CN115772167A

CN115772167A - Compound containing urea structure and application thereof

Info

Publication number: CN115772167A
Application number: CN202211058894.0A
Authority: CN
Inventors: 蔡倩; 张章; 吴开富; 何蕊; 肖国荣; 黄晶; 邱孔茜
Original assignee: Jinan University
Current assignee: Jinan University
Priority date: 2021-09-08
Filing date: 2022-08-30
Publication date: 2023-03-10

Abstract

The invention provides a compound containing a urea structure with a structure shown in a formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the compound can effectively inhibit kinases, especially RET kinase, so as to regulate the activation of downstream multiple pathways, and can be used for preparing medicines for preventing and treating various diseases related to the RET kinase, such as leukemia and tumors.

Description

Compound containing urea structure and application thereof

Technical Field

The invention relates to the field of medicinal chemistry, in particular to a compound containing a urea structure and application thereof.

Background

The receptor tyrosine kinase RET (Rearranged during transfection) plays an important role in the development of the kidney and nervous system. RET can activate downstream signaling pathways through gene fusion, point mutations, overexpression, and the like. When activated abnormally, it can act as an oncogene in a variety of malignant tumors. Among them, RET fusions that retain the kinase domain are the drivers of cancers such as Papillary Thyroid Cancer (PTC), non-small cell lung cancer (NSCLC); whereas the activating RET mutation is associated with different phenotypes of multiple endocrine tumor type 2 (MEN 2) and sporadic Medullary Thyroid Carcinoma (MTC). Thus, RET is an attractive therapeutic target for patients who have become cancerous by alteration of RET.

Early multi-kinase inhibitors (MKIs) with RET inhibitor activity, such as cabozantinib and vandetanib, have been explored clinically for RET driven cancers. Due to low targeting, the multi-kinase inhibitor is easy to produce non-target side effects, such as hypertension, diarrhea and the like, and limits the tolerable dose of patients. Recently, the highly selective RET kinase inhibitor Selpercatinib, developed by Loxo Oncology corporation, was approved by the FDA for marketing in 5 months of 2020; used for treating advanced RET fusion-positive NSCLC and RET mutant/fusion-positive MTC. Another highly selective RET kinase inhibitor Pralsetinib developed by Blueprint Medicines corporation was approved by FDA for marketing in 9 months of 2020; in vitro research shows that the specificity of Pralsetinib for RET is obviously superior to that of other multi-target inhibitors, has better tolerance and only slight inhibition effect on VEGFR-2, and is used for treating adult patients with RET fusion positive NSCLC.

Although Selpercatinib and Pralsetinib have high activity and high selectivity on RET, the development of selective inhibitors with new structures aiming at RET gene fusion, overexpression or key site mutation such as V804M mutation and the like still has important research value. Furthermore, RET G810R, S and C solvent front mutations have been demonstrated as acquired resistance mechanisms in RET-aberrant patients progressing with selective RET inhibitors (Solomon, benjamin j. Et al. Jthorac oncol.2020,15 (4), 541-549), and development of new RET inhibitors to inhibit these mutations is necessary and of great research interest.

Disclosure of Invention

Aiming at the problems, the invention provides a novel compound containing a urea structure, and the compound has good inhibitory activity on RET wild kinase and mutant kinase.

The specific technical scheme is as follows:

a compound having a urea-containing structure represented by formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

wherein the content of the first and second substances,

X ₁ 、X ₂ 、X ₃ 、X ₄ and X ₅ Together form a heteroaryl group, X ₁ 、X ₂ 、X ₃ 、X ₄ And X ₅ Each independently selected from: n, NR ₂ C, CR, or C = O, and X ₁ 、X ₂ 、X ₃ 、X ₄ And X ₅ One, two or three of which are each independently selected from: n, or NR ₂ When X is present ₁ 、X ₂ 、X ₃ 、X ₄ And X ₅ When two or three of the N-substituted aryl groups are all N, an N = N structure is not formed;

A ₁ 、A ₂ 、B ₁ 、B ₂ 、D ₁ 、D ₂ 、E ₁ and E ₂ Each independently selected from: n, or CR ₅ ；

Z is selected from: n, or CR';

R ₁ selected from:

wherein m, n ₁ 、n ₂ Each independently selected from: an integer of 0 to 6;

each Z ₁ 、Z ₂ Each independently selected from: NR ₁₀ O, S or CR ₁₁ R ₁₂ ；

Each Z ₃ 、Z ₄ 、Z ₅ Each independently selected from: o or S;

each Z ₆ Each independently selected from: n or CR ₉ ；

Each R ₂ Each independently selected from: H. c ₁ ～C ₈ Alkyl radical, C ₁ ～C ₈ Alkyl acyl radical, C ₁ ～C ₈ Alkoxycarbonyl group, C ₁ ～C ₈ Alkylamino carbonyl group, C ₃ ～C ₆ Cycloalkyl radical, C ₃ ～C ₆ Cycloalkoxycarbonyl radical, C ₃ ～C ₆ Cycloalkylaminocarbonyl, 3-to 6-membered heterocycloalkyl, C ₅ ～C ₁₀ Arylacyl, 5-to 10-membered heteroarylacyl, C ₁ ～C ₈ Sulfonyl radical, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₆ Alkyl, or 5-to 18-membered heteroaryl; when R is ₂ When not hydrogen, said R ₂ Independently optionally substituted by 1 or more R ₁₃ Substitution;

R ₃ 、R ₄ each independently selected from: H. c ₁ ～C ₈ Alkyl radical, C ₁ ～C ₈ Alkylamino, hydroxy-substituted C ₁ ～C ₈ Alkyl radical, C ₁ ～C ₈ Alkoxy-substituted C ₁ ～C ₈ Alkyl radical, C ₃ ～C ₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₈ Acyl, alkenylacyl, C ₁ ～C ₈ Sulfonyl, 5-to 18-membered heteroaryl, or R ₃ 、R ₄ And together with the carbon atom to which they are attached form 1 or more R ₁₃ Substituted or unsubstituted 3 to 10 membered cycloalkyl or 6 to 10 membered heteroaryl;

each R ₅ Each independently selected from: H. halogen, C ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl, 5-to 18-membered heteroaryl, or-SR ₁₄ (ii) a When R is ₅ Is selected from C ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino radical, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl or 5-to 18-membered heteroaryl, said R ₅ Independently optionally substituted by 1 or more R ₁₃ Substitution;

each R ₆ Each independently selected from: H. c ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino, amino, hydroxyl, cyano, nitro, ester, C ₁ ～C ₈ Acyl, amido, sulfonyl, sulfonamido, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl, or 5-to 18-membered heteroaryl; when R is ₆ Is selected from C ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino radical, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl or 5-to 18-membered heteroaryl, said R ₆ Independently optionally substituted by 1 or more R ₁₃ Substitution;

each R ₇ 、R ₈ Each independently selected from: H. c ₁ ～C ₈ Alkyl radical, C ₁ ～C ₈ Alkylamino, hydroxy-substituted C ₁ ～C ₈ Alkyl radical, C ₁ ～C ₈ Alkoxy-substituted C ₁ ～C ₈ Alkyl radical, C ₁ ～C ₈ Alkylamino substituted C ₁ ～C ₈ Alkyl radical, C ₃ ～C ₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₈ Acyl, alkenylacyl, C ₁ ～C ₈ Sulfonyl, 5-to 18-membered heteroaryl, or R ₇ 、R ₈ Together with the N atom to which they are attached form 1 or more R ₁₃ A substituted or unsubstituted 3-to 10-membered heterocyclic group, or R ₇ 、R ₈ Together with the N atom to which they are attached form 1 or more R ₁₃ Substituted or unsubstituted 5-to 10-membered heteroaryl;

each R ₉ Each independently selected from: H. c ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino, amino, hydroxyl, cyano, nitro, ester, C ₁ ～C ₈ Acyl, amido, sulfonyl, sulfonamido, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl, or 5-to 18-membered heteroaryl; when R is ₉ Is selected from C ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino radical, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl or 5-to 18-membered heteroaryl, said R ₉ Independently optionally substituted by 1 or more R ₁₃ Substitution;

each R ₁₀ Each independently selected from: H. c ₁ ～C ₈ Alkyl, hydroxy substituted C ₁ ～C ₈ Alkyl radical, C ₁ ～C ₈ Alkoxy-substituted C ₁ ～C ₈ Alkyl radical, C ₃ ～C ₈ A cycloalkyl group;

each R ₁₁ 、R ₁₂ Each independently selected from: H. c ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino, amino, hydroxyl, cyano, nitro, ester, C ₁ ～C ₈ Acyl, amido, sulfonyl, sulfonamido, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl, or 5-to 18-membered heteroaryl; when R is ₁₁ 、R ₁₂ Is selected from C ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino radical, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl or 5-to 18-membered heteroaryl, said R ₁₁ 、R ₁₂ Independently optionally substituted by 1 or more R ₁₃ Substitution;

each R ₁₃ Each independently selected from: H. hydroxy, amino, cyano, nitro, halogen, trifluoromethyl, C ₁ ～C ₆ Alkoxy radical, C ₁ ～C ₈ Alkyl radical, C ₃ ～C ₈ Cycloalkyl, 3-to 10-membered heterocyclyl, 6-to 10-membered aryl;

each R ₁₄ Each independently selected from: H. c ₁ ～C ₈ Alkyl, hydroxy-substituted C ₁ ～C ₈ Alkyl radical, C ₁ ～C ₈ Alkoxy-substituted C ₁ ～C ₈ An alkyl group;

each R is independently selected from: H. halogen, C ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl,C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl, or 5-to 18-membered heteroaryl; when R is selected from C ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino radical, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ When alkyl or 5-18 membered heteroaryl, said R is independently optionally substituted with 1 or more R ₁₃ Substitution;

each R' is independently selected from: H. halogen, C ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl, or 5-to 18-membered heteroaryl; when R' is selected from C ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino radical, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ When alkyl or 5-18 membered heteroaryl, said R' is independently optionally substituted with 1 or more R ₁₃ And (4) substitution.

In some of these embodiments, the compound containing a urea structure has a structure represented by formula (II), (III), (IV), (V), (VI), (VII), or (VIII):

wherein the content of the first and second substances,

X ₁ 、X ₃ 、X ₄ each independently selected from: n, NR ₂ CR, or C = O, and X ₁ 、X ₃ 、X ₄ And the five-membered ring does not form an N = N structure.

In some of these embodiments, the compound comprising a urea structure has a structure represented by formula (IX), formula (X), formula (XI), or formula (XII):

r in Compound (IX) and Compound (X) of the present invention ₂ In the case of H, the compound (IX) and the compound (X) are tautomers and represent the same compound.

In some of these embodiments, A ₁ 、A ₂ 、B ₁ 、B ₂ 、D ₁ 、D ₂ 、E ₁ And E ₂ Are all CR ₅ 。

In some embodiments, the compound containing a urea structure has a structure represented by formula (a), formula (B), or formula (C):

wherein each p is independently selected from: an integer between 0 and 4; z ₁ Is O or S; x ₁ Is N or CR.

