JNK degradation active compound and application thereof

Abstract

The present invention relates to bifunctional compounds of Formula 1, which are useful as modulators of JNK (target protein). The compounds according to the present invention exhibit a broad range of pharmacological activities associated with degradation / inhibition of a target protein. Diseases or conditions caused by aggregation or accumulation of target proteins can be treated or prevented with the compounds and compositions of the invention.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry. Specifically, this invention relates to pyrimidine derivatives with JNK degradation activity, pharmaceutical combinations comprising said pyrimidine derivatives, and their use in drugs for JNK-related diseases. Background Technology

[0002] Proteolysis-targeting chimeras (PROTACs) are small, heterobiologically functional molecules that typically consist of three chemical components: a ligand that binds to the target protein (POI), a ligand that binds to the E3 ubiquitin ligase, and a linker that connects the two ligands.

[0003] PROTAC is a targeted chemical knockout strategy that utilizes a system inherent in the organism itself to degrade target proteins via the ubiquitin-proteasome system. The ubiquitin-proteasome system (UPS) is a highly conserved protein containing 76 amino acids (8.6 kDa) responsible for maintaining intracellular protein homeostasis. Specifically, it is maintained by chaperone proteins responsible for correcting protein misfolding and a proteolytic system responsible for clearing unfolded or damaged proteins. The proteolytic system is composed of 26S proteasomes, which are mainly composed of a regulatory subunit (19S regulatory particle) and a 20S proteasome core. The 19S regulatory particle determines the specificity of the proteasome in cleaving substrates; upon binding to a ubiquitin-labeled protein, it deubiquitinates the substrate, guiding it into the catalytic 20S core particle for degradation. The protein to be degraded is repeatedly labeled as a polyubiquitin (Ub) chain by a cascade reaction of three enzymes (E1 ubiquitin activator, E2 ubiquitin conjugate, and E3 ubiquitin ligase). In simple terms, E1 activates ubiquitin via an ATP-dependent mechanism, forming an E1-Ub conjugate. Ub then transfers from the E1 enzyme to the E2 enzyme via trans-thioesterification. In the final step, Ub is transferred to the substrate protein via a ternary complex formed between the E2 and E3 enzymes and the substrate. Depending on the E3 ligase family, Ub can be transferred directly from E2 to the substrate, or sequentially from E2 to the E3 ubiquitin ligase and then indirectly to the substrate. The Ub-labeled substrate is then recognized and degraded by the 26S proteasome.

[0004] Unlike traditional inhibitors that compete for and occupy binding sites, PROTACs exhibit catalytic properties in their mode of action, promoting target protein degradation even at low concentrations. PROTACs possess the potential to directly degrade target proteins (rather than inhibit them) and modulate related signaling pathways, which is unattainable with traditional therapies (inhibitors / activators). PROTACs offer numerous advantages in overcoming resistance to inhibitory or occupation-driven therapies in many disease indications, such as cancer and bacterial infections. In addition to traditional chemotherapy, kinase inhibitors have seen rapid development over the past 20 years. While kinase inhibitors are highly effective cancer treatments, patients frequently develop resistance and cancer recurrence. However, PROTACs, by degrading the entire target protein, will show greater advantage in drug-resistant cancers.

[0005] PROTACs can simultaneously eliminate both the enzymatic and non-enzymatic functions of kinases. Traditional small molecule inhibitors typically inhibit the enzymatic activity of target proteins, while PROTACs not only affect the enzymatic activity of proteins but also influence non-enzymatic activity by degrading the entire protein. Therefore, PROTACs have the advantage of expanding the dosing space of existing targets and modulating proteins that are difficult to control with traditional small molecule inhibitors.

[0006] The degradation of target proteins is time-dependent, typically rapid, catalytic, and cyclical, allowing them to exert their effects at low doses. Once the pre-existing cellular protein reserves are depleted, PROTACs only need to degrade a smaller, de novo resynthesized protein library to maintain the knockout; for many proteins with moderate turnover rates, resynthesis is slow, allowing even low tissue concentrations of PROTACs to maintain effective degradation. Even after complete removal of PROTACs, cells may require a considerable amount of time to restore their protein library to levels sufficient to reconstruct physiological signals, resulting in a significantly prolonged duration of action. Therefore, PROTACs have the potential to prolong the duration of drug efficacy.

[0007] The concept of hydrophobic tags (HyTs) inducing protein degradation was first proposed in 2011. A major driving force behind protein folding is the embedding of hydrophobic residues within the protein core; conversely, the exposure of these hydrophobic residues is considered a marker of unfolded proteins, which are eliminated by the ubiquitin-proteasome system or autophagy. HyT-PDs are bifunctional small molecules composed of a target protein ligand (POI) and a highly hydrophobic group that induces degradation, linked by a linker. Hydrophobic tagging technology has been used for various targets. HyTs induce protein degradation by mimicking the characteristics of misfolded proteins, facilitating the recognition of cellular quality control mechanisms. HyT-PDs can achieve protein degradation through different protein quality control mechanisms, including the ubiquitin-proteasome system (UPS) and lysosomal autophagy.

[0008] Currently, no JNK degradation agent drugs have been developed. Developing new JNK degradation agent compounds is of great significance for the treatment of JNK-related diseases such as neurodegenerative diseases, tumors, diabetes, inflammatory diseases, and pulmonary fibrosis. Summary of the Invention

[0009] The purpose of this invention is to provide a JNK degrading agent, which can be used as a medicine for the prevention and / or treatment of JNK-related diseases.

[0010] Another object of the present invention is to provide a pharmaceutical composition comprising the said compound.

[0011] Another object of the present invention is to provide the use of the compound in the preparation of a medicament for treating JNK-related diseases and a method for treating JNK-related diseases using the compound or a pharmaceutical composition.

[0012] In a first aspect, the present invention provides compounds of Formula 1, or tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof.

[0013]

[0014] Where JL represents the ligand that binds to the target protein JNK, D represents the ligand that binds to E3 ubiquitin ligase or a hydrophobic tag, and L represents the linker that connects the two ligands.

[0015] In a specific implementation, JL is:

[0016]

[0017] In the formula,

[0018] R1 is selected from: H, halogen, cyano, or optionally substituted C.1-10 Alkyl, optionally substituted C 1-10 Alkyl group, -C(O)R5;

[0019] R2 is selected from: H, hydroxyl group, or optionally substituted C. 1-10 Alkyl, optionally substituted C 5-10 Aryl, halogen, cyano, nitro, -C 0-6 -C(O)R5、-C 0-6 -OR6、-C 0-6 -N(R7)2, optionally substituted sulfonyl group, optionally substituted phosphonoyl group, optionally substituted 5-7 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S;

[0020] Alternatively, two adjacent R2 atoms, together with the carbon atoms attached to them, form a 3-10 membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, or S.

[0021] x is 0, 1, 2, 3, 4 or 5;

[0022] Ring A is selected from: C 5-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic alkenyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-10 membered bicyclic aryl or bicyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-10 membered bicyclic carbocyclic or bicyclic heterocyclic containing 1, 2 or 3 heteroatoms independently selected from N, O or S;

[0023] R3 is selected from: H, hydroxyl, halogen, cyano, nitro, -C 0-6 -C(O)R5、-C 0-6 -OR6、-C 0-6 -N(R7)2, optionally substituted sulfonyl group, optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl group, optionally substituted C 1-10 Alkoxy, optional substituted C 5-10 aryl or heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S;

[0024] Where the valence allows, y can be 0, 1, 2, 3, 4, or 5;

[0025] R4 is H;

[0026] Each R5 is independently selected from: H, optionally substituted hydroxyl group, optionally substituted amino group, optionally substituted C group. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 5-10 aryl, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S;

[0027] Each R6 is independently selected from: H, or optionally substituted C. 1-3 Acyl group, optionally substituted C 1-10 Alkyl, optionally substituted C 5-10 aryl, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S;

[0028] Each R7 is independently selected from: H, or optionally substituted C. 1-3 Acyl group, optionally substituted C 1-10 Alkyl, optionally substituted C 5- 10 aryl, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S.

[0029] In a specific implementation, R1 is selected from: H, halogen;

[0030] R2 is selected from: H, hydroxyl, halogen, cyano, nitro, or optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, -C 0-6 -C(O)R5、-C 0-6 -OR6、-C 0-6 -N(R7)2;

[0031] x is 0, 1, 2, or 3;

[0032] Ring A is selected from: phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S;

[0033] R3 is selected from: H, hydroxyl, halogen, cyano, nitro, or optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Alkoxy;

[0034] Where the oxidation state allows, y can be 0, 1, or 2;

[0035] R4 is H;

[0036] R5 is independently selected from: H, hydroxyl group, optionally substituted amino group, optionally substituted C group. 1-6 Alkoxy;

[0037] R6 is independently selected from: H, or optionally substituted C. 1-6 alkyl;

[0038] R7 is independently selected from: H, or C (optionally substituted). 1-6 alkyl.

[0039] In a specific implementation, JL is:

[0040]

[0041] In a specific implementation, L represents a key, or C represents a key. 1-20 Saturated or unsaturated hydrocarbon chains, wherein the C 1-20 One or more carbon atoms in the hydrocarbon chain may be independently substituted by the following: -O-, -S-, -C(O)-, -S(O)2-, -N(R7)-, -N(R7)-C(O)-, -C(O)-N(R7)-, -OC(O)-, -C(O)-O-, -N(R7)-S(O)2-, -S(O)2-N(R7)-, or independently substituted by the following: C 5-10 aryl, 5-10 heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic alkenyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-10 membered bicyclic aryl or bicyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-10 membered bicyclic carbocyclic or bicyclic heterocyclic containing 1, 2 or 3 heteroatoms independently selected from N, O or S, all of which may be optionally substituted where appropriate;

[0042] Each R7 is independently selected from: H, or optionally substituted C. 1-6 alkyl.

[0043] In specific implementations, L represents a bond, -C(O)-, or is selected from the following group:

[0044]

[0045]

[0046] In a specific embodiment, D is a ligand linking CRBN, VHL, or RNF126. In a specific embodiment, D is selected from the group consisting of:

[0047]

[0048] R8 is selected from: hydroxyl, halogen, cyano, halogen-substituted or unsubstituted C. 1-6 Alkyl, halogenated or unsubstituted C 1-6 Alkoxy, C 1-6 Alkyne, -O-aryl, 5-10 aryl, or heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; or, two R8s together with the carbon atom attached to them to form a 5-10 aryl or a heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a 5-10 cycloalkyl, or a heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S.

[0049] In a specific implementation, D stands for hydrophobic label.

[0050] In a specific implementation, D is selected from the following group:

[0051]

[0052] In specific embodiments, the present invention provides compounds selected from the group consisting of tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof:

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069] Preferably, the compound is selected from the group consisting of:

[0070]

[0071]

[0072]

[0073]

[0074]

[0075] In a second aspect, the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises the compound described in the first aspect or its tautomers, mesosomes, racemates, enantiomers, diastereomers, mixtures thereof or pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable transporter.

[0076] In a third aspect, the present invention provides the use of the compound described in the first aspect or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof in the preparation of JNK degrading agents.

[0077] In a preferred embodiment, the JNK degrading agent is a drug for treating and / or preventing JNK-related diseases.

[0078] In a preferred embodiment, the JNK-related diseases include fibrosis, neurodegenerative diseases, diabetes, inflammatory diseases, tumors, and central nervous system diseases.

