Compounds Containing Urea Structures and Their Applications

Abstract

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

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly relates to a compound containing a urea structure and its applications. Background Art

[0002] 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 mutation, overexpression, etc. When abnormally activated, it can act as an oncogene for various malignancies. Among them, RET fusions retaining the kinase domain are driving factors for cancers such as papillary thyroid carcinoma (PTC) and non-small cell lung cancer (NSCLC); while activating RET mutations are associated with different phenotypes of multiple endocrine neoplasia type 2 (MEN2) and sporadic medullary thyroid carcinoma (MTC). Therefore, RET is an attractive therapeutic target for patients with cancers caused by RET alterations.

[0003] Early multi-kinase inhibitors (MKIs) with RET inhibitor activity, such as cabozantinib and vandetanib, have been explored in clinical practice for RET-driven cancers. Such multi-kinase inhibitors, due to their low target specificity, are prone to produce off-target side effects such as hypertension and diarrhea, which limit the tolerable dose for patients. Recently, the highly selective RET kinase inhibitor Selpercatinib developed by Loxo Oncology was approved by the FDA for marketing in May 2020; it is used to treat 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 for marketing in September 2020; in vitro studies have shown that Pralsetinib has significantly better selectivity for RET than other multi-target inhibitors, and has good tolerance, with only a slight inhibitory effect on VEGFR-2, and is used to treat adult patients with RET fusion-positive NSCLC.

[0004] Although selpercatinib and pralsetinib are highly active and selective against RET, it is still of great research value to develop selective inhibitors with new structures for RET gene fusions, overexpressions, or key site mutations such as the V804M mutation. In addition, the RET G810R, S, and C solvent front mutations as acquired resistance mechanisms have been confirmed in RET-abnormal patients treated with selective RET inhibitors (Solomon, Benjamin J. et al. J Thorac Oncol. 2020, 15(4), 541-549). Therefore, it is necessary and of great research significance to develop new RET inhibitors to inhibit these mutations. Summary of the Invention

[0005] To address the above problems, the present invention provides a new class of compounds containing a urea structure, which have good inhibitory activity against wild-type and mutant RET kinases.

[0006] The specific technical solutions are as follows:

[0007] A compound containing a urea structure having the structure shown in formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0008]

[0009] Wherein,

[0010] X1, X2, X3, X4, and X5 together form a heteroaryl group, and X1, X2, X3, X4, and X5 are each independently selected from: N, NR2, C, CR, or C=O, and one, two, or three of X1, X2, X3, X4, and X5 are each independently selected from: N, or NR2. When two or three of X1, X2, X3, X4, and X5 are both N, an N=N structure is not formed;

[0011] A1, A2, B1, B2, D1, D2, E1, and E2 are each independently selected from: N, or CR5;

[0012] Z is selected from: N, or CR';

[0013] R1 is selected from:

[0014]

[0015] Wherein, m, n, n1, and n2 are each independently selected from integers between 0 and 6;

[0016] Each Z1 and Z2 is independently selected from: NR 10 , O, S, or CR 11 R 12 ;

[0017] Each of Z3, Z4, and Z5 is independently selected from: O or S;

[0018] Each of Z6 is independently selected from: N or CR9;

[0019] Each of R2 is independently selected from: H, C1-C8 alkyl, C1-C8 alkyl acyl, C1-C8 alkoxycarbonyl, C1-C8 alkyl aminocarbonyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxycarbonyl, C3-C6 cycloalkyl aminocarbonyl, 3-6 membered heteroalkyl, C5-C 10 aryl acyl, 5-10 membered heteroaryl acyl, C1-C8 sulfonyl, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C6 alkyl, or 5-18 membered heteroaryl; when R2 is not hydrogen, the R2 is independently optionally substituted by one or more R 13 substituted;

[0020] R3 and R4 are independently selected from: H, C1-C8 alkyl, C1-C8 alkyl amine, hydroxy-substituted C1-C8 alkyl, C1-C8 alkoxy-substituted C1-C8 alkyl, C3-C8 cycloalkyl, 3-18 membered heteroalkyl, C1-C8 acyl, alkenyl acyl, C1-C8 sulfonyl, 5-18 membered heteroaryl, or R3, R4 and the carbon atom to which they are attached together form one or more R 13 substituted or unsubstituted 3-10 membered cycloalkyl or 6-10 membered heteroaryl;

[0021] Each of R5 is independently selected from: H, halogen, C1-C 18 alkyl, C3-C 18 cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkyl amine, amino, hydroxy, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl, 5-18 membered heteroaryl, or -SR 14 ; when R5 is selected from C1-C 18 alkyl, C3-C 18 cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkyl amine, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl or 5-18 membered heteroaryl, the R5 is independently optionally substituted by one or more R13 Substituted;

[0022] Each R6 is independently selected from: H, C1-C 18 alkyl, C3-C 18 cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, amino, hydroxy, cyano, nitro, ester, C1-C8 acyl, amide, sulfonyl, sulfonamido, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl, or 5-18 membered heteroaryl; when R6 is selected from C1-C 18 alkyl, C3-C 18 cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl or 5-18 membered heteroaryl, the R6 is independently optionally substituted by one or more R 13 Substituted;

[0023] Each R7, R8 is independently selected from: H, C1-C8 alkyl, C1-C8 alkylamino, hydroxy-substituted C1-C8 alkyl, C1-C8 alkoxy-substituted C1-C8 alkyl, C1-C8 alkylamino-substituted C1-C8 alkyl, C3-C8 cycloalkyl, 3-18 membered heteroalkyl, C1-C8 acyl, alkenyl acyl, C1-C8 sulfonyl, 5-18 membered heteroaryl, or R7, R8 together with the N atom to which they are attached form one or more R 13 substituted or unsubstituted 3-10 membered heterocyclic group, or R7, R8 together with the N atom to which they are attached form one or more R 13 substituted or unsubstituted 5-10 membered heteroaryl;

[0024] Each R9 is independently selected from: H, C1-C 18 alkyl, C3-C 18 cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, amino, hydroxy, cyano, nitro, ester, C1-C8 acyl, amide, sulfonyl, sulfonamido, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl, or 5-18 membered heteroaryl; when R9 is selected from C1-C 18 alkyl, C3-C18 cycloalkyl, 3- to 18-membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl or 5- to 18-membered heteroaryl, R9 is independently optionally substituted by one or more R 13 substituents;

[0025] each R 10 is independently selected from: H, C1-C8 alkyl, hydroxy-substituted C1-C8 alkyl, C1-C8 alkoxy-substituted C1-C8 alkyl, C3-C8 cycloalkyl;

[0026] each R 11 , R 12 is independently selected from: H, C1-C 18 alkyl, C3-C 18 cycloalkyl, 3- to 18-membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, amino, hydroxy, cyano, nitro, ester, C1-C8 acyl, amide, sulfonyl, sulfonamido, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl, or 5- to 18-membered heteroaryl; when R 11 , R 12 is selected from C1-C 18 alkyl, C3-C 18 cycloalkyl, 3- to 18-membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl or 5- to 18-membered heteroaryl, R 11 , R 12 is independently optionally substituted by one or more R 13 substituents;

[0027] each R 13 is independently selected from: H, hydroxy, amino, cyano, nitro, halogen, trifluoromethyl, C1-C6 alkoxy, C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl;

[0028] each R 14 is independently selected from: H, C1-C8 alkyl, hydroxy-substituted C1-C8 alkyl, C1-C8 alkoxy-substituted C1-C8 alkyl;

[0029] Each R is independently selected from: H, halogen, C1-C 18 alkyl, C3-C 18 cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, amino, hydroxy, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl, or 5-18 membered heteroaryl; when R is selected from C1-C 18 alkyl, C3-C 18 cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl or 5-18 membered heteroaryl, the R is independently optionally substituted by one or more R 13 substituted;

[0030] Each R' is independently selected from: H, halogen, C1-C 18 alkyl, C3-C 18 cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, amino, hydroxy, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl, or 5-18 membered heteroaryl; when R' is selected from C1-C 18 alkyl, C3-C 18 cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl or 5-18 membered heteroaryl, the R' is independently optionally substituted by one or more R 13 substituted.

[0031] In some embodiments, the compound containing a urea structure has a structure represented by formula (II), (III), (IV), (V), (VI), (VII) or (VIII):

[0032]

[0033] Wherein,

[0034] X1, X3, and X4 are each independently selected from: N, NR2, CR, or C═O, and an N═N structure is not formed in the five-membered ring where X1, X3, and X4 are located.

[0035] In some embodiments, the compound containing a urea structure has a structure represented by formula (IX), formula (X), formula (XI), or formula (XII):

[0036]

[0037] When R2 in the compound (IX) and the compound (X) of the present invention is H, the compound (IX) and the compound (X) are tautomers and represent the same compound.

[0038] In some embodiments, A1, A2, B1, B2, D1, D2, E1, and E2 are all CR5.

[0039] In some embodiments, the compound containing a urea structure has a structure represented by the following formula (A), formula (B), or formula (C):

[0040]

[0041] Wherein, each p is independently selected from: an integer between 0 and 4; Z1 is O or S; X1 is N or CR.

[0042] In some embodiments, R6 is H; the sum of m and n is selected from: 0, 1, 2, 3.

[0043] In some embodiments, m is 0, 1, 2, or 3, n is 0, 1, 2, or 3, n1 is 0, 1, 2, or 3, and n2 is 0, 1, 2, or 3.

[0044] In some embodiments, each R6 is independently selected from: H, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C1-C3 alkoxy, C1-C3 alkylamino, amino, hydroxy, cyano, nitro, ester, C1-C3 acyl, amide, sulfonyl, sulfonamido, C6-C 10 aryl, C6-C 10 aryl-substituted C1-C3 alkyl, or 5-10 membered heteroaryl; when R6 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C1-C3 alkoxy, C1-C3 alkylamino, C6-C 10 aryl, C6-C 10 aryl-substituted C1-C3 alkyl or 5-10 membered heteroaryl, the R6 is independently optionally substituted by one or more R13 Substitution.