In some of these embodiments, R ₆ Is H; the sum of m and n is selected from: 0.1, 2 and 3.

In some of these embodiments, m is 0,1, 2, or 3,n is 0,1, 2, or 3,n ₁ Is 0,1, 2 or 3,n ₂ Is 0,1, 2 or 3.

In some of these embodiments, each R ₆ Each independently selected from: H. c ₁ ～C ₆ Alkyl radical, C ₃ ～C ₈ Cycloalkyl, 3-to 8-membered heterocycloalkyl, C ₁ ～C ₃ Alkoxy radical, C ₁ ～C ₃ Alkylamino radicalAmino, hydroxyl, cyano, nitro, ester group, C ₁ ～C ₃ Acyl, amido, sulfonyl, sulfonamido, C ₆ ～C ₁₀ Aryl radical, C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₃ Alkyl, or 5-to 10-membered heteroaryl; when R is ₆ Is selected from C ₁ ～C ₆ Alkyl radical, C ₃ ～C ₈ Cycloalkyl, 3-to 8-membered heterocycloalkyl, C ₁ ～C ₃ Alkoxy radical, C ₁ ～C ₃ Alkylamino radical, C ₆ ～C ₁₀ Aryl radical, C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₃ When alkyl or 5-to 10-membered heteroaryl, the R ₆ Independently optionally substituted by 1 or more R ₁₃ And (4) substitution.

In some of these embodiments, R ₆ Selected from: H. c ₁ ～C ₃ An alkyl group.

In some of these embodiments, each R ₇ 、R ₈ Each independently selected from: H. c ₁ ～C ₃ Alkyl radical, C ₁ ～C ₃ Alkylamino, hydroxy-substituted C ₁ ～C ₃ Alkyl radical, C ₁ ～C ₃ Alkoxy-substituted C ₁ ～C ₃ Alkyl radical, C ₁ ～C ₃ Alkylamino substituted C ₁ ～C ₃ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, 3-to 6-membered heterocycloalkyl, C ₁ ～C ₃ Acyl, alkenylacyl, C ₁ ～C ₃ Sulfonyl, 5-to 10-membered heteroaryl, or R ₇ 、R ₈ Together with the N atom to which they are attached form 1 or more R ₁₃ A substituted or unsubstituted 3-to 8-membered heterocyclic group, or R ₇ 、R ₈ Together with the N atom to which they are attached form 1 or more R ₁₃ Substituted or unsubstituted 5 to 10 heteroaryl.

In some of these embodiments, each R ₇ ，R ₈ Each independently selected from: H. c ₁ ～C ₃ Alkyl, or R ₇ 、R ₈ Together with the N atom to which they are attached form 1 or more R ₁₃ A substituted or unsubstituted 5-to 6-membered heterocyclic group.

In some of these embodiments, each R ₇ 、R ₈ Each independently selected from: H. methyl, ethyl, propyl, or R ₇ 、R ₈ Together with the N atom to which they are attached form 1 or more R ₁₃ A substituted or unsubstituted morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl group.

In some of these embodiments, R ₁ Selected from:

in some of these embodiments, each R ₂ Each independently selected from: H. c ₁ ～C ₃ Alkyl radical, C ₁ ～C ₃ Alkyl acyl radical, C ₁ ～C ₃ Alkoxycarbonyl group, C ₁ ～C ₃ Alkylamino carbonyl, C ₃ ～C ₆ Cycloalkyl radical, C ₃ ～C ₆ Cycloalkoxycarbonyl radical, C ₃ ～C ₆ Cycloalkylaminocarbonyl, 3-to 6-membered heterocycloalkyl, C ₅ ～C ₁₀ Arylacyl, 5-to 10-membered heteroarylacyl, C ₁ ～C ₈ Sulfonyl radical, C ₆ ～C ₁₀ Aryl radical, C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₃ Alkyl, or 5-to 10-membered heteroaryl; when R is ₂ When not hydrogen, the R ₂ Independently optionally substituted by 1 or more R ₁₃ And (4) substitution.

In some of these embodiments, R ₃ 、R ₄ Each independently selected from: H. c ₁ ～C ₃ Alkyl radical, C ₁ ～C ₃ Alkylamino, hydroxy-substituted C ₁ ～C ₃ Alkyl radical, C ₁ ～C ₃ Alkoxy-substituted C ₁ ～C ₃ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, 3-to 8-membered heterocycloalkyl, C ₁ ～C ₃ Acyl, alkenylacyl, C ₁ ～C ₃ Sulfonyl, 5-to 10-membered heteroaryl, or R ₃ 、R ₄ And is connected theretoAre taken together to form 1 or more R ₁₃ Substituted or unsubstituted 3 to 6 membered cycloalkyl.

In some of these embodiments, each R ₅ Each independently selected from: H. halogen, C ₁ ～C ₃ Alkyl radical, C ₃ ～C ₈ Cycloalkyl, 3-to 8-membered heterocycloalkyl, C ₁ ～C ₃ Alkoxy radical, C ₁ ～C ₃ Alkylthio radical, C ₁ ～C ₃ Alkylamino, amino, hydroxyl, mercapto, cyano, nitro, ester, amido, sulfonyl, sulfonamido, C ₆ ～C ₁₀ Aryl radical, C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₆ Alkyl, 5-to 10-membered heteroaryl; when R is ₅ Is selected from C ₁ ～C ₃ Alkyl radical, C ₃ ～C ₈ Cycloalkyl, 3-to 8-membered heterocycloalkyl, C ₁ ～C ₃ Alkoxy radical, C ₁ ～C ₃ Alkylamino radical, C ₆ ～C ₁₀ Aryl radical, C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₆ When alkyl or 5-to 10-membered heteroaryl, the R ₅ Independently optionally substituted by 1 or more R ₁₃ And (4) substitution.

In some of these embodiments, the compound containing a urea structure has the structure shown in formula (D), formula (E), or formula (F):

wherein each p is independently selected from: 0.1 or 2;

X ₁ is N or CH;

each R ₅ Each independently selected from: H. fluorine, bromine, chlorine, C ₁ ～C ₃ Alkyl radical, C ₁ ～C ₃ An alkoxy group;

r's' ₅ Each independently selected from: H. fluorine, C ₁ ～C ₃ An alkoxy group.

In some of these embodiments, each R is independently selected from: H. halogen, C ₁ ～C ₃ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, 3-to 6-membered heterocycloalkyl, C ₁ ～C ₃ Alkoxy radical, C ₁ ～C ₃ Alkylamino, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C ₆ ～C ₁₀ Aryl radical, C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₃ Alkyl, or 5-to 10-membered heteroaryl; when R is selected from C ₁ ～C ₃ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, 3-to 6-membered heterocycloalkyl, C ₁ ～C ₃ Alkoxy radical, C ₁ ～C ₃ Alkylamino radical, C ₆ ～C ₁₀ Aryl radical, C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₃ When alkyl or 5-to 10-membered heteroaryl, said R is independently optionally substituted with 1 or more R ₁₃ And (4) substitution.

In some of these embodiments, each R' is independently selected from: H. halogen, C ₁ ～C ₃ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, 3-to 6-membered heterocycloalkyl, C ₁ ～C ₃ Alkoxy radical, C ₁ ～C ₃ Alkylamino, amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, sulfonamido, C ₆ ～C ₁₀ Aryl radical, C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₃ Alkyl, or 5-to 10-membered heteroaryl; when R' is selected from C ₁ ～C ₃ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, 3-to 6-membered heterocycloalkyl, C ₁ ～C ₃ Alkoxy radical, C ₁ ～C ₃ Alkylamino radical, C ₆ ～C ₁₀ Aryl radical, C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₃ When alkyl or 5-to 10-membered heteroaryl, said R' is independently optionally substituted with 1 or more R ₁₃ And (4) substitution.

In some of these embodiments, each R ₁₃ Each independently selected from: H. hydroxy, amino, cyano, nitro, halogen, trifluoromethyl, C ₁ ～C ₃ Alkoxy radical, C ₁ ～C ₃ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, 3-to 6-membered heterocyclic group, 6-to 10-membered aryl group.

The invention also provides application of the compound.

The application of the compound containing the urea structure or the pharmaceutically acceptable salt or the stereoisomer thereof in preparing RET kinase inhibitors.

In some of these embodiments, the RET kinase is a wild-type RET kinase, a RET kinase carrying a V804M mutation, a RET kinase carrying a G810C mutation, and/or a RET kinase carrying a G810R mutation.

The compound containing the urea structure or the pharmaceutically acceptable salt or the stereoisomer thereof can be applied to the preparation of medicines for preventing and/or treating diseases related to the abnormal expression of RET kinase.

In some of these embodiments, the disease associated with aberrant expression of RET kinase is a tumor.

In some of these embodiments, the tumor is: leukemia, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, gastrointestinal stromal tumor, histiocytic lymphoma, and nasopharyngeal carcinoma.

The invention also provides a medicinal composition for preventing and/or treating tumors.

The specific technical scheme is as follows:

a medicinal composition for preventing and/or treating tumor is prepared from an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the compound containing the urea structure or pharmaceutically acceptable salt or stereoisomer thereof.

Based on the technical scheme, the invention has the following beneficial effects:

the compound containing the urea structure and the pharmaceutically acceptable salts and isomers thereof can effectively inhibit the activity of kinase, especially RET kinase, including wild and various mutant RET kinases, and further can regulate the activation of downstream multiple pathways, and can be used for preparing medicines for preventing and treating various diseases related to the abnormal expression of the RET kinase, such as leukemia and tumor.

Detailed Description

In the compounds of the invention, when any variable (e.g. R) ² Etc.) occur more than one time in any constituent, then the definition of each occurrence is independent of the definitions of each other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. The line drawn from a substituent into the ring system indicates that the indicated bond can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It is to be understood that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by those skilled in the art and by the methods set forth below from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stable. The phrase "optionally substituted with one or more substituents" is considered equivalent to the phrase "optionally substituted with at least one substituent" and preferred embodiments in this case will have from 0 to 3 substituents.

The term "alkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C ₁ -C ₆ Alkyl radical "middle" C ₁ -C ₆ The definition of "includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain arrangement. For example, "C ₁ -C ₆ Alkyl "specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term "alkoxy" refers to a group having the structure-O-alkyl, such as-OCH ₃ 、-OCH ₂ CH ₃ 、-OCH ₂ CH ₂ CH ₃ 、-O-CH ₂ CH(CH ₃ ) ₂ 、-OCH ₂ CH ₂ CH ₂ CH ₃ 、-O-CH(CH ₃ ) ₂ And so on. The term "heterocycloalkyl" is a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent in which one or more ring atoms are selected from the group consisting of N, O or the heteroatoms of S (O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon, for example: morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothienyl, and the like, and N-oxides thereof, and the attachment of the heterocyclic substituent may be through a carbon atom or through a heteroatom. The term "heteroaryl" refers to an aromatic ring containing 1 or more heteroatoms selected from O, N or S, and heteroaryl groups within the scope of the present invention include, but are not limited to: quinolyl, pyrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl; "heteroaryl" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group. Attachment of the heterocyclic substituent may be through a carbon atom or through a heteroatom.