[0079] In a preferred embodiment, the fibrosis includes, but is not limited to, pulmonary fibrosis;

[0080] The neurodegenerative diseases mentioned include, but are not limited to, Alzheimer's disease and Parkinson's disease;

[0081] The inflammatory diseases include, but are not limited to, arthritis and heart inflammation;

[0082] The tumors include, but are not limited to, lung cancer, liver cancer, pancreatic cancer, and cervical cancer;

[0083] The central nervous system diseases mentioned include, but are not limited to, cerebral ischemia-reperfusion.

[0084] In a fourth aspect, the present invention provides a method for treating and / or preventing JNK-related diseases, the method comprising the step of administering a therapeutic and / or preventive effective amount of the compound of the first aspect or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, or a combination of drugs of the second aspect, to a subject in need of such treatment and / or prevention.

[0085] In a preferred embodiment, the JNK-related diseases include fibrosis, neurodegenerative diseases, diabetes, inflammatory diseases, tumors, and central nervous system diseases.

[0086] In a preferred embodiment, the fibrosis includes, but is not limited to, pulmonary fibrosis;

[0087] The neurodegenerative diseases mentioned include, but are not limited to, Alzheimer's disease and Parkinson's disease;

[0088] The inflammatory diseases include, but are not limited to, arthritis and heart inflammation;

[0089] The tumors include, but are not limited to, lung cancer, liver cancer, pancreatic cancer, and cervical cancer;

[0090] The central nervous system diseases mentioned include, but are not limited to, cerebral ischemia-reperfusion.

[0091] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0092] Figure 1 The compounds PA6, PA7, PB6, and PB7 of the present invention were shown to have degradation activity against JNK1. Detailed Implementation

[0093] Through extensive and in-depth research, the inventors unexpectedly discovered a series of compounds with JNK degradation activity, particularly JNK1 degradation activity, which enables the preparation of therapeutic drugs for JNK-related diseases, thereby treating JNK-related diseases. This invention was completed based on this discovery.

[0094] Terminology Definition

[0095] The terms used herein to refer to groups, substituents, or structures of compounds have the same meaning as understood by those skilled in the art. For clarity, the terms used in this specification are defined as follows.

[0096] In this invention, "a", "a type" or "a class" means at least one / a type or more than one / a type.

[0097] In this article, the form "C" 1-n The expression "" refers to a group having 1-n carbon atoms, for example, "C 1-10 The expression “C6-C10” indicates that the group has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; similarly, “C6-C10” indicates that the group has 6, 7, 8, 9, or 10 carbon atoms. Furthermore, the description of the range of carbon atom counts in this document also includes sub-ranges. For example, when referring to 1-10 carbon atoms, this document also includes cases with 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, and 1-3 carbon atoms.

[0098] As used herein, the term "alkyl" has the same meaning as commonly understood by those skilled in the art, referring to various saturated or unsaturated straight-chain, side-chain, or cyclic hydrocarbon groups. For example, the alkyl group referred to herein refers to a lower alkyl group with 1-10 carbon atoms; preferably a lower alkyl group with 1-8 carbon atoms; more preferably a lower alkyl group with 1-6 carbon atoms. In specific embodiments, the alkyl group referred to herein includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, etc. Similarly, the terms "alkenyl" or "alkynyl" as used herein refer to various unsaturated straight-chain, side-chain, or cyclic hydrocarbon groups containing carbon-carbon double or triple bonds.

[0099] As used herein, the terms "aryl" or "aromatic ring" have the same meaning as commonly understood by those skilled in the art, referring to a cyclic conjugated aromatic system; for example, the term "C6-C10 aryl" refers to an aromatic cyclic group with 6 to 10 carbon atoms that does not contain heteroatoms in the ring, such as phenyl or naphthyl. The term "heteroaryl," as used herein, refers to a cyclic conjugated aromatic system containing one or more heteroatoms such as N, O, or S in the ring; for example, pyridyl or pyrazinyl.

[0100] As used herein, the term "halogen" has the meaning commonly understood by one of ordinary skill in the art. In specific embodiments, halogen refers to fluorine, chlorine, bromine, or iodine.

[0101] The terms “L”, “Linker”, “connector”, or “joint” used in this article have the same meaning: they all refer to the linking group, including bonds, used to connect different parts to form the whole compound.

[0102] The term "ligand binding to E3 ubiquitin ligase" as used herein refers to ligands that bind directly or indirectly to E3 ubiquitin ligase, including but not limited to small molecule ligands. In specific embodiments, the ligand binding to E3 ubiquitin ligase is a ligand that links CRBN, VHL, or RNF126.

[0103] The term "hydrophobic tag" as used in this article refers to small molecules that are hydrophobic. These small molecules, when labeled onto proteins, can mimic the characteristics of misfolded proteins, thereby inducing protein degradation.

[0104] As used herein, the term "substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. A specific substituent may be a substituent described above or a specific substituent appearing in the various embodiments. Therefore, in this invention, the substituents in Formula 1 can each independently be the corresponding group in the specific compounds of the embodiments; that is, this invention includes combinations of the substituents in Formula 1 above, as well as combinations of some of the substituents shown in Formula 1 with other specific substituents appearing in the embodiments.

[0105] Unless otherwise specified, a substituted group may have a particular substituent at any substituted site on that group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocyclic groups, may be attached to another ring, such as a cycloalkyl group, thereby forming a spirobicyclic system, for example, where the two rings share a common carbon atom.

[0106] In particular, the various substituents defined above also include groups formed by further substitution of these substituents, which may also contain other groups. For example, the hydrogen atoms on alkyl and aryl groups are replaced by amino, halogen, or other groups to become groups belonging to the above definitions.

[0107] In a specific embodiment, "optionally substituted" means optionally substituted by one or more substituents selected from the following: cyano, halogen, hydroxyl, optionally substituted amino, nitro, carboxyl, ester, oxo, deuterated, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 Alkoxy, optional substituted C 1-3 Acyloxy group, optionally substituted C 5-10 Aryl or heteroaryl, optionally substituted 3-7 membered cycloalkyl or heterocyclic, optionally substituted sulfonyl, optionally substituted acyl.

[0108] The compounds of the present invention

[0109] To overcome the shortcomings of the prior art, the present invention provides pyrimidine derivatives, drug combinations thereof, and their applications that can be used for JNK-related diseases.

[0110] Therefore, the present invention provides a pyrimidine derivative, the structural formula of which is shown in Formula 1:

[0111]

[0112] In the compounds of this invention, JL is a ligand that binds to the target protein JNK, D is a ligand that binds to E3 ubiquitin ligase or a hydrophobic tag, and L is a linker that connects the two ligands. JL, D, and L are each as described above.

[0113] Based on the compounds of the present invention, the present invention also provides a pharmaceutical composition comprising the above-described compounds or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof or pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier.

[0114] Based on the teachings of this invention, those skilled in the art will understand that the compounds of this invention can be used to prepare JNK degrading agents, particularly JNK1 degrading agents. In specific embodiments, the JNK degrading agents of this invention are medicines for treating and / or preventing JNK-related diseases.

[0115] Those skilled in the art are familiar with specific JNK-related diseases, such as neurodegenerative diseases, diabetes, inflammatory diseases, central nervous system diseases, fibrosis, etc. This invention is particularly concerned with fibrosis, especially pulmonary fibrosis.

[0116] Based on the teachings of this invention, those skilled in the art can prepare the compounds of this invention into various dosage forms and determine the dosage, administration method, and administration time according to the actual situation of the patient to be treated, including but not limited to age, gender, disease severity, and previous treatment history. Furthermore, based on the teachings of this invention, those skilled in the art can understand that the compounds of this invention are compounds with therapeutic activity; in other words, the compounds of this invention have the potential to be used as drugs. Therefore, those skilled in the art can qualitatively and quantitatively detect various characteristics of the compounds of this invention as drugs using conventional techniques, including but not limited to therapeutic activity, toxicity, bioavailability, and drug-likeness. Performing these tests is obvious to those skilled in the art and requires no inventive effort.

[0117] Advantages of this invention:

[0118] 1. The compounds of this invention exhibit excellent JNK degradation activity;

[0119] 2. The compounds of this invention lay a new material foundation for the development of therapeutic drugs for JNK-related diseases.

[0120] The technical solution of the present invention is further described below with reference to specific implementation examples. However, the following implementation examples do not constitute a limitation on the present invention. All application methods based on the principles and technical means of the present invention are within the scope of the present invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0121] There are no particular restrictions on the source of any raw materials used in this invention; they can be purchased from the market or prepared using conventional methods known to those skilled in the art.

[0122] Example

[0123] Example 1. Preparation of compounds PA1-PA11, Y1-Y23, PM4, YM1, YM4 and YM19

[0124]

[0125] Synthesis of 4-((5-bromo-4-((2-carbamoylphenyl)amino)pyrimidin-2-yl)amino)benzoic acid: In a 100 mL round-bottom flask, 5-bromo-2,4-dichloropyrimidine (1 eq) and o-aminobenzoamide (1.2 eq) were weighed, dissolved in isopropanol, and then DIPEA (3 eq) was added. After stirring at room temperature, the mixture was refluxed at 90 °C overnight. After the reaction was complete as detected by TLC, the reaction solution was cooled to room temperature, and a solid precipitated. The residue was collected and washed with isopropanol. No further purification was required to obtain a pale yellow solid. This pale yellow solid (1 eq) and 4-aminobenzoic acid (2 eq) were weighed, and 20 mL of sec-butanol and 400 μL of TFA were added. The mixture was sealed and reacted overnight at 100 °C. A solid precipitated out. After cooling to room temperature, the filter residue was collected and washed with sec-butanol to obtain 4-((5-bromo-4-((2-carbamoylphenyl)amino)pyrimidin-2-yl)amino)benzoic acid.

[0126] 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (1 eq), a Boc-protected aliphatic amine (1.2 eq), and DIPEA (0.5 eq) were dissolved in DMF and reacted at 90 °C for 6 h. The reaction was quenched after TLC detection. The mixture was extracted three times (50 mL * 3) with ethyl acetate. The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the intermediate. The intermediate obtained in the first step was dissolved in dichloromethane, and trifluoroacetic acid (V...) was slowly added with stirring. DCM V TFA=10:3), react at room temperature for 30 min. After the reaction was complete as determined by TLC, the solvent was removed by rotary evaporation (dichloromethane was added several times for rotary evaporation) to obtain the intermediate of the second step, which was directly used in the next step. Take the intermediate obtained in the second step (1.3 eq) and 4-((5-bromo-4-((2-carbamoylphenyl)amino)pyrimidin-2-yl)amino)benzoic acid (1.0 eq) into a double-necked flask, evacuate under argon protection, dissolve in ultra-dry DMF, add DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF at room temperature with stirring, and stir the mixture overnight at room temperature. After the reaction was completed as determined by TLC, quench the reaction, extract three times with ethyl acetate (50 mL * 3), combine the organic phases, wash successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then precipitate by column chromatography to obtain the final product.

[0127] PA1: Yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.69(s,1H),11.13(s,1H),9.80(s,1H),8.72(d,J=8.4Hz,1H),8.50(t,J=5.8Hz,1H ),8.37(d,J=3.4Hz,2H),7.85(dd,J=7.9,1.6Hz,1H),7.79(s,5H),7.61–7.54(m,2H),7.20–7.11(m,2H),7.0 3(d,J=7.0Hz,1H),6.79(t,J=6.2Hz,1H),5.07(dd,J=12.9,5.4Hz,1H),3.33(s,4H),2.94–2.85(m,1H),2.58 (dd,J=20.0,6.5Hz,2H),2.04(dq,J=10.8,5.2,4.6Hz,1H),1.81(p,J=6.6Hz,2H).MS(ESI):m / z742.16[M+H] + .