[0045] In some embodiments, R6 is selected from: H, C1-C3 alkyl.

[0046] In some embodiments, each of R7 and R8 is independently selected from: H, C1-C3 alkyl, C1-C3 alkylamino, hydroxy-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkylamino-substituted C1-C3 alkyl, C3-C6 cycloalkyl, 3-6 membered heteroalkyl, C1-C3 acyl, alkenyl acyl, C1-C3 sulfonyl, 5-10 membered heteroaryl, or R7 and R8 together with the N atom to which they are attached form one or more R 13 Substituted or unsubstituted 3-8 membered heterocyclic group, or R7 and R8 together with the N atom to which they are attached form one or more R 13 Substituted or unsubstituted 5-10 membered heteroaryl.

[0047] In some embodiments, each of R7 and R8 is independently selected from: H, C1-C3 alkyl, or R7 and R8 together with the N atom to which they are attached form one or more R 13 Substituted or unsubstituted 5-6 membered heterocyclic group.

[0048] In some embodiments, each of R7 and R8 is independently selected from: H, methyl, ethyl, propyl, or R7 and R8 together with the N atom to which they are attached form one or more R 13 Substituted or unsubstituted morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl.

[0049] In some embodiments, R1 is selected from:

[0050] In some embodiments, each of R2 is independently selected from: H, C1-C3 alkyl, C1-C3 alkylacyl, C1-C3 alkoxycarbonyl, C1-C3 alkylaminocarbonyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxycarbonyl, C3-C6 cycloalkylaminocarbonyl, 3-6 membered heteroalkyl, C5-C 10 Arylacyl, 5-10 membered heteroarylacyl, C1-C8 sulfonyl, C6-C 10 Aryl, C6-C 10 Aryl-substituted C1-C3 alkyl, or 5-10 membered heteroaryl; when R2 is not hydrogen, said R2 is independently optionally substituted with one or more R 13 Substituted.

[0051] In some of these embodiments, R3 and R4 are each independently selected from: H, C1-C3 alkyl, C1-C3 alkylamino, hydroxy-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C3-C6 cycloalkyl, 3-8 membered heteroalkyl, C1-C3 acyl, alkenyl acyl, C1-C3 sulfonyl, 5-10 membered heteroaryl, or R3, R4 and the carbon atom to which they are attached together form one or more R 13 Substituted or unsubstituted 3-6 membered cycloalkyl.

[0052] In some of these embodiments, each R5 is independently selected from: H, halogen, C1-C3 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkylamino, amino, hydroxy, mercapto, cyano, nitro, ester group, amide group, sulfonyl, sulfonamido, C6-C 10 aryl, C6-C 10 aryl-substituted C1-C6 alkyl, 5-10 membered heteroaryl; when R5 is selected from C1-C3 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C1-C3 alkoxy, C1-C3 alkylamino, C6-C 10 aryl, C6-C 10 aryl-substituted C1-C6 alkyl or 5-10 membered heteroaryl, the R5 is independently optionally substituted with one or more R 13 substituted.

[0053] In some of these embodiments, the compound containing a urea structure has a structure represented by the following formula (D), formula (E) or formula (F):

[0054]

[0055] wherein each p is independently selected from: 0, 1 or 2;

[0056] X1 is N or CH;

[0057] Each R5 is independently selected from: H, fluorine, bromine, chlorine, C1-C3 alkyl, C1-C3 alkoxy;

[0058] Each R'5 is independently selected from: H, fluorine, C1-C3 alkoxy.

[0059] In some of these embodiments, each R is independently selected from: H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, 3-6 membered heteroalkyl, C1-C3 alkoxy, C1-C3 alkylamino, amino, hydroxy, cyano, nitro, ester group, amide group, sulfonyl, sulfonamido, C6-C 10 aryl, C6-C 10An aryl-substituted C1-C3 alkyl group, or a 5-10 membered heteroaryl group; when R is selected from a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 3-6 membered heterocycloalkyl group, a C1-C3 alkoxy group, a C1-C3 alkylamino group, a C6-C 10 aryl group, a C6-C 10 When the aryl-substituted C1-C3 alkyl group or the 5-10 membered heteroaryl group, the R is independently optionally substituted by one or more R 13 substituents.

[0060] In some embodiments, each R' is independently selected from: H, halogen, C1-C3 alkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C1-C3 alkoxy group, C1-C3 alkylamino group, amino group, hydroxy group, cyano group, nitro group, ester group, amide group, sulfonyl group, sulfonamido group, C6-C 10 aryl group, a C6-C 10 An aryl-substituted C1-C3 alkyl group, or a 5-10 membered heteroaryl group; when R' is selected from a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 3-6 membered heterocycloalkyl group, a C1-C3 alkoxy group, a C1-C3 alkylamino group, a C6-C 10 aryl group, a C6-C 10 When the aryl-substituted C1-C3 alkyl group or the 5-10 membered heteroaryl group, the R' is independently optionally substituted by one or more R 13 substituents.

[0061] In some embodiments, each R 13 is independently selected from: H, hydroxy group, amino group, cyano group, nitro group, halogen, trifluoromethyl group, C1-C3 alkoxy group, C1-C3 alkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocyclic group, 6-10 membered aryl group.

[0062] The present invention also provides the use of the above compounds.

[0063] Use of the above urea structure-containing compound or its pharmaceutically acceptable salt or its stereoisomer in the preparation of a RET kinase inhibitor.

[0064] In some 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.

[0065] Use of the above urea structure-containing compound or its pharmaceutically acceptable salt or its stereoisomer in the preparation of a drug for preventing and / or treating a disease associated with abnormal RET kinase expression.

[0066] 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.

[0067] In some of these embodiments, the disease associated with abnormal RET kinase expression is a tumor.

[0068] In some of these embodiments, the tumors are: 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, histiocytic lymphoma, nasopharyngeal carcinoma.

[0069] The present invention also provides a pharmaceutical composition for preventing and / or treating tumors.

[0070] The specific technical solution is as follows:

[0071] A pharmaceutical composition for preventing and / or treating tumors, prepared from an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises the above-mentioned compound containing a urea structure or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0072] Based on the above technical solution, the present invention has the following beneficial effects:

[0073] The compound containing a urea structure provided by the present invention, its pharmaceutically acceptable salts and isomers can effectively inhibit the activity of kinases, especially RET kinases, including wild-type and various mutant RET kinases, and further can regulate the activation of multiple downstream pathways, and can be used to prepare drugs for preventing and treating various diseases associated with abnormal RET kinase expression, such as leukemia and tumors. Detailed implementation manners

[0074] In the compounds of the present invention, when any variable (such as R 2If a substituent (e.g., etc.) appears more than once in any component, its definition for each occurrence is independent of the definition for each other occurrence. Similarly, combinations of substituents and variables are permitted, provided that the combination renders the compound stable. A line from a substituent into a ring system indicates that the bond so indicated can be attached to any ring atom capable of substitution. If the ring system is polycyclic, this means that the bond is attached only to any appropriate carbon atom of an adjacent ring. It is to be understood that one of ordinary skill in the art can select the substituents and substitution patterns of the compounds of the invention to provide compounds that are chemically stable and readily synthesized from readily available starting materials by the techniques of the art and the methods set forth hereinafter. If a substituent itself is substituted by more than one group, it is to be understood that these groups can be on the same carbon atom or different carbon atoms, provided that 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 such cases the preferred embodiments will have 0 - 3 substituents.

[0075] As used herein, the term "alkyl" means a branched or straight-chain saturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example, the definition of "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight-chain or branched arrangement. For example, "C1-C6 alkyl" specifically 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, etc. 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 "heterocycloalkyl" is a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent in which one or more ring atoms are heteroatoms selected from N, O, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. For example: morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuryl, tetrahydrothienyl, etc., and their N-oxides. The connection of the heterocyclic substituent can be achieved through a carbon atom or through a heteroatom. The term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N, or S. Heteroaryls within the scope of the present invention include, but are not limited to: quinolinyl, pyrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl; "heteroaryl" is also understood to include any N-oxide derivatives of heteroaryls containing nitrogen. The connection of the heterocyclic substituent can be achieved through a carbon atom or through a heteroatom.

[0076] As will be understood by those skilled in the art, as used herein, "halo" or "halogen" means chlorine, fluorine, bromine, and iodine.

[0077] Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl substituents may be unsubstituted or substituted. For example, C1-C6 alkyl may be substituted with one, two, or three substituents selected from OH, halogen, alkoxy, dialkylamino, or heterocyclic groups such as morpholinyl, piperidinyl, etc.

[0078] The present invention includes the compounds of formula (I)-(XII), the free forms of the compounds of formula (A)-(F), as well as their pharmaceutically acceptable salts and stereoisomers. Some specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to amine compounds in non-salt form. The pharmaceutically acceptable salts included not only include the exemplary salts of the specific compounds described herein, but also include typical pharmaceutically acceptable salts of all the free forms of the compounds of formula (I)-(XII) and formula (A)-(F). The free forms of the specific salts of the compounds can be separated 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 dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free form is somewhat different from its respective salt form in certain physical properties such as solubility in polar solvents, but for the purposes of the invention, such acid salts and base salts are equivalent to their respective free forms in other pharmaceutical aspects.

[0079] The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography or by reacting the 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.

[0080] Accordingly, the 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 reacting the basic compounds of the present invention with inorganic or organic acids. For example, the conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic 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, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, trifluoroacetic acid, etc.

[0081] If the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared with pharmaceutically acceptable non-toxic bases, including inorganic bases 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, manganous 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 include salts of primary amines, secondary amines and tertiary amines, substituted amines including 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, ethanolamine, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, pyrrolidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0082] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. ’1977:66:1-19 describes in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

[0083] Since under physiological conditions the deprotonated acidic moiety in the compound, such as a carboxyl group, can be anionic, and this charge can then be balanced and offset by a protonated or alkylated basic moiety with a cation inside, such as a quaternary nitrogen atom, it should be noted that the compounds of the present invention are potential inner salts or zwitterions.