As understood by those skilled in the art, "halo" or "halo" as used herein means chloro, fluoro, bromo, and iodo.

Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl substituents may be unsubstituted or substituted. For example, C ₁ -C ₆ Alkyl groups may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclyl, e.g. morpholinyl, piperidinyl and the like.

The invention includes compounds of formulae (I) - (XII), free forms of compounds of formulae (A) - (F), and also pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine-based compounds. The term "free form" refers to the amine compound in a non-salt form. Included within pharmaceutically acceptable salts are not only exemplary salts of the particular compounds described herein, but are also all typical pharmaceutically acceptable salts of the compounds of formulas (I) - (XII), and of the free forms of the compounds of formulas (A) - (F). The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base, such as a dilute aqueous NaOH solution, a dilute aqueous potassium carbonate solution, dilute aqueous ammonia, and a dilute aqueous sodium bicarbonate solution. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.

Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.

Thus, pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present invention and an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those 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, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-monobenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.

If the compounds of the invention are acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, piperdine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

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.

It should be noted that the compounds of the present invention are potential internal salts or zwitterions, since the acidic moiety, e.g. the carboxylate group, deprotonated in the compound under physiological conditions may be anionic and this charged charge may then be balanced out by a protonated or alkylated basic moiety, e.g. a tetravalent nitrogen atom, bearing a cation internally.

In one embodiment, the invention provides a method of treating hyperproliferative diseases or conditions, such as tumors, in humans and other mammals, using compounds having the formulas (I) - (XII), formulas (A) - (F), and pharmaceutically acceptable salts thereof.

In one embodiment, the compounds of the present invention and pharmaceutically acceptable salts thereof can be used for treating or controlling non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, and other hyperproliferative diseases.

Combination drug

The compounds of formulae (I) - (XII), formulae (A) - (F) may be combined with other drugs known to treat or ameliorate similar conditions. When the combination is administered, the administration mode & dosage of the original drug is kept unchanged, while the compounds of formulae (I) - (XII), formulae (A) - (F) are administered simultaneously or subsequently. When the compounds of the formulae (I) to (XII) and (A) to (F) are administered simultaneously with one or more other drugs, it is preferable to use a pharmaceutical composition containing one or more known drugs together with the compounds of the formulae (I) to (XII) and (A) to (F). The combination also includes administering the compounds of formulae (I) - (XII), formulae (A) - (F) and one or more other known agents over an overlapping period of time. When the compounds of formulae (I) - (XII), formulae (A) - (F) are administered in combination with one or more other drugs, the dose of the compounds of formulae (I) - (XII), formulae (A) - (F), or known drugs may be lower than when they are administered alone.

Drugs or active ingredients that may be used in pharmaceutical combination with compounds of formulae (I) - (XII), formulae (A) - (F) include, but are not limited to:

estrogen receptor modulators, androgen receptor modulators, retinal-like receptor modulators, cytotoxins/cytostatics, antiproliferatives, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, bcr-Abl inhibitors, c-Kit inhibitors, met inhibitors, raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon- α, interleukin-12, COX-2 inhibitors, p53 activators, VEGF antibodies, EGF antibodies, and the like.

In one embodiment, drugs or active ingredients that may be used in combination with the compounds of formulae (I) - (XII), formulae (A) - (F) include, but are not limited to: aldesleukin, alendronic acid, interferon, a Qu Nuoying, allopurinol sodium, palonosetron hydrochloride, altretamine, aminoglutethimide, amifostine, amrubicin, ambridine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, aroxin, 5-azacytidine, azathioprine, BCG or tie BCG, betamethasone acetate, betamethasone sodium phosphate formulations, sodium betamethasone phosphate formulations, and combinations thereof bexarotene, bleomycin sulfate, bromouracil, bortezomib, busulfan, calcitonin, aleuzumab injection, capecitabine, carboplatin, kang Shide, cefesone, west Mo Bai interleukin, daunorubicin, chlorambucil, cisplatin, cladribine, chlorine Qu Linsuan, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin liposome, dexamethasone, and pharmaceutically acceptable salts thereof dexamethasone phosphate, estradiol valerate, dinil interleukin 2, dibumel, deslorelin, delazoxan, diethylstilbestrol, DAFUKANG, docetaxel, doxifluridine, doxorubicin, dronabinol, azulene-166-chitosan complex, eligard, labyrine, epirubicin hydrochloride, aprepirubicin, epirubicin, alfacitinin, erythropoietin, eptaplatin, levamisole, estradiol formulations, 17-beta-estradiol, estramustine sodium phosphate, ethisterol, amifostine, hydroxyphosphoric acid, valpiride, etoposide, faprazole, tamoxifen formulations, filgrastim, finasteride, feristine, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, flumethamine, foglisentan, 1-beta-D-arabinosyl-thiabendazole-5' -testosterone Fotemustine, fulvestrant, gamma globulin, gemcitabine, gemtuzumab ozogamicin, imatinib mesylate, carmustine wafer capsule, goserelin, glanesilone hydrochloride, histrelin, and metin, hydrocortisone, erythro-hydroxynonyladenine, hydroxyurea, titatane Bei Mo mab, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alpha-2A, interferon alpha-2B, interferon alpha-nl, interferon alpha-n 3, interferon beta, interferon gamma-la, interleukin-2, intron A, iressa, irinotecan, katerel, lentinan sulfate, letrozole, leucovorin, leuprorelin acetate, levotetramisoimidazole, levofolinic acid, levothyroxine sodium preparation, lomustine, levothyroxine sodium lonidamine, dronabinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-ryopurine, mesna, methotrexate, methyl aminolevulinate, miltefosine, milbemycin, mitomycin C, mitotane, mitoxantrone, trilobanone, trilostane, doxorubicin citrate liposome, nedaplatin, pegylated filgrastim, omprex interleukin, neupogen, nilutamide, tamoxifen, NSC-631570, recombinant human interleukin 1-beta, octreotide, ondansetron hydrochloride, hydrocortisone oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate formulation, pemetrexed, winter Luo Xin, staphyline, streptolysin formulation, piroctone hydrochloride, bordetellurocin, plicamycin, sodium, nemamfenamiphene, and nemaderin, <xnotran> , , , , , , , -186, , -A, , , , , , , , , , , , -89, , , , , tastolactone, , , , , , , , , , , , , , , , A , , , , , , , , , , , , , , , , , , , acolbifene, r-lb, affinitak, , , asoprisnil, , , BAY43-9006, , CCI-779, CDC-501, , , , , , DN-101, -MTC, dSLIM, , edotecarin, , , A , , , -166DOTMP, , γ, -PEG, ixabepilone, , L-651582, </xnotran> Lanopeptide, lasofoxifene, libra, lonafamib, milbexifene, minox Qu Suanzhi, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatret, orlistat, oncomelanism, ono-TCS, osidem, paclitaxel polyglutamate, sodium pamoate, PN-401, QS-21, quartzocean, R-1549, raloxifene, ranpirnase, 13-cis retinoic acid, satraplatin, seocalcitol, T-138067, tarceva, paclitaxel, thymosin alpha l, gastrodine, tipifylline, tipifarnib, tirapazamine, TLK-286, toremifene, trans-7R, valsalvo, vapreotide, valatib, vepin, vinpocetine, 100, and mixtures thereof.

The reagents used in the following examples are commercially available.

The invention is further described in the following examples, which are not intended to limit the scope of the invention.

Example 1: preparation of Compound CQ-1232

Preparation of Compound 3 (a-b):

dissolving the compound 1 (50g, 308.6 mmol) in 250ml of isopropanol, stirring at room temperature for 3 hours, spin-drying, dissolving in 300ml of dichloromethane, dripping 19ml of hydrazine (50% aqueous solution) at 0 ℃, reacting at room temperature overnight, washing with water after the reaction is finished, and spin-drying an organic phase to obtain 24g of crude product 3 which can be directly used in the next step without further purification.

Preparation of Compound 10 (c-g):

(c) Dissolving the compound 4 (9.5g, 69.8mmol) and potassium carbonate (19.3g, 140mmol) in 100ml of acetone, adding benzyl bromide (9.1ml, 77mmol), reacting at 60 ℃ overnight, after the reaction is finished, carrying out suction filtration and spin drying to obtain 14g of crude product 5, and directly using the crude product in the next step without further purification.

(d) Compound 5 (10.6 g, 47mmol) and compound 3 (22.2g, 188mmol) were dissolved in 80ml of methanol, glacial acetic acid (0.54ml, 9.4 mmol) was added thereto, and after 8 hours of reflux reaction at 80 ℃, cooling to room temperature and suction filtration were carried out to give 14g of compound 6 in a yield of 91%.

¹ H NMR(400MHz,CDCl ₃ )δ7.68–7.82(m,3H),7.29-7.49(m,5H),6.96(d,J＝8.8Hz,2H),5.04–5.17(m,3H),2.16(s,3H),1.33(d,J＝6.0Hz,6H).

(e) Dissolving compound 6 (4 g, 12.27mmol) in 25ml of dry tetrahydrofuran, under the protection of argon, dripping 20ml of lithium diisopropylamide (2M tetrahydrofuran solution) at 0 ℃, stirring for 1 hour, turning to-78 ℃, dripping 25ml of tetrahydrofuran solution of compound 7 (3.3 g,18.4 mmol), slowly raising the temperature to room temperature for reaction after dripping, quenching with saturated ammonium chloride aqueous solution after the reaction is finished, extracting with ethyl acetate, mixing organic phase with silica gel, and passing through a column to obtain 2g of crude product 8.

(f) Compound 8 (2g, 4.47mmol) is dissolved in 30ml of tetrahydrofuran, 10ml of methanesulfonic acid (3N aqueous solution) is added, after refluxing at 80 ℃ for 4 hours, extraction is carried out with ethyl acetate, washing is carried out three times with saturated sodium bicarbonate solution, and the organic phase is stirred with silica gel and is then subjected to column chromatography to give 650mg of compound 9, yield 34%.

¹ H NMR(400MHz,CDCl ₃ )δ8.29(d,J＝8.8Hz,2H),7.86(d,J＝8.4Hz,2H),7.61(d,J＝8.8Hz,2H),7.26–7.49(m,5H),7.05(d,J＝8.8Hz,2H),6.72(s,1H),5.07–5.18(m,3H),1.29(d,J＝6.4Hz,6H).

(g) The method comprises the following steps Dissolving compound 9 (650 mg, 1.42mmol) in 20ml ethyl acetate, adding 65mg palladium carbon, ventilating with hydrogen gas for three times, reacting at room temperature for 6 hours, filtering, and spin-drying to obtain 480mg compound 10 with 99% yield.