[0128] PA2: Yellow solid. 1H NMR (400MHz, DMSO-d6) δ11.69(s,1H),11.12(s,1H),9.79(s,1H),8.71(d,J=8.5Hz,1H),8.42(t,J=5.7Hz,1H ),8.36(d,J=3.2Hz,2H),7.84(dd,J=8.0,1.6Hz,1H),7.79(d,J=6.2Hz,5H),7.56(qd,J=6.8,3.2Hz,2H),7.1 9–7.11(m,2H),7.02(d,J=7.0Hz,1H),6.60(t,J=6.0Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),3.36–3.28(m,4H) ,2.89(ddd,J=17.5,14.1,5.3Hz,1H),2.62–2.56(m,1H),2.09–1.96(m,2H),1.65–1.58(m,4H).MS(ESI):m / z 754.17[M+H] + .

[0129] PA3: Yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.69(s,1H),11.12(s,1H),9.78(s,1H),8.72(d,J=8.4Hz,1H),8.42–8.34(m,3H ),7.85(dd,J=7.9,1.6Hz,1H),7.79(s,1H),7.77(s,3H),7.17(t,J=7.6Hz,1H),7.11(d,J=8.6Hz,1H),7. 02(d,J=7.0Hz,1H),6.56(t,J=6.0Hz,1H),5.05(dd,J=12.9,5.4Hz,1H),3.28(dt,J=18.9,6.6Hz,4H),2. 62–2.55(m,2H),2.07–1.96(m,2H),1.59(dq,J=14.7,7.2Hz,4H),1.40(q,J=7.9,7.2Hz,2H).MS(ESI):m / z 768.19[M+H] + .

[0130] PA4: Yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 11.11 (s, 1H), 9.76 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.36 (s, 1H), 8.33–8.24 (m, 2H), 7.85–7.78 (m, 2H), 7.76 (s, 4H), 7.56 (td, J = 9.0, 6.9 Hz, 2H), 7.18 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.55 (s, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.27 (dd, J = 20.2, 5.8 Hz, 4H), 2.88 (ddd, J = 17.3, 14.0, 5.3 Hz, 2H), 2.06–1.99 (m, 2H), 1.62–1.52 (m, 4H), 1.40–1.34 (m, 4H). MS (ESI): m / z 782.21 [M+H] + 。

[0131] PA5: Yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 11.12 (s, 1H), 9.78 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 5.0 Hz, 3H), 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.79 (s, 1H), 7.77 (s, 4H), 7.60–7.53 (m, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.54 (t, J = 6.0 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.31–3.22 (m, 4H), 2.88 (ddd, J = 17.9, 13.9, 5.3 Hz, 2H), 2.05–1.96 (m, 2H), 1.54 (dd, J = 18.0, 11.1 Hz, 4H), 1.37–1.31 (m, 6H). MS (ESI): m / z 796.22 [M+H] + 。

[0132] PA6: Yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 11.12 (s, 1H), 9.78 (s, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.36 (d, J = 3.5 Hz, 3H), 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.79 (s, 1H), 7.77 (s, 4H), 7.56 (dt, J = 8.5, 6.8 Hz, 2H), 7.17 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.53 (t, J = 6.0 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.27 (dt, J = 18.3, 6.8 Hz, 4H), 2.88 (ddd, J = 17.4, 14.1, 5.5 Hz, 1H), 2.58 (d, J = 17.8 Hz, 2H), 2.05–1.99 (m, 1H), 1.54 (dt, J = 21.4, 6.6 Hz, 4H), 1.31 (d, J = 3.9 Hz, 6H), 1.23 (s, 2H). MS (ESI): m / z 810.24 [M+H] + 。

[0133] PA7: Yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 11.12 (s, 1H), 9.78 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 6.2 Hz, 3H), 7.85 (dd, J = 7.9, 1.6 Hz, 1H), 7.79 (s, 1H), 7.77 (s, 4H), 7.56 (ddd, J = 8.5, 7.0, 5.2 Hz, 2H), 7.20–7.14 (m, 1H), 7.07 (d, J = 8.7 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.52 (t, J = 6.0 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 3.24 (dt, J = 13.5, 6.7 Hz, 4H), 2.89 (ddd, J = 16.6, 13.7, 5.1 Hz, 1H), 2.62–2.56 (m, 1H), 2.08–1.94 (m, 2H), 1.53 (dt, J = 16.8, 6.8 Hz, 4H), 1.30–1.26 (m, 9H), 1.23 (s, 2H). MS (ESI): m / z 840.27 [M+H] + 。

[0134] PA8: Yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 11.12 (s, 1H), 9.78 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 6.3 Hz, 3H), 7.85 (dd, J = 7.9, 1.6 Hz, 1H), 7.79 (s, 1H), 7.77 (s, 4H), 7.56 (dt, J = 8.5, 6.8 Hz, 2H), 7.19–7.14 (m, 1H), 7.07 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.52 (t, J = 6.0 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.25 (dq, J = 13.6, 6.6 Hz, 4H), 2.89 (ddd, J = 17.1, 14.2, 5.4 Hz, 1H), 2.58 (d, J = 17.9 Hz, 1H), 2.01 (dt, J = 16.1, 6.4 Hz, 2H), 1.53 (dt, J = 16.8, 6.9 Hz, 4H), 1.28 (s, 4H), 1.25–1.22 (m, 11H). MS (ESI): m / z 868.30 [M+H] + 。

[0135] PA9: Yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 11.12 (s, 1H), 9.79 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.44 (t, J = 5.6 Hz, 1H), 8.36 (s, 2H), 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.79 (s, 1H), 7.77 (s, 4H), 7.56 (qd, J = 6.6, 3.0 Hz, 2H), 7.16 (dt, J = 7.7, 3.3 Hz, 2H), 7.03 (d, J = 7.1 Hz, 1H), 6.64 (t, J = 5.8 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.65 (t, J = 5.4 Hz, 2H), 3.58 (t, J = 6.1 Hz, 2H), 3.49 (q, J = 5.5 Hz, 2H), 3.44 (t, J = 5.8 Hz, 2H), 2.88 (ddd, J = 17.0, 13.9, 5.5 Hz, 1H), 2.60 (s, 1H), 2.01 (ddd, J = 11.8, 7.3, 3.6 Hz, 2H). MS (ESI): m / z 770.17 [M+H] + 。

[0136] PA10: Yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 11.11 (s, 1H), 9.76 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 8.35–8.30 (m, 2H), 7.84–7.78 (m, 2H), 7.76 (s, 4H), 7.55 (dd, J = 8.6, 7.1 Hz, 2H), 7.17 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.61 (d, J = 5.9 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 3.58 (ddt, J = 18.2, 15.8, 5.7 Hz, 10H), 3.44 (m, 2H), 2.58 (d, J = 16.5 Hz, 2H), 2.01 (ddt, J = 12.0, 9.5, 4.4 Hz, 2H). MS (ESI): m / z 814.19 [M+H] + 。

[0137] PA11: Yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 11.12 (s, 1H), 9.79 (s, 1H), 8.70 (d, J = 8.5 Hz, 1H), 8.42 (t, J = 5.7 Hz, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 7.84 (dd, J = 7.9, 1.6 Hz, 1H), 7.78 (d, J = 4.3 Hz, 5H), 7.56 (ddd, J = 9.4, 7.2, 2.2 Hz, 2H), 7.19–7.14 (m, 1H), 7.11 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.59 (t, J = 5.8 Hz, 1H), 5.06 (dd, J = 12.9, 5.3 Hz, 1H), 3.59 (t, J = 5.4 Hz, 2H), 3.55–3.50 (m, 9H), 3.43 (q, J = 8.0, 6.7 Hz, 5H), 2.94–2.83 (m, 1H), 2.56 (s, 1H), 2.00 (d, J = 7.4 Hz, 2H). MS (ESI): m / z 858.22 [M+H] + 。

[0138] Y1: Yellow solid. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),11.11(s,1H),9.73(s,1H),8.69(d,J =8.4Hz,1H),8.34(s,1H),8.30(s,1H),7.83–7.71(m,5H),7.57–7.51(m,1H) ,7.42–7.35(m,4H),7.19–7.13(m,1H),5.12(dd,J=12.8,5.4Hz,1H),3.72(s ,4H),2.94–2.82(m,1H),2.64–2.52(m,2H),2.07–1.99(m,1H).MS(ESI):m / z 754.16[M+H] + .

[0139] Y2: Yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),11.10(s,1H),9.73(s,1H),8.69(d,J=7.4Hz,1H),8.34(s ,1H),8.30(s,1H),7.76(ddd,J=24.3,14.9,7.8Hz,5H),7.53(t,J=7.8Hz,1H),7.36(dd,J=17.7, 7.9Hz,4H),7.16(t,J=7.6Hz,1H),5.11(d,J=12.2Hz,1H),4.18(s,1H),3.46(d,J=12.4Hz,2H), 2.86(d,J=15.0Hz,1H),2.59(d,J=17.9Hz,2H),2.03(s,1H),1.24(d,J=8.6Hz,3H).MS(ESI):m / z 766.17[M+H] + .

[0140] Y3: Yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 11.10 (s, 1H), 9.70 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 7.81 (dd, J = 8.0, 1.6 Hz, 1H), 7.75 (d, J = 8.2 Hz, 3H), 7.60 (dd, J = 8.6, 7.1 Hz, 1H), 7.55–7.49 (m, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.18–7.13 (m, 1H), 7.11 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.80 (s, 1H), 5.07 (dd, J = 13.0, 5.4 Hz, 1H), 3.48 (d, J = 43.8 Hz, 4H), 3.40 (d, J = 5.9 Hz, 2H), 2.94–2.82 (m, 1H), 2.69–2.54 (m, 4H), 2.07–1.99 (m, 1H). MS (ESI): m / z 797.20 [M+H] + .

[0141] Y4: Yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 11.10 (s, 1H), 9.77 (s, 1H), 8.70 (d, J = 8.5 Hz, 1H), 8.39–8.24 (m, 3H), 7.85–7.74 (m, 6H), 7.71 (t, J = 7.8 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.36 (dd, J = 7.8, 5.3 Hz, 2H), 7.16 (t, J = 7.6 Hz, 1H), 5.10 (dd, J = 12.9, 5.4 Hz, 1H), 3.43 (d, J = 6.2 Hz, 2H), 3.32 (s, 4H), 2.94–2.80 (m, 1H), 2.71–2.52 (m, 8H), 2.02 (dd, J = 13.0, 7.2 Hz, 1H). MS (ESI): m / z 797.20 [M+H] + .

[0142] Y5: Yellow solid. 1H NMR (400MHz, DMSO-d6) δ11.63(s,1H),11.10(s,1H),9.73(s,1H),8.69(d,J=8.4Hz,1H),8 .34(s,1H),8.30(s,1H),7.76(ddd,J=23.7,15.0,7.8Hz,5H),7.53(t,J=7.8Hz,1H),7.37 (dt,J=14.3,6.0Hz,4H),7.20–7.12(m,1H),5.15–5.07(m,1H),4.18(s,1H),2.86(d,J=15 .0Hz,1H),2.59(d,J=18.2Hz,2H),2.01(d,J=17.5Hz,1H),1.25–1.22(m,3H).MS(ESI):m / z 766.17[M+H] + .