[0084] In one embodiment, the present invention provides a method for treating hyperproliferative diseases or conditions such as tumors in humans or other mammals using the compounds of formulas (I)-(XII), (A)-(F) and their pharmaceutically acceptable salts.

[0085] In one embodiment, the compounds of the present invention and their pharmaceutically acceptable salts can be used to treat or control hyperproliferative diseases such as 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, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, etc.

[0086] Combined medication

[0087] The compounds of formula (I)-(XII) and formula (A)-(F) can be used in combination with other drugs known for treating or ameliorating similar conditions. When administered in combination, the mode of administration and dosage of the original drugs remain unchanged, while the compounds of formula (I)-(XII) and formula (A)-(F) are taken simultaneously or subsequently. When the compounds of formula (I)-(XII) and formula (A)-(F) are taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compounds of formula (I)-(XII) and formula (A)-(F) is preferably used. The combination therapy also includes taking the compounds of formula (I)-(XII) and formula (A)-(F) and one or more other known drugs over overlapping time periods. When the compounds of formula (I)-(XII) and formula (A)-(F) are used in combination with one or more other drugs, the dosage of the compounds of formula (I)-(XII) and formula (A)-(F) or the known drugs may be lower than their dosages when used alone.

[0088] Drugs or active ingredients that can be used in combination with the compounds of formula (I)-(XII) and formula (A)-(F) include, but are not limited to:

[0089] Estrogen receptor modulators, androgen receptor modulators, retinoid-like receptor modulators, cytotoxins / cytostatic agents, anti-proliferatives, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, 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, histone 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, p53 activators, VEGF antibodies, EGF antibodies, etc.

[0090] In one embodiment, the drugs or active ingredients that can be used in combination with the compounds of formula (I)-(XII) and formula (A)-(F) include but are not limited to: Aldesleukin, Alendronic acid, Interferon, Atrynol, Allopurinol, Sodium allopurinol, Palonosetron hydrochloride, Altretamine, Aminoglutethimide, Amifostine, Amrubicin, Amsacrine, Anastrozole, Dolasetron, Aranesp, Arglabin, Arsenic trioxide, Arimidex, 5-Azacytidine, Azathioprine, Bacillus Calmette-Guerin or Tice Bacillus Calmette-Guerin, Betahistine, Betamethasone acetate, Betamethasone sodium phosphate preparation, Bexarotene, Bleomycin sulfate, Bromodeoxyuridine, Bortezomib, Busulfan, Calcitonin, Alemtuzumab injection, Capecitabine, Carboplatin, Casodex, Cefesone, Simotil, Daunorubicin, Chlorambucil, Cisplatin, Cladribine, Cladribine, Clodronic acid, Cyclophosphamide, Cytarabine, Dacarbazine, Actinomycin D, Daunorubicin liposome, Dexamethasone, Dexamethasone phosphate, Estradiol valerate, Denileukin diftitox, Depo-Medrol, Deslorelin, Dexrazoxane, Diethylstilbestrol, Diflucan, Docetaxel, Doxifluridine, Doxorubicin, Dronabinol, Yttrium-166-chitosan complex, Eligard, Rasburicase, Epirubicin hydrochloride, Aprepitant, Epirubicin, Epoetin alfa, Erythropoietin, Iproplatin, Levamisole tablets, Estradiol preparation, 17-β-Estradiol, Estramustine phosphate sodium, Ethinyl estradiol, Amifostine, Hydroxyphosphate, Vifor, Etoposide, Formestane, Tamoxifen preparation, Filgrastim, Finasteride, Fostriecin, Floxuridine, Fluconazole, Fludarabine, 5-Fluorodeoxyuridine monophosphate, 5-Fluorouracil, Fluoxymesterone, Flutamide, Forasteride, 1-β-D-Arabinofuranosylcytosine-5’-stearoylphosphate, Fotemustine, Fulvestrant, Gamma globulin, Gemcitabine, Gemtuzumab, Imatinib mesylate, Carmustine wafer capsule, Goserelin, Granisetron hydrochloride, Histrelin, Mylotarg, Hydrocortisone, Erythro-hydroxy-nonyladenine, Hydroxyurea, Ibritumomab tiuxetan, Idarubicin, Ifosfamide, Interferon α, Interferon-α2, Interferon α-2A, Interferon α-2B, Interferon α-nl, Interferon α-n3, Interferon β, Interferon γ-la, Interleukin-2, Intron A, Iressa, Irinotecan, Camptosar, Lentinan sulfate, Letrozole, Leucovorin, Leuprorelin, Leuprorelin acetate, Levamisole, Calcium levoleucovorin, Levothyroxine sodium, Levothyroxine sodium preparation, Lomustine, Lonidamine, Dronabinol, Nitrogen mustard, Mecobalamin, Medroxyprogesterone acetate, Megestrol acetate, Melphalan, Esterified estrogen, 6-Mercaptopurine, Mesna, Methotrexate, Methyl aminolevulinate, Miltefosine, Minocycline, Mitomycin C, Mitotane, Mitoxantrone, Trilostane, Doxorubicin citrate liposome, Nedaplatin, Pegfilgrastim, Oprelvekin, Neupogen,Nilutamide, Tamoxifen, NSC-631570, Recombinant Human Interleukin 1-β, Octreotide, Ondansetron Hydrochloride, Prednisolone Oral Solution, Oxaliplatin, Paclitaxel, Sodium Prednisolone Phosphate Preparation, Pegaspargase, Peginterferon Alfa-2a, Pentostatin, Picibanil, Pilocarpine Hydrochloride, Pirarubicin, Plicamycin, Porfimer Sodium, Prednimustine, Stiprednisone, Prednisone, Premarin, Procarbazine, Recombinant Human Erythropoietin, Raltitrexed, Rebif, Rhenium-186 Etidronate, Rituximab, Redoxon-A, Romurtide, Pilocarpine Hydrochloride Tablets, Octreotide, Sargramostim, Semustine, Sizofiran, Sobuzoxane, Methylprednisolone Sodium Succinate, Pamidronic Acid, Stem Cell Therapy, Streptozocin, Strontium Chloride-89, Levothyroxine Sodium, Tamoxifen, Tamsulosin, Talacton, Docetaxel, Tiotropium, Temozolomide, Teniposide, Testosterone Propionate, Methyltestosterone, Thioguanine, Thiotepa, Thyrotropin, Tiludronic Acid, Topotecan, Toremifene, Tositumomab, Trastuzumab, Treosulfan, Tretinoin, Methotrexate Tablets, Trimethylmelamine, Trimetrexate, Triptorelin Acetate, Triptorelin Pamoate, UFT, Uridine, Valrubicin, Vesnarinone, Vinblastine, Vincristine, Vindesine, Vinorelbine, Verrucarine, Dexrazoxane, Zinostatin Stimalamer, Zofran, Paclitaxel Protein Stabilized Preparation, Acolbifene, Interferon Gamma-1b, Affinitak, Aminopterin, Arzoxifene, Asoprisnil, Atamestane, Atrasentan, BAY43-9006, Avastin, CCI-779, CDC-501, Celecoxib, Cetuximab, Clinacanthus Nutans Extract, Cyproterone Acetate, Decitabine, DN-101, Doxorubicin-MTC, dSLIM, Dutasteride, Edotecarin, Eflornithine, Exatecan, Fenretinide, Histamine Dihydrochloride, Histrelin Hydrogel Implant, Holmium-166 DOTMP, Ibandronic Acid, Interferon Gamma, Intron-PEG, Ixabepilone, Keyhole Limpet Hemocyanin, L-651582, Lanreotide, Lasofoxifene, Libra, Lonafamib, Miproxifene, Minociprazole, MS-209, Liposomal MTP-PE, MX-6, Nafarelin, Nemorubicin, Novastatine, Nolatrexed, Olimersen, Onco-TCS, Osidem, Paclitaxel Polyglyglutamate, Sodium Picosulfate, PN-401, QS-21, Quazepam, R-1549, Raloxifene, Bombesin, 13-cis-Retinoic Acid, Satraplatin, Seocalcitol, T-138067, Tarceva, Docetaxel Docosahexaenoate, Thymosin Alpha1, Gazolafurin, Tipifarnib, Tirapazamine, TLK-286, Toremifene, trans-MID-lo7R, Vapreotide, Vapreotide, Vatalanib, Verteporfin, Vinflunine,Z-100 and zoledronic acid or their combination.

[0091] The reagents used in the following examples are all commercially available.

[0092] The following examples further describe the present invention, but the examples are not used to limit the protection scope of the present invention.

[0093] Example 1: Preparation of Compound CQ-1232

[0094]

[0095] Preparation of Compound 3 (a-b):

[0096] Dissolve Compound 1 (50 g, 308.6 mmol) in 250 ml of isopropanol, stir at room temperature for 3 hours, then spin dry, and dissolve again in 300 ml of dichloromethane. At 0 °C, add dropwise 19 ml of hydrazine (50% aqueous solution), then transfer to room temperature and react overnight. After the reaction is completed, wash with water, spin dry the organic phase to obtain 24 g of crude product 3, which can be directly used for the next step without further purification.

[0097] Preparation of Compound 10 (c-g):

[0098] (c): Dissolve Compound 4 (9.5 g, 69.8 mmol) and potassium carbonate (19.3 g, 140 mmol) in 100 ml of acetone, then add benzyl bromide (9.1 ml, 77 mmol), and react at 60 °C overnight. After the reaction is completed, filter by suction and spin dry to obtain 14 g of crude product 5, which can be directly used for the next step without further purification.

[0099] (d): Dissolve Compound 5 (10.6 g, 47 mmol) and Compound 3 (22.2 g, 188 mmol) in 80 ml of methanol, then add glacial acetic acid (0.54 ml, 9.4 mmol), reflux at 80 °C for 8 hours, cool to room temperature, and filter by suction to obtain 14 g of Compound 6, with a yield of 91%.

