Aryl-substituted degraders of CDK12 / 13, their preparation methods, and pharmaceutical compositions and uses thereof

Abstract

The present invention relates to a degrading agent for cyclin-dependent kinase 12 / 13 (CDK12 / 13) containing an aryl substituent, a preparation method thereof, and pharmaceutical compositions and uses thereof. The CDK12 / 13 degrading agent of the present invention has a structure represented by formula (I). The compound can be used as a protein kinase degrading agent, and can effectively and highly selectively degrade CDK12 / 13 protein and inhibit the proliferation, migration, and invasion of various tumor cells. [Formula 1] JPEG2026507677000196.jpg33164

Description

[Technical Field]

[0001] The present invention belongs to the field of chemicals, and in particular relates to a degrading agent for cyclin-dependent kinase 12 / 13 (CDK12 / 13), and pharmaceutical compositions and uses thereof. [Background technology]

[0002] Protein kinases are key regulators of cellular function and constitute one of the largest and most functionally diverse gene families. Protein kinases direct the activity, localization, and overall function of many proteins through the phosphorylation of substrate proteins, and are involved in almost all cellular activities. Abnormalities in the expression, activation, and localization of protein kinases are closely associated with the development and progression of various diseases and are important drivers of various disorders, such as tumors and inflammation. As of December 31, 2020, the FDA has approved a total of 62 kinase inhibitors as marketed drugs. Research has shown that non-kinase functions of proteins play an important role in diseases such as tumors. Non-kinase functions of kinases such as CDK6, FAK, EGFR, PIPK3, PDK1, BRAF, CRAF, CHK2, ZAP70, AKT, and Aurora kinase A have been reported in the literature. Therefore, simply inhibiting kinase activity does not completely inhibit the non-kinase functions of kinases, which can lead to potential adverse effects, such as low efficacy and drug resistance. Therefore, the development of protein degraders is expected to comprehensively inhibit the enzymatic activity of kinases and non-kinase functions, thereby exerting powerful therapeutic effects. Protein degraders based on the PROTAC principle are currently the most successful and mature protein degradation strategies and have been successfully used to develop degraders against multiple kinases and other targets.

[0003] PROTACs are a class of small molecule compounds that can specifically recognize and induce the degradation of target proteins. Their molecular structure consists of three parts: a target protein-recognition ligand, a linker, and an E3-recognition ligand. The advantage of PROTACs is that they not only effectively inhibit the kinase activity of target proteins, but also rapidly degrade and eliminate them. In theory, only catalytic amounts of the drug are required to degrade almost all proteins in cells (including membrane proteins), resulting in high safety, drug resistance, and broad applicability. Currently, degraders for target proteins such as ERR, ABL, BET, and CDK4 / 6 have been successfully developed. These results indicate that they can not only treat gene-driven tumor growth but also overcome drug resistance to inhibitors. In 2018, Pfizer announced an investment of US$830 million in the research and development of protein degradation drugs based on PROTAC technology. In March 2019, WuXi AppTec's partner, Arinas, announced that its androgen receptor-targeting protein degrader, ARV-110, had entered clinical trials, making it the world's first protein degrader to enter clinical research.

[0004] CDK12 / 13 (cyclin-dependent kinase 12 / 13) is a member of the cyclin-dependent kinase family (CDK) of serine / threonine protein kinases and performs its biological functions by forming a complex with cyclin K. CDK12 / 13 contain 1,490 and 1,512 amino acids, respectively, and share 46% homology. The kinase domain consists of 300 amino acids with a high homology of 92%. CDK12 / 13 phosphorylates the C-terminal domain (CTD) of RNA polymerase II (RNA Pol II) and forms a complex with cyclin K. The CTD is a highly repetitive sequence consisting of seven amino acids (YSPTSPS). The human CTD contains 52 repeat units. CDK12 / 13 phosphorylates mainly Ser2 and regulates transcription and post-transcriptional mRNA processing. Genetic studies have shown that CDK12 promotes transcription of full-length gene products by inhibiting the cleavage of intronic polyadenylation sites, and that many homologous recombination repair genes (e.g., BRCA1 / 2, ATM, ATR, FANCD2, and FANCI) contain more intronic polyadenylation sites. Therefore, the expression of these genes is more sensitive to the loss or inhibition of CDK12. Compared to other transcriptional CDKs, CDK12 / 13 contains an additional N-terminal arginine / serine-rich (RS) motif commonly found in proteins involved in pre-mRNA splicing. Proline-rich motif (PRIM) motifs are also found at the N- and C-termini and may function as binding sites for proteins containing SH3, WW, or actin-binding protein (profilin) ​​domains. These structures suggest that CDK12 / 13 may have non-kinase functions (e.g., protein-protein interactions) and may play important roles in mRNA splicing and 3'-end processing of mRNAs. Therefore, using only CDK12 / 13 kinase inhibitors as probe tool molecules to study the biological functions of CDK12 / 13 is far from sufficient.The use of proteolysis-targeting chimeric molecules (PROTACs) to induce CDK12 / 13 degradation while simultaneously inhibiting its kinase and non-kinase functions has gained increasing interest among researchers in recent years, as it holds great potential in studying the biological functions of CDK12 / 13 and treating diseases. Summary of the Invention

[0005] Based on this, the present invention provides a class of trans-1,4-cyclohexanediamine compounds and their use as CDK12 / 13 degraders, which can effectively and highly selectively degrade CDK12 / 13 protein kinases and inhibit the proliferation, migration, and invasion of various tumor cells.

[0006] In a first aspect of the present invention, provided is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a prodrug molecule thereof: [ka] wherein Z is CH or CO; V is [ka] is selected from the group consisting of X and Y are each independently selected from the group consisting of N, CH, or CR3, and R3 is selected from the group consisting of halogen, cyano, hydroxyl, amino, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkoxy, C3-C8 cycloalkyl, or 3- to 8-membered heterocyclyl; B is [ka] each of U and W is independently selected from the group consisting of N or CH; and each of m, p, m', and p' is independently 0, 1, 2, or 3; Ring A is [ka] is selected from the group consisting of Q and W are each independently selected from CH or N; R' is independently selected from hydrogen, halogen, cyano, hydroxy, substituted hydroxy, amino, substituted amino, C1-C5 alkyl, halogenated C1-C5 alkyl, C1-C5 alkoxy, halogenated C1-C5 alkoxy, or C3-C8 cycloalkyl; and when Q and W are independently selected from CH, R' may be a substituent of Q or W; D, E, F, and G are each independently selected from the group consisting of CH, N, or CR6, where R6 is selected from the group consisting of halogen, trifluoromethyl, hydroxy, cyano, amino, methyl, methoxy, or trifluoromethoxy; R1 is selected from the group consisting of H, -NHR7, -OR7, or -(C(R9)R8)R7; R7 is -R 10 , -CH2R 10 or -(CH2)2R 10 and R8 and R9 are each independently selected from the group consisting of hydrogen, halogen, cyano, methyl, halomethyl, methoxy, halomethoxy, ethyl, haloethyl, ethoxy, haloethoxy, hydroxy, amino, or a 3-8 membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from O, S, or N; or R8 and R9 together with the C atom to which they are attached form a 3- to 7-membered heterocyclic ring; R 10 teeth, 1) Cyano, C1-C5 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C3-C 10 cycloalkyl, a substituted or unsubstituted 5- to 12-membered aromatic ring, or a substituted or unsubstituted 3- to 12-membered heterocyclic ring; 2) [ka] is selected from the group consisting of Q1, Q2, Q3, Q4 and Q5 each independently represent CH, N or CR 11 is selected from Each R 11 is independently selected from the group consisting of halogen, cyano, hydroxy, amino, nitro, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, or C3-C8 cycloalkyl; R2 is H, C1-C3 alkyl, [ka] is selected from the group consisting of B, [ka] is selected from the group consisting of NH, O, CO, or CH; each of U and W is independently selected from the group consisting of N or CH; and each of m, p, m', and p' is independently 0, 1, 2, or 3; The linker is [ka] and where: R L1 , R L2 , R L3 , R L4 and R L5 are the same or different and each independently represent a chemical bond, CH2, CHD, CD2, C=O, O, NH, SO, SO2, P=O, NHCO, NHSO2, OCH2, OCH2CH2, CH2OCH2, NHCH2, NMeCH2, NHCH2CH2, NMeCH2CH2, CH2NHCO, NHCOCH2, [ka] and selected from the substituted or unsubstituted groups in the group consisting of: R L6is a ring, optionally selected from the following structures: [ka] [ka] [ka] Each n is independently 0, 1, 2, 3, 4, 5, or 6; each of r and m is independently 0, 1, or 2; and each of U and W is independently selected from the group consisting of N or CH. p L1 , p L2 , p L3 , p L4 , p L5 and p L6 is independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0007] B is [ka] and each of m, p, m', and p' is independently 0, 1, 2, or 3; The linker is [ka] and where: R L1 , R L2 , R L3 , R L4 , R L5 and R L6 are the same or different and each independently represent a chemical bond, CH2, CHD, CD2, C=O, O, NH, SO, SO2, P=O, NHCO, NHSO2, OCH2, OCH2CH2, CH2OCH2, NHCH2, NMeCH2, NHCH2CH2, NMeCH2CH2, CH2NHCO, NHCOCH2, [ka] [ka] [ka] [ka] [ka] and selected from the substituted or unsubstituted groups in the group consisting of: each n is independently 0, 1, 2, 3, 4, 5, or 6; each of r and m is independently 0, 1, or 2; each of U and W is independently selected from the group consisting of N or CH; p L1 , p L2 , p L3 , p L4 , p L5 and p L6 is independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0008] In some embodiments, V is [ka] is selected from the group consisting of:

[0009] In some embodiments, X and Y are each independently selected from the group consisting of N, CH, or CR; R3 is selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, or halogenated C1-C3 alkoxy.

[0010] In some embodiments, B is [ka] selected from the group consisting of NH, O, or CO; Each of U and W is independently selected from the group consisting of N or CH; and each of m, p, m', and p' is independently 0, 1, 2, or 3.

[0011] In some embodiments, ring A is [ka] is selected from W is selected from the group consisting of CH or N.

[0012] R' is optionally selected from hydrogen, halogen, cyano, hydroxy, amino, C1-C5 alkyl, halogenated C1-C5 alkyl, C1-C5 alkoxy, halogenated C1-C5 alkoxy, or C3-C8 cycloalkyl.

[0013] In some embodiments, D, E, F, and G are CH or CR6, and R6 is selected from the group consisting of halogen.

[0014] In some embodiments, R1 is -NHR7 and R7 is -CH2R 10 and R 10 is defined as above.

[0015] In another preferred embodiment, R 10 is cyano, C1-C5 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C3-C 10 Cycloalkyl, 4- to 7-membered heterocyclyl, or C6-C 10 aryl, wherein the aryl is selected from the group consisting of one or more CR 11 is replaced by R 11 is defined as above.

[0016] In some embodiments, B, [ka] When selected from the group consisting of NH, O, or CO, The linker is [ka] is selected from the group consisting of B, [ka] wherein the linker is a chemical bond, [ka] wherein each n is independently 0, 1, 2, 3, 4, 5, or 6; each of r and m is independently 0, 1, or 2; and each of U and W is independently selected from the group consisting of N or CH.

[0017] In some embodiments, the compound has a structure according to Formula (II): [ka] In the formula, B is [ka] wherein each of U and W is independently selected from the group consisting of N or CH; and each of m, p, m', and p' is independently 0, 1, 2, or 3; R ’ is optionally selected from hydrogen, halogen, cyano, hydroxy or amino; R 11 and R6 is optionally selected from hydrogen or halogen; X and Y are independently selected from CH, N, or CR3, where R3 is selected from halogen, cyano, hydroxy, or amino; Z is optionally selected from CH2 or CO.

[0018] In some embodiments, the compound is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka]

[0019] In a second aspect of the present invention, provided is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a prodrug molecule thereof: [ka] wherein Z is selected from the group consisting of CH or CO; V is [ka] is selected from the group consisting of X and Y are selected from the group consisting of N, CH, or CR3, and R3 is selected from the group consisting of halogen, cyano, hydroxyl, amino, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkoxy, C3-C8 cycloalkyl, or 3- to 8-membered heterocyclyl; B is [ka] each of U and W is independently selected from the group consisting of N or CH; and each of m and p is independently 0, 1, or 2; Ring A is [ka] is selected from the group consisting of M and T are each independently selected from the group consisting of N or CR4; I, J, and K are each independently selected from the group consisting of N, O, S, CR4, and NR4; R4 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, C1-C5 alkyl, halogenated C1-C5 alkyl, C1-C5 alkoxy, halogenated C1-C5 alkoxy, C3-C8 cycloalkyl, -CH2R5, -(CH2)2R5, -(CH2)3R5, or 3-8 membered heterocyclyl; R5 is selected from the group consisting of cyano, hydroxy, amino, C3-C8 cycloalkyl, or 3- to 8-membered heterocyclyl; D, E, F, and G are each independently selected from the group consisting of CH, N, or CR6, where R6 is selected from the group consisting of halogen, trifluoromethyl, hydroxy, cyano, amino, methyl, methoxy, or trifluoromethoxy; R1 is selected from the group consisting of H, -NHR7, -OR7, or -(C(R9)R8)R7; R7 is -R 10 , -CH2R 10 or -(CH2)2R 10 and R8 and R9 are each independently selected from the group consisting of hydrogen, halogen, cyano, methyl, halomethyl, methoxy, halomethoxy, ethyl, haloethyl, ethoxy, haloethoxy, hydroxy, amino, or a 3-8 membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from O, S, or N; or R8 and R9 together with the C atom to which they are attached form a 3- to 7-membered heterocyclic ring; R 10 teeth, 1) Cyano, C1-C5 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C3-C 10 cycloalkyl, a substituted or unsubstituted 5- to 12-membered aromatic ring, or a substituted or unsubstituted 3- to 12-membered heterocyclic ring; 2) [ka] is selected from the group consisting of Q1, Q2, Q3, Q4 and Q5 each independently represent CH, N or CR 11 is selected from Each R 11 is independently selected from the group consisting of halogen, cyano, hydroxy, amino, nitro, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, or C3-C8 cycloalkyl; R2 is H, C1-C3 alkyl, [ka] is selected from the group consisting of The linker is [ka] and R L1 ~R L6 are the same or different and each independently represent a bond, CH2, CHD, CD2, C=O, O, NH, SO, SO2, P=O, NHCO, NHSO2, OCH2, OCH2CH2, CH2OCH2, NHCH2, NMeCH2, NHCH2CH2, NMeCH2CH2, CH2NHCO, NHCOCH2, [ka] [ka] [ka] [ka] and selected from the substituted or unsubstituted groups in the group consisting of: Each n is independently 0, 1, 2, 3, 4, 5, or 6; each of r and m is independently 0, 1, or 2; and each of U and W is independently selected from the group consisting of N or CH. The substitutions include hydrogen, deuterium, C1-C 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, halogenated C1-C 18 Alkylhydroxy, C3-C 20 Cycloalkyl, C1-C 18 Alkoxy, deuterated C1-C 18 Alkoxy, halogenated C1-C 18 Alkoxy, C6-C 14 refers to substitution with one or more groups selected from the group consisting of aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amino, amido, sulfonamido, or ureido; p L1 ~p L6 are independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0020] In some embodiments, V is [ka] is selected from the group consisting of:

[0021] In some embodiments, X and Y are each independently selected from the group consisting of N, CH, or CR; R3 is selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, or halogenated C1-C3 alkoxy.

[0022] In some embodiments, B is [ka] selected from the group consisting of NH, O, or CO; Each of U and W is independently selected from the group consisting of N or CH, and each of m and p is independently 0 or 1.

[0023] In some embodiments, ring A is [ka] is selected from the group consisting of T is selected from the group consisting of CH or N.

[0024] In some embodiments, R4 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, C1-C5 alkyl, halogenated C1-C5 alkyl, C1-C5 alkoxy, halogenated C1-C5 alkoxy, C3-C8 cycloalkyl, -CH2R5, -(CH2)2R5, -(CH2)3R5, or 3-8 membered heterocyclyl.

[0025] In some embodiments, D, E, F, and G are CH.

[0026] In some embodiments, R1 is -NHR7, R7 is -CH2R 10 and R 10 is defined as above.

[0027] In another preferred embodiment, R 10 is cyano, C1-C5 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C3-C 10 Cycloalkyl, 4- to 7-membered heterocyclyl, or C6-C 10 aryl, wherein the aryl is selected from the group consisting of one or more CR 11 is replaced by R 11 is defined as above.

[0028] In some embodiments, the linker is [ka] wherein each n is independently 0, 1, 2, 3, 4, 5, or 6; each of r and m is independently 0, 1, or 2; and each of U and W is independently selected from the group consisting of N or CH.

[0029] In another preferred embodiment, the linker is [ka] is selected from the group consisting of Each n is independently 0, 1, 2, 3, 4, 5, or 6; each of r and m is independently 0, 1, or 2; and each of U and W is independently selected from the group consisting of N or CH.

[0030] In some embodiments, the compound has a structure represented by Formula (II) or Formula (III): [ka] wherein U and W are independently selected from CH or N; X and Y are independently selected from CH, N, or CR; Z is optionally selected from CH or CO; n and m are independently selected from 0 or 1.

[0031] In some embodiments, the compound is selected from the group consisting of: [ka] [ka] [ka] [ka]

[0032] In a third aspect of the present invention, there is provided a method for producing a medicament for the treatment of pulmonary arthritis, comprising: A pharmaceutical composition comprising (1) as an active ingredient, a compound of the first or second aspect of the present invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof, and, optionally, (2) a pharmaceutically acceptable carrier.

[0033] In a fourth aspect of the invention, there is provided the use of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or a pharmaceutical composition of the third aspect of the invention, for the preparation of an agent for degrading CDK12 / 13 protein kinases.

[0034] In a fifth aspect of the invention, there is provided the use of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or a pharmaceutical composition of the third aspect of the invention, for the preparation of a medicament for the prevention and / or treatment of a disease mediated by CDK12 / 13 serine / threonine protein kinases.

[0035] In some embodiments, the disease mediated by CDK12 / 13 serine / threonine protein kinase is selected from the group consisting of prostate cancer, breast cancer, uterine cancer, ovarian cancer, non-small cell lung cancer, small cell lung cancer, Ewing's sarcoma, lung adenocarcinoma, squamous cell lung cancer, pancreatic cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumor, colon cancer, rectal cancer, or glioma.

[0036] It is understood that within the scope of the present invention, the above-mentioned technical features and the technical features specifically described below in the present invention (e.g., in the Examples) may be combined with each other to form novel or preferred technical solutions that are not repeated one by one due to space limitations. [Brief explanation of the drawings]

[0037] [Figure 1](A) WB results of CDK12 and CDK13 protein degradation after 15 hours of treatment of MDA-MB-231 cells with 0.1 μM of several compounds. (B) WB results of CDK12 and CDK13 protein degradation after 15 hours of treatment of MDA-MB-231 cells with 0.3 μM of several compounds. (C) CDK12 / 13 levels obtained by quantifying the intensity values ​​of the bands in the WB image (Figure A), with DMSO as the reference standard. (D) CDK12 / CDK13 levels obtained by quantifying the intensity values ​​of the bands in the WB image (Figure B), with DMSO as the reference standard. [Figure 2] (A) WB measurement of the time course of CDK12 and CDK13 protein degradation in MDA-MB-231 cells by representative compounds. (B) WB measurement of intracellular CDK12 / 13 protein levels after 15 minutes of treatment of MDA-MB-231 cells with different concentrations of representative compounds. [Figure 3] 1 shows the results of measuring the inhibitory activity of compounds against triple-negative breast cancer cells MDA-MB-231. [Figure 4] (A) WB results of CDK12 and CDK13 protein degradation after 6 hours of treatment of 22RV1 cells with several compounds at a concentration of 500 nM. (B) Compound YJZ9069 dose-dependently degrades CDK12 and CDK13 in 22RV1 cells and dose-dependently inhibits the phosphorylation of serine 2 (phoSer2) in the C-terminal domain of RNA polymerase II (RNA Pol II). (C) WB results of CDK12 and CDK13 protein degradation after 6 hours of treatment of LnCap cells with several compounds at a concentration of 500 nM. (D) Protein levels were measured by quantifying the intensity values ​​of the bands in the WB images (Figures A and C), using DMSO as a reference standard. [Figure 5]1 shows the results of WB measurement of intracellular CDK12 and CDK13 protein levels after treating 22RV1 cells with different concentrations of representative compounds YJZ9069, YJZ1201, YJZ1202, YJZ1203, YJZ1204, YJZ1097, YJZ1205, and YJZ1206 for 6 hours. [Figure 6] 1 shows the results of measuring the growth inhibitory activity of compounds against the prostate cancer cell line VCap. DETAILED DESCRIPTION OF THE INVENTION

[0038] After extensive and thorough research, the present inventors unexpectedly discovered a class of trans-1,4-cyclohexanediamine compounds, and after carrying out a series of biological activity tests, found that the compounds have excellent CDK12 / 13 inhibitory properties, and based on this, the present invention was made.

[0039] In the following examples of the present invention, the experimental methods for which specific conditions are not clearly indicated are generally carried out according to general conditions or conditions recommended by manufacturers. The various general chemical reagents used in the examples are all commercially available products.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art of the present invention. The terms used in the specification of the present invention are for the purpose of describing specific examples only and are not used to limit the present invention.

