Protac compounds targeting degradation of prmt5 and applications thereof

Abstract

The application discloses a PROTAC compound for targeted degradation of PRMT5 and application thereof, and relates to a compound shown in the following formula, a related analogue of the compound or a pharmaceutically acceptable salt, metabolite or prodrug thereof: wherein X represents a ligand combined to a PRMT5 protein, Z represents a ligand of an E3 ubiquitin ligase, and Y represents a connecting group connecting X and Z; the application takes CRBN as the E3 ligase, and a series of PROTAC degradation compounds for targeting PRMT5 are designed and synthesized. The compound can effectively induce degradation of PRMT5, significantly inhibit proliferation, growth, migration, infiltration, clonal formation and metastasis of tumor cells, promote apoptosis of cancer cells, promote autophagy of tumor cells, prevent or overcome BTK inhibitor drug resistance, and / or prolong the survival period of tumor patients, and has a wide application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of antitumor drugs, and particularly relates to a PROTACs compound for targeted degradation of PRMT5 and application thereof. BACKGROUND

[0002] Protein arginine methyltransferase (PRMT5) is a member of the protein arginine methyltransferase family responsible for epigenetic regulation and post-translational modification, which catalyzes the transfer of the methyl group of S-adenosyl methionine (SAM) to the guanidino nitrogen atom of the substrate arginine to achieve symmetric dimethylation of arginine on the substrate protein. Studies have shown that PRMT5, as an epigenetic regulator, can be responsible for the methylation modification of histones such as H4R3, H3R8, and H3R2, thereby regulating gene expression. PRMT5 can also perform post-translational modification functions, which catalyze the methylation of non-histone proteins to regulate mRNA splicing, DNA replication and damage repair, and cell cycle and other biological processes.

[0003] PRMT5 is significantly highly expressed in various tumors: in breast cancer cells, the expression of PRMT5 is significantly higher than that in normal breast cells, and PRMT5 promotes the occurrence and development of breast cancer by regulating the methylation of proteins such as AKT1, KLF5, and KLF4; PRMT5 is also significantly highly expressed in lung cancer cells; the survival of acute myeloid leukemia cells is related to the catalytic activity of PRMT5; the expression of PRMT5 in prostate cancer cells is significantly higher than that in benign prostatic hyperplasia tissues, which regulates the expression of AR by interacting with Sp1 and forming a complex with Brg1, thereby affecting the growth of prostate cancer cells (Oncogene. 2017 Mar 2; 36(9): 1223-1231.). In summary, PRMT5 is closely related to the occurrence and development of various cancers, and therefore, PRMT5 has attracted much attention as a new tumor treatment target.

[0004] The protein targeted chimera (PROTAC) technology is a new means of inducing protein degradation. PROTAC molecules are usually composed of a target protein ligand, an E3 ligase ligand, and a linker connecting the two ligands. Under the action of such small molecules, the target protein and the E3 ligase are close to each other in space to achieve ubiquitination of the target protein, and finally the ubiquitin proteasome-dependent protein degradation occurs. Compared with traditional inhibitors, PROTAC also shows great potential in selectivity, overcoming drug resistance, and inhibiting the non-enzyme function of multiple target proteins (Nat Rev Cancer. 2021 Oct; 21(10): 638-654.). Taking the human homolog of the enhancer of the Drosophila Zeste gene 2 (EZH2) as an example, the currently developed inhibitors targeting EZH2 can only inhibit its enzymatic activity to induce cancer-related gene silencing to achieve anti-tumor activity. However, the non-enzymatic activity of EZH2 is also crucial for the activation of cancer progression-related genes, which leads to incomplete inhibition of its carcinogenic activity by inhibitors, and the development of PROTAC molecules targeting EZH2 achieves complete blocking of its carcinogenic function. In addition, compared with inhibitors, the PROTAC degrader targeting EZH2 also shows significant anti-proliferative activity in cell lines resistant to inhibitors. In summary, the use of PROTAC technology to induce the degradation of target protein PRMT5 may also achieve complete blocking of carcinogenic function, which is a potential strategy for targeting PRMT5 to treat cancer. SUMMARY

[0005] The present application provides a class of PROTACs compounds targeting the degradation of PRMT5, which can effectively induce the degradation of PRMT5 and significantly inhibit the proliferation of tumor cells. The present application designs and synthesizes a series of PROTAC degradation compounds targeting PRMT5 with CRBN as E3 ligase. Compared with the recently reported MS4322 (which needs 6-8 days to exert the maximum degradation effect, J Med Chem. 2020 Sep 10; 63(17): 9977-9989.), this class of degraders can achieve rapid degradation of PRMT5 in two days, and show significant anti-proliferative activity in triple-negative breast cancer cells, which can effectively induce cell cycle arrest and apoptosis. Mechanism studies show that this class of degraders can regulate the expression of the "difficult to target" transcription factor KLF5, which is also very important for breast cancer treatment, by degrading PRMT5 protein. In addition, in the patient-derived organoids of TNBC, it can also effectively achieve anti-proliferative activity. In mice, it achieves a certain anti-tumor activity and shows good tolerability. In summary, the present application provides a class of PROTACs molecules that can effectively degrade PRMT5 and is expected to prepare a drug targeting PRMT5-related malignant tumors.

[0006] The application provides a kind of targeted degradation PRMT5 PROTACs compound, it is compound shown in formula (I) or its stereoisomer, geometric isomer, tautomer, nitroxide, metabolite, pharmaceutically acceptable salt or prodrug:

[0007]

[0008] Wherein, X represents the ligand combined to PRMT5 protein, Z represents the ligand of E3 ubiquitin ligase, Y represents the connecting group connecting X and Z.

[0009] According to the embodiments of the application, the above-mentioned compound can further include at least one of the following additional technical features:

[0010] In formula (I), according to the embodiments of the application, representative X includes structures as formula (II), formula (III):

[0011]

[0012]

[0013] In formula (I), Z is selected from the following structures of formula (IV)-(VI):

[0014]

[0015] Wherein:

[0016] A is selected from any one of CH2, C(O), SO, SO2;

[0017] R is selected from any one of F or H;

[0018] M is selected from Any one of them;

[0019] P is selected from any one of the following groups: H, F or CF3;

[0020] Q is selected from any one of the following groups: -NH- or -CH2-.

[0021] In formula (IV)-(VI), according to the embodiments of the application, representative Z includes:

[0022]

[0023] In formula (I), Y is selected from the following structures:

[0024]

[0025] Wherein:

[0026] m is an integer between 0-12; preferably, 0, 2, 3, 4, 5, 6, 7, 8, 9, 10;

[0027] n is an integer between 1-10; preferably, 1, 2, 3, 4, 5;

[0028] q is an integer between 0-8; preferably, 0, 2;

[0029] t is an integer between 0-8; preferably, 5.

[0030] The present application provides PROTACs compounds targeting degradation of PRMT5 according to the above-mentioned formulae (I)-(VI), including but not limited to the following compounds:

[0031] N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propionyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0032] N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propionyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0033] N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propionyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0034] N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propionyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0035] N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaodecane-18-yl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0036] N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0037] N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0038] N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0039] N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0040] N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0041] N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)nonanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0042] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(3-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)ethoxy)propyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide;

[0043] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(3-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)ethoxy)propyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide;

[0044] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(3-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)ethoxy)propyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide;

[0045] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(3-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)ethoxy)propyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide;

[0046] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(3-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)ethoxy)propyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide;

[0047] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(3-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)ethoxy)propyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide;

[0048] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(3-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)ethoxy)propyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide;

[0049] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(l l-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)undecanoyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide;

[0050] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(l 2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)dodecanoyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide;

[0051] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(l 0-((2-(2,6- dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)amino)decanoyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide;

[0052] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(8-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0053] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(8-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)octyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0054] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(8-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)octyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0055] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(8-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)octyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0056] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(5-((2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)amino)pentanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0057] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(8-((2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)amino)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0058] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propionyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0059] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)propionyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0060] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(5-((2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)amino)pentanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0061] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(6-((2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0062] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(4-((2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)amino)butanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0063] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(10-((2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine- 4-carboxamide;

[0064] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(8-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oct-7-ynoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide;

[0065] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(l l-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)undec-10-ynoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide;

[0066] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(2-(4-((4-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)methyl)piperidin-l-yl)acetyl) piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0067] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(3-(4-(4-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)butyl)piperazin-l-yl)propionyl) piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0068] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(l-((l-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidine-4-carbonyl) piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0069] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(l-(3-(l-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperidine-4-carbonyl) piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0070] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(4-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4- yl)methyl)piperazin-l-yl)methyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0071] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)methyl)piperidin- 1-yl)benzoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0072] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(4-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4- yl)propyl)piperazin-l-yl)benzoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0073] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(5-(7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-2- yl)pentanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0074] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(4-(9-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3- yl)butanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0075] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)heptanoyl)piperidin- 4-yl)amino)pyrimidine-4-carboxamide;

[0076] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(l l-(4-(2,6- dioxopiperidin-3-yl)phenoxy)undecanoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide;

[0077] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(l 0-((4-(2,6- dioxopiperidin-3-yl)phenyl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide;

[0078] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(7-(4-(4-((2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-l-yl)heptanoyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide;

[0079] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(2-((6-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)hexyl)amino)-2-oxoethyl) piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0080] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(8-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)octanoyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide;

[0081] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(7-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)heptanoyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide;

[0082] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(6-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)hexanoyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide;

[0083] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)acetylamino)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0084] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)acetylamino)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0085] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)methyl)piperidin-l-yl)acetyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide;

[0086] N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((4-(10-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)decanamido)cyclohexyl)amino)pyrimidine-4-carboxamide.

[0087] The present application also provides a pharmaceutical composition comprising the PROTACs compound targeting degradation of PRMT5.

[0088] As a further description to the above-mentioned solution, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0089] The present application also provides an application of the PROTACs compound or the pharmaceutical composition in preparing a drug for degrading or inhibiting PRMT5.

[0090] The present application also provides an application of the PROTACs compound or the pharmaceutical composition in preparing a drug for preventing or treating tumors.

[0091] As a preference, the tumor is at least one of breast cancer, cervical cancer, non-small cell lung cancer, B-cell lymphoma, mantle cell lymphoma and melanoma.

[0092] The present application provides a preparation method of several representative compounds as follows:

[0093] Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(10- ((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)decanoyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide (YZ-18):

[0094] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,3-dione and 1-2 molar times of 10-amino decanoic acid tert-butyl ester in DMSO, add 1.5-2.5 molar times of DIEA, protect under nitrogen, stir at 80-95°C overnight. TLC test the reaction, after the reaction is completed, extract with ethyl acetate and water, collect the organic phase, concentrate and purify by column chromatography (elute with DCM:MeOH=80-120:1) to obtain the intermediate;

[0095] Dissolve the intermediate in DCM, add TFA, stir at room temperature overnight to carry out the ester cleavage reaction, after the reaction is completed, distill under reduced pressure to obtain the intermediate after removal of the tert-butyloxy group.

[0096] Dissolve the intermediate after removal of the tert-butyloxy group and 0.5-1.5 molar times of intermediate P1 in DMSO, add 1-2 molar times of HATU and 2-5 molar times of DIEA in sequence, stir the reaction at room temperature, extract with EA and water, collect the organic phase, concentrate and purify by column chromatography (elute with DCM:MeOH=30-80:1) to obtain the target product YZ-18.

[0097] Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)methyl)piperidin-l- yl)benzoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-41):

[0098] DMSO, 0.8-1.5 molar equivalents of DIEA was added, and the mixture was stirred at 80-95°C overnight under nitrogen protection. The reaction mixture was extracted with EA and water, and the organic phase was collected and washed with saturated NaCl solution. The organic phases were combined and concentrated, and the target product 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoic acid tert-butyl ester was obtained by column chromatography (DCM:MeOH=30-80:1). The target product was dissolved in DCM, and TFA was added. The mixture was stirred at room temperature overnight to remove the tert-butyloxy group, and then distilled under reduced pressure to obtain the intermediate 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoic acid;

[0099] The intermediate P1 and 0.5-1.5 molar equivalents of 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoic acid were dissolved in DMSO, and 1.5-3 molar equivalents of HATU and 3-5 molar equivalents of DIEA were added in sequence. The mixture was stirred at room temperature, and after the reaction was completed, the mixture was extracted, the organic phase was collected, concentrated, and purified by column chromatography (DCM:MeOH=30-80:1) to obtain the target product YZ-41.

[0100] Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(11-(4-(2,6-dioxopiperidin-3-yl)phenoxy)undecanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-46):

[0101] The intermediate P1 and 0.5-1.5 molar equivalents of 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoic acid were dissolved in DMSO, and 1.5-3 molar equivalents of HATU and 3-5 molar equivalents of DIEA were added in sequence. The mixture was stirred at room temperature, and after the reaction was completed, the mixture was extracted, the organic phase was collected, concentrated, and purified by column chromatography (DCM:MeOH=30-80:1) to obtain the target product YZ-41.

[0102] Intermediate 4-(2,6-bis(benzyloxy)pyridin-3-yl)phenol and 1-2 molar equivalents of 11-bromoundecanoic acid tert-butyl ester were dissolved in DMF, 3-5 molar equivalents of cesium carbonate were added, stirred at room temperature; EA and water were extracted, the organic phase was collected, concentrated and purified by column chromatography (PE:EA=5-12:1) to obtain intermediate 11-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)undecanoic acid tert-butyl ester.

[0103] Intermediate 11-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)undecanoic acid tert-butyl ester was dissolved in methanol, an appropriate amount of Pd / C was added under nitrogen protection, and hydrogen was replaced again after nitrogen protection. Stir at room temperature overnight. After the reaction was completed, filter, distill under reduced pressure, and the obtained crude product 11-(4-(2,6-dioxopiperidin-3-yl)phenoxy)undecanoic acid tert-butyl ester was dissolved in DCM, TFA was added, and stirred at room temperature overnight. After the reaction was completed, distill under reduced pressure, and the obtained crude product 11-(4-(2,6-dioxopiperidin-3-yl)phenoxy)undecanoic acid was obtained.

[0104] 11-(4-(2,6-dioxopiperidin-3-yl)phenoxy)undecanoic acid and 0.5-2 molar equivalents of intermediate P1 were dissolved in DMSO, 1-2 molar equivalents of HTAU and 2-5 molar equivalents of DIEA were added in turn, stirred at room temperature, and the reaction was detected by TLC. EA and water were extracted, the organic phase was collected, concentrated, and purified by column chromatography (DCM:MeOH=30-80:1) to obtain the target product YZ-46.

[0105] Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(10-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-47):

[0106] 2,6-bis(benzyloxy)-3-bromopyridine, 0.5-1.5 molar equivalents of 4-aminobenzoic acid pinacol ester, and 2-4 molar equivalents of potassium carbonate were dissolved in 1,4-dioxane and water, stirred at room temperature, and a catalyst palladium dichloride bis-triphenylphosphine was added under nitrogen protection. Stir again at 95-110°C overnight under nitrogen protection. Filter, distill under reduced pressure, and purify by column chromatography (PE:EA=1-3:1) to obtain intermediate 4-(2,6-bis(benzyloxy)pyridin-3-yl)aniline;

[0107] Intermediate 4-(2,6-bis(benzyloxy)pyridin-3-yl)aniline and 1-2 molar equivalents of tert-butyl 10-bromodecanoate were dissolved in DMF, 3-5 molar equivalents of cesium carbonate were added, and stirring was performed at 80-95°C overnight. EA and water were extracted, the organic phase was collected, concentrated, and purified by column chromatography (PE:EA = 3-10:1) to obtain intermediate tert-butyl 10-((4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)amino)decanoate.

[0108] Intermediate tert-butyl 10-((4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)amino)decanoate was dissolved in ethanol, an appropriate amount of Pd / C was added, and stirring was performed at room temperature overnight under nitrogen protection and hydrogen replacement. After the reaction was completed, suction filtration was performed, and the obtained crude product tert-butyl 10-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)decanoate was then dissolved in DCM, TFA was added, and stirring was performed at room temperature overnight. After the reaction was completed, vacuum distillation was performed, and the obtained crude product 10-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)decanoic acid was then dissolved in DCM, TFA was added, and stirring was performed at room temperature overnight. After the reaction was completed, vacuum distillation was performed, and the obtained crude product 10-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)decanoic acid

[0109] Intermediate 10-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)decanoic acid and 0.8-1.5 molar equivalents of intermediate P1 were dissolved in DMSO, 1-2 molar equivalents of HATU and 2-5 molar equivalents of DIEA were sequentially added, and stirring was performed at room temperature. EA and water were extracted, the organic phase was collected, concentrated, and purified by column chromatography (DCM:MeOH = 30-80:1) to obtain the target product YZ-47.

[0110] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application, prepared from a compound of the present application having a particular substituent with a relatively non-toxic acid or base. When a compound of the present application contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, amine, organic amine or magnesium salts or similar salts. When a compound of the present application contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the acid in a pure solution or in a suitable inert solvent. The practice of the present application embraces inorganic acid salts, including, for example, salts of hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid and the like; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like; also salts of amino acids (e.g., arginine and the like), and salts of organic acids like gluconic acid. Certain specific compounds of the present application contain both basic and acidic functionalities and, as such, can be converted into either base or acid addition salts.

[0111] In addition to salt forms, the compounds provided herein can exist in a variety of

[0112] Certain compounds of the present application can possess asymmetric carbon atoms (optical centers) or double bonds. The racemates, diastereomers, geometric isomers and individual isomers are all intended to be within the scope of the present application, including cis- and trans-forms, (-)- and (+)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, as well as racemic mixtures and other mixtures thereof, and all isomers whether purified by synthesis or resolution. The following methods and techniques can be used for chemical syntheses and characterizations and are described in more detail in "Compendium of Synthetic Organic Methods", Vol. 1-8, by J. Smil, Wiley-Interscience; "March's Advanced Organic Chemistry", 5th Ed., by M. B. Smith, J. March, and D. B. Wakefield, John Wiley & Sons, New York, NY (1991); and "Organic Syntheses", Vols. 1-50, John Wiley & Sons, New York, NY.

[0113] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be labeled with isotopes such as deuterium ( 2 H), tritium ( 3 H) or C-14 ( 14C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0114] The present invention provides a pharmaceutical composition comprising a therapeutic dose of the aforementioned compound. "Pharmaceutical composition" refers to a mixture comprising one or more compounds of the present invention, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, or other components such as saline, pharmaceutically acceptable carriers, and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0115] The pharmaceutical composition is formulated into an injectable fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup, a transdermal patch or an excipient. According to a specific embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, an excipient, a diluent, an adjuvant, a vehicle or a combination thereof.

[0116] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0117] The present invention relates to a method for degrading PRMT5 protein by using bifunctional small molecules, comprising administering any one of the above compounds to a patient or subject, optionally in combination with another bioactive agent for the treatment of a disease, wherein the disease type is mainly cancer.

[0118] The present invention proposes the use of the above-mentioned PROTACs compounds and their related analogs or pharmaceutically acceptable salts, metabolites or prodrugs for targeting the degradation of PRMT5, or the pharmaceutical compositions thereof in the preparation of PRMT5 regulators and anti-tumor drugs, wherein the drugs are used to degrade PRMT5 protein through bifunctional small molecules.

