaporated under vacuum at 60 °C to obtain a concentrated solution. Water was added and the pH was adjusted to weakly alkaline with a saturated sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate, and the organic layer was mixed with silica gel and separated by column chromatography to obtain 223 mg of compound 53c, with a yield of 96%.

[0421] 1 H NMR (400MHz, DMSO) δ9.48(s,1H),8.33(s,1H),7.06(d,J=8.8Hz,2H),6.84(s,1H),6.51(d,J=8.4Hz,2H),4.84(s,2H),1.54(s,6H).

[0422] Preparation of compound CQ1292:

[0423] Compound 51c (223 mg, 0.68 mmol) and compound 51g (143 mg, 0.57 mmol) were dissolved in 6 mL of dichloromethane, and acetic acid (32 μL, 0.57 mmol) was added. The mixture was stirred at 0 °C for 3 hours, and sodium triacetoxyborohydride (432 mg, 2.0 mmol) was added. The mixture was then moved to room temperature and reacted overnight. The next day, most of the organic solvent was removed by rotary evaporation under vacuum. The mixture was extracted with water and ethyl acetate, and the organic layer was washed with a saturated sodium bicarbonate aqueous solution. The organic layer was mixed with silica gel and separated by column chromatography to obtain 87 mg of compound CQ1292, with a yield of 27%.

[0424] 1 H NMR (400MHz, DMSO) δ11.89(s,1H),9.47(s,1H),8.34(d,J=19.2Hz,2H),8.23(d,J=3.6Hz,1H),7.90(dd,J=19.2,8.0Hz,2H),7.21-7 .04(m,3H),6.95(d,J=8.4Hz,1H),6.84(s,1H),6.53(d,J=8.4Hz,2H),5.88(s,1H),4.34(d,J=4.0Hz,2H),3.90(s,3H),1.53(s,6H).

[0425] Example 52: Preparation of compound CQ-XMJ-C06

[0426] Preparation of compound 52b:

[0427] Compound 52a (10 g, 53.2 mmol) was dissolved in 170 mL of N,N-dimethylamide. Sodium hydride (2.5 g, 63.8 mmol) was added in portions at 0 °C, followed by dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (12.4 g, 74.5 mmol). After the addition was complete, the mixture was allowed to react at room temperature. Once the reaction was complete, the mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was stirred with silica gel. The mixture was then separated by column chromatography to obtain 16.6 g of compound 52b, with a yield of 98%.

[0428] 1 H NMR (400MHz, DMSO) δ7.88 (d, J = 3.6 Hz, 1H), 6.74 (d, J = 3.6 Hz, 1H), 5.58 (s, 2H), 3.46-3.55 (m, 2H), 0.78-0.85 (m, 2H), -0.11 (s, 9H).

[0429] Preparation of compound 52c:

[0430] Compound 52b (16.6 g, 52.2 mmol) was dissolved in 180 mL of 1,4-dioxane, and 1 M potassium tert-butoxide in tetrahydrofuran solution (213 mL, 213 mmol) was added. The reaction was allowed to proceed overnight, and the mixture was extracted with water and ethyl acetate the next day. The organic phase was stirred with silica gel and separated by column chromatography to give 6.2 g of compound 52c, with a yield of 33%.

[0431] 1 H NMR (400MHz, CDCl3) δ7.08(d,J=3.6Hz,1H),6.49(d,J=3.6Hz,1H),5.53(s,2H),3.43-3.58(m,2H),1.69(s,9H),0.86-0.93(m,2H),-0.05(s,9H).

[0432] Preparation of compound 52d:

[0433] Compound 52c (6.2 g, 17.4 mmol) was dissolved in 35 mL of dry tetrahydrofuran. Under argon protection, the mixture was stirred at -78 °C for 15 minutes. A 2 M lithium diisopropylamine solution in tetrahydrofuran / n-heptane (13 mL, 22.6 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 hour. Then, 35 mL of a tetrahydrofuran solution containing iodine (5.7 g, 22.6 mmol) was added, and the reaction was allowed to proceed overnight. Dry N,N-dimethylamide (3.8 mL, 48 mmol) was added dropwise, and the reaction was continued at -30 °C. After the reaction was complete, the mixture was quenched with a saturated sodium thiosulfate aqueous solution, extracted with ethyl acetate, and the organic layer was stirred with silica gel and passed through a column to give 7.3 g of compound 52d, with a yield of 87%.

[0434] 1 H NMR (400MHz, CDCl3) δ6.82(s,1H),5.56(s,2H),3.53-3.60(m,2H),1.68(s,9H),0.88-0.96(m,2H),-0.04(s,9H).

[0435] Preparation of compound 52f:

[0436] Compound 52d (7.3 g, 15.15 mmol), compound 54e (5 g, 18.18 mmol), tetrakis(triphenylphosphine)palladium (0.87 g, 0.76 mmol), cesium carbonate (14.8 g, 45.45 mmol), and 1,4-dioxane / water (5:1) mixed solvent were mixed and reacted under argon protection at 100 °C. After the reaction was completed, ethyl acetate and water were added for extraction. The organic phase was stirred with silica gel and column chromatography was performed to obtain 5.9 g of compound 52f, with a yield of 77%.

[0437] 1 H NMR (400MHz, CDCl3) δ8.23(d,J=8.8Hz,2H),7.62(d,J=8.8Hz,2H),7.37(d,J=16.4Hz,1H),7.27(d,J=1 6.4Hz,2H),6.85(s,1H),5.71(s,2H),3.54-3.64(m,2H),1.72(s,9H),0.91-0.98(m,2H),-0.04(s,9H).

[0438] Preparation of compound 52i:

[0439] Compound 52f (5.2 g, 10.33 mmol), palladium acetate (166 mg, 0.52 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (322 mg, 0.52 mg), cesium carbonate (5 g, 15.5 mmol), compound 54 g (2.44 g, 13.44 mmol), and 105 mL of 1,4-dioxane were mixed and reacted at 100 °C for 6 hours under argon protection. The mixture was extracted with water and ethyl acetate, and the organic phase was rotary evaporated under vacuum. The concentrated solution was then reacted with sodium acetate (4 g, 49.58 mmol) and hydroxyl hydrochloride. Amine (2.8 g, 41.32 mmol) was mixed with 104 mL of methanol and reacted overnight at room temperature. After the reaction was complete, the methanol was evaporated, and the mixture was extracted with water and ethyl acetate. The organic layer was concentrated under vacuum to obtain a concentrate. The concentrate was mixed with iron powder (970 mg, 17.4 mmol), ammonium chloride (1.24 g, 23.2 mmol), and 29 mL of 80% ethanol aqueous solution and reacted at 85 °C. After the reaction was complete, the mixture was filtered while hot, and the filter cake was washed with ethyl acetate and water, respectively. The filtrate was separated, and the organic phase was mixed with silica gel and passed through a column to obtain 1.4 g of compound 52i, with a yield of 34%.

[0440] 1 H NMR (400MHz, DMSO) δ10.38(s,1H),7.19(d,J=8.4Hz,2H),6.90(d,J=16.0Hz,1H),6.80(d,J=16.4Hz,1H),6. 51-6.57(m,3H),6.27(s,2H),5.44(s,2H),5.26(s,2H),3.45-3.55(m,2H),0.79-0.89(m,2H),-0.09(s,9H).

[0441] Preparation of compound 52j:

[0442] Compound 52i (533 mg, 1.34 mmol) was dissolved in 4 mL of chloroform and 4 mL of trifluoroacetic acid and reacted at room temperature. After the reaction was complete, the reaction solution was evaporated to dryness, and ethylenediamine (1.45 g, 24 mmol) and 7 mL of methanol / tetrahydrofuran (1:1) mixed solvent were added. The mixture was stirred at room temperature for 1 hour, extracted with ethyl acetate and saturated sodium chloride, and the organic layer was mixed with silica gel and separated by column chromatography to obtain 250 mg of compound 52j, with a yield of 70%.

[0443] 1H NMR (400MHz, DMSO) δ11.19(s,1H),10.27(s,1H),7.12(d,J=8.4Hz,2H),6.79(d,J=16.4 Hz,1H),6.64(d,J=16.8Hz,1H),6.53(d,J=8.0Hz,2H),6.09-6.24(m,3H),5.20(s,2H).

[0444] Preparation of compound CQ-XMJ-C06:

[0445] Compound 52j (55 mg, 0.21 mmol), compound 1j (97 mg, 0.31 mmol), and 4-dimethylaminopyridine (2.5 mg, 0.021 mmol) were dissolved in 2 mL of N,N-dimethylamide. Triethylamine (63 mg, 0.62 mmol) was added, and the mixture was reacted overnight at 70 °C. After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium chloride aqueous solution. The organic phase was stirred with silica gel and separated by column chromatography to obtain 35 mg of compound CQ-XMJ-C06, with a yield of 35%.

[0446] 1 H NMR (400MHz, DMSO) δ11.32(s,1H),10.30(s,1H),9.68(s,1H),8.88(s,1H),7.44(d,J=8.8 Hz,2H),7.38(d,J=8.8Hz,2H),6.84-6.97(m,3H),6.31(s,1H),6.20(s,2H),1.56(s,6H).

[0447] Example 53: Preparation of compound CQ1281

[0448] The synthesis route and method are similar to those in Example 39.

[0449] 1 H NMR(400MHz, DMSO)δ13.15(s,1H)δ9.66(s,3H),8.88(s,1H),8.27–8.45(m,2H),8.00&8.21(2s, 1H),7.54(s,1H),7.41–7.48(m,4H),6.93–7.07(m,2H),6.90(s,1H),3.89(s,3H),1.55(s,6H).

[0450] Example 54: Preparation of compound CQ1353

[0451] Preparation of compound 54a:

[0452] Compound 54d (195 mg, 0.51 mmol), compound 54e (209 mg, 0.76 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (19 mg, 0.025 mmol), potassium carbonate (210 mg, 1.52 mmol), and 5 mL of a 4-dioxane / water (5:1) mixture were mixed and reacted under argon protection at 100 °C. After the reaction was complete, the mixture was extracted with ethyl acetate and water, and the organic phase was stirred with silica gel and passed through a column to obtain 178 mg of compound 54a, with a yield of 86%.

[0453] 1 H NMR(400MHz,Chloroform-d)δ8.47(t,J=2.4Hz,1H),8.32(s,1H),8.15(d,J=8.4Hz,2H) ,7.98(s,1H),7.47(d,J=8.4Hz,2H),7.41(s,1H),6.96(d,J=16.4Hz,1H),6.89(d,J=16 .0,1H),4.99-5.12(m,1H),4.05-4.17(m,1H),3.93(s,3H),3.50-3.60(m,1H),2.48-2. 62(m,1H),2.02-2.14(m,1H),1.82-1.92(m,1H),1.66-1.78(m,1H),1.50-1.63(m,2H).

[0454] Preparation of compound 54b:

[0455] Compound 54a (178 mg, 0.44 mmol) was dissolved in 3 mL of dichloromethane and 3 mL of trifluoroacetic acid and reacted at room temperature for 30 minutes. After the organic solvent was removed by rotary evaporation under vacuum, iron powder (147 mg, 2.63 mmol), ammonium chloride (188 mg, 3.51 mmol), and 10 mL of 80% aqueous ethanol solution were added and reacted at 80 °C. After the reaction was completed, the mixture was filtered while hot, and the filter cake was washed with ethyl acetate and water, respectively. The filtrate was separated, and the organic phase was mixed with silica gel and passed through a column to obtain 125 mg of compound 54b, with a yield of 97%.

[0456] 1 H NMR(400MHz,DMSO-d6)δ13.16(s,1H),8.26-8.60(m,2H),8.04(s,1H),7.53(s, 1H),7.04-7.32(m,4H),6.74-6.88(m,2H),6.58(d,J=8.0Hz,2H),3.89(s,3H).

[0457] Preparation of compound CQ1353:

[0458] Compound 54b (125 mg, 0.43 mmol), compound 1j (202 mg, 0.64 mmol), and 4-dimethylaminopyridine (5.3 mg, 0.043 mmol) were dissolved in 3 mL of N,N-dimethylamide. Triethylamine (131 mg, 0.87 mmol) was added, and the mixture was reacted overnight at 80 °C. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The organic phase was stirred with silica gel and separated by column chromatography to obtain 138 mg of compound CQ1353, with a yield of 63%.

[0459] 1 H NMR (400MHz, DMSO) δ13.22&13.32(2s,1H),9.66(s,1H),8.88(s,1H),8.27–8.45(m,2H),8.00&8.21 (2s,1H),7.54(s,1H),7.41–7.48(m,4H),6.93–7.07(m,2H),6.90(s,1H),3.89(s,3H),1.55(s,6H).

[0460] Example 55: Preparation of compound CQ1356

[0461] The synthesis route and method are similar to those in Example 54.

[0462] 1 H NMR (400MHz, DMSO) δ13.15&13.29(2s,1H),9.66(s,1H),8.89(s,1H),7.95–8.28(m,2H),7.88(s,1H),7.40–7. 50(m,4H),7.22–7.36(m,2H),6.92–7.15(m,2H),6.90(s,1H),3.95(s,3H),2.83(d,J=3.6Hz,3H),1.55(s,6H).

[0463] Example 56: Preparation of compound CQ1384

[0464] The synthesis route and method are similar to those in Example 17.

[0465] 1H NMR (400MHz, DMSO) δ13.19&13.41(2s,1H),9.69(s,1H),8.94(s,2H),8.80(s,1H),8.17-8.39(m,2H),7.86&8.13( 2s,1H),7.64(s,1H),7.38-7.58(m,4H),7.24(d,J=16.0Hz,1H),7.05(d,J=16.0Hz,1H),6.90(s,1H),1.55(s,6H).

[0466] Example 57: Preparation of compound CQ1385

[0467] The synthesis route and method are similar to those in Example 17.

