PROTAC compound as well as preparation method and application thereof

Abstract

The invention discloses a PROTAC compound or a pharmaceutically acceptable salt thereof as well as a preparation method and application thereof, the structure of the PROTAC compound is as shown in formula (I), and Linker is an optionally substituted connecting chain; and the E3 linker ligand is a CRBN ligand. According to the PROTAC compound or the pharmaceutically acceptable salt thereof, the abundance of FTO is reduced by degrading target protein FTO in tumor cells, the cell proliferation inhibition activity is improved, and the PROTAC compound or the pharmaceutically acceptable salt thereof shows a stronger cell proliferation inhibition effect than an FTO inhibitor. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis and application, and in particular to a PROTAC compound and a preparation method and application thereof. Background Art

[0002] RNA methylation 6 -methyladenosine (m 6 A) modification was discovered in 1974. Due to technical limitations, this field remained dormant until 2011, when the fat content and obesity-associated protein (FTO) was reported to be able to remove m 6 A modified and proved m 6 Like other epigenetic modifications, A modification has dynamic and reversible characteristics and is regulated by methyltransferases, demethylases, and recognition proteins. FTO catalyzes the removal of m 6 The study of A modification restarted the biological research of RNA methylation modification and opened up a new field of RNA epigenetic research.

[0003] More than 170 types of RNA modifications have been discovered, among which m 6 A has the highest abundance among many modifications and is present throughout RNA-related biological processes, including pre-mRNA splicing, nuclear export, translation, RNA stability and degradation, and other RNA metabolic processes, and is of great significance to gene expression regulation. 6 A modification disorder is closely related to the occurrence and development of many diseases. 6 Basic biology and chemical biology research on "RNA epigenetics" with A modification as the core research content is booming, and it also promotes original new drug discovery research in this field.

[0004] FTO promotes the occurrence and development of acute myeloid leukemia (AML), and knocking down FTO significantly delays the progression of AML. Further mechanistic studies have shown that FTO regulates the expression of downstream target genes in cells, such as tumor suppressor genes ASB2 and RARA, and oncogenes MYC and CEBPA. 6 The abundance of modified A affects the pathogenesis of tumors. FTO small molecule inhibitors inhibit the catalytic function of FTO and interfere with m 6 The modified abundance of A upregulates the transcription of tumor suppressor genes ASB2 and RARA, and downregulates the abundance of oncogenes MYC and CEBPA, thereby exerting anti-AML efficacy.

[0005] However, most of the reported small molecule inhibitors of FTO change m by regulating the catalytic activity of FTO. 6Among the modified FTO abundance, only R-2HG can slightly reduce the abundance of FTO in tumor cells and trigger downstream biological effects. In addition, during the process of tumor cell resistance, FTO abundance is significantly upregulated, suggesting that downregulating FTO can reverse resistance. Therefore, it is necessary to find a class of chemical tools to reduce FTO abundance, which can not only enrich m 6 The regulation of A abundance can also promote the feasibility verification and drugability research of this type of degraders in anti-tumor treatment.

[0006] The development and progression of diseases are often closely linked to the dysregulation of pathogenic proteins. Small molecule drugs often compete with endogenous substrates to occupy the catalytically active pockets of pathogenic proteins, thereby modulating their function and achieving therapeutic goals. In recent years, scientists have proposed a new research approach: degradation technologies, which aim to reduce the abundance of pathogenic proteins and achieve anti-tumor effects. The most widely studied of these is PROTAC. This bifunctional small molecule connects an E3 ligase ligand and a target protein ligand via a linker, forming a "dumbbell-shaped" structure. This recruits the E3 ligase within tumor cells to the target protein, where it is ubiquitinated and subsequently degraded by the proteasome, thereby reducing its abundance. PROTACs also exhibit advantages such as enhanced anti-tumor activity and improved target protein isoform selectivity. Through continued exploration, the research of PROTAC degraders has made significant progress, with several candidate compounds entering clinical trials. However, within the field of RNA epigenetics, the discovery of degraders targeting RNA modifications mediated by the protein FTO remains a niche topic. Therefore, research targeting FTO for anti-tumor effects is of paramount importance. Summary of the Invention

[0007] The present invention provides a PROTAC compound or a pharmaceutically acceptable salt thereof, which degrades the target protein FTO in tumor cells, reduces the abundance of FTO, and enhances the cell proliferation inhibitory activity. It has the potential to treat a variety of diseases associated with abnormal FTO expression, such as leukemia, lymphoma, myelodysplastic syndrome, obesity, metabolic syndrome (MS), type 2 diabetes (T2D), Alzheimer's disease, breast cancer, renal cancer, colorectal cancer, pancreatic cancer, liver cancer, small cell lung cancer, human bone marrow rhabdomyosarcoma, pancreatic cancer, and malignant glioblastoma.

[0008] The technical solutions of the present invention are as follows:

[0009] A PROTAC compound or a pharmaceutically acceptable salt thereof, wherein the structure of the PROTAC compound is shown in formula (I):

[0010]

[0011] In the formula, A1, A2, A3, and A4 are each independently CR' or N;

[0012] R' is selected from the group consisting of: H, halogen, carbonyl, carboxyl, hydroxyl, amino, nitro, cyano, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 alkoxycarbonyl, substituted or unsubstituted C1-C6 acylamino, substituted or unsubstituted C2-C12 ester, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 alkenylamide, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C3-C8 cycloalkoxy;

[0013] X is CH2, NH, O or S;

[0014] R a 、R b 、R c 、R d Each is independently H, halogen, hydroxy, amino, nitro, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkoxy;

[0015] Y is a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group, or a substituted or unsubstituted 3-12 membered heterocyclyl group;

[0016] Linker is an optionally substituted linker chain comprising a branched or unbranched, cyclic or acyclic, saturated or unsaturated chain of 6 to 15 carbon atoms in length, wherein 1 to 6 of the 6 to 15 carbon atoms are optionally independently replaced by O, N or S;

[0017] The E3 ligase ligand is CRBN ligand.

[0018] Preferably, R' is selected from the group consisting of: H, halogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkoxy.

[0019] Preferably, Y is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted thietanyl, and substituted or unsubstituted azetidinyl.

[0020] More preferably, Y is selected from:

[0021]

[0022] Wherein, R1, R2, R3, and R4 are each independently selected from the group consisting of: H, halogen, hydroxyl, amino, carbonyl, carboxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 alkoxycarbonyl, substituted or unsubstituted C1-C6 acylamino, and substituted or unsubstituted C3-C8 heterocycloalkyl.

[0023] Preferably, substitution means that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of deuterium, halogen, carbonyl (=O), carboxyl, hydroxyl, amino, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkoxycarbonyl, C1-C6 acylamino, C2-C12 ester, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted five-membered or six-membered heteroaryl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl.

[0024] Preferably, the E3 ligase ligand is selected from:

[0025]

[0026] Wherein, X1 and Y1 are independently CH or N; X2 is CH2 or Z is O, CH or R5 is H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, or substituted or unsubstituted C3-C6 cycloalkoxy.

[0027] Preferably, the Linker is selected from:

[0028]

[0029] Wherein, n1, n2, and m are independently integers of 0-4;

[0030] R6 is selected from

[0031] R7 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group.

[0032] Preferably, the PROTAC compound is selected from:

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041] The pharmaceutically acceptable salt is a salt of the PROTAC compound formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid.

[0042] In another aspect, the present invention further provides a method for preparing the above-mentioned PROTAC compound or a pharmaceutically acceptable salt thereof, comprising:

[0043] (1) The CRBN ligand reacts with the linker precursor compound to obtain a CRBN ligand derivative with an amino group at the end;

[0044] (2) reacting the compound of formula (II) with a CRBN ligand derivative having an amino terminal to obtain a PROTAC compound of formula (I);

[0045]

[0046] On the other hand, the present invention also provides a pharmaceutical composition comprising the PROTAC compound or a pharmaceutically acceptable salt thereof.

[0047] The pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0048] On the other hand, the present invention also provides a use of the PROTAC compound or a pharmaceutically acceptable salt thereof in the preparation of an FTO inhibitor or FTO degrader.

[0049] On the other hand, the present invention also provides a use of the PROTAC compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament, wherein the medicament is used to treat at least one of leukemia, lymphoma, myelodysplastic syndrome, obesity, metabolic syndrome (MS), type 2 diabetes (T2D), Alzheimer's disease, breast cancer, renal cancer, colorectal cancer, pancreatic cancer, liver cancer, small cell lung cancer, human bone marrow rhabdomyosarcoma, pancreatic cancer, and malignant glioblastoma.

[0050] Compared with the prior art, the present invention has the following beneficial effects:

[0051] First, there are currently no reports of PROTAC inhibitors or degraders targeting FTO. The present invention discloses a PROTAC degrader targeting FTO for the first time. Second, the AML cell proliferation inhibitory activity of the PROTAC degrader targeting FTO of the present invention is much stronger than that of the FTO inhibitor, and the activity is greatly improved. DETAILED DESCRIPTION

[0052] The present invention will be further described in detail below with reference to the examples. It should be noted that the examples described below are intended to facilitate understanding of the present invention and do not have any limiting effect on the present invention.

[0053] Synthesis of intermediate CR01

[0054]

[0055] Step 1: In a 250 mL round-bottom flask, add 4-fluorothalidomide (2.76 g, 10.0 mmol, 1.0 eq) and 4-tert-butyloxycarbonylaminopiperidine (2.40 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours until the 4-fluorothalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash sequentially with deionized water (200 mL x 3) and saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR01-1 (3.86 g yellow solid). LRMS: 457 [M+H] + .

[0056] Step 2: In a 250 mL round-bottom flask, weigh CR01-1 (3.86 g, 8.29 mol) and add hydrogen chloride / 1,4-dioxane (83 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR01-1 is complete. The mixture is then dried to give the crude hydrochloride of CR01 (yellow solid). LRMS: 357 [M+H] + .

[0057] Synthesis of intermediate CR02

[0058]

[0059] Step 1: In a 250 mL round-bottom flask, add 4-fluorothalidomide (2.76 g, 10.0 mmol, 1.0 eq) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (2.72 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours. TLC indicates that 4-fluorothalidomide is completely consumed. Cool, add 100 mL of deionized water to the system, extract with ethyl acetate (150 mL × 3), combine the organic phases, wash with deionized water (200 mL × 3), then with saturated brine (200 mL × 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR02-1 (yellow solid, 3.34 g). LRMS: 483 [M+H] + .

[0060] Step 2: In a 250 mL round-bottom flask, weigh CR02-1 (3.34 g, 6.93 mol) and add hydrogen chloride / 1,4-dioxane (69 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR02-1 is complete. The mixture is then dried to give a crude yellow solid, CR02 hydrochloride. LRMS: 383 [M+H] + .

[0061] Synthesis of intermediate CR03:

[0062]

[0063] Step 1: In a 250 mL round-bottom flask, add 4-fluorothalidomide (2.76 g, 10.0 mmol, 1.0 eq) and 4-Boc-aminomethylpiperidine (2.57 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours until the 4-fluorothalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash sequentially with deionized water (200 mL x 3) and saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR03-1 (yellow solid, 2.96 g). LRMS: 471 [M+H] + .

[0064] Step 2: In a 25 mL round-bottom flask, weigh CR03-1 (2.96 g, 6.30 mol) and add hydrogen chloride / 1,4-dioxane (63 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR03-1 is complete. The mixture is then dried to give a crude yellow solid, CR03 hydrochloride. LRMS: 371 [M+H] + .

[0065] Synthesis of intermediate CR04

[0066]

[0067] Step 1: In a 250 mL round-bottom flask, add 4-fluorothalidomide (2.76 g, 10.0 mmol, 1.0 eq) and N-Boc-4,4-bipiperidine (2.72 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours. TLC indicates that the 4-fluorothalidomide is completely consumed. Cool, add 100 mL of deionized water to the system, extract with ethyl acetate (150 mL x 3), combine the organic phases, wash with deionized water (200 mL x 3), then with saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain 3.34 g of the intermediate CR04-1 as a yellow solid. LRMS: 483 [M+H]. + .

[0068] Step 2: In a 250 mL round-bottom flask, weigh CR04-1 (3.34 g, 6.93 mol) and add hydrogen chloride / 1,4-dioxane (69 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR04-1 is complete. The mixture is then dried to give a crude yellow solid, CR04 hydrochloride. LRMS: 383 [M+H] + .

[0069] Synthesis of intermediate CR05

[0070]

[0071] Step 1: In a 250 mL round-bottom flask, add 4-fluorothalidomide (2.76 g, 10.0 mmol, 1.0 eq) and tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (3.40 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours until the 4-fluorothalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash sequentially with deionized water (200 mL x 3) and saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR05-1 (yellow solid, 3.87 g). LRMS: 540 [M+H] + .

[0072] Step 2: In a 250 mL round-bottom flask, weigh CR05-1 (3.87 g, 7.17 mol) and add hydrogen chloride / 1,4-dioxane (72 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR05-1 is complete. The mixture is then dried to give a crude yellow solid, CR05 hydrochloride. LRMS: 440 [M+H] + .

[0073] Synthesis of intermediate CR06

[0074]

[0075] Step 1: In a 250 mL round-bottom flask, add 4-fluorothalidomide (2.76 g, 10.0 mmol, 1.0 eq) and 1-tert-butyloxycarbonyl-4-aminomethylpiperidine (2.57 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours until the 4-fluorothalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash sequentially with deionized water (200 mL x 3) and saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain 4.05 g of the intermediate CR06-1 as a yellow solid. LRMS: 471 [M+H]. + .

[0076] Step 2: In a 250 mL round-bottom flask, weigh CR06-1 (4.05 g, 8.61 mol) and add hydrogen chloride / 1,4-dioxane (86 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR06-1 is complete. The mixture is then dried to give the crude CR06 hydrochloride (yellow solid). LRMS: 371 [M+H] + .

[0077] Synthesis of intermediate CR07:

[0078]

[0079] Step 1: In a 250 mL round-bottom flask, add 4-fluorothalidomide (2.76 g, 10.0 mmol, 1.0 eq) and 3-(Boc-amino)pyrrolidine (2.24 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours. TLC indicates complete consumption of 4-fluorothalidomide. Cool, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash sequentially with deionized water (200 mL x 3) and saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain 3.17 g of the intermediate CR07-1 as a yellow solid. LRMS: 457 [M+H]. + .

[0080] Step 2: In a 25 mL round-bottom flask, weigh CR07-1 (2.96 g, 6.94 mol) and add hydrogen chloride / 1,4-dioxane (69 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR07-1 is complete. The mixture is then dried to give a crude yellow solid, CR07 hydrochloride. LRMS: 357 [M+H] + .

[0081] Synthesis of intermediate CR08

[0082]

[0083] Step 1: In a 250 mL round-bottom flask, add 4-fluorothalidomide (2.76 g, 10.0 mmol, 1.0 eq) and 2-amino-7-BOC-7-azaspiro[3.5]nonane (2.88 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours until the 4-fluorothalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash sequentially with deionized water (200 mL x 3) and saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR08-1 (yellow solid, 3.12 g). LRMS: 497 [M+H] + .

[0084] Step 2: In a 250 mL round-bottom flask, weigh CR08-1 (3.12 g, 6.28 mol) and add hydrogen chloride / 1,4-dioxane (63 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR08-1 is complete. The mixture is then dried to give the crude CR08 hydrochloride (yellow solid). LRMS: 397 [M+H] + .

[0085] Synthesis of intermediate CR09

[0086]

[0087] Step 1: In a 250 mL round-bottom flask, add 4-fluorothalidomide (2.76 g, 10.0 mmol, 1.0 eq) and tert-butyl 7-azaspiro[3.5]nonane-2-carbamate (2.88 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours until the 4-fluorothalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash sequentially with deionized water (200 mL x 3) and saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR09-1 (yellow solid, 3.42 g). LRMS: 497 [M+H] + .

[0088] Step 2: In a 250 mL round-bottom flask, weigh CR09-1 (3.42 g, 6.90 mol) and add hydrogen chloride / 1,4-dioxane (69 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR09-1 is complete. The mixture is then dried to give the crude CR09 hydrochloride (yellow solid). LRMS: 397 [M+H] + .