¹ H NMR(400MHz,DMSO)δ9.73(s,1H),7.74(d,J＝8.8Hz,2H),7.15(d,J＝8.4Hz,2H),6.86(d,J＝8.8Hz,2H),6.80(s,1H),6.62(d,J＝8.4Hz,2H),5.37(s,2H),4.94–5.07(m,1H),1.21(d,J＝6.4Hz,6H).

Preparation of Compound 13 ((h-i)):

(h) Acetonitrile (2.3 ml,44.1 mmol) was dissolved in 50ml of dry tetrahydrofuran, stirred at-78 ℃ for 15 minutes, 28ml of n-butyllithium (1.6M in hexane) was added, the mixture was moved to-30 ℃ and stirred for 30 minutes, and then compound 11 (5g, 29.4 mmol) was added dropwise, the reaction was allowed to proceed overnight, quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, and the organic phase was dried by spinning to give 5.1g of crude product 12 which was used directly in the next step.

(i) Hydroxylamine hydrochloride (3.94g, 56.6 mmol) is dissolved in 50ml water, sodium bicarbonate (4.8g, 56.6 mmol) is added at 0 ℃, pH is adjusted to 8, 30ml of a methanol solution of a compound 12 is added, after refluxing at 65 ℃ for 6 hours, cooling to room temperature, pH is adjusted to 1 by concentrated hydrochloric acid, after refluxing at 70 ℃ for 3 hours, after the reaction is finished, pH is adjusted to 8 by a 4N sodium hydroxide solution, ethyl acetate is extracted, and the organic phase is stirred with silica gel and is subjected to column chromatography to obtain a compound 1.3g of a compound 13, wherein the yield is 23%.

¹ H NMR(400MHz,CDCl ₃ )δ5.77(s,1H),4.20(s,2H),1.47(s,6H).

Preparation of compound 14:

(j) Compound 13 (1.3g, 6.7mmol) and potassium carbonate (1.38g, 10mmol) were dissolved in 20ml of tetrahydrofuran, and phenyl chloroformate (1ml, 8mmol) was added thereto, and after reaction at room temperature for 4 hours, water and ethyl acetate were added thereto, extraction was carried out, spin-drying was carried out, 20ml of n-hexane was added thereto, stirring was carried out for 1 hour, suction filtration was carried out, and the cake was dried to obtain 1.78g of Compound 14, yield 85%.

¹ H NMR(400MHz,CDCl ₃ )δ8.07(s,1H),7.37-7.45(m,2H),7.24–7.31(m,1H),7.16-7.22(m,2H),6.85(s,1H),1.57(s,6H).

Preparation of compound CQ-1232:

(k) Dissolving compound 10 (200mg, 0.59mmol), compound 14 (280mg, 0.89mmol) and 4-dimethylaminopyridine (7mg, 0.06mmol) in 3ml of N, N-dimethylformamide, adding triethylamine (0.25ml, 1.77mmol), reacting overnight at room temperature, adding water and ethyl acetate after the reaction is finished, extracting, adding silica gel to the organic phase, stirring the mixture with the silica gel, and separating by column to obtain 200mg of compound 15 with the yield of 61%.

¹ H NMR(400MHz,CDCl ₃ )δ9.10(s,1H),8.98(s,1H),7.68(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,2H),7.36(d,J＝8.4Hz,2H),6.82(d,J＝8.4Hz,2H),6.48-6.57(m,2H),5.04–5.14(m,1H),1.60(s,6H),1.21(d,J＝6.0Hz,6H).

(l) Dissolving 15 (100mg, 0.18mmol), 16 (44ul, 0.36mmol) and triphenylphosphine (94mg, 0.36mmol) in 1ml of dry tetrahydrofuran, dropping diisopropyl azodicarboxylate (71ul, 0.36mmol) at 0 ℃ under the protection of argon gas, returning to room temperature for overnight reaction, after the reaction is completed, quenching with saturated sodium bicarbonate solution, extracting with ethyl acetate, mixing the organic phase with a sample, and separating by column to obtain 48mg of CQ-1232 with a yield of 40%.

¹ H NMR(400MHz,CDCl ₃ )δ9.16(s,1H),8.48(s,1H),7.83(d,J＝8.8Hz,2H),7.57(d,J＝8.4Hz,2H),7.39(d,J＝8.8Hz,2H),6.95(d,J＝8.8Hz,2H),6.61(s,1H),6.34(s,1H),5.05–5.16(m,1H),4.17(t,J＝5.6Hz,2H),3.76(t,J＝4.4Hz,4H),2.85(t,J＝5.6Hz,2H),2.63(t,J＝5.6Hz,4H),1.59(s,6H),1.24(d,J＝6.0Hz,6H).

Example 2: preparation of compound CQ-1231

Preparation of compound 19:

(a) Compound 17 (4.6 g,32.7 mmol), compound 18 (5 g,32.7 mmol), and potassium hydroxide (5.5 g, 98.1mol) were dissolved in 100ml of anhydrous ethanol, and the mixture was refluxed at 80 ℃ overnight, after completion of the reaction, the solvent was removed, water was added, extraction was performed with ethyl acetate, and the sample was stirred with organic phase over silica gel, and then the mixture was separated by column to give compound 19 (5.4 g), and the yield was 60%.

¹ H NMR(400MHz,DMSO)δ10.44(brs,1H),7.94(t,J＝8.8Hz,1H),7.75-7.82(m,2H),7.69-7.74(m,2H),6.83(t,J＝8.4Hz,1H),6.61–6.75(m,2H),6.20(s,2H).

Preparation of compound 20:

(b) Compound 19 (5g, 18.2mmol) and p-toluenesulfonylhydrazide (5.1g, 27.3mmol) were dissolved in 100ml of anhydrous ethanol, and iodine (455mg, 1.8mmol) was added thereto, and after refluxing at 110 ℃ for 20 minutes, potassium carbonate (7.5g, 54.6 mmol) was added thereto, and after completion of the reaction, the solvent was dried by spinning, water was added, ethyl acetate was extracted, the organic phase was stirred with silica gel, and the mixture was separated by column chromatography to give compound 20 (2.5 g), which was obtained in 48% yield.

¹ H NMR(400MHz,DMSO)δ12.98(s,1H),10.08(s,1H),7.62–7.78(m,1H),7.40-7.49(m,1H),7.29-7.38(m,1H),6.58–6.87(m,4H),5.31(s,2H).

Preparation of compound 21:

(c) Compound 20 (400mg, 1.39mmol), compound 14 (656g, 2.09mmol), and 4-dimethylaminopyridine (17mg, 0.14mmol) were dissolved in 5ml of n, n-dimethylformamide, and triethylamine (0.58ml, 4.17mmol) was added thereto, and the reaction was carried out overnight at room temperature, after completion of the reaction, water and ethyl acetate were added to extract, the organic phase was dried by spinning, 10ml of DCM/MeOH (40.

¹ H NMR(400MHz,DMSO)δ13.15(s,1H),9.85-10.36(m,2H),8.86(s,1H),8.17(t,J＝8.8Hz,1H),7.57-7.77(m,3H),6.89–6.98(m,2H),6.64-6.76(m,2H),1.57(s,6H).

Preparation of compound CQ-1231:

(d) Dissolving compound 20 (100mg, 0.2mmol), compound 16 (48ul, 0.4mmol) and triphenylphosphine (105mg, 0.4mmol) in 1ml of dry tetrahydrofuran, adding diisopropyl azodicarboxylate (79ul, 0.4mmol) dropwise at 0 ℃ under the protection of argon, then switching to room temperature for reaction overnight, after the reaction is finished, quenching with saturated sodium bicarbonate solution, extracting with ethyl acetate, adding organic phase and stirring with silica gel, and passing through a column to obtain 15mg of compound CQ-1231 with the yield of 12%.

¹ H NMR(400MHz,DMSO)δ13.26(s,1H),10.05(s,1H),8.88(s,1H),8.10-8.23(m,1H),7.58-7.87(m,3H),6.80–7.10(m,4H),4.08-4.23(m,2H),3.54-3.67(m,4H),2.61-2.77(m,2H),2.42-2.48(m,4H),1.56(s,6H).

Example 3: preparation of compound CQ-1223

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ13.07(s,1H),9.71(s,1H),8.93(s,1H),7.69–7.81(m,4H),7.53(d,J＝8.4Hz,2H),6.98-7.06(m,3H),6.92(s,1H),4.13(t,J＝5.6Hz,2H),3.59(t,J＝4.8Hz,4H),2.71(t,J＝5.6Hz,2H),2.46-2.50(m,4H),1.57(s,6H).

Example 4: preparation of compound CQ-1227

Dissolving a compound CQ-1223 (150mg, 0.26mmol) in 5ml of methanol, adding methanesulfonic acid (83ul, 1.28mmol), placing at 70 ℃ for refluxing overnight, after the reaction is finished, spin-drying the solvent, adding 2ml of ethanol, cooling to separate out a solid, performing suction filtration, washing with 5ml of ethanol, and drying a filter cake to obtain 88mg of a compound CQ-1227 with the yield of 44%.

¹ H NMR(400MHz,DMSO)δ9.91(s,1H),9.76(s,1H),9.02(s,1H),7.73-7.84(m,4H),7.55(d,J＝8.8Hz,2H),7.11(d,J＝8.8Hz,2H),7.05(s,1H),6.91(s,1H),4.38-4.45(m,2H),3.96-4.05(m,2H),3.73(t,J＝11.6Hz,2H),3.51-3.65(m,4H),3.17-3.30(m,2H),2.37(s,6H),1.57(s,6H).

Example 5: preparation of compound CQ-1226

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ13.11(s,1H),9.73(s,1H),8.95(s,1H),7.67-7.83(m,4H),7.46-7.59(m,2H),6.95-7.06(m,3H),6.92(s,1H),4.04(t,J＝6.4Hz,2H),2.38(t,J＝7.2Hz,2H),2.17(s,6H),1.82-1.9(m,2H),1.57(s,6H).

Example 6: preparation of Compound CQ-1230

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ13.15(s,1H),10.03(s,1H),8.87(s,1H),8.17(t,J＝8.4Hz,1H),7.60-7.77(m,4H),7.09(s,1H),7.04(d,J＝8.4Hz,2H),6.92(s,1H),4.14(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.71(t,J＝6.0Hz,2H),2.45-2.50(m,4H),1.57(s,6H).

Example 7: preparation of compound CQ-1235

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ7.68-7.80(m,4H),7.55(d,J＝8.4Hz,2H),6.88-7.05(m,4H),4.10(t,J＝5.6Hz,2H),2.69(t,J＝5.6Hz,2H),2.41-2.51(m,4H),2.22-2.40(m,4H),2.14(s,3H),1.56(s,6H).

Example 8: preparation of Compound CQ-1233

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ13.09(s,1H),9.73(s,1H),8.95(s,1H),7.69-7.84(m,4H),7.55(d,J＝8.8Hz,2H),6.89-7.04(m,4H),4.03(t,J＝6.4Hz,2H),3.57(t,J＝4.8Hz,4H),2.42(t,J＝7.2Hz,2H),2.31-2.40(m,4H),1.82-1.94(m,2H),1.56(s,6H).