[0468] 1 H NMR (400MHz, DMSO) δ13.14&13.30(2s,1H),10.01&10.25(2s,1H),8.70&8.88(2s,1H),7.77-8.22( m,4H),7.24-7.69(m,2H),7.07-7.23(m,4H),6.89(s,1H),3.95(s,3H),2.82(s,3H),1.55(s,6H).

[0469] Example 58: Preparation of compound CQ1386

[0470] The synthesis route and method are similar to those in Example 17.

[0471] 1 H NMR(400MHz,DMSO-d6)δ13.26(s,1H),10.42(s,1H),8.69(s,1H),8.45-8.5 5(s,1H),8.17(d,J=8.8Hz,1H),7.81-7.95(m,2H),7.72-7.77(m,1H),7.69( d,J=2.0Hz,1H),7.57-7.64(m,1H),7.46-7.56(m,2H),7.21(d,J=16.4Hz,1 H),7.12(d,J=16.4Hz,1H),6.88(s,1H),2.80(d,J=4.4Hz,3H),1.56(s,6H).

[0472] Example 59: Preparation of compound CQ1387

[0473] The synthesis route and method are similar to those in Example 17.

[0474] 1 H NMR (400MHz, DMSO-d6) δ13.14(s,1H),10.42(s,1H),8.69(s,1H),8.16(d,J=8.8Hz,1H),7.61-7.80(m,2H),7.49(dd,J=8.8, 2.4Hz,1H),7.16(d,J=16.4Hz,1H),7.07(d,J=16.4Hz,1H),6.96-7.04(m,2H),6.84-6.95(m,2H),6.04(s,2H),1.56(s,6H).

[0475] Example 60: Preparation of compound CQ1388

[0476] The synthesis route and method are similar to those in Example 17.

[0477] 1 H NMR(400MHz,DMSO-d6)δ13.16&13.35(2s,1H),10.43(s,1H),8.71(s,1H),7.81-8.24(m,4H),7.72(s,1H) ,7.53(d,J=8.4Hz,1H),7.09-7.27(m,4H),6.89(s,1H),3.95(s,3H),2.82(d,J=4.8Hz,3H),1.56(s,6H).

[0478] Example 61: Preparation of compound CQ1389

[0479] The synthesis route and method are similar to those in Example 17.

[0480] 1 H NMR(400MHz,DMSO-d6)δ13.10&13.30(2s,1H),10.42(s,1H),8.69(s,1H),7.69-8.21(m,5H),7.51 (d,J=8.4Hz,1H),7.33(d,J=8.8Hz,1H),7.06-7.23(m,2H),6.88(s,1H),3.95(s,3H),1.56(s,6H).

[0481] Example 62: Preparation of compound CQ1390

[0482] The synthesis route and method are similar to those in Example 17.

[0483] 1 H NMR (400MHz, DMSO-d6) δ13.40(s,1H),10.43(s,1H),8.70(s,1H),8.59(t,J=2.0Hz,1H),8.50(d,J=2.8Hz,1H),8.17(d,J=8.8Hz ,1H),8.00(s,1H),7.81-7.89(m,1H),7.79(d,J=2.0Hz,1H),7.54(dd,J=8.8,2.0Hz,1H),7.21(s,2H),6.89(s,1H),1.56(s,6H).

[0484] Example 63: Preparation of compound CQ1391

[0485] The synthesis route and method are similar to those in Example 2.

[0486] 1 H NMR (400MHz, DMSO-d6) δ13.49(s,1H),9.78(s,1H),9.12(s,1H),8.66(d,J=1.6Hz,1H),8.39(s,1H),8.21(d,J=2.8 Hz,1H),7.81(t,J=2.0Hz,1H),7.56(d,J=8.4Hz,2H),7.51(d,J=8.4Hz,2H),6.91(s,1H),3.86(s,3H),1.56(s,6H).

[0487] Example 64: Preparation of compound CQ-YGP-B5

[0488] Preparation of compound 64c:

[0489] Compound 64a (2 g, 9.565 mmol), compound 64b (1.147 g, 11.478 mmol), and cesium carbonate (1.525 g, 11.478 mmol) were dissolved in 20 mL of dimethyl sulfoxide and stirred overnight at 100 °C. When the starting material was exhausted, the filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 2.563 g of a white solid, yield 92.04%.

[0490] 1H NMR(400MHz, CDCl3) δ8.49(d,J=2.8Hz,1H),8.24(dd,J=9.3,2.7Hz,1H),7.18(d,J =9.2Hz,1H),3.39(t,J=7.1Hz,2H),3.00(s,3H),2.53(t,J=7.1Hz,2H),2.23(s,6H)

[0491] Preparation of compound 64d:

[0492] Compound 64c (2.558 g), reduced iron powder (2.942 g, 55.82 mmol), and ammonium chloride (3.760 g, 70.288 mmol) were mixed and 30 mL of ethanol / water (4:1, v / v) was added. The mixture was then moved to 80 °C and reacted overnight. After the starting material was exhausted, the mixture was filtered while hot. The filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution and dried with anhydrous sodium sulfate. The mixture was then separated by column chromatography with silica gel powder to obtain 1.006 g of white solid, with a yield of 43.85%.

[0493] 1 H NMR (400MHz, CDCl3) δ7.22(d,J=8.5Hz,1H),6.88(s,1H),6.82(d,J=8.6Hz,1H),3. 81(s,2H),3.16(t,J=7.5Hz,2H),2.65(t,J=7.6Hz,2H),2.60(s,3H),2.47(s,6H).

[0494] Preparation of compound 64f:

[0495] Compounds 64d (1.006 g, 3.852 mmol), 64e (1.352 g, 5.008 mmol), 4-dimethylaminopyridine (47 mg, 0.385 mmol), and triethylamine (2.142 mL, 15.408 mmol) were dissolved in 8 mL of N,N-dimethylacetamide. After the addition was complete, the mixture was moved to 90 °C and reacted overnight. When the starting material was exhausted, the filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain a white solid at 1.053 μL, with a yield of 67.63%.

[0496] 1H NMR (600MHz, CDCl3) δ8.21(s,1H),8.16(s,1H),7.53(d,J=2.6Hz,1H),7.46(d,J=8.6Hz,1H),7.37–7.29(m,2H),7. 26(d,J=6.0Hz,2H),7.19(d,J=8.7Hz,1H),3.01(s,1H),2.95(s,2H),2.55(s,3H),2.45–2.39(m,2H),2.25(s,6H).

[0497] Preparation of compound CQ-YGP-B5:

[0498] Compounds 64f (300 mg, 0.742 mmol), 64i (268 mg, 0.891 mmol), cuprous iodide (14 mg, 0.0742 mmol), and diphenylphosphine palladium chloride (26 mg, 0.071 mmol) were mixed under argon protection. Triethylamine (0.62 mL, 4.452 mmol) and 5 mL tetrahydrofuran were then added, and the mixture was reacted at 70 °C overnight. After the reaction was complete, the solvent was evaporated, and the mixture was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 178 mg of a white solid, with a yield of 27.02%.

[0499] 1 H NMR (400MHz, DMSO) δ13.56(s,1H),9.05(d,J=10.6Hz,2H),8.87(s,1H),8.32(d,J=2.8Hz,1H),8.17(s,1H),7.98–7.87(m,2H),7.66–7.56 (m,2H),7.54(d,J=8.7Hz,2H),7.44(d,J=8.5Hz,2H),3.88(s,3H),2.97(t,J=7.7Hz,2H),2.60(s,4H),2.34(d,J=8.1Hz,2H),2.18(s,6H).

[0500] Example 65: Preparation of compound CQ-YGP-B6

[0501] The synthesis route and method are similar to those in Example 64.

[0502] 1H NMR (400MHz, DMSO) δ13.55(s,1H),9.02(d,J=33.9Hz,2H),8.87(s,1H),8.32(s,1H),8.19(s,1H),7.97(t,J=2.2Hz,1H),7.85(d,J=2.6Hz,1H),7. 58(dd,J=9.0,2.6Hz,1H),7.53(d,J=8.5Hz,2H),7.43(d,J=8.4Hz,2H),7 .25(d,J=9.1Hz,1H),4.21(s,2H),3.88(s,3H),2.85(s,2H),2.38(s,6H).

[0503] Example 66: Preparation of compound CQ-YGP-A94

[0504] The synthesis route and method are similar to those in Example 64.

[0505] 1 H NMR (400MHz, DMSO) δ13.56 (s, 1H), 9.05 (s, 1H), 8.97 (s, 1H), 8.87 (d, J = 1.7Hz, 1H), 8 .32(d,J=2.8Hz,1H),8.17(s,1H),8.01–7.93(m,1H),7.84(d,J=2.7Hz,1H),7.54(dd ,J=11.1,7.7Hz,3H),7.43(d,J=8.3Hz,2H),7.27(d,J=9.0Hz,1H),4.57(s,1H),3.88 (s,3H),2.66(d,J=13.0Hz,2H),2.42(s,2H),2.29(s,3H),1.95(s,2H),1.73(s,2H).

[0506] Example 67: Preparation of compound CQ-WKF-L70

[0507] The synthesis route and method are similar to those in Example 64.

[0508] 1H NMR (400MHz, DMSO) δ13.61(d,J=118.5Hz,1H),9.37(d,J=13.9Hz,1H),9.14(s,1H),8.89(s,1H),8.29(d,J=16.5Hz,1H),8.16(s,1H),7. 97(s,1H),7.74(d,J=8.8Hz,1H),7.66(s,1H),7.56(d,J=7.7Hz,3H),7.46(dd,J=8.6,3.4Hz,3H),7.06(s,1H),3.88(s,3H),2.17(s,3H).

[0509] Example 68: Preparation of compound CQ-WKF-L69

[0510] The synthesis route and method are similar to those in Example 64.

[0511] 1 H NMR (400MHz, DMSO) δ13.56 (s, 1H), 8.89 (d, J = 16.1Hz, 2H), 8.66 (s, 1H), 8.32 (s ,1H),8.16(s,1H),7.97(s,1H),7.68(s,1H),7.51(d,J=8.3Hz,2H),7.42(d,J= 8.4Hz,3H),6.90(d,J=9.1Hz,1H),4.35(d,J=7.7Hz,1H),3.88(s,3H),2.74(s, 2H), 2.23 (s, 3H), 2.16 (s, 2H), 1.90 (d, J = 12.4Hz, 2H), 1.52 (d, J = 11.8Hz, 2H).

[0512] Example 69: Preparation of compound CQ-WKF-L56

[0513] The synthesis route and method are similar to those in Example 64.

[0514] 1H NMR (400MHz, DMSO) δ13.56 (s, 1H), 8.89 (d, J = 16.1Hz, 2H), 8.66 (s, 1H), 8.32 (s ,1H),8.16(s,1H),7.97(s,1H),7.68(s,1H),7.51(d,J=8.3Hz,2H),7.42(d,J= 8.4Hz,3H),6.90(d,J=9.1Hz,1H),4.35(d,J=7.7Hz,1H),3.88(s,3H),2.74(s, 2H), 2.23 (s, 3H), 2.16 (s, 2H), 1.90 (d, J = 12.4Hz, 2H), 1.52 (d, J = 11.8Hz, 2H).

[0515] Example 70: Preparation of compound CQ-WKF-L35

[0516] The synthesis route and method are similar to those in Example 64.

[0517] 1 H NMR (400MHz, DMSO) δ13.64(d,J=119.2Hz,1H),9.09(s,1H),9.01(s,1H),8.90(s,1H),8.30(d,J=12.4Hz,2H),8.01–7.94(m,2H),7.67(d,J=8.5 Hz,1H),7.62–7.57(m,1H),7.55(d,J=8.7Hz,2H),7.45(d,J=8.3Hz,2H),3.89(s,3H),3.60(t,J=4.6Hz,4H),3.56(s,2H),2.39(d,J=5.1Hz,4H)

[0518] Example 71: Preparation of compound CQ-1392

[0519] The synthesis route and method are similar to those in Example 64.

[0520] 1H NMR (400MHz, DMSO) δ13.62(s,1H),9.40(s,2H),8.94(s,1H),8.40–8.06(m,2H),7.96(dd,J=4.7,2.2Hz,2H),7.86(d,J=2.1Hz ,2H),7.62(q,J=8.8Hz,2H),7.54(d,J=8.5Hz,1H),7.38(d,J=8.3Hz,1H),3.89(s,4H),3.55(s,3H),2.42(s,8H),2.23(s,3H).

[0521] Example 72: Preparation of compound CQ-YGP-A90

[0522] Preparation of compound 72b:

[0523] Compound 72a (3 g, 17.3 mmol) was dissolved in 60 mL of dichloromethane under argon protection, and then trifluoromethanesulfonic anhydride (4.35 mL, 25.93 mmol) and pyridine (2.8 mL, 34.6 mmol) were added. The mixture was stirred overnight at room temperature. When the starting material was exhausted, the filtrate was extracted with water and dichloromethane. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 4.932 g of yellow solid, with a yield of 93.3%.

[0524] 1 H NMR (400MHz, CDCl3) δ8.44(d,J=2.8Hz,1H),8.25(dd,J=9.1,2.6Hz,1H),7.58(d,J=9.1

[0525] Preparation of compound 72c:

[0526] Compound 72b (4.932 g, 16.165 mmol), cuprous iodide (154 mg, 0.808 mmol), and di-triphenylphosphine palladium chloride (567 mg, 0.808 mmol) were added under argon protection. Trimethylsilylacetylene (3.43 mL, 24.25 mmol) and triethylamine (6.74 mL, 48.495 mmol) were then added to 54 mL of tetrahydrofuran. The mixture was stirred overnight at room temperature. When the starting material was exhausted, the filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 3.25 g of a yellow solid, yield 79.23%.

[0527] 1H NMR (400MHz, CDCl3) δ8.32–8.23(m,1H),8.10–8.02(m,1H),7.64(d,J=8.5Hz,1H),0.33–0.25(m,10H).