[0089] Synthesis of intermediate CR10

[0090]

[0091] Step 1: In a 250 mL round-bottom flask, add 4-fluorothalidomide (2.76 g, 10.0 mmol, 1.0 eq) and tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (2.55 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours until the 4-fluorothalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash sequentially with deionized water (200 mL x 3) and saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR10-1 (yellow solid, 2.94 g). LRMS: 469 [M+H] + .

[0092] Step 2: In a 250 mL round-bottom flask, weigh CR10-1 (2.94 g, 6.28 mol) and add hydrogen chloride / 1,4-dioxane (63 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR10-1 is complete. The mixture is then dried to give the crude CR10 hydrochloride salt (yellow solid). LRMS: 369 [M+H] + .

[0093] Synthesis of intermediate CR11:

[0094]

[0095] Step 1: In a 250 mL round-bottom flask, add 3-fluorothalidomide (2.76 g, 10.0 mmol, 1.0 eq) and 4-Boc-aminomethylpiperidine (2.57 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours until the 3-fluorothalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash sequentially with deionized water (200 mL x 3) and saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR11-1 (yellow solid, 3.63 g). LRMS: 471 [M+H] + .

[0096] Step 2: In a 25 mL round-bottom flask, weigh CR11-1 (3.63 g, 7.71 mol) and add hydrogen chloride / 1,4-dioxane (77 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR11-1 is complete. The mixture is then dried to give the crude hydrochloride of CR11 (yellow solid). LRMS: 371 [M+H] + .

[0097] Synthesis of intermediate CR12

[0098]

[0099] Step 1: In a 250 mL round-bottom flask, add 3-fluorothalidomide (2.76 g, 10.0 mmol, 1.0 eq) and tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (3.40 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours until 3-fluorothalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash sequentially with deionized water (200 mL x 3) and saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR12-1 (yellow solid, 3.14 g). LRMS: 540 [M+H] + .

[0100] Step 2: In a 250 mL round-bottom flask, weigh CR12-1 (3.14 g, 5.81 mol) and add hydrogen chloride / 1,4-dioxane (58 mL). Stir the resulting solution at room temperature overnight. TLC is used to monitor the reaction of CR12-1. The mixture is then dried to give the crude hydrochloride of CR12 (yellow solid). LRMS: 440 [M+H] + .

[0101] Synthesis of intermediate CR13

[0102]

[0103] Step 1: In a 250 mL round-bottom flask, add 3-fluorothalidomide (2.76 g, 10.0 mmol, 1.0 eq) and 2-amino-7-BOC-7-azaspiro[3.5]nonane (2.88 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours until 3-fluorothalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash sequentially with deionized water (200 mL x 3) and saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR13-1 (yellow solid, 4.37 g). LRMS: 497 [M+H] + .

[0104] Step 2: In a 250 mL round-bottom flask, weigh CR13-1 (4.37 g, 8.80 mol) and add hydrogen chloride / 1,4-dioxane (88 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR13-1 is complete. The mixture is then dried to give the crude hydrochloride of CR13 (yellow solid). LRMS: 397 [M+H] + .

[0105] Synthesis of intermediate CR14:

[0106]

[0107] Step 1: In a 250 mL round-bottom flask, add 4,5-difluorothalidomide (2.94 g, 10.0 mmol, 1.0 eq) and 4-Boc-aminomethylpiperidine (2.57 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours until the 4,5-difluorothalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash sequentially with deionized water (200 mL x 3) and saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR14-1 (yellow solid, 3.21 g). LRMS: 489 [M+H] + .

[0108] Step 2: In a 25 mL round-bottom flask, weigh CR14-1 (3.21 g, 6.56 mol) and add hydrogen chloride / 1,4-dioxane (66 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR14-1 is complete. The mixture is then dried to give the crude hydrochloride of CR14 (yellow solid). LRMS: 389 [M+H] + .

[0109] Synthesis of intermediate CR15

[0110]

[0111] Step 1: In a 250 mL round-bottom flask, add 4,5-difluorothalidomide (2.94 g, 10.0 mmol, 1.0 eq) and 1-tert-butyloxycarbonyl-4-aminomethylpiperidine (2.57 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours until the 4,5-difluorothalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash sequentially with deionized water (200 mL x 3) and saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR15-1 (yellow solid, 4.35 g). LRMS: 489 [M+H] + .

[0112] Step 2: In a 250 mL round-bottom flask, weigh CR15-1 (4.35 g, 8.90 mol) and add hydrogen chloride / 1,4-dioxane (89 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR15-1 is complete. The mixture is then dried to give the crude hydrochloride of CR15 (yellow solid). LRMS: 389 [M+H] + .

[0113] Synthesis of intermediate CR16

[0114]

[0115] Step 1: In a 250 mL round-bottom flask, add 4,5-difluorothalidomide (2.94 g, 10.0 mmol, 1.0 eq) and tert-butyl 7-azaspiro[3.5]nonane-2-carbamate (2.88 g, 12.0 mmol, 1.2 eq), dissolve in anhydrous DMSO (50 mL), heat to 100°C, and react for 6 hours until 4,5-difluorothalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash with deionized water (200 mL x 3), then with saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR16-1 (yellow solid, 2.45 g). LRMS: 515 [M+H] + .

[0116] Step 2: In a 250 mL round-bottom flask, weigh CR16-1 (2.45 g, 4.76 mol) and add hydrogen chloride / 1,4-dioxane (48 mL). Stir the resulting solution at room temperature overnight. TLC is used to monitor the reaction of CR16-1. The mixture is then dried to give the crude hydrochloride of CR16 (yellow solid). LRMS: 415 [M+H] + .

[0117] Synthesis of intermediate CR17

[0118]

[0119] Step 1: In a 250 mL round-bottom flask, add 3-hydroxythalidomide (2.74 g, 10.0 mmol, 1.0 eq), tert-butyl (1-(2-bromo-2-oxoethyl)piperidin-4-yl)carbamate (3.86 g, 12.0 mmol, 1.2 eq), potassium iodide (332 mg, 2.0 mmol, 0.2 eq), and anhydrous K2CO3 (2.76 g, 20.0 mmol, 2.0 eq) dissolved in anhydrous DMF (50 mL). Heat to 60°C and react for 6 hours until 3-hydroxythalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash with deionized water (200 mL x 3), then with saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR17-1 (yellow solid, 2.64 g). LRMS: 515 [M+H] + .

[0120] Step 2: In a 250 mL round-bottom flask, weigh CR17-1 (2.64 g, 5.13 mol) and add hydrogen chloride / 1,4-dioxane (51 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR17-1 is complete. The mixture is then dried to give the crude hydrochloride of CR17 (yellow solid). LRMS: 415 [M+H] + .

[0121] Synthesis of intermediate CR18

[0122]

[0123] Step 1: In a 250 mL round-bottom flask, add 3-hydroxythalidomide (2.74 g, 10.0 mmol, 1.0 eq), tert-butyl 2-((2-bromo-2-oxoethyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (4.34 g, 12.0 mmol, 1.2 eq), potassium iodide (332 mg, 2.0 mmol, 0.2 eq), and anhydrous K2CO3 (2.76 g, 20.0 mmol, 2.0 eq) dissolved in anhydrous DMF (50 mL). Heat to 60°C and react for 6 hours until 3-hydroxythalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash with deionized water (200 mL x 3), then with saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness. The product was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain 2.14 g of the intermediate CR18-1 as a yellow solid. LRMS: 555 [M+H] + .

[0124] Step 2: In a 250 mL round-bottom flask, weigh CR18-1 (2.64 g, 3.86 mol) and add hydrogen chloride / 1,4-dioxane (39 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR18-1 is complete. The mixture is then dried to give the crude CR18 hydrochloride (yellow solid). LRMS: 455 [M+H] + .

[0125] Synthesis of intermediate CR19

[0126]

[0127] Step 1: In a 250 mL round-bottom flask, add HATU (7.60 g, 20.0 mmol, 2.0 eq) and (7-azaspiro[3.5]nonan-2-yl)glycine (2.38 g, 12.0 mmol, 1.2 eq). Dissolve the mixture in anhydrous DMF (50 mL). Stir at room temperature for 10 min. Then add DIEA (5.17 g, 40.0 mmol, 4.0 eq) and 4-aminothalidomide (2.74 g, 10.0 mmol, 1.0 eq). Heat to 60°C and react overnight until the 4-aminothalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash with deionized water (200 mL x 3), then with saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness. The product was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain 3.24 g of the intermediate CR19-1 as a yellow solid. LRMS: 554 [M+H]+ .

[0128] Step 2: In a 250 mL round-bottom flask, weigh CR19-1 (3.24 g, 5.85 mol) and add hydrogen chloride / 1,4-dioxane (59 mL). Stir the resulting solution at room temperature overnight. TLC is used to monitor the reaction of CR19-1. The mixture is then dried to give the crude hydrochloride of CR19 (yellow solid). LRMS: 454 [M+H] + .

[0129] Synthesis of intermediate CR20

[0130]

[0131] Step 1: In a 250 mL round-bottom flask, add HATU (7.60 g, 20.0 mmol, 2.0 eq) and (7-azaspiro[3.5]nonan-2-yl)glycine (2.38 g, 12.0 mmol, 1.2 eq) and dissolve in anhydrous DMF (50 mL). Stir at room temperature for 10 min. Then add DIEA (5.17 g, 40.0 mmol, 4.0 eq) and lenalidomide (2.59 g, 10.0 mmol, 1.0 eq). Heat to 60°C and react overnight until the lenalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash with deionized water (200 mL x 3), then with saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness. The product was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain 3.47 g of the intermediate CR20-1 as a yellow solid. LRMS: 540 [M+H] + .

[0132] Step 2: In a 250 mL round-bottom flask, weigh CR20-1 (3.47 g, 6.31 mol) and add hydrogen chloride / 1,4-dioxane (63 mL). Stir the resulting solution at room temperature overnight. TLC is used to monitor the reaction of CR20-1. The mixture is then dried to give the crude CR20 hydrochloride (yellow solid). LRMS: 440 [M+H] + .

[0133] Synthesis of intermediate CR21

[0134]

[0135] Step 1: In a 250 mL round-bottom flask, add HATU (7.60 g, 20.0 mmol, 2.0 eq) and 2-(4-((tert-Butoxycarbonyl)amino)piperidin-1-yl)acetic acid (3.10 g, 12.0 mmol, 1.2 eq). Dissolve the mixture in anhydrous DMF (50 mL). Stir at room temperature for 10 min. Then add DIEA (5.17 g, 40.0 mmol, 4.0 eq) and lenalidomide (2.59 g, 10.0 mmol, 1.0 eq). Heat to 60°C and react overnight until the lenalidomide is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash with deionized water (200 mL x 3), then with saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness. The product was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain 3.23 g of the intermediate CR21-1 as a yellow solid. LRMS: 500 [M+H] + .

[0136] Step 2: In a 250 mL round-bottom flask, weigh CR21-1 (3.23 g, 6.47 mol) and add hydrogen chloride / 1,4-dioxane (65 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR21-1 is complete. The mixture is then dried to give the crude hydrochloride of CR21 (yellow solid). LRMS: 400 [M+H] + .

[0137] Synthesis of intermediate CR22

[0138]

[0139] Step 1: In a 250 mL round-bottom flask, under nitrogen atmosphere, 1-oxo-4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole (3.23 g, 10.0 mmol, 1.0 eq), 5-hexynoic acid (2.24 g, 20.0 mmol, 2.0 eq), Pd(pph3)Cl2 (140 mg, 0.20 mmol, 0.2 eq), CuI (38 mg, 0.20 mmol, 0.2 eq), TEA (10.12 g, 100 mmol, 10.0 eq), and DMF (100 mL) were added sequentially. The reaction system was heated to 90°C and stirred overnight. The reaction was allowed to proceed overnight until the 1-oxo-4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole was completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, extract with ethyl acetate (150 mL x 3), combine the organic phases, wash with deionized water (200 mL x 3), then with saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. Filter with suction, and concentrate the filtrate to dryness to obtain 2.95 g of the intermediate CR22-1 as a yellow solid. LRMS: 354 [M+H] + .

[0140] Step 2: In a 250 mL round-bottom flask, HATU (5.29 g, 13.92 mmol, 2.0 eq) and CR22-1 (2.95 g, 8.35 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (35 mL). After stirring at room temperature for 10 min, DIEA (3.60 g, 27.84 mmol, 4.0 eq) and tert-butyl 7-azaspiro[3.5]nonane-2-carbamate (1.67 g, 6.96 mmol, 1.0 eq) were added. The mixture was heated to 60°C and allowed to react overnight until the amine was completely consumed as determined by TLC. After cooling, 100 mL of deionized water was added to the system, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined and washed sequentially with deionized water (200 mL × 3) and saturated brine (200 mL × 3), and then dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness. The product was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain 1.90 g of the intermediate CR22-2 as a yellow solid. LRMS: 576 [M+H] + .

[0141] Step 3: In a 250 mL round-bottom flask, weigh CR22-2 (1.90 g, 3.30 mol) and add hydrogen chloride / 1,4-dioxane (33 mL). Stir the resulting solution at room temperature overnight. TLC is used to monitor the reaction until CR22-2 is completely reacted. The mixture is then dried to give the crude hydrochloride of CR22 (yellow solid). LRMS: 476 [M+H] + .

[0142] Synthesis of intermediate CR23

[0143]

[0144] Step 1: In a 250 mL round-bottom flask, add HATU (7.60 g, 20.0 mmol, 2.0 eq) and 4-bromo-2-fluorobenzoic acid (2.63 g, 12.0 mmol, 1.2 eq). Dissolve the mixture in anhydrous DMF (50 mL). Stir at room temperature for 10 min. Then add DIEA (5.17 g, 40.0 mmol, 4.0 eq) and 3-amino-2,6-piperidinedione (1.28 g, 6.96 mmol, 1.0 eq). Heat to 60°C and react overnight until the amine is completely consumed, as determined by TLC. Cool the mixture, add 100 mL of deionized water, and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash with deionized water (200 mL x 3), then with saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness. The mixture was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain 2.01 g of the intermediate CR23-1 as a yellow solid. LRMS: 329 [M+H] + .

[0145] Step 2: In a 100 mL round-bottom flask, under nitrogen atmosphere, CR23-1 (2.01 g, 6.11 mmol, 1.2 eq), tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (1.44 g, 5.09 mmol, 1.0 eq), Pd(OAc)2 (229 mg, 1.02 mmol, 0.2 eq), XantPhos (540 mg, 1.02 mmol, 0.2 eq), Cs2CO3 (3.33 g, 10.2 mmol, 2.0 eq), and Toluene (25 mL) were added sequentially. The reaction system was heated to 110°C for 24 hours. The mixture was concentrated by rotary evaporation and separated by silica gel column chromatography (PE / EA, 1 / 1, v / v) to obtain 2.08 g of the intermediate CR23-2 as a yellow solid. LRMS: 532 [M+H] + .

[0146] Step 3: In a 250 mL round-bottom flask, weigh CR23-2 (2.08 g, 3.91 mol) and add hydrogen chloride / 1,4-dioxane (39 mL). Stir the resulting solution at room temperature overnight. TLC is used to monitor the reaction of CR23-2. The mixture is then dried to give the crude hydrochloride of CR23 (yellow solid). LRMS: 432 [M+H] + .

[0147] Synthesis of intermediate CR25:

[0148]

[0149] Step 1: In a 25 mL round-bottom flask, 4-fluorothalidomide (333 mg, 1.2 mmol, 1.2 eq) and 1,1-dimethylethyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (200 mg, 1.0 mmol, 1.0 eq) were added sequentially and dissolved in anhydrous DMSO (10 mL). DIEA (388 mg, 3.0 mmol, 3.0 eq) was then added and heated to 100°C for 6 hours. TLC was performed until 1,1-dimethylethyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was completely consumed. Cool the mixture, add 50 mL of deionized water, and extract with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness. The product was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain 299 mg of the intermediate CR25-1 as a yellow solid. LRMS: 455 [M+H] + .