[0041] As used herein, the terms "comprise" and "have," and any variations thereof, are intended to include a non-exclusive inclusion. For example, a process, method, apparatus, product, or device comprising a series of steps is not limited to the recited steps or modules, but may optionally further include unrecited steps, or may optionally further include other steps inherent to such process, method, product, or device.

[0042] The term "multiple" as used herein refers to two or more than two. The term "and / or" represents a relation between combinations, meaning that three relationships can exist. For example, A and / or B can mean three situations: A exists alone, A and B both exist, or B exists alone. The symbol " / " generally means that there is an "or" relationship between the combinations.

[0043] In the compounds of the present invention, any variable (e.g., R 10 or R 11 ) occurs more than once in any constituent, the definition of that variable at each occurrence is independent of its definition at each other occurrence. Similarly, combinations of substituents and variables are permissible so long as such combinations result in stable compounds. Lines drawn from substituents to ring systems mean that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, it is meant that such bond is attached only to any suitable carbon atom on the adjacent ring. It is understood that one of ordinary skill in the art can select substituents and substitution patterns for compounds of the present invention to provide chemically stable compounds that are readily synthesized from readily available starting materials according to techniques in the art and the methods described below. When a substituent itself is substituted with multiple groups, it is understood that these groups may be on the same or different carbon atoms as long as the structure is stable.

[0044] As used herein, the term "alkyl" is intended to include branched or straight-chain saturated aliphatic hydrocarbon radicals having the specified number of carbon atoms. For example, the "C1-C8" in "C1-C8 alkyl" is defined to include groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms in a straight or branched arrangement. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon radical having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.

[0045] As used herein, the term "alkenyl" includes straight-chain or branched alkenyl groups. For example, C2-C6 alkenyl refers to straight-chain or branched alkenyl groups having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, etc.

[0046] As used herein, the term "alkynyl" includes straight-chain or branched alkynyl groups. For example, C2-C6 alkynyl refers to a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, etc.

[0047] As used herein, the term "cycloalkyl" refers to a cyclic saturated aliphatic hydrocarbon radical having a specified number of carbon atoms. For example, C3-C 10 Alkenyl refers to a cyclic saturated aliphatic hydrocarbon radical having 3 to 10 carbon atoms. It can be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Bicyclic ring forms, such as bridged or spirocyclic forms, are also possible.

[0048] As used herein, the term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or partially saturated cyclic group having a specified number of ring atoms (e.g., 3 to 10 ring atoms), where 1 to 3 of the atoms are heteroatoms selected from N, S, and O. It can be a monocyclic ring, a bicyclic ring, or a polycyclic ring, e.g., a fused ring, a bridged ring, or a spirocyclic ring. Specific examples can be oxetanyl, azetanyl, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuryl, morpholinyl, pyrrolidinyl, and the like.

[0049] As used herein, the term "alkylamino" refers to an amino group substituted with an alkyl group. For example, "C1-C6 alkylamino" refers to an amino group substituted with a C1-C6 alkyl group, which may be mono- or di-substituted, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, ditert-butylamino, etc.

[0050] As used herein, the term "alkyloxy" refers to a group having an alkyl-oxy structure. For example, "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like.

[0051] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced with a halogen, said alkyl group being defined above.

[0052] As used herein, the term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms have been replaced with a halogen, wherein the alkoxy group is defined as above.

[0053] As will be understood by those skilled in the art, as used herein, "halogen" is intended to include F, Cl, Br, and I. Preferably, the halogen or halogen atom is selected from F, Cl, and Br. "Halogenated" refers to substitution with an atom selected from F, Cl, Br, and I.

[0054] Unless otherwise specified as "substituted or unsubstituted", groups in the present invention include halogen, cyano, nitro, hydroxy, amino, C1-C6 alkyl-amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C1-C6 alkoxy, allyl, benzyl, C6-C 12 It may be substituted with a substituent selected from the group consisting of aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 cycloalkyl-carbonyl, C1-C6 alkyl-sulfonyl, and the like.

[0055] The present invention includes the free form of the compound of Formula (I) (as used herein, Formula (I) includes Formula (II)), as well as pharmaceutically acceptable salts, stereoisomers, and prodrug molecules thereof. The term "free form" refers to the compound in non-salt form. The pharmaceutically acceptable salts encompassed include not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the free form of the compound of Formula (I) or Formula (II). The free form of the specific salt of the compound can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous NaOH, potassium carbonate, ammonia, and sodium bicarbonate. While the free form differs somewhat from the respective salt forms in some physical properties, such as solubility in polar solvents, for purposes of the present invention, such acid and base salts are otherwise pharmaceutically equivalent to the respective free form.

[0056] The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic or acidic moiety according to conventional chemical methods. Generally, salts of alkaline compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric amount or excess amount of an inorganic or organic acid in the desired salt form 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.

[0057] Therefore, the pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting the alkali compounds of the present invention with inorganic or organic acids. For example, the conventional non-toxic salts include salts prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitric acid, as well as 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-acetoxymonobenzoic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, or trifluoroacetic acid.

[0058] When the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts obtained from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts, zinc salts, etc., with ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts being particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary 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, aminoethanol, ethanolamine, ethyldiamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0059] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '1977:66:1-19, describes in further detail the preparation of the above and other exemplary pharmaceutically acceptable salts.

[0060] Unless otherwise specified, the structural formulae depicted in the present invention are intended to include all isomers (e.g., enantiomers, diastereomers, and geometric (or conformational) isomers), e.g., R and S configurations containing asymmetric centers, (Z) and (E) isomers containing double bonds, etc. Thus, the individual stereochemical isomers of the present compounds as enantiomers, diastereomers, or geometric (or conformational) isomers, or mixtures thereof, are within the scope of the present invention.

[0061] As used herein, the term "tautomer" means structural isomers of different energy that can interconvert across a low energy barrier. For example, proton tautomers (i.e., prototropic) include interconversions via proton migration, e.g., 1H-indazole and 2H-indazole. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0062] As used herein, the term "solvate" refers to a complex in which a compound of the invention is coordinated with solvent molecules in a specific ratio.

[0063] As used herein, the term "hydrate" refers to a complex in which a compound of the present invention is coordinated with water.

[0064] The compounds of the present invention may also be in prodrug form. As used herein, the term "prodrug" refers to a compound that produces an active compound through metabolic processes (e.g., in vivo or in vitro). In some embodiments, a prodrug may be inactive or have lower activity than the free drug, but may provide favorable therapeutic, administration, or metabolic properties. Exemplary prodrug moieties of the present invention may be linked to the free drug through the hydroxy, amino, phosphate, or phosphorothioate backbone of the nucleotide, or may include an ester, carbamate, carbonyl, thioester, amide, isocyanate, urea, thiourea, or other physiologically acceptable metabolically labile moiety. In some embodiments, the prodrug is activated by enzymatic hydrolysis.

[0065] The present disclosure also includes isotopically labeled compounds which are the same as compounds of formula (I) (including compounds of formula (II)), except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes suitable for incorporation into compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 31 P, 35 S, 18 F and 36 Heavy isotopes (e.g., deuterium, i.e., 2 Heavy isotopes may be preferred in some circumstances, as substitution with H) may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. The compounds can be combined with positron-emitting isotopes for medical imaging and positron emission tomography (PET) studies to examine receptor distribution. Suitable positron-emitting isotopes that can be incorporated into compounds of formula (I) or formula (II) include: 11 C. 13 N, 15 O and 18 F. Isotopically labeled compounds of formula (I) or formula (II) can generally be prepared by following conventional techniques known to those skilled in the art or methods similar to those described herein by substituting the appropriate isotopically labeled reagent for the non-isotopically labeled reagent.

[0066] The compounds disclosed herein may exist in solvated and unsolvated forms with pharmaceutically acceptable solvents, such as water or ethanol, and the present invention is intended to encompass both solvated and unsolvated forms. In embodiments, the compounds are amorphous. In embodiments, the compounds are a single polymorph. In another embodiment, the compounds are a mixture of polymorphs. In another embodiment, the compounds are in a crystalline form.

[0067] Pharmaceutical compositions and methods of administration Because the compounds of the present invention are CDK12 / 13 protein degraders, the compounds and their pharmaceutically acceptable salts, as well as other compound forms disclosed herein, can be included in pharmaceutical compositions useful for the treatment, prevention, and alleviation of diseases associated with CDK12 / 13 activity.

[0068] The pharmaceutical composition of the present invention contains an effective amount, e.g., a safe and effective amount, of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. The "effective amount" refers to an amount sufficient to induce a desired biological response (e.g., treatment of a disorder). The "safe and effective amount" refers to an amount of compound sufficient to significantly improve a condition without causing severe side effects. Generally, the pharmaceutical composition contains 1-3000 mg of the compound of the present disclosure per dose (active substance dose ranging from 3-30 mg / kg), more preferably 10-2000 mg of the compound of the present invention per dose. Preferably, the "dose" is a capsule or tablet.

[0069] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be of sufficient purity and sufficiently low toxicity to be suitable for human use. "Compatible" in this specification means that the components of the composition can be mixed with the compounds of the present disclosure and with each other without significantly reducing the effectiveness of the compounds. Examples of pharmaceutically acceptable carrier ingredients include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, and cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid and magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, and olive oil), polyols (e.g., propylene glycol, glycerol, mannitol, and sorbitol), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, and pyrogen-free water.

[0070] The method of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative administration methods include (but are not limited to) oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), or topical administration.

[0071] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; and (d) disintegrants, such as agar, charcoal. The capsules, tablets, and pills may further contain a buffering agent.

[0072] The solid dosage forms, such as tablets, sugar-coated tablets, capsules, pills, and granules, can be prepared with coating and shell materials, such as enteric coating and other materials known in the art.They can also contain opacifiers and active compounds, or compounds contained in compositions that are released slowly in a part of the digestive tract.Examples of useful encapsulating materials are polymers and waxes.If necessary, the active compound can also be in the form of microencapsulation with one or more of the above-mentioned excipients.

[0073] The liquid dosage form for oral administration can include pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir.In addition to the active compound, the liquid dosage form can contain the inert diluent commonly used in this field, such as water or other solvent, solubilizer and emulsifier, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propanediol, 1,3-butanediol, dimethylformamide and oil, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or their mixture.

[0074] Besides these inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0075] In addition to the active compounds, the suspensions may further contain suspending agents such as ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar-agar, or mixtures thereof.

[0076] Compositions for injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0077] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required.

[0078] The compounds of the present disclosure may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0079] When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is appropriate for a mammal (e.g., human) in need of treatment, and the dosage is a pharmaceutically effective amount when administered, and the daily dosage for a human weighing 60 kg is generally 1 to 2000 mg, preferably 6 to 600 mg. Of course, the specific dosage should also be determined by comprehensively considering factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0080] Uses and Treatment Methods As described above, the compounds of the present invention are CDK12 / 13 protein degraders, and therefore, the compounds or compositions containing the compounds can be used to treat, prevent, and alleviate diseases associated with CDK12 / 13 activity or abnormal expression. In some embodiments, disclosed herein is the use of a compound of the present invention in the preparation of a medicament for preventing and / or treating a CDK12 / 13 serine / threonine protein kinase-mediated disease. In some embodiments, disclosed herein is a compound of the present invention for preventing and / or treating a CDK12 / 13 serine / threonine protein kinase-mediated disease. In some embodiments, disclosed herein is a method for treating a CDK12 / 13 serine / threonine protein kinase-mediated disease in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound of the present invention. In some embodiments, the CDK12 / 13 serine / threonine protein kinase-mediated disease includes prostate cancer, breast cancer, uterine cancer, ovarian cancer, non-small cell lung cancer, small cell lung cancer, Ewing's sarcoma, lung adenocarcinoma, squamous cell lung cancer, pancreatic cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, or nasopharyngeal carcinoma, head and neck tumor, colon cancer, rectal cancer, or glioma.

[0081] When used in the uses and methods disclosed herein, the compounds and compositions of the present disclosure can be used in combination with other known therapies. As used herein, "concomitant" administration refers to the delivery of two (or more) different therapies to a subject while the subject is suffering from a disorder, for example, the delivery of the two or more therapies after the subject is diagnosed with the disorder and before the disorder is cured or resolved, or before treatment is discontinued for other reasons. In some embodiments, administration overlaps because delivery of one treatment is still ongoing when delivery of the second treatment begins. This may be referred to herein as "simultaneous" or "co-delivery." In other embodiments, delivery of one treatment ends before delivery of the other treatment begins. In some embodiments in either case, the treatments are more effective when administered in combination. For example, the second treatment may be more effective, or the same effect may be achieved with less of the second treatment, or the second treatment may provide a greater reduction in symptoms, or a similar condition may be observed with the first treatment, compared to administering the second treatment without the first treatment. In some embodiments, the delivery results in a greater reduction in symptoms or other parameters associated with a disease than would be observed if one treatment were delivered without the other. The effects of the two treatments may be partially additive, fully additive, or greater than additive. The delivery may be such that the effect of the first treatment delivered remains detectable when the second treatment is delivered.

[0082] The compounds or compositions disclosed herein and at least one additional therapeutic agent can be administered simultaneously, in the same or separate compositions, or sequentially, where the compound described herein can be administered first and the additional agent can be administered subsequently, or the order of administration can be reversed.

[0083] In some embodiments, the compounds described herein are administered in combination with other therapies, including surgery, radiation, transplantation (e.g., stem cell transplantation or bone marrow transplantation), chemotherapy, immunotherapy, cryotherapy, and / or hyperthermia. Such combination therapy may allow for the administration of lower doses of the drug and / or other agents, thereby avoiding potential toxicities or complications associated with the treatment.

[0084] In some embodiments, the compounds described herein are administered together with at least one additional therapeutic agent, for example, a chemotherapeutic agent.In certain embodiments, the compounds described herein are administered in combination with one or more additional chemotherapeutic agents.The chemotherapeutic agent may be identified in the "A to Z List of Cancer Drugs" published by the National Cancer Institute.

[0085] The main advantages of the present invention are: 1. The degrading agent for cyclin-dependent kinase 12 / 13 (CDK12 / 13) provided by the present invention can effectively degrade CDK12 and CDK13 protein kinases, and can be used to prepare medicaments for preventing or treating diseases mediated by CDK12 and / or CDK13 protein kinases, such as prostate cancer, breast cancer, uterine cancer, ovarian cancer, non-small cell lung cancer, small cell lung cancer, Ewing's sarcoma, lung adenocarcinoma, squamous cell lung cancer, pancreatic cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumor, colon cancer, rectal cancer, and glioma.

[0086] 2. The degrading agent for cyclin-dependent kinase 12 / 13 (CDK12 / 13) provided by the present invention has potent degrading activity.

[0087] 3. The degrading agent for cyclin-dependent kinase 12 / 13 (CDK12 / 13) provided by the present invention has high selectivity for degrading protein kinases.

[0088] The invention will now be described in more detail with reference to specific examples.

[0089] Example 1: Compound zlc-4-77 [ka] Step 1: Preparation of intermediate 3-86 [ka] In a three-neck round-bottom flask, trans-cyclohexane-1,4-diamine 2 (1.2 g, 10.5 mmol), potassium phosphate (1.3 g, 6 mmol), CuI (57 mg, 0.3 mmol), and d-proline (35 mg, 0.3 mmol) were sequentially added to a system of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (1.02 g, 3 mmol) in anhydrous DMSO (15 mL). After completion, the atmosphere was purged with argon three times and the temperature was raised to 100 °C. After completion of the reaction as monitored by TLC, the reaction mixture was brought to room temperature, filtered through Celite, and washed three times with DCM / MeOH (10:1). The filtrate was concentrated under reduced pressure, wet loaded, and purified by normal-phase silica gel column chromatography to give the desired compound 3-86 (off-white solid, 480 mg, 43% yield). 1 H NMR (400 MHz, DMSO-d6) δ 6.74 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.9 Hz, 2H), 4.88 (d, J = 8.2 Hz, 1H), 3.42 (t, J = 5.1 Hz, 4H), 3.03 (s, 1H), 2.83 (t, J = 5.1 Hz, 4H), 2.76 (s, 1H), 1.95 (d, J = 12.8 Hz, 2H), 1.85 (d, J = 12.4 Hz, 2H), 1.41 (s, 9H), 1.26 (q, J = 10.9 Hz, 2H), 1.11 (q, J = 11.6 Hz, 2H).C 21 H 34 N4O2 [M+H] +HRMS(ESI) calculated: 375.2755, found: 375.2739.

[0090] Step 2: Preparation of intermediate 4-39 [ka] In a 100 mL round-bottom flask, 5-cyano-2-fluoropyridine 3 (451 mg, 3.7 mmol) and CsCO (1.45 g, 4.44 mol) were added sequentially to a system of 3-86 (1.38 g, 3.7 mmol) in DMF (7.5 mL). Upon completion, the mixture was allowed to react at room temperature overnight. After completion as monitored by TLC, the reaction was filtered, and the filtrate was concentrated under reduced pressure. Purification by normal phase silica gel column chromatography afforded intermediate 4-39 (white solid, 1.4 g, 80%). 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 1 Hz, 1H), 6.75 (d, J = 6.9 Hz, 2H), 6.52 (d, J = 8.3 Hz, 3H), 4.92 (s, 1H), 3.75 (s, 1H), 3.42 (s, 4H), 3.12 (s, 1H), 2.83 (s, 4H), 1.98 (s, 4H), 1.41 (s, 9H), 1.36 - 1.28 (m, 2H), 1.25 - 1.17 (m, 2H).

[0091] Step 3: Preparation of intermediate 4-44 [ka] In a 25 mL round-bottom flask, benzyl isocyanate 4 (1.2 g, 9 mmol) and DIPEA (1.6 mL) were added sequentially to a system of 4-39 (1.438 g, 3 mmol) in DMF (3 mL). Upon completion, the temperature was raised to 95 °C. After 6 h, the reaction was complete as monitored by TLC. The reaction was brought to room temperature, concentrated under reduced pressure, and purified by normal phase silica gel chromatography to give the desired intermediate 4-44 (white solid, 1.3 g, 72% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.46 (d, J = 6.6 Hz, 1H), 7.28 - 7.24 (m, 2H), 7.18 - 7.14 (m, 3H), 7.03 - 6.98 (m, 4H), 6.46 (d, J = 8.7 Hz, 1H), 5.58-5.56 (m, 1H), 4.26 (t, J = 11.9 Hz, 1H), 4.14 (d, J = 5.4 Hz, 2H), 3.45 (s, 5H), 3.16 (s, 4H), 1.90 (d, J = 11.1 Hz, 2H), 1.76 (d, J = 11.6 Hz, 2H), 1.42 (d, J = 1.6 Hz, 9H), 1.27 (m, 2H), 1.14 - 1.04 (m, 2H).

[0092] Step 4: Preparation of Intermediate 4-46 [ka] In a 25 mL round-bottom flask, CF3COOH (1 mL) was added dropwise to a system of 4-44 (1.83 g, 3 mmol) in CHCl (2 mL). The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and extracted with saturated sodium bicarbonate-CHCl / MeOH (10:1) system. The resulting material was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to give the desired intermediate 4-46 (white solid, 1.43 g, 94%). 1H NMR (500 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.48 (s, 1H), 7.28 - 7.25 (m, 2H), 7.18 - 7.15 (m, 3H), 7.00 - 6.95 (m, 4H), 6.47 (d, J = 8.9 Hz, 1H), 5.56 (s, 1H), 4.26 (m, 1H), 4.14 (d, J = 5.9 Hz, 2H), 3.48 (s, 1H), 3.37 - 3.34 (m, 1H),3.11 - 3.09 (m, 4H), 2.85 - 2.83 (m, 4H), 1.90 (d, J = 11.4 Hz, 2H), 1.76 (d, J = 10.7 Hz, 2H), 1.33 - 1.27 (m, 2H), 1.13 - 1.06 (m, 2H).

[0093] Step 5: Preparation of Intermediate 4-65 [ka] To a system of 4-46 (153 mg, 0.3 mmol) in DMF (2 mL) in a 25 mL round-bottom flask, potassium carbonate (83 mg, 0.6 mmol) and 1-Boc-4-bromomethylpiperidine (167 mg, 0.6 mmol) were added sequentially. After completion, the temperature was raised to 80 °C and the mixture was stirred overnight. After completion of the reaction, the reaction mass was concentrated under reduced pressure and purified by normal phase silica gel column chromatography to give the desired intermediate 4-65 (white solid, 110 mg, 52%). 1H NMR (500 MHz, DMSO-d6) δ 8.29 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 6.6 Hz, 1H), 7.28 - 7.26 (m, 2H), 7.18 - 7.14 (m, 3H), 7.03 - 6.96 (m, 4H), 6.46 (d, J = 8.8 Hz, 1H), 5.59 (t, J = 5.6 Hz, 1H), 4.28 - 4.23 (s, 1H), 4.14 - 4.13(d, J = 6.0 Hz, 2H), 3.92 (s, 2H), 3.50 (s, 1H), 3.17 (s, 4H), 2.47 (s, 4H), 2.17 (d, J = 6.6 Hz, 2H), 1.90 (d, J = 9.7 Hz, 2H), 1.77 - 1.68 (m, 5H), 1.39 (s, 9H), 1.33 - 1.26 (m, 2H), 1.13 - 1.08 (m, 2H), 0.98 - 0.94 (m, 2H), 0.84 - 0.81 (m, 2H). C 41 H 55 N8O3の[M+H] + Hoseki MS (ESI), calculated value: 707.4, measured value: 707.5.