[0528] Preparation of compound 72d:

[0529] Compound 72c (3.25 g, 12.81 mmol) and potassium carbonate (5.31 g, 38.42 mmol) were dissolved in 40 mL of methanol and stirred at room temperature for 2 h. When the starting material was exhausted, the filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 2.23 g of a yellow solid, with a yield of 90.23%.

[0530] 1 H NMR (400MHz, CDCl3) δ6.91 (d, J = 2.6Hz, 1H), 6.85–6.76 (m, 2H), 4.43 (s, 1H).

[0531] Preparation of compound 72e:

[0532] Compound 72d (2.23 g), reduced iron powder (4.11 g, 73.68 mmol), and ammonium chloride (5.25 g, 98.24 mmol) were mixed and 40 mL of ethanol / water mixed solvent (4:1, v / v) was added. The mixture was then moved to 80 °C and reacted overnight. After the starting material was exhausted, the mixture was filtered while hot. The filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution and dried with anhydrous sodium sulfate. The mixture was then separated by column chromatography with silica gel powder to obtain 1.132 g of white solid, with a yield of 60.24%.

[0533] 1 H NMR (400MHz, CDCl3) δ7.29(d,J=8.3Hz,1H),6.68(d,J=2.4Hz,1H),6.48(dd,J=8.4,2.4Hz,1H),3.88(s,2H),3.23(s,1H).

[0534] Preparation of compound 72f:

[0535] Compound 72e (1.13 g, 7.508 mmol), phenyl chloroformate (1.419 g, 9.009 mmol), and potassium carbonate (5.31 g, 38.42 mmol) were added to 19 mL of tetrahydrofuran and stirred overnight at room temperature. When the starting material was exhausted, the filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to give 2.23 g of a white solid, yield 47.14%.

[0536] 1 H NMR (400MHz, CDCl3) δ7.61(d,J=2.3Hz,1H),7.46(d,J=8.5Hz,1H),7.38(t,J=7 .8Hz,2H),7.24(d,J=2.0Hz,2H),7.19–7.13(m,2H),6.98(s,1H),3.30(s,1H).

[0537] Preparation of 72g of compound:

[0538] Compound 72f (959 mg, 3.141 mmol), compound 72i (660 mg, 2.416 mmol), 4-dimethylaminopyridine (29.5 mg, 0.2416 mmol), and triethylamine (1.746 mL, 12.564 mmol) were added to 4 mL of N,N-dimethylacetamide and stirred overnight at 90 °C. When the starting material was exhausted, the filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 630 mg of a white solid, yield 44.48%.

[0539] 1H NMR (600MHz, DMSO) δ9.15(d,J=6.2Hz,2H),7.94(d,J=2.2Hz,1H),7.81(d,J=2.2Hz,1H),7.63(d,J=8.5Hz,1H),7.57(dd,J =8.4,2.3Hz,1H),7.50(d,J=8.5Hz,1H),7.32(dd,J=8.5,2.2Hz,1H),4.41(s,1H),3.52(s,2H),2.38(s,8H),2.15(s,3H).

[0540] Preparation of compound CQ-YGP-A90:

[0541] 72 g (346 mg, 0.769 mmol) of compound 72k (277 mg, 0.922 mmol), cuprous iodide (14 mg, 0.0769 mmol), and diphenylphosphine palladium chloride (27 mg, 0.03845 mmol) were mixed under argon protection, and then triethylamine (0.7 mL, 4.614 mmol) and 5 mL tetrahydrofuran were added. The mixture was then moved to 70 °C and reacted overnight. After the reaction was complete, the solvent was evaporated, and the mixture was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 178 mg of white solid, with a yield of 27.02%.

[0542] 1H NMR (400MHz, DMSO) δ13.62(s,1H),9.40(s,2H),8.94(s,1H),8.33(d,J=2.8Hz,1H),8.22(s,1H),7.96(dt,J=4.7,2.0Hz,2H),7.86(d, J=2.1Hz,1H),7.62(d,J=6.7Hz,2H),7.54(d,J=8.5Hz,1H),7.38(d,J=8.3Hz,1H),3.89(s,3H),3.55(s,2H),2.41(s,8H),2.23(s,3H).

[0543] Example 73: Preparation of compound CQ-XMJ-F73

[0544] The synthesis route and method are similar to those in Example 72.

[0545] 1 H NMR (600MHz, DMSO) δ13.62(s,1H),9.69(s,1H),9.60(s,1H),8.88(s,1H),8.32(d,J=2.7Hz,1H),8.23(s,1H),8.03–7.87(m ,2H),7.63(d,J=3.9Hz,3H),7.48(t,J=8.4Hz,1H),7.28–7.13(m,1H),3.88(s,3H),3.59(s,2H),2.77(s,8H),2.47(s,3H).

[0546] Example 74: Preparation of compound CQ-XMJ-F62

[0547] The synthesis route and method are similar to those in Example 72.

[0548] 1 H NMR (400MHz, DMSO) δ13.60(s,1H),9.85(s,1H),8.84(s,1H),8.54(s,1H),8.37–8.13(m,3H),7.97(d,J=20.5Hz,2H),7.7 1–7.60(m,2H),7.56(d,J=8.0Hz,1H),7.49–7.40(m,1H),3.88(s,3H),3.53(s,2H),2.35(d,J=20.9Hz,8H),2.15(s,3H).

[0549] Example 75: Preparation of compound CQ-XMJ-F87

[0550] The synthesis route and method are similar to those in Example 72.

[0551] 1 H NMR (600MHz, DMSO) δ13.62(s,1H),9.69(s,1H),9.60(s,1H),8.88(s,1H),8.32(d,J=2.7Hz,1H),8.23(s,1H),8.03–7.87(m ,2H),7.63(d,J=3.9Hz,3H),7.48(t,J=8.4Hz,1H),7.28–7.13(m,1H),3.88(s,3H),3.59(s,2H),2.77(s,8H),2.47(s,3H).

[0552] Example 76: Preparation of compound CQ-XMJ-F68

[0553] The synthesis route and method are similar to those in Example 72.

[0554] 1 H NMR(400MHz,DMSO)δ13.56(s,1H),9.48(s,1H),8.86(s,1H),8.31(s,1H),8.15(s,2H),7.98(s,3H),7 .73–7.50(m,2H),7.47–7.23(m,2H),3.88(s,3H),3.53(s,2H),2.39(s,8H),2.26(s,3H),2.19(s,3H).

[0555] Example 77: Preparation of compound CQ-XMJ-F97

[0556] The synthesis route and method are similar to those in Example 72.

[0557] 1 H NMR (600MHz, DMSO) δ13.55(s,1H),9.31(s,1H),9.14(s,1H),8.90(d,J=1.8Hz,1H),8.32(d,J=2.8Hz,1H),8.17(s,1H),8.03 –7.86(m,2H),7.67–7.54(m,2H),7.52–7.29(m,3H),3.88(s,3H),3.55(s,2H),2.55–2.43(m,8H),2.41(s,3H),2.30(s,3H).

[0558] Example 78: Preparation of compound CQ-XMJ-F77

[0559] The synthesis route and method are similar to those in Example 72.

[0560] 1 H NMR (600MHz, DMSO) δ13.61(s,1H),10.30(s,1H),9.66(s,1H),8.86(d,J=1.7Hz,1H),8.46(dd,J=2.3,0.8Hz,1H),8.33(d,J=2.8Hz,1H ),8.21(s,1H),8.02(d,J=2.1Hz,1H),7.97–7.80(m,2H),7.75–7.60(m,3H),3.88(s,3H),3.55(s,2H),2.49–2.21(m,8H),2.16(s,3H).

[0561] Example 79: Preparation of compound CQ-1408

[0562] Preparation of compound 79c:

[0563] Compound 79a (2.765 g, 14.21 mmol), compound 79b (2.58 g, 14.21 mmol), cuprous iodide (269 mg, 1.42 mmol), and tetraphenylphosphine palladium (820 mg, 0.71 mmol) were mixed, and then triethylamine (11.8 mL, 85.26 mmol) and 30 mL tetrahydrofuran were added. The mixture was moved to 80 °C and reacted overnight. After the reaction was complete, the solvent was evaporated, and the mixture was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 2.125 g of yellow solid, with a yield of 57.02%.

[0564] 1 H NMR (400MHz, DMSO) δ13.35 (s, 1H), 8.26 (d, J = 8.4Hz, 2H), 7.81 (d, J = 8.4Hz, 2H), 6.63 (s, 1H).

[0565] Preparation of compound 79d

[0566] Compound 79c (1.92 g, 8.972 mmol) was dissolved in 40 mL of N,N-dimethylformamide and cooled to 0 °C. Then, N-iodosuccinimide (6.056 g, 26.916 mmol) was added in portions. After the addition was complete, the mixture was allowed to react at room temperature overnight. When the starting material was exhausted, the reaction was quenched with saturated sodium thiosulfate solution, extracted with ethyl acetate, and washed three times with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, mixed with silica gel powder, and separated by column chromatography to obtain 2.326 g of yellow solid, with a yield of 60%.

[0567] 1 H NMR (400MHz, DMSO) δ13.35 (s, 1H), 8.26 (d, J = 8.4Hz, 2H), 7.81 (d, J = 8.4Hz, 2H).

[0568] Preparation of compound 79e

[0569] Compound 79d (2.326 g, 7.16 mmol) was dissolved in 45 mL of tetrahydrofuran, and diethyl phthalate (1.529 g, 18.231 mmol) and p-toluenesulfonic acid (3.316 g, 18.213 mmol) were added. The reaction was carried out at room temperature. After the starting material was exhausted, the mixture was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was stirred with silica gel. The mixture was separated by column chromatography to give 2.326 g of white solid, with a yield of 57.23%.

[0570] 1 H NMR (600MHz, DMSO) δ8.27(s,1H),8.17(d,J=8.4Hz,1H),8.00(d,J=1.7Hz,1H),7.78(dd,J=8.4,1.7Hz,1H),5.47(dd,J=9.7,2.2Hz,1H),3.91(d,J =11.4Hz,1H),3.64(ddd,J=11.5,9.5,4.0Hz,1H),2.11–2.03(m,1H),1.9 2(d,J=11.2Hz,2H),1.67(td,J=10.6,5.5Hz,1H),1.55(d,J=5.0Hz,3H).

[0571] Preparation of compound 79f

[0572] Compound 79e (1.722 g, 4.033 mmol), reduced iron powder (1.350 g, 24.197 mmol), and ammonium chloride (1.726 g, 32.264 mmol) were mixed and 30 mL of a mixed solvent of ethanol / water (4:1, v / v) was added. The mixture was then moved to 80 °C and reacted overnight. After the starting material was exhausted, the mixture was filtered while hot. The filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution and dried with anhydrous sodium sulfate. The sample was mixed with silica gel powder and separated by column chromatography to obtain 1.26 g of white solid, with a yield of 73.38%.

[0573] 1 H NMR (400MHz, DMSO) δ8.17(s,1H),7.38(d,J=1.9Hz,1H),7.23(dd,J=8.4,1.9Hz,1H),6.82(d,J=8.4Hz,1H),5.94(s,2H),5.41(dd,J=9.7, 2.4Hz,1H),3.91(d,J=11.7Hz,1H),3.63(t,J=12.6Hz,1H),2.09(s,1H),1.92(s,2H),1.66(dd,J=10.4,4.9Hz,1H),1.54(d,J=6.9Hz,2H).

[0574] Preparation of compound 79h

[0575] Compound 79f (922 mg, 2.265 mmol), 79 g (692 mg, 2.945 mmol), palladium acetate (50.8 mg, 0.2265 mmol), 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (216 mg, 0.453 mmol), and potassium carbonate (939 mg, 6.795 mmol) were mixed under argon protection. 12 mL of dioxane / water (5:1, v / v) was added, and the mixture was reacted at 100 °C overnight. After the starting material was exhausted, the mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed three times with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The mixture was then separated by column chromatography with silica gel powder to obtain 812 mg of a white solid, with a yield of 69.38%.

[0576] Preparation of compound 79i

[0577] Compound 79h (821 mg, 1.93 mmol) and potassium carbonate (400 mg, 2.895 mmol) were dissolved in 10 mL of tetrahydrofuran, and then phenyl chloroformate (0.3 mL, 2.316 mmol) was added. After the addition was complete, the mixture was moved to room temperature and reacted overnight. When the starting material was exhausted, the filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 686 mg of white solid, with a yield of 69.93%.

[0578] Preparation of compound 79k

[0579] Compounds 79i (300 mg, 0.568 mmol), 79j (155 mg, 0.568 mmol), 4-dimethylaminopyridine (35 mg, 0.284 mmol), and triethylamine (0.32 mL, 2.272 mmol) were dissolved in 5 mL of tetrahydrofuran. After the addition was complete, the mixture was moved to 80 °C and reacted overnight. When the starting material was exhausted, the filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The sample was mixed with silica gel powder and separated by column chromatography to obtain 260 mg of white solid, with a yield of 67.31%.

[0580] Preparation of compound CQ-1408:

[0581] Compound 79k (260 mg, 0.2 mmol) was dissolved in 2 mL of dichloromethane, and then 2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours, evaporated to dryness, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate, evaporated to dryness, mixed with silica gel powder, and separated by column chromatography to obtain 65 mg of white solid.

[0582] 1 H NMR (400MHz, DMSO) δ13.57(s,1H),9.89(s,1H),8.71–8.51(m,2H),8.40(s,1H),8.30(d,J=8.6Hz,1H),8.21(d,J=2.8Hz,1H),7.98(d,J=2.2Hz,1H) ,7.79(t,J=2.3Hz,1H),7.71–7.66(m,1H),7.60(d,J=2.2Hz,1H),7.55–7. 48(m,1H),3.86(s,3H),3.59(s,2H),2.72(d,J=44.3Hz,8H),2.33(s,3H).

[0583] Example 80: Preparation of compound CQ-1409

[0584] The synthesis route and method are similar to those in Example 79.