[0143] Y6: Yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),11.01(s,1H),9.66(s,1H),8.67(d,J=8.4Hz,1 H),8.34(s,1H),8.30(s,1H),7.82(d,J=7.8Hz,1H),7.80–7.53(m,5H),7.53–7.47(m ,1H),7.21–7.12(m,2H),6.85(s,1H),5.02(d,J=65.4Hz,1H),3.79(d,J=35.7Hz,4H) ,3.48(s,4H),2.57(s,1H),2.32(s,1H),2.20–1.59(m,4H).MS(ESI):m / z766.17[M+H] + .

[0144] Y7: Yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 11.11 (s, 1H), 9.71 (s, 1H), 8.68 (d, J = 8.3 Hz, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.59 (dd, J = 8.5, 7.1 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 8.3 Hz, 2H), 7.14 (t, J = 8.1 Hz, 2H), 7.02 (d, J = 7.0 Hz, 1H), 6.82 (d, J = 6.4 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.55 (s, 4H), 3.38 (d, J = 6.1 Hz, 2H), 2.95–2.83 (m, 1H), 2.62–2.52 (m, 2H), 2.41 (d, J = 7.1 Hz, 6H), 2.07–1.98 (m, 1H), 1.80–1.72 (m, 2H). MS (ESI): m / z 809.22 [M+H] + 。

[0145] Y8: Yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 11.10 (s, 1H), 9.76 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 5.4 Hz, 2H), 8.31 (s, 1H), 7.82 (dd, J = 7.9, 1.5 Hz, 1H), 7.77 (s, 4H), 7.70 (t, J = 7.8 Hz, 1H), 7.58–7.52 (m, 1H), 7.35 (dd, J = 9.9, 7.7 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 5.10 (dd, J = 12.9, 5.4 Hz, 1H), 3.32 (s, 5H), 2.93–2.82 (m, 1H), 2.59 (d, J = 17.8 Hz, 5H), 2.46 (s, 2H), 2.06–1.98 (m, 1H), 1.79–1.70 (m, 2H). MS (ESI): m / z 809.22 [M+H] + 。

[0146] Y9: Yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 11.10 (s, 1H), 9.71 (s, 1H), 8.68 (d, J = 8.3 Hz, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.86–7.67 (m, 4H), 7.55 (dt, J = 28.5, 7.9 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 7.19–7.09 (m, 2H), 7.02 (d, J = 7.1 Hz, 1H), 6.57 (s, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.50 (s, 4H), 2.88 (t, J = 14.4 Hz, 1H), 2.58 (d, J = 17.8 Hz, 2H), 2.37 (s, 6H), 2.01 (d, J = 12.1 Hz, 1H), 1.56 (d, J = 28.5 Hz, 4H). MS (ESI): m / z 823.23 [M+H] + 。

[0147] Y10: Yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 11.10 (s, 1H), 9.75 (s, 1H), 8.70 (d, J = 8.6 Hz, 1H), 8.35 (s, 1H), 8.31 (s, 2H), 7.82 (d, J = 7.5 Hz, 1H), 7.76 (s, 4H), 7.70 (t, J = 7.8 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.34 (t, J = 8.4 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 5.09 (dd, J = 12.8, 5.3 Hz, 1H), 3.29 (s, 6H), 2.85 (d, J = 12.6 Hz, 1H), 2.58 (d, J = 18.2 Hz, 6H), 2.37 (s, 2H), 2.02 (s, 1H), 1.54 (s, 4H). MS (ESI): m / z 823.23 [M+H] + 。

[0148] Y11: Yellow solid. 1H NMR (400MHz, DMSO-d6) δ11.66(s,1H),11.10(s,1H),9.76(s,1H),8.70(d,J=8.6Hz,1H),8.36( s,1H),8.31(s,2H),7.77(s,6H),7.68(t,J=7.7Hz,1H),7.55(t,J=7.8Hz,1H),7.33(t,J=8.1H z,2H),7.17(t,J=7.5Hz,1H),5.09(dd,J=13.0,5.4Hz,1H),3.70(d,J=11.5Hz,2H),2.94–2.81 (m,3H),2.61(s,2H),2.02(d,J=13.0Hz,1H),1.84(d,J=12.1Hz,2H),1.54(s,3H).MS(ESI):m / z 794.21[M+H] + .

[0149] Y12: Yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),11.10(s,1H),9.77(s,1H),8.70(d,J=8.5Hz,1H),8.36( s,1H),8.31(s,1H),7.83(d,J=7.4Hz,2H),7.77(s,5H),7.57(dt,J=19.4,7.9Hz,2H),7.17(t,J =7.4Hz,1H),7.11(d,J=8.3Hz,1H),7.04(d,J=7.0Hz,1H),5.07(dd,J=13.0,5.4Hz,1H),3.39( s,4H),2.87(d,J=13.2Hz,1H),2.59(d,J=15.3Hz,3H),2.00(q,J=6.8,6.3Hz,4H).MS(ESI):m / z 838.24[M+H] + .

[0150] Y13: Yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 11.10 (s, 1H), 9.76 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 7.82 (dd, J = 7.9, 1.6 Hz, 1H), 7.76 (d, J = 1.8 Hz, 5H), 7.61–7.52 (m, 2H), 7.20–7.15 (m, 1H), 7.13 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.77 (s, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 3.56 (qd, J = 6.1, 4.5 Hz, 2H), 3.26 (dt, J = 11.1, 5.6 Hz, 2H), 3.15 (dt, J = 10.6, 5.9 Hz, 2H), 2.95–2.83 (m, 1H), 2.61 (s, 2H), 2.36 (s, 10H), 2.02 (dd, J = 13.2, 6.4 Hz, 1H). MS (ESI): m / z 854.26 [M+H] + .

[0151] Y14: Yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 11.10 (s, 1H), 9.73 (s, 1H), 8.72 (d, J = 8.5 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.10 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 17.8 Hz, 6H), 7.63–7.58 (m, 1H), 7.57–7.52 (m, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.05 (d, J = 7.0 Hz, 1H), 6.22 (d, J = 8.3 Hz, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 3.81 (s, 1H), 3.57 (d, J = 10.5 Hz, 1H), 2.94–2.82 (m, 1H), 2.64–2.54 (m, 2H), 2.11–1.87 (m, 5H), 1.49 (dt, J = 37.8, 12.2 Hz, 4H). MS (ESI): m / z 780.19 [M+H] + .

[0152] Y15: Yellow solid. 1H NMR (400MHz, DMSO-d6) δ11.68(s,1H),11.10(s,1H),9.72(s,1H),8.73(d,J=8.4Hz,1H),8.35(s,1H),8.30(s,1 H),8.14(d,J=7.7Hz,1H),7.84–7.74(m,6H),7.61(dd,J=8.6,7.1Hz,1H),7.55(ddd,J=8.6,7.2,1.5Hz,1H),7.2 0–7.14(m,2H),7.06(d,J=7.1Hz,1H),6.50(d,J=7.8Hz,1H),5.07(dd,J=12.9,5.4Hz,1H),3.97(s,1H),3.84(s, 1H),2.89(ddd,J=17.4,14.1,5.5Hz,1H),2.65–2.54(m,2H),2.09–2.00(m,1H),1.89–1.62(m,8H).MS(ESI):m / z 780.19[M+H] + .

[0153] Y16: Yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.67(s,1H),11.11(s,1H),9.76(s,1H),8.70(d,J=8.4Hz,1H),8.35(s,1H) ,8.31(s,1H),7.83(dd,J=7.9,1.7Hz,1H),7.77(s,5H),7.61–7.52(m,2H),7.20–7.14(m,1H),7.12( d,J=8.6Hz,1H),7.02(d,J=7.0Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),3.27(d,J=16.1Hz,4H),2.97–2 .81(m,2H),2.69–2.52(m,4H),2.37(s,8H),2.02(dd,J=14.3,7.5Hz,2H),1.72(s,4H).MS(ESI):m / z 866.27[M+H] + .

[0154] Y17: Yellow solid. 1H NMR (400MHz, DMSO-d6) δ11.66(s,1H),11.11(s,1H),9.80(s,1H),8.70(d,J=8.4Hz,1H),8.36(s,1H),8.32 (s,1H),7.84–7.75(m,4H),7.71(dd,J=8.4,7.2Hz,1H),7.61–7.52(m,3H),7.36(t,J=7.5Hz,2H),7.20–7.1 4(m,1H),5.09(dd,J=12.8,5.4Hz,1H),4.39(s,1H),4.20(s,1H),4.07(d,J=8.8Hz,1H),3.91(s,1H),3.43– 3.36(m,4H),3.22(s,1H),2.93–2.82(m,1H),2.63–2.52(m,6H),2.02(dd,J=12.9,6.4Hz,1H).MS(ESI):m / z 809.20[M+H] + .

[0155] Y18: Yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),11.10(s,1H),9.71(s,1H),8.70(d,J=8.5Hz,1H),8.34( s,1H),8.29(s,1H),7.82(dd,J=7.9,1.6Hz,1H),7.77(d,J=8.2Hz,4H),7.56–7.50(m,1H),7.4 2(dd,J=15.2,7.8Hz,2H),7.35(d,J=8.3Hz,2H),7.16(t,J=7.3Hz,1H),5.11(dd,J=12.7,5.5H z,1H),2.94–2.83(m,3H),2.68–2.52(m,4H),2.04(d,J=13.0Hz,3H),1.59(s,2H).MS(ESI):m / z 835.23[M+H] + .

[0156] Y19: Yellow solid. 1H NMR (400MHz, DMSO-d6) δ11.67(s,1H),11.12(s,1H),9.72(s,1H),8.71(d,J=8.9Hz,1H),8.34(s, 1H),8.31(s,1H),7.85–7.73(m,6H),7.55–7.41(m,3H),7.32(d,J=8.3Hz,2H),7.16(t,J=7.8Hz, 1H),5.12(dd,J=12.7,5.5Hz,1H),3.85(s,2H),3.69(s,2H),2.94–2.85(m,1H),2.61(d,J=17.7H z,2H),2.18(s,1H),2.09–2.01(m,1H),1.80(s,2H),1.19(dd,J=17.6,10.4Hz,2H).MS(ESI):m / z 851.25[M+H] + .

[0157] Y20: Yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),11.08(s,1H),9.71(s,1H),8.69(d,J=8.5Hz,1H),8.34(s,1H),8.30(s,1H), 7.81(dd,J=7.9,1.6Hz,1H),7.75(d,J=8.6Hz,3H),7.58(dd,J=8.5,7.0Hz,1H),7.55–7.50(m,1H),7.32(d,J=8.6H z,2H),7.18–7.11(m,2H),6.81(d,J=8.6Hz,1H),5.05(dd,J=12.7,5.4Hz,1H),4.28(s,2H),4.00(s,2H),3.27(t,J =6.1Hz,1H),2.87(ddd,J=18.6,15.2,5.3Hz,1H),2.62–2.52(m,2H),2.39(s,4H),2.04–1.96(m,1H).MS(ESI):m / z 809.20[M+H] + .