[0094] ステップ6: Preparation of compound zlc-4-77

change

[0095] Example 2: Preparation of compound zlc-4-79 [ka] Step 1: Preparation of intermediate 4-66 To a system of 4-46 (153 mg, 0.3 mmol) in DMF (2 mL) in a 25 mL round-bottom flask, HATU (137 mg, 0.36 mmol), DIPEA (0.1 mL, 0.6 mmol), and 1-N-Boc-3-azetidinecarboxylic acid (67 mg, 0.33 mmol) were added sequentially. Upon completion, the reaction was stirred at room temperature overnight. After the reaction was observed to be complete, water was added to quench the reaction. The solid was precipitated and filtered, and the filter cake was washed (CHCl / MeOH=10:1), dried over anhydrous sodium sulfate, and purified by normal phase silica gel chromatography to give the desired intermediate 4-66 (white solid, 120 mg, 59%). 1H NMR (500 MHz, DMSO-d6) δ 8.29 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.48 (s, 1H), 7.28 - 7.25 (m, 2H), 7.18 - 7.14 (m, 3H), 7.03 - 6.99 (m, 4H), 6.46 (d, J = 8.9 Hz, 2H), 5.61 - 5.59 (m, 1H), 4.28 - 4.23 (m, 1H), 4.14 (d, J = 5.8 Hz, 2H), 3.72 - 3.68 (m, 1H), 3.63 - 3.60 (m, 4H), 3.40 (s, 2H), 3.19 - 3.17 (m, 3H), 3.16 - 3.12 (m, 4H), 1.90 (d, J = 10.9 Hz, 2H), 1.76 (d, J = 12.3 Hz, 2H), 1.37 (s, 9H), 1.32 - 1.27 (m, 2H), 1.13 - 1.06 (m, 2H).C 39 H 49 N8O4 [M+H] + MS(ESI) calculated: 693.4, found: 692.8.

[0096] Step 2: Preparation of compound zlc-4-79 [ka] The synthesis method is the same as that in step f of Example 1. 1H NMR (600 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.28 - 7.26 (m, 2H), 7.19 - 7.15 (m, 3H), 7.05 - 7.01 (m, 4H), 6.84 (d, J = 1.8 Hz, 1H), 6.70 (dd, J = 8.4, 2.0 Hz, 1H), 6.47 (d, J = 8.9 Hz, 1H), 5.58 (t, J = 5.5 Hz, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.28 - 4.25 (m, 3H), 4.18 - 4.15 (m, 4H), 4.00 - 3.97 (m, 1H), 3.65 (s, 2H), 3.49 (s, 3H), 3.22 (m, 4H), 2.91 - 2.84 (m, 1H), 2.59 - 2.53 (m, 2H), 2.03 - 2.00 (m, 1H), 1.91 (d, J = 10.3 Hz, 2H), 1.77 (d, J = 10.6 Hz, 2H), 1.31 (m, 2H), 1.10 (m, 2H). 13 C NMR (151 MHz, DMSO) δ 172.80, 170.10, 169.35, 167.43, 167.15, 159.24, 156.77, 154.98, 153.10, 149.92, 141.30, 133.80, 131.60, 128.76, 128.03, 126.71, 126.25, 124.83, 119.12, 117.24, 115.97, 114.30, 104.56, 94.00, 53.63, 52.92, 48.72, 48.07, 47.75, 44.42, 43.48, 41.30, 31.30, 31.21, 30.98, 30.20, 22.19, 14.09. C 47 H 49 N 10 O6の[M+H] +HRMS(ESI) calculated: 849.3831, found: 849.3839.

[0097] Example 3: Preparation of compound zlc-4-91 [ka] Step 1: Preparation of intermediate 4-64 [ka] The compounds p-bromoiodobenzene (5.0 g, 17.7 mmol), N-BOC-trans-1,4-cyclohexanediamine (3.2 g, 14.7 mmol), Pd2(dba)3 (1.37 g, 1.5 mmol), Xantphos (1.7 g, 2.94 mmol), and tert-ButONa (2.8 g, 29.4 mmol) were mixed and dissolved in 150 mL of toluene. After three argon flushes, the reaction mixture was heated to 100 °C overnight. After completion of the reaction, the mixture was filtered through Celite and concentrated by rotary evaporation under reduced pressure. The residue was purified by column chromatography to give the desired compound 4-64 (yellow solid, 3.9 g, 72% yield). 1 H NMR (500 MHz, DMSO-d6) δ 7.16 - 7.13 (m, 2H), 6.79 (d, J = 7.9 Hz, 1H), 6.49 (dd, J = 8.9, 2.0 Hz, 2H), 5.63 (d, J = 8.0 Hz, 1H), 3.21 - 3.19 (m, 1H), 3.06 - 3.03 (m, 1H), 1.93 (d, J = 12.6 Hz, 2H), 1.77 (d, J = 12.5 Hz, 2H), 1.28 - 1.21 (m, 1H), 1.16 - 1.11 (m, 2H).

[0098] Step 2: Preparation of intermediate 4-68 [ka] Intermediate 4-64 (3.9 g, 10.6 mmol) was dissolved in 4 mL of DMF, and benzyl isocyanate (4.2 g, 31.7 mmol) and DIPEA (1.59 g, 12.3 mmol) were added. The mixture was reacted at 95 °C for 5 h. The solvent was removed by rotary evaporation, and the residue was purified by column chromatography to give the desired compound 4-68 (yellow solid, 3.7 g, 69% yield). 1 H NMR (500 MHz, DMSO-d6) δ 7.64 - 7.62 (m, 2H), 7.27 - 7.25 (m, 2H), 7.19 - 7.15 (m, 3H), 7.12 - 7.10 (m, 2H), 6.69 (d, J = 7.9 Hz, 1H), 6.01 (t, J = 6.1 Hz, 1H), 4.24 - 4.16 (m, 1H), 4.13 (d, J = 6.1 Hz, 2H), 2.94 (m, 1H), 1.72 (d, J = 11.7 Hz, 4H), 1.34 (s, 9H), 1.24 - 1.21 (m, 2H), 1.03 - 0.96 (d, J = 12.1 Hz, 2H).

[0099] Step 3: Preparation of intermediate 4-69 [ka] Intermediate 4-68 (3.7 g, 7.3 mmol) was dissolved in 5 mL of DCM and 2.5 mL of trifluoroacetic acid (TFA) was added. The mixture was heated to 55 °C and refluxed for 6 h. The solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by column chromatography to give the desired compound 4-69 (yellow solid, 2.5 g, 70% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.65 - 7.63 (m, 2H), 7.28 - 7.25 (m, 2H), 7.19 - 7.11 (m, 5H), 6.04 (m, 1H), 4.23 - 4.18 (m, 1H), 4.12 (d, J = 5.3 Hz, 2H), 2.79 (m, 1H), 1.89 (d, J = 12.8 Hz, 2H), 1.79 (d, J = 12.2 Hz, 2H), 1.38 (m, 2H), 1.09 - 1.01 (m, 2H).

[0100] Step 4: Preparation of Intermediate 4-87 [ka] Compound 4-69 (2.5 g, 5.1 mmol) was dissolved in 15 mL of DMF. 5-Cyano-2-fluoropyridine (744 mg, 6.1 mol) and CsCO (2.0 g, 6.1 mol) were added, and the mixture was stirred at room temperature for 15 minutes and then heated to 60 °C for 40 minutes. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by column chromatography to give the desired compound 4-87 (white solid, 1.9 g, 70% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.30 (d, J = 2.2 Hz, 1H), 7.65 - 7.60 (m, 3H), 7.48 (d, J = 6.5 Hz, 1H), 7.29 - 7.26 (m, 2H), 7.19 - 7.13 (m, 5H), 6.47 (d, J = 8.9 Hz, 1H), 6.03 (t, J = 5.9 Hz, 1H), 4.30 - 4.23 (m, 1H), 4.14 (d, J = 6.0 Hz, 2H), 3.51 (s, 1H), 1.91 (d, J = 11.0 Hz, 1H), 1.78 (d, J = 11.4 Hz, 2H), 1.31 (m, 2H), 1.10 (m, 2H).

[0101] Step 5: Preparation of Intermediate 4-88 [ka] In a 25 mL Shrek flask, compound 4-87 (1.51 g, 3 mmol), tert-butyl 4-piperazin-1-ylpiperidine-1-carboxylate (986 mg, 3.6 mmol), Pd2(dba)3 (274 mg, 0.3 mmol), Xantphos (347 mg, 0.6 mmol), and tert-ButONa (576 g, 6 mmol) were added sequentially. The mixture was purged with argon three times, and toluene (6 mL) was added. The temperature was raised to 110 °C, and the mixture was allowed to react overnight. Upon completion, the reaction was filtered through Celite, concentrated under reduced pressure, and purified by column chromatography to give the desired compound 4-88 (yellow solid, 1.27 g, 61%). 1 H NMR (500 MHz, DMSO-d6) δ 8.29 (d, J = 1.7 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.28 - 7.25 (m, 2H), 7.18 - 7.14 (m, 3H), 7.00 - 6.95 (m, 5H), 6.46 (d, J = 9.0 Hz, 1H), 5.59 (s, 1H), 4.28 - 4.23 (m, 1H), 4.14 (d, J = 5.9 Hz, 2H), 3.95 (s, 2H), 3.16 (s, 4H), 2.73 (s, 1H), 2.61 (s, 4H), 2.40 - 2.37 (m, 1H), 1.90 (d, J = 10.8 Hz, 2H), 1.77 (m, 4H), 1.39 (s, 9H), 1.33 - 1.23 (m, 6H), 1.13 - 1.05 (m, 2H).

[0102] Step 6: Preparation of compound zlc-4-91 [ka] The synthesis method is the same as that in step f of Example 1. 1H NMR (600 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 11.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.45 (m, 2H), 7.28 - 7.25 (m, 2H), 7.18 - 7.15 (m, 3H), 7.01 - 6.96 (m, 4H), 6.46 (d, J = 8.9 Hz, 1H), 5.57 (m, 1H), 5.11 (dd, J = 12.9, 5.4 Hz, 2H), 4.28 - 4.26 (m, 1H), 4.15 (d, J = 5.7 Hz, 2H), 3.67 (d, J = 11.5 Hz, 2H), 3.49 (s, 1H), 3.19 (s, 4H), 2.93 - 2.86 (m, 3H), 2.66 (s, 4H), 2.61 - 2.58 (m, 1H), 2.54 - 2.52 (d, J = 13.2 Hz, 1H), 2.49 - 2.44 (d, J = 15.7 Hz, 1H), 2.04 - 2.02 (m, 1H), 1.93 - 1.90 (m, 4H), 1.76 (d, J = 10.4 Hz, 2H), 1.62 - 1.57 (m, 2H), 1.33 - 1.27 (m, 2H), 1.13 - 1.07 (d, 2H). 13 C NMR (151 MHz, DMSO) δ 172.76, 169.91, 166.69, 166.21, 159.25, 158.09, 156.81, 156.41, 153.09, 150.15, 145.47, 141.34, 131.50, 128.77, 128.14, 128.01, 126.69, 126.22, 122.98, 119.11, 115.29, 113.72, 112.00, 111.83, 93.99, 59.76, 52.92, 49.33, 49.05, 48.77, 48.02, 43.48, 31.31, 30.96, 30.20, 27.88, 22.09, 14.09. C 48 H 52 N 10O5's [M+H] + HRMS(ESI) calculated: 867.4101, found: 867.4104.

[0103] Example 4: Preparation of compound zlc-4-93 [ka] See Example 1 for synthesis methods. 1 H NMR (600 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.47 (s, 1H), 7.33 (s, 1H), 7.27 - 7.25 (m, 3H), 7.18 - 7.15 (m, 3H), 7.00 - 6.95 (m, 4H), 6.46 (d, J = 8.9 Hz, 1H), 5.58 - 5.56 (m, 1H), 5.08 - 5.05 (dd, J = 12.8, 5.5 Hz, 1H), 4.28 - 4.23 (m, 1H), 4.14 (d, J = 5.8 Hz, 2H), 4.09 (d, J = 12.5 Hz, 2H), 3.48 (s, 1H), 3.17 (s, 4H), 3.01 - 2.97 (m, 2H), 2.91 - 2.85 (m, 1H), 2.63 (s, 4H), 2.60 - 2.50 (m, 4H), 2.03 - 2.00 (m, 1H), 1.90 (d, J = 10.3 Hz, 4H), 1.76 (d, J = 10.5 Hz, 2H), 1.51 - 1.46 (m, 2H), 1.33 - 1.27 (m, 2H), 1.12 - 1.06 (m, 2H). 13C NMR (151 MHz, DMSO) δ 172.81, 170.11, 167.61, 166.96, 159.24, 156.80, 154.75, 153.09, 150.14, 141.34, 134.04, 131.49, 128.14, 128.01, 126.69, 126.22, 125.01, 119.12, 117.70, 115.30, 107.82, 93.98, 59.76, 52.90, 48.74, 48.00, 46.61, 43.47, 31.30, 30.98, 30.19, 27.21, 22.19, 14.09.C 48 H 53 N 10 O5's [M+H] + HRMS(ESI) calculated: 849.4195, found: 849.4199.

[0104] Example 5: Preparation of compound zlc-5-6 [ka] See Example 1 for synthesis methods. 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 10.2 Hz, 1H), 7.47 (d, J = 7.0 Hz, 1H), 7.28 - 7.25 (m, 2H), 7.18 - 7.15 (m, 3H), 7.02 - 6.97 (m, 4H), 6.78 (d, J = 1.5 Hz, 1H), 6.65 (dd, J = 8.4, 1.7 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 5.58 (m, 1H), 5.07 - 5.03 (m, 1H), 4.29 - 4.24 (m, 1H), 4.17 - 4.14 (m, 4H), 3.73 - 3.70 (m, 2H), 3.50 (s, 1H), 3.50-3.46 (m, 1H),3.19 (s, 4H), 3.05 (s, 1H), 2.90 - 2.84 (m, 1H), 2.66 (d, J = 5.4 Hz, 2H), 2.60 - 2.54 (m, 6H), 2.02 - 2.00 (m, 1H), 1.91 (d, J = 9.7 Hz, 2H), 1.77 (d, J = 10.2 Hz, 2H), 1.33 - 1.26 (m, 2H), 1.13 - 1.06 (m, 2H). 13 C NMR (151 MHz, DMSO) δ 172.80, 170.11, 167.49, 167.18, 159.24, 156.80, 155.19, 153.10, 150.12, 141.34, 133.82, 131.50, 128.22, 128.02, 126.69, 126.23, 124.80, 119.12, 116.68, 115.42, 114.06, 104.35, 93.98, 61.76, 55.75, 52.85, 48.70, 47.63, 43.46, 31.30, 30.98, 30.20, 27.00, 22.21. C 47 H 51 N 10 O5の[M+H] +HRMS(ESI) calculated: 835.4038, found: 835.4043.

[0105] Example 6: Preparation of compound zlc-5-11 [ka] See Example 1 for synthesis methods. 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.31 - 8.28 (m, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 7.34 (s, 1H), 7.28 - 7.25 (m, 3H), 7.18 - 7.15 (m, 3H), 6.99 (m, 4H), 6.46 (d, J = 8.8 Hz, 1H), 5.59 - 5.57 (m, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.28 - 4.14 (m, 1H), 4.14 (d, J = 5.6 Hz, 2H), 3.79 (d, J = 9.4 Hz, 2H), 3.44 (m, 4H), 2.92 - 2.85 (m, 1H), 2.75 - 2.70 (m, 2H), 2.65 (m, 4H), 2.60 - 2.56 (m, 2H), 2.41 - 2.36 (m, 1H), 2.03 - 2.00 (m, 1H), 1.91 (s, 4H), 1.76 (d, J = 11.0 Hz, 2H), 1.53 - 1.51 (m, 2H), 1.33 - 1.25 (m, 2H), 1.13 - 1.06 (m, 2H). 13C NMR (126 MHz, DMSO) δ 172.87, 170.14, 167.60, 167.02, 159.26, 156.85, 153.14, 150.15, 141.36, 133.87, 131.53, 128.06, 127.91, 126.71, 126.27, 124.94, 119.17, 115.82, 94.00, 59.81, 52.91, 48.79, 48.42, 47.47, 43.49, 31.34, 31.01, 30.24, 22.21, 14.13.C 48 H 53 N 10 O5's [M+H] + HRMS(ESI) calculated: 849.4195, found: 849.4192.

[0106] Example 7: Preparation of compound zlc-5-15 [ka] See Example 1 for synthesis methods. 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.29 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.49 (s, 1H), 7.28 - 7.25 (m, 2H), 7.18 - 7.15 (m, 3H), 7.03 - 6.98 (m, 4H), 6.82 (s, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 8.9 Hz, 1H), 5.62 - 5.60 (m, 1H), 5.08 - 5.04 (m, 1H), 4.28 - 4.23 (m, 1H), 4.14 (d, J = 5.2 Hz, 4H), 3.92 (s, 2H), 3.39 (s, 1H), 3.23 (s, 4H), 2.91 - 2.84 (m, 1H), 2.64 - 2.51 (m, 6H), 2.02 - 2.01 (m, 1H), 1.90 (d, J = 11.6 Hz, 2H), 1.77 - 1.75 (m, 2H), 1.35 - 1.22 (m, 3H), 1.17 - 1.05 (m, 2H). 13 C NMR (126 MHz, DMSO) δ 172.87, 170.17, 167.51, 167.20, 159.26, 156.83, 154.94, 153.14, 150.06, 141.37, 133.86, 131.57, 128.05, 126.72, 126.27, 124.91, 119.17, 116.92, 115.45, 114.27, 104.56, 94.00, 55.06, 54.19, 52.91, 49.16, 48.74, 47.40, 43.49, 31.33, 31.01, 30.23, 22.23, 14.13. C 46 H 49 N 10 O5の[M+H] + Hoseki HRMS (ESI), calculated value: 821.3882, measured value: 821.3884.

[0107] Example 8: Preparation of compound zlc-5-20

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[0108] Example 9: Preparation of compound zlc-5-31 [ka] See Example 1 for synthesis methods. 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.30 (d, J = 1.8 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.54 - 7.46 (m, 1H), 7.34 (s, 1H), 7.28 - 7.24 (m, 3H), 7.19 - 7.15 (m, 3H), 7.05 - 7.00 (m, 4H), 6.47 (d, J = 8.9 Hz, 1H), 5.60 - 5.59 (m, 1H), 5.07 (dd, J = 12.8, 5.3 Hz, 1H), 4.29 - 4.24 (m, 1H), 4.15 (d, J = 5.5 Hz, 2H), 4.08 (d, J = 12.6 Hz, 2H), 3.71 (s, 2H), 3.61 (s, 2H), 3.49 (s, 1H), 3.23 (s, 2H), 3.17 (s, 2H), 3.11 - 3.02 (m, 3H), 2.92 - 2.85 (m, 1H), 2.60 - 2.54 (m, 2H), 2.03 - 2.00 (m, 1H), 1.90 (d, J = 10.5 Hz, 2H), 1.78 - 1.73 (m, 4H), 1.67 - 1.60 (m, 2H), 1.33 - 1.27 (m, 2H), 1.13 - 1.06 (m, 2H). 13 C NMR (151 MHz, DMSO) δ 172.81, 172.34, 170.10, 167.60, 166.96, 159.24, 156.77, 154.82, 153.09, 149.92, 141.30, 134.05, 131.60, 128.70, 128.02, 126.70, 126.24, 125.03, 119.11, 117.64, 115.88, 107.85, 93.99, 52.92, 48.73, 48.41, 47.84, 46.72, 44.62, 43.48, 41.07, 36.80, 31.30, 30.98, 30.20, 27.42, 22.19, 14.09. C 49 H 53 N 10O6 [M+H] + HRMS(ESI) calculated: 877.4144, found: 877.4139.

[0109] Example 10: Preparation of compound zlc-5-103 [ka] See Example 1 for synthesis methods. 1 H NMR (600 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.30 - 8.28 (m, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.47 (s, 1H), 7.36 (s, 1H), 7.28 - 7.25 (m, 3H), 7.18 - 7.15 (m, 3H), 6.97 (d, J = 8.6 Hz, 2H), 6.49 (d, J = 8.7 Hz, 2H), 6.46 (d, J = 9.0 Hz, 1H), 5.51 (t, J = 5.7 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.28 - 4.24 (m, 1H), 4.15 (d, J = 5.9 Hz, 2H), 3.98 (t, J = 7.1 Hz, 2H), 3.70 - 3.68 (m, 2H), 3.50 - 3.42 (m, 5H), 3.38 - 3.37 (m, 2H), 2.91 - 2.85 (m, 1H), 2.60 - 2.52 (m, 3H), 2.02 - 2.00 (m, 1H), 1.90 (d, J = 10.2 Hz, 2H), 1.76 (d, J = 10.6 Hz, 2H), 1.33 - 1.23 (m, 4H), 1.12 - 1.06 (m, 2H). 13C NMR (151 MHz, DMSO) δ 173.28, 170.55, 168.03, 167.45, 159.72, 157.38, 155.70, 153.58, 151.37, 141.79, 134.31, 131.92, 128.50, 127.19, 127.15, 126.71, 125.37, 119.59, 118.93, 118.37, 112.19, 108.49, 94.46, 56.10, 54.60, 53.37, 49.25, 49.10, 47.17, 43.94, 31.78, 31.45, 30.67, 22.65.C 46 H 49 N 10 O5's [M+H] + HRMS(ESI) calculated: 821.3882, found: 821.3884.