[0100] 1 H NMR (400 MHz, CDCl3) δ 7.68–7.82 (m, 3H), 7.29-7.49 (m, 5H), 6.96 (d, J = 8.8 Hz, 2H), 5.04–5.17 (m, 3H), 2.16 (s, 3H), 1.33 (d, J = 6.0 Hz, 6H).

[0101] (e): Compound 6 (4 g, 12.27 mmol) was dissolved in 25 ml of dry tetrahydrofuran under argon protection. 20 ml of lithium diisopropylamide (2 M solution in tetrahydrofuran) was added dropwise at 0 °C. After stirring for 1 hour, the temperature was transferred to -78 °C, and then 25 ml of a tetrahydrofuran solution of compound 7 (3.3 g, 18.4 mmol) was added dropwise. After the addition, the reaction was slowly warmed to room temperature. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was mixed with silica gel and loaded onto a column to obtain 2 g of crude product 8.

[0102] (f): Compound 8 (2 g, 4.47 mmol) was dissolved in 30 ml of tetrahydrofuran, and 10 ml of methanesulfonic acid (3 N aqueous solution) was added. After refluxing at 80 °C for 4 hours, it was extracted with ethyl acetate and washed three times with saturated sodium bicarbonate solution. The organic phase was mixed with silica gel and loaded onto a column to obtain 650 mg of compound 9, with a yield of 34%.

[0103] 1 H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.26–7.49 (m, 5H), 7.05 (d, J = 8.8 Hz, 2H), 6.72 (s, 1H), 5.07–5.18 (m, 3H), 1.29 (d, J = 6.4 Hz, 6H).

[0104] (g): Compound 9 (650 mg, 1.42 mmol) was dissolved in 20 ml of ethyl acetate, 65 mg of palladium-carbon was added, and then the gas was exchanged with hydrogen three times. The reaction was carried out at room temperature for 6 hours, filtered by suction, and concentrated by rotary evaporation to obtain 480 mg of compound 10, with a yield of 99%.

[0105] 1 H NMR (400 MHz, DMSO) δ 9.73 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 6.80 (s, 1H), 6.62 (d, J = 8.4 Hz, 2H), 5.37 (s, 2H), 4.94–5.07 (m, 1H), 1.21 (d, J = 6.4 Hz, 6H).

[0106] Preparation of Compound 13 ((h-i)):

[0107] (h): Dissolve acetonitrile (2.3 ml, 44.1 mmol) in 50 ml of dry tetrahydrofuran. After stirring at -78 °C for 15 minutes, add 28 ml of n-butyllithium (1.6 M hexane solution), then transfer to -30 °C and stir for 30 minutes. Then dropwise add compound 11 (5 g, 29.4 mmol), react overnight, quench with saturated aqueous ammonium chloride solution, extract with ethyl acetate, evaporate the organic phase to dryness to obtain 5.1 g of crude product 12, which is directly used for the next step.

[0108] (i): Dissolve hydroxylamine hydrochloride (3.94 g, 56.6 mmol) in 50 ml of water. Add sodium bicarbonate (4.8 g, 56.6 mmol) at 0 °C to adjust the pH to ~8. Then add 30 ml of the methanol solution of compound 12. After refluxing at 65 °C for 6 hours, cool to room temperature, adjust the pH to ~1 with concentrated hydrochloric acid, then place at 70 °C and reflux for 3 hours. After the reaction is completed, adjust the pH to ~8 with 4N sodium hydroxide solution, extract with ethyl acetate, add silica gel to the organic phase, mix well and chromatograph to obtain 1.3 g of compound 13, with a yield of 23%.

[0109] 1 H NMR (400 MHz, CDCl3) δ 5.77 (s, 1H), 4.20 (s, 2H), 1.47 (s, 6H).

[0110] Preparation of compound 14:

[0111] (j) Dissolve compound 13 (1.3 g, 6.7 mmol) and potassium carbonate (1.38 g, 10 mmol) in 20 ml of tetrahydrofuran. Then add phenyl chloroformate (1 ml, 8 mmol), react at room temperature for 4 hours, add water, extract with ethyl acetate, evaporate to dryness, then add 20 ml of n-hexane, stir for 1 hour, filter by suction, and dry the filter cake to obtain 1.78 g of compound 14, with a yield of 85%.

[0112] 1 H NMR (400 MHz, CDCl3) δ 8.07 (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).

[0113] Preparation of compound CQ-1232:

[0114] (k): Compound 10 (200 mg, 0.59 mmol), compound 14 (280 mg, 0.89 mmol), 4-dimethylaminopyridine (7 mg, 0.06 mmol) were dissolved in 3 ml of N,N-dimethylformamide, then triethylamine (0.25 ml, 1.77 mmol) was added, and the reaction was carried out overnight at room temperature. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The organic phase was mixed with silica gel and purified by column chromatography to obtain 200 mg of compound 15 with a yield of 61%.

[0115] 1 H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.98 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 6.48 - 6.57 (m, 2H), 5.04–5.14 (m, 1H), 1.60 (s, 6H), 1.21 (d, J = 6.0 Hz, 6H).

[0116] (l): Compound 15 (100 mg, 0.18 mmol), compound 16 (44 μl, 0.36 mmol), triphenylphosphine (94 mg, 0.36 mmol) were dissolved in 1 ml of dry tetrahydrofuran under argon protection. At 0 °C, diisopropyl azodicarboxylate (71 μl, 0.36 mmol) was added dropwise, and then the reaction was transferred to room temperature and carried out overnight. After the reaction was completed, it was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was mixed and purified by column chromatography to obtain 48 mg of compound CQ-1232 with a yield of 40%.

[0117] 1 H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.48 (s, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.61 (s, 1H), 6.34 (s, 1H), 5.05–5.16 (m, 1H), 4.17 (t, J = 5.6 Hz, 2H), 3.76 (t, J = 4.4 Hz, 4H), 2.85 (t, J = 5.6 Hz, 2H), 2.63 (t, J = 5.6 Hz, 4H), 1.59 (s, 6H), 1.24 (d, J = 6.0 Hz, 6H).

[0118] Example 2: Preparation of Compound CQ-1231

[0119]

[0120] Preparation of Compound 19:

[0121] (a): Dissolve Compound 17 (4.6 g, 32.7 mmol), Compound 18 (5 g, 32.7 mmol), and potassium hydroxide (5.5 g, 98.1 mol) in 100 ml of anhydrous ethanol. Reflux at 80 °C overnight. After the reaction is complete, remove the solvent by rotary evaporation, add water, extract with ethyl acetate. Add silica gel to the organic phase, mix well, and separate by column chromatography to obtain 5.4 g of Compound 19 with a yield of 60%.

[0122] 1 H NMR (400 MHz, DMSO) δ 10.44 (brs, 1H), 7.94 (t, J = 8.8 Hz, 1H), 7.75 - 7.82 (m, 2H), 7.69 - 7.74 (m, 2H), 6.83 (t, J = 8.4 Hz, 1H), 6.61–6.75 (m, 2H), 6.20 (s, 2H).

[0123] Preparation of Compound 20:

[0124] (b): Dissolve Compound 19 (5 g, 18.2 mmol) and p-toluenesulfonylhydrazide (5.1 g, 27.3 mmol) in 100 ml of anhydrous ethanol. Then add iodine (455 mg, 1.8 mmol). After refluxing at 110 °C for 20 minutes, add potassium carbonate (7.5 g, 54.6 mmol). React overnight. After the reaction is complete, evaporate the solvent, add water, extract with ethyl acetate. Add silica gel to the organic phase, mix well, and separate by column chromatography to obtain 2.5 g of Compound 20 with a yield of 48%.

[0125] 1 H NMR (400 MHz, DMSO) δ 12.98 (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).

[0126] Preparation of Compound 21:

[0127] (c): Dissolve Compound 20 (400 mg, 1.39 mmol), Compound 14 (656 g, 2.09 mmol), and 4-dimethylaminopyridine (17 mg, 0.14 mmol) in 5 ml of N,N-dimethylformamide. Then add triethylamine (0.58 ml, 4.17 mmol). React at room temperature overnight. After the reaction is complete, add water, extract with ethyl acetate. Evaporate the organic phase, then add 10 ml of DCM / MeOH (40:1), stir for 1 hour, filter by suction, and dry the filter cake to obtain 400 mg of Compound 21 with a yield of 57%.

[0128] 1 1H NMR (400 MHz, DMSO) δ 13.15 (s, 1H), 9.85 - 10.36 (m, 2H), 8.86 (s, 1H), 8.17 (t, J = 8.8 Hz, 1H), 7.57 - 7.77 (m, 3H), 6.89–6.98 (m, 2H), 6.64 - 6.76 (m, 2H), 1.57 (s, 6H).

[0129] Preparation of compound CQ - 1231:

[0130] (d): Dissolve compound 20 (100 mg, 0.2 mmol), compound 16 (48 μl, 0.4 mmol), and triphenylphosphine (105 mg, 0.4 mmol) in 1 ml of dry tetrahydrofuran. Under argon protection, at 0 °C, dropwise add diisopropyl azodicarboxylate (79 μl, 0.4 mmol), then transfer to room temperature and react overnight. After the reaction is completed, quench with saturated sodium bicarbonate solution, extract with ethyl acetate, add silica gel to the organic phase and mix well, and purify by column chromatography to obtain 15 mg of compound CQ - 1231, with a yield of 12%.

[0131] 1 1H NMR (400 MHz, DMSO) δ 13.26 (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).

[0132] Example 3: Preparation of compound CQ - 1223

[0133]

[0134] The synthetic route is similar to that of Example 2.