[0150] Step 2: In a 25 mL round-bottom flask, weigh CR25-1 (299 mg, 0.66 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). The resulting solution was stirred at room temperature overnight. TLC was performed until the reaction of CR25-1 was complete. The mixture was then dried to give the crude hydrochloride of CR25 (yellow solid, 280 mg). LRMS: 355 [M+H] + .

[0151] Synthesis of intermediate CR26:

[0152]

[0153] Step 1: In a 25 mL round-bottom flask, add 4-fluorothalidomide (288 mg, 1.05 mmol, 1.2 eq) and tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (200 mg, 0.87 mmol, 1.0 eq) in sequence. Dissolve in anhydrous DMSO (10 mL). Then add DIEA (337 mg, 2.61 mmol, 3.0 eq). Heat to 100°C and react for 6 hours. TLC indicates complete consumption of tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate. Cool, add 50 mL of deionized water, and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with deionized water (100 mL x 3), then with saturated brine (100 mL x 3), and dry over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness. The mixture was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain 192 mg of the intermediate CR26- as a yellow-green solid. LRMS: 486 [M+H] +.

[0154] Step 2: In a 25 mL round-bottom flask, weigh CR26-1 (299 mg, 0.66 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR26-1 is complete. The mixture is then dried to give the crude hydrochloride of CR26 (yellow solid, 102 mg). LRMS: 386 [M+H] + .

[0155] Synthesis of intermediate CR27:

[0156]

[0157] Step 1: In a 25 mL round-bottom flask, 3-fluorothalidomide (333 mg, 1.2 mmol, 1.2 eq) and 1,1-dimethylethyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (200 mg, 1.0 mmol, 1.0 eq) were added sequentially and dissolved in anhydrous DMSO (10 mL). DIEA (388 mg, 3 mmol, 3.0 eq) was then added and heated to 100°C for 6 hours. TLC was performed until 1,1-dimethylethyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was completely consumed. Cool the mixture, add 50 mL of deionized water, and extract with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness. The product was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain 321.8 mg of the intermediate CR27-1 as a yellow-green solid. LRMS: 455 [M+H] + .

[0158] Step 2: In a 25 mL round-bottom flask, weigh CR27-1 (320 mg, 0.71 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR27-1 is complete. The mixture is then dried to give the crude hydrochloride of CR27 (yellow solid, 303 mg). LRMS: 355 [M+H] + .

[0159] Synthesis of intermediate CR28:

[0160]

[0161] Step 1: In a 25 mL round-bottom flask, add 4-fluorothalidomide (215 mg, 0.78 mmol, 1.2 eq) and tert-butyl 4-(piperazin-1-yl)piperidine-1-carboxylate (175 mg, 0.65 mmol, 1.0 eq) in sequence. Dissolve in anhydrous DMSO (10 mL). Then add DIEA (252 mg, 1.95 mmol, 3.0 eq). Heat to 100°C and react for 6 hours. TLC indicates complete consumption of tert-butyl 4-(piperazin-1-yl)piperidine-1-carboxylate. Cool, add 50 mL of deionized water, and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with deionized water (100 mL x 3), then with saturated brine (100 mL x 3), and dry over anhydrous sodium sulfate. The mixture was filtered, concentrated to dryness, and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain 1114 mg of the intermediate CR28-1 as a yellow solid. LRMS: 526 [M+H] + .

[0162] Step 2: In a 25 mL round-bottom flask, weigh CR28-1 (114 mg, 0.22 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR28-1 is complete. The mixture is then dried to give a crude yellow solid, CR28 hydrochloride (129 mg). LRMS: 426 [M+H] + .

[0163] Synthesis of intermediate CR29:

[0164]

[0165] Step 1: In a 25 mL round-bottom flask, 4-fluorothalidomide (274 mg, 0.99 mmol, 1.2 eq) and 1-(tert-butoxycarbonyl)-3-(1-piperazine)azetidine (200 mg, 0.83 mmol, 1.0 eq) were added sequentially and dissolved in anhydrous DMSO (10 mL). DIEA (252 mg, 2.49 mmol, 3.0 eq) was then added. The mixture was heated to 100°C and reacted for 6 hours until the 1-(tert-butoxycarbonyl)-3-(1-piperazine)azetidine was completely consumed, as determined by TLC. The mixture was cooled, deionized water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), and then dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness. The product was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain 241 mg of the intermediate CR29-1 as a yellow solid. LRMS: 498 [M+H] + .

[0166] Step 2: In a 25 mL round-bottom flask, weigh CR29-1 (241 mg, 0.48 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). The resulting solution was stirred at room temperature overnight. TLC was performed until the reaction of CR29-1 was complete. The mixture was then dried to give the crude CR29 hydrochloride (yellow solid, 251 mg). LRMS: 398 [M+H] + .

[0167] Synthesis of intermediate CR30:

[0168]

[0169] Step 1: In a 100 mL round-bottom flask, add 4-fluorothalidomide (887 mg, 3.22 mmol, 1.2 eq) and tert-butyl piperazine-1-carboxylate (500 mg, 2.68 mmol, 1.0 eq) in sequence, dissolve in anhydrous DMSO (20 mL), then add DIEA (1.04 g, 8.05 mmol, 3.0 eq). Heat to 100°C and react for 6 hours until the tert-butyl piperazine-1-carboxylate is completely consumed, as determined by TLC. Cool, add 100 mL of deionized water, and extract with ethyl acetate (200 mL x 3). Combine the organic phases, wash with deionized water (200 mL x 3), then with saturated brine (200 mL x 3), and dry over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR30-1 (yellow-green solid, 830 mg). LRMS: 443 [M+H] + .

[0170] Step 2: In a 100 mL round-bottom flask, weigh CR30-1 (830 mg, 1.88 mmol) and add hydrogen chloride / 1,4-dioxane (25 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR30-1 is complete. The mixture is then dried to give the crude hydrochloride of CR30-2 (white-green solid, 756 mg). LRMS: 343 [M+H] + .

[0171] Step 3: In a 25 mL round-bottom flask, dissolve 1-Boc-azetidine-3-carboxylic acid (175.3 mg, 0.87 mmol, 1.1 eq) and HATU (451.7 mg, 1.19 mmol, 1.5 eq) in anhydrous DMF (10 mL). Stir at room temperature for 5 min, then add DIEA (307 mg, 2.38 mmol, 3.0 eq) and the compound from the previous step, CR30-2 (300 mg, 0.79 mmol, 1.0 eq). Stir overnight at room temperature until the reaction is complete, as determined by TLC. Cool the mixture, add 50 mL of deionized water, and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with deionized water (100 mL x 3), then with saturated brine (100 mL x 3), and dry over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain intermediate CR30-3 (yellow-green solid, 362 mg). LRMS: 526 [M+H] + .

[0172] Step 4: In a 25 mL round-bottom flask, weigh CR30-3 (150 mg, 0.29 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR30-3 is complete. The mixture is then dried to give the crude CR30 hydrochloride (yellow solid, 167 mg). LRMS: 426 [M+H] + .

[0173] Synthesis of intermediate CR31:

[0174]

[0175] Step 1: In a 100 mL round-bottom flask, 3-fluorothalidomide (532 mg, 1.93 mmol, 1.2 eq) and tert-butyl piperazine-1-carboxylate (300 mg, 1.61 mmol, 1.0 eq) were added sequentially and dissolved in anhydrous DMSO (15 mL). DIEA (625 mg, 4.83 mmol, 3.0 eq) was then added. The mixture was heated to 100°C and reacted for 6 hours until the tert-butyl piperazine-1-carboxylate was completely consumed as determined by TLC. The mixture was cooled, deionized water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed sequentially with deionized water (200 mL × 3) and saturated brine (200 mL × 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR31-1 (light yellow solid, 389 mg). LRMS: 443 [M+H] + .

[0176] Step 2: In a 25 mL round-bottom flask, weigh CR31-1 (150 mg, 0.34 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR31-1 is complete. The mixture is then dried to give the crude hydrochloride of CR31-2 (yellow solid, 168 mg). LRMS: 343 [M+H] + .

[0177] Step 3: In a 25 mL round-bottom flask, dissolve 1-Boc-azetidine-3-carboxylic acid (94 mg, 0.46 mmol, 1.1 eq) and HATU (240.9 mg, 0.63 mmol, 1.5 eq) in anhydrous DMF (5 mL). Stir at room temperature for 5 min, then add DIEA (164 mg, 1.27 mmol, 3.0 eq) and compound CR31-2 (160 mg, 0.42 mmol, 1.0 eq) from the previous step. Stir overnight at room temperature until the reaction is complete, as determined by TLC. Cool the mixture, add 50 mL of deionized water, and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with deionized water (100 mL x 3), then with saturated brine (100 mL x 3), and dry over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain intermediate CR31-3 (yellow-green solid, 107 mg). LRMS: 526 [M+H] + .

[0178] Step 4: In a 25 mL round-bottom flask, weigh CR31-3 (107 mg, 0.20 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR31-3 is complete. The mixture is then dried to give the crude hydrochloride of CR31 (yellow solid, 107 mg). LRMS: 426 [M+H] + .

[0179] Synthesis of intermediate CR32:

[0180]

[0181] Step 1: In a 25 mL round-bottom flask, dissolve 1-Boc-pyrrolidine-3-carboxylic acid (125 mg, 0.58 mmol, 1.1 eq) and HATU (301 mg, 0.79 mmol, 1.5 eq) in anhydrous DMF (6 mL). Stir at room temperature for 5 min, then add DIEA (205 mg, 1.58 mmol, 3.0 eq) and compound CR30-2 (200 mg, 0.53 mmol, 1.0 eq). Stir overnight at room temperature until the reaction is complete, as determined by TLC. Cool the mixture, add 50 mL of deionized water, and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with deionized water (100 mL x 3), then with saturated brine (100 mL x 3), and dry over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain intermediate CR32-1 (golden solid, 217 mg). LRMS: 540 [M+H] + .

[0182] Step 2: In a 25 mL round-bottom flask, weigh CR32-1 (217 mg, 0.40 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR32-1 is complete. The mixture is then dried to give the crude intermediate CR32 hydrochloride (yellow solid, 251 mg). LRMS: 440 [M+H] + .

[0183] Synthesis of intermediate CR33:

[0184]

[0185]

[0186] Step 1: In a 25 mL round-bottom flask, dissolve 1-Boc-4-piperidinecarboxylic acid (133 mg, 0.58 mmol, 1.1 eq) and HATU (301 mg, 0.79 mmol, 1.5 eq) in anhydrous DMF (6 mL). Stir at room temperature for 5 minutes, then add DIEA (205 mg, 1.58 mmol, 3.0 eq) and compound CR30-2 (200 mg, 0.53 mmol, 1.0 eq). Stir overnight at room temperature. TLC confirms the completion of the 1-Boc-4-piperidinecarboxylic acid reaction. Cool the mixture, add 50 mL of deionized water, and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with deionized water (100 mL x 3), then with saturated brine (100 mL x 3), and dry over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain intermediate CR33-1 (yellow solid, 204 mg). LRMS: 554 [M+H] + .

[0187] Step 2: In a 25 mL round-bottom flask, weigh CR33-1 (191 mg, 0.35 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR33-1 is complete. The mixture is then dried to give the crude intermediate CR33 hydrochloride (yellow solid, 215 mg). LRMS: 454 [M+H] + .

[0188] Synthesis of intermediate CR34:

[0189]

[0190] Step 1: In a 25 mL round-bottom flask, dissolve 1-Boc-pyrrolidine-3-carboxylic acid (125 mg, 0.58 mmol, 1.1 eq) and HATU (301 mg, 0.79 mmol, 1.5 eq) in anhydrous DMF (6 mL). Stir at room temperature for 5 minutes, then add DIEA (205 mg, 1.58 mmol, 3.0 eq) and the compound CR31-2 (200 mg, 0.53 mmol, 1.0 eq) from the previous step. Stir overnight at room temperature. TLC confirms the completion of the reaction. Cool the mixture, add 50 mL of deionized water, and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with deionized water (100 mL x 3), then with saturated brine (100 mL x 3), and dry over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain intermediate CR34-1 (yellow solid, 171 mg). LRMS: 540 [M+H] + .

[0191] Step 2: In a 25 mL round-bottom flask, weigh CR31-3 (171 mg, 0.32 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR34-1 is complete. The mixture is then dried to give the crude intermediate CR34 hydrochloride (yellow solid, 176 mg). LRMS: 440 [M+H] + .

[0192] Synthesis of intermediate CR35:

[0193]

[0194] Step 1: In a 25 mL round-bottom flask, dissolve 1-Boc-4-piperidinecarboxylic acid (133 mg, 0.58 mmol, 1.1 eq) and HATU (301 mg, 0.79 mmol, 1.5 eq) in anhydrous DMF (6 mL). Stir at room temperature for 5 minutes, then add DIEA (205 mg, 1.58 mmol, 3.0 eq) and the compound CR31-2 (200 mg, 0.53 mmol, 1.0 eq) from the previous step. Stir overnight at room temperature. TLC confirms the completion of the 1-Boc-4-piperidinecarboxylic acid reaction. Cool the mixture, add 50 mL of deionized water, and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with deionized water (100 mL x 3), then with saturated brine (100 mL x 3), and dry over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain intermediate CR35-1 (yellow solid, 202 mg). LRMS: 554 [M+H] + .

[0195] Step 2: In a 25 mL round-bottom flask, weigh CR35-1 (202 mg, 0.36 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR35-1 is complete. The mixture is then dried to give the crude intermediate CR35 hydrochloride (yellow solid, 209 mg). LRMS: 454 [M+H] + .

[0196] Synthesis of intermediate CR36:

[0197]

[0198] Step 1: In a 25 mL round-bottom flask, 4-fluorothalidomide (720 mg, 2.62 mmol, 1.2 eq) and 1-(N-Boc-aminoethyl)piperazine (500 mg, 2.18 mmol, 1.0 eq) were added sequentially and dissolved in anhydrous DMSO (22 mL). DIEA (845 mg, 6.54 mmol, 3.0 eq) was then added and heated to 100°C for 6 hours. TLC was performed until the 1-(N-Boc-aminoethyl)piperazine was completely consumed. The mixture was cooled, deionized water (50 mL) was added, and extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain intermediate CR36-1 (yellow-green solid, 646 mg). LRMS: 486 [M+H] + .

[0199] Step 2: In a 50 mL round-bottom flask, weigh CR36-1 (646 mg, 1.33 mmol) and add hydrogen chloride / 1,4-dioxane (20 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR36-1 is complete. The mixture is then dried to give the crude intermediate CR36 hydrochloride (yellow solid, 726 mg). LRMS: 386 [M+H] + .

[0200] Synthesis of intermediate CR37:

[0201]

[0202] Step 1: In a 25 mL round-bottom flask, dissolve 4-Boc-1-piperazineacetic acid (177 mg, 0.73 mmol, 1.1 eq) and HATU (376 mg, 0.99 mmol, 1.5 eq) in anhydrous DMF (7 mL). Stir at room temperature for 5 min, then add DIEA (256 mg, 1.98 mmol, 3.0 eq) and compound CR30-2 (250 mg, 0.66 mmol, 1.0 eq). Stir overnight at room temperature. TLC confirms the completion of the 4-Boc-1-piperazineacetic acid reaction. Cool the mixture, add 50 mL of deionized water, and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with deionized water (100 mL x 3), then with saturated brine (100 mL x 3), and dry over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain intermediate CR37-1 (yellow solid, 206 mg). LRMS: 569 [M+H] + .

[0203] Step 2: In a 25 mL round-bottom flask, weigh CR37-1 (206 mg, 0.36 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR37-1 is complete. The mixture is then dried to give the crude intermediate CR37 hydrochloride (yellow solid, 256 mg). LRMS: 469 [M+H] + .

[0204] Synthesis of intermediate CR38:

[0205]

[0206] Step 1: In a 100 mL round-bottom flask, 3-fluorothalidomide (1.44 g, 5.23 mmol, 1.2 eq) and tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (1.0 g, 4.36 mmol, 1.0 eq) were added sequentially and dissolved in anhydrous DMSO (20 mL). DIEA (1.69 mg, 13.08 mmol, 3.0 eq) was then added. The mixture was heated to 100°C and reacted for 6 hours until the tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate was completely consumed as determined by TLC. The mixture was cooled, deionized water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed sequentially with deionized water (200 mL × 3) and saturated brine (200 mL × 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain intermediate CR38-1 (yellow-green solid, 1.62 g). LRMS: 486 [M+H] + .