[0119] The PROTACs compounds and their related analogs or pharmaceutically acceptable salts, metabolites or prodrugs for targeting PRMT5 degradation described in the present invention, or the pharmaceutical compositions described herein, are used to inhibit the proliferation, growth, migration, infiltration, cloning and metastasis of cancer cells, promote apoptosis of cancer cells, promote autophagy of tumor cells, prevent or overcome BTK inhibitor resistance, and / or prolong the survival of tumor patients. The tumors include at least one of breast cancer, cervical cancer, non-small cell lung cancer, B-cell lymphoma, mantle cell lymphoma and melanoma. BRIEF DESCRIPTION OF THE DRAWINGS

[0120] Figure 1 The degradation activity of some compounds of the present invention in triple-negative breast cancer cells HCC1806 and HCC1937;

[0121] Figure 2Effect of compound YZ-18 on the proliferation of HCC1806, HCC1937, MDA-MB-231, MDA-MB-468, MCF10A and 184A1 cells;

[0122] Figure 3 Ability of compound YZ-18 to induce cell cycle in breast cancer cells;

[0123] Figure 4 Ability of compound YZ-18 to induce apoptosis in triple negative breast cancer cells;

[0124] Figure 5 Effect of compound YZ-18 on the survival rate of cancer cells;

[0125] Figure 6 Inhibitory activity of compound YZ-18 on the proliferation of triple negative breast cancer organoid cells;

[0126] Figure 7 Inhibitory ability of compound YZ-18 on the growth of HCC1806 triple negative breast cancer nude mouse xenograft tumor;

[0127] Figure 8 Inhibitory ability of compound YZ-18 on the tissue weight of HCC1806 triple negative breast cancer nude mouse xenograft tumor;

[0128] Figure 9 Effect of compound YZ-18 alone on the body weight of nude mice. DETAILED DESCRIPTION

[0129] The present application is further described in detail below in conjunction with specific examples and drawings, and the protection scope of the present application is not limited to the following examples.

[0130] The present application provides a bifunctional small molecule and its derivatives or pharmaceutically acceptable salts, and a pharmaceutical composition containing such compounds. The present application relates to a protein degradation targeting chimera (PROTACs) bifunctional small molecule, which can selectively induce PRMT5 protein degradation. The present application successfully prepared the PRMT5-targeted degradation PROTACs compound by connecting the PRMT5 small molecule ligand and the ligand of CRBN E3 ubiquitin ligase using different kinds and lengths of linkers.

[0131] The purity of the compounds of the present application was determined by Agilent 1200 series LC system with UV detection at 254 nm. The NMR spectra were recorded on a Bruker 500 spectrometer using DMSO-d6 as solvent. The purification of the intermediates and final products was performed by column chromatography (silica gel 200-300 mesh) purchased from Qingdao Marine Chemical Plant. Unless otherwise specified, all reactions were followed by TLC. The term "overnight" or "stirred overnight" generally refers to 8-18 hours. The term "room temperature" generally refers to 10-40 °C.

[0132] Example 1: Preparation of the compounds of the present application

[0133] Preparation of key intermediate (S)-N-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-(piperidin-4-ylamino)pyrimidine-4-carboxamide (P1):

[0134]

[0135] 6-chloropyrimidine-4-carboxylic acid (2.0 g, 12.36 mmol) was dissolved in 39 mL of DCM (dichloromethane) and stirred at 40 °C. 4.6 mL of (COCl)2(oxalyl chloride) was added slowly, followed by 3 drops of DMF (N,N-dimethylformamide). After stirring for 3 h, the reaction was monitored by TLC. After the reaction was completed, the crude 6-chloropyrimidine-4-carbonyl chloride was obtained by distillation under reduced pressure and was used directly in the next step.

[0136] Intermediate 6-chloropyrimidine-4-carbonyl chloride (12.36 mmol) and (S)-l-amino-3-(3,4-dihydroisoquinolin-2(lH)-yl)propan-2-ol (3.0 g, 12.36 mmol) were dissolved in DCM (15 mL) and TEA (triethylamine) (4.1 g, 37.08 mmol) was added dropwise slowly. The reaction was stirred at room temperature. After the reaction was completed, the product was obtained by distillation under reduced pressure and purified by column chromatography (silica gel, DCM:MeOH = 80: 1) to give intermediate (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide (2.6 g, 7.49 mmol, yield 61%).

[0137] Intermediate (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)pyrimidine-4-carboxamide (2.6 g, 7.49 mmol) and tert-butyl 4-amino- 1-piperidinecarboxylate (3.0 g, 14.97 mmol) were dissolved in 10 mL of i-PrOH (isopropanol), triethylamine (1.5 g, 14.97 mmol) was added and stirred at 80 °C overnight. The bulk of the isopropanol was removed by distillation under reduced pressure and the residue was purified by column chromatography on silica gel (DCM:MeOH = 80:1) to give intermediate (S)-tert-butyl 4-((6-((3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)carbamoyl)pyrimidin-4-yl)amino)piperidine-l-carboxylate (3.6 g, 7.03 mmol, 99% yield).

[0138] Intermediate (S)-tert-butyl 4-((6-((3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)carbamoyl)pyrimidin-4-yl)amino)piperidine-l-carboxylate (3.6 g, 7.03 mmol) was dissolved in DCM (15 mL), trifluoroacetic acid (TFA) (3 mL) was added and stirred at room temperature overnight. After completion of the reaction, the solvent was removed by distillation under reduced pressure and the residue (S)-N-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-(piperidin-4-ylamino)pyrimidine-4-carboxamide (P1) was used directly in the subsequent reaction.

[0139] Preparation of key intermediate (S)-6-((4-aminocyclohexyl)amino)-N-(3-(3,4- dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide (P2)

[0140]

[0141] Intermediate (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)pyrimidine-4-carboxamide (430 mg, 1.2 mmol) and N-Boc-l,4- cyclohexanediamine (532 mg, 2.5 mmol) were dissolved in n-BuOH (5 mL), TEA (251 mg, 2.5 mmol) was added and stirred at 80 °C overnight. The solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography on silica gel (DCM:MeOH = 50:1) to give intermediate (S)-tert-butyl (4-((6-((3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)carbamoyl)pyrimidin-4-yl)amino)cyclohexyl)carbamate (610 mg, 1.2 mmol, 97% yield).

[0142] (S)-(4-((6-((3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)carbamoyl)pyrimidin-4- yl)amino)cyclohexyl)carbamic acid tert-butyl ester was dissolved in DCM (10 mL), added with hydrochloric acid dioxane solution (3 mL), stirred at room temperature overnight. After the reaction was completed, distilled under reduced pressure, the obtained crude product was used as intermediate (S)-6-((4-aminocyclohexyl)amino)-N-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)pyrimidine-4-carboxamide without further purification, directly used in the next step reaction.

[0143]

[0144]

[0145] Preparation of key intermediate 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)acetic acid

[0146]

[0147] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-l,3-dione (1 g, 3.6 mmol) and tert- butyl bromoacetate (854 mg, 4.4 mmol) were dissolved in DMF (5 mL), added with potassium carbonate (756 mg, 5.5 mmol), stirred at room temperature overnight. Extracted with ethyl acetate (EA) and water, collected the organic phase, washed with saturated NaCl solution, combined the organic phase, dried with anhydrous sodium sulfate, distilled under reduced pressure, purified by column chromatography (DCM:MeOH = 100: 1) to obtain tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)acetate (890 mg, yield 64%).

[0148] Tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetate (890 mg, 2.3 mmol) was dissolved in DCM (10 mL), added with TFA (2 mL), stirred at room temperature overnight. After the reaction was completed, distilled under reduced pressure, the obtained crude product was used as intermediate 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)acetic acid without further purification, directly used in the next step.

[0149] Preparation of key intermediate (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl) glycine

[0150]

[0151] 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (1 g, 3.7 mmol) and tert-butyl bromoacetate (856 mg, 4.4 mmol) were dissolved in DMF (6 mL), and potassium carbonate (760 mg, 5.5 mmol) was added, and stirred at 50 °C. The reaction was checked by thin layer chromatography (TLC), extracted with ethyl acetate and water, and the organic phase was collected, washed with saturated NaCl solution, and the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH = 100:1) gave the intermediate tert-butyl (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)glycinate (1.2 g, yield: 84%).

[0152] The intermediate tert-butyl (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)glycinate (1.2 g, 3.1 mmol) was dissolved in DCM (10 mL), and TFA (2 mL) was added, and stirred at room temperature. After the reaction was completed, it was distilled under reduced pressure, and the obtained crude product was used as the intermediate (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)glycine without further purification, and directly used in the next step.

[0153] Example 1-1. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-1):

[0154]

[0155] 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l,3-dione (200 mg, 0.72 mmol) and tert-butyl 3-(2-aminoethoxy)propanoate (205 mg, 1.09 mmol) were dissolved in dimethyl sulfoxide (DMSO) (3 mL), and N,N-diisopropylethylamine (DIEA) (187 mg, 1.45 mmol) was added, and stirred at 90 °C for overnight under nitrogen protection. The reaction was checked by TLC. After the reaction was completed, it was extracted with ethyl acetate and water, and the organic phase was collected, washed with saturated NaCl solution, and the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH = 100:1) gave the intermediate tert-butyl 3-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoate (92 mg, yield 28%).

[0156] Intermediate 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)propanoic acid tert-butyl ester (45 mg, 0.10 mmol) was dissolved in DCM (3 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature overnight. The reaction was monitored by TLC. After the reaction was completed, the solvent was distilled under reduced pressure, and the resulting intermediate 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoic acid was used in the next step without further purification.

[0157] Intermediate 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)propanoic acid (0.10 mmol) and intermediate P1 (0.10 mmol) were dissolved in DMSO (2 mL), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate (HATU) (50 mg, 0.13 mmol), DIEA (40 mg, 0.31 mmol) were added successively, and the mixture was stirred at room temperature. The reaction mixture was extracted with EA and water, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH = 50:1) gave the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (13 mg, yield 17%) (YZ-1). 1HNMR (500 MHz, DMSO-d6) δ 11.09 (d, J = 4.1 Hz, 1H), 8.77-8.73 (m, 1H), 8.28 (s, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.61-7.55 (m, 1H), 7.14 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 6.1 Hz, 3H), 7.06-7.00 (m, 3H), 6.61-6.56 (m, 1H), 5.07-5.02 (m, 1H), 4.97 (d, J = 4.7 Hz, 1H), 4.22 (d, J = 12.9 Hz, 1H), 4.07 (s, 1H), 3.91-3.81 (m, 2H), 3.70-3.66 (m, 2H), 3.63-3.58 (m, 4H), 3.49-3.40 (m, 3H), 3.19-3.11 (m, 1H), 2.91-2.65 (m, 7H), 2.62-2.52 (m, 4H), 2.05-1.98 (m, 1H), 1.88 (s, 2H), 1.40-1.20 (m, 4H); HRMS (ESI): calcd for C 44 H 60 N7O6[M+H] + : 782.4600, found 782.4614. Example 1-2. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-2):

[0158] Similar to Example 1-1, but replacing tert-butyl 3-(2-aminoethoxy)propanoate with tert-butyl 3-(2-(2-aminoethoxy)ethoxy)propanoate, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-2). 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.79-8.72 (m, 1H), 8.29 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.61-7.56 (m, 1H), 7.14 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 6.1 Hz, 3H), 7.07-7.00 (m, 3H), 6.63-6.59 (m, 1H), 5.09-5.03 (m, 1H), 4.97 (d, J = 4.7 Hz, 1H), 4.22 (d, J = 13.1 Hz, 1H), 4.07 (s, 1H), 3.92-3.87 (m, 1H), 3.83 (d, J = 13.7 Hz, 1H), 3.64-3.60 (m, 6H), 3.58-3.55 (m, 2H), 3.54-3.51 (m, 2H), 3.48-3.45 (m, 2H), 3.17-3.10 (m, 1H), 2.93-2.65 (m, 8H), 2.56 (d, J = 7.3 Hz, 2H), 2.06-2.00 (m, 1H), 1.88 (s, 2H), 1.38-1.21 (m, 6H).

[0159] Example 1-3. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-3):

[0160] Similar to Example 1-1, but replacing tert-butyl 3-(2-aminoethoxy)propanoate with tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-3): 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.77-8.72 (m, 1H), 8.28 (s, 1H), 7.74 (d, J = 7.4 Hz, 1H), 7.61-7.55 (m, 1H), 7.14 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 6.0 Hz, 3H), 7.06-7.00 (m, 3H), 6.64-6.57 (m, 1H), 5.09-5.01 (m, 1H), 4.96 (d, J = 4.7 Hz, 1H), 4.21 (d, J = 12.9 Hz, 1H), 4.07 (s, 1H), 3.88 (d, J = 6.0 Hz, 1H), 3.83 (d, J = 13.9 Hz, 1H), 3.63-3.59 (m, 6H), 3.57-3.54 (m, 2H), 3.54-3.52 (m, 2H), 3.51-3.46 (m, 6H), 3.18-3.11 (m, 1H), 2.93-2.65 (m, 8H), 2.56 (d, J = 6.3 Hz, 2H), 2.05-1.99 (m, 1H), 1.90 (d, J = 17.2 Hz, 2H), 1.40-1.20 (m, 6H); HRMS (ESI): calcd for C 44 H 55 N9NaO 10 [M+Na] + : 892.3964, found 892.3979.

[0161] Example 1-4. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(l-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)-3,6,9,12-tetraoxypentadecan-15-oyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-4):

[0162] Similar to Example 1-1, but replacing 3-(2-aminoethoxy)propionic acid tert-butyl ester with 15-amino-4,7,10,13-tetraoxypentadecanoic acid tert-butyl ester, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(l-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)-3,6,9,12-tetraoxypentadecan-15-oyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-4): 1HNMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.77-8.73 (m, 1H), 8.31 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.61-7.54 (m, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 6.5 Hz, 3H), 7.07-7.01 (m, 3H), 6.62-6.57 (m, 1H), 5.09-5.00 (m, 2H), 4.22 (d, J = 12.9 Hz, 1H), 4.08 (s, 1H), 3.91 (s, 1H), 3.84 (d, J = 13.6 Hz, 1H), 3.63-3.59 (m, 4H), 3.57-3.51 (m, 5H), 3.51-3.45 (m, 10H), 3.20-3.11 (m, 1H), 2.93-2.76 (m, 6H), 2.64-2.52 (m, 6H), 2.06-1.99 (m, 1H), 1.90 (d, J = 17.1 Hz, 2H), 1.44-1.17 (m, 5H).

[0163] Example 1-5. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(l-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)- 3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-5):

[0164] Similar to Example 1-1, but replacing 3-(2-aminoethoxy)propanoic acid tert-butyl ester with 1-amino-3,6,9,12,15-pentaoxaoctadecan-18-oic acid tert-butyl ester, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(l-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)- 3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-5). 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.76-8.73 (m, 1H), 8.29 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.61-7.55 (m, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 7.1 Hz, 3H), 7.07-7.00 (m, 3H), 6.62-6.58 (m, 1H), 5.08-5.02 (m, 1H), 4.96 (s, 1H), 4.22 (d, J = 13.1 Hz, 1H), 4.08 (s, 1H), 3.91-3.81 (m, 2H), 3.63-3.59 (m, 5H), 3.56-3.52 (m, 4H), 3.50-3.47 (m, 12H), 3.18-3.12 (m, 1H), 2.92-2.53 (m, 12H), 2.06-1.98 (m, 2H), 1.88 (s, 2H), 1.39-1.19 (m, 6H).

[0165] Example 1-6. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)butanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide:

[0166] Similar to Example 1-1, but replacing 3-(2-aminoethoxy)propanoic acid tert-butyl ester with 4-aminobutanoic acid tert-butyl ester. The target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)butanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-6). 1H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.80-8.73 (m, 1H), 8.29 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.32-7.26 (m, 1H), 7.12-7.08 (m, 3H), 7.06 (d, J = 1.2 Hz, 1H), 7.03-6.99 (m, 1H), 6.93 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.71-5.66 (m, 1H), 5.14-5.08 (m, 1H), 4.98 (d, J = 4.6 Hz, 1H), 4.23 (d, J = 17.2 Hz, 2H), 4.12 (d, J = 17.1 Hz, 2H), 3.89 (d, J = 5.6 Hz, 1H), 3.83 (d, J = 13.8 Hz, 1H), 3.61 (d, J = 9.2 Hz, 2H), 3.45-3.39 (m, 1H), 3.18-3.13 (m, 3H), 2.84-2.80 (m, 3H), 2.77-2.72 (m, 1H), 2.71-2.66 (m, 1H), 2.65-2.62 (m, 1H), 2.47-2.43 (m, 2H), 2.32-2.26 (m, 1H), 2.06-2.00 (m, 1H), 1.89 (s, 2H), 1.83-1.79 (m, 2H), 1.34 (d, J = 10.2 Hz, 2H), 1.23 (s, 2H).

[0167] Example 1-7. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)pentanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-7):

[0168] Similar to Example 1-1, but replacing 3-(2-aminoethoxy)propanoic acid tert-butyl ester with 5-aminopentanoic acid tert-butyl ester. The target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)pentanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-7). 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.77 (s, 1H), 8.30 (s, 1H), 7.77 (d, J = 7.4 Hz, 1H), 7.61 - 7.55 (m, 1H), 7.15 - 7.08 (m, 4H), 7.08 - 7.01 (m, 3H), 6.60 - 6.56 (m, 1H), 5.09 - 4.94 (m, 2H), 4.23 (d, J = 13.0 Hz, 1H), 4.09 (s, 1H), 3.93 - 3.79 (m, 2H), 3.62 (d, J = 6.7 Hz, 1H), 3.44 - 3.38 (m, 2H), 3.19 - 3.11 (m, 1H), 2.89 - 2.77 (m, 4H), 2.38 (d, J = 7.2 Hz, 2H), 2.05 - 1.99 (m, 1H), 1.94 - 1.83 (m, 2H), 1.64 - 1.53 (m, 5H), 1.39 - 1.14 (m, 10H).

[0169] Example 1-8. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)hexanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-8):

[0170] Similar to Example 1-1, but replacing 3-(2-aminoethoxy)propanoic acid tert-butyl ester with 6-aminohexanoic acid tert-butyl ester. The target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)hexanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-8). 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.77 (s, 1H), 8.29 (s, 1H), 7.76 (s, 1H), 7.62-7.55 (m, 1H), 7.13-7.09 (m, 4H), 7.06 (s, 1H), 7.04-7.01 (m, 2H), 6.58-6.54 (m, 1H), 5.09-5.02 (m, 1H), 4.99 (s, 1H), 4.25 (s, 1H), 4.09 (s, 1H), 3.93-3.81 (m, 2H), 3.67-3.55 (m, 2H), 3.20-3.13 (m, 1H), 2.87-2.54 (m, 8H), 2.36-2.31 (m, 2H), 2.06-1.97 (m, 1H), 1.89 (s, 2H), 1.63-1.51 (m, 3H), 1.40-1.32 (m, 1H), 1.24 (s, 10H). HRMS (ESI): calcd for C 41 H 49 N9NaO7[M+Na] + :802.3647, found802.3653.