[0110] Example 11: Preparation of compound zlc-5-104 [ka] See Example 1 for synthesis methods. 1H NMR (600 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.29 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.48 (s, 1H), 7.28 - 7.25 (m, 3H), 7.21 - 7.15 (m, 4H), 6.97 (d, J = 8.5 Hz, 2H), 6.67 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 8.9 Hz, 1H), 5.53 (s, 1H), 5.05 (dd, J = 12.8, 5.5 Hz, 1H), 4.29 - 4.25 (m, 1H), 4.15 (d, J = 5.8 Hz, 2H), 4.02 (d, J = 12.3 Hz, 2H), 3.41 (m, 3H), 3.10 (m, 2H), 2.96 - 2.84 (m, 5H), 2.59 - 2.53 (m, 4H), 2.43 (s, 1H), 2.28 - 2.23 (m, 2H), 2.01 - 1.97 (m, 2H), 1.91 - 1.90 (m, 2H), 1.79 - 1.75 (m, 5H), 1.31 - 1.27 (m, 2H), 1.24 - 1.23 (m, 2H), 1.13 - 1.09 (m, 2H). C 51 H 57 N 10 O5's [M+H] + HRMS(ESI) calculated: 889.4508, found: 889.4515.

[0111] Example 12: Preparation of compound zlc-5-105 [ka] See Example 1 for synthesis methods. 1H NMR (600 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.29 (d, J = 2.3 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.29 - 7.25 (m, 3H), 7.21 (dd, J = 8.7, 2.1 Hz, 1H), 7.18 - 7.14 (m, 3H), 6.95 (d, J = 8.6 Hz, 2H), 6.47 - 6.44 (m, 3H), 5.47 (t, J = 5.5 Hz, 1H), 5.06 (dd, J = 12.8, 5.5 Hz, 1H), 4.27 - 4.23 (m, 1H), 4.14 (d, J = 5.9 Hz, 2H), 4.01 (d, J = 12.9 Hz, 2H), 3.90 (s, 4H), 3.30 (s, 4H),2.95 - 2.91 (m, 2H), 2.91 - 2.85 (m, 1H), 2.60 - 2.52 (m, 2H), 2.27 (s, 1H), 2.02 - 2.00 (m, 1H), 1.90 (d, J = 12.1 Hz, 2H), 1.75 (d, J = 11.8 Hz, 4H), 1.30 - 1.24 (m, 4H), 1.17 - 1.11 (m, 2H), 1.08 - 1.06 (m, 2H). 13 C NMR (151 MHz, DMSO) δ 173.29, 170.59, 168.11, 167.43, 159.71, 157.35, 155.40, 153.57, 151.12, 141.74, 134.52, 131.89, 128.51, 125.49, 119.59, 118.02, 117.81, 112.31, 108.16, 94.46, 70.25, 64.88, 62.14, 53.35, 49.20, 47.71, 43.94, 34.71, 31.77, 31.45, 30.65, 29.90, 22.66. C 50 H 55 N 10 O5の[M+H] +Hoseki HRMS (ESI), calculated value: 875.4351, measured value: 875.4354.

[0112] Example 13: Preparation of compound zlc-5-106

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[0113] Example 14: Preparation of compound zlc-6-1 [ka] See Example 1 for synthesis methods. 1H NMR (600 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.28 - 7.25 (m, 2H), 7.18 - 7.15 (m, 3H), 7.02 - 6.97 (m, 4H), 6.91 (d, J = 1.7 Hz, 1H), 6.82 (dd, J = 8.6, 2.0 Hz, 1H), 6.47 (d, J = 8.9 Hz, 1H), 5.58 - 5.56 (m, 1H), 5.05 (dd, J = 12.7, 5.5 Hz, 1H), 4.28 - 4.24 (m, 1H), 4.15 (d, J = 5.8 Hz, 2H), 3.60 - 3.57 (m, 1H), 3.53 - 3.49 (m, 2H), 3.43 - 3.39 (m, 2H), 3.21 (s, 4H), 3.17 - 3.15 (m, 1H), 2.91 - 2.85 (m, 1H), 2.67 - 2.64 (m, 1H), 2.59 - 2.52 (m, 5H), 2.42 (d, J = 7.0 Hz, 2H), 2.18 - 2.15 (m, 1H), 2.02 - 1.96 (m, 1H), 1.90 (d, J = 10.3 Hz, 2H), 1.81 - 1.76 (m, 3H), 1.31 - 1.29 (m, 2H), 1.13 - 1.07 (m, 2H). 13C NMR (151 MHz, DMSO) δ 173.29, 170.63, 168.20, 167.71, 159.72, 157.29, 153.58, 152.35, 150.61, 141.80, 134.49, 131.98, 128.50, 127.16, 126.71, 125.45, 119.59, 115.96, 115.84, 115.73, 105.93, 94.46, 61.37, 53.57, 53.39, 52.68, 49.15, 48.14, 47.69, 43.94, 35.99, 31.78, 31.46, 30.67, 29.74, 22.56.C 48 H 53 N 10 O5's [M+H] + HRMS(ESI) calculated: 849.4195, found: 849.4191.

[0114] Example 15: Preparation of compound zlc-6-35 [ka] See Example 1 for synthesis methods. 1H NMR (600 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.47 (s, 1H), 7.36 - 7.34 (m, 1H), 7.28 - 7.25 (m, 3H), 7.18 - 7.14 (m, 3H), 6.95 (d, J = 8.5 Hz, 2H), 6.47 - 6.45 (m, 3H), 5.48 - 5.47 (m, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.27 - 4.23 (m, 1H), 4.14 (d, J = 5.9 Hz, 2H), 3.97 (m, 2H), 3.54 - 3.50 (m, 2H), 3.45 (s, 4H), 3.00 - 2.95 (m, 1H), 2.64 (d, J = 7.3 Hz, 2H), 2.61 - 2.57 (m, 2H), 2.54 - 2.52 (m, 5H), 2.03 - 1.99 (m, 1H), 1.90 (d, J = 10.4 Hz, 2H), 1.75 (d, J = 11.6 Hz, 2H), 1.31 - 1.27 (m, 2H), 1.11 - 1.05 (m, 2H). 13 C NMR (151 MHz, DMSO) δ 172.82, 170.09, 167.57, 166.99, 159.25, 156.92, 155.24, 153.11, 150.90, 141.29, 133.87, 131.44, 128.05, 126.70, 126.49, 124.91, 119.13, 118.35, 117.85, 111.48, 107.93, 94.00, 56.11, 52.87, 52.34, 48.78, 46.88, 43.48, 31.30, 30.98, 30.20, 29.03, 27.22. C 47 H 51 N 10 O5の[M+H] + Hoseki HRMS (ESI), calculated value: 835.4038, measured value: 835.4045.

[0115] Example 16: Preparation of compound zlc-6-37

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[0116] Example 17: Preparation of compound zlc-6-38 [ka] See Example 1 for synthesis methods. 1H NMR (600 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.92 (d, J = 2.9 Hz, 3H), 7.60 (d, J = 8.9 Hz, 1H), 7.47 (s, 1H), 7.28 - 7.25 (m, 2H), 7.18 - 7.15 (m, 3H), 7.02 - 6.99 (s, 4H), 6.46 (d, J = 8.9 Hz, 1H), 5.57 (t, J = 5.8 Hz, 1H), 5.16 (dd, J = 12.9, 5.4 Hz, 1H), 4.28 - 4.23 (m, 1H), 4.14 (d, J = 6.0 Hz, 2H), 3.68 (s, 2H), 3.39 -3.36 (m, 1H), 3.27 -3.22 (m, 4H), 2.92 -2.86 (m, 1H), 2.72 -2.69(m, 4H), 2.62 - 2.59 (m, 1H), 2.56 -2.53 (m, 1H), 2.08 -2.04 (m, 1H), 1.93 - 1.87 (m, 2H), 1.76 (d, J = 11.4 Hz, 2H), 1.32 - 1.26 (m, 2H), 1.12 -1.06 (m, 2H). 13 C NMR (151 MHz, DMSO) δ 172.75, 169.76, 166.50, 166.42, 156.80, 153.11, 150.14, 141.33, 137.58, 131.83, 131.52, 130.28, 128.77, 128.32, 128.03, 126.70, 126.24, 125.74, 123.83, 119.13, 115.55, 93.99, 90.49, 83.72, 52.91, 51.46, 49.12, 47.62, 46.75, 43.47, 31.31, 30.92, 30.20, 21.93. C 46 H 46 N9O5の[M+H] + Hoseki HRMS (ESI), calculated value: 804.3616, measured value: 804.3623.

[0117] Example 18: Preparation of compound zlc-6-42

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[0118] Example 19: Preparation of compound zlc-6-101 [ka] See Example 1 for synthesis methods. 1H NMR (600 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.29 (d, J = 2.1 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.48 (s, 1H), 7.32 (s, 1H), 7.28 - 7.23 (m, 3H), 7.18 - 7.15 (m, 3H), 6.99 (s, 4H), 6.50 - 6.43 (m, 1H), 5.54 - 5.52 (m, 1H), 5.06 (dd, J = 12.8, 5.5 Hz, 1H), 4.28 - 4.24 (m, 1H), 4.15 (d, J = 5.8 Hz, 2H), 3.51 (s, 6H), 3.22 (s, 4H), 2.91 - 2.85 (m, 1H), 2.60 - 2.57 (m, 2H), 2.03 - 1.99 (m, 1H), 1.91 (d, J = 10.6 Hz, 2H), 1.77 (d, J = 10.4 Hz, 2H), 1.63 -1.59 (m, 8H), 1.33 - 1.28 (m, 2H), 1.14 - 1.07 (m, 2H). 13 C NMR (151 MHz, DMSO) δ 172.83, 170.14, 167.67, 167.00, 159.25, 156.84, 154.97, 153.11, 141.31, 134.04, 131.46, 128.05, 127.66, 126.70, 126.26, 125.00, 119.13, 117.35, 115.47, 107.50, 94.00, 69.79, 52.90, 48.74, 43.48, 42.89, 34.82, 34.12, 31.31, 30.99, 30.21, 29.14, 22.21. C 48 H 52 N9O5の[M+H] + Hoseki HRMS (ESI), calculated value: 834.4086, measured value: 834.4073.

[0119] Example 20: Preparation of compound zlc-6-102

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[0120] Example 21: Preparation of compound zlc-6-103 [ka] See Example 1 for synthesis methods. 1H NMR (600 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.30 (d, J = 2.2 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.28 - 7.26 (m, 2H), 7.19 - 7.15 (m, 3H), 7.06 - 7.03 - 6.99 (m, 4H), 6.80 (d, J = 1.8 Hz, 1H), 6.67 (dd, J = 8.4, 2.0 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 5.56 (t, J = 5.6 Hz, 1H), 5.05 (dd, J = 12.8, 5.5 Hz, 1H), 4.29 - 4.23 (m, 1H), 4.15 (d, J = 5.8 Hz, 1H), 3.83 (m, 4H), 3.43 - 3.41 (m, 2H), 3.22 (m, 3H), 2.91 - 2.85 (m, 1H), 2.59 - 2.53 (m, 2H), 2.02 - 1.89 (m, 1H), 1.91 - 1.89 (m, 6H), 1.77 (d, J = 10.1 Hz, 2H), 1.33 - 1.27 (m, 2H), 1.13 - 1.07 (m, 2H). 13 C NMR (151 MHz, DMSO) δ 172.83, 170.12, 167.53, 167.21, 159.26, 156.83, 155.20, 153.12, 150.21, 141.33, 133.86, 131.53, 128.04, 126.71, 126.26, 124.87, 122.51, 119.14, 116.69, 115.95, 114.18, 104.42, 94.00, 60.78, 52.92, 48.73, 45.32, 43.49, 34.65, 34.21, 31.32, 30.99, 30.21, 22.23, 20.45. C 46 H 48 N9O5の[M+H] + Hakoseki HRMS (ESI), calculated value: 806.3773, measured value: 806.3767.

[0121] Example 22: Preparation of compound zlc-7-36

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[0122] Example 23: 3-benzyl-1-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (YJZ9069) [ka] Step 1: Preparation of tert-butyl 4-(4-(((1r,4r)-4-aminocyclohexyl)amino)phenyl)piperazine-1-carboxylate (compound 3) [ka] Potassium phosphate (31 g, 146 mmol), trans-cyclohexane-1,4-diamine 2 (29.3 g, 256.4 mmol), tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate 1 (25 g, 73.26 mmol), CuI (1.39 g, 7.3 mmol), and d-proline (843 mg, 7.3 mmol) were dissolved in anhydrous DMSO (500 mL). The resulting suspension was protected with argon gas and purged with argon three times. The reaction mixture was then heated and stirred at 100 °C for 10 h, filtered through Celite, and the residue was washed with ethyl acetate two to three times. The filtrate was evaporated under reduced pressure and purified on a silica gel column to give 12 g of the desired compound as an off-white solid (44% yield). 1 H NMR (400 MHz, DMSO-d6) δ 6.74 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.9 Hz, 2H), 4.88 (d, J = 8.2 Hz, 1H), 3.42 (t, J = 5.1 Hz, 4H), 3.03 (s, 1H), 2.83 (t, J = 5.1 Hz, 4H), 2.76 (s, 1H), 1.95 (d, J = 12.8 Hz, 2H), 1.85 (d, J = 12.4 Hz, 2H), 1.41 (s, 9H), 1.26 (q, J = 10.9 Hz, 2H), 1.11 (q, J = 11.6 Hz, 2H).C 21 H 34 N4O2 [M+H] + HRMS(ESI) calculated: 375.2755, found: 375.2739.

[0123] Step 2: Preparation of tert-butyl 4-(4-(((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)amino)phenyl)piperazine-1-carboxylate (compound 5) [ka] To a solution of tert-butyl 4-(4-(((1r,4r)-4-aminocyclohexyl)amino)phenyl)piperazine-1-carboxylate 3 (9 g, 24 mmol) in DMF (40 mL) was added 2-chloroquinazoline 4 (4 g, 24 mol) and CsCO (9.4 g, 28.9 mol). The mixture was stirred at room temperature for 15 min and then heated to 60 °C for 40 min. The reaction was then filtered, and the filtrate was concentrated by rotary evaporation under reduced pressure. The residue was purified by column chromatography to give 11.2 g of an off-white solid (93% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 8.2 Hz, 2H), 6.52 (d, J = 8.3 Hz, 2H), 4.95 (s, 1H), 3.86 (d, J = 9.8 Hz, 1H), 3.43 (t, J = 5.0 Hz, 4H), 3.18 - 3.01 (m, 1H), 2.84 (s, 4H), 2.01 (d, J = 11.6 Hz, 4H), 1.50 - 1.32 (m, 11H), 1.30 - 1.15 (m, 2H).

[0124] Step 3: Preparation of tert-butyl 4-(4-(3-benzyl-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)ureido)phenyl)piperazine-1-carboxylate (compound 7) [ka] tert-Butyl 4-(4-(((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)amino)phenyl)piperazine-1-carboxylate 5 (11.2 g, 22.25 mmol), DIPEA (8.6 g, 66.76 mmol), and benzyl isocyanate 6 (8.9 g, 66.76 mmol) were dissolved in 15 mL of DMF. The mixture was stirred at 95 °C for 4 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give 10.2 g of a white solid (72% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.31 - 7.22 (m, 3H), 7.21 - 7.13 (m, 4H), 7.08 - 6.98 (m, 4H), 5.58 (t, J = 6.1 Hz, 1H), 4.28 (t, J = 12.3 Hz, 1H), 4.16 (d, J = 5.8 Hz, 2H), 3.58 (s, 1H), 3.47 (t, J = 5.1 Hz, 4H), 3.18 (t, J = 5.2 Hz, 4H), 1.96 (d, J = 12.0 Hz, 2H), 1.79 (d, J = 12.3 Hz, 2H), 1.50 - 1.33 (m, 12H), 1.13 (q, J = 13.5, 12.5 Hz, 2H).

[0125] Step 4: Preparation of 3-benzyl-1-(4-(piperazin-1-yl)phenyl)-1-(1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound 8) [ka] tert-Butyl 4-(4-(3-benzyl-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)ureido)phenyl)piperazine-1-carboxylate 7 (7.3 g, 11.5 mmol) was dissolved in DCM (20 mL) and TFA (10 mL) was added. The mixture was stirred and refluxed at 50° C. overnight. The reaction mixture was then concentrated under reduced pressure and purified by column chromatography to give 4.3 g of a clear oil (70% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.74 (dd, J = 8.0, 1.5 Hz, 1H), 7.63 (t, J = 8.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.31 - 7.21 (m, 3H), 7.21 - 7.13 (m, 4H), 7.00 (q, J = 9.1 Hz, 4H), 5.56 (t, J = 6.1 Hz, 1H), 4.28 (tt, J = 12.1, 3.7 Hz, 1H), 4.16 (d, J = 6.0 Hz, 2H), 3.65 - 3.53 (m, 1H), 3.11 (dd, J = 6.3, 3.7 Hz, 4H), 2.84 (t, J = 5.0 Hz, 4H), 1.96 (d, J = 10.9 Hz, 2H), 1.79 (d, J = 10.8 Hz, 2H), 1.41 (q, J = 13.1 Hz, 2H), 1.13 (q, J = 13.0 Hz, 2H).

[0126] Step 5: Preparation of 3-benzyl-1-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl) (compound YJZ9069) 2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carboxylic acid 9 (39.9 mg, 0.12 mmol), HATU (45.1 mg, 0.12 mmol), DIPEA (21.3 mg, 0.16 mmol), and compound 8 (59 mg, 0.11 mmol) were dissolved in DMF (6 mL). The mixture was stirred at room temperature for 15 minutes, and then the reaction was subjected to rotary evaporation under reduced pressure and purified by silica gel column chromatography to give 70 mg of the title compound as a white solid (75% yield). [ka] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.05 (s, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.39 (t, J = 8.1 Hz, 2H), 7.27 (q, J = 9.9, 8.7 Hz, 3H), 7.22 - 7.13 (m, 4H), 7.11 - 7.02 (m, 4H), 5.60 (t, J = 6.0 Hz, 1H), 5.26 (s, 2H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.27 (d, J = 12.4 Hz, 1H), 4.17 (d, J = 6.0 Hz, 2H), 3.62 (s, 4H), 3.31 (s, 1H), 3.24 (s, 2H), 2.96 - 2.82 (m, 1H), 2.65 - 2.53 (m, 2H), 2.10 - 2.00 (m, 1H), 1.97 (d, J = 10.8 Hz, 2H), 1.80 (d, J = 11.8 Hz, 2H), 1.41 (q, J = 12.5 Hz, 2H), 1.13 (q, J = 12.3 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.31, 170.43, 167.29, 165.76, 165.61, 162.50, 157.33, 156.06, 150.34, 141.73, 137.09, 134.48, 133.55, 132.13 (2C), 129.17, 128.52 (3C), 128.32, 127.17 (4C), 126.75, 122.21, 120.67, 119.95, 116.60, 116.40 (2C), 116.00, 66.57, 53.54, C 47 H 47 N9O7 [M+H] + HRMS (ESI) calculated: 850.36712, found: 850.3646. HPLC analysis: MeOH-HO (80:20), 12.08 min, purity 97.4%.

[0127] Example 24: 3-benzyl-1-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)oxy)acetyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ1090) [ka] This synthesis method is similar to that shown in Example 23. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.05 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.32 - 7.24 (m, 3H), 7.23 (d, J = 8.2 Hz, 1H), 7.21 - 7.13 (m, 4H), 7.11 - 7.00 (m, 4H), 5.60 (t, J = 5.8 Hz, 1H), 5.21 (s, 2H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.27 (t, J = 12.3 Hz, 1H), 4.17 (d, J = 6.0 Hz, 2H), 3.70 - 3.52 (m, 5H), 3.31 (s, 2H), 3.24 (s, 2H), 2.95 - 2.83 (m, 1H), 2.65 - 2.54 (m, 2H), 2.10 - 2.01 (m, 1H), 1.97 (d, J = 11.4 Hz, 2H), 1.80 (d, J = 11.9 Hz, 2H), 1.41 (q, J = 12.4 Hz, 2H), 1.14 (q, J = 12.0 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 173.30, 170.42, 167.42, 167.27, 165.69, 164.15, 162.50, 157.32, 150.32, 141.74, 134.47, 134.17, 132.13 (2C), 129.19, 128.52 (3C), 128.32, 127.17 (4C), 126.74, 125.65, 123.70, 122.21, 121.69, 119.95, 116.39 (2C), 109.58, 66.60, 53.54, 49.45, 49.13, 48.34, 48.16, 44.28, 43.94, 41.64, 40.44, 31.75, 31.41, 30.87 (2C), 22.52. C 47 H47 N9O7 [M+H] + HRMS (ESI) calculated: 850.36712, found: 850.3633. HPLC analysis: MeOH-HO (75:25), 6.96 min, purity 95.0%.