[0207] Step 2: In a 50 mL round-bottom flask, weigh CR38-1 (1.62 g, 3.44 mmol) and add hydrogen chloride / 1,4-dioxane (20 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR38-1 is complete. The mixture is then dried to give the crude intermediate CR38 hydrochloride (yellow solid, 1.52 g). LRMS: 386 [M+H] + .

[0208] Synthesis of intermediate CR39:

[0209]

[0210] Step 1: In a 25 mL round-bottom flask, 4-fluorothalidomide (611 mg, 2.22 mmol, 1.2 eq) and tert-butyl 4-(3-aminopropyl)piperazine-1-carboxylate (450 mg, 1.85 mmol, 1.0 eq) were added sequentially and dissolved in anhydrous DMSO (10 mL). DIEA (717 mg, 5.55 mmol, 3.0 eq) was then added and heated to 100°C for 6 hours. TLC was performed until the tert-butyl 4-(3-aminopropyl)piperazine-1-carboxylate was completely consumed. The mixture was cooled, 50 mL of deionized water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain intermediate CR39-1 (yellow-green solid, 233 mg). LRMS: 500 [M+H] + .

[0211] Step 2: In a 25 mL round-bottom flask, weigh CR39-1 (230 mg, 0.46 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). The resulting solution was stirred at room temperature overnight. TLC was performed until the reaction of CR39-1 was complete. The mixture was then dried to give the crude intermediate CR39 hydrochloride (yellow solid, 313 mg). LRMS: 400 [M+H] + .

[0212] Synthesis of intermediate CR40:

[0213]

[0214] Step 1: In a 25 mL round-bottom flask, 3-fluorothalidomide (611 mg, 2.22 mmol, 1.2 eq) and tert-butyl 4-(3-aminopropyl)piperazine-1-carboxylate (450 mg, 1.85 mmol, 1.0 eq) were added sequentially and dissolved in anhydrous DMSO (10 mL). DIEA (717 mg, 5.55 mmol, 3.0 eq) was then added and heated to 100°C for 6 hours. TLC was performed until the tert-butyl 4-(3-aminopropyl)piperazine-1-carboxylate was completely consumed. The mixture was cooled, 50 mL of deionized water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain intermediate CR40-1 (yellow-green solid, 407 mg). LRMS: 500 [M+H] + .

[0215] Step 2: In a 50 mL round-bottom flask, weigh CR40-1 (407 mg, 0.81 mmol) and add hydrogen chloride / 1,4-dioxane (20 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR40-1 is complete. The mixture is then dried to give the crude intermediate CR40 hydrochloride (yellow solid, 419 mg). LRMS: 400 [M+H] + .

[0216] Synthesis of intermediate CR41:

[0217]

[0218]

[0219] Step 1: In a 25 mL round-bottom flask, add 4-fluorothalidomide (154 mg, 0.56 mmol, 1.2 eq) and tert-butyl 4-(3-aminobutyl)piperazine-1-carboxylate (120 mg, 0.47 mmol, 1.0 eq) in sequence, dissolve in anhydrous DMSO (3 mL), then add DIEA (180 mg, 1.40 mmol, 3.0 eq). Heat to 100°C and react for 6 hours until the tert-butyl 4-(3-aminobutyl)piperazine-1-carboxylate is completely consumed, as determined by TLC. Cool, add 50 mL of deionized water, and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with deionized water (100 mL x 3), then with saturated brine (100 mL x 3), and dry over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain intermediate CR41-1 (yellow-green solid, 44 mg). LRMS: 514 [M+H] + .

[0220] Step 2: In a 25 mL round-bottom flask, weigh CR41-1 (44 mg, 0.085 mmol) and add hydrogen chloride / 1,4-dioxane (5 mL). The resulting solution was stirred at room temperature overnight. TLC was performed until the reaction of CR41-1 was complete. The mixture was then dried to give the crude intermediate CR41 hydrochloride (yellow solid, 68 mg). LRMS: 414 [M+H] + .

[0221] Synthesis of intermediate CR42:

[0222]

[0223] Step 1: To a 25 mL round-bottom flask, add 4-fluorothalidomide (163 mg, 0.59 mmol, 1.2 eq) and tert-butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate (120 mg, 0.49 mmol, 1.0 eq) in sequence. Dissolve in anhydrous DMSO (3 mL). Then add DIEA (191 mg, 1.48 mmol, 3.0 eq). Heat to 100°C and react for 6 hours. TLC indicates complete consumption of tert-butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate. Cool, add 50 mL of deionized water, and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with deionized water (100 mL x 3), then with saturated brine (100 mL x 3), and dry over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain intermediate CR42-1 (yellow-green solid, 133 mg). LRMS: 500 [M+H] + .

[0224] Step 2: In a 25 mL round-bottom flask, weigh CR42-1 (133 mg, 0.27 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR42-1 is complete. The mixture is then dried to give the crude intermediate CR42 hydrochloride (yellow solid, 123 mg). LRMS: 400 [M+H] + .

[0225] Synthesis of intermediate CR43:

[0226]

[0227] Step 1: To a 25 mL round-bottom flask, add 3-fluorothalidomide (163 mg, 0.59 mmol, 1.2 eq) and tert-butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate (120 mg, 0.49 mmol, 1.0 eq) in sequence. Dissolve in anhydrous DMSO (3 mL). Then add DIEA (191 mg, 1.48 mmol, 3.0 eq). Heat to 100°C and react for 6 hours until the tert-butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate is completely consumed, as determined by TLC. Cool the mixture, add 50 mL of deionized water, and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with deionized water (100 mL x 3), then with saturated brine (100 mL x 3), and dry over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain intermediate CR43-1 (yellow-green solid, 104 mg). LRMS: 500 [M+H] + .

[0228] Step 2: In a 25 mL round-bottom flask, weigh CR43-1 (104 mg, 0.21 mmol) and add hydrogen chloride / 1,4-dioxane (10 mL). Stir the resulting solution at room temperature overnight. TLC confirms that the reaction of CR43-1 is complete. The mixture is then dried to give the crude intermediate CR43 hydrochloride (yellow solid, 110.5 mg). LRMS: 400 [M+H] + .

[0229] Chemical Synthesis Example 1: Synthesis of QP48

[0230]

[0231] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-1 (125 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR01 hydrochloride (107 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR01 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP48 (yellow solid, 89 mg). LRMS: 685 [M+H] + . 1 H NMR(500MHz, CDCl3)δ9.13(s,1H),8.66(d,J=5.1Hz,2H),8.10(s,1H),7.71(d,J=8.4Hz,1H),7.55(d,J=5.2Hz,2H),7.44(s,2H), 7.38(d,J=7.9Hz,1H),7.33(d,J=2.3Hz,1H),7.16(t,J=7.8Hz,1H),7.10(dd,J=8.6,2.4Hz,1H),6.65(t,J=7.5Hz,1H),6.28(d,J =8.4Hz,1H),6.08(d,J=7.9Hz,1H),4.95(dd,J=12.3,5.4Hz,1H),4.30(dtd,J=11.1,7.2,4.0Hz,1H),3.99(dd,J=10.6,7.0Hz,2H ),3.25-3.13(m,2H),2.95-2.54(m,9H),2.24(dd,J=13.4,4.0Hz,2H),2.14(ddd,J=12.4,5.7,2.5Hz,1H),1.20(t,J=7.5Hz,6H).

[0232] Chemical Synthesis Example 2: Synthesis of QP50

[0233]

[0234] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-1 (125 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR21 hydrochloride (120 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until complete consumption of CR21 was detected by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The product was filtered, concentrated to dryness, and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP50 (yellow solid, 82 mg). LRMS: 728 [M+H] + . 1 H NMR (500MHz, CDCl3) δ9.19(s,1H),9.13(s,1H),8.65(d,J=5.2Hz,2H),8.20(s,1H),7.76(d,J=7.5Hz,1H),7.66(d,J=7 .9Hz,1H),7.55(d,J=5.2Hz,2H),7.51(t,J=7.7Hz,1H),7.42(d,J=13.7Hz,3H),7.17(t,J=7.8Hz,1H),6.66(t,J=7.5H z,1H),6.28(d,J=8.4Hz,1H),6.16(d,J=7.7Hz,1H),5.22(dd,J=13.3,5.1Hz,1H),4.48(s,2H),4.17-4.04(m,1H),3.2 3(s,2H),3.04-2.76(m,4H),2.74-2.50(m,6H),2.40(qd,J=13.2,4.9Hz,1H),2.30-2.13(m,3H),1.19(t,J=7.5Hz,6H).

[0235] Chemical Synthesis Example 3: Synthesis of QP52

[0236]

[0237] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-1 (125 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR03 hydrochloride (111 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR03 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to afford QP52 as a yellow solid, 81 mg. LRMS: 699 [M+H] + . 1 H NMR (500MHz, CDCl3) δ9.09(s,1H),8.66(d,J=5.1Hz,2H),8.07(s,1H),7.68(d,J=8.5Hz,1H),7.55(d,J=5.1Hz,2H),7.42(d, J=19.3Hz,3H),7.29(d,J=2.3Hz,1H),7.17(t,J=7.8Hz,1H),7.06(dd,J=8.6,2.4Hz,1H),6.66(t,J=7.5Hz,1H),6.30(dd,J=1 8.1,7.3Hz,2H),4.94(dd,J=12.3,5.4Hz,1H),4.00(d,J=13.0Hz,2H),3.43(t,J=6.3Hz,2H),3.01(td,J=12.7,2.5Hz,2H),2 .94-2.54(m,8H),2.13(ddd,J=11.2,6.5,3.5Hz,1H),2.07-1.90(m,3H),1.44(tt,J=14.1,6.9Hz,3H),1.19(t,J=7.5Hz,6H).

[0238] Chemical Synthesis Example 4: Synthesis of QP53

[0239]

[0240] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-1 (125 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR08 hydrochloride (119 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR08 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to afford QP53 as a yellow solid, 87 mg. LRMS: 725 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.65(d,J=5.2Hz,2H),8.11(s,1H),7.62(d,J=8.2Hz,1H),7.55(d,J=5.2Hz,2H),7 .43(s,2H),7.19-7.08(m,2H),6.95(s,1H),6.88(d,J=2.1Hz,1H),6.77-6.66(m,2H),6.30(d,J=8.2Hz,1 H),4.93(dd,J=12.2,5.4Hz,1H),4.72(d,J=5.5Hz,1H),4.04(q,J=7.1Hz,1H),3.65(d,J=44.0Hz,4H),2. 97-2.47(m,10H),2.12(dq,J=10.4,3.7,3.2Hz,1H),1.75(dd,J=12.2,7.7Hz,5H),1.20(t,J=7.5Hz,6H).

[0241] Chemical Synthesis Example 5: Synthesis of QP54

[0242]

[0243] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-1 (125 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR04 hydrochloride (127 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until the CR04 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated to dryness, and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP54 (yellow solid, 99 mg). LRMS: 753 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.65(d,J=5.2Hz,2H),8.07(s,1H),7.67(d,J=8.4Hz,1H),7.54(d,J=5.2Hz,2H),7.43(s, 2H),7.27(d,J=2.5Hz,1H),7.15(d,J=7.5Hz,1H),7.10(t,J=7.8Hz,1H),7.04(dd,J=8.5,2.3Hz,1H),6.97(s,1H ),6.72(t,J=7.4Hz,1H),6.29(d,J=8.2Hz,1H),4.93(dd,J=12.2,5.4Hz,1H),3.99(d,J=13.1Hz,2H),3.03-2.5 4(m,12H),2.13(ddd,J=10.7,6.6,3.5Hz,1H),1.84(t,J=10.5Hz,4H),1.49-1.29(m,6H),1.19(t,J=7.5Hz,6H).

[0244] Chemical Synthesis Example 6: Synthesis of QP55

[0245]

[0246] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-1 (125 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR11 hydrochloride (111 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until complete consumption of CR11 was detected by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP55 (yellow solid, 68 mg). LRMS: 699 [M+H] + . 1 H NMR (500MHz, CDCl3) δ9.11 (s, 1H), 8.65 (d, J = 5.1Hz, 2H), 8.14 (s, 1H), 7.62-7.53 (m, 3H), 7 .48-7.36(m,4H),7.17(dd,J=17.1,8.2Hz,2H),6.66(t,J=7.5Hz,1H),6.34(t,J=6.1Hz,1H ),6.27(d,J=8.4Hz,1H),4.97(dd,J=12.3,5.4Hz,1H),3.79(t,J=12.4Hz,2H),3.46(t,J=6 .3Hz,2H),2.99-2.55(m,10H),2.17-2.08(m,1H),2.01–1.86(m,3H),1.19(t,J=7.5Hz,6H).

[0247] Chemical Synthesis Example 7: Synthesis of QP57

[0248]

[0249] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-5 (133 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR03 hydrochloride (111 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR03 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to dryness, and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to afford QP57 (yellow solid, 78 mg). LRMS: 729 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.65(d,J=5.3Hz,2H),8.52(s,1H),8.13(s,1H),7.68(d,J=8.5Hz,1H),7.55(d,J=5.2Hz,2H),7.43(s,2H), 7.28(d,J=2.3Hz,1H),7.05(dd,J=8.5,2.4Hz,1H),6.99(d,J=2.9Hz,1H),6.81(dd,J=9.1,2.8Hz,1H),6.35(t,J=6.2Hz,1H),6.2 5(d,J=9.0Hz,1H),4.94(dd,J=12.3,5.4Hz,1H),3.98(d,J=13.0Hz,2H),3.77(s,3H),3.41(t,J=6.3Hz,2H),3.05-2.94(m,2H),2 .93-2.52(m,8H),2.13(ddd,J=11.3,6.3,3.4Hz,1H),1.94(t,J=9.7Hz,3H),1.42(tt,J=14.2,7.5Hz,3H),1.19(t,J=7.5Hz,6H).

[0250] Chemical Synthesis Example 8: Synthesis of QP58

[0251]

[0252] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-5 (133 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR04 hydrochloride (127 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until the CR04 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated to dryness, and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP58 (yellow solid, 89 mg). LRMS: 783 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.64(d,J=5.1Hz,2H),8.13(s,1H),7.67(d,J=8.5Hz,1H),7.54(d,J=5 .1Hz,2H),7.42(s,2H),7.04(dd,J=8.6,2.4Hz,1H),6.78-6.67(m,2H),6.47(s,1H),6.26(d, J=8.8Hz,1H),4.93(dd,J=12.2,5.4Hz,1H),3.98(d,J=12.9Hz,2H),3.74(s,3H),3.00-2.53( m,11H),2.17-2.07(m,1H),1.84(d,J=11.8Hz,4H),1.48-1.31(m,5H),1.19(t,J=7.5Hz,6H).

[0253] Chemical Synthesis Example 9: Synthesis of QP59

[0254]

[0255] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-1 (125 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR06 hydrochloride (111 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR06 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP59 (yellow solid, 84 mg). LRMS: 699 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.65(d,J=5.2Hz,2H),8.13(s,1H),7.62(d,J=8.3Hz,1H),7.54(d,J=5.2Hz,2H),7.43(s,2H),7 .16(d,J=7.5Hz,1H),7.11(t,J=7.8Hz,1H),6.99-6.94(m,2H),6.78-6.70(m,2H),6.30(d,J=8.3Hz,1H),4.93(dd,J= 1H), 4.68 (t, J = 6.0 Hz, 1H), 3.20 (t, J = 6.4 Hz, 2H), 2.80 (ddddd, J = 73.1, 36.7, 32.0, 18.9, 11.1 Hz, 10H), 2.17-2.08 (m, 1H), 1.95 (dd, J = 52.1, 13.2 Hz, 3H), 1.31 (t, J = 12.3 Hz, 3H), 1.19 (t, J = 7.5 Hz, 6H). Chemical Synthesis Example 10: Synthesis of QP60

[0256]

[0257] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-4 (135 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR03 hydrochloride (111 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR03 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), and then dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness. The mixture was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to give QP60 (yellow solid, 120 mg). LRMS: 728 [M+H] + . 1 H NMR (500MHz, DMSO) δ12.44(s,1H),11.07(s,1H),9.74(s,1H),8.67(t,J=5.9Hz,1H),7.66(dd,J=12.8,8.1Hz,2H),7 .46(s,2H),7.33(d,J=2.4Hz,1H),7.30-7.21(m,2H),6.81(t,J=7.5Hz,1H),6.33(d,J=8.3Hz,1H),5.06(dd,J=12.8 ,5.4Hz,1H),4.09(d,J=13.0Hz,2H),3.21(t,J=6.4Hz,2H),3.06-2.94(m,2H),2.88(ddd,J=17.5,13.5,5.3Hz,1H), 2.57(td,J=16.0,15.0,4.1Hz,2H),2.24(s,6H),2.00(dd,J=12.1,6.0Hz,1H),1.87-1.77(m,2H),1.34-1.21(m,3H).