[0171] Example 1-9. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(7-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-9):

[0172] Similar to Example 1-1, but replacing 3-(2-aminoethoxy)propanoic acid tert-butyl ester with 7-aminoheptanoic acid tert-butyl ester. The target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(7-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-9). 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.78-8.72 (m, 1H), 8.29 (s, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.61-7.57 (m, 1H), 7.09 (d, J = 8.4 Hz, 4H), 7.05 (s, 1H), 7.02 (d, J = 7.1 Hz, 2H), 6.57-6.50 (m, 1H), 5.09-5.01 (m, 1H), 4.97 (s, 1H), 4.23 (d, J = 12.9 Hz, 1H), 4.09 (s, 1H), 3.95-3.78 (m, 3H), 3.62 (s, 2H), 3.45-3.38 (m, 1H), 3.19-3.10 (m, 1H), 2.89-2.72 (m, 6H), 2.33-2.28 (m, 2H), 2.07-1.98 (m, 1H), 1.88 (s, 3H), 1.61-1.45 (m, 5H), 1.39-1.29 (m, 6H), 1.22 (d, J = 17.9 Hz, 4H). HRMS (ESI): calcd for C 42 H 52 N9O7[M+H] + : 794.3984, found 794.3973.

[0173] Example 1-10. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-10):

[0174] Similar to Example 1-1, but replacing 3-(2-aminoethoxy)propanoic acid tert-butyl ester with 8-aminooctanoic acid tert-butyl ester, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-10). 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.76 (d, J = 6.5 Hz, 1H), 8.30 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.61-7.56 (m, 1H), 7.13-7.08 (m, 4H), 7.07-7.00 (m, 3H), 6.55-6.51 (m, 1H), 5.08-5.01 (m, 1H), 4.97 (s, 1H), 4.23 (d, J = 13.1 Hz, 1H), 4.09 (s, 1H), 3.93-3.78 (m, 2H), 3.62 (s, 2H), 3.42 (d, J = 13.6 Hz, 1H), 3.19-3.11 (m, 1H), 2.92-2.66 (m, 4H), 2.58 (d, J = 19.2 Hz, 1H), 2.33-2.27 (m, 2H), 2.06-1.99 (m, 1H), 1.91 (d, J = 1.7 Hz, 4H), 1.59-1.56 (m, 2H), 1.52-1.46 (m, 2H), 1.38-1.20 (m, 14H). HRMS (ESI): calcd for C 43 H 54 N9O7[M+H] + :808.4141, found 808.4164.

[0175] Example 1-11. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(9-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)nonanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-11):

[0176] Similar to Example 1-1, but replacing 3-(2-aminoethoxy)propanoic acid tert-butyl ester with 9-aminononanoic acid tert-butyl ester, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(9-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)nonanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-11). 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.78-8.72 (m, 1H), 8.29 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.14-6.99 (m, 7H), 6.93 (d, J = 2.1 Hz, 1H), 6.86-6.81 (m, 1H), 5.05-4.94 (m, 2H), 4.23 (d, J = 13.0 Hz, 1H), 3.89 (s, 1H), 3.82 (d, J = 13.7 Hz, 1H), 3.62 (s, 2H), 3.46-3.39 (m, 1H), 3.15 (d, J = 5.8 Hz, 2H), 2.88-2.73 (m, 6H), 2.32-2.27 (m, 2H), 2.01-1.96 (m, 1H), 1.87 (d, J = 18.1 Hz, 2H), 1.59-1.54 (m, 2H), 1.47 (s, 2H), 1.34 (d, J = 7.8 Hz, 2H), 1.30-1.20 (m, 14H).

[0177] Example 1-12. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(10-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-12):

[0178] Similar to Example 1-1, but replacing 3-(2-aminoethoxy)propionic acid tert-butyl ester with 10-aminodecanoic acid tert-butyl ester, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(10-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-12). 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.78 - 8.72 (m, 1H), 8.29 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.62 - 7.54 (m, 1H), 7.14 - 7.07 (m, 4H), 7.05 (s, 1H), 7.01 (d, J = 7.0 Hz, 2H), 6.55 - 6.49 (m, 1H), 5.09 - 4.93 (m, 2H), 4.24 (s, 1H), 4.09 (s, 1H), 3.89 (s, 1H), 3.82 (d, J = 13.6 Hz, 1H), 3.62 (s, 2H), 3.42 (d, J = 13.4 Hz, 2H), 3.29 (d, J = 6.4 Hz, 2H), 3.19 - 3.10 (m, 1H), 2.93 - 2.72 (m, 6H), 2.60 (s, 1H), 2.56 (s, 1H), 2.32 - 2.25 (m, 2H), 2.07 - 1.99 (m, 1H), 1.60 - 1.54 (m, 2H), 1.50 - 1.44 (m, 2H), 1.36 - 1.23 (m, 16H). HRMS (ESI): calcd for C 45 H 58 N9O7[M+H] + : 836.4454, found 836.4479.

[0179] Example 1-13. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-13):

[0180]

[0181] Intermediate 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoic acid tert-butyl ester (92 mg, yield 28%) was obtained by dissolving intermediate 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoic acid tert-butyl ester (200 mg, 0.72 mmol) and tert-butyl 3-(2-aminoethoxy)propanoate (205 mg, 1.09 mmol) in DMSO (3 mL), adding DIEA (187 mg, 1.45 mmol), stirring at 90 °C for overnight. TLC was used to monitor the reaction. After the reaction was completed, the reaction mixture was extracted with ethyl acetate and water, the organic phase was collected, washed with saturated NaCl solution, combined organic phases, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification was performed by column chromatography (DCM:MeOH = 100:1) to obtain the intermediate 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoic acid tert-butyl ester (92 mg, yield 28%).

[0182] Intermediate 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoic acid (0.10 mmol) was dissolved in DCM (3 mL), TFA (1 mL) was added, and stirring was performed at room temperature for overnight. TLC was used to monitor the reaction. After the reaction was completed, the reaction mixture was distilled under reduced pressure to obtain the intermediate 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoic acid.

[0183] Intermediate 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoic acid (0.10 mmol) and intermediate P1 (0.10 mmol) were dissolved in DMSO (2 mL), HATU (50 mg, 0.13 mmol) and DIEA (40 mg, 0.31 mmol) were sequentially added, and stirring was performed at room temperature. The reaction mixture was extracted with EA and water, the organic phase was collected, washed with saturated NaCl solution, combined organic phases, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification was performed by column chromatography (DCM:MeOH = 50:1) to obtain the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (12 mg, yield 15%) (YZ-13). 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.77-8.73 (m, 1H), 8.29 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.15-7.11 (m, 1H), 7.09 (d, J = 6.3 Hz, 3H), 7.06-7.00 (m, 3H), 6.92-6.87 (m, 1H), 5.06-5.00 (m, 1H), 4.97 (s, 1H), 4.23 (d, J = 13.1 Hz, 1H), 4.12-4.03 (m, 1H), 3.89 (d, J = 6.5 Hz, 1H), 3.83 (d, J = 13.4 Hz, 1H), 3.69-3.65 (m, 2H), 3.63-3.58 (m, 4H), 3.20-3.14 (m, 1H), 2.92-2.79 (m, 5H), 2.72 (d, J = 27.5 Hz, 2H), 2.63-2.54 (m, 5H), 2.02-1.96 (m, 1H), 1.90 (d, J = 13.3 Hz, 2H), 1.42-1.20 (m, 6H).

[0184] Example 1-14. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-14):

[0185] Similar to Example 1-13, but replacing tert-butyl 3-(2-aminoethoxy)propanoate with tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate. The target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-14). 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.78-8.72 (m, 1H), 8.29 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.60-7.55 (m, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.11-7.08 (m, 3H), 7.07-7.00 (m, 3H), 6.63-6.57 (m, 1H), 5.09-5.02 (m, 1H), 4.97 (s, 1H), 4.21 (d, J = 11.1 Hz, 1H), 4.07 (s, 1H), 3.92-3.86 (m, 1H), 3.83 (d, J = 13.8 Hz, 1H), 3.64-3.58 (m, 6H), 3.57-3.52 (m, 4H), 3.52-3.38 (m, 9H), 3.18-3.10 (m, 1H), 2.86-2.72 (m, 5H), 2.58-2.53 (m, 3H), 2.06-1.98 (m, 1H), 1.88 (s, 2H), 1.40-1.20 (m, 5H).

[0186] Example 1-15. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(7-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-15):

[0187] Similar to Example 1-13, but replacing 3-(2-aminoethoxy)propionic acid tert-butyl ester with 7-aminoheptanoic acid tert-butyl ester. The target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(7-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-15). 1H NMR (500 MHz, DMSO-d6) δ 11.05 (d, J = 2.7 Hz, 1H), 8.75 (d, J = 6.4 Hz, 1H), 8.29 (d, J = 2.7 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.13 - 6.99 (m, 7H), 6.94 (s, 1H), 6.84 (d, J = 8.2 Hz, 1H), 5.06 - 4.99 (m, 1H), 4.97 (s, 1H), 4.23 (s, 1H), 4.09 (s, 1H), 3.89 (s, 1H), 3.82 (d, J = 13.3 Hz, 1H), 3.61 (d, J = 8.8 Hz, 2H), 3.42 (d, J = 13.5 Hz, 1H), 3.17 - 3.13 (m, 4H), 2.85 - 2.73 (m, 4H), 2.34 - 2.29 (m, 2H), 2.02 - 1.84 (m, 5H), 1.60 - 1.46 (m, 5H), 1.39 - 1.32 (m, 4H), 1.27 - 1.22 (m, 4H).

[0188] Example 1-16. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-16):

[0189] Similar to Example 1-13, but replacing 3-(2-aminoethoxy)propanoic acid tert-butyl ester with 8-aminooctanoic acid tert-butyl ester. The target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-16). 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.77-8.73 (m, 1H), 8.29 (s, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 6.0 Hz, 4H), 7.05 (d, J = 1.2 Hz, 1H), 7.01 (d, J = 6.5 Hz, 1H), 6.94 (d, J = 2.2 Hz, 1H), 6.86-6.82 (m, 1H), 5.06-5.00 (m, 1H), 4.97 (s, 1H), 4.23 (d, J = 12.6 Hz, 1H), 3.89 (d, J = 5.3 Hz, 1H), 3.82 (d, J = 13.5 Hz, 1H), 3.67-3.56 (m, 2H), 3.45-3.39 (m, 1H), 3.29 (s, 1H), 3.15 (d, J = 5.4 Hz, 2H), 2.89-2.65 (m, 7H), 2.57 (d, J = 18.9 Hz, 2H), 2.33-2.28 (m, 2H), 2.01-1.96 (m, 1H), 1.88 (d, J = 24.9 Hz, 2H), 1.60-1.46 (m, 5H), 1.39-1.27 (m, 8H), 1.23 (s, 2H). Example 1-17. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(9-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)nonanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-17):

[0190] Similar to Example 1-13, but replacing 3-(2-aminoethoxy)propionic acid tert-butyl ester with 9-aminononanoic acid tert-butyl ester. The target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(9-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)nonanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-17). 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.77-8.72 (m, 1H), 8.29 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 5.4 Hz, 4H), 7.05 (s, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.94 (s, 1H), 6.86-6.81 (m, 1H), 5.05-5.00 (m, 1H), 4.97 (s, 1H), 4.23 (d, J = 12.7 Hz, 1H), 3.93-3.87 (m, 1H), 3.82 (d, J = 13.5 Hz, 1H), 3.62 (s, 2H), 3.16-3.11 (m, 3H), 2.89-2.72 (m, 6H), 2.32-2.27 (m, 2H), 2.02-1.96 (m, 1H), 1.89 (d, J = 12.3 Hz, 3H), 1.60-1.52 (m, 3H), 1.52-1.44 (m, 3H), 1.36 (d, J = 8.8 Hz, 4H), 1.32-1.26 (m, 8H), 1.23 (s, 2H).

[0191] Example 1-18. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(10-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-18):

[0192] Similar to Example 1-13, but replacing 3-(2-aminoethoxy)propionic acid tert-butyl ester with 10-aminodecanoic acid tert-butyl ester. The target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(10-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-18). 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.77-8.73 (m, 1H), 8.29 (d, J = 1.2 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.11-7.07 (m, 4H), 7.05 (d, J = 1.2 Hz, 1H), 7.01 (d, J = 6.4 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 6.85-6.82 (m, 1H), 5.02 (dd, J = 12.7, 5.4 Hz, 1H), 4.96 (d, J = 4.7 Hz, 1H), 4.23 (d, J = 13.1 Hz, 1H), 4.12-4.06 (m, 2H), 3.91-3.86 (m, 1H), 3.82 (d, J = 13.5 Hz, 1H), 3.65-3.57 (m, 2H), 3.46-3.39 (m, 1H), 3.17 (d, J = 5.2 Hz, 2H), 3.14 (d, J = 5.9 Hz, 2H), 2.84-2.81 (m, 2H), 2.79-2.72 (m, 2H), 2.71-2.66 (m, 1H), 2.29 (t, J = 7.4 Hz, 2H), 2.03-1.95 (m, 1H), 1.95-1.83 (m, 2H), 1.60-1.53 (m, 2H), 1.51-1.45 (m, 2H), 1.39-1.21 (m, 16H); HRMS (ESI): calcd for C 45 H 58 N9O7[M+H] + : 836.4454, found 836.4456.

[0193] Example 1-19. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(ll-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)undecanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-19):

[0194] Similar to Example 1-13, but replacing 3-(2-aminoethoxy)propanoic acid tert-butyl ester with 11-aminoundecanoic acid tert-butyl ester. The target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(ll-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)undecanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-19). 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.77-8.72 (m, 1H), 8.29 (d, J = 1.2 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.11-7.07 (m, 4H), 7.05 (d, J = 1.2 Hz, 1H), 7.03-6.99 (m, 1H), 6.93 (d, J = 2.2 Hz, 1H), 6.85-6.82 (m, 1H), 5.05-4.99 (m, 1H), 4.96 (d, J = 4.8 Hz, 1H), 4.23 (d, J = 13.0 Hz, 1H), 4.12-4.04 (m, 1H), 3.91-3.86 (m, 1H), 3.82 (d, J = 13.7 Hz, 1H), 3.45-3.39 (m, 1H), 3.18-3.11 (m, 4H), 2.84-2.81 (m, 2H), 2.76-2.72 (m, 1H), 2.71-2.66 (m, 1H), 2.31-2.27 (m, 2H), 2.01-1.96 (m, 1H), 1.87 (d, J = 17.1 Hz, 3H), 1.59-1.54 (m, 2H), 1.47 (s, 3H), 1.38-1.29 (m, 6H), 1.25 (d, J = 15.3 Hz, 14H); HRMS (ESI): calcd for C 46 H 60 N9O7[M+H] + : 850.4610, found 850.4613. Example 1-20. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(12-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)dodecanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-20):

[0195] Similar to Example 1-13, but replacing 3-(2-aminoethoxy)propionic acid tert-butyl ester with 12-aminododecanoic acid tert-butyl ester. The target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(12-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)dodecanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-20). 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.77-8.72 (m, 1H), 8.29 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.14-6.99 (m, 6H), 6.93 (d, J = 2.1 Hz, 1H), 6.86-6.81 (m, 1H), 5.06-4.94 (m, 2H), 4.23 (d, J = 12.7 Hz, 1H), 4.09 (s, 1H), 3.89 (s, 1H), 3.82 (d, J = 13.5 Hz, 1H), 3.62 (s, 2H), 3.41 (d, J = 6.0 Hz, 1H), 3.29 (s, 1H), 3.14 (d, J = 6.4 Hz, 2H), 2.84 (d, J = 6.3 Hz, 2H), 2.77 (d, J = 13.2 Hz, 2H), 2.69 (s, 1H), 2.59 (d, J = 3.9 Hz, 1H), 2.55 (d, J = 4.9 Hz, 1H), 2.32-2.26 (m, 2H), 2.01-1.96 (m, 1H), 1.60-1.52 (m, 2H), 1.47 (s, 2H), 1.39-1.21 (m, 20H).

[0196] Example 1-21. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(10-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5- yl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-21):

[0197]

[0198] DMSO, DIEA (263 mg, 2.0 mmol) was added, and the mixture was stirred at 90 °C for 6 h under nitrogen protection. The reaction was monitored by TLC. After the reaction was completed, the mixture was extracted with EA and water, and the organic phase was collected, washed with saturated NaCl solution, combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The intermediate, 10-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)amino)decanoic acid (90 mg, yield 20%), was obtained by column chromatography (DCM:MeOH = 100:1).

[0199] Intermediate 10-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)amino)decanoic acid (90 mg, 0.20 mmol) and P1 (80 mg, 0.20 mmol) were dissolved in DMSO (2 mL), and HATU (96 mg, 0.25 mmol) and DIEA (75 mg, 0.59 mmol) were added successively, and stirred at room temperature. After the reaction was completed, EA and water were extracted, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH = 100:1) gave the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(10-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-21) (23 mg, yield 13%). 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.77-8.72 (m, 1H), 8.29 (d, J = 1.1 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 10.4 Hz, 1H), 7.12-7.03 (m, 5H), 7.03-6.99 (m, 1H), 6.92-6.87 (m, 1H), 5.08-5.02 (m, 1H), 4.97 (d, J = 4.7 Hz, 1H), 4.23 (d, J = 12.9 Hz, 1H), 4.09 (d, J = 5.2 Hz, 1H), 3.88 (d, J = 5.8 Hz, 1H), 3.82 (d, J = 13.3 Hz, 1H), 3.66-3.56 (m, 2H), 3.46-3.38 (m, 1H), 3.28-3.22 (m, 2H), 3.19-3.10 (m, 3H), 2.84-2.81 (m, 2H), 2.79-2.65 (m, 3H), 2.61-2.55 (m, 1H), 2.32-2.26 (m, 2H), 2.04-1.97 (m, 1H), 1.89 (s, 2H), 1.61-1.53 (m, 2H), 1.47 (s, 3H), 1.36-1.29 (m, 5H), 1.25 (d, J = 18.0 Hz, 9H). HRMS (ESI): calcd for C 45 H 57 FN9O7[M+H] + :854.4359, found 854.4364.

[0200] Example 1-22. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-22):

[0201]

[0202] Intermediate tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)octanoate (120 mg, yield 35%) was obtained by dissolving 2-(2,6-dioxopiperidin- 3-yl)-4-hydroxyisoindoline-l,3-dione (200 mg, 0.73 mmol) and tert-butyl 8- bromooctanoate (244 mg, 0.88 mmol) in DMF (3 mL), adding DIEA (190 mg, 1.5 mmol), protecting with nitrogen for 3-4 times, stirring at 90 °C overnight. After the reaction was completed, EA and water were extracted, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH = 100: 1) gave the intermediate tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)octanoate (120 mg, yield 35%).