[0128] Example 25: 3-benzyl-1-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)oxy)acetyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ1094) [ka] This synthesis method is similar to that shown in Example 23. 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.05 (s, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.31 - 7.21 (m, 5H), 7.21 - 7.13 (m, 4H), 7.08 - 7.00 (m, 4H), 5.60 (t, J = 5.9 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 5.03 (s, 2H), 4.43 - 4.21 (m, 3H), 4.16 (d, J = 6.0 Hz, 2H), 3.71 - 3.53 (m, 5H), 3.30 (s, 2H), 3.23 (s, 2H), 2.96 - 2.84 (m, 1H), 2.68 - 2.53 (m, 2H), 2.04 - 1.90 (s, 3H), 1.80 (d, J = 12.1 Hz, 2H), 1.41 (q, J = 12.3 Hz, 2H), 1.20 - 1.06 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.41, 171.47, 168.57, 166.31, 162.50, 158.74, 157.33, 150.34, 141.75, 134.97, 134.48, 133.27, 132.11 (2C), 129.16, 128.52 (3C), 128.32, 127.16 (4C), 126.74, 124.92, 122.21, 120.65, 119.95, 116.38 (2C), 107.67, 66.52, 53.54, 52.21 (2C), 48.45, 48.18, 47.28, 44.44, 43.93, 41.63, 40.43, 31.74, 31.66, 30.86. 47 H 49 N9O6 [M+H] + HRMS (ESI) calculated: 836.38786, found: 836.3843. HPLC analysis: MeOH-HO (75:25), 6.33 min, purity 95.6%.

[0129] Example 26: 3-benzyl-1-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)glycine)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ1091) [ka] This synthesis method is similar to that shown in Example 23. 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.05 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.31 - 7.25 (dd, J = 8.5, 6.5 Hz, 2H), 7.23 (d, J = 8.2 Hz, 1H), 7.21 - 7.11 (m, 6H), 7.09 - 9.00 (m, 5H), 5.60 (t, J = 5.6 Hz, 1H), 5.05 (dd, J = 12.9, 5.5 Hz, 1H), 4.27 (t, J = 12.3 Hz, 1H), 4.22 (d, J = 5.1 Hz, 2H), 4.16 (d, J = 6.2 Hz, 2H), 3.68 (s, 4H), 3.58 (s, 1H), 3.30 (s, 2H), 3.24 (s, 2H), 2.93 - 2.81 (m, 1H), 2.62 - 2.53 (m, 2H), 2.45 - 1.89 (m, 3H), 1.80 (d, J = 12.1 Hz, 2H), 1.41 (q, J = 12.2 Hz, 2H), 1.14 (d, J = 13.3 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 173.34, 170.66, 168.23, 167.70, 167.35, 162.50, 159.29, 157.33, 154.52, 152.04, 150.36, 141.74, 134.47, 132.12 (2C), 129.17, 128.52 (4C), 128.32, 127.17 (4C), 126.74, 125.28, 122.21, 119.95, 117.14, 116.39 (2C), 53.54, 49.11 (2C), 48.40, 48.18, 44.73, 44.30, 43.94, 41.83, 40.43, 31.75, 31.44, 30.87 (2C), 22.69. C 47 H 48 N 10O6 [M+H] + HRMS (ESI) calculated: 849.38311, found: 849.3803. HPLC analysis: MeOH-HO (75:25), 7.47 min, purity 96.8%.

[0130] Example 27: 3-benzyl-1-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)glyceryl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ1095) [ka] This synthesis method is similar to that shown in Example 23. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.05 (s, 1H), 7.74 (d, J = 7.3 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.28 (t, J = 7.6 Hz, 3H), 7.23 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.1 Hz, 4H), 7.10 - 6.99 (m, 5H), 6.94 (d, J = 2.2 Hz, 1H), 5.97 (t, J = 5.1 Hz, 1H), 5.60 (t, J = 6.0 Hz, 1H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.35 - 4.23 (d, J = 16.5 Hz, 2H), 4.19 - 4.12 (m, 3H), 4.07 (d, J = 5.1 Hz, 2H), 3.69 (d, J = 17.3 Hz, 4H), 3.59 (s, 1H), 3.31 (s, 2H), 3.23 (s, 2H), 2.96 - 2.84 (m, 1H), 2.69 - 2.55 (m, 2H), 2.43 - 2.30 (m, 1H), 1.97 (d, J = 11.7 Hz, 2H), 1.80 (d, J = 11.7 Hz, 2H), 1.41 (q, J = 12.6, 12.2 Hz, 2H), 1.14 (q, J = 13.5, 11.1 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.41, 171.47, 168.57, 166.31, 162.50, 158.74, 157.33, 150.34, 141.75, 134.97, 134.48, 133.27, 132.11 (2C), 129.16, 128.52 (3C), 128.32, 127.16 (4C), 126.74, 124.92, 122.21, 120.65, 119.95, 116.38 (2C), 107.67, 66.52, 53.54, 52.21, C 47 H 50 N 10 O5's [M+H] + HRMS (ESI) calculated: 835.40384, found: 835.4012. HPLC analysis: MeOH-HO (75:25), 6.70 min, purity 95.8%.

[0131] Example 28: 3-benzyl-1-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)azetidine-3-carbonyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ1093) [ka] This synthesis method is similar to that shown in Example 23. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.05 (s, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.24 (d, J = 8.2 Hz, 1H), 7.21 - 7.13 (m, 4H), 7.10 - 7.00 (m, 4H), 6.85 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 8.4, 2.2 Hz, 1H), 5.58 (t, J = 6.2 Hz, 1H), 5.06 (dd, J = 12.9, 5.5 Hz, 1H), 4.34 - 4.22 (m, 3H), 4.22 - 4.08 (m, 4H), 4.05 - 3.94 (m, 1H), 3.66 (s, 2H), 3.58 (s, 1H), 3.51 (s, 2H), 3.29 - 3.16 (m, 4H), 2.94 - 2.82 (m, 1H), 2.70 - 2.52 (m, 2H), 2.06 - 1.90 (m, 3H), 1.80 (d, J = 11.9 Hz, 2H), 1.41 (q, J = 12.3 Hz, 2H), 1.19 - 1.06 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.34, 170.59, 169.88, 167.92, 167.65, 162.50, 157.33, 155.46, 150.39, 141.70, 134.49, 134.25, 132.11 (2C), 129.20, 128.53 (3C), 128.32, 127.17 (4C), 126.76, 125.33, 122.22, 119.95, 117.67, 116.46 (2C), 114.80, 105.02, 54.09 (2C), C 49 H 50 N 10 O6 [M+H] + HRMS (ESI) calculated: 875.39876, found: 875.3958. HPLC analysis: MeOH-HO (75:25), 8.69 min, purity 97.7%.

[0132] Example 29: 3-benzyl-1-(4-(4-((E)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)acryloyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ1114) [ka] This synthesis method is similar to that shown in Example 23. 1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.05 (s, 1H), 8.48 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.71 (s, 2H), 7.63 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.31 - 7.21 (m, 3H), 7.21 - 7.13 (m, 4H), 7.07 (s, 4H), 5.59 (t, J = 6.4 Hz, 1H), 5.19 (dd, J = 13.0, 5.4 Hz, 1H), 4.27 (t, J = 11.9 Hz, 1H), 4.17 (d, J = 5.8 Hz, 2H), 3.95 (s, 2H), 3.76 (s, 2H), 3.58 (s, 1H), 2.97 - 2.83 (m, 1H), 2.69 - 2.56 (m, 2H), 2.13 - 2.04 (m, 2H), 1.96 (d, J = 11.9 Hz, 2H), 1.80 (d, J = 11.9 Hz, 2H), 1.41 (q, J = 12.1 Hz, 2H), 1.16 (q, J = 12.1 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 173.26, 170.31, 167.43, 167.23, 164.45, 162.49, 157.29, 150.37, 142.28, 141.79, 140.14, 135.37, 134.45, 132.59, 132.13 (2C), 131.66, 129.21, 128.51(3C), 128.31, 127.18(4C), 126.72, 124.38, 122.87, 122.63, 122.18, 119.95, 116.38 (2C), 53.54, 49.57 (2C), 48.90, 48.27, 45.38, 43.95, 42.19, 40.50, 31.76, 31.41, 30.88 (2C), 22.45. C 48 H 47 N9O6の[M+H]+ HRMS (ESI) calculated: 846.37221, found: 846.3687. HPLC analysis: MeOH-HO (75:25), 14.00 min, purity 99.3%.

[0133] Example 30: 3-benzyl-1-(4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)benzoyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ1130) [ka] This synthesis method is similar to that shown in Example 23. 1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.05 (s, 1H), 8.30 - 8.21 (m, 2H), 8.03 (d, J = 7.7 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.92 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.55 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.31 - 7.23 (m, 3H), 7.21 - 7.13 (m, 4H), 7.11 - 6.98 (m, 4H), 5.57 (t, J = 6.8 Hz, 1H), 5.19 (dd, J = 12.6, 5.3 Hz, 1H), 4.28 (t, J = 12.1 Hz, 1H), 4.16 (d, J = 5.7 Hz, 2H), 3.82 (s, 1H), 3.57 (s, 4H), 3.25 (s, 4H), 2.97 - 2.84 (m, 1H), 2.69 - 2.58 (m, 2H), 2.14 - 2.04 (m, 1H), 1.96 (d, J = 11.4 Hz, 2H), 1.80 (d, J = 12.0 Hz, 2H), 1.41 (q, J = 12.1 Hz, 2H), 1.14 (q, J = 12.1 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.26, 170.33, 169.02, 167.42, 167.39, 162.48, 157.27, 150.37, 146.31, 141.76, 138.78, 137.40, 134.44, 133.72, 132.81, 132.13 (2C), 130.67, 129.99, 129.25, 128.96, 128.51 (3C), 128.31, 127.93, 127.17 (4C), 126.72, 126.26, 124.58, 122.21, 122.18, 119.96, 116.46 (2C), 53.53, 49.57 (2C), 49.12, 48.28, 47.52, 43.95, 40.51, 31.75, 31.42 (2C), 30.88 (2C), 22.47.C 52 H 49 N9O6 [M+H] + HRMS (ESI) calculated: 896.38786, found: 896.3845. HPLC analysis: MeOH-HO (75:25), 19.82 min, purity 98.9%.

[0134] Example 31: 3-benzyl-1-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-1-pyrazole-3-carbonyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ1131) [ka] This synthesis method is similar to that shown in Example 23. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.19 (s, 1H), 9.05 (s, 1H), 8.49 (s, 1H), 8.44 (d, J = 8.3 Hz, 1H), 8.16 (s, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.31 - 7.21 (m, 3H), 7.21 - 7.13 (m, 4H), 7.11 - 6.97 (m, 4H), 5.60 (t, J = 6.2 Hz, 1H), 5.21 (dd, J = 13.0, 5.4 Hz, 1H), 4.29 (t, J = 12.2 Hz, 1H), 4.17 (d, J = 6.0 Hz, 2H), 3.83 (s, 4H), 3.58 (s, 1H), 3.31 (s, 4H), 2.98 - 2.85 (m, 1H), 2.69 - 2.57 (m, 2H), 2.15 - 2.04 (m, 1H), 1.97 (d, J = 12.6 Hz, 2H), 1.80 (d, J = 11.9 Hz, 2H), 1.41 (q, J = 12.9, 12.4 Hz, 2H), 1.14 (q, J = 12.9, 12.1 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.24, 170.29, 166.93, 166.88, 162.48, 162.33, 157.29, 150.33, 144.34, 143.30, 141.78, 134.44, 133.77, 132.17 (2C), 130.30, 129.21, 129.05, 128.51(3C), 128.31, 127.18 (4C), 126.73, 125.67, 125.25, 124.64, 122.17, 119.98, 119.96, C 49 H 47 N 11 O6 [M+H] + HRMS (ESI) calculated: 886.37835, found: 886.3749. HPLC analysis: MeOH-HO (75:25), 14.54 min, purity 96.4%.

[0135] Example 32: 3-benzyl-1-(4-(2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ1078) [ka] This synthesis method is similar to that shown in Example 23. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.31 - 7.21 (m, 3H), 7.21 - 7.13 (m, 4H), 7.10 - 6.99 (s, 4H), 5.59 (t, J = 6.0 Hz, 1H), 5.25 (s, 2H), 5.18 (dd, J = 12.7, 5.0 Hz, 1H), 4.28 (t, J = 10.4 Hz, 1H), 4.17 (d, J = 6.0 Hz, 2H), 3.67 - 3.56 (m, 5H), 3.32 (s, 2H), 3.24 (s, 2H), 3.02 (s, 3H), 3.00 - 2.88 (m, 1H), 2.81 - 2.70 (m, 1H), 2.60 - 2.54 (m, 1H), 2.06 (d, J = 9.7 Hz, 1H), 1.97 (d, J = 11.6 Hz, 2H), 1.80 (d, J = 11.9 Hz, 2H), 1.42 (q, J = 12.8, 12.4 Hz, 2H), 1.14 (q, J = 12.3, 11.6 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 172.28, 170.18, 167.28, 165.76, 165.60, 162.50, 157.33, 156.07, 150.34, 141.72, 137.14, 134.48, 133.54, 132.12 (2C), 129.17, 128.52 (3C), 128.32, 127.17 (4C), 126.75, 122.21, 120.71, 119.95, 116.58, 116.39 (2C), 116.03, 66.61, 53.54, 49.81, 49.13, 48.31, 48.15, 44.34, 43.94, 41.70, 40.43, 31.75, 31.55, 30.87. 48 H 49 N9O7 [M+H] + HRMS (ESI) calculated: 864.38277, found: 864.3804. HPLC analysis: MeOH-HO (75:25), 9.27 min, purity 97.5%.

[0136] Example 33: 3-benzyl-1-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-((1-propyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)cyclohexyl)urea (compound YJZ9108) [ka] This synthesis method is similar to that shown in Example 23. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.73 (s, 1H), 7.89 (s, 1H), 7.79 (dd, J = 8.5, 7.3 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.28 (dd, J = 8.4, 6.4 Hz, 3H), 7.21 - 7.13 (m, 3H), 7.09 - 7.00 (m, 4H), 5.57 (s, 1H), 5.25 (s, 2H), 5.11 (dd, J = 12.9, 5.4 Hz, 1H), 4.26 (s, 1H), 4.16 (d, J = 6.0 Hz, 2H), 4.09 (t, J = 6.8 Hz, 2H), 3.62 (s, 4H), 3.51 (s, 1H), 3.30 (s, 2H), 3.24 (s, 2H), 2.96 - 2.82 (m, 1H), 2.64 - 2.53 (m, 2H), 2.09 - 1.92 (m, 3H), 1.84 - 1.70 (m, 4H), 1.40 (q, J = 12.7 Hz, 2H), 1.16 - 1.03 (m, 2H), 0.76(s, 3H).

[0137] Example 34: N-(4-(4-(3-(3-benzyl-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)ureido)phenyl)piperazin-1-yl)butyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamide (compound YJZ9049) [ka] This synthesis method is similar to that shown in Example 23. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.05 (s, 1H), 7.97 (t, J = 4.9 Hz 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.33 - 7.21 m, 4H), 7.21 - 7.13 (m, 4H), 6.97 (d, J = 8.5 Hz, 1H), 6.69 (s, 1H), 6.61 (d, J = 7.6 Hz, 1H), 5.60 (t, J = 6.2 Hz, 1H), 5.12 (dd, J = 13.0, 5.4 Hz, 1H), 4.78 (s, 2H), 4.25 (t, J = 12.4 Hz, 1H), 4.18 (d, J = 5.9 Hz, 2H), 3.61 (d, J = 9.3 Hz, 1H), 3.25 - 3.08 (m, 6H), 2.96 - 2.83 (m, 1H), 2.63 - 2.53 (m, 2H), 2.48 - 2.44 (m, 2H), 2.32 (d, J = 6.6 Hz, 2H), 2.03 (d, J = 12.5 Hz, 1H), 1.97 (d, J = 12.0 Hz, 2H), 1.83 (d, J = 11.8 Hz, 2H), 1.48 (s, 4H), 1.40 (t, J = 12.4 Hz, 2H), 1.27 - 1.13 (m, 4H).

[0138] Example 35: N-(5-(4-(3-(3-benzyl-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)ureido)phenyl)piperazin-1-yl)pentyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamide (compound YJZ9048) [ka] The synthesis method and method of Example 23 are the same as those shown in Example 23. 1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.05 (s, 1H), 7.94 (t, J = 5.8 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.33 - 7.24 (m, 3H), 7.22 (d, J = 8.0 Hz, 1H), 7.20 - 7.14 (m, 4H), 6.97 (d, J = 8.5 Hz, 1H), 6.69 (s, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.60 (t, J = 6.1 Hz, 1H), 5.12 (dd, J = 12.9, 5.3 Hz, 1H), 4.77 (s, 2H), 4.28 (t, J = 12.3 Hz, 1H), 4.17 (d, J = 5.9 Hz, 2H), 3.61 (s, 1H), 3.20 - 3.11 (m, 6H), 2.96 - 2.82 (m, 1H), 2.65 - 2.53 (m, 2H), 2.47 (s, 2H), 2.29 (t, J = 7.4 Hz, 2H), 2.03 (dd, J = 11.8, 6.3 Hz, 1H), 1.97 (d, J = 11.6 Hz, 2H), 1.83 (d, J = 11.9 Hz, 2H), 1.44 (dd, J = 22.9, 10.2 Hz, 6H), 1.30 (d, J = 7.3 Hz, 2H), 1.26 - 1.14 (m, 2H).

[0139] Example 36: N-(6-(4-(3-(3-benzyl-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)ureido)phenyl)piperazin-1-yl)hexyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamide (compound YJZ9043) [ka] This synthesis method is similar to that shown in Example 23. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.05 (s, 1H), 7.93 (t, J = 5.7 Hz, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.33 - 7.24 (m, 3H), 7.22 (d, J = 7.8 Hz, 1H), 7.20 - 7.14 (m, 4H), 6.97 (d, J = 8.6 Hz, 1H), 6.69 (s, 1H), 6.61 (d, J = 7.6 Hz, 1H), 5.59 (t, J = 6.0 Hz, 1H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.77 (s, 2H), 4.27 (t, J = 11.8 Hz, 1H), 4.18 (d, J = 6.0 Hz, 2H), 3.62 (s, 1H), 3.16 (t, J = 6.2 Hz, 8H), 2.95 - 2.84 (m, 1H), 2.64 - 2.54 (m, 2H), 2.49 - 2.45 (m, 2H), 2.30 (t, J = 7.5 Hz, 2H), 2.08 - 2.00 (m, 1H), 1.97 (d, J = 12.1 Hz, 2H), 1.83 (d, J = 11.9 Hz, 2H), 1.50 - 1.35 (m, 6H), 1.33 - 1.26 (m, 4H), 1.23 - 1.14 (m, 2H).

[0140] Example 37: N-(7-(4-(3-(3-benzyl-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)ureido)phenyl)piperazin-1-yl)heptyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamide (compound YJZ9047) [ka] This synthesis method is similar to that shown in Example 23. 1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.05 (s, 1H), 7.92 (t, J = 5.6 Hz, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.28 (q, J = 8.2, 7.8 Hz, 3H), 7.22 (d, J = 7.8 Hz, 1H), 7.21 - 7.15 (m, 4H), 6.97 (d, J = 8.5 Hz, 1H), 6.69 (s, 1H), 6.61 (d, J = 7.6 Hz, 1H), 5.76 (s, 1H), 5.60 (t, J = 6.1 Hz, 1H), 5.12 (dd, J = 13.0, 5.4 Hz, 1H), 4.77 (s, 2H), 4.25 (t, J = 12.6 Hz, 1H), 4.18 (d, J = 6.0 Hz, 2H), 3.62 (s, 1H), 3.16 (dd, J = 8.9, 5.0 Hz, 7H), 2.95 - 2.84 (m, 1H), 2.65 - 2.54 (m, 2H), 2.48 (s, 2H), 2.30 (t, J = 7.5 Hz, 2H), 2.08 - 2.01 (m, 1H), 1.97 (d, J = 12.3 Hz, 2H), 1.83 (d, J = 11.9 Hz, 2H), 1.51 - 1.34 (m, 6H), 1.33 - 1.13 (m, 10H).

[0141] Example 38: 3-benzyl-1-(3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)butanoyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ9058) [ka] This synthesis method is similar to that shown in Example 23. 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.05 (s, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.61 (dt, J = 15.9, 7.8 Hz, 2H), 7.39 (d, J = 8.5 Hz, 1H), 7.35 - 7.24 (m, 3H), 7.22 (d, J = 7.9 Hz, 1H), 7.20 - 7.14 (m, 5H), 7.03 -6.97 (m, 2H), 6.72 (s, 1H), 6.70 - 6.61 (m, 2H), 5.61 (t, J = 6.1 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.26 (t, J = 12.1 Hz, 1H), 4.18 (d, J = 6.0 Hz, 2H), 3.68 - 3.54 (m, 5H), 3.23 - 3.09 (m, 4H), 2.93 - 2.82 (m, 1H), 2.62 - 2.54 (m, 2H), 2.46 (t, J = 7.0 Hz, 2H), 2.06 - 1.93 (m, 4H), 1.89 - 1.78 (m, 4H), 1.42 (q, J = 12.4 Hz, 2H), 1.18 (q, J = 12.0 Hz, 2H).