Example 9: preparation of compound CQ-1234

Preparation of compound 22: the synthetic route is analogous to example 2.

Preparation of Compound CQ-1234:

dissolving the compound 22 (100mg, 0.16mmol) in 2ml of trifluoroacetic acid, stirring at room temperature for 1 hour, then spin-drying, adjusting the pH to 8 by using a saturated sodium bicarbonate solution, extracting by using ethyl acetate, spin-drying an organic phase, adding silica gel for sample mixing, and separating by using a column to obtain 51mg of a compound CQ-1234 with the yield of 60%.

¹ H NMR(400MHz,DMSO)δ13.12(s,1H),9.15(s,1H),7.68-7.83(m,4H),7.54(d,J＝8.4Hz,2H),6.89-7.07(m,4H),4.06(t,J＝5.6Hz,2H),2.87(t,J＝5.2Hz,2H),2.36(s,3H),1.56(s,6H).

Example 10: preparation of Compound CQ-1244

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ13.07(s,1H),9.76(s,1H),9.01(s,1H),7.77(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.39-7.45(m,1H),7.34(d,J＝8.0Hz,1H),7.00-7.10(m,2H),6.93(s,1H),4.11(t,J＝6.0Hz,2H),3.85(s,3H),3.59(t,J＝4.4Hz,4H),2.71(t,J＝6.0Hz,2H),2.43-2.50(m,4H),1.57(s,6H).

Example 11: preparation of compound CQ-1246

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ13.21(s,1H),10.06(s,1H),8.88(s,1H),8.18(t,J＝8.4Hz,1H),7.60-7.76(m,2H),7.41(m,1H),7.33(d,J＝8.4Hz,1H),7.15(s,1H),7.07(d,J＝8.0Hz,1H),6.92(s,1H),4.11(t,J＝6.0Hz,2H),3.85(s,3H),3.59(t,J＝4.8Hz,4H),2.71(t,J＝5.6Hz,2H),2.45-2.55(m,4H),1.57(s,6H)

Example 12: preparation of Compound CQ-1255

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ13.24(s,1H),9.74(s,1H),8.96(s,1H),7.90(s,1H),7.65-7.85(m,3H),7.45-7.65(m,2H),7.17-7.30(m,1H),7.09(s,1H),6.93(s,1H),3.99-4.31(m,2H),3.35-3.69(m,4H),2.63-2.80(m,2H),2.40-2.60(m,4H),1.55(s,6H).

Example 13: preparation of Compound CQ-1256

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ13.20(s,1H),9.73(s,1H),8.95(s,1H),7.69-7.81(m,2H),7.66(d,J＝12.8Hz,1H),7.49-7.61(m,3H),7.16-7.33(m,1H),7.08(s,1H),6.92(s,1H),4.11-4.30(m,2H),3.50-3.65(m,4H),2.67-2.79(m,2H),2.40-2.58(m,4H),1.56(s,6H).

Example 14: preparation of Compound CQ-1257

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ13.17&12.88(two s,1H),9.71(s,1H),8.93(s,1H),7.70-7.86(m,2H),7.54(d,J＝8.0Hz,2H),7.43(s,1H),6.85-6.98(m,2H),6.85(d,J＝8.4Hz,1H),6.79(s,1H),4.11(t,J＝5.2Hz,2H),3.50-3.66(m,4H),2.70(t,J＝5.2Hz,2H),2.33-2.48(m,4H),1.56(s,6H).

Example 15: preparation of compound CQ-1258

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ13.35&13.08(two s,1H),9.73&9.70(two s,1H),8.98&8.91(two s,1H),7.38-7.93(m,5H),6.94-7.21(m,3H),6.92(s,1H),4.05-4.28(m,2H),3.59(t,J＝4.8Hz,4H),2.70(t,J＝4.8Hz,2H),2.46-2.52(m,4H),1.56(s,6H).

Example 16: preparation of compound CQ-1259

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ13.32&13.14(two s,1H),9.71(s,1H),8.95(s,1H),7.66-7.92(m,3H),7.45-7.61(m,2H),6.82-7.04(m,4H),4.15(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.71(t,J＝5.6Hz,2H),2.41-2.49(m,4H),1.56(s,6H).

Example 17: preparation of compound CQ-1260

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ13.10(s,1H),10.07(s,1H),8.28(s,1H),7.86-8.03(m,1H),7.56-7.80(m,4H),6.98-7.07(m,3H),6.89(s,1H),4.13(t,J＝5.6Hz,2H),3.56-3.64(m,4H),2.70(t,J＝5.6Hz,2H),2.45-2.49(m,4H),2.30(s,3H),1.56(s,6H).

Example 18: preparation of Compound CQ-1269

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ13.30&13.14(two s,1H),9.78(s,1H),9.18(s,1H),7.67-8.02(m,3H),7.62(d,J＝13.6Hz,1H),7.15-7.34(m,1H),6.95-7.08(m,2H),6.79-6.95(m,2H),4.07-4.19(m,2H),3.51-3.64(m,4H),2.64-2.77(m,2H),2.38-2.49(m,4H),1.56(s,6H).

Example 19: preparation of Compound CQ-1270

The synthetic route is analogous to example 2.

¹ H NMR(400MHz,DMSO)δ13.17&12.87(two s,1H),9.71(s,1H),8.87(s,1H),7.66-7.86(m,2H),7.37-7.58(m,3H),6.95-7.09(m,2H),6.92(s,1H),6.79(s,1H),4.13(t,J＝5.6Hz,2H),3.59(t,J＝4.8Hz,4H),2.72(t,J＝5.2Hz,2H),2.38-2.48(m,4H),1.56(s,6H).

Example 20: preparation of compound CQ-1245

Preparation of Compound 23

(a) 4-hydroxybenzonitrile (10g, 84mmol), K ₂ CO ₃ (17.4g, 126mmol) was dissolved in 100mL DMF and BnBr (15.8g, 92.4mmol) was added and the reaction was carried out at 50 ℃ until the starting material was consumed, followed by addition of water, extraction with ethyl acetate and spin-drying to give 16.5 compound 23 in 94% yield.

¹ H NMR(400MHz,CDCl ₃ )δ7.58(d,J＝8.8Hz,2H),7.46–7.33(m,5H),7.02(d,J＝8.8Hz,2H),5.12(s,2H).

Preparation of Compound 24

(b) The compound 23 (8g, 37.7mmol) was dissolved in tetrahydrofuran, and the resulting solution was added to a tetrahydrofuran solution of LiHDMS (41.5ml, 41.5mmol) under argon protection to react at room temperature, after the reaction was completed, a 5N isopropanol hydrochloride solution was added to quench the reaction, the reaction was extracted with ethyl acetate, and the organic phase was purified by column chromatography using silica gel to obtain 7.2g of the compound 24 in 73% yield.

¹ H NMR(400MHz,DMSO-d ⁶ )δ9.38(s,2H),9.17(s,2H),7.90(d,J＝9.2Hz,2H),7.47–7.33(m,5H),7.21(d,J＝8.8Hz,2H),5.23(s,2H).

Preparation of Compound 26

(c) The compound 24 (3.2g, 12.169mol) and KHCO are added ₃ (3g, 30.4mmol) was dissolved in 40ml of THF/H ₂ O (4:1), heated to 90 ℃ and a THF solution (30 ml) of Compound 25 (3.6 g,14.6 mmol) was slowly added dropwiseStirring is continued until the raw materials are exhausted, spin-drying is carried out, water is added, ethyl acetate is used for extraction, silica gel is added for sample stirring, and 2.1g of the compound 26 is obtained by column separation with the yield of 47%.

¹ H NMR(400MHz,DMSO-d ⁶ )δ12.80(s,1H),8.25(d,J＝8.8Hz,2H),8.10(d,J＝8.8Hz,2H),8.05(s,1H),7.96(d,J＝8.8Hz,2H),7.49-7.31(m,5H),7.14(d,J＝8.8Hz,2H),5.17(s,2H).

Preparation of Compound 27

(d) Dissolving the compound 26 (845mg, 2.48mmol) and palladium/carbon (200 mg) in 20ml of methanol, carrying out hydrogen gas exchange reaction at room temperature overnight, carrying out suction filtration after the reaction is finished, and carrying out spin drying on the filtrate to obtain 240mg of the compound 27 with the yield of 38.6%.

¹ H NMR(400MHz,DMSO-d ⁶ )δ9.90(brs,1H),7.85(d,J＝8.8Hz,2H),7.50(d,J＝8.4Hz,2H),7.28(s,1H),6.87(d,J＝8.8Hz,2H),6.61(d,J＝8.4Hz,2H).

Preparation of compound CQ-1245

(e) Compound 27 (170mg, 0.67mmol), compound 14 (320mg, 1.02mmol) and DMAP (19mg0.07mmol) were dissolved in 3ml of N, N-dimethylformamide, triethylamine (0.2mg, 2.01mmol) was added, the reaction was carried out overnight at room temperature, after the reaction was completed, ethyl acetate was extracted, and the organic phase was dried by spinning to obtain 254mg of crude product 28, which was used in the next step without further purification.

(f) Compound 28 (150mg, 0.32mmol), compound 16 (83.4 mg, 0.64mmol), triphenylphosphine (166.8mg, 0.64mmol) were dissolved in 1ml of anhydrous tetrahydrofuran, 1ml of a tetrahydrofuran solution of diisopropyl azodicarboxylate (129.4 mg, 0.64mmol) was added at 0 ℃ and the mixture was allowed to stand at room temperature for overnight reaction, after completion of the reaction, sodium bicarbonate solution and ethyl acetate were added for extraction, and the mixture was further subjected to column chromatography with silica gel to give 52mg of compound in 27.9% yield.

¹ H NMR(400MHz,DMSO)δ12.42(s,1H),9.69(s,1H),8.90(s,1H),7.92(d,J＝8.4Hz,2H),7.76(d,J＝8.0Hz,2H),7.55(s,1H),7.47(d,J＝8.0Hz,2H),7.04(d,J＝8.4Hz,2H),6.91(s,1H),4.14(t,J＝5.2Hz,2H),3.55-3.64(m,4H),2.68-2.78(m,2H),2.50-2.57(m,4H),1.56(s,6H).

Example 21: preparation of Compound CQ-1253

Preparation of Compound 30

(a) Compound 24 (4.1g, 15.3mmol), compound 29 (1.5g, 10.1mmol), cesium carbonate (9.95g, 30mmol), cuprous bromide (73mg, 0.51mmol) were dissolved in 30ml of dimethyl sulfoxide, reacted overnight at 120 ℃ and cooled to room temperature, extracted with ethyl acetate and water, organic phase was added and the mixture was stirred with silica gel, and the mixture was separated by column chromatography to give 1.8g of compound 30 with a yield of 48%.

¹ H NMR(400MHz,DMSO)δ14.64(s,1H),8.42-8.25(m,4H),8.02(d,J＝8.8Hz,2H),7.52-7.30(m,5H),7.19(d,J＝8.0Hz,2H),5.18(s,2H).