[0203] Intermediate tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)octanoate (120 mg, yield 35%) was obtained by dissolving 2-(2,6-dioxopiperidin- 3-yl)-4-hydroxyisoindoline-l,3-dione (200 mg, 0.73 mmol) and tert-butyl 8- bromooctanoate (244 mg, 0.88 mmol) in DMF (3 mL), adding DIEA (190 mg, 1.5 mmol), protecting with nitrogen for 3-4 times, stirring at 90 °C overnight. After the reaction was completed, EA and water were extracted, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH = 100: 1) gave the intermediate tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)octanoate (120 mg, yield 35%).

[0204] Intermediate P1 (60 mg, 0.12 mmol) and 8-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)octanoic acid (54 mg, 0.12 mmol) were dissolved in DMSO (2 mL), and HATU (60 mg, 0.16 mmol) and DIEA (50 mg, 0.36 mmol) were added sequentially, and stirred at room temperature. After the reaction was completed, EA and water were extracted, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH = 50:1) gave the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-22) (12 mg, yield 12%). 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.79-8.71 (m, 1H), 8.29 (d, J = 1.1 Hz, 1H), 7.83-7.78 (m, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.14-6.99 (m, 6H), 5.11-5.05 (m, 1H), 4.96 (d, J = 4.8 Hz, 1H), 4.23-4.18 (m, 2H), 4.12-4.05 (m, 1H), 3.92-3.86 (m, 1H), 3.82 (d, J = 13.4 Hz, 1H), 3.61 (d, J = 8.8 Hz, 2H), 3.45-3.40 (m, 1H), 3.18-3.11 (m, 1H), 2.86-2.80 (m, 3H), 2.77-2.65 (m, 3H), 2.62-2.55 (m, 2H), 2.34-2.27 (m, 2H), 2.07-2.00 (m, 1H), 1.89 (s, 2H), 1.79-1.72 (m, 2H), 1.54-1.42 (m, 5H), 1.39-1.28 (m, 6H), 1.24 (d, J = 7.2 Hz, 2H).

[0205] Example 1-23. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2- hydroxypropyl)-6-((1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)octyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-23)

[0206]

[0207] Intermediate 2-(2,6-dioxopiperidin-3-yl)-4-((8-hydroxyoctyl)amino)isoindoline-1,3-dione (169 mg, 0.42 mmol) and p-toluenesulfonyl chloride (240 mg, 1.3 mmol) were dissolved in DCM (10 mL) under ice bath condition, TEA (140 mg, 1.3 mmol) was added, and the mixture was stirred overnight. The reaction was monitored by TLC. After the reaction was completed, the mixture was extracted with DCM and water, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH = 100:1) gave intermediate 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl 4-methylbenzenesulfonate (190 mg, yield: 82%).

[0208] Intermediate 2-(2,6-dioxopiperidin-3-yl)-4-((8-hydroxyoctyl)amino)isoindoline-1,3-dione (169 mg, 0.42 mmol) and p-toluenesulfonyl chloride (240 mg, 1.3 mmol) were dissolved in DCM (10 mL) under ice bath condition, TEA (140 mg, 1.3 mmol) was added, and the mixture was stirred overnight. The reaction was monitored by TLC. After the reaction was completed, the mixture was extracted with DCM and water, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH = 100:1) gave intermediate 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl 4-methylbenzenesulfonate (190 mg, yield: 82%).

[0209] Intermediate 2-(2,6-dioxopiperidin-3-yl)-4-((8-hydroxyoctyl)amino)isoindoline-1,3-dione (169 mg, 0.42 mmol) and p-toluenesulfonyl chloride (240 mg, 1.3 mmol) were dissolved in DCM (10 mL) under ice bath condition, TEA (140 mg, 1.3 mmol) was added, and the mixture was stirred overnight. The reaction was monitored by TLC. After the reaction was completed, the mixture was extracted with DCM and water, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH = 100:1) gave intermediate 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl 4-methylbenzenesulfonate (190 mg, yield: 82%). 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.75 (s, 1H), 8.28 (s, 1H), 7.74 (s, 1H), 7.61-7.55 (m, 1H), 7.12-7.00 (m, 7H), 6.55-6.51 (m, 1H), 5.08-5.01 (m, 1H), 4.98 (s, 1H), 3.88 (s, 2H), 3.61 (d, J = 8.8 Hz, 2H), 2.92-2.81 (m, 3H), 2.72 (d, J = 31.5 Hz, 1H), 2.08-1.97 (m, 1H), 1.56 (d, J = 7.3 Hz, 2H), 1.46 (s, 7H), 1.38-1.19 (m, 22H).

[0210] Example 1-24. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)octyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-24):

[0211] Similar to Example 1-23, but replacing 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline- 1,3-dione with 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-l,3-dione, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)octyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-24). 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.76 (s, 1H), 8.31 (s, 1H), 7.84-7.79 (m, 2H), 7.52 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 7.3 Hz, 1H), 7.09 (d, J = 22.1 Hz, 4H), 7.03 (s, 1H), 5.11-5.06 (m, 1H), 4.98 (s, 1H), 4.23-4.19 (m, 2H), 3.90 (s, 1H), 3.63 (s, 2H), 3.46-3.39 (m, 2H), 2.93-2.87 (m, 2H), 2.87-2.80 (m, 3H), 2.07-1.94 (m, 5H), 1.80-1.73 (m, 3H), 1.46 (d, J = 8.5 Hz, 4H), 1.40-1.28 (m, 10H), 1.24 (s, 6H).

[0212] Example 1-25. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)octyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-25):

[0213] Similar to Example 1-23, but replacing 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline- 1,3-dione with 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,3-dione, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)octyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-25). 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.75-8.70 (m, 1H), 8.28 (s, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.11-7.08 (m, 4H), 7.05 (s, 1H), 7.02-6.99 (m, 1H), 6.94 (d, J = 2.2 Hz, 1H), 6.86-6.82 (m, 1H), 5.06-4.99 (m, 1H), 4.96 (d, J = 4.7 Hz, 1H), 3.90-3.86 (m, 1H), 3.82 (s, 1H), 3.61 (d, J = 8.3 Hz, 2H), 3.45-3.39 (m, 1H), 3.17-3.13 (m, 2H), 2.92-2.85 (m, 1H), 2.86-2.80 (m, 4H), 2.77-2.64 (m, 3H), 2.60-2.53 (m, 2H), 2.30-2.22 (m, 2H), 2.02-1.94 (m, 3H), 1.85 (s, 2H), 1.59-1.54 (m, 2H), 1.45-1.39 (m, 4H), 1.36 (d, J = 8.0 Hz, 2H), 1.33-1.24 (m, 8H).

[0214] Example 1-26. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(5-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)pentyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide (YZ-26):

[0215]

[0216] To 3-(4-amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 0.77 mmol) and 1,5-dibromopentane (355 mg, 1.5 mmol) in N-methylpyrrolidone (NMP) (3 mL) was added DIEA (300 mg, 2.3 mmol) and stirred at 90 °C for 3-4 times under nitrogen protection. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was extracted with ethyl acetate and water, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The intermediate, 3-(4-((5-bromopentyl)amino)-l-oxoisoindolin-2-yl)piperidine-2,6-dione (250 mg, yield: 80%) was purified by column chromatography (DCM:MeOH = 100:1).

[0217] Intermediate 3-(4-((5-bromopentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50 mg, 0.12 mmol) and intermediate P1 (50 mg, 0.12 mmol) were dissolved in DMF (2 mL), TEA (99 mg, 0.98 mmol) was added, and the mixture was stirred at 90 °C for 3-4 times under nitrogen protection. The reaction was detected by TLC. After the reaction was completed, ethyl acetate and water were extracted, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification was performed by column chromatography (DCM:MeOH = 50:1) to obtain N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-26) (11 mg, yield: 12%). 1 H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.76 (s, 1H), 8.30 (s, 1H), 7.85-7.78 (m, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 20.4 Hz, 5H), 7.02 (s, 1H), 5.10-5.05 (m, 1H), 4.98 (s, 1H), 4.25-4.20 (m, 2H), 4.12-4.06 (m, 1H), 3.90 (s, 1H), 3.62 (s, 2H), 3.46-3.39 (m, 2H), 3.17 (d, J = 5.0 Hz, 1H), 2.93-2.80 (m, 5H), 2.74 (s, 4H), 2.58 (d, J = 18.7 Hz, 3H), 2.06-1.98 (m, 3H), 1.86-1.76 (m, 4H), 1.69 (s, 2H), 1.49 (s, 4H), 1.23 (s, 2H).

[0218] Example 1-27. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2- hydroxypropyl)-6-((1-(8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino) octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-27):

[0219]

[0220] Intermediate 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanoic acid tert-butyl ester (65 mg, 0.14 mmol) was dissolved in DCM (3 mL), TFA (1 mL) was added, and stirred at room temperature overnight. After the reaction was completed, it was distilled under reduced pressure, and the obtained crude product 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanoic acid was directly used in the next step.

[0221] Intermediate 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanoic acid tert-butyl ester (65 mg, 0.14 mmol) was dissolved in DCM (3 mL), TFA (1 mL) was added, and stirred at room temperature overnight. After the reaction was completed, it was distilled under reduced pressure, and the obtained crude product 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanoic acid was directly used in the next step.

[0222] Intermediate 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanoic acid tert-butyl ester (65 mg, 0.14 mmol) was dissolved in DCM (3 mL), TFA (1 mL) was added, and stirred at room temperature overnight. After the reaction was completed, it was distilled under reduced pressure, and the obtained crude product 8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanoic acid was directly used in the next step. 1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.77-8.73 (m, 1H), 8.29 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.31-7.24 (m, 1H), 7.16-6.84 (m, 7H), 6.74 (d, J = 8.1 Hz, 1H), 5.57-5.52 (m, 1H), 5.14-5.07 (m, 1H), 4.97 (s, 1H), 4.30-4.05 (m, 3H), 3.95-3.76 (m, 3H), 3.68-3.56 (m, 2H), 3.45-3.39 (m, 1H), 3.15-3.08 (m, 4H), 2.97-2.86 (m, 1H), 2.82 (d, J = 6.3 Hz, 2H), 2.77 (d, J = 12.9 Hz, 1H), 2.71-2.58 (m, 1H), 2.36-2.23 (m, 4H), 2.10-1.99 (m, 1H), 1.91 (d, J = 19.1 Hz, 3H), 1.64-1.44 (m, 6H), 1.35-1.29 (m, 4H), 1.23 (s, 3H).

[0223] Example 1-28. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-28):

[0224] Similar to Example 1-27, but replacing 8-bromooctanoic acid tert-butyl ester with 3-(2-(2-bromoethoxy)ethoxy)propanoic acid tert-butyl ester, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-28). 1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.00 (s, 1H), 9.44 (s, 1H), 8.77 (s, 1H), 7.80 (s, 1H), 7.31 - 7.05 (m, 6H), 6.94 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 5.60 - 5.55 (m, 1H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.23 (d, J = 17.1 Hz, 2H), 4.16 - 4.06 (m, 2H), 3.83 (d, J = 13.3 Hz, 1H), 3.66 - 3.57 (m, 4H), 3.56 - 3.50 (m, 3H), 3.40 (s, 2H), 3.13 - 3.04 (m, 6H), 2.96 - 2.87 (m, 2H), 2.84 - 2.77 (m, 1H), 2.56 (d, J = 6.0 Hz, 6H), 2.03 (d, J = 13.4 Hz, 1H), 1.89 (s, 2H), 1.40 - 1.22 (m, 6H).

[0225] Example 1-29. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-29):

[0226] Similar to Example 1-27, but replacing 8-bromooctanoic acid tert-butyl ester with 3-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)propanoic acid tert-butyl ester, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-29). 1HNMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.75 (s, 1H), 8.29 (s, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.30-7.25 (m, 1H), 7.14-6.99 (m, 6H), 6.94 (d, J = 7.3 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 5.59-5.55 (m, 1H), 5.14-5.08 (m, 1H), 4.96 (s, 1H), 4.23 (d, J = 17.1 Hz, 2H), 4.12 (d, J = 17.0 Hz, 2H), 3.93-3.79 (m, 3H), 3.45-3.38 (m, 2H), 3.17 (d, J = 5.2 Hz, 1H), 3.13 (d, J = 12.5 Hz, 1H), 2.96-2.87 (m, 2H), 2.81 (d, J = 14.4 Hz, 3H), 2.78-2.65 (m, 3H), 2.62 (s, 1H), 2.60-2.54 (m, 3H), 2.06-1.99 (m, 2H), 1.88 (s, 3H), 1.43-1.18 (m, 14H); HRMS (ESI): calcd for C 44 H 57 N9NaO9[M+Na] + : 878.4171, found 878.4173.

[0227] Example 1-30. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(5-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)pentanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-30):

[0228] Similar to Example 1-27, but replacing 8-bromooctanoic acid tert-butyl ester with 5-bromopentanoic acid tert-butyl ester, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(5-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)pentanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-30). 1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.78-8.72 (m, 1H), 8.29 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.31-7.26 (m, 1H), 7.13-6.99 (m, 6H), 6.93 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 5.69-5.64 (m, 1H), 5.14-5.08 (m, 1H), 4.97 (s, 1H), 4.23 (d, J = 17.1 Hz, 2H), 4.12 (d, J = 17.1 Hz, 2H), 3.94-3.79 (m, 3H), 3.66-3.56 (m, 2H), 3.45-3.39 (m, 1H), 3.19-3.11 (m, 3H), 2.86-2.78 (m, 4H), 2.71 (d, J = 27.6 Hz, 3H), 2.60 (d, J = 3.8 Hz, 1H), 2.32-2.26 (m, 1H), 2.07-1.99 (m, 2H), 1.89 (s, 2H), 1.84-1.78 (m, 2H), 1.34 (d, J = 7.5 Hz, 2H), 1.23 (s, 3H).

[0229] Example 1-31. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(6-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino) hexanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-31):

[0230] Similar to Example 1-27, but replacing 8-bromooctanoic acid tert-butyl ester with 6-bromohexanoic acid tert-butyl ester, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(6-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-31). 1H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.07 (s, 2H), 8.77 (d, J = 6.4 Hz, 1H), 8.38 (s, 1H), 7.87 (s, 1H), 7.32 - 7.23 (m, 1H), 7.23 - 7.12 (m, 3H), 7.08 (s, 2H), 6.92 (d, J = 7.4 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 5.63 - 5.58 (m, 1H), 5.15 - 5.08 (m, 1H), 4.23 (d, J = 17.3 Hz, 3H), 4.12 (d, J = 17.1 Hz, 3H), 3.83 (d, J = 13.4 Hz, 1H), 3.20 - 3.08 (m, 5H), 2.97 - 2.88 (m, 3H), 2.83 - 2.75 (m, 2H), 2.61 (d, J = 17.8 Hz, 1H), 2.38 - 2.23 (m, 4H), 2.13 - 2.07 (m, 1H), 2.03 (d, J = 12.7 Hz, 1H), 1.89 (d, J = 18.3 Hz, 2H), 1.63 - 1.50 (m, 5H), 1.42 - 1.30 (m, 4H).

[0231] Example 1-32. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)amino)butanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-32):

[0232] Similar to Example 1-27, but replacing 8-bromooctanoic acid tert-butyl ester with 4-bromobutyric acid tert-butyl ester, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)butanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-32). 1H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.80-8.74 (m, 1H), 8.30 (s, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.32-7.26 (m, 1H), 7.10 (d, J = 6.9 Hz, 3H), 7.06 (s, 1H), 7.02 (d, J = 7.1 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 5.64-5.58 (m, 1H), 5.16-5.08 (m, 1H), 4.99 (s, 1H), 4.23 (d, J = 17.1 Hz, 2H), 4.17-4.08 (m, 2H), 3.90 (s, 1H), 3.85 (d, J = 13.6 Hz, 1H), 3.62 (s, 1H), 3.43 (d, J = 13.5 Hz, 1H), 3.31 (s, 2H), 3.20-3.12 (m, 4H), 2.98-2.87 (m, 2H), 2.83 (s, 2H), 2.61 (d, J = 17.8 Hz, 2H), 2.37 (s, 2H), 2.35-2.24 (m, 2H), 2.07-2.00 (m, 1H), 1.89 (s, 1H), 1.64-1.58 (m, 4H), 1.24 (s, 2H).

[0233] Example 1-33. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(10-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-33):

[0234] Similar to Example 1-27, but replacing 8-bromooctanoic acid tert-butyl ester with 10-bromodecanoic acid tert-butyl ester, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(10-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-33). 1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.78-8.71 (m, 1H), 8.29 (s, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.31-7.24 (m, 1H), 7.13-6.98 (m, 6H), 6.92 (d, J = 7.4 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 5.57-5.52 (m, 1H), 5.15-5.07 (m, 1H), 4.96 (d, J = 4.7 Hz, 1H), 4.22 (d, J = 17.2 Hz, 2H), 4.12 (d, J = 17.1 Hz, 2H), 3.92-3.78 (m, 3H), 3.61 (d, J = 8.8 Hz, 2H), 3.13-3.08 (m, 2H), 2.86-2.80 (m, 3H), 2.80-2.65 (m, 4H), 2.32-2.27 (m, 3H), 2.07-2.00 (m, 1H), 1.89 (d, J = 18.4 Hz, 2H), 1.60-1.55 (m, 2H), 1.50-1.45 (m, 2H), 1.40-1.32 (m, 4H), 1.32-1.25 (m, 10H), 1.23 (s, 2H).

[0235] Example 1-34. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(8-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oct-7- ynyl) piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-34):

[0236]

[0237] Compound 3-(4-bromo-l-oxo-2,3-dihydro-lH-isoindol-2-yl)hexahydropyridine- 2,6-dione (500 mg, 1.5 mmol), 7-octynoic acid (260 mg, 1.9 mmol) and cuprous iodide (Cul) (60 mg, 0.31 mmol) were dissolved in anhydrous DMF (2 mL), protected with nitrogen for 3-4 times, added triethylamine (470 mg, 4.6 mmol), protected with nitrogen again, added catalyst bis(triphenylphosphine)palladium dichloride (109 mg, 0.15 mmol), protected with nitrogen again for 3 times, and then heated and stirred at 90°C overnight. Distilled under reduced pressure, extracted with EA and water, collected the organic phase, washed with saturated NaCl solution, combined the organic phase, dried with anhydrous sodium sulfate. Purified by column chromatography (DCM:MeOH=80:1) to obtain intermediate 8-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oct-7-ynoic acid.

[0238] Intermediate P1 (85 mg, 0.17 mmol) and 8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7-ynoic acid (64 mg, 0.17 mmol) were dissolved in DMSO (2 mL), and HATU (83 mg, 0.22 mmol) and DIEA (65 mg, 0.50 mmol) were sequentially added, and stirred at room temperature. The organic phase was collected, washed with saturated NaCl solution, and the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH = 50:1) gave the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-34) (24 mg, yield: 20%). 1 H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.78-8.72 (m, 1H), 8.30 (s, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.55-7.48 (m, 1H), 7.10 (s, 3H), 7.06 (s, 1H), 7.02 (s, 1H), 5.17-5.11 (m, 1H), 4.97 (s, 1H), 4.46 (d, J = 17.7 Hz, 1H), 4.32 (d, J = 17.7 Hz, 1H), 4.23 (s, 1H), 4.08 (s, 1H), 3.89 (s, 1H), 3.83 (d, J = 13.6 Hz, 1H), 3.62 (s, 2H), 3.44-3.39 (m, 1H), 3.18-3.12 (m, 1H), 2.89-2.66 (m, 7H), 2.36-2.32 (m, 2H), 2.05-1.97 (m, 2H), 1.89 (s, 3H), 1.61-1.53 (m, 4H), 1.48-1.43 (m, 2H), 1.33 (s, 2H), 1.24 (d, J = 7.0 Hz, 4H).