[0142] Example 39: 3-benzyl-1-(3-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)hexyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ9052) [ka] This synthesis method is similar to that shown in Example 23. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.05 (s, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.57 (dd, J = 8.6, 7.1 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.35 - 7.25 (m, 3H), 7.23 (d, J = 7.8 Hz, 1H), 7.21 - 7.13 (m, 4H), 7.09 (d, J = 8.6 Hz, 1H), 7.03 - 6.97 (m, 2H), 6.73 (s, 1H), 6.65 (d, J = 7.5 Hz, 1H), 6.54 (t, J = 5.9 Hz, 1H), 5.62 (t, J = 6.1 Hz, 1H), 5.04 (dd, J = 12.9, 5.3 Hz, 1H), 4.29 (t, J = 12.0 Hz, 1H), 4.18 (d, J = 6.0 Hz, 2H), 3.60 (s, 5H), 3.32 - 3.26 (m, 1H), 3.16 (d, J = 19.2 Hz, 4H), 2.93 - 2.81 (m, 1H), 2.62 - 2.53 (m, 2H), 2.37 (t, J = 7.3 Hz, 2H), 2.06 - 1.91 (m, 3H), 1.83 (d, J = 11.8 Hz, 2H), 1.59 (dp, J = 14.9, 7.2 Hz, 4H), 1.48 - 1.34 (m, 4H), 1.18 (q, J = 12.6 Hz, 2H).

[0143] Example 40: 3-benzyl-1-(3-(4-(8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)octyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ9053) [ka] This synthesis method is similar to that shown in Example 23. 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.04 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.59 - 7.54 (m, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.35 - 7.25 (m, 3H), 7.22 (d, J = 8.0 Hz, 1H), 7.20 - 7.14 (m, 4H), 7.08 (d, J = 8.6 Hz, 1H), 7.04 - 6.98 (m, 2H), 6.73 (s, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.52 (t, J = 6.0 Hz, 1H), 5.62 (t, J = 6.0 Hz, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.26 (t, J = 12.1 Hz, 1H), 4.17 (d, J = 6.0 Hz, 2H), 3.59 (s, 5H), 3.31 - 3.24 (m, 1H), 3.16 (d, J = 20.5 Hz, 4H), 2.93 - 2.81 (m, 1H), 2.62 - 2.53 (m, 2H), 2.35 (t, J = 7.4 Hz, 2H), 2.06 - 1.91 (m, 3H), 1.83 (d, J = 12.0 Hz, 2H), 1.61 - 1.48 (m, 4H), 1.41 (q, J = 12.5 Hz, 2H), 1.36 - 1.27 (m, 6H), 1.18 (q, J = 12.5 Hz, 2H).

[0144] Example 41: 3-benzyl-1-(3-(4-(10-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)decanoyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ9055) [ka] This synthesis method is similar to that shown in Example 23. 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.04 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.57 (dd, J = 8.6, 7.1 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.35 - 7.24 (m, 3H), 7.23 (d, J = 7.9 Hz, 1H), 7.21 - 7.13 (m, 4H), 7.07 (d, J = 8.6 Hz, 1H), 7.04 - 6.97 (m, 2H), 6.73 (s, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.51 (t, J = 5.9 Hz, 1H), 5.62 (t, J = 5.9 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.27 (t, J = 12.1 Hz, 1H), 4.17 (d, J = 6.0 Hz, 2H), 3.59 (s, 5H), 3.27 (p, J = 6.6 Hz, 2H) 3.16 (d, J = 20.9 Hz, 4H), 2.94 - 2.82 (m, 1H), 2.63 - 2.55 (m, 2H), 2.34 (t, J = 7.4 Hz, 2H), 2.06 - 1.90 (m, 3H), 1.83 (d, J = 11.9 Hz, 2H), 1.61 - 1.48 (m, 4H), 1.41 (q, J = 12.3 Hz, 2H), 1.36 - 1.12 (m, 12H).

[0145] Example 42: N-(3-(3-benzyl-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)ureido)phenyl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)butanamide (compound YJZ9062) [ka] This synthesis method is similar to that shown in Example 23. 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.13 (s, 1H), 9.04 (s, 1H), 7.72 (dd, J = 11.5, 7.9 Hz, 2H), 7.66 - 7.55 (m, 2H), 7.48 (s, 1H), 7.43 - 7.35 (m, 2H), 7.30 - 7.21 (m, 3H), 7.21 - 7.12 (m, 5H), 7.03 (d, J = 7.0 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.69 (t, J = 6.2 Hz, 1H), 5.79 (t, J = 6.1 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.27 (t, J = 11.8 Hz, 1H), 4.16 (d, J = 6.0 Hz, 2H), 3.58 (s, 1H), 2.94 - 2.81 (m, 1H), 2.64 - 2.53 (m, 2H), 2.45 (t, J = 7.2 Hz, 2H), 2.07 - 1.86 (m, 5H), 1.80 (d, J = 12.1 Hz, 2H), 1.42 (q, J = 12.2 Hz, 2H), 1.28 - 1.11 (m, 4H).

[0146] Example 43: N-(3-(3-benzyl-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)ureido)phenyl)-8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)octanamide (compound YJZ9059) [ka] This synthesis method is similar to that shown in Example 23. 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.03 (s, 1H), 9.04 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.65 - 7.52 (m, 2H), 7.49 (s, 1H), 7.43 - 7.34 (m, 2H), 7.30 - 7.20 (m, 4H), 7.20 - 7.14 (m, 4H), 7.07 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 6.52 (t, J = 5.9 Hz, 1H), 5.79 (t, J = 5.9 Hz, 1H), 5.04 (dd, J = 13.0, 5.4 Hz, 1H), 4.28 (t, J = 12.1 Hz, 1H), 4.16 (d, J = 5.9 Hz, 2H), 3.58 (s, 1H), 3.29 (p, J = 6.7 Hz, 2H)2.94 - 2.80 (m, 1H), 2.63 - 2.54 (m, 2H), 2.32 (t, J = 7.3 Hz, 2H), 2.06 - 1.91 (m, 3H), 1.79 (d, J = 12.0 Hz, 2H), 1.66 - 1.51 (s, 4H), 1.43 (q, J = 12.3 Hz, 2H), 1.37 - 1.31 (m, 4H), 1.28 - 1.22 (m, 2H), 1.21 - 1.10 (m, 2H).

[0147] Example 44: 3-benzyl-1-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)azetidin-3-ylmethyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ1102) [ka] Step 1: Preparation of tert-butyl 3-(4-(4-(3-benzyl-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)ureido)phenyl)piperazin-1-yl)methyl)azetidine-1-carboxylate (compound 11) [ka] KHCO (345 mg, 2.5 mmol) was added to compound 8 (620 mg, 1.2 mmol) and tert-butyl 3-(bromomethyl)azetidine-1-carboxylate 10 (630 mg, 2.5 mmol) mixed with DMF (40 mL). After stirring at 80 °C for 5 h, the reaction was filtered. The filtrate was concentrated by rotary evaporation under reduced pressure and purified by column chromatography to give 560 mg of a white solid (65% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.27 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.21 - 7.12 (m, 4H), 7.01 (q, J = 9.2 Hz, 4H), 5.57 (t, J = 6.1 Hz, 1H), 4.26 (t, J = 12.1 Hz, 1H), 4.16 (d, J = 6.0 Hz, 2H), 3.92 (s, 2H), 3.67 - 3.44 (m, 4H), 3.31 (s, 2H), 3.17 (d, J = 6.2 Hz, 4H), 2.89 (s, 1H), 2.73 (s, 1H), 2.57 (d, J = 7.2 Hz, 2H), 1.96 (d, J = 11.3 Hz, 2H), 1.79 (d, J = 11.9 Hz, 2H), 1.47 - 1.31 (m, 11H), 1.13 (q, J = 12.6 Hz, 2H).

[0148] Step 2: Preparation of 1-(4-(4-(azetidin-3-ylmethyl)piperazin-1-yl)phenyl)-3-benzyl-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (Compound 12) [ka] tert-Butyl 3-(4-(4-(3-benzyl-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)ureido)phenyl)piperazin-1-yl)methyl)azetidine-carboxylate 11 (100 mg, 0.14 mmol) was dissolved in DCM (4 mL) and TFA (2 mL) was added. The mixture was stirred and refluxed at 50° C. overnight. The reaction mixture was then concentrated under reduced pressure and purified by column chromatography to give 60 mg of a white solid (70% yield).

[0149] Step 3: 3-benzyl-1-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)azetidin-3-ylmethyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ1102) [ka] 2-(2,6-Dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione 13 (42.9 mg, 0.16 mmol) was dissolved in 6 mL of DMSO and DIPEA (25.1 mg, 0.19 mmol), and compound 12 (84.5 mg, 0.13 mmol) was added at room temperature. The resulting mixture was stirred at 120 °C for 8 hours. After the reaction, the solvent was removed in vacuo, and the residue was purified by column chromatography to give 71 mg of compound as a yellow solid (yield 63%). 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.05 (s, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.40 (d, J = 8.5 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.5 Hz, 4H), 7.09 - 6.95 (m, 4H), 6.79 (d, J = 2.1 Hz, 1H), 6.66 (dd, J = 8.4, 2.1 Hz, 1H), 5.58 (t, J = 6.1 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.30 (t, J = 12.4 Hz, 2H), 4.22 - 4.09 (m, 4H), 3.72 (dd, J = 8.4, 5.4 Hz, 2H), 3.59 (s, 1H), 3.21 (t, J = 4.8 Hz, 4H), 3.06 (p, J = 6.9 Hz, 1H), 2.95 - 2.81 (m, 1H), 2.67 (d, J = 7.2 Hz, 2H), 2.63 - 2.53 (m, 6H), 2.08 - 1.89 (m, 3H), 1.79 (d, J = 11.7 Hz, 2H), 1.41 (q, J = 12.3, 11.6 Hz, 2H), 1.13 (q, J = 12.4 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.33, 170.61, 167.99, 167.68, 162.49, 157.35, 155.66, 150.60, 141.76, 134.46, 134.28, 132.02 (2C), 128.68, 128.52 (3C), 128.31, 127.16 (4C), 126.74, 125.30, 122.20, 119.95, 117.11, 115.90 (2C), 114.55, 104.80, 62.22, 56.21 (2C), C 49 H 52 N 10 O5's [M+H] + HRMS (ESI) calculated: 861.41949, found: 861.4163. HPLC analysis: MeOH-HO (80:20), 11.34 min, purity 98.3%.

[0150] Example 45 Preparation of 3-benzyl-1-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)-piperazine-1-)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (Compound YJZ1105) [ka] The synthesis method is similar to that shown in Example 44. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.05 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.63 (t, J = 7.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.30 - 7.24 (m, 3H), 7.23 (d, J = 8.1 Hz, 1H), 7.20 - 7.12 (m, 4H), 7.01 (q, J = 8.8 Hz, 4H), 5.57 (t, J = 6.0 Hz, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.26 (t, J = 12.1 Hz, 1H), 4.16 (d, J = 6.0 Hz, 2H), 4.09 (d, J = 10.1 Hz, 2H), 3.65 - 3.53 (m, 1H), 3.26 - 3.12 (m, 4H), 3.00 (t, J = 12.3 Hz, 2H), 2.94 - 2.82 (m, 1H), 2.65 (t, J = 4.9 Hz, 4H), 2.62 - 2.59 (m, 1H), 2.59 - 2.53 (m, 2H), 2.07 - 1.86 (m, 5H), 1.78 (d, J = 11.6 Hz, 2H), 1.50 (q, J = 11.1 Hz, 2H), 1.41 (q, J = 12.5 Hz, 4H), 1.13 (q, J = 12.5, 11.9 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.37, 170.61, 168.11, 167.48, 162.50, 157.39, 155.22, 150.62, 141.70, 134.48, 131.99 (2C), 128.56, 128.52 (3C), 128.32, 127.14 (4C), 126.75, 125.53, 125.24, 122.23, 119.94, 118.17, 118.01, 115.79 (2C), 108.24, 60.99, 53.51, 49.20 (3C) 48.38 (2C) 50 H 54 N 10 O5's [M+H] + HRMS (ESI) calculated: 875.43514, found: 875.4322. HPLC analysis: MeOH-HO (80:20), 11.36 min, purity 99.2%.

[0151] Example 46: 3-benzyl-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)azetidin-3-yl(piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ1103) [ka] The synthesis method is similar to that shown in Example 44. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.05 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.23 (d, J = 7.9 Hz, 1H), 7.21 - 7.14 (m, 4H), 7.08 - 6.98 (m, 4H), 6.82 (d, J = 2.1 Hz, 1H), 6.68 (dd, J = 8.4, 2.1 Hz, 1H), 5.58 (t, J = 6.3 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.34 - 4.23 (m, 1H), 4.15 (t, J = 7.6 Hz, 4H), 3.94 (dd, J = 8.8, 4.9 Hz, 2H), 3.66 - 3.51 (m, 1H), 3.45 - 3.37 (m, 1H), 3.26 (t, J = 5.7 Hz, 4H), 2.94 - 2.80 (m, 1H), 2.64 - 2.53 (m, 6H), 2.06 - 1.99 (m, 1H), 1.96 (d, J = 14.5 Hz, 2H), 1.79 (d, J = 11.7 Hz, 2H), 1.41 (q, J = 12.4 Hz, 2H), 1.13 (q, J = 12.8 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.33, 170.61, 167.97, 167.67, 162.49, 157.35, 155.42, 150.54, 141.76, 134.47, 134.29, 132.04 (2C), 128.76, 128.52 (3C), 128.31, 127.16 (4C), 126.73, 125.35, 122.20, 119.95, 117.33, 115.94 (2C), 114.72, 104.97, 55.50 (2C), 54.62, C 48 H 50 N 10 O5's [M+H] + HRMS (ESI) calculated: 847.40384, found: 847.4000. HPLC analysis: MeOH-HO (75:25), 13.02 min, purity 97.9%.

[0152] Example 47: 3-benzyl-1-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)pyrrolidin-3-yl(piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (compound YJZ1096) [ka] The synthesis method is similar to that shown in Example 44. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.05 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.68 - 7.59 (m, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.28 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 8.1 Hz, 1H), 7.18 (t, J = 7.3 Hz, 4H), 7.04 (s, 4H), 6.99 (s, 1H), 6.87 (d, J = 9.0 Hz, 1H), 5.58 (d, J = 7.0 Hz, 1H), 5.06 (dd, J = 12.7, 5.4 Hz, 1H), 4.30 (t, J = 12.4 Hz, 1H), 4.16 (d, J = 5.9 Hz, 2H), 3.75 (t, J = 8.4 Hz, 1H), 3.66 - 3.53 (m, 2H), 3.42 (q, J = 8.8 Hz, 2H), 3.31 - 3.27 (m, 1H), 3.24 (t, J = 6.2 Hz, 4H), 3.02 (p, J = 7.6 Hz, 1H), 2.95 - 2.82 (m, 1H), 2.67 (s, 4H), 2.63 - 2.53 (m, 2H), 2.34 - 2.26 (m, 1H), 2.05 - 1.88 (m, 4H), 1.79 (d, J = 11.7 Hz, 2H), 1.41 (q, J = 12.4 Hz, 2H), 1.13 (q, J = 12.8 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.35, 170.65, 168.20, 167.74, 162.49, 157.36, 152.27, 150.57, 141.76, 134.46, 132.03 (2C), 128.74, 128.52 (4C), 128.31, 127.15 (4C), 126.74, 125.41, 122.21, 119.95, 116.22, 115.92 (2C), 115.71, 106.05, 63.97, 53.52, 52.42, 51.76 (2C), C 49 H 52 N 10 O5's [M+H] + HRMS (ESI) calculated: 861.41949, found: 861.4168. HPLC analysis: MeOH-HO (75:25), 15.48 min, purity 98.2%.

[0153] Example 48: 3-benzyl-1-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (YJZ1097) [ka] The synthesis method is similar to that shown in Example 44. 1H NMR (600 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.05 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.32 (s, 1H), 7.30 - 7.26 (m, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.21 - 7.13 (m, 4H), 7.02 (q, J = 8.7 Hz, 4H), 5.58 (t, J = 6.1 Hz, 1H), 5.07 (dd, J = 12.8, 5.5 Hz, 1H), 4.29 (t, J = 11.7 Hz, 1H), 4.16 (d, J = 6.0 Hz, 2H), 4.06 (d, J = 12.8 Hz, 2H), 3.65 - 3.54 (m, 1H), 3.26 - 3.15 (s, 4H), 2.99 (t, J = 12.3 Hz, 2H), 2.93 - 2.83 (m, 1H), 2.64 - 2.54 (m, 2H), 2.52 (m, 4H), 2.21 (d, J = 5.2 Hz, 2H), 2.05 - 1.99 (m, 1H), 1.99 - 1.93 (m, 2H), 1.92 - 1.85 (m, 1H), 1.85 - 1.75 (m, 4H), 1.41 (q, J = 12.4 Hz, 2H), 1.20 - 1.09 (m, 4H). 13C NMR (151 MHz, DMSO-d6) δ 173.30, 170.60, 168.12, 167.45, 162.48, 157.32, 155.48, 150.62, 141.81, 134.52, 134.42, 132.02 (2C), 128.67, 128.51 (3C), 128.31, 127.16 (4C), 126.71, 125.49, 125.28, 122.17, 119.96, 118.06, 117.80, 115.83 (2C), 108.21, 64.18, 53.68 C 51 H 56 N 10 O5's [M+H] + HRMS (ESI) calculated: 889.45079, found: 889.4473. HPLC analysis: MeOH-HO (80:20), 15.05 min, purity 96.9%.

[0154] Example 49: 3-benzyl-1-(4-(4-(1-(2-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperidin-4-yl)-piperazin-1-yl)phenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (YJZ1201) [ka] The synthesis method is similar to that shown in Example 44. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.05 (s, 1H), 7.77 - 7.68 (m, 2H), 7.63 (t, J = 7.9 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.23 (d, J = 7.0 Hz, 1H), 7.21 - 7.13 (m, 4H), 7.07 - 6.95 (m, 4H), 5.57 (t, J = 6.8 Hz, 1H), 5.11 (dd, J = 13.1, 5.3 Hz, 1H), 4.28 (t, J = 11.4 Hz, 1H), 4.16 (d, J = 5.8 Hz, 2H), 3.68 (d, J = 11.7 Hz, 2H), 3.58 (s, 1H), 3.21 (s, 4H), 2.99 - 2.82 (m, 3H), 2.68 (s, 4H), 2.64 - 2.54 (m, 3H), 2.08 - 1.89 (m, 5H), 1.78 (d, J = 9.6 Hz, 2H), 1.61 (q, J = 12.2 Hz, 3H), 1.41 (q, J = 14.5, 13.7 Hz, 2H), 1.13 (q, J = 13.1 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.25, 170.40, 167.17, 166.69, 162.47, 158.57 (d, J = 253.3 Hz, 1C), 157.32, 150.63, 146.01(d, J = 8.8 Hz, 1C), 141.82, 134.43, 132.02 (2C), 129.26 (d, J = 2.2 Hz, 1C), 128.65, 128.50 (3C), 128.30, 127.16 (4C), 126.71, 123.51(d, J = 9.6 Hz, 1C), 122.17, 119.96, 115.79 (2C), 114.23 (d, J = 4.8 Hz, 1C), 112.49 (d, J = 25.3 Hz, 1C), 60.86, 53.52, 52.46, 49.84, 49.81, C 50 H 53 N 10 O5F [M+H] + HRMS (ESI) calculated: 893.42572, found: 893.4229. HPLC analysis: MeOH-HO (80:20), 11.79 min, purity 95.8%.

[0155] Example 50: 1-(4-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)-piperazin-1-yl)phenyl)-3-(2-fluorobenzyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (YJZ1203) [ka] The synthesis method is similar to that shown in Example 44. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.05 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.34 (s, 1H), 7.29 - 7.14 (m, 6H), 7.14 - 7.08 (m, 1H), 7.03 (q, J = 8.6 Hz, 4H), 5.59 (s, 1H), 5.07 (dd, J = 13.4, 5.5 Hz, 1H), 4.31 - 4.17 (m, 3H), 4.10 (d, J = 12.7 Hz, 2H), 3.58 (s, 1H), 3.20 (s, 4H), 3.00 (t, J = 12.3 Hz, 2H), 2.95 - 2.82 (m, 1H), 2.66 (s, 4H), 2.63 - 2.53 (m, 3H), 2.07 - 1.86 (m, 5H), 1.79 (d, J = 11.9 Hz, 2H), 1.50 (q, J = 11.5 Hz, 2H), 1.44 - 1.33 (m, 2H), 1.20 - 1.09 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.30, 170.59, 168.09, 167.44, 162.47, 161.01 (d, J = 243.4 Hz, 1C), 157.23, 155.23, 150.66, 134.51, 134.43, 131.98 (2C), 129.03 (d, J = 4.7 Hz, 2C), 128.58, 128.55, 128.53, 128.44 (d, J = 14.2 Hz, 1C), 128.30, 125.49, 125.29, 124.61(d, J = 3.3 Hz, 1C), 122.17, 119.96, 118.18, 118.10, 115.81 (2C), 115.12 (d, J = 21.1 Hz, 1C), 108.29, 61.02, 53.57, 49.25 (2C), 49.21, C 50 H 53 N 10 O5F [M+H] + HRMS (ESI) calculated: 893.42572, found: 893.4224. HPLC analysis: MeOH-HO (80:20), 9.19 min, purity 96.2%.