[0585] 1H NMR (400MHz, DMSO) δ13.49(s,1H),9.63(s,1H),8.65(d,J=1.8Hz,1H),8.41(s,1H),8.27(s,1H),8.20(d,J=2.8Hz,1H),8.06–7.94(m,2H ),7.81(d,J=3.0Hz,1H),7.62(s,2H),7.46–7.33(m,2H),3.86(s,3H),3.60(s,2H),2.94(s,5H),2.61(s,3H),2.53(s,4H),2.28(s,3H).

[0586] Example 81: Preparation of compound CQ-1412

[0587] Preparation of compound 81b

[0588] Compound 81a (2 g, 7.590 mmol), cuprous iodide (14 mg, 0.0769 mmol), and diphenylphosphine palladium chloride (27 mg, 0.03845 mmol) were mixed under argon protection. Then, trimethylsilyne (1.6 mL, 111.384 mmol), diethanolamine (1.390 mL, 22.77 mmol), and 15 mL of tetrahydrofuran were added, and the mixture was reacted at 60 °C overnight. After the reaction was complete, the solvent was evaporated, and the mixture was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain a white solid at 1.938 μL, with a yield of 91.02%.

[0589] 1 H NMR (400MHz, CDCl3) δ7.49(d,J=1.6Hz,1H),7.31(dd,J=7.9,1.6Hz,1H),7.21(d,J=7.9Hz,1H),3.76(s,2H),0.24(s,9H).

[0590] Preparation of compound 81c

[0591] Compound 81b (1.84 g, 6.57 mmol) was dissolved in 20 mL of tetrahydrofuran, and tetrabutylamine fluoride (9 mL, 13.143 mmol) was added dropwise at 0 °C. The mixture was then transferred to room temperature and reacted for 2 h. After the reaction was complete, the solvent was evaporated, and the mixture was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain a 1.5 g white solid, with a yield of 91.02%.

[0592] 1H NMR (400MHz, CDCl3) δ7.54 (dd, J=15.6, 1.8Hz, 1H), 7.36 (td, J=7.9, 1.8Hz, 1H), 7.23 (s, 1H), 3.77 (s, 1H), 1.61 (s, 3H).

[0593] Preparation of compound 81d

[0594] Compound 81c (1.5 g, 12.02 mmol) and lithium hydroxide (1.11 g, 48.07 mmol) were added to 24 mL of a methanol / water (1:1, v / v) mixture. The mixture was then moved to room temperature and reacted overnight. After the starting material was exhausted, the mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed three times with saturated sodium chloride solution. The phase was then dried with anhydrous sodium sulfate, mixed with silica gel powder, and separated by column chromatography to obtain a white solid at 1.18 μL, with a yield of 92.57%.

[0595] 1 H NMR (400MHz, CDCl3) δ7.54 (dd, J=15.6, 1.8Hz, 1H), 7.36 (td, J=7.9, 1.8Hz, 1H), 7.23 (s, 1H), 3.77 (s, 1H)

[0596] Preparation of compound 81f

[0597] Compounds 81d (688 mg, 3.54 mmol), 81e (600 mg, 2.36 mmol), N,N-diisopropylethylamine (1.83 g, 14.16 mmol), and 2-(1H-benzotriazolyl-L-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate (1.6 g, 4.72 mmol) were dissolved in 5 mL of tetrahydrofuran. The mixture was then reacted overnight at room temperature. After the starting material was exhausted, the mixture was diluted with water, extracted with ethyl acetate, washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain a white solid at 1.04 g, yield 65.43%.

[0598] 1 H NMR (400MHz, DMSO) δ10.36(s,1H),7.86(d,J=2.2Hz,1H),7.57(dd,J=8.5,2.2Hz,1H),7.47(d,J=8.4Hz,1H),7.38 (d,J=1.3Hz,1H),7.28–7.22(m,2H),4.13(s,1H),3.69(s,2H),3.34(s,2H),2.15(d,J=16.0Hz,7H),1.97(s,3H).

[0599] Preparation of compound CQ1412

[0600] Compounds 81f (400 mg, 0.891 mmol), 81i (322 mg, 1.069 mmol), cuprous iodide (17 mg, 0.0891 mmol), and diphenylphosphine palladium chloride (32 mg, 0.04455 mmol) were mixed under argon protection. Triethylamine (0.75 mL, 4.614 mmol) and 5 mL tetrahydrofuran were then added, and the mixture was reacted overnight at 70 °C. After the reaction was complete, the solvent was evaporated, and the mixture was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 73 mg of a white solid, with a yield of 27.02%.

[0601] 1 H NMR (400MHz, DMSO) δ13.65(s,1H),10.58(s,1H),8.86(s,1H),8.34(d,J=2.8Hz,1H),8.24(s,1H),8.07(d,J=2.2Hz,1H),7.95(dd,J=2.9,1.7H z,1H),7.82–7.76(m,1H),7.68(s,1H),7.61(d,J=1.6Hz,1H),7.52–7.4 5(m,2H),3.91(d,J=4.9Hz,5H),3.56(s,2H),2.43(s,8H),2.25(s,3H).

[0602] Example 82: Preparation of compound 1413

[0603] The synthesis route and method are similar to those in Example 81.

[0604] 1 H NMR (400MHz, DMSO) δ13.70(s,1H),10.88(s,1H),8.86(d,J=1.7Hz,1H),8.36(d,J=2.8Hz,1H),8.28(s,1H),8.17(d,J=2.2Hz,1H), 7.97–7.88(m,2H),7.77–7.65(m,3H),7.60(dd,J=7.9,1.5Hz,1H),3.91(s,3H),3.60(s,2H),2.46(d,J=16.5Hz,8H),2.27(s,3H).

[0605] Example 83: Preparation of compound CQ-1414

[0606] The synthesis route and method are similar to those in Example 81.

[0607] 1 H NMR (400MHz, DMSO) δ13.57(s,1H),11.47(s,1H),8.86(s,1H),8.35(s,2H),7.95(dd,J=2.8,1.6Hz, 1H),7.60(d,J=1.4Hz,1H),7.53–7.43(m,2H),6.95(s,1H),3.94(s,2H),3.90(s,3H),1.55(s,6H).

[0608] Example 84: Preparation of compound CQ-1418

[0609] The synthesis route and method are similar to those in Example 81.

[0610] 1 H NMR (400MHz, DMSO) δ13.75(d,J=118.0Hz,1H),11.79(s,1H),8.86(s,1H),8.37(s,2H),7.93(s ,1H),7.70(s,1H),7.66(d,J=7.8Hz,1H),7.58(s,1H),7.09(s,1H),3.90(s,3H),1.60(s,6H).

[0611] Example 85: Preparation of compound CQ-1416

[0612] Preparation of compound 85c

[0613] Compounds 85a (1 g, 2.597 mmol), 85b (479 mg, 3.117 mmol), cuprous iodide (60 mg, 0.3117 mmol), and diphenylphosphine palladium chloride (108 mg, 0.156 mmol) were mixed under argon protection. Triethylamine (1.08 mL, 7.791 mmol) and 9 mL of tetrahydrofuran were then added, and the mixture was reacted at 70 °C overnight. After the reaction was complete, the solvent was evaporated, and the mixture was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 600 mg of a white solid, with a yield of 56.62%.

[0614] Preparation of compound 85e

[0615] Compounds 85c (600 mg, 1.47 mmol), 85d (478 mg, 1.764 mmol), 4-dimethylaminopyridine (18 mg, 0.147 mmol), and triethylamine (0.61 mL, 4.41 mmol) were dissolved in 4 mL of N,N-dimethylacetamide. After the addition was complete, the mixture was moved to 90 °C and reacted overnight. When the starting material was exhausted, the filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The sample was mixed with silica gel powder and separated by column chromatography to obtain 400 mg of white solid, with a yield of 47.31%.

[0616] Preparation of compound CQ1416

[0617] Compound 85e (400 mg, 1.22 mmol) was dissolved in 4 mL of dichloromethane, and then 4 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours, evaporated to dryness, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate, evaporated to dryness, mixed with silica gel powder, and separated by column chromatography to obtain 65 mg of white solid.

[0618] 1 H NMR (400MHz, DMSO) δ13.67(d,J=118.1Hz,1H),10.52(s,1H),8.82(d,J=30.1Hz,2H),8.42–8.14 (m,3H),7.93(s,1H),7.65(s,1H),7.47(d,J=8.7Hz,1H),6.88(s,1H),3.88(s,3H),1.76(s,6H).

[0619] Example 86: Preparation of compound CQ-1410

[0620] The synthesis route and method are similar to those in Example 85.

[0621] 1 H NMR(400MHz,DMSO)δ13.69(d,J=118.0Hz,1H),10.34(s,1H),8.85(s,2H),8.45–8.22(m,3H),7.95 (s,1H),7.65(d,J=2.0Hz,1H),7.48(dd,J=8.7,2.0Hz,1H),6.49(s,1H),3.89(s,3H),1.31(s,9H).

[0622] Example 87: Preparation of compound CQ-1420

[0623] The synthesis route and method are similar to those in Example 85.

[0624] 1H NMR(400MHz,DMSO)δ13.53(s,1H),9.86(s,1H),9.24(s,1H),8.88(s,1H),8.32(s,2H),7.94(s,1 H),7.55(dd,J=50.6,10.2Hz,2H),7.22(d,J=8.6Hz,1H),6.91(s,1H),3.88(s,3H),1.56(s,6H).

[0625] Example 88: Preparation of compound CQ-YGP-B30

[0626] The synthesis route and method are similar to those in Example 85.

[0627] 1 H NMR (400MHz, DMSO) δ13.55(s,1H),9.88(s,1H),8.55(s,1H),8.27(d,J=8.7Hz,1H ),8.21(t,J=5.8Hz,2H),7.99(s,1H),7.86(d,J=8.0Hz,1H),7.78(s,1H),7.72(d ,J=8.0Hz,1H),7.67(d,J=7.6Hz,2H),7.58(d,J=8.8Hz,1H),7.48(d,J=8.7Hz,1H ),3.92(s,3H),3.56(s,2H),3.28(s,2H),2.44(s,7H),2.28(s,3H),1.13(s,3H).

[0628] Example 89: Preparation of compound CQ-1415

[0629] The synthesis route and method are similar to those in Example 85.

[0630] 1 H NMR (400MHz, DMSO) δ13.53(s,1H),10.71(s,1H),9.74(s,1H),8.85(s,1H),8.39(d,J=56.6H z,3H),7.92(d,J=8.7Hz,2H),7.72(d,J=8.7Hz,1H),6.95(s,1H),3.87(s,3H),1.57(s,6H).

[0631] Example 90: Preparation of compound CQ-WKF-L47

[0632] The synthesis route and method are similar to those in Example 85.

[0633] 1 H NMR (400MHz, DMSO) δ13.72(d,J=120.1Hz,1H),9.96(s,1H),9.21(s,1H),8.87(s,1H),8.67(d,J=2.6Hz,1H),8.41–8 .25(m,2H),8.06–7.98(m,2H),7.95(d,J=16.2Hz,1H),7.54(d,J=8.5Hz,1H),6.92(s,1H),3.91(s,4H),1.56(s,6H).

[0634] Example 91: Preparation of compound CQ-1393

[0635] The synthesis route and method are similar to those in Example 85.

[0636] 1 H NMR(400MHz,DMSO-d6)δ13.43(s,1H),9.73(s,1H),9.01(s,1H),8.15(s,1H),7 .48(d,J=8.4Hz,2H),7.17-7.38(m,5H),6.90(s,1H),3.90(s,3H),1.56(s,6H).

[0637] Example 92: Preparation of compound CQ-XMJ-F15

[0638] The synthesis route and method are similar to those in Example 54.

[0639] 1 H NMR (400MHz, DMSO) δ13.26(d,J=57.5Hz,1H),10.39(s,1H),8.64(s,1H),8.33–7.95(m,3H),7.89(d,J=7.8Hz,1H),7.64(s,1 H),7.48(d,J=8.6Hz,1H),7.30(s,2H),7.15(d,J=16.3Hz,1H),6.88(s,2H),3.95(s,3H),2.82(d,J=4.6Hz,3H),1.56(s,6H).

[0640] Example 93: Preparation of compound CQ-XMJ-F42

[0641] The synthesis route and method are similar to those in Example 54.

[0642] 1H NMR (400MHz, DMSO) δ13.26(d,J=59.6Hz,1H),9.98(s,1H),8.81(d,J=2.6Hz,1H),8.29–7.94(m,3H),7.89(t,J=8.1Hz,1H),7.47 (t,J=11.2Hz,1H),7.30(d,J=14.1Hz,3H),7.12(s,1H),6.90(s,2H),3.95(d,J=12.1Hz,3H),2.83(d,J=4.5Hz,3H),1.56(s,6H).

[0643] Example 94: Preparation of compound CQ-XMJ-F14

[0644] The synthesis route and method are similar to those in Example 54.

[0645] 1 H NMR (400MHz, DMSO) δ13.22(d,J=58.0Hz,1H),10.04(s,1H),8.10(d,J=102.1Hz,3H),7.92–7.79(m,2H),7.32(d,J=2 2.5Hz,4H),7.07(d,J=16.3Hz,1H),6.87(s,2H),4.03–3.88(m,3H),2.82(d,J=4.7Hz,3H),2.24(s,3H),1.55(s,6H).

[0646] Example 95: Preparation of compound CQ-YGP-A47

[0647] The synthesis route and method are similar to those in Example 54.

[0648] 1 H NMR (400MHz, DMSO-d) δ13.30&13.15(2s,1H),9.66(s,1H),8.88(s,1H),8.20-8.25(m,1H),8.19&7.97(2s,1H),7.86(t,J=7.6Hz,1H) ,7.40-7.48(m,4H),7.23-7.34(m,2H),6.87-7.10(m,3H),3.96&3.93(2s,3H),3.27-3.33(m,2H),1.55(s,6H),1.13(t,J=7.6Hz,3H).