[0258] Chemical Synthesis Example 11: Synthesis of QP61

[0259]

[0260] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-2 (136 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR03 hydrochloride (111 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR03 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to dryness, and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP60 (yellow solid, 87 mg). LRMS: 729 [M+H] + . 1 H NMR (500MHz, CDCl3) δ9.40(s,1H),8.05(s,1H),7.68(d,J=8.5Hz,1H),7.46(d,J=7.9Hz,1H),7.05(dd,J= 8.5,2.4Hz,1H),6.84(t,J=7.5Hz,1H),6.49(d,J=8.3Hz,1H),6.37(t,J=6.3Hz,1H),4.93(dd,J=12.2,5.4 Hz,1H),4.03-3.95(m,2H),3.42(t,J=6.4Hz,2H),3.06-2.95(m,2H),2.94-2.68(m,4H),2.46(s,3H),2.3 1(s,3H),2.13(ddd,J=10.9,6.3,3.4Hz,1H),1.96(dd,J=27.6,12.9Hz,3H),1.42(qd,J=12.3,4.0Hz,2H).

[0261] Chemical Synthesis Example 12: Synthesis of QP63

[0262]

[0263] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-1 (125 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR14 hydrochloride (117 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until complete consumption of CR14 was detected by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP63 (yellow solid, 81 mg). LRMS: 717 [M+H] + . 1 H NMR (500MHz, CDCl3) δ9.10 (s, 1H), 8.66 (d, J = 5.1Hz, 2H), 8.16 (s, 1H), 7.61-7.52 (m, 2H), 7.50-7.37 ( m,5H),7.17(ddd,J=8.5,7.0,1.5Hz,1H),6.71-6.62(m,1H),6.33(t,J=6.1Hz,1H),6.28(dd,J=8.4,1 .1Hz,1H),4.93(dd,J=12.4,5.3Hz,1H),3.70(d,J=12.0Hz,2H),3.46(t,J=6.3Hz,2H),2.94-2.55(m, 10H), 2.13(dtd,J=11.7,4.5,2.0Hz,1H),2.00-1.87(m,3H),1.61-1.50(m,3H),1.19(t,J=7.5Hz,6H).

[0264] Chemical Synthesis Example 13: Synthesis of QP65

[0265]

[0266] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-6 (137 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR03 hydrochloride (111 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR03 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to dryness, and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to afford QP65 (yellow solid, 81 mg). LRMS: 734 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.06(s,1H),8.02(s,1H),7.68(d,J=8.5Hz,1H),7.40(dd,J=7.8,1.5Hz,1H),7.34(s,2H),7.29(d, J=2.3Hz,1H),7.20-7.11(m,3H),7.06(dd,J=8.6,2.4Hz,1H),6.81-6.74(m,1H),6.65(ddd,J=8.1,7.2,1.2Hz,1H),6.35 -6.25(m,2H),4.94(dd,J=12.3,5.3Hz,1H),4.00(d,J=13.2Hz,2H),3.42(t,J=6.3Hz,2H),3.01(t,J=12.5Hz,2H),2.94- 2.52(m,7H),2.13(ddd,J=10.7,4.9,2.6Hz,1H),2.04-1.90(m,3H),1.43(q,J=11.9,11.0Hz,2H),1.18(t,J=7.6Hz,6H).

[0267] Chemical Synthesis Example 14: Synthesis of QP66

[0268]

[0269] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-6 (137 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR08 hydrochloride (119 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR08 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), and then dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness. The mixture was separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to give QP66 (yellow solid, 103 mg). LRMS: 760 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.00(s,1H),7.62(d,J=8.3Hz,1H),7.33(s,2H),7.17-7.07(m ,3H),6.92-6.86(m,2H),6.82-6.67(m,3H),6.32-6.27(m,1H),4.93(dd,J=12.2,5.3 Hz,1H),4.68(d,J=5.4Hz,1H),4.05(q,J=7.1Hz,1H),3.65(d,J=35.6Hz,4H),2.94-2 .49(m,9H),2.17-2.09(m,1H),1.74(dd,J=22.7,11.7Hz,5H),1.19(t,J=7.6Hz,6H).

[0270] Chemical Synthesis Example 15: Synthesis of QP67

[0271]

[0272] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-7 (129 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR03 hydrochloride (111 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR03 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to afford QP67 (a yellow solid, 81 mg). LRMS: 711 [M+H] + . 1 H NMR(400MHz, CDCl3)δ9.44(s,1H),8.74-8.66(m,2H),8.05(s,1H),7.72-7.63(m,3H),7.53-7.42(m, 3H),7.29(dd,J=8.1,1.9Hz,2H),7.05(dd,J=8.6,2.4Hz,1H),6.91-6.81(m,1H),6.51(dd,J=8.3,1.1 Hz,1H),6.37(t,J=6.2Hz,1H),4.94(dd,J=12.2,5.3Hz,1H),3.99(d,J=13.1Hz,2H),3.42(t,J=6.4Hz ,2H),3.08-2.94(m,2H),2.94-2.66(m,3H),2.18-2.09(m,1H),2.08-1.84(m,3H),1.51-1.35(m,3H).

[0273] Chemical Synthesis Example 16: Synthesis of QP68

[0274]

[0275] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-8 (133 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR03 hydrochloride (111 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR03 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP68 (yellow solid, 83 mg). LRMS: 723 [M+H] + . 1 H NMR(400MHz, CDCl3)δ9.28(s,1H),8.68-8.58(m,2H),7.68(d,J=8.5Hz,1H),7.50-7.44(m,2H),7.41(dd,J=7.9,1.5Hz,1H), 7.29(d,J=2.3Hz,1H),7.21(ddd,J=8.6,7.2,1.5Hz,1H),7.05(d,J=16.4Hz,3H),6.73-6.67(m,1H),6.52(dd,J=8.3,1.1Hz, 1H),6.31(t,J=6.1Hz,1H),4.94(dd,J=12.3,5.3Hz,1H),4.00(d,J=13.1Hz,2H),3.43(t,J=6.3Hz,2H),3.01(dd,J=13.7,11 .4Hz,2H),2.94-2.66(m,4H),2.22-2.08(m,2H),2.07-1.90(m,5H),1.52-1.37(m,3H),0.91(d,J=22.5Hz,5H),0.68(s,5H).

[0276] Chemical Synthesis Example 17: Synthesis of QP69

[0277]

[0278] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-7 (129 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR08 hydrochloride (119 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR08 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to afford QP53 as a yellow solid, 88 mg. LRMS: 737 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.72-8.66(m,2H),8.08(s,1H),7.65(s,2H),7.61(d,J=8.2Hz,1H),7.49-7.45(m, 2H),7.33(s,1H),7.24-7.18(m,2H),6.94(t,J=7.4Hz,1H),6.87(d,J=2.1Hz,1H),6.68(dd,J=8.3,2.2Hz ,1H),6.58(d,J=8.1Hz,1H),4.92(dd,J=12.2,5.3Hz,1H),4.70(d,J=5.5Hz,1H),4.02(q,J=7.1Hz,1H),3 .61(s,4H),2.93-2.66(m,4H),2.51(t,J=10.0Hz,2H),2.17-2.07(m,1H),1.71(dd,J=23.6,12.3Hz,6H).

[0279] Chemical Synthesis Example 18: Synthesis of QP70

[0280]

[0281] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-9 (125 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR03 hydrochloride (111 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR03 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP70 (yellow solid, 93 mg). LRMS: 717 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.33(s,1H),8.70-8.62(m,2H),7.68(d,J=8.5Hz,1H),7.57(d,J=2.1Hz,1H),7.50-7.41(m,3H),7. 29(d,J=2.3Hz,1H),7.23(d,J=1.5Hz,1H),7.11(d,J=2.1Hz,1H),7.06(dd,J=8.7,2.4Hz,1H),6.81-6.72(m,1H),6.50(d d,J=8.4,1.1Hz,1H),6.34(t,J=6.1Hz,1H),4.94(dd,J=12.3,5.3Hz,1H),4.00(d,J=13.2Hz,2H),3.43(t,J=6.4Hz,2H), 3.07-2.94(m,2H),2.93-2.66(m,3H),2.21-2.08(m,2H),2.08-1.88(m,4H),1.50-1.36(m,3H),0.97(s,2H),0.72(s,2H).

[0282] Chemical Synthesis Example 19: Synthesis of QP71

[0283]

[0284] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-9 (125 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR08 hydrochloride (119 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR08 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to afford QP71 as a yellow solid, 89 mg. LRMS: 743 [M+H]. + . 1 H NMR (400MHz, CDCl3) δ8.66(s,2H),8.06(s,1H),7.62(d,J=8.3Hz,1H),7.57(d,J=2.1Hz,1H),7.47(d,J=5.3Hz,2H),7 .32(s,1H),7.23-7.15(m,3H),6.91-6.81(m,2H),6.69(dd,J=8.3,2.2Hz,1H),6.55(d,J=8.2Hz,1H),4.93(dd,J=12. 2,5.2Hz,1H),4.69(d,J=5.5Hz,1H),4.03(q,J=7.1Hz,1H),3.63(d,J=36.2Hz,5H),2.95-2.64(m,4H),2.53(t,J=10. 0Hz,2H),2.16-2.06(m,1H),1.94(td,J=8.6,4.5Hz,1H),1.82-1.65(m,6H),0.98(d,J=8.2Hz,2H),0.73-0.62(m,2H).

[0285] Chemical Synthesis Example 20: Synthesis of QP73

[0286]

[0287] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-3 (130 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR08 hydrochloride (119 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR08 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to afford QP73 as a yellow solid, 80 mg. LRMS: 739 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.39 (s, 1H), 8.04 (s, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.47 (d, J = 7.8Hz, 1H), 7.29 (m,3H),6.95(d,J=2.2Hz,1H),6.84(t,J=7.5Hz,1H),6.68(dd,J=8.6,2.3Hz,1H),6.54-6.43(m,2 H),4.92(dd,J=12.2,5.3Hz,1H),3.71-3.51(m,4H),3.51-3.40(m,2H),3.27(dd,J=10.0,6.8Hz,1 H),2.92-2.64(m,4H),2.45(s,3H),2.31(s,3H),2.17-2.06(m,1H),1.95(dd,J=12.7,7.7Hz,1H).

[0288] Chemical Synthesis Example 21: Synthesis of QP76

[0289]

[0290] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-2 (136 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR16 hydrochloride (124 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until complete consumption of CR16 was detected by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP76 (yellow solid, 74 mg). LRMS: 773 [M+H]. + . 1 H NMR (400MHz, CDCl3) δ8.01 (s, 1H), 7.42 (d, J = 9.7Hz, 1H), 7.24-7.15 (m, 2H), 6.9 4(d,J=7.0Hz,2H),6.57(d,J=8.1Hz,1H),4.92(dd,J=12.2,5.3Hz,1H),4.78(d,J =4.9Hz,1H),4.05(d,J=8.1Hz,1H),3.61(s,5H),2.97-2.66(m,3H),2.55(t,J=1 0.0Hz,2H),2.45(s,3H),2.30(s,3H),2.18-2.08(m,1H),1.75(t,J=25.6Hz,6H).

[0291] Chemical Synthesis Example 22: Synthesis of QP78

[0292]

[0293] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-2 (136 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR15 hydrochloride (117 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until complete consumption of CR15 was detected by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP78 (yellow solid, 90 mg). LRMS: 747 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.97 (s, 1H), 7.41 (d, J = 9.8Hz, 1H), 7.24-7.18 (m, 2H), 7.08(d,J=7.0Hz,1H),6.93(t,J=7.4Hz,1H),6.57(d,J=8.2Hz,1H),4.91(dd, J=12.3,5.2Hz,1H),4.75(s,1H),3.23(s,2H),2.95-2.67(m,3H),2.45(d,J= 1.7Hz,3H),2.30(d,J=1.7Hz,3H),2.18-2.07(m,1H),1.92(d,J=38.5Hz,3H).

[0294] Chemical Synthesis Example 23: Synthesis of QP79

[0295]

[0296] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-3 (130 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR16 hydrochloride (124 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until complete consumption of CR16 was detected by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP79 (yellow solid, 65 mg). LRMS: 757 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.98 (s, 1H), 7.42 (d, J = 9.7Hz, 1H), 7.28 (s, 1H), 7.25-7.18 (m, 1H), 7.17-7.11(m,1H),6.99-6.90(m,3H),6.74(dd,J=8.3,4.2Hz,1H),4.92(dd,J=12.2,5.3Hz ,1H),4.78(s,1H),4.05(d,J=7.3Hz,1H),3.59(s,4H),2.95-2.66(m,3H),2.55(t,J=10.0H z,2H),2.44(d,J=1.1Hz,3H),2.30(d,J=1.0Hz,3H),2.18-2.07(m,1H),1.83-1.64(m,5H).

[0297] Chemical Synthesis Example 24: Synthesis of QP80

[0298]

[0299] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-2 (136 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR08 hydrochloride (119 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR08 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to dryness, and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP80 (yellow solid, 67 mg). LRMS: 755 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.00 (s, 1H), 7.61 (d, J = 8.2Hz, 1H), 7.26 (s, 2H), 7.25-7.18 (m, 2H), 6.93(t,J=7.4Hz,1H),6.87(d,J=2.2Hz,1H),6.68(dd,J=8.3,2.2Hz,1H),6.57(d,J=8.1H z,1H),4.93(dd,J=12.3,5.3Hz,1H),4.70(d,J=5.5Hz,1H),3.61(m,4H),2.94-2.67(m,3H ),2.52(t,J=10.1Hz,2H),2.45(s,3H),2.31(s,3H),2.16-2.09(m,1H),1.81-1.62(m,6H).

[0300] Chemical Synthesis Example 25: Synthesis of QP84

[0301]

[0302] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-2 (136 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR10 hydrochloride (111 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR10 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to afford QP84 as a yellow solid, 83 mg. LRMS: 727 [M+H] + . 1 H NMR (500MHz, CDCl3) δ9.18(s,1H),7.96(s,1H),7.63(d,J=8.3Hz,1H),7.35(d,J=8.1Hz,1H ),7.28(s,1H),7.24(s,1H),6.88(s,1H),6.82(t,J=7.6Hz,1H),6.69(dd,J=8.3,2.2Hz,1H ),6.51(d,J=8.3Hz,1H),4.93(dd,J=12.3,5.3Hz,1H),4.40(d,J=56.6Hz,4H),2.95-2.68( m,6H),2.46(d,J=2.5Hz,3H),2.31(d,J=2.3Hz,3H),2.26-2.09(m,4H),2.06-1.95(m,1H).

[0303] Chemical Synthesis Example 26: Synthesis of QP87

[0304]

[0305] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-3 (130 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR06 hydrochloride (111 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR06 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to dryness, and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to afford QP87 (a yellow solid, 89 mg). LRMS: 713 [M+H]. + . 1 H NMR (500MHz, CDCl3) δ8.01 (s, 1H), 7.61 (d, J = 8.2Hz, 1H), 7.206 (m, 1H), 7.20 (d d,J=7.6,1.6Hz,1H),7.14(t,J=1.6Hz,1H),6.99–6.90(m,3H),6.74(td,J=8.4 ,7.5,3.0Hz,2H),4.92(dd,J=12.3,5.3Hz,1H),3.18(d,J=6.6Hz,2H),2.92–2. 68(m,4H),2.45(s,4H),2.30(s,4H),2.16–2.06(m,2H),1.91(d,J=39.8Hz,4H).