[0156] Example 51: 3-benzyl-1-(6-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)pyrazin-1-yl)pyridin-3-yl]-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (YJZ1205) [ka] The synthesis method is similar to that shown in Example 44. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.05 (s, 1H), 7.91 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.70 - 7.58 (m, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.34 (s, 2H), 7.31 - 7.21 (m, 4H), 7.21 - 7.13 (m, 4H), 6.88 (d, J = 9.0 Hz, 1H), 6.05 (t, J = 6.6 Hz, 1H), 5.07 (dd, J = 12.8, 5.3 Hz, 1H), 4.26 (t, J = 12.8 Hz, 1H), 4.12 (dd, J = 18.7, 9.2 Hz, 4H), 3.60 (s, 1H), 3.52 (s, 4H), 3.00 (t, J = 12.4 Hz, 2H), 2.94 - 2.81 (m, 1H), 2.70 - 2.53 (m, 7H), 2.07 - 1.93 (m, 3H), 1.90 (d, J = 12.2 Hz, 2H), 1.78 (d, J = 11.7 Hz, 2H), 1.57 - 1.33 (m, 4H), 1.09 (q, J = 12.9 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 173.30, 170.59, 168.09, 167.44, 162.47, 158.32, 157.45, 155.22, 149.85, 141.82, 140.60, 134.51, 134.43, 128.48 (3C), 128.31, 127.18 (4C), 126.68, 125.49, 124.43, 122.17, 119.97, 118.17, 118.09, 108.28, 107.40, 61.12, 55.39, 53.49, 49.21(2C), 49.10 (2C), 47.10 (2C), 45.29, 43.96, 31.70, 31.45, 30.85 (2C), 27.66 (2C), 22.66. C 49 H 53 N 11 O5の[M+H] +HRMS (ESI) calculated: 876.43039, found: 876.4276. HPLC analysis: MeOH-HO (80:20), 6.94 min, purity 97.8%.

[0157] Example 52: 3-benzyl-1-(6-(4-(1-(1-(2-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperidin-4-yl)pyrrolidin-1-yl)pyridin-3-yl]-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (YJZ1206) [ka] The synthesis method is similar to that shown in Example 44. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.05 (s, 1H), 7.92 (s, 1H), 7.73 (t, J = 9.7 Hz, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 9.1 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.21 (d, J = 7.5 Hz, 1H), 7.21 - 7.13 (m, 3H), 6.90 (d, J = 9.0 Hz, 1H), 6.05 (t, J = 5.4 Hz, 1H), 5.11 (dd, J = 13.0, 5.3 Hz, 1H), 4.28 (t, J = 12.3 Hz, 1H), 4.15 (d, J = 6.0 Hz, 2H), 3.68 (d, J = 11.9 Hz, 2H), 3.63 - 3.48 (m, 5H), 2.99 - 2.82 (m, 3H), 2.64 (s, 4H), 2.59 - 2.52 (m, 3H), 2.08 - 1.87 (m, 5H), 1.79 (d, J = 11.7 Hz, 2H), 1.61 (d, J = 12.0 Hz, 2H), 1.41 (q, J = 13.6, 13.0 Hz, 2H), 1.10 (d, J = 12.8 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 173.25, 170.40, 167.17, 166.69, 162.47, 158.33, 157.45, 156.89 (d, J = 253.4 Hz, 1C), 149.86, 146.00 (d, J = 8.49 Hz, 1C), 141.83, 140.60, 134.42, 129.26 (d, J = 2.2 Hz, 1C), 128.48 (3C), 128.30, 127.19 (4C), 126.69, 125.28, 124.42, 123.52 (d, J = 9.9 Hz, 1C), 122.17, 119.97, 114.24 (d, J = 4.5 Hz, 1C), 112.48 (d, J = 25.5 Hz, 1C), 107.40, 60.96, 55.39, 53.50, 49.84 (2C), C 49 H 52 N 11 O5F [M+H] + HRMS (ESI) calculated: 894.42097, found: 894.4176. HPLC analysis: MeOH-HO (80:20), 8.79 min, purity 98.9%.

[0158] Example 53: 3-benzyl-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)piperidin-1-ylphenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (YJZ1202) [ka] Step 1: Preparation of tert-butyl ((1r,4r)-4-((4-bromophenyl)amino)cyclohexyl)carbamate (compound 16) [ka] Compound 14 (5.0 g, 17.7 mmol), compound 15 (3.2 g, 14.7 mmol), Pd2(dba)3 (1.37 g, 1.5 mmol), Xantphos (1.7 g, 2.94 mmol), and tert-ButONa (2.8 g, 29.4 mmol) were mixed and dissolved in 150 mL of toluene. After purging with argon three times, the reaction mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction mixture was filtered through Celite and concentrated by rotary evaporation under reduced pressure. The residue was purified by column chromatography to give 3.9 g of a yellow solid (72% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.15 (d, J = 6.8 Hz, 2H), 6.76 (d, J = 7.9 Hz, 1H), 6.50 (d, J = 8.9 Hz, 2H), 5.60 (d, J = 8.0 Hz, 1H), 3.27 - 3.13 (m, 1H), 3.12 - 2.99 (m, 1H), 1.94 (d, J = 12.7 Hz, 2H), 1.79 (d, J = 12.4 Hz, 2H), 1.38 (s, 9H), 1.26 (q, J = 12.2, 11.3 Hz, 2H), 1.14 (q, J = 12.2 Hz, 2H).

[0159] Step 2: Preparation of tert-butyl ((1r,4r)-4-(3-benzyl-1-(4-bromophenyl)ureido)cyclohexyl)carbamate (compound 17) [ka] Compound 16 (3.9 g, 10.6 mmol) was dissolved in 4 mL of DMF, and benzyl isocyanate 6 (4.2 g, 31.7 mmol) and DIPEA (1.59 g, 12.3 mmol) were added. The mixture was reacted at 95 °C for 5 h. The solvent was removed by rotary evaporation, and the residue was purified by column chromatography to give 3.7 g of a yellow solid (69% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 8.4 Hz, 2H), 7.30 - 7.22 (m, 2H), 7.20 - 7.14 (m, 3H), 7.11 (d, J = 7.5 Hz, 2H), 6.66 (d, J = 8.0 Hz, 1H), 5.98 (t, J = 6.2 Hz, 1H), 4.22 - 4.07 (m, 3H), 3.02 - 2.87 (m, 1H), 1.73 (d, J = 10.8 Hz, 4H), 1.35 (s, 9H), 1.24 (q, J = 12.5 Hz, 2H), 1.01 (q, J = 12.5, 12.0 Hz, 2H).

[0160] Step 3: Preparation of 1-((1r,4r)-4-aminocyclohexyl)-3-benzyl-1-(4-bromophenyl)urea (compound 18) [ka] Compound 17 (3.7 g, 7.3 mmol) was dissolved in 5 mL of DCM and 2.5 mL of trifluoroacetic acid (TFA) was added. The mixture was heated to 55° C. and refluxed for 6 h. The solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by column chromatography to give 2.5 g of the desired compound as a yellow solid (70% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 8.0 Hz, 2H), 7.30 - 7.22 (m, 2H), 7.21 - 7.14 (m, 3H), 7.11 (d, J = 8.0 Hz, 2H), 5.95 (t, J = 6.1 Hz, 1H), 4.20 (t, J = 11.9 Hz, 1H), 4.14 (d, J = 6.1 Hz, 2H), 2.26 (t, J = 7.8 Hz, 1H), 1.80 - 1.60 (m, 4H), 1.10 (q, J = 11.9, 11.2 Hz, 2H), 0.98 (q, J = 12.5, 12.1 Hz, 2H).

[0161] Step 4: Preparation of 3-benzyl-1-(4-bromophenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (Compound 19) [ka] Compound 18 (2.5 g, 5.1 mmol) was dissolved in 15 mL of DMF. 2-Chloroquinazoline 4 (1.0 g, 6.1 mol) and CsCO (2.0 g, 6.1 mol) were added, and the mixture was stirred at room temperature for 15 min and then heated to 60 °C for 40 min. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by column chromatography to give 1.9 g (70% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.69 - 7.59 (m, 3H), 7.40 (d, J = 8.5 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.21 - 7.12 (m, 6H), 6.02 (t, J = 6.2 Hz, 1H), 4.29 (t, J = 12.5 Hz, 1H), 4.16 (d, J = 5.9 Hz, 2H), 3.68 - 3.53 m, 1H), 1.98 (d, J = 13.6 Hz, 2H), 1.81 (d, J = 12.1 Hz, 2H), 1.42 (q, J = 12.4 Hz, 2H), 1.13 (q, J = 12.5 Hz, 2H).

[0162] Step 5: Preparation of tert-butyl 4-(1-(4-(3-benzyl-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)ureido)phenyl)piperidin-4-yl)piperazine-1-carboxylate (Compound 21) [ka] Compound 19 (1.9 g, 3.6 mmol), compound 20 (1.25 g, 4.6 mmol), Pd2(dba)3 (327 mg, 0.36 mmol), Xantphos (414 mg, 0.72 mmol), and tert-ButONa (688 mg, 7.2 mmol) were mixed and dissolved in 80 mL of toluene. After purging with argon three times, the reaction mixture was heated to 100 °C overnight. After completion of the reaction, the mixture was filtered through Celite and concentrated by rotary evaporation under reduced pressure. The residue was purified by column chromatography to give 1785 mg of a pale yellow solid (69% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.66 - 7.60 (m, 1H), 7.40 (d, J = 9.1 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.24 - 7.13 (m, 5H), 7.04 - 6.95 (m, 4H), 5.53 (t, J = 7.4 Hz, 1H), 4.29 (t, J = 12.6 Hz, 1H), 4.16 (d, J = 6.0 Hz, 2H), 3.79 (d, J = 12.1 Hz, 2H), 3.65 - 3.51 (m, 1H), 3.30 (s, 4H), 2.71 (t, J = 12.1 Hz, 2H), 2.46 (s, 4H), 2.35 (t, J = 11.5 Hz, 1H), 2.01 - 1.91 (m, 2H), (d, J = 15.7 Hz, 2H), 1.87 (d, J = 11.8 Hz, 2H), 1.78 (d, J = 12.0 Hz, 2H), 1.48 (q, J = 12.0 Hz, 2H), 1.44 - 1.32 (m, 11H), 1.13 (q, J = 12.5 Hz, 2H). The above reaction product was dissolved in 5 mL of dichloromethane and 2.5 mL of trifluoroacetic acid was added. The mixture was refluxed for 4 hours at 55° C. After removal of the Boc protecting group, 1.1 g was obtained and used in the next step.

[0163] Step 6: Preparation of 3-benzyl-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)piperidin-1-ylphenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (YJZ1202) [ka] YJZ1102 was obtained by the same method as in Step 3 of Example 44 using compound 21. 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.05 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.34 (s, 1H), 7.31 - 7.21 (m, 4H), 7.21 - 7.13 (m, 4H), 7.01 (s, 4H), 5.55 (t, J = 6.5 Hz, 1H), 5.08 (dd, J = 13.0, 5.4 Hz, 1H), 4.28 (t, J = 12.3 Hz, 1H), 4.16 (d, J = 6.0 Hz, 2H), 3.81 (d, J = 11.7 Hz, 2H), 3.59 (s, 1H), 3.44 (s, 4H), 2.95 - 2.83 (m, 1H), 2.74 (t, J = 11.8 Hz, 2H), 2.66 (s, 4H), 2.63 - 2.53 (m, 2H), 2.40 (t, J = 11.0 Hz, 1H), 2.06 - 1.87 (m, 5H), 1.79 (d, J = 11.9 Hz, 2H), 1.53 (q, J = 11.9 Hz, 2H), 1.41 (q, J = 12.5 Hz, 2H), 1.13 (q, J = 12.6 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.29, 170.56, 168.04, 167.47, 162.47, 157.33, 155.73, 150.64, 141.80, 134.42, 134.32, 131.99 (2C), 128.51 (3C), 128.38, 128.30, 127.16 (4C), 126.71, 125.36, 122.17, 119.96, 118.76, 118.21, 116.24 (2C), 108.28, 61.03, 53.53, 49.24, C 50 H 54 N 10 O5's [M+H] + HRMS (ESI) calculated: 875.43514, found: 875.4315. HPLC analysis: MeOH-HO (80:20), 9.43 min, purity 95.2%.

[0164] Example 54: 3-benzyl-1-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)-piperazin-1-yl)-3-fluorophenyl)-1-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)urea (YJZ1204) [ka] The synthesis method is similar to that shown in Example 53. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.05 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.40 (d, J = 8.5 Hz, 1H), 7.34 (s, 1H), 7.31 - 7.21 (m, 4H), 7.21 - 7.14 (m, 4H), 7.06 (t, J = 9.2 Hz, 1H), 7.02 - 6.91 (m, 2H), 5.92 (t, J = 6.4 Hz, 1H), 5.07 (dd, J = 13.2, 5.4 Hz, 1H), 4.24 (t, J = 13.3 Hz, 1H), 4.10 (d, J = 12.7 Hz, 2H), 3.67 - 3.54 (m, 1H), 3.08 (s, 4H), 3.00 (t, J = 12.3 Hz, 2H), 2.94 - 2.82 (m, 1H), 2.67 (s, 4H), 2.63 - 2.53 (m, 3H), 2.07 - 1.93 (m, 3H), 1.90 (d, J = 12.4 Hz, 2H), 1.81 (d, J = 11.8 Hz, 2H), 1.50 (q, J = 11.8 Hz, 2H), 1.40 (q, J = 12.2 Hz, 2H), 1.14 (q, J = 11.9 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.30, 170.59, 168.09, 167.44, 162.48, 157.02, 155.23, 153.97 (d, J = 246.4 Hz, 1C), 141.77, 139.82 (d, J = 8.1 Hz, 1C), 134.51, 134.44, 132.01 (d, J = 9.2 Hz, 1C), 128.49 (3C), 128.32, 128.04, 127.17 (4C), 126.70, 125.49, 122.18, 119.97, 119.43, 119.30 (d, J = 14.5 Hz, 1C), 118.09 (d, J = 14.1 Hz, 1C), 108.29, 61.06, 53.80, 50.74, 49.27 (2C), 49.21 (2C), 49.06, 47.10 (2C), 43.94, 40.51, 31.76, 31.45, 30.77 (2C), 27.64 (2C), 22.66.C 50 H 53 N 10 O5F [M+H] + HRMS (ESI) calculated: 893.42572, found: 893.4225. HPLC analysis: MeOH-HO (80:20), 10.01 min, purity 95.8%.

[0165] Example 55: Testing the degradation activity of representative compounds against CDK12 / 13 in MDA-MB-231 cells Experimental Method: The cell line MDA-MB-231 was obtained from the American Type Culture Collection (ATCC). For detection, conventional Western blot was used as follows: MDA-MB-231 cells were cultured in 12-well plates at 2x10 5Cells were seeded at a density of 1 mL per well at 1000 kJ / mL and cultured overnight in an incubator to allow attachment. A specific concentration of compound was then added and allowed to act for 15 hours. Cells were lysed with lysis buffer, and protein samples were collected. An appropriate amount of the sample was taken for SDS-PAGE electrophoresis. After electrophoresis, the proteins were transferred to a polyvinylidene fluoride (PVDF) membrane using a wet electrophoretic transfer system. The electrophoretically transferred PVDF membrane was cut into several strips and then placed in blocking solution (5% skim milk powder diluted in TBS containing 0.1% Tween 20) and blocked for 1.5 hours at room temperature. Primary antibody solutions were prepared by diluting the primary antibody against the corresponding target protein in TBS containing 0.1% Tween 20 according to the dilution requirements of different antibodies, e.g., 1:1000 (CST), 1:3000 (Proteintech, Bethyl), and 1:200 (Santacruz). The blocked membrane was placed in the corresponding primary antibody solution and incubated at 4°C for 12–14 hours. Next, the cells were washed three times with TBS containing 0.1% Tween 20 for 5 minutes each time. After washing, the membrane was placed in secondary antibody solution (horseradish peroxidase-conjugated goat anti-rabbit IgG, diluted 1:2000 in TBS containing 0.1% Tween 20) and incubated at room temperature for 2 hours. After washing the membrane three times as described above, the membrane was developed with StarSignal plus reagent (GenStar®) and Omni-ECL reagent (Yazyme®) and photographed on an Amersham Imager 800 system.

[0166] The results in Figure 1 show that some compounds, such as compounds ZLC4-77, ZLC4-91, ZLC5-6, ZLC5-11, ZLC7-36, ZLC5-106, ZLC6-1, ZLC6-37, ZLC6-42, and ZLC6-103, can effectively reduce CDK12 and CDK13 protein levels in cells. The results in Figure 2 show that compounds ZLC4-91 and ZLC5-11 can degrade CDK12 and CDK13 proteins in MDA-MB-231 cells in a time-dependent manner, and that these proteins were almost completely degraded after 15 hours of treatment at a concentration of 1 μM. Furthermore, these compounds exerted a time-dependent degrading effect on cyclin K, a partner protein of CDK12 and CDK13. After 15 hours, cyclin K protein in the cells was almost completely degraded.

[0167] The present inventors further measured the degradation of CDK12 and CDK13 proteins in MDA-MB-231 cells by representative compounds at different concentrations. These experimental results show that these representative compounds can degrade CDK12 and CDK13 proteins in MDA-MB-231 cells in a dose-dependent manner, and that these target proteins can be effectively degraded at a concentration of 1 μM (Figure 2).

[0168] Figure 1 shows (A) the WB results of CDK12 and CDK13 protein degradation after 15 hours of treatment of MDA-MB-231 cells with 0.1 μM of several compounds; (B) the WB results of CDK12 and CDK13 protein degradation after 15 hours of treatment of MDA-MB-231 cells with 0.3 μM of several compounds; (C) the CDK12 / CDK13 levels obtained by quantifying the band density values ​​in the WB image (Figure A), with DMSO as the reference standard; and (D) the CDK12 / CDK13 levels obtained by quantifying the band density values ​​in the WB image (Figure B), with DMSO as the reference standard.

[0169] Figure 2 shows (A) WB measurements of the time course of CDK12 and CDK13 protein degradation in MDA-MB-231 cells by representative compounds, and (B) WB measurements of intracellular CDK12 / 13 protein levels after 15 minutes of treatment of MDA-MB-231 cells with different concentrations of representative compounds.

[0170] Example 56: Testing the growth inhibitory activity of compounds against triple-negative breast cancer cells MDA-MB-231 The cell proliferation inhibitory activity of the compounds was measured using the Cell Counting Kit-8 cell viability assay (Selleck.cn). The cells were seeded into 384-well plates (CORNING® PS 3701) containing the corresponding medium and incubated in a 37°C incubator with 5% CO2. After overnight incubation, high-concentration stock solutions of each compound to be tested were prepared. The compounds were added to the 384-well plate in a concentration gradient using an Echo® 650 liquid handler (LABCYTE®). After administration, the cell plate was placed in a 37°C incubator with 5% CO2 and incubated for 5 days. Next, 5 μL of cck-8 reagent was added to each well of the 384-well plate using a MULTIDROP® (Thermo Scientific™) and the plate was returned to the incubator and incubated for 1.5–2 hours. After incubation, the plate was removed and centrifuged to remove air bubbles. The absorbance of each well at 450 nm and 650 nm was acquired using EnVision® (PerkinElmer®). Data were processed and analyzed using GraphPad Prism software (GraphPad Software Inc.).

[0171] The results in Figure 3 show that compounds that can effectively reduce CDK12 and CDK13 protein levels, such as ZLC4-77, ZLC4-91, ZLC5-6, ZLC5-31, and ZLC6-1, can effectively inhibit the proliferation of triple-negative breast cancer cells MDA-MB-231. The IC 50 were 610.4 nM, 622.5 nM, 497.9 nM, 389.0 nM and 288.6 nM, respectively.

[0172] Example 57: In vivo pharmacokinetic studies of representative compounds (zlc-4-91 and zlc-4-93) as degraders of cyclin-dependent kinase 12 / 13 (CDK12 / 13) Pharmacokinetic and bioavailability studies in rats. SD rats received a single oral (10 mg / kg), intravenous (2.5 mg / kg), and intraperitoneal (10 mg / kg) dose, followed by blood samples at appropriate time points. Heparin was added for anticoagulation, and the samples were centrifuged at 8000 rpm for 6 minutes. The supernatants were collected and stored at -20°C for HPLC-MS analysis. The blood samples were subjected to protein precipitation with acetonitrile at 12000 rpm for 10 minutes, and the supernatants were used for HPLC-MS analysis. The data were fitted with parameters in DAS2.0 to obtain compartmental and noncompartmental model parameters, respectively. The oral bioavailability of the compounds was calculated based on the area under the plasma concentration-time curve (AUC) data. The results are shown in Table 1. These experimental results (Table 1) demonstrate that the representative compounds zlc-4-91 and zlc-4-93 have excellent oral pharmacokinetic properties. [Table 1]

[0173] Example 58: Testing the degradation activity of representative compounds against CDK12 / 13 in 22RV1 cells Experimental Method: The cell line, i.e., the 22RV1 cell line, was obtained from the American Type Culture Collection (ATCC). Conventional Western blotting was used for detection as follows: 22RV1 cells were seeded in a 12-well plate at a specific number and cultured overnight in an incubator to allow attachment. A specific concentration of compound was then added and allowed to act for 6 hours. The cells were lysed with lysis buffer, and samples were collected. An appropriate amount of sample was then taken for SDS-PAGE electrophoresis. After electrophoresis, proteins were transferred to nitrocellulose membranes using a semi-dry electrophoretic transfer system. The nitrocellulose membranes were placed in blocking solution (5% nonfat milk powder diluted in TBS containing 0.1% Tween 20) and blocked for 2 hours at room temperature. These membranes were then placed in primary antibody solution (diluted 1:1000 in TBS containing 0.1% Tween 20) and incubated overnight at 4°C. The cells were washed three times with TBS containing 0.1% Tween 20 for 15 minutes each time. The membrane was placed in a secondary antibody solution (horseradish peroxidase-conjugated goat anti-rabbit IgG, diluted 1:1000 in TBS containing 0.1% Tween 20) and incubated for 1 hour at room temperature. After washing the membrane three times as described above, the membrane was developed with ECL plus reagent and photographed using an Amersham Imager 600 system.