[0239] Example 1-35. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(11-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)undec-10-ynoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-35)

[0240]

[0241] Compound 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (300 mg, 0.93 mmol), 10-undecynoic acid (340 mg, 1.9 mmol) and CuI (35 mg, 0.19 mmol) were dissolved in DMF (5 mL), and nitrogen was supplied for 3-4 times. Triethylamine (375 mg, 3.7 mmol) was added, and nitrogen was supplied again. A catalyst, bis(triphenylphosphine)palladium dichloride (260 mg, 0.37 mmol), was added, and nitrogen was supplied again for 3 times. After that, it was heated and stirred at 90°C for overnight. EA and water were extracted, and the organic phase was collected. The organic phase was washed with a saturated NaCl solution, and the organic phases were combined. The combined organic phase was dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH=80:1) gave intermediate 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)undec-10-ynoic acid (180 mg, yield: 45%).

[0242] Intermediate 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)undec-10-ynoic acid (60 mg, 0.14 mmol) and intermediate P1 (58 mg, 0.14 mmol) were dissolved in DMSO (3 mL), and HATU (70 mg, 0.18 mmol) and DIEA (54 mg, 0.42 mmol) were sequentially added, and stirred at room temperature. EA and water were extracted, and the organic phase was collected. The organic phase was washed with a saturated NaCl solution, and the organic phases were combined. The combined organic phase was dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH=50:1) gave the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(11-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)undec-10-ynoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (23 mg, yield 20%) (YZ-35). 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.77-8.73 (m, 1H), 8.30 (s, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.70-7.57 (m, 3H), 7.52-7.44 (m, 1H), 7.16-6.99 (m, 6H), 5.14-5.07 (m, 1H), 4.47-4.40 (m, 2H), 4.31 (d, J = 17.5 Hz, 1H), 4.27-4.19 (m, 1H), 4.08 (s, 1H), 3.90 (d, J = 8.2 Hz, 1H), 3.82 (d, J = 13.5 Hz, 1H), 3.70-3.58 (m, 2H), 3.50 (d, J = 6.6 Hz, 1H), 3.45-3.37 (m, 1H), 3.19-3.10 (m, 1H), 2.87-2.73 (m, 4H), 2.63-2.52 (m, 1H), 2.33-2.24 (m, 3H), 2.04-1.96 (m, 1H), 1.94-1.82 (m, 2H), 1.61-1.52 (m, 2H), 1.51-1.37 (m, 4H), 1.32-1.28 (m, 8H), 1.23 (s, 4H). HRMS (ESI): calcd for C 46 H 57 N8O6[M+H] + : 817.4396, found 817.4399.

[0243] Example 1 -36. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)methyl)piperidin-l-yl)acetyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-36):

[0244]

[0245] Intermediate 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (450 mg, 0.83 mmol) was dissolved in DCM (10 mL), TFA (2 mL) was added and stirred at room temperature overnight. Distillation under reduced pressure gave the crude product 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidine-1-carboxylic acid which was used directly in the next step.

[0246] Intermediate 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (450 mg, 0.83 mmol) was dissolved in DCM (10 mL), TFA (2 mL) was added and stirred at room temperature overnight. Distillation under reduced pressure gave the crude product 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidine-1-carboxylic acid which was used directly in the next step.

[0247] Intermediate 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (450 mg, 0.83 mmol) was dissolved in DCM (10 mL), TFA (2 mL) was added and stirred at room temperature overnight. Distillation under reduced pressure gave the crude product 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidine-1-carboxylic acid which was used directly in the next step.

[0248] tert-Butyl 2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)acetate (55 mg, 0.099 mmol) was dissolved in DCM (3 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature overnight. Distillation under reduced pressure gave crude 2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid, which was used directly in the next step.

[0249] Intermediate P1 (40 mg, 0.099 mmol) were dissolved in DMSO (3 mL), HATU (49 mg, 0.13 mmol), DIEA (38 mg, 0.30 mmol) were added successively, and the mixture was stirred at room temperature. Extraction was performed with EA and water, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH = 50:1) gave the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-36) (12 mg, yield 14%). 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.78-8.72 (m, 1H), 8.30 (s, 1H), 7.76 (d, J = 7.4 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.27-7.23 (m, 1H), 7.10 (d, J = 6.3 Hz, 3H), 7.06 (s, 1H), 7.02 (d, J = 6.3 Hz, 1H), 5.12-5.03 (m, 1H), 4.97 (d, J = 4.7 Hz, 1H), 4.25 (d, J = 13.0 Hz, 1H), 4.12-4.07 (m, 1H), 3.92-3.87 (m, 1H), 3.84 (d, J = 13.4 Hz, 1H), 3.66-3.56 (m, 2H), 3.45-3.41 (m, 4H), 3.17 (d, J = 5.3 Hz, 2H), 2.93-2.87 (m, 1H), 2.86-2.78 (m, 3H), 2.78-2.66 (m, 3H), 2.59 (d, J = 19.0 Hz, 2H), 2.35-2.28 (m, 4H), 2.05-1.99 (m, 1H), 1.95-1.84 (m, 2H), 1.54-1.42 (m, 5H), 1.34-1.22 (m, 12H).

[0250] Example 1-37. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)butyl)piperazin-l-yl)propanoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-37):

[0251]

[0252] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,3-dione (300 mg, 1.1 mmol) and tert-butyl 4-(3-aminopropyl)piperazine-l-carboxylate (320 mg, 1.3 mmol) in DMSO (2 mL), add DIEA (280 mg, 2.2 mmol), protect with nitrogen for 3-4 times, stir at 90 °C overnight. Extract with EA and water, collect the organic phase, wash with saturated NaCl solution, combine the organic phase, dry over anhydrous sodium sulfate, and distill under reduced pressure. Purify by column chromatography (DCM:MeOH = 80: 1) to obtain tert-butyl 4-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)propyl)piperazine-l-carboxylate (230 mg, yield 42%).

[0253] tert-Butyl 4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)propyl)piperazine-1-carboxylate (230 mg, 0.46 mmol) was dissolved in DCM (5 mL), hydrochloric acid dioxane solution (1.5 mL) was added, and stirring was performed at room temperature overnight. DCM and saturated sodium bicarbonate were extracted, the organic phase was collected, and distillation under reduced pressure was performed to obtain the crude product 2-(2,6-dioxopiperidin-3-yl)-5-((3-(piperazin-1- yl)propyl)amino)isoindoline-1,3-dione (120 mg, yield 65%).

[0254] tert-Butyl 4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)propyl)piperazine-1-carboxylate (230 mg, 0.46 mmol) was dissolved in DCM (5 mL), hydrochloric acid dioxane solution (1.5 mL) was added, and stirring was performed at room temperature overnight. DCM and saturated sodium bicarbonate were extracted, the organic phase was collected, and distillation under reduced pressure was performed to obtain the crude product 2-(2,6-dioxopiperidin-3-yl)-5-((3-(piperazin-1- yl)propyl)amino)isoindoline-1,3-dione (120 mg, yield 65%).

[0255] tert-Butyl 4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)propyl)piperazine-1-carboxylate (230 mg, 0.46 mmol) was dissolved in DCM (5 mL), hydrochloric acid dioxane solution (1.5 mL) was added, and stirring was performed at room temperature overnight. DCM and saturated sodium bicarbonate were extracted, the organic phase was collected, and distillation under reduced pressure was performed to obtain the crude product 2-(2,6-dioxopiperidin-3-yl)-5-((3-(piperazin-1- yl)propyl)amino)isoindoline-1,3-dione (120 mg, yield 65%).

[0256] Intermediate P1 (92 mg, 0.19 mmol) and 4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)propyl)piperazin-1-yl)butanoic acid (80 mg, 0.19 mmol) were dissolved in DMSO (3 mL), and HATU (91 mg, 0.24 mmol) and DIEA (72 mg, 0.56 mmol) were added successively and stirred at room temperature. The reaction was detected by TLC. EA and water were extracted, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was used for separation and purification (DCM:MeOH = 50:1) to obtain the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)piperazin-1-yl)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-37) (52 mg, yield 32%). 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.78-8.72 (m, 1H), 8.29 (d, J = 1.1 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.17-7.12 (m, 1H), 7.11-7.08 (m, 3H), 7.06 (d, J = 1.2 Hz, 1H), 7.03-6.99 (m, 1H), 6.95 (d, J = 2.1 Hz, 1H), 6.87-6.82 (m, 1H), 5.06-5.00 (m, 1H), 4.97 (d, J = 4.8 Hz, 1H), 4.24 (d, J = 12.9 Hz, 1H), 4.09 (s, 1H), 3.89 (d, J = 5.8 Hz, 1H), 3.83 (d, J = 13.5 Hz, 1H), 3.66-3.56 (m, 2H), 3.45-3.38 (m, 1H), 3.22-3.18 (m, 2H), 2.92-2.86 (m, 1H), 2.85-2.80 (m, 3H), 2.78-2.66 (m, 3H), 2.61-2.57 (m, 1H), 2.56 (d, J = 5.0 Hz, 1H), 2.39-2.29 (m, 9H), 2.27 (d, J = 8.8 Hz, 3H), 2.01-1.96 (m, 1H), 1.89 (d, J = 14.2 Hz, 2H), 1.75-1.61 (m, 5H), 1.40-1.20 (m, 6H); HRMS (ESI): calcd for C 46 H 60 N 11O7[M+H] + : 878.4672, found 878.4665.

[0257] Example 1-38. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(l-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidin-4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-38):

[0258]

[0259] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,3-dione (300 mg, 1.1 mmol) and 4-piperidinecarbinol (160 mg, 1.4 mmol) in DMSO (2 mL), add DIEA (420 mg, 3.3 mmol), protect under nitrogen for 3-4 times, stir at 90 °C overnight. Extract with EA and water, collect the organic phase, wash with saturated NaCl solution, combine the organic phase, dry over anhydrous sodium sulfate, distill under reduced pressure. Purify by column chromatography (DCM:MeOH = 100:1) to obtain 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-l-yl)isoindoline-l,3-dione (350 mg, yield 85%).

[0260] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-l-yl)isoindoline-l,3-dione (350 mg, 0.94 mmol) and p-toluenesulfonyl chloride (540 mg, 2.8 mmol) in DCM (10 mL), add TEA (310 mg, 2.8 mmol), stir overnight. TLC test the reaction. Extract with DCM and water, collect the organic phase, wash with saturated NaCl solution, combine the organic phase, dry over anhydrous sodium sulfate, distill under reduced pressure. Purify by column chromatography (DCM:MeOH = 100:1) to obtain (l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl) 4-methylbenzenesulfonate (300 mg, yield 61%).

[0261] Methyl (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)methyl) piperidine-4-carboxylate (150 mg, 0.29 mmol) and tert-butyl 4-piperidinecarboxylate (70 mg, 0.37 mmol) were dissolved in DMF (3 mL), DIEA (110 mg, 0.86 mmol) was added, and the mixture was stirred at 70 °C overnight. The reaction was extracted with EA and water, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (DCM:MeOH = 50:1) gave tert-butyl 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidine-4-carboxylate (90 mg, yield 58%).

[0262] Tert-butyl 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)methyl)piperidine-4-carboxylate (90 mg, 0.17 mmol) was dissolved in DCM (5 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, it was distilled under reduced pressure, and the obtained crude product, 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid, was directly used in the next step.

[0263] Tert-butyl 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)methyl)piperidine-4-carboxylate (90 mg, 0.17 mmol) was dissolved in DCM (5 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, it was distilled under reduced pressure, and the obtained crude product, 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid, was directly used in the next step. 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.78-8.73 (m, 1H), 8.30 (s, 1H), 7.76 (d, J = 7.4 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.29-7.23 (m, 1H), 7.23-7.16 (m, 1H), 7.14-7.00 (m, 6H), 5.09-5.04 (m, 1H), 4.97 (d, J = 4.7 Hz, 1H), 4.27 (s, 1H), 4.11 (s, 1H), 3.67-3.56 (m, 2H), 3.46-3.39 (m, 1H), 3.24-3.16 (m, 1H), 3.14-3.07 (m, 1H), 2.92-2.73 (m, 8H), 2.71-2.65 (m, 1H), 2.62-2.54 (m, 3H), 2.28-2.21 (m, 1H), 2.09 (d, J = 12.4 Hz, 1H), 2.04-1.98 (m, 2H), 1.96-1.76 (m, 6H), 1.68 (s, 3H), 1.63-1.45 (m, 5H), 1.24 (s, 6H).

[0264] Example 1-39. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(l-(3-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidin-4-yl)propyl)piperidine-4-carbonyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-39):

[0265] Similar to Example 1-38, but replacing 4-piperidinemethanol with 4-(3- hydroxypropyl)-piperidine, the target product obtained by silica gel column chromatography is N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(l-(3-(l-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperidine-4- carbonyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-39). 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.78 - 8.72 (m, 1H), 8.30 (s, 1H), 7.76 (d, J = 7.4 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.25 - 7.21 (m, 1H), 7.15 - 7.07 (m, 3H), 7.06 (d, J = 1.1 Hz, 1H), 7.04 - 6.99 (m, 1H), 5.10 - 5.03 (m, 1H), 4.97 (d, J = 4.7 Hz, 1H), 4.25 (s, 1H), 4.04 (d, J = 13.1 Hz, 2H), 3.89 (d, J = 9.1 Hz, 2H), 3.67 - 3.56 (m, 3H), 3.45 - 3.39 (m, 1H), 3.23 - 3.15 (m, 1H), 2.98 - 2.91 (m, 3H), 2.90 - 2.86 (m, 2H), 2.85 - 2.82 (m, 2H), 2.78 - 2.67 (m, 3H), 2.58 - 2.53 (m, 2H), 2.25 (s, 2H), 2.04 - 1.99 (m, 1H), 1.92 (d, J = 8.7 Hz, 4H), 1.78 - 1.72 (m, 2H), 1.58 (s, 5H), 1.46 (s, 1H), 1.23 (d, J = 9.1 Hz, 8H), 1.15 (d, J = 10.6 Hz, 2H); HRMS (ESI): calcd for C 49 H 62 N 10 NaO7[M+Na] + :925.4695, found 925.4691.

[0266] Example 1 -40. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(4-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidin-4-yl)methyl)piperazin-l-yl)benzoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-40):

[0267]

[0268] Methyl (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl) 4-methylbenzenesulfonate (290 mg, 0.56 mmol) and tert-butyl 4-(piperazin-1- yl)benzoate (220 mg, 0.84 mmol) were dissolved in DMF (3 mL), TEA (122 mg, 1.1 mmol) was added, and the mixture was stirred at 90 °C overnight. EA and water were used to extract, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and purified by column chromatography (DCM:MeOH = 50:1) to obtain tert-butyl 4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)methyl)piperazin-1-yl)benzoate (100 mg, yield 29%).

[0269] Tert-butyl 4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)methyl)piperazin-1-yl)benzoate (100 mg, 0.16 mmol) was dissolved in DCM (5 mL), TFA (1.5 mL) was added, and the mixture was stirred at room temperature overnight. Distillation under reduced pressure was performed, and the obtained intermediate 4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzoic acid was directly used in the next step without further purification.

[0270] The intermediate 4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)methyl)piperazin-1-yl)benzoic acid (0.16 mmol) and the intermediate P1 (80 mg, 0.16 mmol) were dissolved in DMSO (2 mL), HATU (80 mg, 0.21 mmol) and DIEA (63 mg, 0.49 mmol) were added in sequence, and the mixture was stirred at room temperature. TLC was used to detect the reaction. EA and water were used to extract, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and purified by column chromatography (DCM:MeOH = 50:1) to obtain the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-40) (12 mg, yield: 8.4%). 1H NMR (500 MHz, DMSO-de) d 11.06 (s, 1H), 8.78 - 8.72 (m, 1H), 8.29 (d, J = 1.1 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.13 - 7.04 (m, 4H), 7.04 - 6.98 (m, 1H), 6.95 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 2.2 Hz, 1H), 6.83 - 6.77 (m, 1H), 5.08 - 5.01 (m, 1H), 4.96 (d, J = 4.8 Hz, 1H), 4.13 (s, 3H), 3.92 - 3.84 (m, 2H), 3.66 - 3.58 (m, 3H), 3.54 - 3.47 (m, 1H), 3.46 - 3.34 (m, 3H), 3.25 - 3.19 (m, 4H), 3.16 - 3.01 (m, 3H), 2.93 - 2.87 (m, 1H), 2.86 - 2.80 (m, 3H), 2.77 - 2.72 (m, 1H), 2.71 - 2.65 (m, 1H), 2.61 - 2.55 (m, 1H), 2.45 - 2.39 (m, 2H), 2.38 - 2.31 (m, 1H), 2.22 - 2.15 (m, 1H), 2.04 - 1.97 (m, 1H), 1.91 (s, 2H), 1.73 - 1.59 (m, 4H), 1.44 - 1.31 (m, 3H), 1.29 - 1.19 (m, 3H). HRMS (ESI): calcd for C 52 H 62 N 11 O7[M+H] + :952.4828, found 952.4839.

[0271] Example 1 -41. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)methyl)piperidin-l-yl)benzoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-41):

[0272]

[0273] DMSO (2 mL), DIEA (36 mg, 0.28 mmol) was added, and the mixture was stirred at 90 °C overnight. The reaction mixture was extracted with EA and water, and the organic phase was collected, washed with saturated NaCl solution, combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 50:1) to give tert-butyl 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate (34 mg, yield: 20%).

[0274] Tert-butyl 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate (34 mg, 0.05 mmol) was dissolved in DCM (5 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature overnight. The resulting intermediate 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoic acid was used directly in the next step without further purification.

[0275] Tert-butyl 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate (34 mg, 0.05 mmol) was dissolved in DCM (5 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature overnight. The resulting intermediate 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoic acid was used directly in the next step without further purification. 1HNMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.78-8.72 (m, 1H), 8.29 (s, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.27-7.24 (m, 3H), 7.11-7.08 (m, 3H), 7.06 (d, J = 1.2 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 5.11-5.04 (m, 1H), 4.97 (s, 1H), 4.08 (d, J = 51.4 Hz, 3H), 3.89 (s, 1H), 3.80 (d, J = 12.3 Hz, 2H), 3.61 (d, J = 9.0 Hz, 2H), 3.44 (s, 6H), 3.11 (s, 2H), 2.93-2.86 (m, 1H), 2.82 (d, J = 5.3 Hz, 2H), 2.78-2.72 (m, 3H), 2.69 (s, 1H), 2.58 (d, J = 18.3 Hz, 2H), 2.22 (d, J = 6.9 Hz, 2H), 2.04-1.99 (m, 1H), 1.84-1.73 (m, 4H), 1.42-1.33 (m, 3H), 1.23 (s, 8H). HRMS (ESI): calcd for C 52 H 62 N 11 O7[M+H] + :952.4828, found952.4826.