[0135] 1 1H NMR (400 MHz, DMSO) δ 13.07 (s, 1H), 9.71 (s, 1H), 8.93 (s, 1H), 7.69–7.81 (m, 4H), 7.53 (d, J = 8.4 Hz, 2H), 6.98 - 7.06 (m, 3H), 6.92 (s, 1H), 4.13 (t, J = 5.6 Hz, 2H), 3.59 (t, J = 4.8 Hz, 4H), 2.71 (t, J = 5.6 Hz, 2H), 2.46 - 2.50 (m, 4H), 1.57 (s, 6H).

[0136] Example 4: Preparation of Compound CQ-1227

[0137] Dissolve compound CQ-1223 (150 mg, 0.26 mmol) in 5 ml of methanol, add methanesulfonic acid (83 μl, 1.28 mmol), reflux at 70 °C overnight. After the reaction is completed, evaporate the solvent under reduced pressure, add 2 ml of ethanol, cool to precipitate a solid, filter by suction, wash with 5 ml of ethanol, and dry the filter cake to obtain 88 mg of compound CQ-1227 with a yield of 44%.

[0138]

[0139] 1 H NMR (400 MHz, DMSO) δ 9.91 (s, 1H), 9.76 (s, 1H), 9.02 (s, 1H), 7.73 - 7.84 (m, 4H), 7.55 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 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 = 11.6 Hz, 2H), 3.51 - 3.65 (m, 4H), 3.17 - 3.30 (m, 2H), 2.37 (s, 6H), 1.57 (s, 6H).

[0140] Example 5: Preparation of Compound CQ-1226

[0141]

[0142] The synthetic route is similar to that of Example 2.

[0143] 1 H NMR (400 MHz, DMSO) δ 13.11 (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 = 6.4 Hz, 2H), 2.38 (t, J = 7.2 Hz, 2H), 2.17 (s, 6H), 1.82 - 1.9 (m, 2H), 1.57 (s, 6H).

[0144] Example 6: Preparation of Compound CQ-1230

[0145]

[0146] The synthetic route is similar to that of Example 2.

[0147] 1 H NMR (400 MHz, DMSO) δ 13.15 (s, 1H), 10.03 (s, 1H), 8.87 (s, 1H), 8.17 (t, J = 8.4 Hz, 1H), 7.60 - 7.77 (m, 4H), 7.09 (s, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.92 (s, 1H), 4.14 (t, J = 5.6 Hz, 2H), 3.59 (t, J = 4.4 Hz, 4H), 2.71 (t, J = 6.0 Hz, 2H), 2.45 - 2.50 (m, 4H), 1.57 (s, 6H).

[0148] Example 7: Preparation of Compound CQ-1235

[0149]

[0150] The synthetic route is similar to that of Example 2.

[0151] 1 H NMR (400 MHz, DMSO) δ 7.68 - 7.80 (m, 4H), 7.55 (d, J = 8.4 Hz, 2H), 6.88 - 7.05 (m, 4H), 4.10 (t, J = 5.6 Hz, 2H), 2.69 (t, J = 5.6 Hz, 2H), 2.41 - 2.51 (m, 4H), 2.22 - 2.40 (m, 4H), 2.14 (s, 3H), 1.56 (s, 6H).

[0152] Example 8: Preparation of Compound CQ-1233

[0153]

[0154] The synthetic route is similar to that of Example 2.

[0155] 1 H NMR (400 MHz, DMSO) δ 13.09 (s, 1H), 9.73 (s, 1H), 8.95 (s, 1H), 7.69 - 7.84 (m, 4H), 7.55 (d, J = 8.8 Hz, 2H), 6.89 - 7.04 (m, 4H), 4.03 (t, J = 6.4 Hz, 2H), 3.57 (t, J = 4.8 Hz, 4H), 2.42 (t, J = 7.2 Hz, 2H), 2.31 - 2.40 (m, 4H), 1.82 - 1.94 (m, 2H), 1.56 (s, 6H).

[0156] Example 9: Preparation of Compound CQ-1234

[0157]

[0158] Preparation of Compound 22: The synthetic route is similar to that of Example 2.

[0159] Preparation of Compound CQ-1234:

[0160] Dissolve Compound 22 (100 mg, 0.16 mmol) in 2 ml of trifluoroacetic acid. After stirring at room temperature for 1 hour, evaporate the solvent under reduced pressure. Adjust the pH to ~8 with saturated sodium bicarbonate solution, extract with ethyl acetate. Evaporate the organic phase under reduced pressure, add silica gel and mix well, and separate by column chromatography to obtain 51 mg of Compound CQ-1234 with a yield of 60%.

[0161] 1 H NMR (400 MHz, DMSO) δ 13.12 (s, 1H), 9.15 (s, 1H), 7.68 - 7.83 (m, 4H), 7.54 (d, J = 8.4 Hz, 2H), 6.89 - 7.07 (m, 4H), 4.06 (t, J = 5.6 Hz, 2H), 2.87 (t, J = 5.2 Hz, 2H), 2.36 (s, 3H), 1.56 (s, 6H).

[0162] Example 10: Preparation of Compound CQ-1244

[0163]

[0164] The synthetic route is similar to that of Example 2.

[0165] 1 H NMR (400 MHz, DMSO) δ 13.07 (s, 1H), 9.76 (s, 1H), 9.01 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.39 - 7.45 (m, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.00 - 7.10 (m, 2H), 6.93 (s, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.85 (s, 3H), 3.59 (t, J = 4.4 Hz, 4H), 2.71 (t, J = 6.0 Hz, 2H), 2.43 - 2.50 (m, 4H), 1.57 (s, 6H).

[0166] Example 11: Preparation of Compound CQ-1246

[0167]

[0168] The synthetic route is similar to that of Example 2.

[0169] 11H NMR (400 MHz, DMSO) δ 13.21 (s, 1H), 10.06 (s, 1H), 8.88 (s, 1H), 8.18 (t, J = 8.4 Hz, 1H), 7.60 - 7.76 (m, 2H), 7.41 (m, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.85 (s, 3H), 3.59 (t, J = 4.8 Hz, 4H), 2.71 (t, J = 5.6 Hz, 2H), 2.45 - 2.55 (m, 4H), 1.57 (s, 6H)

[0170] Example 12: Preparation of Compound CQ - 1255

[0171]

[0172] The synthetic route is similar to that of Example 2.

[0173] 1 1H NMR (400 MHz, DMSO) δ 13.24 (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).

[0174] Example 13: Preparation of Compound CQ - 1256

[0175]

[0176] The synthetic route is similar to that of Example 2.

[0177] 11H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 9.73 (s, 1H), 8.95 (s, 1H), 7.69 - 7.81 (m, 2H), 7.66 (d, J = 12.8 Hz, 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).

[0178] Example 14: Preparation of Compound CQ - 1257

[0179]

[0180] The synthetic route is similar to that of Example 2.

[0181] 1 1H NMR (400 MHz, DMSO) δ 13.17 & 12.88 (two s, 1H), 9.71 (s, 1H), 8.93 (s, 1H), 7.70 - 7.86 (m, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.43 (s, 1H), 6.85 - 6.98 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.79 (s, 1H), 4.11 (t, J = 5.2 Hz, 2H), 3.50 - 3.66 (m, 4H), 2.70 (t, J = 5.2 Hz, 2H), 2.33 - 2.48 (m, 4H), 1.56 (s, 6H).

[0182] Example 15: Preparation of Compound CQ - 1258

[0183]

[0184] The synthetic route is similar to that of Example 2.

[0185] 1 1H NMR (400 MHz, DMSO) δ 13.35 & 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 = 4.8 Hz, 4H), 2.70 (t, J = 4.8 Hz, 2H), 2.46 - 2.52 (m, 4H), 1.56 (s, 6H).

[0186] Example 16: Preparation of Compound CQ-1259

[0187]

[0188] The synthetic route is similar to that of Example 2.

[0189] 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).

[0190] Example 17: Preparation of Compound CQ-1260

[0191]

[0192] The synthetic route is similar to that of Example 2.

[0193] 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).

[0194] Example 18: Preparation of Compound CQ-1269

[0195]

[0196] The synthetic route is similar to that of Example 2.

[0197] 11H NMR (400 MHz, DMSO) δ 13.30 & 13.14 (two s, 1H), 9.78 (s, 1H), 9.18 (s, 1H), 7.67 - 8.02 (m, 3H), 7.62 (d, J = 13.6 Hz, 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).

[0198] Example 19: Preparation of Compound CQ - 1270

[0199]

[0200] The synthetic route is similar to that of Example 2.

[0201] 1 1H NMR (400 MHz, DMSO) δ 13.17 & 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 = 5.6 Hz, 2H), 3.59 (t, J = 4.8 Hz, 4H), 2.72 (t, J = 5.2 Hz, 2H), 2.38 - 2.48 (m, 4H), 1.56 (s, 6H).

[0202] Example 20: Preparation of Compound CQ - 1245

[0203]

[0204] Preparation of Compound 23

[0205] (a): Dissolve 4 - hydroxybenzonitrile (10 g, 84 mmol) and K2CO3 (17.4 g, 126 mmol) in 100 ml of DMF, then add BnBr (15.8 g, 92.4 mmol). React at 50 °C until the raw materials are exhausted. Add water, extract with ethyl acetate, and evaporate to dryness to obtain 16.5 g of Compound 23 with a yield of 94%.

[0206] 1 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.8 Hz, 2H), 7.46–7.33 (m, 5H), 7.02 (d, J = 8.8 Hz, 2H), 5.12 (s, 2H).

[0207] Preparation of Compound 24

[0208] (b): Dissolve Compound 23 (8 g, 37.7 mmol) in tetrahydrofuran, and add it to a solution of LiHDMS (41.5 ml, 41.5 mmol) in tetrahydrofuran under argon protection. React at room temperature. After the reaction is completed, quench with 5N hydrochloric acid isopropanol solution, extract with ethyl acetate, add silica gel to the organic phase, mix well and purify by column chromatography to obtain 7.2 g of Compound 24, with a yield of 73%.