Preparation of Compound 32

(b) Compound 30 (1.5g, 4.03mmol) was dissolved in 50ml of tetrahydrofuran, compound 31 (2.21ml, 24.18mmol) and p-toluenesulfonic acid (139mg, 0.806mmol) were added, the mixture was refluxed at 85 ℃ overnight, THF was removed, ethyl acetate and water were added for extraction, the organic phase was stirred with silica gel, and 1.3g of compound 32 was isolated by column chromatography in a yield of 70%.

¹ H NMR(400MHz,CDCl ₃ )δ8.37(d,J＝9.2Hz,2H),8.29(d,J＝9.2Hz,2H),7.77(d,J＝8.8Hz,2H),7.49-7.33(m,5H),7.14(d,J＝8.8Hz,2H),5.37(dd,J＝10.0,2.8Hz,1H),5.16(s,2H),4.25–4.17(m,1H),3.76-3.67(m,1H),2.67–2.53(m,1H),2.21-2.19(m,1H),1.97-1.89(m,1H),1.86-1.78(m,1H),1.69-1.66(m,1H),1.56-1.48(m,1H).

Preparation of Compound 33

(c) Compound 32 (1.3 g, 2.85mmol) is dissolved in 40ml MeOH, 260mg palladium on carbon (10%), H ₂ Ventilating for three times, reacting at room temperature until the raw materials are exhausted, filtering, adding silica gel into filtrate for sample mixing, and separating by a column to obtain 336mg of a compound 33 with the yield of 34%.

¹ H NMR(400MHz,DMSO)δ10.03&9.70(two s,1H),7.88–7.68(m,2H),7.64-7.41(m,2H),6.99-6.81(m,2H),6.77–6.56(m,2H),5.67&5.38(two s,2H),5.35–5.26(m,1H),4.09-4.03(m,1H),3.70-3.60(m,1H),2.44-2.29(m,1H),1.98-1.95(m,1H),1.92-1.83(m,1H),1.71-1.50(m,3H).

Preparation of Compound CQ-1253

(d) Compound 33 (330mg, 0.98mmol), compound 14 (4611mg, 1.47mmol) and 4-dimethylaminopyridine (12mg, 0.01mmol) were dissolved in 5ml of N, N-dimethylformamide, triethylamine (298mg, 2.94mmol) was added thereto, and the reaction was carried out at 70 ℃ overnight. After the reaction is finished, ethyl acetate and water are added for extraction, and the organic phase is dried in a spinning mode and is directly used for the next step.

(e) The crude product of the previous step, compound 16 (262mg, 2mmol), triphenylphosphine (524mg, 2mmol) was dissolved in anhydrous tetrahydrofuran (5 ml), ar protected, diisopropyl azodicarboxylate (404mg, 2mmol) was added dropwise at 0 ℃ and the mixture was allowed to react overnight at room temperature. After the reaction is finished, spin-drying, dissolving in 5ml of methanol, adding 5ml of 2N HCl/MeOH solution, stirring for 1h at room temperature, adding water, neutralizing with saturated sodium bicarbonate solution, extracting with ethyl acetate, mixing the organic phase with a sample, and separating by a column to obtain 98mg of a compound CQ-1253 with the yield of 17% in the three steps.

¹ H NMR(400MHz,DMSO)δ14.23(s,1H),9.75(s,1H),9.01(s,1H),7.95-8.08(m,4H),7.50-7.67(m,2H),6.99-7.17(m,2H),6.93(s,1H),4.10-4.22(m,2H),3.54-3.66(m,4H),2.69-2.80(m,2H),2.44-2.49(m,4H),1.57(s,6H).

Example 22: preparation of compound CQ-1254

Preparation of compound 39:

(a) Compound 35 (4.7g, 20.6mmol), compound 36 (2g, 10.3mmol), cesium carbonate (10g, 30.9mmol), tetratriphenylphosphine palladium (596mg, 0.52mmol) were mixed in a 100ml reaction flask, protected with Ar, 18ml dioxane/water (5:1) mixed solvent was added, reaction was allowed to proceed overnight at 100 ℃, ethyl acetate and water were added, the organic phase was spin-dried, and PE: stirring 20ml of EA (1:1) for 1h, carrying out suction filtration, and drying a filter cake to obtain 1.6g of a crude product compound 37;

(b) The crude product 37 (910mg, 3.64mmol) and 38 (1.03g, 7.28mmol) obtained in the above step were dissolved in 12ml of dimethyl sulfoxide, potassium carbonate (1.51g, 10.92mmol) was added thereto, the reaction was allowed to proceed overnight at 100 ℃, ethyl acetate and water were added to the solution to extract, the organic phase was stirred and applied to a column to obtain 1.9g of 39, and the yield was 76%.

¹ H NMR(400MHz,DMSO)δ8.54-8.58(m,1H),8.36-8.44(m,3H),8.03(d,J＝9.2Hz,2H),7.81(d,J＝8.8Hz,2H),7.31–7.50(m,5H),7.08(d,J＝8.8Hz,2H),5.14(s,2H).

Preparation of compound 40:

(c) Compound 39 (1mg, 2.7mmol) was dissolved in 10ml of trifluoroacetic acid and reacted at 50 ℃ for 4 hours. After the reaction is finished, water is added, saturated sodium bicarbonate solution is used for neutralization, ethyl acetate is used for extraction, the organic phase is subjected to spin-drying sample mixing, 580mg of compound 40 is obtained through column separation, and the yield is 77%.

¹ H NMR(400MHz,DMSO)δ9.49(s,1H),8.54(s,1H),8.39(d,J＝9.2Hz,2H),8.29(s,1H),8.02(d,J＝9.2Hz,2H),7.69(d,J＝8.4Hz,2H),6.81(d,J＝8.4Hz,2H).

Preparation of compound 42:

(d) Compound 40 (200mg, 0.71mmol) and compound 41 (586 mg, 2.13mmol) were dissolved in 5ml of acetonitrile, cesium carbonate (1.15g, 3.55mmol) was added, and the mixture was refluxed at 80 ℃ overnight. After the reaction is finished, ethyl acetate and water are added for extraction, the organic phase is mixed with a sample, and the mixture is subjected to column separation to obtain 220mg of a compound 42 with the yield of 78%.

¹ H NMR(400MHz,DMSO)δ8.55(s,1H),8.40(d,J＝9.2Hz,2H),8.38(s,1H),8.03(d,J＝8.8Hz,2H),7.79(d,J＝8.4Hz,2H),7.00(d,J＝8.8Hz,2H),4.12(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.71(t,J＝5.6Hz,2H),2.46-2.49(m,4H).

Preparation of Compound CQ-1254

(e) Compound 42 (200mg, 0.508mmol) was dissolved in 2ml of a mixed solvent of ethanol/water (4:1), and reduced iron powder (142mg, 2.54mmol) and ammonium chloride (217mg, 4.06mmol) were added to react at 80 ℃ for 1 hour. After the reaction was completed, suction filtration was performed with celite, ethyl acetate and water were added to the filtrate, and the organic phase was spin-dried to obtain 150mg of crude product 43, which was used directly in the next step.

(f) Crude product 43 (150mg, 0.412mg), compound 14 (194mg, 0.618mmol) and 4-dimethylaminopyridine (5mg, 0.04mmol) were dissolved in 2ml of N, N-dimethylformamide, triethylamine (125mg, 1.24mmol) was added, and the reaction was allowed to proceed at 70 ℃ overnight. After the reaction is finished, ethyl acetate and water are added for extraction, the organic phase is mixed with a sample, and the compound CQ-1254 of 110mg is obtained by column separation with the yield of 46%.

¹ H NMR(400MHz,DMSO)δ9.76(s,1H),9.00(s,1H),8.22(s,1H),8.10(s,1H),7.76(d,J＝8.0Hz,2H),7.54-7.69(m,4H),6.98(d,J＝8.0Hz,2H),6.92(s,1H),4.11(t,J＝5.6Hz,2H),3.51-3.65(m,4H),2.64-2.76(m,2H),2.43-2.50(m,4H),1.56(s,6H).

Example 23: preparation of Compound CQ-1252

Preparation of Compound 51

(a) Compound 44 (5g, 32.9mmol), benzyl bromide (6.8g, 40mmol) and potassium carbonate (6.8g, 49mol) were dissolved in 50ml of acetone, reacted at 60 ℃ overnight, after completion of the reaction, cooled to room temperature, extracted with ethyl acetate, and spin-dried to give 7.7g of crude product 45, which was used in the next step without further purification.

(b) Compound 45 (7.7g, 31.84mmol), 50% hydrazine hydrate (15.9g, 318.2mmol) was dissolved in 100ml methanol and 50ml tetrahydrofuran, reacted overnight at 70 ℃, after the reaction was completed, the solvent was dried by spinning, extraction was performed with dichloromethanol, and dried by spinning to obtain 7.2g of crude product 46, which was used in the next step without further purification.

(c) Compound 47 (2.76g, 16.53mmol), HOBT (3.12g, 23.14mmol) were dissolved in 200mlN, N-dimethylformamide, EDCI (4.42g, 23.14mmol) was added at 0 ℃ and after 1 hour reaction at room temperature compound 46 (4 g, 16.53mmol) was added and after 3 hours reaction at room temperature water was added, suction filtration and ether washing gave 6.02g of crude compound 48 which was used in the next step without further purification.

(d) Dissolving compound 48 (6.02g, 15.39mmol) in 50ml thionyl chloride, reacting overnight at 90 ℃ under the protection of argon, after the reaction is finished, removing thionyl chloride by spinning, pulping dichloromethane, and performing suction filtration to obtain 4.91g of crude product compound 49, wherein the crude product compound 49 is directly used in the next step without further purification.

(e) Dissolving a compound 49 (1.5g, 3.84mmol) and palladium/carbon (400 mg) in 50ml of methanol, carrying out hydrogen gas extraction and reaction at room temperature overnight, carrying out suction filtration after the reaction is finished, adding acetone into a filter cake to dissolve the filter cake, heating, carrying out suction filtration while the solution is hot, and obtaining 847mg of a crude product 50 which is directly used in the next step without further purification.

(f) Compound 50 (300mg, 1.19mmol), compound 14 (562.1mg, 1.79mmol) and DMAP (14.7mg, 0.12mmol) were dissolved in 6ml of N, N-dimethylformamide, triethylamine (361.2mg, 3.57mmol) was added thereto, and the mixture was reacted at 70 ℃ overnight, after completion of the reaction, extracted with ethyl acetate, dried by spinning, and the mixture was purified by 5ml of PE: EA (1:1) was slurried and suction filtered to obtain 150mg of compound 51 in 29% yield.

¹ H NMR(400MHz,DMSO)δ10.34(s,1H),9.81(s,1H),9.22(s,1H),8.03(d,J＝8.0Hz,2H),7.94(d,J＝8.0Hz,2H),7.70(d,J＝8.8Hz,2H),6.97(d,J＝8.8Hz,2H),6.93(s,1H),1.56(s,6H).