[0158] Y21: Yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 11.09 (s, 1H), 9.70 (s, 1H), 8.69 (d, J = 8.5 Hz, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 7.81 (dd, J = 7.8, 1.6 Hz, 1H), 7.75 (d, J = 8.4 Hz, 3H), 7.70–7.65 (m, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.36–7.29 (m, 4H), 7.15 (t, J = 7.6 Hz, 1H), 5.09 (dd, J = 12.8, 5.4 Hz, 1H), 3.75 (d, J = 11.5 Hz, 2H), 3.51 (s, 4H), 2.93–2.83 (m, 3H), 2.64–2.53 (m, 5H), 2.46 (s, 2H), 2.06–1.99 (m, 1H), 1.87 (d, J = 12.0 Hz, 2H), 1.65 (d, J = 12.2 Hz, 2H). MS (ESI): m / z 835.23 [M+H] + 。

[0159] Y22: Yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 11.09 (s, 1H), 9.70 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 7.85–7.79 (m, 1H), 7.75 (d, J = 8.0 Hz, 3H), 7.67 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.32 (dd, J = 8.1, 5.3 Hz, 4H), 7.16 (t, J = 7.6 Hz, 1H), 5.09 (dd, J = 12.8, 5.4 Hz, 1H), 3.69 (d, J = 11.5 Hz, 2H), 3.52 (s, 4H), 2.87 (t, J = 11.0 Hz, 3H), 2.63–2.52 (m, 2H), 2.40 (s, 4H), 2.23 (d, J = 6.9 Hz, 2H), 2.06–1.98 (m, 1H), 1.83 (d, J = 12.5 Hz, 2H), 1.73 (s, 1H). MS (ESI): m / z 851.25 [M+H] + 。

[0160] Y23: Yellow solid. 1H NMR (400MHz, DMSO-d6) δ11.63(s,1H),11.08(s,1H),9.69(s,1H),8.69(d,J=8.4Hz,1H),8.33( s,1H),8.29(s,1H),7.84–7.79(m,1H),7.74(d,J=8.4Hz,3H),7.68(t,J=7.8Hz,1H),7.52(t,J= 8.0Hz,1H),7.33(dd,J=12.1,8.2Hz,4H),7.15(t,J=7.6Hz,1H),5.09(dd,J=12.9,5.4Hz,1H),2 .94–2.82(m,1H),2.64–2.52(m,2H),2.08–2.00(m,1H),1.69(s,4H),1.53(s,4H).MS(ESI):m / z 820.22[M+H] + .

[0161] PM4: Yellow solid. 1 H NMR(400MHz,DMSO-d6)δ11.66(s,1H),11.05(s,1H),9.73(s,1H),8.70(d,J=8.4Hz,1H),8 .35(s,1H),8.30(d,J=5.9Hz,2H),7.82(d,J=7.8Hz,1H),7.76(s,5H),7.54(t,J=8.5Hz,2H ),7.20–7.11(m,2H),6.96(s,1H),6.91–6.83(m,1H),5.02(dd,J=12.9,5.3Hz,1H),3.25– 3.14(m,3H),2.93–2.81(m,1H),2.59(s,2H),2.04–1.94(m,2H),1.63(s,4H).MS(ESI):m / z 754.17[M+H] + .

[0162] YM1: Yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 11.08 (s, 1H), 9.73 (s, 1H), 8.70 (d, J = 8.5 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 7.82 (dd, J = 7.9, 1.6 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.75 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.57–7.52 (m, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 8.7, 2.3 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 3.68 (s, 4H), 3.56 (s, 4H), 2.94–2.84 (m, 1H), 2.63–2.53 (m, 2H), 2.07–1.98 (m, 1H). MS (ESI): m / z 752.16 [M+H] + 。

[0163] YM4: Yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 11.08 (s, 1H), 9.75 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 8.29 (d, J = 8.5 Hz, 2H), 7.82 (dd, J = 7.9, 1.5 Hz, 1H), 7.77 (s, 5H), 7.68 (d, J = 8.5 Hz, 1H), 7.55 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.27 (dd, J = 8.7, 2.3 Hz, 1H), 7.19–7.13 (m, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 3.44 (d, J = 12.8 Hz, 6H), 2.89 (ddd, J = 17.2, 13.8, 5.4 Hz, 1H), 2.57 (d, J = 24.0 Hz, 8H), 2.06–1.98 (m, 1H). MS (ESI): m / z 797.20 [M+H] + 。

[0164] YM19: Yellow solid. 1H NMR (400MHz, DMSO-d6) δ11.62(s,1H),11.08(s,1H),9.68(s,1H),8.69(d,J=8.4Hz,1H),8.33(s,1H),8.29(s,1H ),7.81(dd,J=7.9,1.6Hz,1H),7.73(d,J=8.8Hz,3H),7.68(d,J=8.5Hz,1H),7.54–7.48(m,1H),7.34(d,J=2.2Hz, 1H),7.30(d,J=8.4Hz,2H),7.27–7.23(m,1H),7.18–7.12(m,1H),5.07(dd,J=12.9,5.4Hz,1H),3.44(s,4H),2.8 7(d,J=12.8Hz,1H),2.58(d,J=23.8Hz,2H),2.22(s,2H),2.05–1.98(m,1H),1.81(d,J=37.3Hz,3H).MS(ESI):m / z 851.25[M+H] + .

[0165] Example 2. Preparation of compounds PB1-PB10 and V1-V4

[0166]

[0167] Take different amino acids (1.0 eq), di-tert-butyl dicarbonate (1.1 eq), and triethylamine (2.0 eq), and add them to a mixed solvent of acetone and water (V). 丙酮 V 水=1.5:1), and the reaction was stirred at room temperature for 4-8 h. After the reaction was completed by TLC, the reaction was quenched, the organic solvent was removed by rotary evaporation, 10 mL of water was added, and the aqueous layer was acidified with hydrochloric acid to pH 4-5. A large amount of solid precipitated out. The mixture was filtered, the filter cake was washed with water and dried. No further optimization was required to obtain the intermediate. The intermediate obtained in the first step (1.2 eq) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (1 eq) were placed in a double-necked flask, evacuated, and protected with argon. The mixture was dissolved in ultra-dry DMF, and DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF were added under stirring at room temperature. The mixture was stirred at room temperature and reacted overnight. After TLC detection, the reaction was quenched, and the mixture was extracted three times (50 mL x 3) with dichloromethane. The combined organic phases were washed with saturated brine (50 mL), and the combined organic layers were washed sequentially with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the intermediate. The intermediate was further reacted (same as in Example 1) to obtain the final product.

[0168] PB1: White solid. 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),9.75(s,1H),8.99(s,1H),8.70(s,1H),8.46–8.24(m,4H),7.87(dd,J= 38.9,8.4Hz,2H),7.77(s,5H),7.56(t,J=7.9Hz,1H),7.48–7.35(m,4H),7.18(t,J=7.5Hz,1H),5.17–5.08(m ,1H),4.92(s,1H),4.58–4.51(m,1H),4.43(s,1H),4.29(s,1H),3.62(s,2H),3.24(s,2H),2.46(s,3H),2.32 (s,1H),2.22(s,1H),2.12(s,1H),1.99(s,1H),1.76(s,2H),1.37(d,J=6.9Hz,3H),0.95(s,9H).MS(ESI):m / z 941.30[M+H] + .

[0169] PB2: Light green solid. 11H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 9.79 (s, 1H), 8.99 (s, 1H), 8.72 (d, J = 8.8 Hz, 1H), 8.45 (d, J = 7.8 Hz, 1H), 8.40–8.34 (m, 3H), 7.88–7.83 (m, 2H), 7.79 (s, 1H), 7.78 (s, 4H), 7.59–7.54 (m, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.20–7.15 (m, 1H), 5.19 (d, J = 3.5 Hz, 1H), 4.92 (q, J = 7.0 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.61 (d, J = 3.5 Hz, 2H), 3.24 (d, J = 6.2 Hz, 2H), 2.46 (s, 3H), 2.36–2.26 (m, 1H), 2.16 (dd, J = 13.9, 7.5 Hz, 1H), 2.04 (d, J = 11.2 Hz, 1H), 1.78 (ddd, J = 12.8, 8.5, 4.6 Hz, 1H), 1.52 (s, 4H), 1.37 (d, J = 7.0 Hz, 3H), 0.94 (s, 9H). MS (ESI): m / z 955.31 [M+H] + .

[0170] PB3: White solid. 11H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 9.76 (s, 1H), 8.99 (s, 1H), 8.70 (d, J = 8.1 Hz, 1H), 8.45–8.24 (m, 4H), 7.90–7.70 (m, 7H), 7.55 (t, J = 7.9 Hz, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H), 5.13 (d, J = 3.5 Hz, 1H), 4.91 (d, J = 7.4 Hz, 1H), 4.52 (d, J = 9.4 Hz, 1H), 4.42 (t, J = 8.2 Hz, 1H), 4.28 (s, 1H), 3.61 (s, 2H), 3.28–3.19 (m, 2H), 2.46 (s, 3H), 2.30–2.21 (m, 1H), 2.15 (q, J = 7.2 Hz, 1H), 2.00 (d, J = 8.2 Hz, 1H), 1.80 (d, J = 11.9 Hz, 1H), 1.52 (p, J = 7.7 Hz, 4H), 1.37 (d, J = 6.9 Hz, 3H), 1.31–1.25 (m, 2H), 0.93 (s, 9H). MS (ESI): m / z 969.33 [M+H] + .

[0171] PB4: White solid. 11H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 9.76 (s, 1H), 8.99 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.40 (d, J = 7.7 Hz, 1H), 8.35 (s, 1H), 8.30 (dd, J = 12.7, 6.4 Hz, 2H), 7.80 (d, J = 30.5 Hz, 7H), 7.55 (t, J = 8.1 Hz, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.17 (t, J = 7.5 Hz, 1H), 5.12 (d, J = 3.5 Hz, 1H), 4.91 (t, J = 7.2 Hz, 1H), 4.52 (d, J = 9.4 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.60 (s, 2H), 3.24 (d, J = 6.6 Hz, 2H), 2.45 (s, 3H), 2.28–2.21 (m, 1H), 2.11 (dt, J = 13.9, 7.3 Hz, 1H), 2.02 (d, J = 13.0 Hz, 1H), 1.80 (d, J = 11.3 Hz, 1H), 1.49 (d, J = 12.4 Hz, 4H), 1.37 (d, J = 6.9 Hz, 3H), 1.27 (d, J = 14.6 Hz, 6H), 0.93 (s, 9H). MS (ESI): m / z 997.36 [M+H] + 。

[0172] PB5: White solid. 11H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 9.74 (s, 1H), 8.98 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.41–8.33 (m, 2H), 8.28 (dd, J = 13.3, 7.9 Hz, 2H), 7.86–7.79 (m, 2H), 7.78 (s, 1H), 7.76 (s, 4H), 7.55 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.17 (t, J = 7.6 Hz, 1H), 5.11 (d, J = 3.5 Hz, 1H), 4.91 (t, J = 7.3 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.61 (d, J = 3.7 Hz, 2H), 3.23 (t, J = 6.7 Hz, 2H), 2.45 (s, 3H), 2.28–2.20 (m, 1H), 2.10 (dt, J = 13.9, 7.1 Hz, 1H), 2.01 (dd, J = 12.5, 7.9 Hz, 1H), 1.83–1.75 (m, 1H), 1.48 (d, J = 20.2 Hz, 4H), 1.37 (d, J = 7.0 Hz, 3H), 1.29–1.22 (m, 10H), 0.93 (s, 9H). MS (ESI): m / z 1025.39 [M+H] + 。

[0173] PB6: White solid. 11H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 9.75 (s, 1H), 8.98 (s, 1H), 8.71 (d, J = 8.6 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.36–8.29 (m, 3H), 7.86–7.78 (m, 3H), 7.76 (s, 4H), 7.55 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.17 (t, J = 7.5 Hz, 1H), 5.14 (d, J = 3.6 Hz, 1H), 4.91 (t, J = 7.3 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.60 (d, J = 3.8 Hz, 2H), 3.23 (d, J = 6.9 Hz, 2H), 2.45 (s, 3H), 2.25 (dt, J = 14.7, 7.5 Hz, 1H), 2.11 (q, J = 6.9 Hz, 1H), 2.02 (t, J = 10.7 Hz, 1H), 1.83–1.75 (m, 1H), 1.48 (d, J = 20.8 Hz, 4H), 1.37 (d, J = 6.9 Hz, 3H), 1.31–1.28 (m, 3H), 1.24 (d, J = 6.9 Hz, 9H), 0.93 (s, 9H). MS (ESI): m / z 1039.41 [M+H] + 。

[0174] PB7: White solid. 11H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.73 (s, 1H), 8.98 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 10.0 Hz, 2H), 8.30 (s, 1H), 8.26 (d, J = 5.8 Hz, 1H), 7.84–7.74 (m, 7H), 7.54 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.19–7.14 (m, 1H), 5.09 (d, J = 3.6 Hz, 1H), 4.96–4.87 (m, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.1 Hz, 1H), 4.27 (s, 1H), 3.60 (s, 2H), 3.22 (t, J = 6.8 Hz, 2H), 2.45 (s, 3H), 2.24 (dt, J = 14.5, 7.6 Hz, 1H), 2.10 (q, J = 7.1 Hz, 1H), 2.00 (t, J = 10.9 Hz, 1H), 1.83–1.76 (m, 1H), 1.49 (d, J = 13.1 Hz, 4H), 1.37 (d, J = 7.0 Hz, 3H), 1.28 (s, 4H), 1.26–1.22 (m, 10H), 0.93 (s, 9H). MS (ESI): m / z 1053.42 [M+H] + .