[0276] Example 1-42. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(4-(4-(3-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidin-4-yl)propyl)piperazin-l-yl)benzoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-42):

[0277]

[0278] To a solution of 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)propyl 4-methylbenzenesulfonate (190 mg, 0.34 mmol) and tert-butyl 4-(1-piperazinyl)benzoate (110 mg, 0.41 mmol) in DMF (3 mL) was added TEA (89 mg, 0.69 mmol) and stirred at 90 °C overnight. EA and water were used to extract, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and purified by column chromatography (DCM:MeOH = 100:1) to give tert-butyl 4-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperazin-1- yl)benzoate (190 mg, yield 45%).

[0279] To a solution of tert-butyl 4-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)propyl)piperazin-1-yl)benzoate (100 mg, 0.16 mmol) in DCM (5 mL) was added TFA (1 mL) and stirred at room temperature. The reaction was monitored by TLC. After the reaction was completed, it was distilled under reduced pressure, and the obtained crude product 4-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperazin-1-yl)benzoic acid was directly used in the next step.

[0280] To a solution of 4-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperazin-1- yl)benzoic acid (0.16 mmol) and intermediate P1 (65 mg, 0.16 mmol) in DMSO (2 mL) was added HATU (77 mg, 0.20 mmol) and DIEA (60 mg, 0.47 mmol) successively and stirred at room temperature. The reaction was monitored by TLC. EA and water were used to extract, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and purified by column chromatography (DCM:MeOH = 50:1) to give the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(4-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperazin-1-yl)benzoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-42). 1HNMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.78-8.72 (m, 1H), 8.29 (d, J = 1.2 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 8.7 Hz, 2H), 7.24-7.21 (m, 1H), 7.11-7.08 (m, 3H), 7.06 (d, J = 1.2 Hz, 1H), 7.01 (d, J = 6.2 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 5.09-5.02 (m, 1H), 4.97 (d, J = 4.6 Hz, 1H), 4.18-4.00 (m, 6H), 3.89 (d, J = 5.9 Hz, 1H), 3.66-3.56 (m, 2H), 3.46-3.38 (m, 1H), 3.29 (d, J = 7.1 Hz, 1H), 3.23-3.18 (m, 4H), 3.17 (d, J = 5.2 Hz, 4H), 2.97-2.91 (m, 2H), 2.85-2.81 (m, 2H), 2.78-2.65 (m, 2H), 2.58 (d, J = 18.5 Hz, 1H), 2.30 (s, 2H), 2.04-1.97 (m, 1H), 1.91 (s, 2H), 1.76 (d, J = 12.4 Hz, 2H), 1.50 (d, J = 7.8 Hz, 4H), 1.42-1.34 (m, 2H), 1.28-1.10 (m, 8H); HRMS (ESI): calcd for C 54 H 66 N 11 O7[M+H] + :980.5141, found 980.5139. Example 1-43. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(5-(7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pentanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-43):

[0281]

[0282] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (250 mg, 0.91 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (250 mg, 1.1 mmol) in DMSO (3 mL), add DIEA (240 mg, 1.8 mmol), protect with nitrogen, and stir at 90°C overnight. Extract with EA and water, collect the organic phase, wash with saturated NaCl solution, combine the organic phases, dry over anhydrous sodium sulfate, distill under reduced pressure, and purify by column chromatography (DCM:MeOH=100:1) to obtain tert-butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (325 mg, yield: 74%).

[0283] Dissolve tert-butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (325 mg, 0.66 mmol) in DCM (10 mL), add a hydrochloric acid dioxane solution (2 mL), and distill under reduced pressure after the reaction is completed. The obtained crude product 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]non-7-yl)isoindole-1,3-dione is used in the next step without further purification.

[0284] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]non-7-yl)isoindole-1,3-dione (0.66 mmol) in DMF (3 mL), add tert-butyl 5-bromopentanoate (314 mg, 1.3 mmol) and TEA (145 mg, 1.3 mmol), and stir at 90°C overnight. Extract with EA and water, collect the organic phase, wash with saturated NaCl solution, combine the organic phases, dry over anhydrous sodium sulfate, distill under reduced pressure, and purify by column chromatography (DCM:MeOH=80:1) to obtain intermediate tert-butyl 5-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pentanoate (195 mg, yield: 61%).

[0285] tert-Butyl 5-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7- diazaspiro [3.5] nonan-2-yl)pentanoate (195 mg, 0.36 mmol) was dissolved in DCM (5 mL), and a hydrochloric acid dioxane solution (2 mL) was added. After the reaction was completed, distillation was performed under reduced pressure, and the obtained crude product 5-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7- diazaspiro [3.5] nonan-2-yl)pentanoic acid.

[0286] Intermediate P1 (80 mg, 0.19 mmol) and 5-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)-2,7-diazaspiro [3.5] nonan-2-yl)pentanoic acid (85 mg, 0.19 mmol) were dissolved in DMSO (3 mL), and HATU (96 mg, 0.25 mmol) and DIEA (75 mg, 0.58 mmol) were sequentially added and stirred at room temperature. The reaction was detected by TLC. Extraction was performed with EA and water, the organic phase was collected, washed with a saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and purified by column chromatography (DCM:MeOH = 50:1) to obtain the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2- hydroxypropyl)-6-((1-(5-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7- diazaspiro [3.5] nonan-2-yl)pentanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-43) (32 mg, yield: 20%). 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 10.94 (s, 1H), 8.80-8.72 (m, 1H), 8.35 (s, 1H), 7.84 (d, J = 20.7 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.40-7.35 (m, 1H), 7.30-7.25 (m, 1H), 7.18-7.03 (m, 5H), 5.11-5.01 (m, 1H), 4.24 (d, J = 11.2 Hz, 1H), 4.16-4.05 (m, 3H), 3.92 (s, 2H), 3.87-3.75 (m, 4H), 3.52-3.39 (m, 5H), 2.93-2.78 (m, 5H), 2.62-2.55 (m, 2H), 2.37 (d, J = 6.3 Hz, 2H), 2.05-1.79 (m, 8H), 1.58-1.45 (m, 5H), 1.42-1.32 (m, 2H), 1.30-1.22 (m, 5H). HRMS (ESI): calcd for C 47 H 59 N 10 O7[M+H] + :875.4563, found 875.4551.

[0287] Example 1-44. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(4-(9-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)- 3,9-diazaspiro[5.5]undecan-3-yl)butanoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-44):

[0288]

[0289] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,3-dione (250 mg, 0.91 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (276 mg, 1.1 mmol) in DMSO (3 mL), add DIEA (240 mg, 1.8 mmol), protect under nitrogen, stir at 90 °C overnight. Extract with EA and water, collect the organic phase, wash with saturated NaCl solution, combine the organic phases, dry over anhydrous sodium sulfate, distill under reduced pressure, and purify by column chromatography (DCM:MeOH = 80: 1) to obtain tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (515 mg, yield: 99%).

[0290] tert-Butyl 9-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (515 mg, 1.0 mmol) was dissolved in DCM (10 mL), and a solution of hydrochloric acid dioxane (1.5 mL) was added. After the reaction was completed, distillation under reduced pressure was performed, and the obtained crude product 2-(2,6-dioxopiperidin-3-yl)-5-(-3,9-diazaspiro[5.5]undecan-3-yl)isoindole-l,3-dione was used in the next step without further purification.

[0291] tert-Butyl 9-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (515 mg, 1.0 mmol) was dissolved in DCM (10 mL), and a solution of hydrochloric acid dioxane (1.5 mL) was added. After the reaction was completed, distillation under reduced pressure was performed, and the obtained crude product 2-(2,6-dioxopiperidin-3-yl)-5-(-3,9-diazaspiro[5.5]undecan-3-yl)isoindole-l,3-dione was used in the next step without further purification.

[0292] tert-Butyl 9-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (515 mg, 1.0 mmol) was dissolved in DCM (10 mL), and a solution of hydrochloric acid dioxane (1.5 mL) was added. After the reaction was completed, distillation under reduced pressure was performed, and the obtained crude product 2-(2,6-dioxopiperidin-3-yl)-5-(-3,9-diazaspiro[5.5]undecan-3-yl)isoindole-l,3-dione was used in the next step without further purification.

[0293] 4-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)butanoic acid (80 mg, 0.16 mmol) and Intermediate P1 (66 mg, 0.16 mmol) were dissolved in DMSO (2 mL). HATU (80 mg, 0.21 mmol) and DIEA (62 mg, 0.48 mmol) were added sequentially, and the mixture was stirred at room temperature. The reaction was monitored by TLC. The mixture was extracted with EA and water, and the organic phase was collected and washed with saturated NaCl solution. The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The mixture was separated and purified by column chromatography (DCM:MeOH=50:1) to give the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(4-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)butanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-44) (35 mg, yield: 24%). 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.80-8.71(m,1H),8.29(s,1H),7.76(d,J=7.2Hz,1H),7.64(d,J=8.4Hz,1H),7.30(s,1H),7. 21(d,J=8.8Hz,1H),7.08(d,J=17.5Hz,4H),7.01(d,J=7.2Hz,1H),5.10-5.02(m,1H),4.97(s,1H),4.24(d,J=12.5Hz,1H),4.09(s,1 H),3.93-3.79(m,3H),3.62(t,J=11.9Hz,3H),3.51-3.40(m,6H),3.17(d,J=12.0Hz,1H),2.87-2.79(m,4H),2.76-2.66(m,3H),2.35 (d,J=15.1Hz,4H),2.00(d,J=14.0Hz,1H),1.96-1.85(m,2H),1.72-1.63(m,2H),1.51(s,9H),1.41-1.31(m,2H),1.29-1.20(m,4H).

[0294] Example 1-45. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin- 1-yl)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-45):

[0295]

[0296] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,3-dione (500 mg, 1.8 mmol) and 1-Boc piperazine (405 mg, 2.2 mmol) in DMSO (5 mL), add DIEA (470 mg, 3.6 mmol), protect under nitrogen, stir at 90 °C overnight. Extract with EA and water, collect the organic phase, wash with saturated NaCl solution, combine the organic phases, dry over anhydrous sodium sulfate, distill under reduced pressure, and purify by column chromatography (DCM:MeOH = 150: 1) to obtain 4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazine-l- carboxylic acid tert-butyl ester (850 mg, yield 95%).

[0297] Dissolve 4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazine-l-carboxylic acid tert-butyl ester (850 mg, 1.9 mmol) in DCM (10 mL), add TFA (2 mL), and stir at room temperature. Monitor the reaction by TLC. After the reaction is complete, distill under reduced pressure, and use the obtained crude product 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-l-yl)isoindoline-l,3-dione directly in the next step without further purification.

[0298] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-l-yl)isoindoline-l,3-dione (100 mg, 0.29 mmol) and 7-bromoheptanoic acid tert-butyl ester (93 mg, 0.35 mmol) in DMF (3 mL), add DIEA (75 mg, 0.58 mmol), and stir at room temperature overnight. Extract with EA and water, collect the organic phase, wash with saturated NaCl solution, combine the organic phases, dry over anhydrous sodium sulfate, distill under reduced pressure, and purify by column chromatography (DCM:MeOH = 50: 1) to obtain 7-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)heptanoic acid tert-butyl ester (120 mg, yield 79%).

[0299] tert-Butyl 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)heptanoate (120 mg, 0.23 mmol) was dissolved in DCM (10 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After the reaction was completed, the solvent was distilled under reduced pressure, and the obtained crude product 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)heptanoic acid was used directly in the next step without further purification.

[0300] 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)heptanoic acid (75 mg, 0.16 mmol) and intermediate PI (65 mg, 0.16 mmol) were dissolved in DMSO (3 mL), and HATU (78 mg, 0.21 mmol) and DIEA (61 mg, 0.48 mmol) were added sequentially, and the mixture was stirred at room temperature. The reaction was monitored by TLC. The reaction was extracted with EA and water, the organic phase was collected, washed with a saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and purified by column chromatography (DCM:MeOH = 50:1) to obtain the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-45) (12 mg, yield 8.7%). 1H NMR (500 MHz, DMSO-de) d 11.07 (s, 1H), 8.81-8.73 (m, 1H), 8.30 (s, 1H), 7.80-7.74 (m, 1H), 7.70-7.61 (m, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.27-7.22 (m, 1H), 7.17 (d, J = 9.1 Hz, 1H), 7.13-7.05 (m, 4H), 7.01 (d, J = 5.1 Hz, 1H), 5.09-5.03 (m, 1H), 4.97 (d, J = 4.6 Hz, 1H), 4.21 (s, 1H), 4.11 (d, J = 38.5 Hz, 3H), 3.89 (s, 1H), 3.65-3.57 (m, 2H), 3.44-3.37 (m, 5H), 3.26-3.11 (m, 3H), 2.90-2.80 (m, 4H), 2.78-2.67 (m, 3H), 2.20 (d, J = 41.0 Hz, 3H), 2.04-1.88 (m, 4H), 1.80 (s, 2H), 1.62 (s, 3H), 1.46 (s, 3H), 1.24 (d, J = 7.5 Hz, 6H). HRMS (ESI): calcd for C 46 H 59 N 10 O7[M+H] + : 863.4563, found 863.4563. Example 1 -46. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(ll-(4-(2,6-dioxopiperidin-3-yl)phenoxy)undecanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-46):

[0301]

[0302] 2,6-bis(benzyloxy)-3-bromopyridine (1 g, 2.7 mmol), 4-hydroxybenzeneboronic acid pinacol ester (770 mg, 3.5 mmol) and potassium carbonate (1.1 g, 8.1 mmol) were dissolved in 1,4-dioxane (10 mL) and water (3 mL) and stirred at room temperature under nitrogen protection for 3-4 times, then a catalyst of dichlorobis(triphenylphosphine)palladium was added, and nitrogen protection was performed again for 3-4 times, and stirred at 100 °C overnight. Filtration under suction, and distilled under reduced pressure. Purified by column chromatography (PE:EA = 5:1) to obtain intermediate 4-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (3 g, yield 95%).

[0303] Intermediate 4-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (150 mg, 0.39 mmol) and tert-butyl 11-bromoundecanoate (150 mg, 0.47 mmol) were dissolved in DMF (2 mL), and cesium carbonate (380 mg, 1.2 mmol) was added, and stirred at room temperature. EA and water were extracted, and the organic phase was collected, washed with saturated NaCl solution, and the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (PE:EA = 8:1) to obtain intermediate tert-butyl 11-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)undecanoate (220 mg, yield 90%).

[0304] Intermediate tert-butyl 11-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)undecanoate (220 mg, 0.35 mmol) was dissolved in methanol (20 mL), and 3-4 times of nitrogen protection was performed, and an appropriate amount of Pd / C was added, and 3-4 times of nitrogen protection was performed again, and hydrogen was replaced, and stirred at room temperature overnight. After the reaction was completed, filtration was performed, and distilled under reduced pressure, and the obtained crude product tert-butyl 11-(4-(2,6-dioxopiperidin-3-yl)phenoxy)undecanoate (170 mg, yield 99%) was directly used in the next step.

[0305] Intermediate tert-butyl 11-(4-(2,6-dioxopiperidin-3-yl)phenoxy)undecanoate (170 mg, 0.38 mmol) was dissolved in DCM (5 mL), and TFA (1 mL) was added, and stirred at room temperature overnight. After the reaction was completed, distilled under reduced pressure, and the obtained crude product 11-(4-(2,6-dioxopiperidin-3-yl)phenoxy)undecanoic acid was directly used in the next step.

[0306] Intermediate 11-(4-(2,6-dioxopiperidin-3-yl)phenoxy)undecanoic acid (80 mg, 0.21 mmol) and intermediate P1 (86 mg, 0.21 mmol) were dissolved in DMSO (2 mL), and HTAU (100 mg, 0.27 mmol) and DIEA (80 mg, 0.62 mmol) were sequentially added, and stirred at room temperature. The reaction was detected by TLC. EA and water were extracted, and the organic phase was collected, washed with saturated NaCl solution, and the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure, and purified by column chromatography (DCM:MeOH = 50:1) to obtain the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(11-(4-(2,6-dioxopiperidin-3-yl)phenoxy)undecanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-46) (37 mg, yield 23%). 1H NMR (500 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.77-8.72 (m, 1H), 8.29 (d, J = 1.2 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.12-7.08 (m, 5H), 7.06 (d, J = 1.2 Hz, 1H), 7.02-7.00 (m, 1H), 6.88-6.85 (m, 2H), 4.97 (d, J = 4.6 Hz, 1H), 4.23 (d, J = 12.8 Hz, 1H), 4.08 (s, 1H), 3.95-3.91 (m, 2H), 3.91-3.87 (m, 1H), 3.82 (d, J = 13.5 Hz, 1H), 3.79-3.74 (m, 1H), 3.66-3.56 (m, 2H), 3.45-3.39 (m, 1H), 3.20-3.10 (m, 1H), 2.84-2.81 (m, 2H), 2.79-2.72 (m, 2H), 2.71-2.66 (m, 1H), 2.65-2.60 (m, 1H), 2.32-2.27 (m, 2H), 2.19-2.10 (m, 1H), 2.04-1.96 (m, 1H), 1.88 (d, J = 24.6 Hz, 2H), 1.72-1.65 (m, 2H), 1.50-1.45 (m, 2H), 1.41-1.37 (m, 2H), 1.35-1.22 (m, 16H).

[0307] Example 1-47. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(10-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)decanoyl)piperidin-4- yl)amino)pyrimidine-4-carboxamide (YZ-47):

[0308]

[0309] To a solution of 2,6-bis(benzyloxy)-3-bromopyridine (4.4 g, 11 mmol), 4- aminobenzeneboronic acid pinacol ester (2 g, 9.1 mmol) and potassium carbonate (3.8 g, 27 mmol) in 1,4-dioxane (20 mL) and water (6 mL) was stirred at room temperature for 3-4 times under nitrogen protection, and then a catalytic amount of dichlorobis(triphenylphosphine)palladium was added. The mixture was stirred at 100 °C overnight under nitrogen protection for another 3-4 times. Filtration under reduced pressure and distillation under reduced pressure. Purification by column chromatography (PE:EA = 2:1) to give intermediate 4-(2,6-bis(benzyloxy)pyridin-3-yl)aniline (2.5 g, yield 72%).

[0310] Intermediate 4-(2,6-bis(benzyloxy)pyridin-3-yl)aniline (150 mg, 0.39 mmol) and tert-butyl 10-bromodecanoate (180 mg, 0.59 mmol) were dissolved in DMF (2 mL), and cesium carbonate (380 mg, 1.2 mmol) was added. Stirring was performed at 90 °C overnight. EA and water were used for extraction, and the organic phase was collected. The organic phase was washed with saturated NaCl solution, combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification was performed by column chromatography (PE:EA = 6:1) to obtain tert-butyl 10-((4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)amino)decanoate (76 mg, yield 32%).