[0209] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.38 (s, 2H), 9.17 (s, 2H), 7.90 (d, J = 9.2 Hz, 2H), 7.47–7.33 (m, 5H), 7.21 (d, J = 8.8 Hz, 2H), 5.23 (s, 2H).

[0210] Preparation of Compound 26

[0211] (c): Dissolve Compound 24 (3.2 g, 12.16 mmol) and KHCO3 (3 g, 30.4 mmol) in 40 ml of THF / H2O (4:1), heat to 90 °C, and slowly dropwise add a solution of Compound 25 (3.6 g, 14.6 mmol) in THF (30 ml). Continue stirring until the raw materials are exhausted, evaporate to dryness, add water, extract with ethyl acetate, add silica gel, and separate by column chromatography to obtain 2.1 g of Compound 26, with a yield of 47%.

[0212] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.80 (s, 1H), 8.25 (d, J = 8.8 Hz, 2H), 8.10 (d, J = 8.8 Hz, 2H), 8.05 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.49 - 7.31 (m, 5H), 7.14 (d, J = 8.8 Hz, 2H), 5.17 (s, 2H).

[0213] Preparation of Compound 27

[0214] (d): Dissolve Compound 26 (845 mg, 2.48 mmol) and palladium / carbon (200 mg) in 20 ml of methanol, evacuate and replace with hydrogen, react at room temperature overnight. After the reaction is completed, filter by suction, evaporate the filtrate to dryness to obtain 240 mg of Compound 27, with a yield of 38.6%.

[0215] 1 H NMR (400 MHz, DMSO-d 6)δ 9.90 (broad singlet, 1H), 7.85 (doublet, J = 8.8 Hz, 2H), 7.50 (doublet, J = 8.4 Hz, 2H), 7.28 (singlet, 1H), 6.87 (doublet, J = 8.8 Hz, 2H), 6.61 (doublet, J = 8.4 Hz, 2H).

[0216] Preparation of Compound CQ-1245

[0217] (e): Dissolve Compound 27 (170 mg, 0.67 mmol), Compound 14 (320 mg, 1.02 mmol), and DMAP (19 mg, 0.07 mmol) in 3 ml of N,N-dimethylformamide, add triethylamine (0.2 mg, 2.01 mmol), and react overnight at room temperature. After the reaction is completed, extract with ethyl acetate. Rotate the organic phase to dryness to obtain 254 mg of crude product 28, which is directly used in the next step without further purification.

[0218] (f): Dissolve Compound 28 (150 mg, 0.32 mmol), Compound 16 (83.4 mg, 0.64 mmol), and triphenylphosphine (166.8 mg, 0.64 mmol) in 1 ml of anhydrous tetrahydrofuran. Add 1 ml of a tetrahydrofuran solution of diisopropyl azodicarboxylate (129.4 mg, 0.64 mmol) at 0 °C, and transfer to room temperature to react overnight. After the reaction is completed, add sodium bicarbonate solution and extract with ethyl acetate. Stir the organic phase with silica gel and pass through a column to obtain 52 mg of the compound with a yield of 27.9%.

[0219] 1 H NMR (400 MHz, DMSO) δ 12.42 (singlet, 1H), 9.69 (singlet, 1H), 8.90 (singlet, 1H), 7.92 (doublet, J = 8.4 Hz, 2H), 7.76 (doublet, J = 8.0 Hz, 2H), 7.55 (singlet, 1H), 7.47 (doublet, J = 8.0 Hz, 2H), 7.04 (doublet, J = 8.4 Hz, 2H), 6.91 (singlet, 1H), 4.14 (triplet, J = 5.2 Hz, 2H), 3.55 - 3.64 (multiplet, 4H), 2.68 - 2.78 (multiplet, 2H), 2.50 - 2.57 (multiplet, 4H), 1.56 (singlet, 6H).

[0220] Example 21: Preparation of Compound CQ-1253

[0221]

[0222] Preparation of Compound 30

[0223] (a): Dissolve compound 24 (4.1 g, 15.3 mmol), compound 29 (1.5 g, 10.1 mmol), cesium carbonate (9.95 g, 30 mmol), and copper(I) bromide (73 mg, 0.51 mmol) in 30 ml of dimethyl sulfoxide, react at 120 °C overnight, cool to room temperature, extract with ethyl acetate and water, add silica gel to the organic phase for mixing, and separate by column chromatography to obtain 1.8 g of compound 30 with a yield of 48%.

[0224] 1 H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 8.42 - 8.25 (m, 4H), 8.02 (d, J = 8.8 Hz, 2H), 7.52 - 7.30 (m, 5H), 7.19 (d, J = 8.0 Hz, 2H), 5.18 (s, 2H).

[0225] Preparation of compound 32

[0226] (b): Dissolve compound 30 (1.5 g, 4.03 mmol) in 50 ml of tetrahydrofuran, add compound 31 (2.21 ml, 24.18 mmol) and p-toluenesulfonic acid (139 mg, 0.806 mmol), reflux at 85 °C overnight, evaporate THF, extract with ethyl acetate and water, add silica gel to the organic phase for mixing, and separate by column chromatography to obtain 1.3 g of compound 32 with a yield of 70%.

[0227] 1 H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 9.2 Hz, 2H), 8.29 (d, J = 9.2 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.49 - 7.33 (m, 5H), 7.14 (d, J = 8.8 Hz, 2H), 5.37 (dd, J = 10.0, 2.8 Hz, 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).

[0228] Preparation of compound 33

[0229] (c): Dissolve compound 32 (1.3 g, 2.85 mmol) in 40 ml of MeOH, add 260 mg of palladium on carbon (10%), purge with H2 three times, react at room temperature until the raw materials are exhausted, filter by suction, add silica gel to the filtrate for mixing, and separate by column chromatography to obtain 336 mg of compound 33 with a yield of 34%.

[0230] 1 1H NMR (400 MHz, DMSO) δ 10.03 & 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).

[0231] Preparation of Compound CQ - 1253

[0232] (d): Dissolve Compound 33 (330 mg, 0.98 mmol), Compound 14 (461 mg, 1.47 mmol), and 4 - dimethylaminopyridine (12 mg, 0.01 mmol) in 5 ml of N,N - dimethylformamide, add triethylamine (298 mg, 2.94 mmol), and react at 70 °C overnight. After the reaction is completed, extract with ethyl acetate and water. The organic phase is evaporated to dryness and directly used for the next step.

[0233] (e): Dissolve the crude product from the previous step, Compound 16 (262 mg, 2 mmol), and triphenylphosphine (524 mg, 2 mmol) in anhydrous tetrahydrofuran (5 ml). Under Ar protection, dropwise add diisopropyl azodicarboxylate (404 mg, 2 mmol) at 0 °C. After dropping, transfer to room temperature and react overnight. After the reaction is completed, evaporate to dryness, dissolve in 5 ml of methanol, then add 5 ml of 2N HCl / MeOH solution, stir at room temperature for 1 h, add water, neutralize with saturated sodium bicarbonate solution, extract with ethyl acetate. The organic phase is loaded onto a column and separated by column chromatography to obtain 98 mg of Compound CQ - 1253, with a three - step yield of 17%.

[0234] 1 1H NMR (400 MHz, DMSO) δ 14.23 (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).

[0235] Example 22: Preparation of Compound CQ - 1254

[0236]

[0237] Preparation of Compound 39:

[0238] (a): Mix Compound 35 (4.7 g, 20.6 mmol), Compound 36 (2 g, 10.3 mmol), cesium carbonate (10 g, 30.9 mmol), and tetrakis(triphenylphosphine)palladium (596 mg, 0.52 mmol) in a 100 ml reaction flask under Ar protection. Add 18 ml of a dioxane / water (5:1) mixed solvent and react at 100 °C overnight. Extract with ethyl acetate and water. Rotate the organic phase to dryness, then stir with 20 ml of PE:EA (1:1) for 1 h, filter by suction, and dry the filter cake to obtain 1.6 g of crude product Compound 37;

[0239] (b): Dissolve the crude product Compound 37 (910 mg, 3.64 mmol) obtained in the previous step and Compound 38 (1.03 g, 7.28 mmol) in 12 ml of dimethyl sulfoxide. Then add potassium carbonate (1.51 g, 10.92 mmol) and react at 100 °C overnight. Extract the organic phase with ethyl acetate and water. Rotate the organic phase to dryness, mix the sample, and separate by column chromatography to obtain 1.9 g of Compound 39 with a yield of 76%.

[0240] 1 H NMR (400 MHz, DMSO) δ 8.54 - 8.58 (m, 1H), 8.36 - 8.44 (m, 3H), 8.03 (d, J = 9.2 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.31–7.50 (m, 5H), 7.08 (d, J = 8.8 Hz, 2H), 5.14 (s, 2H).

[0241] Preparation of Compound 40:

[0242] (c): Dissolve Compound 39 (1 mg, 2.7 mmol) in 10 ml of trifluoroacetic acid and react at 50 °C for 4 h. After the reaction is complete, add water, neutralize with saturated sodium bicarbonate solution, extract with ethyl acetate. Rotate the organic phase to dryness, mix the sample, and separate by column chromatography to obtain 580 mg of Compound 40 with a yield of 77%.

[0243] 1 H NMR (400 MHz, DMSO) δ 9.49 (s, 1H), 8.54 (s, 1H), 8.39 (d, J = 9.2 Hz, 2H), 8.29 (s, 1H), 8.02 (d, J = 9.2 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H).

[0244] Preparation of Compound 42:

[0245] (d): Compound 40 (200 mg, 0.71 mmol) and compound 41 (586 mg, 2.13 mmol) were dissolved in 5 ml of acetonitrile. Cesium carbonate (1.15 g, 3.55 mmol) was added, and the mixture was refluxed at 80 °C overnight. After the reaction was completed, ethyl acetate and water were added for extraction. The organic phase was mixed with silica gel and separated by column chromatography to obtain 220 mg of compound 42 with a yield of 78%.