Preparation of Compound CQ-1252

(g) Compound 51 (150mg, 0.34mmol), compound 16 (89.2mg, 0.68mmol), triphenylphosphine (178.4mg, 0.68mmol) were dissolved in 1ml tetrahydrofuran, a solution of DIAD (137.5mg, 0.68mmol) in tetrahydrofuran was added at 0 ℃ and reacted overnight at room temperature, after completion of the reaction, a solution of sodium bicarbonate and ethyl acetate were added for extraction, the mixture was stirred with silica gel and passed through the column to give 57mg of compound CQ-12152 with a yield of 29%.

¹ H NMR(600MHz,DMSO)δ9.86(s,1H),9.27(s,1H),7.99-8.10(m,4H),7.70(d,J＝8.4Hz,2H),7.17(d,J＝8.4Hz,2H),6.94(s,1H),4.19(t,J＝5.4Hz,2H),3.59(t,J＝3.2Hz,4H),2.72(t,J＝5.4Hz,2H),2.44-2.51(m,4H),1.57(s,6H).

Example 24: preparation of Compound CQ-1262

Preparation of Compound 56

(a) Compound 52 (2g, 9.1mmol), sodium azide (890.6 mg,13.7 mmol), sodium ascorbate (90.1mg, 0.46mmol), cuprous iodide (173.3 mg, 0.9mmol), N, N' -dimethylethylenediamine (123.4 mg,1.4 mmol) were dissolved in absolute ethanol/water (7:3), reacted overnight at 60 ℃, after completion of the reaction, extracted with ethyl acetate and rotary dried to give 1.09g of crude 53, which was used in the next step without further purification.

(b) Compound 53 (1.09g, 8.07mmol), p-nitroacetylene (1.19g, 8.07mmol) and cuprous iodide (154.3mg, 0.81mmol) were dissolved in 30mlN, N-dimethylformamide, reacted at 60 deg.C, after the reaction was completed, extracted with ethyl acetate, and dried to give 2.2g of crude product 54, which was used in the next step without further purification.

(c) In this reaction, compound 54 (1g, 3.54mmol), compound 55 (989.5mg, 5.32mmol) and cesium carbonate (3.46g, 10.62mmol) were dissolved in 20ml of N, N-dimethylformamide, reacted at 60 ℃, after completion of the reaction, extracted with ethyl acetate, and the organic phase was passed through a column packed with silica gel to give 550mg of compound 56, with a yield of 39.3%

¹ H NMR(400MHz,DMSO)δ9.46(s,1H),8.37(d,J＝8.0Hz,2H),8.20(d,J＝8.0Hz,2H),7.85(d,J＝8.0Hz,2H),7.20(d,J＝8.0Hz,2H),4.19(t,J＝5.2Hz,2H),3.53-3.63(m,4H),2.71(tJ＝5.2Hz,2H),2.37-2.49(m,4H).

Preparation of Compound CQ-1262

(d) Dissolving compound 56 (550mg, 1.39mmol) and ammonium chloride (594.8mg, 11.12mmol) in absolute ethanol/water (4:1), adding iron powder (389.2mg, 6.95mmol) under stirring, refluxing at 80 ℃, after the reaction is finished, carrying out suction filtration while hot, extracting with ethyl acetate, and carrying out rotary drying to obtain 147mg of a crude product compound 57 which is directly used in the next step without further purification.

(e) Compound 57 (147mg, 0.4mmol), compound 14 (188.4mg, 0.6mmol), DMAP (4.9mg, 0.04mmol) were dissolved in 3ml N, N-dimethylformamide, triethylamine (121.4mg, 1.2mmol) was added, and the reaction was allowed to proceed overnight at 70 ℃, after completion of the reaction, ethyl acetate was extracted, and the organic phase was stirred with silica gel and passed through a column to give 139mg of compound CQ-1262 in 59% yield.

¹ H NMR(400MHz,DMSO)δ9.74(s,1H),9.12(s,1H),8.97(s,1H),7.87(d,J＝8.8Hz,2H),7.84(d,J＝9.2Hz,2H),7.60(d,J＝8.8Hz,2H),7.18(d,J＝8.8Hz,2H),6.93(s,1H),4.18(t,J＝5.6Hz,2H),3.59(t,J＝4.8Hz,4H),2.73(t,J＝5.6Hz,2H),2.45-2.49(m,4H),1.57(s,6H).

EXAMPLE 25 proliferation inhibitory Activity of Compounds on BAF3 model cells carrying different mutant backgrounds of RET

The proliferation inhibitory activity of the compounds of the invention against the background BAF3 model cells carrying different mutations of RET was tested by the CCK-8 method:

the compounds used in the control experiments were as follows:

selpercatinib is a potent selective RET inhibitor, purchased from Selleck corporation.

The method comprises the following steps:

1) Cell inoculation: various tumor cells in the logarithmic growth phase of cells were seeded at the same density in different 96-well plates (3000-10000 cells/100. Mu.l/well).

2) Preparing a working solution: and (3) diluting stock solutions of the test compound and the control compound by using a corresponding culture medium (containing or not containing a solvent DMSO) required by cell culture as a diluent to obtain working solutions with series concentrations of which the required concentration is 3 times of the final concentration, wherein the content of the solvent DMSO in each concentration group is consistent with that of a solvent control group.

3) Co-incubation: after 24hr of inoculation, 100. Mu.l/well of the mother liquor of the compound series concentration was added to a 96-well plate, mixed well and co-cultured for 72hr. All groups were at least 3 replicates with 6 concentrations of each compound. Blank control group: only the culture medium is added, and cells and medicines are not added, so that the interference of the culture medium on the color comparison is eliminated.

4) And (3) measuring absorbance: after the medium was aspirated from the 96-well plate, 10. Mu.l of CCK-8 solution was added to each well, and after co-culturing for 4hr, the mixture was sufficiently shaken to be uniform, and the absorbance values at A450 and A650 were measured on a microplate reader.

5) Data processing: obtaining the cell survival rate of each processing hole according to the obtained A450-A650 original data (the calculation method is as follows); the cell viability data and corresponding compound concentrations were then input into GraphPadPrism 5Demo software and IC of compounds on different cells was calculated using a non-linear regression model ₅₀ The value is obtained. Calculation of cell viability: cell survival rate (%) = [ (As-Ac)/(Ab-Ac)]×100％](As: experimental wells; ab: vehicle control wells; ac: blank wells). The results are shown in Table 1.

TABLE 1 proliferation inhibitory Activity of Compounds on background BAF3 model cells harboring different mutations of RET (half inhibitory concentration)

Note: "\" means that the activity test was not performed

From the results of table 1, it can be seen that: the compound has stronger inhibitory activity on the proliferation of BAF3 model cells carrying different mutation backgrounds of RET.

EXAMPLE 26 pharmacokinetic experiments with Compound CQ-1227

1. Preparation of control compound a:

(1) Preparation of compound WFK-001:

the synthetic route is as follows:

step a preparation of Compound 59

Compound 58 (1.8g, 7.53mmol), hydrazine hydrate (22.59 mmol) and 20ml of glacial acetic acid were mixed and reacted at 80 ℃ under reflux until compound 58 was substantially converted, water was added to the reaction system, extraction was performed twice with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column-separated to give compound 59 (495 mg, yield 26.2%). ESI-MS M/z 252.1 (M + H) ⁺ .

Step b preparation of Compound 61

Compound 59 (495mg, 1.97mmol), phenyl (5-tert-butylisoxazol-3-amino) formate (compound 60) (768mg, 3mmol), DMAP (13mg, 0.12mmol) and triethylamine (598mg, 5.91mmol) were reacted in THF (15 mL) at 60 ℃ with stirring overnight. After completion of the reaction, the reaction mixture was poured into water, extracted 2 times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain compound 61 (590 mg, yield 72%). ESI-MS m/z418.1(M+H) ⁺ .

Step c preparation of WKF-001

Compound 61 (590mg, 1.42mmol), N- (2-chloroethyl), morpholine hydrochloride (compound 55) (396mg, 2.13mmol), K ₂ CO ₃ (588mg, 4.26mmol) and TBAI (52mg, 0.14mmol) were dissolved in 15ml of DMF, and the reaction was heated at 60 ℃ until most of the starting material had been converted, and the reaction was stopped, water was added to the reaction system, extraction was carried out twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography to give compound WKF-001 (230 mg, yield 31%).

¹ H NMR(400MHz,DMSO-d6)δ13.12(s,1H),9.55(s,1H),8.92(s,1H),7.73-7.75(m,4H),7.53(d,J＝7.6Hz,2H),7.00-7.02(m,3H),6.53(s,1H),4.11(t,J＝5.4Hz,2H),3.58(t,J＝4.4Hz,4H),2.69(t,J＝5.6Hz,2H),2.47(t,J＝4.4Hz,4H),1.30(s,9H).ESI-MS m/z 531.2(M+H) ⁺ .

(2) Preparation of control compound a:

the synthesis method is the same as example 4.

¹ H NMR(400MHz,DMSO)δ9.97(s,1H),9.62(s,1H),9.05(s,1H),7.81(d,J＝8.8Hz,2H),7.76(d,J＝8.8Hz,2H),7.56(d,J＝8.4Hz,2H),7.12(d,J＝8.8Hz,2H),7.08(s,1H),6.52(s,1H),4.42(t,J＝4.4Hz,2H),3.96-4.05(m,2H),3.74(t,J＝12.0Hz,2H),3.50-3.66(m,4H),3.17-3.30(m,2H),2.42(s,6H),1.30(s,9H).

2. Pharmacokinetic experiments: after single intravenous injection or oral gavage of SD rats with compound CQ-1227 or Compound A, blood samples were collected at different time points and the concentration of the test substance in the plasma of rats after administration of the test substance was measured by LC-MS/MS and the relevant parameters were calculated.

3 male rats are selected for intravenous injection, the administration dose is 5mg/Kg, the drug concentration is 1mg/mL, and the administration volume is 5mL/Kg. The blood sampling time is as follows: 0.083h,0.25h,0.5h,1h,2h,4h,8h,24h.

3 male rats are selected for oral administration, the administration dose is 25mg/Kg, the drug concentration is 2.5mg/mL, and the administration volume is 10mL/Kg. The blood sampling time is as follows: 0.25h,0.5h,1h,2h,4h,6h,8h and 24h.

Blood is collected through jugular vein, about 0.20mL of each sample is collected, heparin sodium is used for anticoagulation, and the samples are placed on ice after being collected. And the plasma was centrifuged within 1 hour (centrifugation conditions: 6800g,6 minutes, 2-8 ℃ C.). Plasma samples were stored in a-80 ℃ freezer prior to analysis.

And calculating pharmacokinetic parameters by using Phoenix WinNonlin7.0 through the blood concentration data at different time points, and providing parameters such as AUC0-T, AUC0- ∞, MRT0- ∞, cmax, tmax and T1/2 and the mean value and standard deviation thereof. The results are shown in Table 2.