[0649] Example 96: Preparation of compound CQ-1394

[0650] The synthesis route and method are similar to those in Example 85.

[0651] 1 H NMR(400MHz,DMSO-d6)δ13.82&12.53(2s,1H),10.49(s,1H),8.64-8.97(m,2H),8.15-8.43(m,3H ),7.83-7.99(m,1H),7.64(s,1H),7.47(d,J=8.8Hz,1H),6.89(s,1H),3.88(s,3H),1.56(s,6H).

[0652] Example 97: Preparation of compound CQ-YGP-A73

[0653] The synthesis route and method are similar to those in Example 54.

[0654] 1 H NMR(600MHz,DMSO-d)δ13.29&13.14(2s,1H),9.66(s,1H),8.88(s,1H),8.06 -8.22(m,2H),7.97(s,1H),7.76(d,J=7.8Hz,1H),7.39-7.47(m,4H),7.21-7. 31(m,2H),7.03(s,1H),6.90(s,1H),3.92&3.90(2s,3H),2.83-2.88(m,1H), 1.55(s,6H),0.68-0.73(m,2H),0.53-0.58(m,2H).13CNMR(151MHz,DMSO-d).

[0655] Example 98: Preparation of compound CQ-XMJ-F109

[0656] The synthesis route and method are similar to those in Example 85.

[0657] 1 H NMR (400MHz, DMSO) δ13.67(d,J=117.9Hz,1H),10.87(s,1H),8.85(s,1H),8.66(s,1H),8.42–7.83(m,4H), 7.65(d,J=5.2Hz,1H),7.48(d,J=8.6Hz,1H),6.15(s,1H),5.38(s,1H),3.89(d,J=6.6Hz,3H),1.43(s,6H).

[0658] Example 99: Preparation of compound CQ-1419

[0659] Preparation of compound 99c

[0660] Compounds 99a (1 g, 11.904 mmol), 99b (3.69 g, 14.28 mmol), potassium bicarbonate (1.787 g, 17.856 mmol), and diphenylphosphine nickel chloride (629 mg, 0.959 mmol) were mixed under argon protection, and then 23 mL of dimethyl sulfoxide was added. The mixture was then moved to 90 °C and reacted overnight. After the reaction was complete, the solvent was evaporated, and the mixture was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 1.05 g of white solid, with a yield of 40.62%.

[0661] 1 H NMR (400MHz, DMSO) δ12.61 (s, 1H), 8.06 (dd, J = 9.0, 2.1Hz, 1H), 7.78 (s, 1H), 7.12 (d ,J=2.4Hz,1H),7.04(d,J=9.1Hz,1H),6.03(d,J=2.6Hz,1H),2.51(d,J=4.4Hz,3H).

[0662] Preparation of compound 99d

[0663] Compound 99c (1.04 g, 4.747 mmol) was dissolved in N,N-dimethylformamide, followed by the addition of N-iodosuccinimide (3.205 g, 14.247 mmol) and p-toluenesulfonic acid (25 mg, 0.147 mmol). After the addition was complete, the mixture was allowed to react at room temperature overnight. When the starting material was exhausted, the filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 1.45 g of white solid, with a yield of 88.79%.

[0664] 1 H NMR (600MHz, DMSO) δ13.07(s,1H),8.07(d,J=9.1Hz,1H),8.01(d,J=1.5Hz,1H),7.95(s,1H),7.12–7.08(m,1H),2.54(s,3H).

[0665] Preparation of compound 99e

[0666] Compound 99d (1.45 g, 4.747 mmol) was dissolved in 28 mL of tetrahydrofuran, followed by the addition of 3,4-dihydro-2H-pyran (910 mg, 10.247 mmol) and p-toluenesulfonic acid (1.866 g, 10.84 mmol). After the addition was complete, the mixture was allowed to react at room temperature overnight. When the starting material was exhausted, the filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 1.275 g of white solid, with a yield of 54.83%.

[0667] Preparation of compound 99f

[0668] Compound 99e (1.275 g), reduced iron powder (995 mg, 17.82 mmol), and ammonium chloride (1.272 g, 23.776 mmol) were mixed and 15 mL of ethanol / water (4:1, v / v) was added. The mixture was then moved to 80 °C and reacted overnight. After the starting material was exhausted, the mixture was filtered while hot. The filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution and dried with anhydrous sodium sulfate. The mixture was then separated by column chromatography with silica gel powder to obtain 876 mg of white solid, with a yield of 76.52%.

[0669] 1 H NMR(400MHz, CDCl3) δ7.55(d,J=2.5Hz,1H),6.91–6.78(m,2H),6.60(dd,J=8.4,2.4Hz,1H),5.20(dd,J=7.8, 4.3Hz,1H),4.02(d,J=11.7Hz,1H),3.64(s,1H),2.14(d,J=2.5Hz,3H),2.05–1.91(m,3H),1.69–1.51(m,3H).

[0670] Preparation of compound 99h

[0671] Compound 99f (850 mg, 2.13 mmol), 99g (651 mg, 2.769 mmol), palladium acetate (50.8 mg, 0.2265 mmol), 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (206 mg, 0.453 mmol), and potassium carbonate (889 mg, 6.395 mmol) were mixed under argon protection. 12 mL of dioxane / water (5:1, v / v) was added, and the mixture was reacted at 100 °C overnight. After the starting material was exhausted, the mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 478 mg of white solid, yield 68.38%.

[0672] 1H NMR (400MHz, DMSO) δ8.55–8.43(m,2H),8.11(d,J=3.1Hz,1H),7.59(s,1H),6.83–6.63(m,2H),6.62–6.53(m,1H),5.23(d,J=9.8H z,1H),4.73(s,2H),3.94–3.91(m,1H),3.82(d,J=2.8Hz,3H),3.61(s,1H),2.04(d,J=2.8Hz,3H),1.92(s,2H),1.57–1.43(m,2H).

[0673] Preparation of compound 99j

[0674] Compounds 99h (423 mg, 1.113 mmol), 99i (385 mg, 1.224 mmol), 4-dimethylaminopyridine (13.6 mg, 0.113 mmol), and triethylamine (0.47 mL, 3.339 mmol) were dissolved in 3 mL of N,N-dimethylformamide. After the addition was complete, the mixture was moved to 80 °C and reacted overnight. When the starting material was exhausted, the filtrate was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution and dried with anhydrous sodium sulfate. The sample was mixed with silica gel powder and separated by column chromatography to obtain 362 mg of white solid, with a yield of 53.49%.

[0675] Preparation of compound CQ-1419:

[0676] Compound 99j (260 mg, 0.2 mmol) was dissolved in 5 mL of dichloromethane, and then 5 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours, evaporated to dryness, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate, evaporated to dryness, mixed with silica gel powder, and separated by column chromatography to obtain 192 mg of white solid.

[0677] 1 H NMR (400MHz, DMSO) δ12.74(s,1H),9.92(s,1H),8.41(d,J=35.6Hz,2H),8.11(d,J=17.2Hz,2H),7.67–7.4 6(m,2H),6.96(s,1H),6.90–6.82(m,2H),3.80(t,J=2.2Hz,3H),2.23–2.13(m,3H),1.54(d,J=3.1Hz,7H).

[0678] Example 100: Preparation of compound CQ-WBH-C101

[0679] Preparation of compound 100c

[0680] Compounds 100a (700 mg, 1.587 mmol), 100b (917 mg, 3.174 mmol), potassium carbonate (658 mg, 4.761 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (58 mg, 0.0789 mmol) were mixed under argon protection. Then, 15 mL of 1,4-dioxane and 3 mL of water were added, and the mixture was moved to 100 °C and reacted overnight. After the reaction was complete, the solvent was evaporated, and the mixture was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 714 mg of a brown oily substance, with a yield of 91.68%.

[0681] 1 H NMR(400MHz,Chloroform-d)δ8.37(d,J=8.0Hz,1H),7.95(d,J=9.3Hz,2H),7.80(d,J=5.8Hz,1H),7. 30–7.25(m,2H),7.19(d,J=7.1Hz,2H),6.87(s,2H),5.08(dd,J=10.3,2.3Hz,1H),4.12(dt,J=10.6, 3.5Hz,1H),3.99(s,3H),3.61–3.50(m,3H),3.48(d,J=4.5Hz,1H),2.60(s,3H),2.12–2.01(m,1H),1 .85(d,J=13.4Hz,1H),1.74(d,J=12.9Hz,1H),1.64(s,1H),1.61–1.49(m,2H),1.28(t,J=7.3Hz,3H)

[0682] Preparation of compound 100d

[0683] Compound 100c (714 mg, 1.455 mmol), ammonium chloride (622 mg, 11.64 mmol), and iron powder (489 mg, 8.732 mmol) were dissolved in 20 mL of ethanol and 5 mL of water. The mixture was reacted at 80 °C for 1 h. After the reaction was completed, the iron powder was filtered off, and the filtrate was extracted with water and ethyl acetate. The organic phase was dried by rotary evaporation, and silica gel powder was added and the mixture was stirred and separated by column chromatography to obtain 588 mg of foamy reddish-brown solid, with a yield of 86.53%.

[0684] 1H NMR(400MHz,Chloroform-d)δ8.34(d,J=8.0Hz,1H),7.88(s,1H),7.82(d,J=6.0Hz,1H),7 .24–7.16(m,2H),7.06(d,J=10.8Hz,2H),6.81(d,J=16.3Hz,1H),6.65–6.49(m,2H),5.13 –5.03(m,1H),3.98(s,3H),3.55(p,J=6.6Hz,3H),2.63–2.49(m,1H),2.15(s,3H),2.04(s ,1H),1.84(d,J=13.5Hz,1H),1.74(d,J=12.2Hz,1H),1.52(s,1H),1.28(t,J=7.3Hz,3H).

[0685] Preparation of compound 100e

[0686] Compound 100d (580 mg, 1.259 mmol), phenyl chloroformate (0.25 mL, 1.89 mmol), and triethylamine (0.57 mL, 3.77 mmol) were dissolved in 25 mL of tetrahydrofuran and reacted at room temperature for 2 h. After the reaction was completed, the mixture was quenched with saturated sodium bicarbonate solution and then extracted with ethyl acetate. The organic phase was dried by rotary evaporation, mixed with silica gel powder, and separated by column chromatography to obtain 485 mg of white solid, with a yield of 66.3%.

[0687] 1 H NMR(400MHz,Chloroform-d)δ8.36(d,J=8.0Hz,1H),7.91(s,1H),7.81(t,J=5.5 Hz,2H),7.39(t,J=7.7Hz,2H),7.23(s,1H),7.22–7.17(m,5H),6.85(d,J=16.3H z,1H),6.69(d,J=16.5Hz,1H),3.98(s,3H),3.59–3.51(m,3H),2.32(s,3H),2.0 6(d,J=12.7Hz,2H),1.85(d,J=13.4Hz,1H),1.53(s,1H),1.28(t,J=7.2Hz,3H).

[0688] Preparation of compound 100f

[0689] Compounds 100e (200 mg, 0.735 mmol), 100i (470 mg, 0.809 mmol), triethylamine (0.33 mL, 2.205 mmol), and 4-dimethylaminopyridine (5 mg, 0.036 mmol) were dissolved in 20 mL of tetrahydrofuran and reacted overnight at 100 °C. After the reaction was completed, saturated sodium chloride aqueous solution was added first, followed by extraction with ethyl acetate. The organic phase was dried by rotary evaporation, mixed with silica gel powder, and separated by column chromatography to obtain 321 mg of white solid, with a yield of 57.4%.

[0690] 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.28(s,1H),8.07–7.95(m,3H),7.89(d,J=7.8Hz,1H),7.80(d,J=8.3Hz,1H) ,7.62(d,J=8.5Hz,1H),7.55(d,J=8.6Hz,1H),7.23(dd,J=13.1,6.3Hz,3H),7.13(d,J=7.9Hz,1H),7.00(d,J=16. 3Hz,1H),6.71(d,J=16.6Hz,1H),5.14(d,J=9.9Hz,1H),3.93(s,3H),3.53(s,2H),3.31(s,2H),2.38(s,8H),2.23 (s,3H),2.18(s,3H),1.93(s,1H),1.80(d,J=12.9Hz,1H),1.61–1.44(m,3H),1.23(s,1H),1.14(t,J=7.1Hz,3H).

[0691] Preparation of compound CQ-WBH-C101

[0692] Compound 100f (321 mg, 0.322 mmol) was dissolved in 5 ml of trifluoroacetic acid and 5 ml of dichloromethane and reacted at room temperature for 2 h. After the reaction was completed, the trifluoroacetic acid solution was evaporated to dryness, saturated sodium bicarbonate aqueous solution was added, and then ethyl acetate was added for extraction. After the organic phase was evaporated to dryness, silica gel powder was added and the sample was separated by column chromatography to obtain 140 mg of white solid, with a yield of 49.4%.

[0693] 1H NMR (400MHz, DMSO-d6) δ13.34(s,1H),13.19(s,1H),9.46(s,1H),8.25(d,J=14.9Hz,2H),8.11(s,1H),8.02(s,2H),7.95–7.83(m,2H),7.69– 7.58(m,2H),7.35(d,J=17.8Hz,4H),7.15–7.03(m,2H),3.99(d,J=9.8Hz,3H),3.58(s,2H),2.48(s,8H),2.30(s,6H),1.17(t,J=7.2Hz,3H).

[0694] Example 101: Preparation of compound CQ-WBH-C104

[0695] The synthesis route and method are similar to those in Example 100.

[0696] 1 H NMR(400MHz,DMSO-d6)δ13.28(d,J=59.3Hz,1H),9.77(s,1H),8.41(s,1H),8.24( s,1H),8.13(d,J=8.6Hz,1H),7.99(s,2H),7.87(d,J=7.9Hz,1H),7.72–7.52(m,4 H),7.47(d,J=8.6Hz,1H),7.30(s,3H),7.14(d,J=16.3Hz,1H),7.00(t,J=18.6Hz ,1H),3.96(s,3H),3.55(s,2H),3.32(s,2H),2.28(s,3H),1.14(t,J=7.2Hz,3H).