[0246] 1 H NMR (400 MHz, DMSO) δ 8.55 (s, 1H), 8.40 (d, J = 9.2 Hz, 2H), 8.38 (s, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.59 (t, J = 4.4 Hz, 4H), 2.71 (t, J = 5.6 Hz, 2H), 2.46 - 2.49 (m, 4H).

[0247] Preparation of Compound CQ - 1254

[0248] (e): Compound 42 (200 mg, 0.508 mmol) was dissolved in 2 ml of a mixed solvent of ethanol / water (4:1). Reductive iron powder (142 mg, 2.54 mmol) and ammonium chloride (217 mg, 4.06 mmol) were added, and the reaction was carried out at 80 °C for 1 h. After the reaction was completed, it was filtered through diatomaceous earth. Ethyl acetate and water were added to the filtrate. The organic phase was evaporated to dryness to obtain 150 mg of crude product 43, which was directly used for the next step.

[0249] (f): The crude product 43 (150 mg, 0.412 mg), compound 14 (194 mg, 0.618 mmol) and 4 - dimethylaminopyridine (5 mg, 0.04 mmol) were dissolved in 2 ml of N, N - dimethylformamide. Triethylamine (125 mg, 1.24 mmol) was added, and the reaction was carried out at 70 °C overnight. After the reaction was completed, ethyl acetate and water were added for extraction. The organic phase was mixed with silica gel and separated by column chromatography to obtain 110 mg of compound CQ - 1254 with a yield of 46%.

[0250] 11H NMR (400 MHz, DMSO) δ 9.76 (s, 1H), 9.00 (s, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.54 - 7.69 (m, 4H), 6.98 (d, J = 8.0 Hz, 2H), 6.92 (s, 1H), 4.11 (t, J = 5.6 Hz, 2H), 3.51 - 3.65 (m, 4H), 2.64 - 2.76 (m, 2H), 2.43 - 2.50 (m, 4H), 1.56 (s, 6H).

[0251] Example 23: Preparation of Compound CQ-1252

[0252]

[0253] Preparation of Compound 51

[0254] (a): Dissolve compound 44 (5 g, 32.9 mmol), benzyl bromide (6.8 g, 40 mmol), and potassium carbonate (6.8 g, 49 mmol) in 50 ml of acetone, and react at 60 °C overnight. After the reaction is completed, cool to room temperature, extract with ethyl acetate, and rotary evaporate to obtain 7.7 g of crude product 45, which is directly used for the next step without further purification.

[0255] (b): Dissolve compound 45 (7.7 g, 31.84 mmol) and 50% hydrazine hydrate (15.9 g, 318.2 mmol) in 100 ml of methanol and 50 ml of tetrahydrofuran, and react at 70 °C overnight. After the reaction is completed, rotary evaporate the solvent, extract with dichloromethane, and rotary evaporate to obtain 7.2 g of crude product 46, which is directly used for the next step without further purification.

[0256] (c): Dissolve compound 47 (2.76 g, 16.53 mmol) and HOBT (3.12 g, 23.14 mmol) in 200 ml of N,N-dimethylformamide, add EDCI (4.42 g, 23.14 mmol) at 0 °C, react at room temperature for 1 hour, then add compound 46 (4 g, 16.53 mmol), react at room temperature for 3 h, add water, filter by suction, and wash with ether to obtain 6.02 g of crude product compound 48, which is directly used for the next step without further purification.

[0257] (d): Dissolve compound 48 (6.02 g, 15.39 mmol) in 50 ml of thionyl chloride, react at 90 °C overnight under argon protection. After the reaction is completed, rotary evaporate thionyl chloride, slurry with dichloromethane, and filter by suction to obtain 4.91 g of crude product compound 49, which is directly used for the next step without further purification.

[0258] (e): Compound 49 (1.5 g, 3.84 mmol) and palladium / carbon (400 mg) were dissolved in 50 ml of methanol, ventilated with hydrogen, and reacted at room temperature overnight. After the reaction was completed, the mixture was filtered and dissolved in acetone. The filter cake was heated and filtered while hot to obtain 847 mg of crude product 50, which was used directly in the next step without further purification.

[0259] (f): Compound 50 (300 mg, 1.19 mmol), compound 14 (562.1 mg, 1.79 mmol), and DMAP (14.7 mg, 0.12 mmol) were dissolved in 6 ml of N,N-dimethylformamide, and triethylamine (361.2 mg, 3.57 mmol) was added. The mixture was reacted at 70°C overnight. After completion of the reaction, the mixture was extracted with ethyl acetate, dried by spin drying, and slurried with 5 ml of PE:EA (1:1). The mixture was filtered to obtain 150 mg of compound 51, with a yield of 29%.

[0260] 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).

[0261] Preparation of compound CQ-1252

[0262] (g): Compound 51 (150 mg, 0.34 mmol), compound 16 (89.2 mg, 0.68 mmol), and triphenylphosphine (178.4 mg, 0.68 mmol) were dissolved in 1 ml of tetrahydrofuran. A solution of DIAD (137.5 mg, 0.68 mmol) in tetrahydrofuran was added at 0°C. The mixture was allowed to react overnight at room temperature. After completion of the reaction, sodium bicarbonate solution and ethyl acetate were added for extraction. Silica gel was added to the organic phase and the sample was passed through a column to obtain 57 mg of compound CQ-12152 (yield 29%).

[0263] 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).

[0264] Example 24: Preparation of Compound CQ-1262

[0265]

[0266] Preparation of Compound 56

[0267] (a): Dissolve Compound 52 (2 g, 9.1 mmol), sodium azide (890.6 mg, 13.7 mmol), sodium ascorbate (90.1 mg, 0.46 mmol), copper(I) iodide (173.3 mg, 0.9 mmol), and N,N'-dimethylethylenediamine (123.4 mg, 1.4 mmol) in anhydrous ethanol / water (7:3), and react at 60 °C overnight. After the reaction is complete, extract with ethyl acetate and concentrate in vacuo to obtain 1.09 g of crude product 53, which is used directly in the next step without further purification.

[0268] (b): Dissolve Compound 53 (1.09 g, 8.07 mmol), 4-nitrophenylacetylene (1.19 g, 8.07 mmol), and copper(I) iodide (154.3 mg, 0.81 mmol) in 30 ml of N,N-dimethylformamide, and react at 60 °C. After the reaction is complete, extract with ethyl acetate and concentrate in vacuo to obtain 2.2 g of crude product 54, which is used directly in the next step without further purification.

[0269] (c): Dissolve Compound 54 (1 g, 3.54 mmol), Compound 55 (989.5 mg, 5.32 mmol), and cesium carbonate (3.46 g, 10.62 mmol) in 20 ml of N,N-dimethylformamide, and react at 60 °C. After the reaction is complete, extract with ethyl acetate, add silica gel to the organic phase, mix well, and chromatograph to obtain 550 mg of Compound 56, with a yield of 39.3%.

[0270] 1 H NMR (400 MHz, DMSO) δ 9.46 (s, 1H), 8.37 (d, J = 8.0 Hz, 2H), 8.20 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 4.19 (t, J = 5.2 Hz, 2H), 3.53 - 3.63 (m, 4H), 2.71 (t, J = 5.2 Hz, 2H), 2.37 - 2.49 (m, 4H).

[0271] Preparation of Compound CQ-1262

[0272] (d): Compound 56 (550 mg, 1.39 mmol), ammonium chloride (594.8 mg, 11.12 mmol) were dissolved in anhydrous ethanol / water (4:1). Iron powder (389.2 mg, 6.95 mmol) was added under stirring. The reaction was refluxed at 80 °C. After the reaction was completed, it was filtered while hot, extracted with ethyl acetate, and the solvent was evaporated to obtain 147 mg of crude product compound 57, which was directly used for the next step without further purification.

[0273] (e): Compound 57 (147 mg, 0.4 mmol), compound 14 (188.4 mg, 0.6 mmol), and DMAP (4.9 mg, 0.04 mmol) were dissolved in 3 ml of N,N-dimethylformamide. Triethylamine (121.4 mg, 1.2 mmol) was added. The reaction was carried out at 70 °C overnight. After the reaction was completed, it was extracted with ethyl acetate. The organic phase was mixed with silica gel and purified by column chromatography to obtain 139 mg of compound CQ-1262 with a yield of 59%.

[0274] 1 H NMR (400 MHz, DMSO) δ 9.74 (s, 1H), 9.12 (s, 1H), 8.97 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 9.2 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 6.93 (s, 1H), 4.18 (t, J = 5.6 Hz, 2H), 3.59 (t, J = 4.8 Hz, 4H), 2.73 (t, J = 5.6 Hz, 2H), 2.45 - 2.49 (m, 4H), 1.57 (s, 6H).

[0275] Example 25 Proliferation Inhibitory Activity of Compounds against BAF3 Model Cells with Different RET Mutation Backgrounds

[0276] The proliferation inhibitory activity of the compounds of the present invention against BAF3 model cells with different RET mutation backgrounds was tested by the CCK-8 method:

[0277] The compounds used for the control experiments were as follows:

[0278] Selpercatinib is an effective selective RET inhibitor and was purchased from Selleck.

[0279] The steps were as follows:

[0280] 1) Cell seeding: Various tumor cells in the logarithmic growth phase of the cells were seeded in different 96-well plates at the same density (3000 - 10000 cells / 100 μl / well).

[0281] 2) Preparation of working solution: Use the corresponding culture medium required for cell culture as the diluent (with or without the solvent DMSO), dilute the stock solutions of the test compound and the control compound to obtain a series of working solutions with a final concentration 3 times the desired concentration. The content of DMSO in each concentration group is the same as that in the solvent control group.

[0282] 3) Co-incubation: After inoculation for 24 hours, add 100 μl / well of the mother liquor of the series of compound concentrations to the 96-well plate, mix well and co-culture for 72 hours. There are at least 3 replicates in all groups, and 6 concentrations for each compound. Blank control group: Only add the culture medium, without adding cells and drugs, to exclude the interference of the culture medium on the colorimetric assay.