[0311] Tert-butyl 10-((4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)amino)decanoate (76 mg, 0.12 mmol) was dissolved in ethanol (20 mL), and 3-4 times of nitrogen protection was performed. Appropriate Pd / C was added, and 3-4 times of nitrogen protection was performed again. Hydrogen was replaced, and stirring was performed at room temperature overnight. After the reaction was completed, filtration was performed under suction, and distillation was performed under reduced pressure. The obtained crude product tert-butyl 10-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)decanoate (43 mg, yield 80%) was directly used in the next step.

[0312] Tert-butyl 10-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)decanoate (43 mg, 0.10 mmol) was dissolved in DCM (5 mL), and TFA (1 mL) was added. Stirring was performed at room temperature overnight. After the reaction was completed, distillation was performed under reduced pressure. The obtained crude product 10-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)decanoic acid was directly used in the next step.

[0313] 10-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)decanoic acid (0.10 mmol) and intermediate P1 (41 mg, 0.10 mmol) were dissolved in DMSO (2 mL), and HATU (49 mg, 0.13 mmol) and DIEA (39 mg, 0.30 mmol) were sequentially added. Stirring was performed at room temperature. TLC was used to detect the reaction. EA and water were used for extraction, and the organic phase was collected. The organic phase was washed with saturated NaCl solution, combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification was performed by column chromatography (DCM:MeOH = 50:1) to obtain the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(10-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-47) (28 mg, yield 13%). 1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.80-8.71 (m, 1H), 8.30 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.15-7.00 (m, 5H), 6.88 (d, J = 8.3 Hz, 2H), 6.49 (d, J = 8.3 Hz, 2H), 5.51-5.40 (m, 1H), 4.98 (s, 1H), 4.24 (d, J = 12.8 Hz, 1H), 4.09 (s, 1H), 3.90 (s, 1H), 3.82 (d, J = 13.5 Hz, 1H), 3.71-3.55 (m, 3H), 3.46-3.38 (m, 1H), 3.20-3.11 (m, 1H), 3.00-2.91 (m, 2H), 2.83 (d, J = 6.1 Hz, 2H), 2.77 (d, J = 12.1 Hz, 1H), 2.71 (s, 1H), 2.65-2.55 (m, 2H), 2.34-2.25 (m, 2H), 2.12-2.03 (m, 1H), 2.03-1.96 (m, 1H), 1.91 (d, J = 22.0 Hz, 2H), 1.55-1.45 (m, 4H), 1.40-1.18 (m, 16H). HRMS (ESI): calcd for C 43 H 59 N8O5[M+H] + :767.4603, found 767.4600.

[0314] Example 1-48. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(7-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperazin-l-yl)heptanoyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-48):

[0315]

[0316] To a solution of 4-(4-BOC-piperazin-l-yl)-3-fluoroaniline (1 g, 3.4 mmol) and 3-bromohexahydropyridine-2,6-dione (1.95 g, 10 mmol) in DMF (5 mL) was added sodium bicarbonate (2.8 g, 34 mmol) and stirred at 80 °C overnight. EA and water were used to extract, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and purified by column chromatography (DCM:MeOH = 100:1) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-l-carboxylate (300 mg, yield 22%).

[0317] tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1- carboxylate (300 mg, 0.74 mmol) was dissolved in DCM (10 mL), added with hydrochloric acid dioxane solution (2 mL), stirred at room temperature overnight. After the reaction was completed, distilled under reduced pressure, the obtained crude product 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione was directly used in the next step without purification.

[0318] tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1- carboxylate (300 mg, 0.74 mmol) was dissolved in DCM (10 mL), added with hydrochloric acid dioxane solution (2 mL), stirred at room temperature overnight. After the reaction was completed, distilled under reduced pressure, the obtained crude product 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione was directly used in the next step without purification.

[0319] tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1- carboxylate (300 mg, 0.74 mmol) was dissolved in DCM (10 mL), added with hydrochloric acid dioxane solution (2 mL), stirred at room temperature overnight. After the reaction was completed, distilled under reduced pressure, the obtained crude product 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione was directly used in the next step without purification.

[0320] Intermediate P1 (73 mg, 0.18 mmol) and 7-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperazin-1-yl)heptanoic acid (0.18 mmol) were dissolved in DMSO (3 mL), and HATU (88 mg, 0.23 mmol) and DIEA (70 mg, 0.54 mmol) were added successively and stirred at room temperature. The reaction was detected by TLC. EA and water were extracted, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was used to separate and purify (DCM:MeOH = 50:1) to obtain the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(7-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-48) (22 mg, yield: 15%). 1 H NMR (500 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.78-8.72 (m, 1H), 8.29 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 6.2 Hz, 3H), 7.06 (s, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.85-6.78 (m, 1H), 6.53-6.47 (m, 1H), 6.44-6.39 (m, 1H), 5.80 (d, J = 7.5 Hz, 1H), 4.98 (s, 1H), 4.29-4.20 (m, 2H), 4.09 (s, 1H), 3.93-3.87 (m, 1H), 3.83 (d, J = 13.7 Hz, 1H), 3.68-3.54 (m, 3H), 3.46-3.37 (m, 2H), 3.19-3.11 (m, 1H), 2.90-2.68 (m, 12H), 2.34-2.28 (m, 3H), 2.11-2.05 (m, 1H), 1.96-1.81 (m, 4H), 1.53-1.41 (m, 5H), 1.32-1.27 (m, 5H), 1.23 (s, 3H). HRMS (ESI): calcd for C 44 H 59 FN 10 NaO5[M+H] + :849.4546, found 849.4569.

[0321] Example 1-49. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)hexyl)amino)-2-oxoethyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-49):

[0322]

[0323] Intermediate (S)-N-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6- (piperidin-4-ylamino)pyrimidine-4-carboxamide (100 mg, 0.24 mmol) was dissolved in tetrahydrofuran (15 mL) and cesium carbonate (154 mg, 0.47 mmol) was added, followed by the addition of tert-butyl bromoacetate (92 mg, 0.47 mmol) and stirred at 70 °C overnight. The reaction was monitored by TLC and distilled under reduced pressure and purified by column chromatography on silica gel (DCM:MeOH = 80: 1) to give intermediate (S)-tert-butyl 2-(4-((6-((3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)carbamoyl)pyrimidin-4-yl)amino)piperidin-l-yl)acetate (83 mg, yield 66%).

[0324] Intermediate (S)-tert-butyl 2-(4-((6-((3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)carbamoyl)pyrimidin-4-yl)amino)piperidin-l-yl)acetate (83 mg, 0.16 mmol) was dissolved in DCM (5 mL) and TFA (1 mL) was added and stirred at room temperature overnight. After the reaction was completed, it was distilled under reduced pressure and the crude product obtained was used as intermediate (S)-2-(4-((6-((3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)carbamoyl)pyrimidin-4-yl)amino)piperidin-l-yl)acetic acid without further purification for the next step.

[0325] Intermediate (S)-2-(4-((6-((3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)carbamoyl)pyrimidin-4-yl)amino)piperidin-l-yl)acetic acid (0.16 mmol) and 4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (60 mg, 0.16 mmol) were dissolved in DMSO (2 mL), and HATU (80 mg, 0.21 mmol) and DIEA (62 mg, 0.48 mmol) were added sequentially and stirred at room temperature. The reaction was monitored by TLC. EA and water were extracted, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and purified by column chromatography (DCM:MeOH = 50: 1) to obtain the target product N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)hexyl)amino)-2-oxoethyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-49) (12 mg, yield: 9%). 1 H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.75 (d, J = 6.2 Hz, 1H), 8.28 (s, 1H), 7.75-7.68 (m, 2H), 7.58-7.53 (m, 1H), 7.11-7.06 (m, 4H), 7.03-6.99 (m, 2H), 6.56-6.51 (m, 1H), 5.07-5.02 (m, 1H), 4.99 (s, 1H), 3.88 (s, 1H), 3.82 (s, 1H), 3.61 (d, J = 9.2 Hz, 2H), 3.11-3.05 (m, 3H), 2.88 (d, J = 6.7 Hz, 4H), 2.83 (d, J = 6.1 Hz, 2H), 2.75 (s, 2H), 2.17 (s, 2H), 1.86 (s, 2H), 1.58-1.47 (m, 6H), 1.45-1.38 (m, 4H), 1.36-1.27 (m, 6H), 1.23 (s, 4H). HRMS (ESI): calcd for C 43 H 55 N 10 O7[M+H] + :823.4250, found 823.4267.

[0326] Example 1-50. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)acetylamino)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-50):

[0327]

[0328] Intermediate P1 (40 mg, 0.098 mmol) and 8-((tert-butoxycarbonyl)amino)octanoic acid (25 mg, 0.098 mmol) were dissolved in DMF (2 mL), and HATU (49 mg, 0.13 mmol) and DIEA (38 mg, 0.30 mmol) were added sequentially. The mixture was stirred at room temperature. The organic phase was collected by extraction with EA and water, washed with a saturated NaCl solution, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 100:1) to obtain (S)-(8-(4-((6-((3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)carbamoyl)pyrimidin-4-yl)amino)piperidin-l-yl)-8-oxooctyl)carbamic acid tert-butyl ester (38 mg, 59% yield).

[0329] (S)-(8-(4-((6-((3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)carbamoyl)pyrimidin-4-yl)amino)piperidin-l-yl)-8-oxooctyl)carbamic acid tert-butyl ester (38 mg, 0.058 mmol) was dissolved in DCM (3 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting crude product was used directly in the next step without further purification as (S)-6-((l-(8-aminooctanoyl)piperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide.

[0330] Intermediate (S)-6-((l-(8-aminooctanoyl)piperidin-4-yl)amino)-N-(3-(3,4- dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide (0.058 mmol) and Intermediate 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetic acid (20 mg, 0.058 mmol) were dissolved in DMF (2 mL), HATU (30 mg, 0.075 mmol), DIEA (22 mg, 0.17 mmol) were added successively, stirred at room temperature. EA and water were extracted, organic phase was collected, washed with saturated NaCl solution, combined organic phases were dried over anhydrous sodium sulfate, distilled under reduced pressure, purified by column chromatography (DCM:MeOH = 50: 1) to give N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetylamino)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-50) (8 mg, yield 16%). 1 H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.79-8.73 (m, 1H), 8.29 (s, 1H), 7.96-7.90 (m, 1H), 7.84-7.78 (m, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 6.2 Hz, 3H), 7.05 (s, 1H), 7.01 (d, J = 8.1 Hz, 1H), 5.16-5.09 (m, 1H), 4.98 (s, 1H), 4.23 (d, J = 14.4 Hz, 1H), 4.08 (s, 1H), 3.89 (s, 1H), 3.82 (d, J = 13.4 Hz, 1H), 3.61 (d, J = 9.1 Hz, 2H), 3.45-3.39 (m, 1H), 3.18-3.11 (m, 4H), 2.86-2.80 (m, 3H), 2.76 (d, J = 13.7 Hz, 2H), 2.69 (s, 1H), 2.31-2.27 (m, 2H), 2.07-2.01 (m, 1H), 1.90 (s, 2H), 1.49-1.42 (m, 6H), 1.37-1.21 (m, 12H).

[0331] Example 1-51. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)acetamido)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-51):

[0332] Similar to Example 1-50, but replacing 8-((tert-butoxycarbonyl)amino)octanoic acid with 7-((tert-butoxycarbonyl)amino)heptanoic acid, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)acetamido)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-51). 1 H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.78-8.73 (m, 1H), 8.29 (s, 1H), 7.95-7.91 (m, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 6.3 Hz, 3H), 7.05 (s, 1H), 7.01 (d, J = 7.1 Hz, 1H), 5.15-5.09 (m, 1H), 4.98 (d, J = 4.8 Hz, 1H), 4.77 (s, 2H), 4.23 (d, J = 14.0 Hz, 1H), 4.08 (s, 1H), 3.92-3.86 (m, 1H), 3.82 (d, J = 13.6 Hz, 1H), 3.61 (d, J = 9.2 Hz, 2H), 3.46-3.38 (m, 2H), 3.17-3.12 (m, 3H), 2.82 (d, J = 6.0 Hz, 2H), 2.79-2.73 (m, 2H), 2.68 (d, J = 11.4 Hz, 1H), 2.63-2.56 (m, 2H), 2.32-2.27 (m, 2H), 2.07-2.01 (m, 1H), 1.89 (s, 2H), 1.50-1.41 (m, 5H), 1.32-1.22 (m, 8H).

[0333] Example 1-52. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)acetamido)hexanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-52):

[0334] Similar to Example 1-50, but replacing 8-((tert-butoxycarbonyl)amino)octanoic acid with 6-((tert-butoxycarbonyl)amino)hexanoic acid, the target product obtained by silica gel column chromatography was N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)acetamido)hexanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide. 1 H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.78-8.72 (m, 1H), 8.29 (s, 1H), 7.98-7.93 (m, 1H), 7.84-7.79 (m, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 6.9 Hz, 3H), 7.05 (s, 1H), 7.01 (d, J = 7.1 Hz, 1H), 5.16-5.08 (m, 1H), 4.99 (s, 1H), 4.77 (s, 2H), 4.30-4.19 (m, 2H), 4.09 (s, 1H), 3.89 (s, 1H), 3.81 (d, J = 12.4 Hz, 1H), 3.63 (d, J = 7.8 Hz, 2H), 3.17-3.12 (m, 3H), 2.83 (d, J = 5.8 Hz, 2H), 2.77 (d, J = 12.7 Hz, 2H), 2.32-2.25 (m, 3H), 2.05-2.00 (m, 1H), 1.90 (s, 2H), 1.50-1.43 (m, 4H), 1.25 (d, J = 16.0 Hz, 10H).

[0335] Example 1-53. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)acetamido)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-53):

[0336]

[0337] (S)-6-((1-(8-aminooctanoyl)piperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide (23 mg, 0.058 mmol) and intermediate (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) glycine (20 mg, 0.058 mmol) were dissolved in DMF (2 mL), HATU (30 mg, 0.076 mmol), DIEA (22 mg, 0.17 mmol) were added sequentially, stirred at room temperature. EA and water were extracted, the organic phase was collected, washed with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was used to separate and purify (DCM:MeOH = 50:1) to obtain the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetylamino)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-53) (6 mg, yield: 12%). 1 H NMR (500 MHz, DMSO-d6) δ 8.78-8.72 (m, 1H), 8.29 (s, 1H), 7.91-7.85 (m, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.50-7.45 (m, 1H), 7.12-7.07 (m, 3H), 7.05 (d, J = 1.2 Hz, 1H), 7.04-6.99 (m, 3H), 6.53 (s, 2H), 5.19-5.12 (m, 1H), 4.97 (s, 1H), 4.21 (d, J = 4.1 Hz, 2H), 4.09 (s, 1H), 3.89 (s, 1H), 3.82 (d, J = 13.4 Hz, 1H), 3.62 (s, 2H), 3.18-3.11 (m, 1H), 3.08-2.96 (m, 4H), 2.82 (d, J = 5.6 Hz, 2H), 2.79-2.74 (m, 2H), 2.71-2.58 (m, 1H), 2.31-2.25 (m, 2H), 2.11-2.04 (m, 1H), 1.88 (d, J = 29.1 Hz, 2H), 1.47 (d, J = 9.0 Hz, 2H), 1.40-1.33 (m, 4H), 1.30-1.18 (m, 12H).

[0338] Example 1-54. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)acetamido)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-54):

[0339]

[0340] (S)-6-((l-(7-aminopentanoyl)piperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(lH)- yl)-2-hydroxypropyl)pyrimidine-4-carboxamide (35 mg, 0.067 mmol) and intermediate (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)glycine (22 mg, 0.067 mmol) were dissolved in DMF (2 mL), HATU (33 mg, 0.087 mmol) and DIEA (26 mg, 0.20 mmol) were added successively, and the mixture was stirred at room temperature. The mixture was extracted with EA and water, the organic phase was collected, washed with saturated NaCl solution, and the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and purified by column chromatography (DCM:MeOH = 50: 1) to obtain the target product N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((l-(7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)acetamido)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-54) (8 mg, yield: 14%). 1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.78-8.73 (m, 1H), 8.29 (s, 1H), 7.96-7.91 (m, 1H), 7.84-7.78 (m, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 6.3 Hz, 4H), 7.05 (s, 1H), 7.01 (d, J = 7.1 Hz, 1H), 5.15-5.09 (m, 1H), 4.98 (d, J = 4.8 Hz, 1H), 4.77 (s, 2H), 4.23 (d, J = 14.0 Hz, 1H), 4.08 (s, 1H), 3.92-3.78 (m, 3H), 3.61 (d, J = 9.2 Hz, 2H), 3.18-3.11 (m, 4H), 2.82 (d, J = 6.0 Hz, 2H), 2.78-2.73 (m, 2H), 2.68 (d, J = 11.4 Hz, 1H), 2.31-2.27 (m, 2H), 2.06-2.01 (m, 1H), 1.89 (s, 3H), 1.51-1.39 (m, 6H), 1.31-1.22 (m, 8H).

[0341] Example 1-55. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((l-(2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)methyl)piperidin-l-yl)acetyl)piperidin-4-yl)amino)pyrimidine-4- carboxamide (YZ-55):

[0342]

[0343] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-l-yl)isoindoline-l,3-dione (300 mg, 0.88 mmol) and l-Boc-piperidine-3-carbaldehyde (374 mg, 1.8 mmol) in DMF (5 mL), add sodium triacetoxyborohydride (370 mg, 1.8 mmol), stir at room temperature overnight. Extract with EA and water, collect the organic phase, wash with saturated NaCl solution, combine the organic phases, dry over anhydrous sodium sulfate, distill under reduced pressure, and purify by column chromatography (DCM:MeOH = 100:1) to obtain tert-butyl 3-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l- yl)methyl)piperidine-l-carboxylate (500 mg, yield 99%).

[0344] tert-Butyl 3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidine-1-carboxylate (500 mg, 0.93 mmol) was dissolved in DCM (15 mL), and a solution of hydrochloric acid in dioxane (3 mL) was added. After the reaction was completed, distillation under reduced pressure was performed, and the obtained crude product was used as an intermediate, 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-3-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione, without purification, for the next reaction.

[0345] tert-Butyl 2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)acetate (162 mg, 0.29 mmol) was dissolved in DCM (5 mL), and TFA (2 mL) was added. After stirring at room temperature overnight, distillation under reduced pressure was performed, and the obtained crude product was used as an intermediate, 2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid, without further purification, for the next reaction.

[0346] tert-Butyl 2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)acetate (162 mg, 0.29 mmol) was dissolved in DCM (5 mL), and TFA (2 mL) was added. After stirring at room temperature overnight, distillation under reduced pressure was performed, and the obtained crude product was used as an intermediate, 2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid, without further purification, for the next reaction.