[0697] Example 102: Preparation of compound CQ-WBH-1404

[0698] The synthesis route and method are similar to those in Example 100.

[0699] 1H NMR (400MHz, DMSO-d6) δ13.28(d,J=57.0Hz,1H),9.46(s,1H),8.71(d,J=2.6Hz,1H),8.24(s,2 H),8.10(t,J=8.5Hz,1H),8.00(d,J=2.2Hz,2H),7.89(d,J=8.0Hz,1H),7.65(d,J=8.5Hz,1H), 7.56(dd,J=8.5,2.3Hz,1H),7.47(d,J=12.8Hz,1H),7.30(s,3H),7.13(d,J=16.2Hz,1H),7.01 (d,J=27.6Hz,1H),3.97(s,3H),3.32(s,2H),2.46(s,8H),2.31(s,3H),1.15(t,J=7.2Hz,3H).

[0700] Example 103: Preparation of compound CQ-WBH-C80

[0701] The synthesis route and method are similar to those in Example 100.

[0702] 1 H NMR (400MHz, DMSO-d6) δ13.27(d,J=61.6Hz,1H),9.70(s,1H),8.36(s,1H),8.24(d,J=1 8.4Hz,1H),8.14(d,J=8.3Hz,1H),8.02(s,1H),7.91(d,J=7.7Hz,1H),7.66(d,J=8.5Hz ,1H),7.57(d,J=8.6Hz,1H),7.36(s,2H),7.26–7.11(m,2H),7.07(s,2H),4.00(s,3H), 3.96(s,3H),3.57(s,2H),3.35(s,2H),2.45(s,8H),2.26(s,3H),1.17(t,J=7.3Hz,3H).

[0703] Example 104: Preparation of compound CQ-WBH-C56

[0704] The synthesis route and method are similar to those in Example 100.

[0705] 1H NMR (400MHz, DMSO-d6) δ13.38(s,1H),9.31(d,J=10.9Hz,2H),8.29(d,J=18.1Hz,2H ),8.05(s,1H),7.98(s,1H),7.88(d,J=8.1Hz,1H),7.60(ddd,J=29.8,18.9,11.0Hz ,4H),7.31(d,J=18.7Hz,2H),7.22–7.12(m,2H),7.07(d,J=19.2Hz,1H),3.98(d,J= 4.5Hz,3H),3.58(s,2H),2.47(d,J=12.9Hz,8H),2.30(s,3H),1.17(t,J=7.1Hz,4H).

[0706] Example 105: Preparation of compound CQ-WBH-C81

[0707] The synthesis route and method are similar to those in Example 100.

[0708] 1 H NMR (400MHz, DMSO-d6) δ13.41(s,1H),13.26(s,1H),9.49(d,J=23.6Hz,2H),8.28(d,J= 20.7Hz,2H),8.02(d,J=9.5Hz,1H),7.88(d,J=8.2Hz,1H),7.80(s,1H),7.74(d,J=8.5H z,1H),7.65(s,2H),7.40–7.17(m,4H),7.12(d,J=16.1Hz,1H),3.98(d,J=8.8Hz,3H),3 .58(s,2H),3.33(s,2H),2.70(s,4H),2.49(s,3H),2.36(s,3H),1.16(t,J=7.2Hz,3H).

[0709] Example 106: Preparation of compound CQ-WBH-1423

[0710] The synthesis route and method are similar to those in Example 54.

[0711] 1H NMR (400MHz, DMSO-d6) δ13.27(d,J=58.4Hz,1H),9.76(s,1H),9.08(s,1H),8.25(d,J= 20.9Hz,2H),8.02(s,1H),7.91–7.81(m,1H),7.58(d,J=9.3Hz,1H),7.51(d,J=13.5Hz, 1H),7.29(t,J=11.8Hz,2H),7.21–7.11(m,2H),7.02(t,J=18.4Hz,1H),6.91(t,J=2.4 Hz,1H),3.95(s,3H),3.32(s,2H),1.65–1.49(m,6H),1.14(dq,J=7.7,5.2,4.0Hz,3H).

[0712] Example 107: Preparation of compound CQ-WBH-1422

[0713] The synthesis route and method are similar to those in Example 54.

[0714] 1 H NMR(400MHz,DMSO-d6)δ13.27(d,J=58.4Hz,1H),9.59(s,1H),9.05(s,1H),8.2 5(d,J=19.3Hz,2H),7.85(d,J=7.8Hz,1H),7.64–7.55(m,1H),7.50(d,J=13.5H z,1H),7.27(d,J=18.6Hz,2H),7.20–7.08(m,2H),7.01(t,J=17.8Hz,1H),6.51 (t,J=2.3Hz,1H),3.95(s,3H),1.33–1.27(m,9H),1.13(td,J=7.5,4.1Hz,3H).

[0715] Example 108: Preparation of compound CQ-WBH-1425

[0716] The synthesis route and method are similar to those in Example 54.

[0717] 1H NMR (400MHz, DMSO-d6) δ13.31(d,J=60.2Hz,1H),9.79(s,1H),9.06(s,1H),8.26(d,J=20.6Hz,1H),7.86(d,J=7.9Hz,1H),7.82–7.67(m,2H) ,7.37–7.22(m,3H),7.14(q,J=16.1Hz,2H),6.92(d,J=2.2Hz,1H),3.95(s,3H),3.32–3.29(m,2H),1.56(s,6H),1.13(dd,J=8.5,6.3Hz,3H).

[0718] Example 109: Preparation of compound CQ-WBH-1424

[0719] The synthesis route and method are similar to those in Example 54.

[0720] 1 H NMR (400MHz, DMSO-d6) δ13.29(d,J=60.3Hz,1H),9.59(s,1H),9.02(s,1H),8.24(d,J=23.6Hz,2H),8.00(s,1H),7.86(d,J=7.8Hz,1H),7.8 0–7.66(m,2H),7.36–7.24(m,3H),7.22–7.02(m,2H),6.52(s,1H),3.95(d,J=7.4Hz,3H),3.31(s,2H),1.30(s,9H),1.14(t,J=7.2Hz,3H).

[0721] Example 110: Preparation of compound CQ-WBH-1421

[0722] The synthesis route and method are similar to those in Example 54.

[0723] 1H NMR(400MHz,DMSO-d6)δ13.35(s,1H),10.42(s,1H),8.66(s,1H),8.23(s,1H),8.12(d, J=8.6Hz,1H),7.98(s,1H),7.87(d,J=7.9Hz,1H),7.64(s,1H),7.49(d,J=8.6Hz,1H),7 .29(d,J=11.9Hz,2H),7.15(d,J=16.3Hz,1H),7.09–6.92(m,1H),6.88(d,J=1.6Hz,1H) ,3.96(s,3H),3.32(d,J=7.4Hz,2H),1.76(d,J=1.7Hz,6H),1.14(dd,J=8.0,6.4Hz,3H).

[0724] Example 111: Preparation of compound CQ-WBH-1406

[0725] The synthesis route and method are similar to those in Example 54.

[0726] 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),10.23(s,1H),8.72(s,1H),8.28–8.18(m,2H),8. 15(d,J=8.6Hz,1H),7.98(s,1H),7.88(t,J=7.7Hz,1H),7.64(d,J=11.5Hz,1H),7.49(t ,J=9.3Hz,1H),7.37–7.25(m,2H),7.16(d,J=16.5Hz,1H),6.99(dd,J=38.2,16.2Hz,1H ),6.48(s,1H),3.97(d,J=12.2Hz,3H),3.32(s,2H),1.31(s,9H),1.15(t,J=7.2Hz,3H).

[0727] Example 112: Preparation of compound CQ-WBH-D31

[0728] The synthesis route and method are similar to those in Example 100.

[0729] 1H NMR (400MHz, DMSO-d6) δ9.53 (s, 1H), 8.75 (s, 1H), 8.24 (t, J = 5.7Hz, 1H), 8.12 –8.01(m,3H),7.87(d,J=7.9Hz,1H),7.68(q,J=8.7Hz,2H),7.46(d,J=12.8Hz ,1H),7.33–7.24(m,3H),7.12(d,J=16.1Hz,1H),6.99(d,J=16.2Hz,1H),3.96 (s,3H),3.34–3.30(m,2H),2.84(s,3H),2.38(s,13H),1.13(t,J=7.1Hz,3H).

[0730] Example 113: Preparation of compound CQ-WBH-1405

[0731] The synthesis route and method are similar to those in Example 100.

[0732] 1 H NMR (400MHz, DMSO-d6) δ13.28(s,1H),9.66(s,1H),8.36(s,1H),8.24(t,J=5.8Hz,1H),8.15(d,J=8.6Hz ,1H),7.92–7.85(m,2H),7.63(d,J=2.0Hz,1H),7.58(dd,J=8.7,2.5Hz,1H),7.53–7.44(m,2H),7.35–7.2 6(m,2H),7.14(d,J=16.3Hz,1H),7.00(s,1H),3.97(s,3H),3.31(d,J=7.5Hz,2H),2.94(d,J=10.8Hz,2H ),2.73(t,J=11.2Hz,2H),2.23(s,6H),1.82(d,J=12.0Hz,2H),1.56–1.45(m,2H),1.15(t,J=7.2Hz,3H).

[0733] Example 114: Preparation of compound CQ-WBH-1407

[0734] Preparation of compound 114c

[0735] Compounds 114a (500 mg, 1.13 mmol), 114b (712 mg, 2.267 mmol), potassium carbonate (470 mg, 3.39 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (42 mg, 0.0565 mmol) were mixed under argon protection. Then, 15 mL of 1,4-dioxane and 3 mL of water were added, and the mixture was moved to 100 °C and reacted overnight. After the reaction was complete, the solvent was evaporated, and the mixture was extracted with water and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and separated by column chromatography with silica gel powder to obtain 500 mg of a brown oily substance, with a yield of 84.4%.

[0736] Preparation of compound CQ-WBH-1407

[0737] Compounds 114c (500 mg, 0.95 mmol) and 100i (173.6 mg, 0.63 mmol) were dissolved in THF solution. A tetrahydrofuran solution containing potassium tert-butoxide (435 mg, 3.8 mmol) was slowly added dropwise at 0°C. After maintaining the low temperature for 10 min, the reaction was moved to room temperature and allowed to proceed overnight. After the reaction was completed, water and ethyl acetate were added for extraction. The organic phase was dried by rotary evaporation, and silica gel powder was added for mixing. The mixture was then separated by column chromatography to obtain 40 mg of a foamy reddish-brown solid, with a yield of 9.3%.

[0738] 1 H NMR (400MHz, DMSO-d6) δ13.42(d,J=52.0Hz,1H),10.57(s,1H),8.41(s,1H),8.30–8.19(m,2H),8.18–8.04(m,3H),7.99(d,J=8.4Hz,1H),7.96– 7.84(m,2H),7.73(d,J=8.6Hz,1H),7.43–7.25(m,4H),3.97(s,3H),3.6 0(s,2H),3.30(s,2H),2.47(s,8H),2.29(s,3H),1.14(t,J=7.2Hz,3H).

[0739] Example 115: Preparation of compound CQ-1395

[0740] The synthesis route and method are similar to those in Example 85.

[0741] 1H NMR(400MHz,DMSO-d6)δ13.82&12.53(2s,1H),10.49(s,1H),8.64-8.97(m,2H),8.15-8.43(m,3H ),7.83-7.99(m,1H),7.64(s,1H),7.47(d,J=8.8Hz,1H),6.89(s,1H),3.88(s,3H),1.56(s,6H).

[0742] Example 116: Preparation of compound CQ-1396

[0743] The synthesis route and method are similar to those in Example 85.

[0744] 1 H NMR(400MHz,DMSO-d6)δ13.82&12.53(2s,1H),10.49(s,1H),8.64-8.97(m,2H),8.15-8.43(m,3H ),7.83-7.99(m,1H),7.64(s,1H),7.47(d,J=8.8Hz,1H),6.89(s,1H),3.88(s,3H),1.56(s,6H).

[0745] Example 117: Preparation of compound CQ-1397

[0746] The synthesis route and method are similar to those in Example 85.

[0747] 1 H NMR (400MHz, DMSO-d6) δ13.42(s,1H),9.72(s,1H),9.00(s,1H),7.68-8.37(m,2H),7.19-7.59(m,7H),6.90(s,1H),1.55(s,6H).

[0748] Example 118: Preparation of compound CQ-1399

[0749] The synthesis route and method are similar to those in Example 85.

[0750] 1H NMR(400MHz,DMSO-d6)δ13.78&13.48(2s,1H),9.75(s,1H),9.25(s,1H),9.05(s,1H),8.71-8.48(m,1H ),8.34-8.43(m,1H),8.27(s,1H),7.50-7.61(m,3H),7.46(d,J=8.8Hz,2H),6.91(s,1H),1.56(s,6H).

[0751] Example 119: Preparation of compound CQ-1400

[0752] The synthesis route and method are similar to those in Example 85.

[0753] 1 H NMR(400MHz,DMSO-d6)δ13.25(s,1H),9.73(s,1H),9.01(s,1H),7.67-8.44(m,3H),7.48 (d,J=8.4Hz,2H),7.30-7.42(m,2H),7.17(s,1H),6.90(s,1H),3.95(s,3H),1.56(s,6H).

[0754] Example 120: Preparation of compound CQ-1402

[0755] The synthesis route and method are similar to those in Example 85.

[0756] 1 H NMR (400MHz, DMSO-d6) δ13.80&13.49(2s,1H),10.30(s,1H),8.88&8.81(2s,1H),8.77(s,1H),8.29-8.39(m,1H),8.27(d,J=2.0Hz,1H ),8.18(d,J=8.4Hz,1H),7.95-8.03(m,1H),7.14-7.18(m,1H),7.06-7.12(m,1H),6.90(s,1H),3.92(s,3H),3.88(s,3H),1.56(s,6H).