[0283] 4) Absorbance measurement: After aspirating the culture medium from the 96-well plate, add 10 μl of CCK-8 solution to each well. After co-culturing for 4 hours, shake well to make it uniform, and measure the absorbance values at A450 and A650 on the microplate reader.

[0284] 5) Data processing: Obtain the original data of A450 - A650, and calculate the cell viability of each treatment well (the calculation method is as follows); then input the cell viability data and its corresponding compound concentration into the GraphPad Prism 5 Demo software, and use the non-linear regression model to calculate the IC 50 value. Calculation of cell viability: Cell viability (%) = [(As - Ac) / (Ab - Ac)] × 100% (As: experimental well; Ab: solvent control well; Ac: blank well). The results are shown in Table 1.

[0285] Table 1 Proliferation inhibitory activity (half inhibitory concentration) of the compound on BAF3 model cells carrying different RET mutation backgrounds

[0286]

[0287] Note: "\ " means that this activity test was not carried out

[0288] As can be seen from the results in Table 1: The compounds of the present invention have strong inhibitory activity on the proliferation of BAF3 model cells carrying different RET mutation backgrounds.

[0289] Example 26 Pharmacokinetic experiment of compound CQ-1227

[0290] I. Preparation of control compound A:

[0291] (1) Preparation of compound WFK-001:

[0292]

[0293] Synthesis route:

[0294]

[0295] Step a: Preparation of Compound 59

[0296] Compound 58 (1.8 g, 7.53 mmol), hydrazine hydrate (22.59 mmol), and 20 ml of glacial acetic acid were mixed and refluxed at 80 °C until Compound 58 was basically converted. Water was added to the reaction system, and the mixture was extracted twice 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 59 (495 mg, yield 26.2%). ESI-MS m / z 252.1 (M+H) + .

[0297] Step b: Preparation of Compound 61

[0298] Compound 59 (495 mg, 1.97 mmol), phenyl (5-tert-butylisoxazol-3-ylcarbamate) (Compound 60) (768 mg, 3 mmol), DMAP (13 mg, 0.12 mmol), and triethylamine (598 mg, 5.91 mmol) were stirred in THF (15 mL) at 60 °C overnight. After the reaction was completed, the mixture was poured into water and extracted twice 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 / z 418.1 (M+H) + .

[0299] Step c: Preparation of WKF-001

[0300] Compound 61 (590 mg, 1.42 mmol), N-(2-chloroethyl)morpholine hydrochloride (Compound 55) (396 mg, 2.13 mmol), K2CO3 (588 mg, 4.26 mmol), and TBAI (52 mg, 0.14 mmol) were dissolved in 15 ml of DMF and heated at 60 °C until most of the starting materials were converted, then the reaction was stopped. Water was added to the reaction system, and the mixture was extracted twice 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 WKF-001 (230 mg, yield 31%).

[0301] 11H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 9.55 (s, 1H), 8.92 (s, 1H), 7.73 - 7.75 (m, 4H), 7.53 (d, J = 7.6 Hz, 2H), 7.00 - 7.02 (m, 3H), 6.53 (s, 1H), 4.11 (t, J = 5.4 Hz, 2H), 3.58 (t, J = 4.4 Hz, 4H), 2.69 (t, J = 5.6 Hz, 2H), 2.47 (t, J = 4.4 Hz, 4H), 1.30 (s, 9H). ESI-MS m / z 531.2 (M + H) + .

[0302] (2) Preparation of control compound A:

[0303]

[0304] The synthesis method was the same as that in Example 4.

[0305] 1 1H NMR (400 MHz, DMSO) δ 9.97 (s, 1H), 9.62 (s, 1H), 9.05 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.52 (s, 1H), 4.42 (t, J = 4.4 Hz, 2H), 3.96 - 4.05 (m, 2H), 3.74 (t, J = 12.0 Hz, 2H), 3.50 - 3.66 (m, 4H), 3.17 - 3.30 (m, 2H), 2.42 (s, 6H), 1.30 (s, 9H).

[0306] II. Pharmacokinetic experiment: After single intravenous injection or oral gavage of compound CQ-1227 or compound A to SD rats, 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 determined by LC-MS / MS and related parameters were calculated.

[0307] For intravenous injection, 3 male rats were selected, the dosing dose was 5 mg / Kg, the drug concentration was 1 mg / mL, and the dosing volume was 5 mL / Kg. The blood sampling time points were: 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h.

[0308] For oral administration, 3 male rats were selected, the dosing dose was 25 mg / Kg, the drug concentration was 2.5 mg / mL, and the dosing volume was 10 mL / Kg. The blood sampling time points were: 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h.

[0309] Blood samples were collected via the jugular vein, approximately 0.20 mL for each sample, anticoagulated with sodium heparin, and placed on ice after collection. Plasma was separated by centrifugation within 1 hour (centrifugation conditions: 6800 g, 6 minutes, 2 - 8 °C). Plasma samples were stored in a -80 °C refrigerator before analysis.

[0310] Based on the 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, as well as their mean values and standard deviations. The results are shown in Table 2.

[0311] Table 2 Pharmacokinetic experimental results of compound CQ-1227

[0312]

[0313]

[0314] As can be seen from the above table, compared with the corresponding control compound A (the difference between the two is that the trifluoromethyl group is replaced by a methyl group), compound CQ-1227 has higher blood drug concentrations and longer half-lives when injected and orally administered. It can be seen that the introduction of the trifluoromethyl group in compound CQ-1227 has a better improvement effect on pharmacokinetic properties compared with control compound A.

[0315] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the following embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as within the scope described in this specification.

[0316] The above-described embodiments merely represent several implementation manners of the present invention. Their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the patent for the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention should be subject to the appended claims.

Claims

1. A compound having a urea structure represented by formula (IX), formula (X) or formula (XI), or a pharmaceutically acceptable salt or stereoisomer thereof: Wherein, X1 is selected from: N, CR; A1, A2, B1, B2, D1, D2, E1 and E2 are each independently selected from: CR5; Z is selected from: CR'; R1 is selected from: Wherein, m is 0, 1, 2 or 3, and n is 0, 1, 2 or 3; Each Z1 is independently selected from: NR 10 , O, S or CR 11 R 12 ; Each Z3 is selected from: O or S; Each R2 is independently selected from: H, C1-C8 alkyl, C1-C8 alkyl acyl, C1-C8 alkoxycarbonyl; R3 and R4 are both methyl; Each R5 is independently selected from: H, halogen, C1-C3 alkyl, C1-C3 alkoxy; Each R6 is independently selected from: H, C1-C3 alkyl; Each of R7 and R8 is independently selected from: H, C1-C3 alkyl, C1-C3 alkylamino, hydroxy-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkylamino-substituted C1-C3 alkyl, C3-C6 cycloalkyl, or R7 and R8 together with the N atom to which they are attached form one or more R 13 substituted or unsubstituted 3- to 8-membered heterocyclic group; Each R 10 is independently selected from: H, C1-C8 alkyl; R 11 and R 12 are both H; Each R 13 is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, trifluoromethyl, C1-C6 alkoxy, C1-C8 alkyl; Each R is independently selected from: H, halogen, C1-C3 alkyl; Each R' is independently selected from: H, halogen, C1-C3 alkyl.

2. The compound having a urea structure or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 1, characterized in that, Having a structure represented by the following formula (A), formula (B) or formula (C): Wherein, each p is independently selected from: an integer between 0 and 4; Z1 is O or S; X1 is N or CR.

3. The compound having a urea structure or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 2, characterized in that, R6 is H; the sum of m and n is selected from: 0, 1, 2, 3.

4. The compound having a urea structure or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein R6 is selected from: H.

5. The compound having a urea structure or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 1, wherein Each of R7 and R8 is independently selected from: H, C1-C3 alkyl, or R7 and R8 together with the N atom to which they are attached form one or more substituted or unsubstituted 5- to 6-membered heterocyclic groups. 13 substituted or unsubstituted 5- to 6-membered heterocyclic groups.

6. The compound having a urea structure or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 5, wherein Each of R7 and R8 is independently selected from: H, methyl, ethyl, propyl, or R7 and R8 together with the N atom to which they are attached form one or more R 13 Substituted or unsubstituted morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl.

7. The compound having a urea structure or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein R1 is selected from:

8. The compound containing a urea structure or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1-7, characterized in that, Each R2 is independently selected from: H, C1-C3 alkyl, C1-C3 alkyl acyl, C1-C3 alkoxycarbonyl.

9. The compound having a urea structure or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 8, wherein Each R2 is independently selected from: H, C1-C3 alkoxycarbonyl.

10. The compound having a urea structure according to claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, characterized in that, Having a structure represented by the following formula (D), formula (E) or formula (F): Wherein, each p is independently selected from: 0, 1 or 2; X1 is N or CH; Each R5 is independently selected from: H, fluorine, bromine, chlorine, C1-C3 alkyl, C1-C3 alkoxy; Each R'5 is independently selected from: H, fluorine, C1-C3 alkoxy.

11. The compound containing a urea structure or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-7, characterized in that, Each R 13 is independently selected from: H, hydroxy, amino, cyano, nitro, halogen, trifluoromethyl, C1-C3 alkoxy, C1-C3 alkyl.

12. The compound with a urea structure according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Selected from the following compounds:

13. Use of the compound having a urea structure according to any one of claims 1-12, or a pharmaceutically acceptable salt or stereoisomer thereof, in the preparation of a RET kinase inhibitor.

14. The application according to claim 13, wherein The RET kinase is wild-type RET kinase, RET kinase carrying V804M mutation, RET kinase carrying G810C mutation and / or RET kinase carrying G810R mutation.

15. A pharmaceutical composition for preventing and / or treating tumors, characterized in that, Prepared from an active ingredient and a pharmaceutically acceptable excipient, and the active ingredient comprises the compound having a urea structure according to any one of claims 1-12, or a pharmaceutically acceptable salt or stereoisomer thereof.

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