[0347] Intermediate P1 (60 mg, 0.15 mmol) and 2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid (66 mg, 0.15 mmol) were dissolved in DMSO (3 mL), and HATU (72 mg, 0.19 mmol) and DIEA (56 mg, 0.44 mmol) were added sequentially. The mixture was stirred at room temperature. The organic phase was collected, washed with saturated NaCl solution, and the combined organic phases were dried over anhydrous sodium sulfate, distilled under reduced pressure, and purified by column chromatography (DCM:MeOH = 50:1) to give the target product N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-55) (18 mg, yield: 13%). 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.80-8.73 (m, 1H), 8.29 (s, 1H), 7.80-7.74 (m, 1H), 7.69-7.61 (m, 1H), 7.35-7.30 (m, 1H), 7.27-7.21 (m, 1H), 7.12-7.06 (m, 4H), 7.01 (d, J = 4.5 Hz, 1H), 5.09-5.04 (m, 1H), 4.97 (d, J = 4.6 Hz, 1H), 4.27-3.96 (m, 4H), 3.89 (s, 1H), 3.61 (d, J = 8.6 Hz, 2H), 3.47-3.37 (m, 6H), 3.26-3.10 (m, 3H), 2.85-2.80 (m, 3H), 2.79-2.66 (m, 4H), 2.44-2.39 (m, 2H), 2.29-2.12 (m, 3H), 2.06-1.88 (m, 5H), 1.80 (s, 2H), 1.65 (d, J = 26.0 Hz, 2H), 1.46 (s, 2H), 1.25 (d, J = 11.9 Hz, 6H). HRMS (ESI): calcd for C 47 H 60 N 11 O7[M+H] + : 890.4672, found 890.4671.

[0348] Example 1-56. Preparation of N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)-6-((4-(10-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)decanamido)cyclohexyl)amino)pyrimidine-4-carboxamide (YZ-56):

[0349]

[0350] Intermediate P2 (72 mg, 0.17 mmol) and 10-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)decanoic acid (75 mg, 0.17 mmol) were dissolved in DMSO (3 mL), and HATU (84 mg, 0.22 mmol) and DIEA (66 mg, 0.51 mmol) were added successively. The mixture was stirred at room temperature. The organic phase was collected by extraction with EA and water, washed with saturated NaCl solution, and dried over anhydrous sodium sulfate. The organic phase was combined and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 50:1) to give the target product N-((S)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-6-((4-(10-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)decanamido)cyclohexyl)amino)pyrimidine-4-carboxamide (YZ-56) (23 mg, yield: 16%). 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.76-8.70 (m, 1H), 8.29-8.25 (m, 1H), 7.65 (s, 2H), 7.55 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 12.0 Hz, 1H), 7.09 (d, J = 6.2 Hz, 4H), 7.01 (d, J = 6.3 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 6.85-6.80 (m, 1H), 5.05-4.99 (m, 1H), 4.97 (d, J = 4.8 Hz, 1H), 3.93-3.85 (m, 2H), 3.68-3.59 (m, 3H), 3.47-3.40 (m, 2H), 3.16-3.10 (m, 2H), 2.85-2.81 (m, 2H), 2.78-2.71 (m, 1H), 2.71-2.66 (m, 1H), 2.09-2.05 (m, 2H), 2.02-1.96 (m, 2H), 1.69-1.60 (m, 4H), 1.56 (d, J = 7.7 Hz, 6H), 1.48 (d, J = 10.2 Hz, 2H), 1.35 (s, 2H), 1.30-1.21 (m, 12H).

[0351] Example 2: Evaluation of the PRMT5 degradation effect induced by the compounds of the present application in breast cancer cells

[0352] Example 2-1, Cell culture

[0353] The breast cancer cells HCC1806 and HCC1937 used in the present application and the human normal tissue cell HEK-293T (derived from human embryonic normal kidney) were purchased from the American Type Culture Collection (ATCC).

[0354] The cells were cultured in a medium containing 10% fetal bovine serum (ExCell Bio) and 100 units / ml penicillin, 100 μg / ml streptomycin (VivaCell) in a 37°C constant temperature cell incubator (humidity 95%, CO2concentration 5%). RPMI-1640 (Gibco) and DMEM high-sugar medium (Gibco) were used for cell culture.

[0355] Example 2-2, Evaluation of the PRMT5 degradation activity induced by the compounds of the present application

[0356] A series of PRMT5-targeted PROTACs (YZ-1 to YZ-56) described in Example 1 were dissolved in dimethyl sulfoxide (DMSO) to a final concentration of 4 μmol / L, and the control group was added with an equal amount of DMSO, and then incubated with breast cancer cells HCC1806 and HCC1937 for 48 h. The cells were collected by centrifugation and denatured lysis to collect total cell proteins. Then, the degradation of PRMT5 by the compounds was analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).

[0357] The gray values of PRMT5 and GAPDH, β-actin or Vinculin in different lanes were analyzed by Image J software, and the relative gray ratio of PRMT5 / GAPDH, β-actin or Vinculin corresponding to each compound and the relative gray ratio of PRMT5 / GAPDH, β-actin or Vinculin in the control group were calculated in Excel. The protein degradation rate (%) of PRMT5 was calculated according to the following formula.

[0358]

[0359] The degradation ability of the compounds YZ-1 to YZ-56 of the present application to PRMT5 in breast cancer cells is expressed by the PRMT5 protein degradation rate (%) of the compounds at a concentration of 4 micromole / liter. Among them, “A”, “B”, “C”, “D” respectively represent that the degradation rate of the compounds of the present application to PRMT5 in tumor cells at the concentration is less than 25%, between 25% and 50%, between 50% and 75%, and greater than 75%, and “NT” represents that the degradation ability of the compound to PRMT5 at the specified concentration is not evaluated. The evaluation results of the degradation efficiency of the compounds of the present application to PRMT5 in breast cancer cells HCC1806 and HCC1937 are shown in Table 1. The degradation effect of some of the compounds of the present application to PRMT5 in breast cancer cells HCC1806 and HCC1937 at the specified concentration is shown in Table 2. Figure 1

[0360] Table 1 PRMT5 degradation activity of compounds YZ-1 to YZ-56 of the present application in breast cancer cells

[0361]

[0362]

[0363] The results show that some of the compounds YZ-1 to YZ-56 of the present application exhibit certain degradation activity in breast cancer cells, among which YZ-18 has the best degradation activity, which can effectively induce the degradation of more than 50% of PRMT5 protein level in breast cancer cells HCC1806 and HCC1937 at a concentration of 4 micromole / liter and can significantly down-regulate the protein expression of KLF5.

[0364] Example 3: Evaluation of the anti-proliferation activity of the compounds of the present application in breast cancer cells

[0365] Example 3-1. Determination of the proliferation inhibition activity of the compounds to breast cancer cells by SRB method

[0366] HCC1806 and HCC1937 cells were seeded at 5×10 3 cells / well and 2.5×10 3 ​The cells were seeded at a density of 1 cell / well in 96-well plates and incubated for 16 hours. Then, different concentrations of the compounds were added to the cells, and the same volume of DMSO was added to the control group. After 48 hours of incubation, 50% trichloroacetic acid (100 μL / well) was added to the cells, which were then incubated at 4°C overnight. After fixation, the cells were washed with distilled water for 5 times, and then air-dried. Then, 100 μL of 4% SRB solution was added to each well, and the cells were incubated at room temperature for 30 minutes. The dye solution was removed, and the cells were washed with 1% acetic acid for 5-6 times to remove the unbound dye. After air-drying, 100 μL of 10 mmol / L Tris base solution was added to each well to dissolve the bound SRB dye. The 96-well plate was placed in a microplate reader, and the OD value was measured at 530 nm. The cell survival rate (%) was calculated according to the following formula.

[0367]

[0368] The effects of the compounds of the present application on the proliferation of breast cancer cells were statistically analyzed, and the results are shown in Table 2.

[0369] The inhibitory activities of the compounds YZ-1 to YZ-56 of the present application on the viability of breast cancer cells were represented by the inhibition rate (%) of the compounds at a concentration of 4 μmol / L. Among them, “+”, “++”, “+++” and “++++” respectively represented that the inhibition rate of the compound was less than 25%, between 25% and 50%, between 50% and 75%, and greater than 75%, and “NT” represented that the growth inhibitory activity of the compound at the specified concentration was not evaluated. The inhibitory activities of the compounds of the present application on breast cancer cells HCC1806 and HCC1937 are shown in Table 2.

[0370] Table 2 Results of the tumor inhibitory activities of the compounds YZ-1 to YZ-56 of the present application in breast cancer cells

[0371]

[0372]

[0373] The results showed that the compounds of the present application exhibited certain proliferation inhibitory activities on breast cancer cells HCC1806 and HCC1937. Among them, YZ-18, YZ-41, YZ-46 and YZ-47 exhibited more than 50% of the proliferation inhibitory activities in the two breast cancer cells. These results indicated that the compounds of the present application had good anti-proliferation effects on breast cancer cells.

[0374] Example 3-2. Proliferation inhibitory activities of representative compounds in the examples in breast cancer cells and normal breast epithelial cells.

[0375] To further test the proliferation inhibition activity of the compounds of the present application in breast cancer cells and the toxicity to normal breast epithelial cells, the representative compounds in the examples of the present application were continued to determine the proliferation inhibition activity of the compounds on breast cancer cells and normal breast epithelial cells by SRB method, and Prism v.8.0 (GraphPad) software was used for statistical analysis of the effects of the representative compounds of the present application on the proliferation of breast cancer cells under different concentrations, and IC 50 The test results of YZ-18 are shown in Table 3 and Figure 2 .

[0376] Table 3 IC50 of representative compound YZ-18 in breast cancer cells and normal breast epithelial cells 50

[0377]

[0378] The results showed that the representative compound YZ-18 exhibited weak cytotoxicity to normal breast epithelial cells, and breast cancer cells HCC1806 and HCC1937 were more sensitive to the compound YZ-18.

[0379] Example 3-3. Evaluation of the ability of the representative compound YZ-18 in the examples to induce cell cycle and apoptosis in breast cancer cells.

[0380] The cells were treated with different concentrations of YZ-18 for 48 hours, then trypsinized and fixed with 75% ethanol at 4°C overnight. Subsequently, the cells were treated with 100 μg / mL RNase solution, stained with propidium iodide (PI) for 30 min, and finally analyzed for DNA content using a BD LSR Fortessa flow cytometer. Cells treated with different concentrations of the compound, including floating cells and adherent cells, were collected and centrifuged. The cells were washed with PBS and stained with FITC / Annexin V and propidium iodide using an Annexin detection kit (1133534, BD Pharmingen). The apoptosis rate was detected using an Accuri C6 flow cytometer (BD Biosciences). Figure 3 、 Figure 4 The ability of the representative compound YZ-18 in the examples to induce cell cycle and apoptosis in breast cancer cells.

[0381] The results showed that the representative compound YZ-18 in the examples of the present application could induce a concentration-dependent increase in the number of G1 phase cells and a concentration-dependent decrease in the number of S phase cells, and significantly increase the percentage of Annexin-V positive cells, indicating that the representative compound YZ-18 could effectively induce cell cycle arrest and apoptosis.

[0382] Example 3-4. Evaluation of the anti-proliferative activity of representative compound YZ-18 in human-derived breast cancer organoids

[0383] Tumor tissues were obtained from breast cancer surgery patients at Yunnan Cancer Hospital, and all participants and / or their legal guardians have given informed consent. After surgical collection, fresh breast cancer tissues were immediately placed in DMEM / F12 medium containing 50 pg / mL antibiotics and transported to the laboratory. The tissues were rinsed with sterile 1x PBS, chopped with surgical scissors, and digested with collagenases I, III, and IV (0.5-1 mg / mL), hyaluronidase (0.05-0.1 mg / mL), DMEM / F12, 10 mM HEPES, 2% BSA, 0.48 pg / mL hydrocortisone, 5 mM Y-27632, and 50 pg / mL primocin (37°C, 1-2 h), and the cells were passed through a 100 pm filter, centrifuged at 500 g for 3 min, resuspended in 1x PBS, and treated with red blood cell lysis solution for 3-5 min. After rinsing once more with 1x PBS, the cells were resuspended in basement membrane matrix and seeded into 24-well plates. The cells were allowed to solidify for 30 min before the addition of organoid culture medium. The growth of the organoids was monitored, and the medium was changed regularly. Once the organoids reached sufficient size and number, they were digested, counted, and placed into 96-well plates for treatment with representative compounds. The survival rate of organoid cells after 2 days of treatment with different concentrations of representative compounds was evaluated using an ATPase activity assay kit (Promega). This study has been approved by the Clinical Research Ethics Committee of Yunnan Cancer Hospital (KYCS2023-078).

[0384] Figure 5 、 Figure 6 The inhibitory activity of compound YZ-18 on the proliferation of breast cancer organoid cells. Microscopic observation found that the DMSO control group retained a coherent and orderly structure, while the YZ-18 treatment group was split into smaller aggregates and showed signs of necrosis. In addition, the ATPase activity assay showed that the viability of the organoids was significantly reduced after YZ-18 treatment.

[0385] Example 4: Evaluation of the anti-proliferative activity of the compounds of the present application in other tumor cells

[0386] The cervical cancer cells Hela, human non-small cell lung cancer cells A549, human B lymphoma cells SUDHL-4, human mantle cell lymphoma cells Z-138, and human melanoma cells A375 used in the present application were purchased from the American Type Culture Collection (ATCC).

[0387] The cells were cultured in a medium containing 10% fetal bovine serum (ExCell Bio) and 100 units / ml penicillin, 100 μg / ml streptomycin (VivaCell) in a 37°C constant temperature cell incubator (humidity 95%, CO2concentration 5%). RPMI-1640 (Gibco) and DMEM high glucose medium (Gibco) were used for cell culture.

[0388] Hela, A549, SUDHL-4, Z-138 and A375 cells were seeded in 96-well plates at a density of 5 x 10 3 cells / well and 2.5 x 10 3 cells / well, respectively, and cultured routinely for 16 hours, then different concentrations of the compounds of the present application were added in sequence, at a concentration of 4 μM, and an equal amount of DMSO was added to the control group. After 48 hours of continuous culture, pre-cooled trichloroacetic acid (50%, w / V) was added at 100 μl / well, and the cells were fixed by incubation at 4°C overnight. After fixation, the cells were washed 5 times with distilled water and air-dried. 100 μl of SRB staining solution (4%, w / V) was added to each well, and the cells were stained at room temperature for 30 minutes. The staining solution was removed, and the cells were washed 5-6 times with 1% acetic acid to remove unbound dye. After air-drying, 100 μl of Tris base solution at a concentration of 10 mM was added to each well, and the bound SRB dye was dissolved by shaking. The 96-well plate was placed in a microplate reader, and the OD value was measured at a wavelength of 530 nm. The cell survival rate (%) was calculated according to the following formula.

[0389]

[0390] The effects of the compounds of the present application on the proliferation of Hela, A549, SUDHL-4, Z-138 and A375 cells were statistically analyzed, and the results of the evaluation are shown in Table 4.

[0391] The inhibitory activity of the compounds of the present application on the viability of various tumor cells was expressed as the inhibition rate (%) of the compounds at a concentration of 4 μM. Among them, "+", "++", "+++" and "++++" represent an inhibition rate of the compound of 25% or less, between 25% and 50%, between 50% and 75%, and greater than 75%, respectively.

[0392] Table 4 Results of the cell inhibitory activity of the compounds of the present application in various tumor cells

[0393]

[0394] The results show that some of the compounds of the present application exhibit certain proliferation inhibition activity on Hela, A549, SUDHL-4, Z-138 and A375 cells. These results indicate that the compounds of the present application have good anti-proliferation effect on other tumor cells including cervical cancer cells, human non-small cell lung cancer cells, human B lymphoma cells, human mantle cell lymphoma cells, and human melanoma cells.

[0395] Example 5: Evaluation of the growth inhibition activity of representative compound YZ-18 of the present application on breast cancer cell HCC1806 xenograft tumor in nude mice

[0396] Nude mice (about 6 weeks old) were purchased from SJA Experimental Animal Co., Ltd. (Changsha, China) and were raised in the specific pathogen-free (SPF) animal facility of the Kunming Institute of Zoology, Chinese Academy of Sciences. HCC1806 cells (1 x 10 6 cells per mouse) were injected bilaterally into the fourth pair of mammary fat pads of nude mice. When the tumor volume was close to 50 mm 3 , the nude mice were randomly divided into a control group and a treatment group. The treatment group was injected intraperitoneally with YZ-18 (50 mg / kg) once every other day for a total of 4 injections. The tumor size was measured using a vernier caliper, and the body weight of the nude mice was recorded using a body weight scale every 2 days. After 15 days, tumor samples were collected for analysis. This animal experiment was approved by the Animal Ethics Committee of Kunming Medical University (kmmu20240729).

[0397]

[0398] The use and welfare of the experimental animals complied with the regulations of the International Assessment and Accreditation Committee for Laboratory Animals (AAALAC). The health status and death of the animals were monitored daily, and routine examinations included observation of the effects of the test substances and drugs on the daily behavior of the animals, such as behavioral activity, body weight changes, and appearance signs.

[0399] The results show that compound YZ-18 alone has a certain inhibitory effect on the growth of HCC1806 breast cancer xenograft tumors in nude mice. Figure 7-8 To evaluate the inhibitory effect of YZ-18 on the growth of HCC1806 breast cancer xenograft tumors in nude mice, as shown in Figure 7 and Figure 8 , compound YZ-18 inhibits the growth of HCC1806 breast cancer xenograft tumors in nude mice to some extent, and has no significant effect on the body weight of the nude mice Figure 9 .

[0400] In summary, the compounds of the present application not only exhibit significant PRMT5 protein degradation activity, but also exhibit obvious anti-proliferation effect, and exhibit a certain degree of tumor growth inhibition effect in vivo, and are a class of potential compounds for treating PRMT5-related malignant tumors.

Claims

1. A PROTACs compound targeting PRMT5 degradation or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from one or more of the following compounds: N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-1); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-2); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-3); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxopentadec-15-yl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-4); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-9); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-10); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)nonanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-11); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-12); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-13); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-14); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-15); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-16); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)nonanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-17); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-18); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(11-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)undecanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-19); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)dodecanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-20); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(10-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-21); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-23); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)octyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-24); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-27); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-28); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-29); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-31); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-32); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-33); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-34); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(11-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)undec-10-ynyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-35); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-36); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)piperazin-1-yl)propanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-37); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-carbonyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-38); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperidin-4-carbonyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-39); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-40); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-41); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(4-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperazin-1-yl)benzoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-42); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(5-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pentanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-43); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(4-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)butanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-44); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-45); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(11-(4-(2,6-dioxopiperidin-3-yl)phenoxy)undecanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-46); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(10-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)decanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-47); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(7-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)heptanoyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-48); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-(2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)amino)pyrimidine-4-carboxamide (YZ-55); N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((4-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)decanamido)cyclohexyl)amino)pyrimidine-4-carboxamide (YZ-56).

2. A pharmaceutical composition, characterized in that Including the PROTACs compound targeting PRMT5 degradation according to claim 1 or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 2, characterized in that The pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

4. Use of the PROTACs compound or pharmaceutically acceptable salt thereof according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of a drug for degrading or inhibiting PRMT5.

5. Use of the PROTACs compound or a pharmaceutically acceptable salt thereof according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of a drug for preventing or treating tumors.

6. The use according to claim 5, characterized in that The tumor is at least one of breast cancer, cervical cancer, non-small cell lung cancer, B cell lymphoma, mantle cell lymphoma and melanoma.

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