[0757] Example 121: Preparation of compound CQ-1403

[0758] The synthesis route and method are similar to those in Example 85.

[0759] 1H NMR (600MHz, DMSO-d6) δ13.79&13.49(2s,1H),10.14(s,1H),8.88(d,J=0.8Hz,1H),8.23-8.38(m ,3H),7.85-8.04(m,2H),7.29-7.44(m,2H),6.90(s,1H),3.88(s,3H),2.26(s,3H),1.56(s,6H).

[0760] Example 122: Preparation of compound CQ-WKF-L63

[0761] The synthesis route and method are similar to those in Example 85.

[0762] 1H NMR(400MHz,DMSO-d6)δ13.83&13.53(2s,1H),10.06(s,1H),8.65-9.08(m,2H),8.07-8.52(m,3H), 7.94(s,1H),7.45(d,J=11.6Hz,1H),7.33(d,J=8.8Hz,1H),6.92(s,1H),3.88(s,3H),1.56(s,6H).

[0763] Example 123: Inhibitory activity of compounds against the proliferation of BAF3 model cells and tumor cells carrying different RET mutation backgrounds.

[0764] The inhibitory activity of the compounds of this invention against the proliferation of BAF3 model cells and tumor cells carrying different RET mutation backgrounds was tested using the CCK-8 assay:

[0765] The compounds used in the control experiments are as follows:

[0766] Selpercatinib and Pralsetinib (BLU-667) are effective selective RET inhibitors, purchased from Selleck.

[0767] The experimental steps are as follows:

[0768] 1) Cell seeding: Various BAF3 model cells or tumor cells in the logarithmic growth phase were seeded at the same density in different 96-well plates (3000-10000 cells / 100μl / well).

[0769] 2) Preparation of working solutions: Using the appropriate culture medium required for cell culture as the diluent (with or without DMSO), dilute the stock solutions of the test compound and the control compound to obtain a series of working solutions with concentrations three times the final concentration. The DMSO content in each concentration group is consistent with that in the solvent control group.

[0770] 3) Co-incubation: 24 hours after inoculation, add 100 μl / well of stock solution of the compound at serial concentrations to a 96-well plate, mix well, and co-incubate for 72 hours. All groups should have at least 3 replicates, with 6 concentrations for each compound. Blank control group: Only culture medium is added, without cells or drugs, to eliminate interference from the contrast color of the culture medium.

[0771] 4) Absorbance measurement: After removing the culture medium from the 96-well plate, add 10 μl of CCK-8 solution to each well, co-culture for 4 hours, shake thoroughly to make it uniform, and measure the absorbance at A450 and A650 on the microplate reader.

[0772] 5) Data Processing: The raw A450-A650 data were used to obtain the cell viability of each well (calculation method as follows); then, the cell viability data and their corresponding compound concentrations were input into GraphPadPrism 5Demo software, and a nonlinear regression model was used to calculate the half-maximal inhibitory concentration (IC50) of the compound for different cell types. 50 Cell viability was calculated as follows: Cell viability (%) = [(As-Ac) / (Ab-Ac)] × 100% (As: experimental wells; Ab: solvent control wells; Ac: blank wells). The results are shown in Tables 1 and 2.

[0773] Table 1. Inhibitory activity of compounds against the proliferation of BAF3 model cells carrying different RET mutation backgrounds (IC50) 50 (uM)

[0774] As shown in Table 1, the compounds of the present invention have strong inhibitory activity against the proliferation of BAF3 model cells carrying different RET mutation backgrounds, and most of the compounds have better inhibitory activity against the proliferation of BAF3-CCD6-RET-G810C and BAF3-CCD6-RET-G810R cells than the positive control drug Selpercatinib.

[0775] Table 2. Inhibitory activity of compounds against tumor cell proliferation (IC50) 50 (uM)

[0776] As shown in Tables 1 and 2, the compounds of the present invention have strong inhibitory activity against the proliferation of tumor cells and are superior to the RET inhibitor BLU-667.

[0777] Example 124 Pharmacokinetic Experiment of Compound CQ1394

[0778] Pharmacokinetic experiments: After a single intravenous injection or oral gavage administration of compound CQ-1394 to SD rats, blood samples were collected at different time points. The concentration of the test substance in rat plasma after administration was determined by LC-MS / MS, and relevant parameters were calculated.

[0779] Compound CQ-1394 was administered via intravenous injection and oral gavage at doses of 2 mg / kg and 10 mg / kg, respectively. Blood samples were collected from the orbital venous plexus at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration in both groups. Approximately 0.20 mL of blood samples were temporarily stored on ice. Heparin sodium was used for anticoagulation, and samples were placed on ice after collection. Plasma was centrifuged within one hour (centrifugation conditions: 6800 g, 6 min, 2-8 °C). Plasma samples were stored at -80 °C before analysis.

[0780] Using blood drug concentration data at different time points, pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0, providing parameters such as AUC0-t, AUC0-∞, MRT0-∞, Cmax, Tmax, and T1 / 2, along with their mean and standard deviation.

[0781] The results are shown in Table 3 below. The bioavailability of compound CQ1394 was 10.1%.

[0782] Table 3. Pharmacokinetic data of compound CQ1394 in SD rats.

[0783] Example 125: Test of compound CQ1373 on apoptosis and cell cycle arrest.

[0784] Cells were seeded in 6-well plates and treated with either the specified concentration of the test compound or DMSO for 48 hours. Approximately 5 × 10⁶ cells were collected after treatment. 5 Cells were subjected to subsequent staining. Cells were resuspended in 100 μL of 1×BD binding buffer (catalog number #556454, BD Biosciences), and then stained for 15 minutes at room temperature in the dark using 7-ADD (catalog number #559925, BD Biosciences) and Annexin V-PE (catalog number #556422, BD Biosciences). Staining was terminated by adding 400 μL of 1×BD binding buffer, and cells were resuspended before analysis using a Guava easyCyte flow cytometer (Merck, Inc.).

[0785] Flow cytometry results showed that compound CQ1373 induced apoptosis in wild-type and G810 mutant cells in a concentration-dependent manner. It also induced apoptosis in both CCDC6-RTE fusion and G810C / R mutant cells in a concentration-dependent manner. The apoptosis rates of cells carrying CCDC6-RET, CCDC6-RET-G810C, and CCDC6-RET-G810R at a concentration of 300 nM were 84.65%, 91.44%, and 89.08%, respectively. Furthermore, compound CQ1373 induced significant G0 / G1 cell cycle arrest in both wild-type cells and cells expressing solvent-front mutant RET, with a significant increase in the proportion of cells in the G0 / G1 phase. After treatment with 300 nM of compound CQ1373, the percentages of cells in the G0 / G1 phase were 84.10%, 72.47%, and 78.85% in cells carrying the CCDC6-RET, CCDC6-RET-G810C, and CCDC6-RET-G810R mutants, respectively, while the corresponding percentages in the untreated group were 52.51%, 52.11%, and 52.63% (Figure 1). These results indicate that compound CQ1373 exhibits strong growth-inhibiting efficacy against both wild-type and solvent-front mutant RET cells.

[0786] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A heterocyclic compound having the structure shown in formula (I) or a pharmaceutically acceptable salt thereof, its stereoisomer, its solvent compound, its prodrug, or its deuterated compound: in, n is selected from: 0, 1, 2; U1 and U2 are independently selected from: -NH-, -CH2-, or one of U1 and U2 is absent, and the other is -NH- or -CH2-; Q is selected from: O; L1 does not exist or is selected from: -O-, -CONR7-, -NR7CO-, -C(R7)2-NR7-, -C(R7)2-C(R7)2-, -C(R7)=C(R7)-, L2 does not exist or is selected from: -CONR7-, -NR7CO-, -C(R7)2-NR7-, -C(R7)2-C(R7)2-, -C(R7)=C(R7)-, L1 and L2 cannot both be absent at the same time; Y1, Y2, Y3, Y4 and Y5 are independently selected from: N, C=O, NR1, CR, respectively, and the G ring composed of Y1, Y2, Y3, Y4 and Y5 is an aromatic ring or a heteroaromatic ring; X1, X2, X3, X4, X5, and X6 are independently selected from N, NR1, C=O, and CR8, respectively, and the B ring formed by X1, X2, X3, X4, X5, and X6 is an aromatic ring or a heteroaromatic ring; Z1, Z2, Z3, and Z4 are independently selected from N, NR1, C=O, O, S, and CR9, respectively, and the A ring formed by Z1, Z2, Z3, and Z4 is an aromatic ring or a heteroaromatic ring; V1, V2, and V3 are independently selected from N, O, NR1, and CR1, respectively, and the E ring composed of V1, V2, and V3 is a heteroaromatic ring; Each R1 is independently selected from: H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylacyl, or two adjacent R1 substituents linked together to form R. 11 Substituted or unsubstituted 5-8 membered heterocyclic alkyl, heteroaryl, heteroaryl ketone or cycloalkyl groups; Each R is independently selected from: H, OH, halogen, R 12 Substituted or unsubstituted C1-C8 alkyl, R 12 Substituted or unsubstituted C1-C8 alkoxy groups, R 12 Substituted or unsubstituted C1-C8 alkylamine groups, R 12 Substituted or unsubstituted C3-C8 cycloalkyl, R 12 Substituted or unsubstituted C3-C8 cycloalkyloxy groups, R 12 Substituted or unsubstituted C3-C8 cycloalkylamine groups, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups: oxygen, cyano, nitro, amino, aminosulfonyl, C1-C8 alkylaminosulfonyl, -C(=O)R 10 Or two adjacent R substituents can be linked together to form R. 11 Substituted or unsubstituted 5-8 membered heterocyclic alkyl, heteroaryl, or cycloalkyl groups; or, R1 substituents on adjacent R and G rings linked together to form R. 11 Substituted or unsubstituted 5-8 membered heterocyclic alkyl, heteroaryl or cycloalkyl; Each R7 is independently selected from: H, C1-C8 alkyl, halogen-substituted C1-C8 alkyl, and C3-C8 cycloalkyl; Each R8 group is independently selected from: H, OH, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamine, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, C3-C8 cycloalkylamine, halogen-substituted C1-C8 alkyl, halogen-substituted C1-C8 alkoxy, halogen-substituted C1-C8 alkylamine, halogen-substituted C3-C8 cycloalkyl, halogen-substituted C3-C8 cycloalkyloxy, halogen-substituted C3-C8 cycloalkylamine, cyano, nitro, amino, aminosulfonyl, -C(=O)R 10 ; R9 is selected from: H, halogen, R 12 Substituted or unsubstituted C1-C8 alkyl, R 12 Substituted or unsubstituted C1-C8 alkoxy groups, R 12 Substituted or unsubstituted C1-C8 alkylamine groups, R 12 Substituted or unsubstituted C3-C8 cycloalkyl, R 12 Substituted or unsubstituted C3-C8 cycloalkyloxy, C3-C8 cycloalkylamine carbonyl, C1-C8 alkylamine carbonyl, C1-C8 alkoxy carbonyl, C1-C8 alkylacyl, C1-C8 alkamido, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups, cyano groups, carbamoyl groups, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups -O-, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups -C(=O)-, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups -N(R1)-, R 12 Substituted or unsubstituted 5-8 membered heteroaryl groups; Each R 10 Each of the following is independently selected from: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, C3-C8 cycloalkoxy, C3-C8 cycloalkylamino, halogen-substituted C1-C8 alkyl, halogen-substituted C1-C8 alkoxy, halogen-substituted C1-C8 alkylamino, halogen-substituted C3-C8 cycloalkoxy, halogen-substituted C3-C8 cycloalkylamino, hydroxyl, and amino; Each R 11 Each of the following is independently selected from: hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, C3-C8 cycloalkoxy, C3-C8 cycloalkylamino, halogen-substituted C1-C8 alkyl, halogen-substituted C1-C8 alkoxy, halogen-substituted C1-C8 alkylamino, halogen-substituted C3-C8 cycloalkoxy, halogen-substituted C3-C8 cycloalkylamino, hydroxyl, and amino; Each R 12 Each is independently selected from: hydrogen, halogen, hydroxyl, amino, cyano, C1-C8 alkyl, halogen-substituted C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, C3-C8 cycloalkoxy, C3-C8 cycloalkylamino, 3-8 membered heterocyclic, C3-C8 cycloalkyl, halogen-substituted 3-8 membered heterocyclic, halogen-substituted C3-C8 cycloalkyl, C1-C8 alkyl-substituted 3-8 membered heterocyclic, and C1-C8 alkyl-substituted C3-C8 cycloalkyl.

2. The heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound according to claim 1, characterized in that, Ring B is selected from: Wherein, m is selected from: 0, 1, 2, 3, 4; preferably, ring B is selected from: More preferably, the R8 substituent on ring B is located ortho to the -U1(=Q)U2- group.

3. The heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound according to claim 1, characterized in that, Ring A is selected from: Where x is selected from: 0, 1, 2, 3, 4.

4. The heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound according to claim 3, characterized in that, Ring A is selected from:

5. The heterocyclic compound according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, Ring E is selected from: Among them, W1, W2, W3, and W4 are independently selected from: N, O, C=O, NH, and CR, respectively. 11 .