TABLE 2 results of pharmacokinetic experiments on CQ-1227 compound

As can be seen from the above table, compound CQ-1227 has a higher blood concentration and a longer half-life when injected and orally administered as compared to the corresponding control compound A (the difference is that trifluoromethyl is replaced by methyl). It can be seen that the introduction of trifluoromethyl group in compound CQ-1227 has a better improvement effect on pharmacokinetic properties than the control compound A.

The technical features of the above-mentioned embodiments can be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the following embodiments are not described, however, as long as there is no contradiction between the combinations of the technical features, the combinations should be considered as the scope of the present description.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. A compound having a urea-containing structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

wherein the content of the first and second substances,

Z is selected from: n, or CR';

R ₁ selected from:

each Z ₁ 、Z ₂ Each independently selected from: NR (nitrogen to noise ratio) ₁₀ O, S or CR ₁₁ R ₁₂ ；

Each Z ₃ 、Z ₄ 、Z ₅ Each independently selected from: o or S;

each Z ₆ Each independently selected from: n or CR ₉ ；

Each R ₂ Each independently selected from: H. c ₁ ～C ₈ Alkyl radical, C ₁ ～C ₈ Alkyl acyl radical, C ₁ ～C ₈ Alkoxycarbonyl group, C ₁ ～C ₈ Alkylamino carbonyl, C ₃ ～C ₆ Cycloalkyl, C ₃ ～C ₆ Cycloalkoxycarbonyl radical, C ₃ ～C ₆ Cycloalkylaminocarbonyl, 3-to 6-membered heterocycloalkyl, C ₅ ～C ₁₀ Arylacyl, 5-to 10-membered heteroarylacyl, C ₁ ～C ₈ Sulfonyl radical, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₆ Alkyl, or 5-to 18-membered heteroaryl; when R is ₂ When not hydrogen, the R ₂ Independently optionally substituted by 1 or more R ₁₃ Substitution;

each R ₅ Each independently selected from: H. halogen, C ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C ₆ ～C ₁₈ Aryl radicals、C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl, 5-to 18-membered heteroaryl, or-SR ₁₄ (ii) a When R is ₅ Is selected from C ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino radical, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl or 5-to 18-membered heteroaryl, said R ₅ Independently optionally substituted by 1 or more R ₁₃ Substitution;

each R ₆ Each independently selected from: H. c ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino, amino, hydroxyl, cyano, nitro, ester group, C ₁ ～C ₈ Acyl, amido, sulfonyl, sulfonamido, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl, or 5-to 18-membered heteroaryl; when R is ₆ Is selected from C ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino radical, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl or 5-to 18-membered heteroaryl, said R ₆ Independently optionally substituted by 1 or more R ₁₃ Substitution;

each R ₁₄ Each independently selected from: H. c ₁ ～C ₈ Alkyl, hydroxy substituted C ₁ ～C ₈ Alkyl radical, C ₁ ～C ₈ Alkoxy-substituted C ₁ ～C ₈ An alkyl group;

each R is independently selected from: H. halogen, C ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino, amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, sulfonamido, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ Alkyl, or 5-to 18-membered heteroaryl; when R is selected from C ₁ ～C ₁₈ Alkyl radical, C ₃ ～C ₁₈ Cycloalkyl, 3-to 18-membered heterocycloalkyl, C ₁ ～C ₁₈ Alkoxy radical, C ₁ ～C ₁₈ Alkylamino radical, C ₆ ～C ₁₈ Aryl radical, C ₆ ～C ₁₈ Aryl substituted C ₁ ～C ₁₈ When alkyl or 5-18 membered heteroaryl, said R is independently optionally substituted with 1 or more R ₁₃ Substitution;

2. The urea structure-containing compound according to claim 1, wherein the urea structure-containing compound has a structure represented by formula (II), (III), (IV), (V), (VI), (VII), or (VIII):

wherein the content of the first and second substances,

X ₁ 、X ₃ 、X ₄ each independently selected from: n, NR ₂ CR, or C = O, and X ₁ 、X ₃ 、X ₄ The five-membered ring does not form an N = N structure.

3. The compound containing a urea structure or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 2, characterized by having a structure represented by formula (IX), formula (X), formula (XI), or formula (XII):

4. the compound containing a urea structure according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein a is ₁ 、A ₂ 、B ₁ 、B ₂ 、D ₁ 、D ₂ 、E ₁ And E ₂ Are all CR ₅ 。

5. The compound containing a urea structure according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, having a structure represented by formula (a), formula (B) or formula (C):

6. The compound containing a urea structure according to claim 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is ₆ Is H; the sum of m and n is selected from: 0.1, 2 and 3.

7. The compound containing a urea structure according to any one of claims 1-6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is ₆ Selected from: H. c ₁ ～C ₃ An alkyl group.

8. The compound containing a urea structure according to any one of claims 1-6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R is ₇ 、R ₈ Each independently selected from: H. c ₁ ～C ₃ Alkyl radical, C ₁ ～C ₃ Alkylamino radical, hydroxyl radicalRadical substituted C ₁ ～C ₃ Alkyl radical, C ₁ ～C ₃ Alkoxy-substituted C ₁ ～C ₃ Alkyl radical, C ₁ ～C ₃ Alkylamino substituted C ₁ ～C ₃ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, 3-to 6-membered heterocycloalkyl, C ₁ ～C ₃ Acyl, alkenylacyl, C ₁ ～C ₃ Sulfonyl, 5-to 10-membered heteroaryl, or R ₇ 、R ₈ Together with the N atom to which they are attached form 1 or more R ₁₃ A substituted or unsubstituted 3-to 8-membered heterocyclic group, or R ₇ 、R ₈ Together with the N atom to which they are attached form 1 or more R ₁₃ Substituted or unsubstituted 5 to 10 heteroaryl.

9. The compound containing a urea structure according to claim 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R is ₇ ，R ₈ Each independently selected from: H. c ₁ ～C ₃ Alkyl, or R ₇ 、R ₈ Together with the N atom to which they are attached form 1 or more R ₁₃ A substituted or unsubstituted 5-to 6-membered heterocyclic group.

10. The compound containing a urea structure according to claim 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R is ₇ 、R ₈ Each independently selected from: H. methyl, ethyl, propyl, or R ₇ 、R ₈ Together with the N atom to which they are attached form 1 or more R ₁₃ A substituted or unsubstituted morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl group.

11. The compound containing a urea structure according to claim 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is ₁ Selected from the group consisting of:

12. the compound containing a urea structure according to any one of claims 1-6 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R is ₂ Each independently selected from: H. c ₁ ～C ₃ Alkyl radical, C ₁ ～C ₃ Alkyl acyl radical, C ₁ ～C ₃ Alkoxycarbonyl group, C ₁ ～C ₃ Alkylamino carbonyl, C ₃ ～C ₆ Cycloalkyl radical, C ₃ ～C ₆ Cycloalkoxycarbonyl radical, C ₃ ～C ₆ Cycloalkylaminocarbonyl, 3-to 6-membered heterocycloalkyl, C ₅ ～C ₁₀ Arylacyl, 5-to 10-membered heteroarylacyl, C ₁ ～C ₈ Sulfonyl radical, C ₆ ～C ₁₀ Aryl radical, C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₃ Alkyl, or 5-to 10-membered heteroaryl; when R is ₂ When not hydrogen, the R ₂ Independently optionally substituted by 1 or more R ₁₃ And (4) substitution.

13. The compound containing a urea structure according to any one of claims 1-6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is ₃ 、R ₄ Each independently selected from: H. c ₁ ～C ₃ Alkyl radical, C ₁ ～C ₃ Alkylamino, hydroxy substituted C ₁ ～C ₃ Alkyl radical, C ₁ ～C ₃ Alkoxy-substituted C ₁ ～C ₃ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, 3-to 8-membered heterocycloalkyl, C ₁ ～C ₃ Acyl, alkenylacyl, C ₁ ～C ₃ Sulfonyl, 5-to 10-membered heteroaryl, or R ₃ 、R ₄ And together with the carbon atom to which they are attached form 1 or more R ₁₃ Substituted or unsubstituted 3 to 6 membered cycloalkyl.

14. Compound containing a urea structure according to any one of claims 1-6 or a compound containing a urea structure according to any one of claims 1-6A pharmaceutically acceptable salt or a stereoisomer thereof, wherein each R is ₅ Each independently selected from: H. halogen, C ₁ ～C ₃ Alkyl radical, C ₃ ～C ₈ Cycloalkyl, 3-to 8-membered heterocycloalkyl, C ₁ ～C ₃ Alkoxy radical, C ₁ ～C ₃ Alkylthio radical, C ₁ ～C ₃ Alkylamino, amino, hydroxyl, mercapto, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C ₆ ～C ₁₀ Aryl radical, C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₆ Alkyl, 5-to 10-membered heteroaryl; when R is ₅ Is selected from C ₁ ～C ₃ Alkyl radical, C ₃ ～C ₈ Cycloalkyl, 3-to 8-membered heterocycloalkyl, C ₁ ～C ₃ Alkoxy radical, C ₁ ～C ₃ Alkylamino radical, C ₆ ～C ₁₀ Aryl radical, C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₆ When alkyl or 5-to 10-membered heteroaryl, the R ₅ Independently optionally substituted by 1 or more R ₁₃ And (4) substitution.

15. The compound containing a urea structure according to claims 1-6, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized by having the structure shown in formula (D), formula (E) or formula (F):

wherein each p is independently selected from: 0.1 or 2;

X ₁ is N or CH;

16. According to any one of claims 1-6The compound having a urea structure or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R represents a substituent ₁₃ Each independently selected from: H. hydroxy, amino, cyano, nitro, halogen, trifluoromethyl, C ₁ ～C ₃ Alkoxy radical, C ₁ ～C ₃ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, 3-to 6-membered heterocyclic group, 6-to 10-membered aryl group.

17. The compound containing a urea structure according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that it is selected from the following compounds:

18. use of a compound containing a urea structure according to any one of claims 1-17 or a pharmaceutically acceptable salt or stereoisomer thereof for the preparation of a RET kinase inhibitor.

19. Use of a compound containing a urea structure according to any one of claims 1-17 or a pharmaceutically acceptable salt or stereoisomer thereof for the manufacture of a medicament for the prevention and/or treatment of a disease associated with aberrant expression of RET kinase.

20. The use according to claim 18 or 19, wherein the RET kinase is wild-type RET kinase, RET kinase carrying a V804M mutation, RET kinase carrying a G810C mutation and/or RET kinase carrying a G810R mutation.

21. The use according to claim 19, wherein the disease associated with aberrant expression of RET kinase is a tumor.

22. The use of claim 21, wherein the tumor is: leukemia, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, hepatocarcinoma, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, histiocytic lymphoma, and nasopharyngeal carcinoma.

23. A pharmaceutical composition for preventing and/or treating tumors, which is prepared from an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises the compound containing a urea structure or the pharmaceutically acceptable salt or the stereoisomer thereof according to any one of claims 1 to 17.