[0174] The results in Figure 4 show that some compounds, such as compounds YJZ9069, YJZ1102, YJZ1105, YJZ1201, YJZ1202, YJZ1203, YJZ1204, YJZ1097, YJZ1205, and YJZ1206, can effectively reduce CDK12 and CDK13 protein levels in cells. Among them, compound YJZ9069 can dose-dependently degrade CDK12 and CDK13 proteins in 22RV1 cells. After treating 22RV1 cells with compound YJZ9069 at a concentration of 0.5 μM for 15 hours, CDK12 and CDK13 proteins in the cells were almost completely degraded, and phosphorylation of serine 2 (phoSer2) in the C-terminal domain of RNA polymerase II (RNA Pol II) was dose-dependently inhibited.

[0175] We further measured the degradation of CDK12 and CDK13 proteins in 22RV1 cells by representative compounds YJZ9069, YJZ1201, YJZ1202, YJZ1203, YJZ1204, YJZ1097, YJZ1205, and YJZ1206 at different concentrations (Figure 2). The results of WB experiments showed that representative compounds YJZ9069, YJZ1201, YJZ1202, YJZ1203, YJZ1204, YJZ1097, YJZ1205, and YJZ1206 could dose-dependently reduce CDK12 and CDK13 protein levels in 22RV1 cells, and at a concentration of 100 nM, almost completely degraded CDK12 and CDK13 proteins in the cells (Figure 5).

[0176] Figure 4 shows (A) WB results of CDK12 and CDK13 protein degradation after 6 hours of treatment of 22RV1 cells with several compounds at a concentration of 500 nM. (B) Compound YJZ9069 dose-dependently degrades CDK12 and CDK13 proteins and dose-dependently inhibits the phosphorylation of serine 2 (phoSer2) in the C-terminal domain of RNA polymerase II (RNA Pol II) in 22RV1 cells. (C) WB results of CDK12 and CDK13 protein degradation after 6 hours of treatment of LnCap cells with several compounds at a concentration of 500 nM. (D) Protein levels were measured by quantifying the intensity values ​​of the bands in the WB images (Figures A and C), using DMSO as a reference standard.

[0177] Figure 5 shows the results of WB measurement of intracellular CDK12 and CDK13 protein levels after treating 22RV1 cells with different concentrations of representative compounds YJZ9069, YJZ1201, YJZ1202, YJZ1203, YJZ1204, YJZ1097, YJZ1205, and YJZ1206 for 6 hours.

[0178] Example 59: Testing the growth inhibitory activity of compounds against prostate cancer VCap cells The cell proliferation inhibitory activity of the compounds was measured using a CellTiter-Glo Luminescent Cell Viability Assay (Promega, Madison, WI). Cells were seeded in 96-well plates in their respective media and incubated at 37°C in a 5% CO2 incubator. After overnight incubation, serial dilutions of the compounds were prepared and added to the 96-well plates. A volume of CellTiter-Glo reagent equal to the volume of cell culture medium present in each well was added (e.g., 100 microliters of the reagent was added to 100 microliters of culture medium in a 96-well plate). The contents were mixed on an orbital shaker for 2 minutes to induce cell lysis. The 96-well plate was incubated at room temperature for 10 minutes to stabilize the luminescence signal. Luminescence was recorded: the luminescence signal of each well was acquired using an Infinite M1000 Pro plate reader (Tecan, Zurich, Switzerland), and the data was analyzed using GraphPad Prism software (GraphPad Software Inc, La Jolla, CA).

[0179] The results in Figure 6 show that compounds that can effectively reduce CDK12 and CDK13 protein levels, such as YJZ9069, YJZ1102, YJZ1105, YJZ1201, YJZ1202, YJZ1203, YJZ1204, YJZ1097, YJZ1205, and YJZ1206, can strongly inhibit the proliferation of prostate cancer Vcap cells, and the IC 50 The IC values ​​for the CDK12 and CDK13 proteins were 22.90 nM, 16.31 nM, 15.11 nM, 64.4 nM, 17.46 nM, 18.78 nM, 23.31 nM, 3.93 nM, and 13.50 nM, respectively. Compounds that cannot effectively induce the degradation of CDK12 and CDK13 proteins, such as YJZ9055 and YJZ1078, showed IC values ​​of 2202 nM and >5 μM, respectively, against the VCap cell line. 50 It was shown that the effective inhibition of Vcap cell proliferation by this series of compounds was due to the degradation of CDK12 and CDK13 proteins.

[0180] Example 60: In vivo pharmacokinetic studies of representative compounds YJZ9069, YJZ1102, YJZ1105, YJZ1201, YJZ1202, YJZ1203, YJZ1204, YJZ1097, YJZ1205, and YJZ1206 as degraders of cyclin-dependent kinase 12 / 13 (CDK12 / 13) Pharmacokinetic and bioavailability studies in rats. SD rats received a single oral (10 mg / kg), intravenous (2.5 mg / kg), and intraperitoneal (10 mg / kg) dose, followed by blood samples at appropriate time points. Heparin was added for anticoagulation, and the samples were centrifuged at 8000 rpm for 6 minutes. The supernatants were collected and stored at -20°C for HPLC-MS analysis. The blood samples were subjected to protein precipitation with acetonitrile at 12000 rpm for 10 minutes, and the supernatants were used for HPLC-MS analysis. The data were fitted with parameters in DAS2.0 to obtain compartmental and noncompartmental model parameters, respectively. The oral bioavailability of the compound was calculated based on the area under the plasma concentration-time curve (AUC) data. The results are shown in Tables 2–6. The experimental results (Tables 2 to 6) show that the representative compounds YJZ1102, YJZ1105, YJZ1201, YJZ1202, YJZ1203, YJZ1204, YJZ1097, YJZ1205 and YJZ1206 have excellent oral pharmacokinetic properties. [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0181] All documents mentioned in this specification are incorporated by reference into this application to the same extent as if each document were individually incorporated by reference. The above examples merely represent some embodiments of the present invention, and although the descriptions are relatively specific and detailed, they should not be understood as limiting the scope of the present invention patent. The technical features of the above examples can be arbitrarily combined. For the sake of brevity, not all possible combinations of the technical features in the above examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered within the scope of this specification.

Claims

1. A compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a prodrug molecule thereof: 【Chemistry 1】 In the formula, Z is CH 2 or CO, V is, 【Chemistry 2】 is selected from the group consisting of X and Y are each independently N, CH, or CR 3 and R 3 is halogen, cyano, hydroxyl, amino, C 1 -C 3 Alkyl, halogenated C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, halogenated C 1 -C 3 Alkoxy, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocyclyl; B is, 【Transformation 3】 NH, O, CO, or CH 2 wherein each of U and W is independently selected from the group consisting of N or CH; and each of m, p, m', and p' is independently 0, 1, 2, or 3; Ring A is 【Chemistry 4】 is selected from the group consisting of Q and W are each independently selected from CH or N; R' is independently hydrogen, halogen, cyano, hydroxy, substituted hydroxy, amino, substituted amino, C 1 -C 5 Alkyl, halogenated C 1 -C 5 Alkyl, C 1 -C 5 Alkoxy, halogenated C 1 -C 5 Alkoxy, or C 3 -C 8 cycloalkyl, and when Q and W are independently selected from CH, R′ may be a substituent of Q or W; D, E, F, and G are each independently CH, N, or CR. 6 and R 6 is selected from the group consisting of halogen, trifluoromethyl, hydroxy, cyano, amino, methyl, methoxy, or trifluoromethoxy, and when any one of D, E, F, and G is CH, said atom can serve as a bonding site for a linker, in which case D, E, F, or G is C; R 1 is H, -NHR 7 , -OR 7 , or -(C(R 9 ) R 8 ) R 7 is selected from the group consisting of R 7 is -R 10 , -CH 2 R 10 or -(CH 2 ) 2 R 10 and R 8 and R 9 are each independently selected from the group consisting of hydrogen, halogen, cyano, methyl, halomethyl, methoxy, halomethoxy, ethyl, haloethyl, ethoxy, haloethoxy, hydroxy, amino, or a 3-8 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from O, S or N; Or, R 8 and R 9 together with the C atom to which they are attached form a 3- to 7-membered heterocyclic ring, R 10 teeth, 1) Cyano, C 1 -C 5 Alkyl, halogenated C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 10 cycloalkyl, a substituted or unsubstituted 5- to 12-membered aromatic ring, or a substituted or unsubstituted 3- to 12-membered heterocyclic ring; ２） 【Transformation 5】 is selected from the group consisting of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 are each independently CH, N or CR 11 is selected from Each R 11 are independently halogen, cyano, hydroxy, amino, nitro, C 1 -C 3 Alkyl, halogenated C 1 -C 3 Alkyl, C 1 -C 4 Alkoxy, halogenated C 1 -C 4 Alkoxy, or C 3 -C 8 cycloalkyl; R 2 is H, C 1 -C 3 Alkyl, 【Transformation 6】 is selected from the group consisting of B, 【Transformation 7】 NH, O, CO, or CH 2 and each of U and W is independently selected from the group consisting of N or CH, and each of m, p, m' and p' is independently 0, 1, 2 or 3; The linker is 【Transformation 8】 and where: R L1 , R L2 , R L3 , R L4 and R L5 are the same or different and each independently represent a chemical bond, CH 2 , CHD, CD 2 , C=O, O, NH, SO, SO 2 , P=O, NHCO, NHSO 2 , OCH 2 , OCH 2 CH 2 , C.H. 2 OCH 2 , NHCH 2 , NMeCH 2 , NHCH 2 CH 2 , NMeCH 2 CH 2 , C.H. 2 NHCO, NHCOCH 2 , 【Chemistry 9】 and selected from the substituted or unsubstituted groups in the group consisting of: R L6 is a ring, optionally selected from the following structures: 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】 [Chemistry 10-4] each n is independently 0, 1, 2, 3, 4, 5, or 6; each of r and m is independently 0, 1, or 2; each of U and W is independently selected from the group consisting of N or CH; p L1 , p L2 , p L3 , p L4 , p L5 and p L6 are each independently selected from 0, 1, 2, 3, 4, 5, or 6; B is 【Chemistry 11】 and each of m, p, m', and p' is independently 0, 1, 2, or 3; The linker is 【Chemistry 12】 and where: R L1 , R L2 , R L3 , R L4 , R L5 and R L6 are the same or different and each independently represent a chemical bond, CH 2 , CHD, CD 2 , C=O, O, NH, SO, SO 2 , P=O, NHCO, NHSO 2 , OCH 2 , OCH 2 CH 2 , C.H. 2 OCH 2 , NHCH 2 , NMeCH 2 , NHCH 2 CH 2 , NMeCH 2 CH 2 , C.H. 2 NHCO, NHCOCH 2 , 【Chemistry 13-1】 【Chemistry 13-2】 【Chemistry 13-3】 【Chemistry 13-4】 and selected from the substituted or unsubstituted groups in the group consisting of: each n is independently 0, 1, 2, 3, 4, 5, or 6; each of r and m is independently 0, 1, or 2; each of U and W is independently selected from the group consisting of N or CH; p L1 , p L2 , p L3 , p L4 , p L5 and p L6 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a prodrug molecule thereof.

2. B, 【Chemistry 14】 selected from the group consisting of NH, O, or CO; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein each of U and W is independently selected from the group consisting of N or CH, and each of m, p, m' and p' is independently 0, 1, 2 or 3.

3. Ring A is 【Chemistry 15】 is selected from the group consisting of W is selected from the group consisting of CH or N; R ’ is hydrogen, halogen, cyano, hydroxy, amino, C 1 -C 5 Alkyl, halogenated C 1 -C 5 Alkyl, C 1 -C 5 Alkoxy, halogenated C 1 -C 5 Alkoxy, or C 3 -C 8 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein the compound is selected from: cycloalkyl.

4. The D, E, F, and G are CH or CR 6 and R 6 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein is selected from the group consisting of halogen.

5. B, 【Chemistry 16】 When selected from the group consisting of NH, O, or CO, the linker is 【Chemistry 17】 is selected from the group consisting of B is [Chemistry 18] wherein the linker is a chemical bond, 【Chemistry 19】 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, selected from the group consisting of:

6. Formula (II): 【Chemistry 20】 wherein B is 【Chemistry 21】 is selected from each of U and W is independently selected from the group consisting of N or CH; each of m, p, m', and p' is independently 0, 1, 2, or 3; R ’ is optionally selected from hydrogen, halogen, cyano, hydroxy or amino; R 11 and R 6 is optionally selected from hydrogen or halogen; X and Y are independently CH, N, or CR 3 is selected from R 3 is optionally selected from halogen, cyano, hydroxy or amino; Z is optionally CH 2 or CO, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof.

7. A compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a prodrug molecule thereof: 【Chemistry 22】 In the formula, Z is CH 2 or CO; V is, 【Chemistry 23】 is selected from the group consisting of X and Y are N, CH, or CR 3 and R 3 is halogen, cyano, hydroxyl, amino, C 1 -C 3 Alkyl, halogenated C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, halogenated C 1 -C 3 Alkoxy, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocyclyl; B is, 【Chemistry 24】 NH, O, CO, or CH 2 wherein each of U and W is independently selected from the group consisting of N or CH; and each of m and p is independently 0, 1, or 2; Ring A is 【Chemistry 25】 is selected from the group consisting of M and T are each independently N or CR 4 is selected from the group consisting of I, J and K are each independently N, O, S, CR 4 and NR 4 is selected from the group consisting of R 4 is hydrogen, halogen, cyano, hydroxy, amino, C 1 -C 5 Alkyl, halogenated C 1 -C 5 Alkyl, C 1 -C 5 Alkoxy, halogenated C 1 -C 5 Alkoxy, C 3 -C 8 Cycloalkyl, —CH 2 R 5 , -(CH 2 ) 2 R 5 , -(CH 2 ) 3 R 5 or 3-8 membered heterocyclyl; R 5 is cyano, hydroxy, amino, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocyclyl; D, E, F, and G are each independently CH, N, or CR. 6 is selected from the group consisting of R 6 is selected from the group consisting of halogen, trifluoromethyl, hydroxy, cyano, amino, methyl, methoxy, or trifluoromethoxy; R 1 is H, -NHR 7 , -OR 7 , or -(C(R 9 ) R 8 ) R 7 is selected from the group consisting of R 7 is -R 10 , -CH 2 R 10 or -(CH 2 ) 2 R 10 and R 8 and R 9 are each independently selected from the group consisting of hydrogen, halogen, cyano, methyl, halomethyl, methoxy, halomethoxy, ethyl, haloethyl, ethoxy, haloethoxy, hydroxy, amino, or a 3-8 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from O, S or N; Or, R 8 and R 9 together with the C atom to which they are attached form a 3- to 7-membered heterocyclic ring, R 10 teeth, 1) Cyano, C 1 -C 5 Alkyl, halogenated C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 10 cycloalkyl, a substituted or unsubstituted 5- to 12-membered aromatic ring, or a substituted or unsubstituted 3- to 12-membered heterocyclic ring; ２） 【Chemistry 26】 is selected from the group consisting of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 are each independently CH, N or CR 11 is selected from Each R 11 are independently halogen, cyano, hydroxy, amino, nitro, C 1 -C 3 Alkyl, halogenated C 1 -C 3 Alkyl, C 1 -C 4 Alkoxy, halogenated C 1 -C 4 Alkoxy, or C 3 -C 8 cycloalkyl; R 2 is H, C 1 -C 3 Alkyl, 【Chemistry 27】 is selected from the group consisting of The linker is 【Chemistry 28】 and R L1 ~R L6 are the same or different and each independently represent a bond, CH 2 , CHD, CD 2 , C=O, O, NH, SO, SO 2 , P=O, NHCO, NHSO 2 , OCH 2 , OCH 2 CH 2 , C.H. 2 OCH 2 , NHCH 2 , NMeCH 2 , NHCH 2 CH 2 , NMeCH 2 CH 2 , C.H. 2 NHCO, NHCOCH 2 , 【Chemistry 29-1】 【Chemistry 29-2】 【Chemistry 29-3】 【Chemistry 29-4】 and selected from the substituted or unsubstituted groups in the group consisting of: Each n is independently 0, 1, 2, 3, 4, 5, or 6; each of r and m is independently 0, 1, or 2; and each of U and W is independently selected from the group consisting of N or CH. The substitutions are hydrogen, deuterium, C 1 -C 18 Alkyl, deuterated C 1 -C 18 Alkyl, halogenated C 1 -C 18 Alkyl, halogenated C 1 -C 18 Alkylhydroxy, C 3 -C 20 Cycloalkyl, C 1 -C 18 Alkoxy, deuterated C 1 -C 18 Alkoxy, halogenated C 1 -C 18 Alkoxy, C 6 -C 14 refers to substitution with one or more groups selected from the group consisting of aryl, 5- to 14-membered heteroaryl, 4- to 20-membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amino, amido, sulfonamido, or ureido; p L1 ~p L6 wherein each of the following is independently selected from 0, 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a prodrug molecule thereof.

8. V, 【Transformation 30】 10. The compound of claim 1 or 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, selected from the group consisting of:

9. X and Y are each independently N, CH, or CR 3 is selected from the group consisting of R 3 However, halogen, cyano, hydroxy, amino, C 1 -C 3 Alkyl, halogenated C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or halogenated C 1 -C 3 10. The compound of claim 1 or 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, selected from the group consisting of: alkoxy.

10. B, 【Chemistry 31】 selected from the group consisting of NH, O, or CO; 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein each of U and W is independently selected from the group consisting of N or CH, and each of m and p is independently 0 or 1.

11. Ring A is 【Chemistry 32】 is selected from the group consisting of 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein T is selected from the group consisting of CH or N.

12. R 4 is hydrogen, halogen, cyano, hydroxy, amino, C 1 -C 5 Alkyl, halogenated C 1 -C 5 Alkyl, C 1 -C 5 Alkoxy, halogenated C 1 -C 5 Alkoxy, C 3 -C 8 Cycloalkyl, —CH 2 R 5 , -(CH 2 ) 2 R 5 , -(CH 2 ) 3 R 5 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein the compound is selected from the group consisting of:

13. 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein D, E, F, and G are CH.

14. The R 1 But, -NHR 7 and R 7 But -CH 2 R 10 and R 10 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein: In another preferred embodiment, the R 10 is cyano, C 1 -C 5 Alkyl, halogenated C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 10 cycloalkyl, 4- to 7-membered heterocyclyl, or C 6 -C 10 aryl, wherein said aryl is selected from the group consisting of one or more CR 11 is substituted with R 11 is as defined in claim 7.

15. The linker is 【Transformation 33】 wherein each n is independently 0, 1, 2, 3, 4, 5, or 6; each r and m is independently 0, 1, or 2; and each U and W is independently selected from the group consisting of N or CH, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof. In another preferred embodiment, the linker is 【Transformation 34】 is selected from the group consisting of Each n is independently 0, 1, 2, 3, 4, 5, or 6; each of r and m is independently 0, 1, or 2; and each of U and W is independently selected from the group consisting of N or CH.

16. Formula (II) or Formula (III): 【Chemistry 35】 wherein U and W are independently selected from CH or N; X and Y are independently CH, N, or CR 3 is selected from Z is optionally CH 2 or CO, 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein n and m are independently selected from 0 or 1.

17. The compound is 【Chemistry 36-1】 【Chemistry 36-2】 【Chemistry 36-3】 【Chemistry 36-4】 【Chemistry 36-5】 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, selected from the group consisting of:

18. The compound is 【Chemistry 37-1】 【Chemistry 37-2】 【Chemistry 37-3】 【Chemistry 37-4】 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, selected from the group consisting of:

19. (1) As an active ingredient, a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, stereoisomer, or prodrug molecule thereof; and Optionally, (2) a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

20. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or a pharmaceutical composition according to claim 19, for the preparation of an agent for degrading CDK12 / 13 protein kinase.

21. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or a pharmaceutical composition according to claim 19, for the preparation of a medicament for the prevention and / or treatment of a disease mediated by CDK12 / 13 serine / threonine protein kinases.

22. 22. The use of claim 21, wherein the disease mediated by CDK12 / 13 serine / threonine protein kinase is selected from the group consisting of prostate cancer, breast cancer, uterine cancer, ovarian cancer, non-small cell lung cancer, small cell lung cancer, Ewing's sarcoma, lung adenocarcinoma, squamous cell lung cancer, pancreatic cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumor, colon cancer, rectal cancer, or glioma.

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