[0306] Chemical Synthesis Example 27: Synthesis of QP88

[0307]

[0308] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-3 (130 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR15 hydrochloride (117 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until complete consumption of CR15 was detected by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to dryness, and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP88 (yellow solid, 78 mg). LRMS: 731 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.97 (s, 1H), 7.42 (d, J = 9.8Hz, 1H), 7.33-7.27 (m, 2H), 7.21 (dd, J = 7.6 ,1.6Hz,1H),7.14(t,J=1.6Hz,1H),7.08(d,J=7.0Hz,1H),6.99-6.91(m,2H),6.74(dd,J=8.3 ,4.1Hz,1H),4.91(dd,J=12.4,5.3Hz,1H),4.75(s,1H),3.23(d,J=6.7Hz,2H),2.95-2.67(m, 4H),2.45(s,3H),2.30(s,3H),2.17-2.09(m,1H),1.93(d,J=44.7Hz,3H),1.40-1.27(m,2H).

[0309] Chemical Synthesis Example 28: Synthesis of QP89

[0310]

[0311] In a 25 mL round-bottom flask, HATU (228 mg, 0.60 mmol, 2.0 eq) and FTO-2 (136 mg, 0.36 mmol, 1.2 eq) were added and dissolved in anhydrous DMF (1.5 mL). After stirring at room temperature for 10 min, DIEA (155 mg, 1.2 mmol, 4.0 eq) and crude CR06 hydrochloride (111 mg, 0.30 mmol, 1.0 eq) were added and heated to 60°C. The reaction was allowed to proceed overnight until CR06 was completely consumed, as determined by TLC. After cooling, 20 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness and separated by silica gel column chromatography (PE / EA, 1 / 4, v / v) to obtain QP89 (yellow solid, 93 mg). LRMS: 729 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.96 (s, 1H), 7.61 (d, J = 8.3Hz, 1H), 7.27 (s, 1H), 7.24-7.18 (m, 2H) ,6.94(ddd,J=14.9,7.1,1.6Hz,2H),6.74(dd,J=8.4,2.2Hz,1H),6.57(d,J=8.2Hz,1H), 4.92(dd,J=12.4,5.3Hz,1H),4.61(t,J=6.0Hz,1H),3.18(t,J=6.2Hz,2H),2.92-2.68(m ,4H),2.45(s,3H),2.31(s,3H),2.17-2.09(m,1H),1.91(d,J=42.5Hz,3H),1.31(s,2H).

[0312] Chemical Synthesis Example 29: Synthesis of SP01

[0313]

[0314] In a 25 mL round-bottom flask, FTO-1 (273 mg, 0.79 mmol, 1.1 eq) and HATU (411 mg, 1.08 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (8 mL). After stirring at room temperature for 5 min, DIEA (279 mg, 2.16 mmol, 3.0 eq) and crude CR25 hydrochloride (280 mg, 0.72 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR25 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the target product SP01 (yellow solid, 305 mg). LRMS: 683 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ11.06(s,1H),8.61(d,J=7.0Hz,2H),7.72(d,J=25.2Hz,3H),7.59(d,J=10.3 Hz,2H),7.43(s,1H),7.29(d,J=10.0Hz,2H),7.09(d,J=33.9Hz,2H),6.77-6.61(m,1H),6.06(dd,J= 42.2,8.3Hz,1H),5.10-5.01(m,1H),3.74(s,2H),3.59-3.41(m,2H),3.17(d,J=10.1Hz,1H),2.94-2 .80(m,1H),2.57(q,J=6.7Hz,4H),2.12(td,J=38.7,36.8,7.8Hz,4H),1.15(dt,J=22.7,7.5Hz,6H).

[0315] Chemical Synthesis Example 30: Synthesis of SP02

[0316]

[0317] In a 25 mL round-bottom flask, FTO-1 (92 mg, 0.27 mmol, 1.1 eq) and HATU (138.2 mg, 0.36 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (93 mg, 0.72 mmol, 3.0 eq) and crude CR26 hydrochloride (102 mg, 0.24 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR26 reaction. After cooling, 50 mL of deionized water was added to the system. Extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the target product SP02 (yellow solid, 39 mg). LRMS: 714 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.66(s,2H),8.24(s,1H),7.64(d,J=8.3Hz,1H),7.54(d,J=5.1Hz,2H),7.43( s,2H),7.16(dd,J=7.6,1.6Hz,1H),7.14-7.09(m,1H),7.02-6.98(m,2H),6.78(dd,J=8.3,2.2Hz,1 H),6.73(t,J=7.4Hz,1H),6.30(d,J=8.3Hz,1H),5.20(t,J=4.7Hz,1H),4.93(dd,J=12.2,5.4Hz,1H ),3.77(s,4H),3.30(q,J=5.1Hz,2H),2.91-2.53(m,13H),2.17-2.08(m,1H),1.20(t,J=7.5Hz,6H).

[0318] Chemical Synthesis Example 31: Synthesis of SP03

[0319]

[0320] In a 25 mL round-bottom flask, FTO-1 (146 mg, 0.42 mmol, 1.1 eq) and HATU (219 mg, 0.58 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (5 mL). After stirring at room temperature for 5 min, DIEA (147 mg, 1.14 mmol, 3.0 eq) and crude CR27 hydrochloride (150 mg, 0.38 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR27 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the target product SP03 (yellow solid, 150 mg). LRMS: 683 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ11.13-10.99(m,1H),8.61(d,J=6.7Hz,2H),7.79-7.68(m,2H) ,7.60(s,2H),7.56-7.37(m,2H),7.30(dd,J=21.8,8.6Hz,2H),7.13(s,2H),6.69(d,J= 27.0Hz,1H),6.08(d,J=16.8Hz,1H),5.04(s,2H),4.10(d,J=10.0Hz,1H),3.90-3.64( m,2H),2.87(d,J=19.9Hz,2H),2.57(s,5H),2.28-1.85(m,6H),1.15(d,J=32.6Hz,6H).

[0321] Chemical Synthesis Example 32: Synthesis of SP04

[0322]

[0323] In a 25 mL round-bottom flask, FTO-1 (106 mg, 0.30 mmol, 1.1 eq) and HATU (158 mg, 0.42 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (108 mg, 0.84 mmol, 3.0 eq) and crude CR28 hydrochloride (128 mg, 0.28 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR28 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the target product SP04 (light yellow chloro solid, 32 mg). LRMS: 754 [M+H] + . 1 HNMR(500MHz,DMSO-d6)δ11.10(s,1H),8.63(d,J=5.2Hz,2H),7.78-7.68(m,3H),7.60(s,2H),7.45(s,1H),7.37-7.31(m,1H),7. 16(d,J=7.5Hz,1H),7.10(t,J=7.8Hz,1H),7.03(d,J=5.7Hz,1H),6.70(t,J=7.4Hz,1H),6.09(d,J=8.2Hz,1H),5.08(dd,J=12.7, 5.5Hz,1H),3.96(d,J=12.8Hz,2H),3.66(t,J=12.0Hz,3H),3.22-3.12(m,4H),2.89(td,J=13.3,12.6,7.2Hz,2H),2.57(q,J=8.6 ,8.1Hz,6H),2.23(d,J=11.7Hz,2H),2.20-2.10(m,2H),2.01(q,J=7.5,6.6Hz,2H),1.82(d,J=12.7Hz,2H),1.12(t,J=7.5Hz,6H).

[0324] Chemical Synthesis Example 33: Synthesis of SP05

[0325]

[0326] In a 25 mL round-bottom flask, FTO-1 (132 mg, 0.38 mmol, 1.1 eq) and HATU (197 mg, 0.52 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (5 mL). After stirring at room temperature for 5 min, DIEA (134 mg, 1.04 mmol, 3.0 eq) and crude CR29 hydrochloride (150 mg, 0.34 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR29 reaction. After cooling, 50 mL of deionized water was added to the system. Extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the target product SP05 (yellow-green solid, 118 mg). LRMS: 726.3 [M+H] + . 1 HNMR(500MHz,DMSO-d6)δ11.08(s,1H),8.86(s,1H),8.66-8.59(m,2H),7.77-7.72(m,2H),7.69(d,J=8.5Hz,1H),7.61(s,2H),7 .45(d,J=7.8Hz,1H),7.37(d,J=2.3Hz,1H),7.28(dd,J=8.7,2.3Hz,1H),7.17(t,J=7.8Hz,1H),6.67(t,J=7.5Hz,1H),6.16(d,J= 8.3Hz,1H),5.75(s,1H),5.07(dd,J=12.7,5.4Hz,1H),4.43(s,1H),4.22(d,J=44.7Hz,2H),4.08-3.92(m,1H),3.48(t,J=4.9Hz, 4H), 3.25 (t, J = 6.3Hz, 2H), 2.88 (ddd, J = 17.3, 13.4, 5.4Hz, 1H), 2.56 (q, J = 7.6Hz, 6H), 2.06-1.97 (m, 1H), 1.13 (t, J = 7.5Hz, 6H).

[0327] Chemical Synthesis Example 34: Synthesis of SP06

[0328]

[0329] In a 25 mL round-bottom flask, FTO-1 (132 mg, 0.38 mmol, 1.1 eq) and HATU (197 mg, 0.52 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (5 mL). After stirring at room temperature for 5 min, DIEA (134 mg, 1.04 mmol, 3.0 eq) and crude CR30 hydrochloride (160 mg, 0.35 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR30 reaction. After cooling, 50 mL of deionized water was added to the system. Extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the target product SP06 (yellow solid, 62 mg). LRMS: 754 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.84(s,1H),8.65(d,J=5.2Hz,2H),8.20(s,1H),7.74(d,J=8.4Hz,1H),7.55(d,J=5.1Hz,2H),7.4 3(s,2H),7.36(d,J=7.9Hz,1H),7.30(d,J=2.3Hz,1H),7.14(t,J=7.7Hz,1H),7.08(dd,J=8.6,2.3Hz,1H),6.64(t,J=7.5 Hz,1H),6.27(d,J=8.3Hz,1H),4.95(dd,J=12.4,5.5Hz,1H),4.52(t,J=9.2Hz,2H),3.87(s,2H),3.71(td,J=9.0,4.5Hz, 2H), 3.54 (t, J = 4.9Hz, 2H), 3.47 (t, J = 5.2Hz, 4H), 2.98-2.49 (m, 8H), 2.14 (dt, J = 7.8, 3.3Hz, 1H), 1.20 (t, J = 7.5Hz, 6H).

[0330] Chemical Synthesis Example 35: Synthesis of SP07

[0331]

[0332] In a 25 mL round-bottom flask, FTO-1 (94 mg, 0.27 mmol, 1.1 eq) and HATU (141 mg, 0.37 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (96 mg, 0.74 mmol, 3.0 eq) and crude CR31 hydrochloride (107 mg, 0.25 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR31 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the target product SP07 (yellow solid, 109 mg). LRMS: 754 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.84(s,1H),8.65(d,J=4.9Hz,2H),8.17(s,1H),7.65(t,J=7.8Hz,1H),7.55(d,J=5.1Hz,2H ),7.48(d,J=7.2Hz,1H),7.43(s,2H),7.36(d,J=7.8Hz,1H),7.17(d,J=8.4Hz,1H),7.13(t,J=7.8Hz,1H),6.64(t, J=7.5Hz,1H),6.27(d,J=8.4Hz,1H),4.97(dd,J=12.3,5.4Hz,1H),4.51(s,2H),3.90(s,2H),3.70(td,J=9.2,8.7, 4.3Hz,2H),3.57(t,J=5.0Hz,2H),3.45-3.25(m,4H),2.98-2.51(m,8H),2.21-2.08(m,1H),1.20(t,J=7.5Hz,6H).

[0333] Chemical Synthesis Example 36: Synthesis of SP08

[0334]

[0335] In a 25 mL round-bottom flask, FTO-1 (120 mg, 0.35 mmol, 1.1 eq) and HATU (180 mg, 0.47 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (5 mL). After stirring at room temperature for 5 min, DIEA (122 mg, 0.95 mmol, 3.0 eq) and crude CR32 hydrochloride (150 mg, 0.32 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR32 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the target product SP08 (yellow solid, 72 mg). LRMS: 768 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),8.63(d,J=5.1Hz,2H),7.75(d,J=5.3Hz,2H),7.71(d,J=8.5Hz ,1H),7.61(s,3H),7.39(d,J=25.9Hz,2H),7.26(d,J=8.6Hz,1H),7.10(t,J=7.8Hz,1H),6.70(t,J=7. 4Hz,1H),6.12(d,J=8.3Hz,1H),5.08(dd,J=12.8,5.4Hz,1H),3.60(dd,J=86.5,42.9Hz,13H),2.88( ddd,J=17.3,13.3,5.3Hz,1H),2.57(q,J=10.8,9.8Hz,6H),2.22-1.96(m,3H),1.12(t,J=7.5Hz,6H).

[0336] Chemical Synthesis Example 37: Synthesis of SP09

[0337]

[0338] In a 25 mL round-bottom flask, FTO-1 (117 mg, 0.34 mmol, 1.1 eq) and HATU (175 mg, 0.46 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (5 mL). After stirring at room temperature for 5 min, DIEA (119 mg, 0.92 mmol, 3.0 eq) and crude CR33 hydrochloride (150 mg, 0.31 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR33 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the target product SP09 (yellow solid, 69 mg). LRMS: 782 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.65(d,J=5.4Hz,2H),8.15(s,1H),7.74(d,J=8.5Hz,1H),7.54(d,J=5.2Hz,2H),7.43(s,2H), 7.30(d,J=2.3Hz,1H),7.19(d,J=7.6Hz,1H),7.12(d,J=7.8Hz,1H),7.10-7.06(m,1H),6.99(s,1H),6.72(t,J=7.4Hz ,1H),6.30(d,J=8.2Hz,1H),4.95(dd,J=12.3,5.4Hz,1H),4.45(s,2H),3.79(d,J=36.2Hz,4H),3.47(d,J=19.1Hz,4 H),3.11(d,J=13.6Hz,2H),2.93-2.57(m,8H),2.14(dd,J=8.7,4.4Hz,1H),1.97-1.78(m,4H),1.20(t,J=7.5Hz,6H).

[0339] Chemical Synthesis Example 38: Synthesis of SP10

[0340]

[0341] In a 25 mL round-bottom flask, FTO-1 (162 mg, 0.47 mmol, 1.1 eq) and HATU (242 mg, 0.64 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (5 mL). After stirring at room temperature for 5 min, DIEA (165 mg, 1.27 mmol, 3.0 eq) and crude CR35 hydrochloride (208 mg, 0.42 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR35 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to give the target product SP10 (yellow solid, 185 mg). LRMS: 782 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.65(d,J=5.1Hz,2H),8.22(s,1H),7.64(t,J=7.8Hz,1H),7.54(d,J=5.3Hz,2H),7 .47(d,J=7.2Hz,1H),7.42(s,2H),7.18(t,J=8.6Hz,2H),7.11(t,J=7.8Hz,1H),6.98(s,1H),6.72(t,J= 7.4Hz,1H),6.30(d,J=8.3Hz,1H),4.97(dd,J=12.2,5.4Hz,1H),4.44(s,2H),3.97-3.72(m,4H),3.47-3 .24(m,4H),3.10(s,2H),2.92-2.56(m,8H),2.19-2.10(m,1H),1.98-1.78(m,4H),1.20(t,J=7.5Hz,6H).

[0342] Chemical Synthesis Example 39: Synthesis of SP11

[0343]

[0344] In a 25 mL round-bottom flask, FTO-1 (140 mg, 0.40 mmol, 1.1 eq) and HATU (210 mg, 0.55 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (5 mL). After stirring at room temperature for 5 min, DIEA (143 mg, 1.10 mmol, 3.0 eq) and crude CR34 hydrochloride (175 mg, 0.37 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR34 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the target product SP11 (yellow solid, 119 mg). LRMS: 768 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.65(d,J=5.1Hz,2H),8.17(s,1H),7.64(t,J=7.8Hz,1H),7.55(d,J=5.1Hz,2 H),7.47(d,J=7.2Hz,1H),7.43(s,2H),7.34(s,1H),7.16(d,J=8.4Hz,1H),7.10(t,J=7.8Hz,1H),6. 70(t,J=7.4Hz,1H),6.28(d,J=8.3Hz,1H),4.97(dd,J=12.3,5.4Hz,1H),4.10-3.64(m,8H),3.46-3. 24(m,5H),2.97-2.52(m,8H),2.27(s,1H),2.13(dq,J=10.7,4.0,3.3Hz,1H),1.20(t,J=7.5Hz,6H).