[0175] PB8: White solid. 11H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 9.76 (s, 1H), 8.98 (s, 1H), 8.70 (d, J = 8.5 Hz, 1H), 8.42–8.34 (m, 3H), 8.31 (s, 1H), 7.88 (d, J = 9.3 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.78 (s, 5H), 7.55 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 7.9 Hz, 2H), 7.17 (t, J = 7.6 Hz, 1H), 5.12 (d, J = 3.5 Hz, 1H), 4.90 (q, J = 7.3 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.1 Hz, 1H), 4.28 (s, 1H), 3.68–3.45 (m, 12H), 2.45 (s, 3H), 2.35 (dd, J = 14.2, 6.4 Hz, 1H), 2.02 (t, J = 10.9 Hz, 1H), 1.79 (ddd, J = 13.3, 9.1, 4.9 Hz, 1H), 1.37 (d, J = 7.0 Hz, 3H), 1.30 (s, 1H), 0.93 (s, 9H). MS (ESI): m / z 1015.33 [M+H] + .

[0176] PB9: White solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 9.76 (s, 1H), 8.98 (s, 1H), 8.70 (d, J = 8.5 Hz, 1H), 8.41–8.30 (m, 4H), 7.85 (dd, J = 19.6, 8.5 Hz, 2H), 7.77 (s, 5H), 7.55 (t, J = 7.9 Hz, 1H), 7.45–7.35 (m, 4H), 7.17 (t, J = 7.4 Hz, 1H), 5.12 (d, J = 3.5 Hz, 1H), 4.95–4.87 (m, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.59 (t, J = 6.9 Hz, 4H), 3.57–3.52 (m, 6H), 3.52–3.44 (m, 10H), 2.45 (s, 3H), 2.34 (dt, J = 12.9, 6.1 Hz, 1H), 2.00 (d, J = 8.2 Hz, 1H), 1.83–1.76 (m, 1H), 1.37 (d, J = 7.0 Hz, 3H), 1.24 (s, 1H), 0.93 (s, 9H). MS (ESI): m / z 1103.38 [M+H]+ .

[0177] PB10: White solid. 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),9.73(s,1H),8.98(s,1H),8.70(d,J=8.7Hz, 1H),8.39–8.35(m,1H),8.35(s,1H),8.30(s,1H),8.26(t,J=5.6Hz,1H),7.85–7.80 (m,2H),7.78(d,J=9.3Hz,1H),7.76(s,4H),7.54(ddd,J=8.6,7.3,1.5Hz,1H),7.45 –7.35(m,4H),7.19–7.14(m,1H),5.09(d,J=3.5Hz,1H),4.91(t,J=7.2Hz,1H),4.52 (d,J=9.3Hz,1H),4.42(t,J=8.0Hz,1H),4.28(s,1H),3.61(d,J=4.1Hz,2H),3.23(q ,J=6.6Hz,2H),2.45(s,3H),2.25(dt,J=14.7,7.6Hz,1H),2.11(dt,J=14.0,7.2Hz, 1H),2.01(t,J=10.0Hz,1H),1.79(ddd,J=12.9,8.4,4.6Hz,1H),1.49(dt,J=15.3,6 .4Hz,4H),1.37(d,J=7.0Hz,3H),1.26(d,J=10.3Hz,8H),0.93(s,9H).MS(ESI):m / z 1009.38[M+H] + .

[0178] V1: White solid. 11H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 9.70 (s, 1H), 8.98 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.43 (d, J = 7.7 Hz, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 7.81 (dd, J = 7.7, 1.5 Hz, 1H), 7.78–7.72 (m, 4H), 7.52 (t, J = 7.5 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.15 (t, J = 7.6 Hz, 1H), 5.12 (d, J = 3.4 Hz, 1H), 4.89 (q, J = 7.4 Hz, 1H), 4.51 (d, J = 9.6 Hz, 1H), 4.44 (t, J = 8.2 Hz, 1H), 4.28 (s, 1H), 3.56 (d, J = 11.1 Hz, 6H), 3.15–2.99 (m, 2H), 2.45 (s, 3H), 2.09–1.98 (m, 1H), 1.81–1.71 (m, 1H), 1.38 (d, J = 7.0 Hz, 3H), 0.95 (s, 9H). MS (ESI): m / z 982.32 [M+H] + 。

[0179] V2: White solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.70 (s, 1H), 8.98 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.40–8.27 (m, 4H), 7.81 (dd, J = 7.9, 1.6 Hz, 1H), 7.78–7.72 (m, 3H), 7.55–7.48 (m, 1H), 7.45–7.35 (m, 4H), 7.31 (d, J = 8.6 Hz, 2H), 7.18–7.12 (m, 1H), 5.11 (d, J = 3.5 Hz, 1H), 4.91 (p, J = 6.9 Hz, 1H), 4.54 (d, J = 9.4 Hz, 1H), 4.42 (t, J = 8.1 Hz, 1H), 4.28 (s, 1H), 3.65–3.44 (m, 6H), 2.63 (dt, J = 12.5, 6.9 Hz, 1H), 2.45 (s, 7H), 2.32–2.24 (m, 1H), 2.06–1.98 (m, 1H), 1.79 (ddd, J = 12.9, 8.5, 4.6 Hz, 1H), 1.37 (d, J = 7.0 Hz, 3H), 0.96 (s, 9H). MS (ESI): m / z 996.34 [M+H] + 。

[0180] V3: White solid. 1 H NMR (400MHz, DMSO-d6) δ11.68(s,1H),9.76(s,1H),8.99(s,1H),8.71(d,J=8.6Hz,1H),8.44(dd,J=19.2,7. 8Hz,2H),8.36(s,1H),8.33(s,1H),7.87–7.79(m,2H),7.77(s,6H),7.56(t,J=7.9Hz,1H),7.47–7.36(m,5H) ,7.18(t,J=7.4Hz,1H),5.16(d,J=3.5Hz,1H),4.92(q,J=7.1Hz,1H),4.56(d,J=9.3Hz,1H),4.44(t,J=8.1H z,1H),4.30(s,1H),3.65(s,2H),2.46(s,3H),1.38(d,J=7.0Hz,3H),0.96(s,9H).MS(ESI):m / z953.30[M+H] + .

[0181] V4: Milky white solid. 1H NMR (400MHz, DMSO-d6) δ11.66(s,1H),9.74(s,1H),8.99(s,1H),8.70(d,J=8. 5Hz,1H),8.50(d,J=7.6Hz,1H),8.40(d,J=7.8Hz,1H),8.36(s,1H),8.30(s,1H ),7.83(dd,J=6.3,1.4Hz,1H),7.81–7.77(m,3H),7.76(d,J=5.5Hz,3H),7.55( ddd,J=8.6,7.2,1.5Hz,1H),7.47–7.36(m,4H),7.18(td,J=7.6,1.2Hz,1H),5. 12(d,J=3.5Hz,1H),4.93(t,J=7.2Hz,1H),4.55(d,J=9.3Hz,1H),4.44(t,J=8. 1Hz,1H),4.32(dd,J=16.7,7.8Hz,2H),3.67–3.58(m,2H),2.92(p,J=8.9Hz,1H ),2.46(s,3H),2.42–2.36(m,1H),2.34–2.15(m,3H),2.07–1.98(m,1H),1.80( ddd,J=13.0,8.7,4.7Hz,1H),1.38(d,J=7.0Hz,3H),0.95(s,9H).MS(ESI):m / z 953.30[M+H] + .

[0182] Example 3. Preparation of compounds V5-V9

[0183]

[0184] (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (1 eq) and carboxylic acids of different chain lengths (1.2 eq) were placed in a double-necked flask under vacuum and argon protection. The mixture was dissolved in ultra-dry DMF, and DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF were added with stirring at room temperature. The mixture was stirred overnight at room temperature. After the reaction was detected by TLC, the reaction was quenched. The mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined and washed with saturated brine (50 mL). The organic layers were combined and washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the intermediate. Take the intermediate obtained in the first step (1 eq), N-Boc-piperazine (2 eq), and DIPEA (4 eq) and dissolve them in DMF. React at 90 °C for 12 h. After the reaction is completed, the reaction is quenched by TLC. Extract with ethyl acetate three times (50 mL * 3). Combine the organic phases, wash with saturated brine (50 mL), dry to anhydrous sodium sulfate, concentrate under reduced pressure, and then precipitate by column chromatography to obtain the final product. Alternatively, take the intermediate obtained in the first step (1 eq) and N-Boc-piperazine (2 eq) in a double-necked flask, evacuate under argon protection, dissolve in 15 mL of ultra-dry DMF, add DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in 1 mL of ultra-dry DMF at room temperature with stirring, and stir the mixture overnight at room temperature. After the reaction was detected by TLC, the reaction was quenched, and the mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined and washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the intermediate. The intermediate was further reacted (as in Example 1) to obtain the final product.

[0185] V5: White solid. 11H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.70 (s, 1H), 8.98 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.81 (dt, J = 9.4, 2.6 Hz, 2H), 7.74 (d, J = 9.0 Hz, 3H), 7.55–7.49 (m, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.33–7.28 (m, 2H), 7.15 (td, J = 7.7, 1.2 Hz, 1H), 5.11 (d, J = 3.5 Hz, 1H), 4.94–4.89 (m, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 7.9 Hz, 1H), 4.28 (s, 1H), 3.60 (d, J = 4.8 Hz, 2H), 2.45 (s, 3H), 2.36 (s, 4H), 2.26 (dt, J = 14.1, 7.2 Hz, 3H), 2.12 (dt, J = 14.1, 7.1 Hz, 1H), 2.03 (s, 1H), 1.79 (ddd, J = 12.9, 8.4, 4.6 Hz, 1H), 1.46 (dd, J = 14.3, 7.5 Hz, 4H), 1.37 (d, J = 6.9 Hz, 3H), 1.25 (t, J = 6.4 Hz, 2H), 0.93 (s, 9H). MS (ESI): m / z 1038.38 [M+H] + 。

[0186] V6: White solid. 11H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.72 (s, 1H), 8.98 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.34 (s, 1H), 8.29 (s, 1H), 7.81 (dt, J = 9.1, 2.4 Hz, 2H), 7.78–7.74 (m, 3H), 7.53 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.39–7.33 (m, 4H), 7.15 (td, J = 7.5, 1.2 Hz, 1H), 5.10 (d, J = 3.6 Hz, 1H), 4.92 (p, J = 6.6 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.61 (d, J = 4.4 Hz, 2H), 3.51 (s, 8H), 2.45 (s, 3H), 2.30–2.23 (m, 1H), 2.14 (dd, J = 13.9, 7.3 Hz, 1H), 2.05–1.97 (m, 1H), 1.79 (ddd, J = 12.9, 8.5, 4.6 Hz, 1H), 1.50 (s, 4H), 1.37 (d, J = 6.9 Hz, 3H), 0.93 (s, 9H). MS (ESI): m / z 1052.36 [M+H] + .