6. The heterocyclic compound according to claim 5, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, Ring E is selected from:

7. The heterocyclic compound according to claim 6, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, Ring E is selected from: More preferably 8. The heterocyclic compound according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, G ring is selected from: Among them, Y2 is selected from: N, CR5; Y3 is selected from: N, CR6; R2, R3, R4, R5, and R6 are each independently selected from: H, OH, halogen, R 12 Substituted or unsubstituted C1-C8 alkyl, R 12 Substituted or unsubstituted C1-C8 alkoxy groups, R 12 Substituted or unsubstituted C1-C8 alkylamine groups, R 12 Substituted or unsubstituted C3-C8 cycloalkyl, R 12 Substituted or unsubstituted C3-C8 cycloalkyloxy groups, R 12 Substituted or unsubstituted C3-C8 cycloalkylamine groups, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups, R 12 Substituted or unsubstituted 3-8 membered heterocyclic groups: oxygen, cyano, nitro, amino, aminosulfonyl, C1-C8 alkylaminosulfonyl, -C(=O)R 10 Alternatively, two substituents from R2, R3, R4, R5, and R6 may connect to form R. 11 Substituted or unsubstituted 5-8 membered heterocyclic alkyl, heteroaryl or cycloalkyl groups.

9. The heterocyclic compound according to claim 8, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, G ring is selected from:

10. The heterocyclic compound according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, The heterocyclic compound has the structure shown in formula (II) or formula (III):

11. The heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound according to claim 1, characterized in that, The heterocyclic compound has the structure shown in formula (IV), formula (IV-2), or formula (V): Where x is selected from: 0, 1, 2, 3, 4.

12. The heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound according to claim 1, characterized in that, The heterocyclic compound has the structure shown in formula (VI), formula (VI-2), or (VII):

13. The heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound according to claim 1, characterized in that, The heterocyclic aromatic compound has the structure shown in formula (VIII), formula (VIII-2), formula (IX), formula (IX-2), formula (X), or formula (XI):

14. The heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound according to claim 13, characterized in that, The heterocyclic compound has the structure shown in formula (XII), formula (XII-2), formula (XIII), formula (XIII-2), formula (XIV), or formula (XV):

15. The heterocyclic compound according to any one of claims 1-14, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, L1 is selected from: -O-, -CONR7-, -NR7CO-, -C(R7)2-NR7-, -C(R7)2-C(R7)2-, -C(R7)=C(R7)-, L2 does not exist; Each R7 is independently selected from: H, methyl, ethyl, propyl, and trifluoromethyl.

16. The heterocyclic compound according to claim 15, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, L1 is selected from: -O-, -CONH-, -NHCO-, -CH2-NH-, -CH2CH2-, -CH=CH-, More preferably 17. The heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound according to any one of claims 1-10, characterized in that, U1, U2, and Q together form 18. The heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound according to any one of claims 1-6, 8-14, characterized in that, R1 on ring E is selected from: H, methyl, ethyl, propyl; or two adjacent R1 substituents on ring E are linked together to form R. 11 Substituted 5-6 membered heterocyclic alkyl or heteroaryl, wherein R 11 Selected from: hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, hydroxyl, amino; R1 on the E ring is preferably hydrogen.

19. The heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound according to any one of claims 1-14, characterized in that, Each R8 is independently selected from: H, OH, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylamino, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkylamino, halogen-substituted C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyloxy, halogen-substituted C3-C6 cycloalkylamino, cyano, nitro, amino, aminosulfonyl, -C(=O)R 10 ; Each R in R8 10 Each of the following is independently selected from: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, C3-C6 cycloalkoxy, C3-C6 cycloalkylamino, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkylamino, halogen-substituted C3-C6 cycloalkoxy, halogen-substituted C3-C6 cycloalkylamino, hydroxyl, and amino; The halogen is either chlorine or fluorine; Preferably, each R8 is independently selected from: H, OH, fluorine, chlorine, bromine, trifluoromethyl, methoxy, ethoxy, methyl, ethyl; Preferably, each R8 is independently selected from: H, OH, halogen, C1-C3 alkyl; More preferably, each R8 is independently selected from: H, OH, fluorine, chlorine, methyl, ethyl.

20. The heterocyclic compound according to any one of claims 1-14, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, R is selected from: H, OH, halogen, R 12 Substituted or unsubstituted C1-C3 alkyl groups, R 12 Substituted or unsubstituted C1-C3 alkoxy groups, R 12 Substituted or unsubstituted C1-C3 alkylamine groups, R 12 Substituted or unsubstituted C3-C6 cycloalkyl, R 12 Substituted or unsubstituted C3-C6 cycloalkyloxy groups, R 12 Substituted or unsubstituted C3-C6 cycloalkylamine groups, R 12 Substituted or unsubstituted 3-6 membered heterocyclic groups, R 12 Substituted or unsubstituted 3-6 membered heterocyclic groups: oxygen, cyano, nitro, amino, aminosulfonyl, C1-C3 alkylaminosulfonyl, -C(=O)R 10 Or two adjacent R substituents can be linked together to form R. 11 Substituted or unsubstituted 5-6 membered heterocyclic alkyl, heteroaryl, or cycloalkyl groups; or, R1 substituents on adjacent R and G rings linked together to form R. 11 Substituted or unsubstituted 5-6 membered heterocyclic alkyl, heteroaryl, or cycloalkyl groups; Each R in R 10 Each of the following is independently selected from: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, C3-C6 cycloalkoxy, C3-C6 cycloalkylamino, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkylamino, halogen-substituted C3-C6 cycloalkoxy, halogen-substituted C3-C6 cycloalkylamino, hydroxyl, and amino; Each R in R 12 Each is independently selected from: hydrogen, fluorine, chlorine, hydroxyl, amino, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, C3-C6 cycloalkoxy, C3-C6 cycloalkylamino, 3-6 membered heterocyclic, C3-C6 cycloalkyl, halogen-substituted 3-6 membered heterocyclic, halogen-substituted C3-C6 cycloalkyl, C1-C3 alkyl-substituted 3-6 membered heterocyclic, C1-C3 alkyl-substituted C3-C6 cycloalkyl; Preferably, R is selected from: H, methyl, ethyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, oxacyclobutoxy, hydroxyl, fluorine, chlorine, cyano, trifluoromethyl, trifluoromethoxy, methylaminocarbonyl, aminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, methoxycarbonyl, carboxyl, ethoxycarbonyl. Dimethylamino, methylamino, amino, hydroxymethyl, methylaminosulfonyl, aminosulfonyl; or, two adjacent R substituents linked together to form Or, adjacent R and R1 substituents may be linked together to form...

21. The heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound according to any one of claims 8-9 and 12-14, characterized in that, R2, R3, R4, R5, and R6 are each independently selected from: H, OH, halogen, R 12 Substituted or unsubstituted C1-C3 alkyl groups, R 12 Substituted or unsubstituted C1-C3 alkoxy groups, R 12 Substituted or unsubstituted C1-C3 alkylamine groups, R 12 Substituted or unsubstituted C3-C6 cycloalkyl, R 12 Substituted or unsubstituted C3-C6 cycloalkyloxy groups, R 12 Substituted or unsubstituted C3-C6 cycloalkylamine groups, R 12 Substituted or unsubstituted 3-6 membered heterocyclic groups, R 12 Substituted or unsubstituted 3-6 membered heterocyclic groups: oxygen, cyano, nitro, amino, aminosulfonyl, C1-C3 alkylaminosulfonyl, -C(=O)R 10 Alternatively, two adjacent substituents from R2, R3, R4, R5, and R6 may connect to form R. 11 Substituted or unsubstituted 5-6 membered heterocyclic alkyl, heteroaryl, or cycloalkyl groups; Each of R2, R3, R4, R5, and R6 10 Each of the following is independently selected from: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, C3-C6 cycloalkoxy, C3-C6 cycloalkylamino, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkylamino, halogen-substituted C3-C6 cycloalkoxy, halogen-substituted C3-C6 cycloalkylamino, hydroxyl, and amino; Each of R2, R3, R4, R5, and R6 12 Each is independently selected from: hydrogen, fluorine, chlorine, hydroxyl, amino, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, C3-C6 cycloalkoxy, C3-C6 cycloalkylamino, 3-6 membered heterocyclic, C3-C6 cycloalkyl, halogen-substituted 3-6 membered heterocyclic, halogen-substituted C3-C6 cycloalkyl, C1-C3 alkyl-substituted 3-6 membered heterocyclic, C1-C3 alkyl-substituted C3-C6 cycloalkyl; Preferably, R2, R3, R4, R5, and R6 are each independently selected from: H, methyl, ethyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, oxacyclobutoxy, hydroxyl, fluorine, chlorine, cyano, trifluoromethyl, trifluoromethoxy, methylaminocarbonyl, aminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, methoxycarbonyl, carboxyl, ethoxycarbonyl, etc. Dimethylamino, methylamino, amino, hydroxymethyl, methylaminosulfonyl, aminosulfonyl; or, two adjacent substituents from R2, R3, R4, R5, and R6 linked together to form or 22. The heterocyclic compound according to claim 21, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, R2 is selected from: H, methoxy, fluorine, cyano, methylaminocarbonyl, ethylaminocarbonyl, methoxycarbonyl, aminocarbonyl, trifluoromethyl; Both R3 and R4 are H; or R3 is hydrogen and R4 is fluorine or methoxy. R5 is selected from: H, methoxy group; R6 is selected from: H, methoxy, methylaminocarbonyl, ethylaminocarbonyl, cyclopropylaminocarbonyl, trifluoromethyl, Or R6 and R2 are connected to form Preferably, Y3 is CR6; Preferably, Y2 is N, Y3 is CR6; R2 is methoxy or fluorine, and R6 is H or methoxy. Preferably, Y2 is CH, Y3 is CR6; R2 is hydrogen, methylaminocarbonyl, cyano, or methoxy, and R6 is H, methoxy, methylaminocarbonyl, ethylaminocarbonyl, cyclopropylaminocarbonyl, or... Or R6 and R2 are connected to form 23. The heterocyclic compound of claim 20 or its pharmaceutically acceptable salt, its stereoisomer, its solvent compound, its prodrug, its deuterated compound, characterized in that, G ring is selected from: Preferably, G is selected from:

24. The heterocyclic compound according to claim 20, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, L is G is selected from:

25. The heterocyclic compound according to any one of claims 1-14, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, Each R9 is independently selected from: H, halogen, R 12 Substituted or unsubstituted C1-C4 alkyl groups, R 12 Substituted or unsubstituted C1-C3 alkoxy groups, R 12 Substituted or unsubstituted C1-C4 alkylamine groups, R 12 Substituted or unsubstituted C3-C6 cycloalkyl, R 12 Substituted or unsubstituted C3-C6 cycloalkyloxy, C3-C6 cycloalkylamine carbonyl, C1-C3 alkylamine carbonyl, C1-C3 alkoxy carbonyl, C1-C3 alkylacyl, C1-C3 alkamido, R 12 Substituted or unsubstituted 5-6 membered heterocyclic groups, cyano, carbamoyl, R 12 Substituted or unsubstituted 5-6 membered heterocyclic groups -O-, R 12 Substituted or unsubstituted 5-6 membered heterocyclic groups -C(=O)-, R 12 Substituted or unsubstituted 5-6 membered heterocyclic groups -N(R1)-, R 12 Substituted or unsubstituted 5-6 membered heteroaryl groups; Each R 12 Each is independently selected from: hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkyl-substituted 5-6 membered heterocyclic group, 5-6 membered heterocyclic group, methylamino, and dimethylamino.

26. The heterocyclic compound according to claim 25, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, Each R9 is independently selected from: hydrogen, methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, fluorine, chlorine, cyano, trifluoromethoxy, methylaminocarbonyl, methoxycarbonyl, acetamido, carbamoyl, formyl, methyl-substituted cyclopropyl, trifluoromethyl-substituted n-propyl.

27. The heterocyclic compound according to claim 26, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, Ring A is selected from:

28. The heterocyclic compound according to claim 27, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, characterized in that, L is Ring A is selected from: Or, L is Ring A is selected from: Optimal 29. The heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound according to claim 1, characterized in that, The heterocyclic compound has the structure shown in formula (A) or formula (B): Among them, one of X1 and X2 is N, and the other is CH; R9 is selected from 30. The heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound according to claim 1, characterized in that, Selected from the following compounds:

31. The use of any heterocyclic compound of claims 1-30 or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound in the preparation of RET kinase inhibitors.

32. The use of the heterocyclic compound of any one of claims 1-30, or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound, in the preparation of a medicament for the prevention and / or treatment of diseases associated with abnormal RET kinase expression.

33. The application according to claim 31 or 32, characterized in that, The RET kinase is a wild-type RET kinase, a RET kinase carrying the V804M mutation, a RET kinase carrying the G810C mutation, and / or a RET kinase carrying the G810R mutation.

34. The application according to claim 32, characterized in that, The disease associated with abnormal RET kinase expression is a tumor; preferably, the tumor is: leukemia, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, gastric cancer, histiocytic lymphoma, nasopharyngeal carcinoma, preferably, the tumor is chronic myeloid leukemia, gastric cancer, or lung adenocarcinoma.

35. A pharmaceutical composition for the prevention and / or treatment of tumors, characterized in that, It is prepared from an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient includes the heteroaromatic compound of any one of claims 1-30 or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound.

36. A method for preventing and / or treating tumors, characterized in that, include: The safe and effective amount of any one of claims 1-30, a heterocyclic compound or its pharmaceutically acceptable salt, stereoisomer, solvent compound, prodrug, or deuterated compound thereof, may be administered to a patient. Alternatively, administer to a patient a safe and effective amount of the pharmaceutical composition of claim 35.

37. The method for preventing and / or treating tumors according to claim 36, characterized in that, The tumor in question is one associated with abnormal RET kinase expression.

38. The method for preventing and / or treating tumors according to claim 37, characterized in that, The RET kinase is a wild-type RET kinase, a RET kinase carrying the V804M mutation, a RET kinase carrying the G810C mutation, and / or a RET kinase carrying the G810R mutation.

39. The method for preventing and / or treating tumors according to claim 37, characterized in that, The tumor is leukemia, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, gastric cancer, histiocytic lymphoma, or nasopharyngeal carcinoma. Preferably, the tumor is chronic myeloid leukemia, gastric cancer, or lung adenocarcinoma.

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