[0345] Chemical Synthesis Example 40: Synthesis of SP12

[0346]

[0347] In a 25 mL round-bottom flask, FTO-2 (98 mg, 0.26 mmol, 1.1 eq) and HATU (135 mg, 0.36 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (92 mg, 0.72 mmol, 3.0 eq) and crude CR26 hydrochloride (100 mg, 0.24 mmol, 1.0 eq) were added sequentially. The mixture was stirred at room temperature overnight. TLC confirmed the completion of the CR26 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to dryness, and separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP12 (yellow solid, 71 mg). LRMS: 744 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.00 (s, 1H), 7.63 (d, J = 8.3Hz, 1H), 7.26 (s, 2H), 7.25-7.19 ( m,2H),6.99(d,J=2.1Hz,1H),6.93(td,J=7.3,1.0Hz,1H),6.79(d,J=8.2Hz,1H),6. 57(d,J=8.1Hz,1H),5.18(s,1H),4.92(dd,J=12.2,5.2Hz,1H),3.75(s,4H),3.31(s ,2H),2.94-2.66(m,6H),2.56(s,3H),2.45(s,3H),2.31(s,3H),2.18-2.09(m,1H).

[0348] Chemical Synthesis Example 41: Synthesis of SP13

[0349]

[0350] In a 25 mL round-bottom flask, FTO-2 (98 mg, 0.26 mmol, 1.1 eq) and HATU (135 mg, 0.36 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (92 mg, 0.72 mmol, 3.0 eq) and crude CR36 hydrochloride (100 mg, 0.24 mmol, 1.0 eq) were added sequentially. The mixture was stirred at room temperature overnight. TLC confirmed the completion of the CR36 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to dryness, and separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP13 (yellow solid, 50 mg). LRMS: 744 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 9.80 (s, 1H), 8.59 (d, J = 34.3Hz, 1H), 7. 69(s,2H),7.62(s,2H),7.38(s,1H),7.29(t,J=7.7Hz,2H),6.85(t,J=7.4Hz,1 H),6.36(d,J=8.3Hz,1H),5.07(dd,J=13.0,5.3Hz,1H),3.41(s,5H),2.87(d,J =11.5Hz,2H),2.72-2.51(m,8H),2.44(s,3H),2.26(s,3H),2.05-1.97(m,1H).

[0351] Chemical Synthesis Example 42: Synthesis of SP15

[0352]

[0353] In a 25 mL round-bottom flask, FTO-3 (52 mg, 0.14 mmol, 1.1 eq) and HATU (74 mg, 0.20 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (51 mg, 0.40 mmol, 3.0 eq) and crude CR26 hydrochloride (55 mg, 0.13 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR26 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP15 (yellow solid, 14 mg). LRMS: 728 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.04(s,1H),7.63(d,J=8.3Hz,1H),7.30(s,1H),7.21(dd,J=7.6,1.6Hz,1H),7.15(t ,J=1.6Hz,1H),6.98(dd,J=8.1,2.1Hz,1H),6.96-6.91(m,1H),6.77(dd,J=8.3,2.2Hz,1H),6.74(dd,J=8. 3,4.1Hz,1H),5.20-5.15(m,1H),4.92(dd,J=12.3,5.3Hz,1H),3.73(s,4H),3.29(d,J=5.6Hz,2H),2.93-2 .74(m,3H),2.73-2.68(m,2H),2.54(s,4H),2.45(s,3H),2.30(s,3H),2.12(dtd,J=12.0,4.4,1.9Hz,1H).

[0354] Chemical Synthesis Example 43: Synthesis of SP16

[0355]

[0356] In a 25 mL round-bottom flask, FTO-3 (52 mg, 0.14 mmol, 1.1 eq) and HATU (74 mg, 0.20 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (51 mg, 0.40 mmol, 3.0 eq) and crude CR36 hydrochloride (55 mg, 0.13 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR36 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP16 (yellow solid, 22 mg). LRMS: 728 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),9.72(s,1H),8.61(s,1H),7.67(dd,J=8.1,3.0Hz,2H), 7.48(t,J=1.5Hz,1H),7.40(dd,J=11.4,1.9Hz,1H),7.36-7.29(m,2H),7.25(d,J=8.9Hz,1H), 6.87(t,J=7.8Hz,1H),6.56(dd,J=8.4,4.5Hz,1H),5.07(dd,J=12.9,5.4Hz,1H),3.46(d,J=14 .5Hz,5H),2.98-2.79(m,2H),2.72-2.52(m,8H),2.45(s,3H),2.27(s,3H),2.07-1.95(m,1H).

[0357] Chemical Synthesis Example 44: Synthesis of SP19

[0358]

[0359] In a 25 mL round-bottom flask, FTO-10 (56 mg, 0.13 mmol, 1.1 eq) and HATU (68 mg, 0.18 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (46 mg, 0.36 mmol, 3.0 eq) and crude CR26 hydrochloride (50 mg, 0.12 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR26 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP19 (yellow solid, 24 mg). LRMS: 795 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),11.05(s,1H),8.30(d,J=4.9Hz,1H),7.86(s,2H),7.59(d,J=3.0 Hz,1H),7.55(d,J=8.4Hz,1H),7.26(d,J=5.0Hz,1H),7.06(s,1H),6.99(d,J=2.1Hz,2H),6.90-6.83(m, 2H),6.82(d,J=2.9Hz,1H),6.63(dd,J=3.5,1.9Hz,1H),6.50(d,J=8.9Hz,1H),5.02(dd,J=12.9,5.4Hz ,1H),3.72(s,3H),3.58(d,J=30.1Hz,5H),3.30(d,J=6.1Hz,2H),2.93-2.53(m,5H),2.04-1.93(m,1H).

[0360] Chemical Synthesis Example 45: Synthesis of SP20

[0361]

[0362] In a 25 mL round-bottom flask, FTO-11 (50 mg, 0.13 mmol, 1.1 eq) and HATU (68 mg, 0.18 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (46 mg, 0.36 mmol, 3.0 eq) and crude CR26 hydrochloride (50 mg, 0.12 mmol, 1.0 eq) were added sequentially. Stirring was continued at room temperature overnight. TLC confirmed the completion of the CR26 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), then dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate to dryness were performed, and separation was performed on a silica gel column (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP20 (yellow solid, 42 mg). LRMS: 754 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),7.56(d,J=8.3Hz,1H),7.00(d,J=2.4Hz,2H),6.94 -6.84(m,4H),6.77(d,J=2.9Hz,1H),6.66(s,1H),6.60(dd,J=8.9,3.9Hz,1H),5.03(dd,J =12.8,5.4Hz,1H),3.85(s,3H),3.72(s,3H),3.54(s,4H),3.30(d,J=6.1Hz,2H),2.86(d, J=11.6Hz,1H),2.70-2.53(m,4H),2.45(s,3H),2.27(s,3H),2.00(dd,J=9.1,3.9Hz,1H).

[0363] Chemical Synthesis Example 46: Synthesis of SP21

[0364]

[0365] In a 25 mL round-bottom flask, FTO-12 (51 mg, 0.13 mmol, 1.1 eq) and HATU (68 mg, 0.18 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (46 mg, 0.36 mmol, 3.0 eq) and crude CR26 hydrochloride (50 mg, 0.12 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR26 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP21 (yellow solid, 45 mg). LRMS: 758 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.05 (s, 1H), 7.55 (d, J = 8.3Hz, 1H), 7.40-7.37 (m, 1H), 7.35-7.29 (m,1H),7.09(s,1H),6.99(d,J=2.2Hz,2H),6.88(dt,J=8.5,2.7Hz,2H),6.79(d,J=3.0Hz, 1H),6.64(dd,J=8.9,2.7Hz,1H),5.02(dd,J=12.9,5.4Hz,1H),3.72(s,3H),3.68-3.39(m, 4H),3.29(d,J=6.2Hz,2H),2.95-2.52(m,6H),2.43(s,3H),2.25(s,3H),2.04-1.94(m,1H).

[0366] Chemical Synthesis Example 47: Synthesis of SP23

[0367]

[0368] In a 25 mL round-bottom flask, FTO-3 (63 mg, 0.17 mmol, 1.1 eq) and HATU (90 mg, 0.24 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (62 mg, 0.48 mmol, 3.0 eq) and crude CR37 hydrochloride (80 mg, 0.16 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR37 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated to dryness, and separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP23 (yellow solid, 54 mg). LRMS: 811 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.05(s,1H),7.73(d,J=8.5Hz,1H),7.28(dd,J=9.7,2.0Hz,2H),7.20(dd, J=7.6,1.6Hz,1H),7.14(t,J=1.6Hz,1H),7.08(dd,J=8.5,2.3Hz,1H),6.98-6.90(m,2H),6.73( dd,J=8.3,4.2Hz,1H),4.94(dd,J=12.4,5.3Hz,1H),3.86-3.61(m,7H),3.44(dt,J=15.8,5.9Hz ,4H),3.29(s,2H),2.97-2.67(m,4H),2.60(s,4H),2.45(s,3H),2.30(s,3H),2.21-2.08(m,1H).

[0369] Chemical Synthesis Example 48: Synthesis of SP24

[0370]

[0371] In a 25 mL round-bottom flask, FTO-2 (66 mg, 0.17 mmol, 1.1 eq) and HATU (90 mg, 0.24 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (62 mg, 0.48 mmol, 3.0 eq) and crude CR37 hydrochloride (80 mg, 0.16 mmol, 1.0 eq) were added sequentially. Stirring was continued at room temperature overnight. TLC confirmed the completion of the CR37 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate to dryness were performed, and separation was performed on a silica gel column (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP24 (yellow solid, 49 mg). LRMS: 827 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.11(s,1H),7.73(d,J=8.4Hz,1H),7.29(d,J=2.3Hz,1H),7.26(s,2H),7. 24(d,J=2.2Hz,1H),7.23-7.18(m,2H),7.07(dd,J=8.5,2.3Hz,1H),6.92(td,J=7.5,1.0Hz,1H), 6.56(d,J=8.2Hz,1H),4.94(dd,J=12.3,5.4Hz,1H),3.89-3.59(m,7H),3.44(dt,J=16.3,5.4Hz ,4H),3.28(s,2H),2.97-2.67(m,4H),2.60(s,4H),2.45(s,3H),2.30(s,3H),2.20-2.09(m,1H).

[0372] Chemical Synthesis Example 49: Synthesis of SP25

[0373]

[0374] In a 25 mL round-bottom flask, FTO-1 (98 mg, 0.28 mmol, 1.1 eq) and HATU (146 mg, 0.38 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (5 mL). After stirring at room temperature for 5 min, DIEA (99 mg, 0.77 mmol, 3.0 eq) and crude CR38 hydrochloride (108 mg, 0.26 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR38 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to give the target product SP25 (yellow solid, 121 mg). LRMS: 714 [M+H] + . 1 H NMR(500MHz, CDCl3)δ8.66(s,2H),8.13(s,1H),7.58-7.48(m,3H),7.43(s,2H),7.17(dd,J= 7.6,1.6Hz,1H),7.12(d,J=7.2Hz,2H),7.02(s,1H),6.88(d,J=8.5Hz,1H),6.78(t,J=4.9Hz ,1H),6.72(td,J=7.4,1.1Hz,1H),6.30(d,J=8.2Hz,1H),4.93(dd,J=12.3,5.4Hz,1H),3.80 (s,4H),3.37(q,J=5.7Hz,2H),2.94-2.52(m,13H),2.19-2.07(m,1H),1.20(t,J=7.5Hz,6H).

[0375] Chemical Synthesis Example 50: Synthesis of SP26

[0376]

[0377] In a 25 mL round-bottom flask, FTO-2 (79 mg, 0.21 mmol, 1.1 eq) and HATU (108 mg, 0.28 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (74 mg, 0.57 mmol, 3.0 eq) and crude CR38 hydrochloride (80 mg, 0.19 mmol, 1.0 eq) were added sequentially. Stirring was continued at room temperature overnight. TLC confirmed the completion of the CR38 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate to dryness were performed, and separation was performed on a silica gel column (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP26 (yellow solid, 40 mg). LRMS: 744 [M+H] + . 1 H NMR(500MHz, CDCl3)δ8.02(s,1H),7.50(dd,J=8.5,7.1Hz,1H),7.31(s,1H),7.22(t,J=7.8Hz,2H ),7.11(d,J=7.1Hz,1H),6.92(td,J=7.5,1.0Hz,1H),6.87(d,J=8.5Hz,1H),6.77(t,J=4.9Hz,1H) ,6.56(d,J=7.8Hz,1H),4.92(dd,J=12.4,5.4Hz,1H),3.76(s,4H),3.35(q,J=5.7Hz,2H),2.93-2. 74(m,3H),2.72(dd,J=8.2,4.1Hz,2H),2.56(s,4H),2.45(s,3H),2.31(s,3H),2.17-2.09(m,1H).

[0378] Chemical Synthesis Example 51: Synthesis of SP27

[0379]

[0380] In a 25 mL round-bottom flask, FTO-2 (76 mg, 0.20 mmol, 1.1 eq) and HATU (105 mg, 0.28 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (71 mg, 0.55 mmol, 3.0 eq) and crude CR40 hydrochloride (80 mg, 0.18 mmol, 1.0 eq) were added sequentially. The mixture was stirred at room temperature overnight. TLC confirmed the completion of the CR40 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to dryness, and separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP27 (yellow solid, 69 mg). LRMS: 758 [M+H] + . 1 H NMR(500MHz, CDCl3)δ8.06(s,1H),7.49(dd,J=8.5,7.1Hz,1H),7.33(s,1H),7.22(td,J=7.2,1.6 Hz,2H),7.09(d,J=7.0Hz,1H),6.92(td,J=8.5,8.0,1.5Hz,2H),6.74-6.68(m,1H),6.56(dd,J=8. 0,1.4Hz,1H),4.90(dd,J=12.3,5.4Hz,1H),3.76(s,4H),3.38(d,J=6.0Hz,2H),2.94-2.62(m,4H ),2.50(q,J=6.9,6.5Hz,5H),2.45(s,3H),2.31(s,3H),2.16-2.09(m,1H),1.85(t,J=6.4Hz,2H).

[0381] Chemical Synthesis Example 52: Synthesis of SP28

[0382]

[0383] In a 25 mL round-bottom flask, FTO-3 (75 mg, 0.21 mmol, 1.1 eq) and HATU (108 mg, 0.28 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (74 mg, 0.57 mmol, 3.0 eq) and crude CR38 hydrochloride (80 mg, 0.19 mmol, 1.0 eq) were added sequentially. Stirring was continued at room temperature overnight. TLC confirmed the completion of the CR38 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed sequentially with deionized water (100 mL x 3) and saturated brine (100 mL x 3), then dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate to dryness were performed, and separation was performed on a silica gel column (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP28 (yellow solid, 111 mg). LRMS: 728 [M+H] + . 1 H NMR(500MHz, CDCl3)δ8.00(s,1H),7.50(dd,J=8.5,7.1Hz,1H),7.35(s,1H),7.21(dd,J=7.6,1.6Hz,1H),7.15 (t,J=1.7Hz,1H),7.11(d,J=7.1Hz,1H),6.96(dd,J=11.1,2.1Hz,1H),6.94-6.91(m,1H),6.87(d,J=8.5Hz,1H ),6.77(t,J=4.9Hz,1H),6.74(dd,J=8.2,4.2Hz,1H),4.92(dd,J=12.3,5.4Hz,1H),3.76(s,4H),3.35(q,J=5. 7Hz,2H),2.94-2.74(m,3H),2.72(t,J=6.0Hz,3H),2.56(s,4H),2.45(s,3H),2.31(s,3H),2.18-2.08(m,1H).