[0187] V7: Milky white solid. 11H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 9.69 (s, 1H), 8.98 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 7.83–7.77 (m, 2H), 7.74 (d, J = 8.5 Hz, 3H), 7.52 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.32–7.28 (m, 2H), 7.15 (td, J = 7.6, 1.2 Hz, 1H), 5.09 (d, J = 3.5 Hz, 1H), 4.96–4.86 (m, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (q, J = 3.6 Hz, 1H), 3.64–3.41 (m, 6H), 2.45 (s, 3H), 2.35 (s, 4H), 2.26 (dt, J = 12.1, 7.1 Hz, 3H), 2.11 (dt, J = 14.2, 7.1 Hz, 1H), 2.03–1.97 (m, 1H), 1.79 (ddd, J = 12.8, 8.4, 4.6 Hz, 1H), 1.56–1.40 (m, 4H), 1.37 (d, J = 7.0 Hz, 3H), 1.28–1.24 (m, 4H), 0.93 (s, 9H). MS (ESI): m / z 1052.40 [M+H] + 。

[0188] V8: White solid. 11H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.72 (s, 1H), 8.98 (s, 1H), 8.68 (d, J = 8.5 Hz, 1H), 8.36 (d, J = 7.9 Hz, 1H), 8.34 (s, 1H), 8.29 (s, 1H), 7.84–7.78 (m, 2H), 7.76 (dt, J = 8.5, 2.5 Hz, 3H), 7.53 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.39–7.32 (m, 4H), 7.15 (td, J = 7.5, 1.2 Hz, 1H), 5.10 (d, J = 3.5 Hz, 1H), 4.95–4.87 (m, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.1 Hz, 1H), 4.28 (s, 1H), 3.60 (d, J = 4.1 Hz, 2H), 3.50 (s, 8H), 2.45 (s, 3H), 2.30 (d, J = 7.8 Hz, 2H), 2.27–2.19 (m, 1H), 2.12 (dt, J = 14.2, 7.2 Hz, 1H), 2.03 (s, 1H), 1.79 (ddd, J = 12.8, 8.5, 4.6 Hz, 1H), 1.54–1.46 (m, 4H), 1.37 (d, J = 6.9 Hz, 3H), 1.30–1.25 (m, 2H), 0.93 (s, 9H). MS (ESI): m / z 1066.38 [M+H] + 。

[0189] V9: White solid. 1H NMR (400MHz, DMSO-d6) δ11.62(s,1H),9.69(s,1H),8.98(s,1H),8.68(d,J=8.5Hz,1H),8.37(d,J=7.7Hz,1H),8.33(s,1H),8.29(s,1H),7.80 (t,J=6.7Hz,2H),7.74(d,J=7.9Hz,3H),7.54–7.48(m,1H),7.44–7.36(m,4H),7.30(d,J=8.3Hz,2H),7.15(t,J=7.6Hz,1H),5.11(d,J=3.5Hz, 1H),4.91(p,J=7.1Hz,1H),4.52(d,J=9.3Hz,1H),4.41(t,J=8.0Hz,1H),4.28(s,1H),3.60(s,2H),3.50(s,4H),2.45(s,3H),2.35(s,4H),2. 27(q,J=8.2,7.5Hz,3H),2.19–2.13(m,1H),2.01(s,1H),1.79(s,1H),1.65(d,J=8.8Hz,2H),1.37(d,J=7.0Hz,3H),0.94(s,9H).MS(ESI):m / z 1008.36[M+H] + .

[0190] Example 4. Preparation of compounds PD1-PD12

[0191]

[0192] 4-Bromo-3-fluoroaniline (1 eq) and acrylic acid (5 eq) were dissolved in toluene and reacted at 110 °C for 12 h. After the reaction was detected by TLC, the reaction was quenched, and the mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the intermediate. The intermediate obtained in the first step (1 eq) and urea (3 eq) were dissolved in glacial acetic acid and reacted at 120 °C for 12 h. After the reaction was detected by TLC, the reaction was quenched, and the mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then a small amount of ethyl acetate was added and stirred for 2 h. The mixture was filtered, washed with ethyl acetate (5 mL * 3), and the intermediate obtained in the second step was obtained. The intermediate obtained in step two (1 eq), a Boc-protected fatty amine (1.3 eq), palladium acetate (0.2 eq), XPhos (0.4 eq), and sodium tert-butoxide (3 eq) were placed in a double-necked flask under vacuum and argon protection, dissolved in toluene, and reacted at 105 °C for 12 h. After the reaction was completed, the reaction was quenched by TLC, and the mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the intermediate. The intermediate was further reacted (as in Example 1) to obtain the final product.

[0193] PD1: Milky white solid. 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),10.27(s,1H),9.74(s,1H),8.70(d,J=8.5Hz,1H),8.35(s,1H),8.30(d ,J=4.4Hz,2H),7.82(dd,J=7.9,1.6Hz,1H),7.76(s,5H),7.57–7.52(m,1H),7.17(t,J=7.6Hz,1H),7.04(dd, J=13.1,2.4Hz,1H),6.90(dd,J=8.6,2.4Hz,1H),6.69(t,J=9.3Hz,1H),5.47(d,J=5.6Hz,1H),3.66(t,J=6.7 Hz,2H),3.30–3.26(m,2H),3.12(d,J=5.8Hz,2H),2.66(t,J=6.7Hz,2H),1.60(d,J=6.5Hz,4H).MS(ESI):m / z 704.17[M+H] + .

[0194] PD2: Milky white solid. 11H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 10.26 (s, 1H), 9.73 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.27 (t, J = 5.7 Hz, 1H), 7.82 (dd, J = 7.9, 1.6 Hz, 1H), 7.76 (s, 5H), 7.57–7.52 (m, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.04 (dd, J = 13.0, 2.4 Hz, 1H), 6.91 (dd, J = 8.6, 2.4 Hz, 1H), 6.68 (t, J = 9.3 Hz, 1H), 5.42 (q, J = 5.3 Hz, 1H), 3.67 (t, J = 6.7 Hz, 2H), 3.26 (q, J = 6.3 Hz, 2H), 3.08 (q, J = 6.6 Hz, 2H), 2.67 (t, J = 6.7 Hz, 2H), 1.58 (dq, J = 15.0, 7.5 Hz, 4H), 1.40 (q, J = 7.8 Hz, 2H). MS (ESI): m / z 718.19 [M+H] + 。

[0195] PD3: Milky white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 10.26 (s, 1H), 9.73 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.26 (t, J = 5.6 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.76 (s, 5H), 7.54 (t, J = 7.9 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.04 (dd, J = 13.0, 2.4 Hz, 1H), 6.90 (dd, J = 8.6, 2.3 Hz, 1H), 6.66 (t, J = 9.3 Hz, 1H), 5.42 (t, J = 5.5 Hz, 1H), 3.66 (t, J = 6.7 Hz, 2H), 3.25 (q, J = 6.6 Hz, 2H), 3.07 (q, J = 6.7 Hz, 2H), 2.66 (t, J = 6.6 Hz, 2H), 1.55 (dt, J = 14.3, 7.0 Hz, 4H), 1.41–1.32 (m, 4H). MS (ESI): m / z 732.20 [M+H] + 。

[0196] PD4: Milky white solid. 1H NMR (400MHz, DMSO-d6) δ11.65(s,1H),10.26(s,1H),9.72(s,1H),8.70(d,J=8.4Hz,1H),8.35(s,1H),8.30(s ,1H),8.26(t,J=5.8Hz,1H),7.84–7.81(m,1H),7.75(s,5H),7.54(t,J=7.6Hz,1H),7.17(t,J=7.6Hz,1H),7. 03(dd,J=13.0,2.4Hz,1H),6.93–6.89(m,1H),6.66(t,J=9.3Hz,1H),5.40(s,1H),3.66(t,J=6.7Hz,2H),3.2 4(q,J=6.8Hz,2H),3.07(q,J=6.6Hz,2H),2.66(t,J=6.7Hz,2H),1.58–1.49(m,4H),1.34(s,6H).MS(ESI):m / z 746.22[M+H] + .

[0197] PD5: Milky white solid. 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),10.26(s,1H),9.73(s,1H),8.70(d,J=8.4Hz,1H),8.35(s,1H),8.30(s,1H) ,8.26(t,J=5.7Hz,1H),7.82(dd,J=7.9,1.6Hz,1H),7.76(s,5H),7.57–7.52(m,1H),7.19–7.14(m,1H),7.03(dd, J=13.0,2.4Hz,1H),6.91(dd,J=8.3,2.3Hz,1H),6.65(t,J=9.3Hz,1H),5.42–5.37(m,1H),3.66(t,J=6.7Hz,2H), 3.24(q,J=6.6Hz,2H),3.06(q,J=6.6Hz,2H),2.66(t,J=6.7Hz,2H),1.58–1.48(m,4H),1.31(s,8H).MS(ESI):m / z 760.24[M+H] + .

[0198] PD6: Milky white solid. 11H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 10.27 (s, 1H), 9.73 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.26 (t, J = 5.7 Hz, 1H), 7.83 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (s, 5H), 7.57–7.52 (m, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.03 (dd, J = 13.0, 2.4 Hz, 1H), 6.91 (dd, J = 8.8, 2.4 Hz, 1H), 6.65 (t, J = 9.3 Hz, 1H), 5.42–5.37 (m, 1H), 3.66 (t, J = 6.7 Hz, 2H), 3.23 (q, J = 6.7 Hz, 2H), 3.05 (q, J = 6.7 Hz, 2H), 2.66 (t, J = 6.7 Hz, 2H), 1.53 (p, J = 6.8 Hz, 4H), 1.36–1.33 (m, 2H), 1.30 (s, 8H). MS (ESI): m / z 774.25 [M+H] + .

[0199] PD7: Milky white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 10.26 (s, 1H), 9.73 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.25 (t, J = 5.8 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.76 (s, 5H), 7.54 (t, J = 7.9 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.03 (dd, J = 13.0, 2.4 Hz, 1H), 6.93–6.89 (m, 1H), 6.65 (t, J = 9.3 Hz, 1H), 5.40 (d, J = 6.3 Hz, 1H), 3.66 (t, J = 6.7 Hz, 2H), 3.23 (q, J = 6.7 Hz, 2H), 3.05 (q, J = 6.7 Hz, 2H), 2.66 (t, J = 6.7 Hz, 2H), 1.52 (p, J = 6.9 Hz, 4H), 1.36–1.30 (m, 4H), 1.30–1.26 (m, 8H). MS (ESI): m / z 788.27 [M+H] + .