[0384] Chemical Synthesis Example 53: Synthesis of SP29

[0385]

[0386] In a 25 mL round-bottom flask, FTO-3 (73 mg, 0.20 mmol, 1.1 eq) and HATU (105 mg, 0.28 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (71 mg, 0.55 mmol, 3.0 eq) and crude CR40 hydrochloride (80 mg, 0.18 mmol, 1.0 eq) were added sequentially. The mixture was stirred at room temperature overnight. TLC confirmed the completion of the CR40 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The product was separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP29 (yellow solid, 69 mg). LRMS: 742 [M+H] + . 1 H NMR(500MHz, CDCl3)δ8.11(s,1H),7.48(dd,J=8.5,7.1Hz,1H),7.37(s,1H),7.25-7.19(m,1H),7.14(t ,J=1.6Hz,1H),7.09(d,J=7.1Hz,1H),6.96(dd,J=11.0,2.0Hz,1H),6.94-6.89(m,2H),6.73(dd,J=8.2, 4.2Hz,1H),6.68(t,J=5.6Hz,1H),4.90(dd,J=12.3,5.4Hz,1H),3.76(s,4H),3.38(q,J=6.2Hz,2H),2. 94-2.64(m,4H),2.57-2.47(m,5H),2.45(s,3H),2.30(s,3H),2.17-2.09(m,1H),1.85(t,J=6.5Hz,2H).

[0387] Chemical Synthesis Example 54: Synthesis of SP30

[0388]

[0389] In a 25 mL round-bottom flask, FTO-4 (59 mg, 0.16 mmol, 1.1 eq) and HATU (81 mg, 0.21 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (55 mg, 0.43 mmol, 3.0 eq) and crude CR26 hydrochloride (60 mg, 0.14 mmol, 1.0 eq) were added sequentially. Stirring was continued at room temperature overnight. TLC confirmed the completion of the CR26 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated to dryness, and separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP30 (yellow solid, 32 mg). LRMS: 743 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.22(s,1H),7.63(d,J=8.3Hz,1H),7.28(s,2H),7.22(ddd,J=15.8,7.5 ,1.6Hz,2H),7.13(s,1H),6.99(d,J=2.1Hz,1H),6.91(td,J=7.5,1.1Hz,1H),6.77(dd,J=8.3, 2.2Hz,1H),6.57(d,J=8.1Hz,1H),5.18(t,J=4.6Hz,1H),4.93(dd,J=12.3,5.3Hz,1H),3.73( s,4H),3.29(q,J=5.5Hz,2H),2.92-2.68(m,5H),2.55(s,4H),2.32(s,6H),2.16-2.09(m,1H).

[0390] Chemical Synthesis Example 55: Synthesis of SP31

[0391]

[0392] In a 25 mL round-bottom flask, FTO-7 (56 mg, 0.16 mmol, 1.1 eq) and HATU (81 mg, 0.21 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (55 mg, 0.43 mmol, 3.0 eq) and crude CR26 hydrochloride (60 mg, 0.14 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR26 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated to dryness, and separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP31 (yellow solid, 41 mg). LRMS: 726 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.70(d,J=5.3Hz,2H),8.10(s,1H),7.66(s,2H),7.63(d,J=8.2Hz,1H),7.5 0-7.45(m,2H),7.34(s,1H),7.22(dt,J=7.7,1.8Hz,2H),6.99(d,J=2.1Hz,1H),6.94(d,J=1.1Hz ,1H),6.77(dd,J=8.3,2.2Hz,1H),6.58(d,J=8.0Hz,1H),5.18(t,J=4.7Hz,1H),4.92(dd,J=12.3 ,5.4Hz,1H),3.73(s,4H),3.38-3.16(m,2H),3.03–2.65(m,5H),2.55(s,3H),2.19-1.98(m,1H).

[0393] Chemical Synthesis Example 56: Synthesis of SP32

[0394]

[0395] In a 25 mL round-bottom flask, FTO-2 (57 mg, 0.15 mmol, 1.1 eq) and HATU (79 mg, 0.21 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (53 mg, 0.41 mmol, 3.0 eq) and crude CR42 hydrochloride (60 mg, 0.14 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR42 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated to dryness, and separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP32 (yellow solid, 32 mg). LRMS: 758 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.30 (s, 1H), 7.66 (d, J = 8.5Hz, 1H), 7.27 (d, J = 2.9Hz, 2H), 7.2 5-7.18(m,2H),7.10(d,J=2.4Hz,1H),6.92(d,J=1.0Hz,1H),6.87-6.81(m,1H),6.5 6(d,J=8.2Hz,1H),4.94(dd,J=12.2,5.3Hz,1H),3.61(t,J=6.8Hz,6H),3.11(s,3H) ,2.94-2.67(m,3H),2.66-2.49(m,6H),2.45(s,3H),2.30(s,3H),2.17-2.04(m,1H).

[0396] Chemical Synthesis Example 57: Synthesis of SP33

[0397]

[0398] In a 25 mL round-bottom flask, FTO-2 (55.4 mg, 0.15 mmol, 1.1 eq) and HATU (76 mg, 0.20 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (52 mg, 0.40 mmol, 3.0 eq) and crude CR41 hydrochloride (60 mg, 0.13 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR41 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and separate by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP33 (yellow solid, 32 mg). LRMS: 772 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.45 (s, 1H), 7.60 (d, J = 8.3Hz, 1H), 7.29 (s, 1H), 7.26 (s, 2H), 7.25 -7.17(m,2H),6.99(d,J=2.2Hz,1H),6.92(td,J=7.5,1.1Hz,1H),6.71(dd,J=8.3,2.2Hz ,1H),6.56(d,J=8.1Hz,1H),4.93(s,2H),3.73(s,4H),3.23(q,J=6.3Hz,2H),2.95-2.65 (m,4H),2.51(s,4H),2.45(s,5H),2.30(s,3H),2.16-2.03(m,1H),1.71(q,J=6.7Hz,3H).

[0399] Chemical Synthesis Example 58: Synthesis of SP34

[0400]

[0401] In a 25 mL round-bottom flask, FTO-2 (52.4 mg, 0.14 mmol, 1.1 eq) and HATU (72 mg, 0.19 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (49 mg, 0.38 mmol, 3.0 eq) and crude CR43 hydrochloride (55 mg, 0.13 mmol, 1.0 eq) were added sequentially. Stirring was continued at room temperature overnight. TLC confirmed the completion of the CR43 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated to dryness, and separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP34 (yellow solid, 36 mg). LRMS: 758 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.03(s,1H),7.54(dd,J=8.5,7.0Hz,1H),7.31(d,J=7.0Hz,1H),7.27(s,2H),7.22(d dd,J=8.4,7.4,1.6Hz,1H),7.18(dd,J=7.6,1.5Hz,1H),7.15(d,J=8.5Hz,1H),6.91(td,J=7.5,1.0Hz,1H) ,6.55(d,J=8.2Hz,1H),4.95(dd,J=12.3,5.3Hz,1H),3.69(ddt,J=52.6,14.0,6.7Hz,7H),3.08(s,3H),2. 95-2.71(m,3H),2.69(q,J=6.9,6.3Hz,2H),2.45(s,6H),2.31(s,3H),2.12(dtd,J=11.5,4.4,1.9Hz,1H).

[0402] Chemical Synthesis Example 59: Synthesis of SP35

[0403]

[0404] In a 25 mL round-bottom flask, FTO-2 (67 mg, 0.18 mmol, 1.1 eq) and HATU (92 mg, 0.24 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (62 mg, 0.48 mmol, 3.0 eq) and crude CR39 hydrochloride (70 mg, 0.16 mmol, 1.0 eq) were added sequentially. Stirring was continued at room temperature overnight. TLC confirmed the completion of the CR39 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate to dryness were performed, and separation was performed on a silica gel column (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP35 (yellow solid, 20 mg). LRMS: 758 [M+H] + . 1 H NMR(500MHz, CDCl3)δ8.19(s,1H),7.60(d,J=8.2Hz,1H),7.29(s,1H),7.26(s,3H),7.23(d, J=7.4Hz,1H),7.00-6.87(m,2H),6.71(dd,J=8.3,2.1Hz,1H),6.57(d,J=8.4Hz,1H),5.80(t, J=5.0Hz,1H),4.92(dd,J=12.2,5.4Hz,1H),3.75(s,4H),3.32(q,J=5.9Hz,2H),2.98-2.60(m ,4H),2.64-2.50(m,5H),2.45(s,3H),2.31(s,3H),2.22-2.07(m,1H),1.85(p,J=6.3Hz,2H).

[0405] Chemical Synthesis Example 60: Synthesis of SP36

[0406]

[0407] In a 25 mL round-bottom flask, FTO-3 (64 mg, 0.18 mmol, 1.1 eq) and HATU (92 mg, 0.24 mmol, 1.5 eq) were weighed and dissolved in anhydrous DMF (3 mL). After stirring at room temperature for 5 min, DIEA (62 mg, 0.48 mmol, 3.0 eq) and crude CR39 hydrochloride (70 mg, 0.16 mmol, 1.0 eq) were added sequentially. Stir at room temperature overnight. TLC confirmed the completion of the CR39 reaction. After cooling, 50 mL of deionized water was added to the system, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with deionized water (100 mL × 3) and saturated brine (100 mL × 3), then dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated to dryness, and separated by silica gel column chromatography (DCM / MeOH, 20 / 1, v / v) to obtain the desired product SP36 (yellow solid, 27 mg). LRMS: 742 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.13(s,1H),7.60(d,J=8.3Hz,1H),7.34(s,1H),7.23(dd,J=7.6,1.5Hz, 1H),7.15(d,J=1.9Hz,1H),6.99-6.91(m,2H),6.73(ddd,J=17.1,8.3,3.2Hz,2H),5.81(d,J=6. 0Hz,1H),4.92(dd,J=12.2,5.4Hz,1H),3.76(s,4H),3.33(d,J=5.7Hz,2H),2.96-2.65(m,3H), 2.55(q,J=7.5,6.9Hz,5H),2.45(s,3H),2.31(s,3H),2.20-1.99(m,2H),1.86(d,J=6.3Hz,2H).

[0408] Biological Example 1: Evaluation of Cell Proliferation Inhibitory Activity of FTO Degraders

[0409] The following is a study of the cell proliferation inhibitory activity of the FTO-targeting PROTAC degrader represented by general formula (I) on acute myeloid leukemia NB4 and MV4-11 cells:

[0410] Acute myeloid leukemia cell lines such as NB4 and MV4-11 were cultured separately. Cells were seeded at a density of 5000 per well in 96-well plates and cultured until the cells adhered. Different compounds were added and cultured for 72 hours. 10 μL of CCK8 solution was directly added and incubated for 4 hours. The absorbance at 490 nm was detected, and the inhibition rate was calculated using the DMSO group as the control.

[0411] The following is the FTO-targeting PROTAC degrader represented by general formula (I) at concentrations of 100 nM and 1 μM. The inhibition rate of NB4 and MV4-11 at the 72h time point is greater than 60%, and its half-maximal inhibitory concentration IC is further determined. 50 , as shown in Table 1:

[0412] Table 1 Cell proliferation inhibitory activity of FTO degradation agents

[0413]

[0414]

[0415] The results of CCK8 experiments on AML cell lines NB4 and MV4-11 showed that most of these compounds showed good cell proliferation inhibitory activity.

[0416] Biological Example 2: Evaluation of FTO degradation activity

[0417] Western blot was used to detect the ability of PROTAC to degrade FTO. NB4 and MV4-11 cells were cultured at 1×10 6 After seeding in six-well plates and treating with various concentrations of PROTACs for 48 hours, cells were harvested by centrifugation, washed twice with PBS, and lysed on ice for 30 minutes using RIPA lysis buffer supplemented with a protease inhibitor cocktail. The supernatant was centrifuged at 12,000 rpm at 4°C, and the protein concentration of each sample was determined using a BCA protein assay kit. The protein concentrations of each sample were then adjusted to a similar level by adding additional RIPA lysis buffer. After alignment, the samples were added with 5× SDS loading buffer and heated at 100°C for 10 minutes to fully denature the proteins. Equal amounts of protein were loaded onto 12% SDS-polyacrylamide gels for electrophoresis and transferred to nitrocellulose membranes using a wet transfer method. The membranes were then blocked with 5% skim milk for 1 hour and incubated with antibodies overnight at 4°C. The membranes were washed three times with TBST buffer for 10 minutes each, then incubated with HRP-conjugated goat anti-rabbit or goat anti-mouse secondary antibodies at room temperature for 1 hour. The membranes were then washed three times with TBST buffer for 10 minutes each. Finally, FTO protein levels were detected using chemiluminescence, with GAPDH serving as an internal control. The results were quantitatively analyzed by Image J for the grayscale of FTO in Western Blot, and normalized with the grayscale of internal reference protein GAPDH. GraphPad prism 8 was used to fit the values and calculate the half-maximal degradation concentration (DC 50 values), as shown in Table 2:

[0418] Table 2 FTO degradation activity

[0419]

[0420] Table 2 shows the evaluation of FTO degradation activity of representative compounds. It was found that these compounds can degrade FTO in AML cell lines NB4 and MV4-11 and reduce the abundance of FTO.

[0421] The embodiments described above provide a detailed description of the technical solutions and beneficial effects of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, supplements and equivalent substitutions made within the scope of the principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A PROTAC compound or a pharmaceutically acceptable salt thereof, characterized in that The structure of the PROTAC compound is shown in formula (I): In the formula, A1, A2, A3, and A4 are each independently CR' or N; R' is selected from the group consisting of: H, halogen, carbonyl, carboxyl, hydroxyl, amino, nitro, cyano, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 alkoxycarbonyl, substituted or unsubstituted C1-C6 acylamino, substituted or unsubstituted C2-C12 ester, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 alkenylamide, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C3-C8 cycloalkoxy; X is CH2, NH, O or S; R a 、R b 、R c 、R d Each is independently H, halogen, hydroxy, amino, nitro, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkoxy; Y is a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group, or a substituted or unsubstituted 3-12 membered heterocyclyl group; Linker is an optionally substituted linker chain comprising a branched or unbranched, cyclic or acyclic, saturated or unsaturated chain of 6 to 15 carbon atoms in length, wherein 1 to 6 of the 6 to 15 carbon atoms are optionally independently replaced by O, N or S; The E3 ligase ligand is CRBN ligand.

2. The PROTAC compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R' is selected from the group consisting of H, halogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C8 cycloalkoxy.

3. The PROTAC compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted thietanyl, and substituted or unsubstituted azetidinyl.

4. The PROTAC compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein Y is selected from: Wherein, R1, R2, R3, and R4 are each independently selected from the group consisting of: H, halogen, hydroxyl, amino, carbonyl, carboxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 alkoxycarbonyl, substituted or unsubstituted C1-C6 acylamino, and substituted or unsubstituted C3-C8 cycloalkyl.

5. The PROTAC compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Substitution means that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: deuterium, halogen, carbonyl (=O), carboxyl, hydroxyl, amino, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkoxycarbonyl, C1-C6 acylamino, C2-C12 ester, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted five-membered or six-membered heteroaryl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl.

6. The PROTAC compound or pharmaceutically acceptable salt thereof according to claim 1, wherein The E3 ligase ligand is selected from: Wherein, X1 and Y1 are independently CH or N; X2 is CH2 or Z is O, CH or R5 is H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, or substituted or unsubstituted C3-C6 cycloalkoxy.

7. The PROTAC compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The Linker is selected from: Wherein, n1, n2, and m are independently integers of 0-4; R6 is selected from R7 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group.

8. The PROTAC compound or pharmaceutically acceptable salt thereof according to claim 1, wherein PROTAC compounds are selected from:

9. A method for preparing a PROTAC compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, characterized in that: include: (1) The CRBN ligand reacts with the linker precursor compound to obtain a CRBN ligand derivative with an amino group at the end; (2) reacting the compound of formula (II) with a CRBN ligand derivative having an amino terminal to obtain a PROTAC compound of formula (I); 10. A pharmaceutical composition, characterized in that The invention comprises a PROTAC compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

11. Use of a PROTAC compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of an FTO inhibitor or FTO degrader.

12. A use of a PROTAC compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament, characterized in that: The drug is used to treat at least one of leukemia, lymphoma, myelodysplastic syndrome, obesity, metabolic syndrome, type II diabetes, Alzheimer's disease, breast cancer, kidney cancer, colorectal cancer, pancreatic cancer, liver cancer, small cell lung cancer, human bone marrow rhabdomyosarcoma, pancreatic cancer, and malignant glioblastoma.

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