[0200] PD8: Milky white solid. 1H NMR (400MHz, DMSO-d6) δ11.63(s,1H),10.30(s,1H),9.72(s,1H),8.68(d,J=8.3Hz,1H),8.34(s,1H),8.30(s,1H),7. 81(dd,J=8.0,1.6Hz,1H),7.77(s,1H),7.75(d,J=8.4Hz,2H),7.52(t,J=7.8Hz,1H),7.32(d,J=8.4Hz,2H),7.16(t,J= 7.6Hz,1H),7.07(dd,J=12.9,2.4Hz,1H),6.94(dd,J=8.5,2.4Hz,1H),6.73(t,J=9.3Hz,1H),5.27(s,1H),3.67(t,J=6 .7Hz,2H),3.51(s,4H),3.22(q,J=6.3Hz,2H),2.67(t,J=6.7Hz,2H),2.58(t,J=6.5Hz,2H),2.47(s,4H).MS(ESI):m / z 745.20[M+H] + .

[0201] PD9: Milky white solid. 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),10.37(s,1H),9.75(s,1H),8.70(d,J=8.4Hz,1H),8.35(s, 1H),8.30(s,1H),8.26(d,J=5.1Hz,1H),7.82(d,J=7.9Hz,1H),7.77(s,5H),7.55(t,J=8.0Hz,1H ),7.18(dt,J=15.3,5.1Hz,2H),7.09–7.06(m,1H),7.03(t,J=8.8Hz,1H),3.74(t,J=6.7Hz,2H), 3.42(d,J=6.8Hz,2H),3.03(s,4H),2.69(t,J=6.6Hz,2H),2.62(s,4H),2.55(s,2H).MS(ESI):m / z 745.20[M+H] + .

[0202] PD10: Milky white solid. 1H NMR (400MHz, DMSO-d6) δ11.67(s,1H),10.37(s,1H),9.74(s,1H),8.70(d,J=8.5Hz,1H),8.37(d,J=4.5Hz,1H),8. 35(s,1H),8.30(s,1H),7.83(dd,J=7.9,1.7Hz,1H),7.76(d,J=3.6Hz,5H),7.55(ddd,J=8.6,7.3,1.6Hz,1H),7.2 0–7.15(m,2H),7.05(dd,J=8.7,2.3Hz,1H),7.00(t,J=9.0Hz,1H),3.73(t,J=6.7Hz,2H),3.30(d,J=6.4Hz,2H),3 .02(s,4H),2.69(t,J=6.6Hz,2H),2.55(d,J=6.5Hz,4H),2.42(s,2H),1.73(dt,J=12.9,7.5Hz,2H).MS(ESI):m / z 759.22[M+H] + .

[0203] PD11: Milky white solid. 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),10.36(s,1H),9.73(s,1H),8.70(d,J=8.4Hz,1H),8.35(s,1 H),8.30(s,1H),8.28(d,J=5.7Hz,1H),7.82(dd,J=7.9,1.6Hz,1H),7.76(s,5H),7.57–7.52(m,1H) ,7.20–7.14(m,2H),7.06(dd,J=8.7,2.3Hz,1H),7.01(t,J=9.0Hz,1H),3.73(t,J=6.7Hz,2H),3.28 (d,J=6.0Hz,2H),3.01(s,4H),2.68(t,J=6.7Hz,2H),2.37(s,2H),1.59–1.50(m,4H).MS(ESI):m / z 773.23[M+H] + .

[0204] PD12: Milky white solid. 1H NMR (400MHz, DMSO-d6) δ11.66(s,1H),10.36(s,1H),9.73(s,1H),8.70(d,J=8.5Hz,1H),8.35(s,1H) ,8.30(s,1H),8.29–8.25(m,1H),7.83(d,J=7.9Hz,1H),7.76(d,J=2.0Hz,5H),7.57–7.52(m,1H),7. 19–7.14(m,2H),7.07–7.03(m,1H),7.00(t,J=9.0Hz,1H),3.73(t,J=6.7Hz,2H),3.26–3.22(m,2H), 2.99(s,4H),2.68(t,J=6.6Hz,2H),2.38–2.30(m,2H),1.56–1.45(m,4H),1.33(s,4H).MS(ESI):m / z 801.26[M+H] + .

[0205] Example 5. Preparation of compound MG1

[0206]

[0207] Weigh out 4-((5-bromo-4-((2-carbamoylphenyl)amino)pyrimidin-2-yl)amino)benzoic acid (1 eq), HATU (1.3 eq), and DIPEA (2.6 eq), dissolve in DMF, stir at room temperature for 15 min, then slowly add N-Boc piperazine (1.2 eq) in DMF, react at room temperature for 2 h, and monitor the reaction progress by TLC. After the reaction is complete, quench the reaction with water, extract with EA, wash the combined organic layers with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and purify the crude product by 200-300 mesh silica gel column chromatography (PE / EA) to obtain the first-step intermediate. Weigh out the first-step intermediate, dissolve in ultra-dry DCM, and add TFA (V) under ice bath conditions. DCM :V TFA =3:1), and then stirred at room temperature for 2 h, with TLC monitoring of the reaction progress. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure. The crude product did not require further purification and was used directly for the next step. 3-(4-methoxybenzoyl)acrylic acid (1 eq), HATU (1.3 eq), and DIPEA (2.6 eq) were weighed, dissolved in DMF, and stirred at room temperature for 15 min. Then, a DMF solution of the intermediate from step two (1 eq) was slowly added dropwise, and the reaction was carried out at room temperature for 2 h, with TLC monitoring of the reaction progress. After the reaction was completed, the reaction was quenched with water, extracted with EA, and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was purified by 200-300 mesh silica gel column chromatography (PE / EA) to obtain the target compound MG1.

[0208] 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),9.75(s,1H),8.69(d,J=8.4Hz,1H),8.3 5(s,1H),8.32(s,1H),8.09–8.03(m,2H),7.86–7.82(m,1H),7.79(dt,J=8.5,3 .6Hz,4H),7.58–7.51(m,1H),7.44(d,J=15.2Hz,1H),7.37(d,J=8.4Hz,2H),7. 16(t,J=7.6Hz,1H),7.12–7.07(m,2H),3.87(s,3H),3.62(m,8H).MS(ESI):m / z 684.16[M+H] + .

[0209] Example 6. Preparation of compounds MG2 and MG3

[0210]

[0211] In a 100 mL round-bottom flask, weigh 2-chloro-5-bromo-4-((2-carbamoylphenyl)amino)pyrimidine (1 eq) and 1-Boc-4-aminopiperazine / 1-Boc-4-aminopiperazine (1.2 eq), dissolve in NMP, add DIPEA (3 eq), stir well at room temperature, and then transfer to 140 °C to react overnight. After the reaction is complete as detected by TLC, cool the reaction solution to room temperature, quench with water, extract with EA, extract with saturated brine, combine the EA layers, dry with anhydrous sodium sulfate, concentrate under reduced pressure to remove solvent, and precipitate by silica gel column chromatography to obtain the intermediate. Weigh the intermediate from the first step, dissolve in ultra-dry DCM, and add TFA (V) under ice bath conditions. DCM :V TFA =3:1), and then stirred at room temperature for 2 h, with TLC monitoring of the reaction progress. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure. The crude product did not require further purification and was used directly for the next step. 3-(4-methoxybenzoyl)acrylic acid (1.2 eq), HATU (1.3 eq) and DIPEA (2.6 eq) were weighed, dissolved in DMF, stirred at room temperature for 15 min, and then the corresponding DMF solution of the second-step intermediate (1 eq) was slowly added dropwise. The reaction was carried out at room temperature for 2 h, with TLC monitoring of the reaction progress. After the reaction was completed, the reaction was quenched with water, extracted with EA, and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was purified by 200-300 mesh silica gel column chromatography (PE / EA) to obtain compounds MG2 and MG3.

[0212] MG2: 1H NMR (400MHz, DMSO-d6) δ11.79 (s, 1H), 9.14 (s, 1H), 8.32 (d, J = 21.9Hz,

[0213] 2H),8.16(s,1H),8.06(d,J=8.8Hz,2H),7.87–7.78(m,2H),7.74(s,1H),7.54(t,J=8.1Hz,1H),7.48 (d,J=15.1Hz,1H),7.10(dd,J=8.3,6.3Hz,3H),3.87(s,3H),3.73(s,4H),2.85(s,4H).MS(ESI):m / z 580.13[M+H] + .

[0214] MG3: 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),8.82(s,1H),8.28(s,1H),8.12(s,1H),8.07–8. 03(m,2H),7.80(d,J=4.4Hz,1H),7.78(d,J=2.9Hz,1H),7.73(s,1H),7.53(s,1H),7.47 (d,J=15.1Hz,1H),7.29(s,1H),7.14–7.08(m,3H),4.41(d,J=12.9Hz,1H),4.03(m,1H ),3.87(s,4H),3.26(m,1H),2.91(m,1H),1.99(m,2H),1.51–1.36(m,2H).MS(ESI):m / z 579.14[M+H] + .

[0215] Example 7. Preparation of compounds YUA1-YUA14

[0216]

[0217] Synthesis of YUA-M1: In a 100 mL round-bottom flask, 5-bromo-2,4-dichloropyrimidine (1 eq) and o-aminobenzoamide (1.2 eq) were weighed, dissolved in isopropanol, and DIPEA (3 eq) was added. After stirring at room temperature, the mixture was refluxed at 90 °C overnight. After the reaction was complete as detected by TLC, the reaction solution was cooled to room temperature, and a solid precipitated. The residue was collected and washed with isopropanol. No further purification was required, yielding a pale yellow solid. This pale yellow solid (1 eq) and 4-aminobenzoic acid (2 eq) were weighed, and 20 mL of sec-butanol and 400 μL of TFA were added. The mixture was sealed and reacted overnight at 100 °C. A solid precipitated. After cooling to room temperature, the residue was collected and washed with sec-butanol to obtain the intermediate of the second step.

[0218] 6-(tert-Butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (1.3 eq) and the intermediate from the second step were placed in a double-necked flask under vacuum and argon protection. The mixture was dissolved in ultra-dry DMF, and DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF were added with stirring at room temperature. The mixture was stirred overnight at room temperature. After TLC detection, the reaction was quenched, and the mixture was extracted three times (50 mL * 3) with ethyl acetate. The combined organic phases were washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain a white solid. The white solid obtained in the previous step was dissolved in dichloromethane, and trifluoroacetic acid (V...) was slowly added with stirring. DCM V TFA =10:3), reacted at room temperature for 30 min. After the reaction was complete as detected by TLC, the solvent was removed by rotary evaporation (dichloromethane was added multiple times and evaporated) to obtain YUA-M1.

[0219] Synthesis of the final product: 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione or 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (1 eq), amino fatty acid (2 eq), and DIPEA (1.1 eq) were dissolved in DMF and reacted at 90 °C for 6 h. After the reaction was detected by TLC, the reaction was quenched, and the mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain intermediates. The obtained intermediates (1.3 eq) were placed in a double-necked flask with YUA-M1, evacuated, and protected with argon. The mixture was dissolved in ultra-dry DMF, and DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF were added under stirring at room temperature. The mixture was stirred at room temperature and reacted overnight. After the reaction was detected by TLC, the reaction was quenched, and the product was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined and washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). The product was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the final product.

[0220] YUA1: Yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.63 (d, J=15.8Hz, 1H), 11.12

[0221] (s, 1H), 9.70(s, 1H), 8.68(s, 1H), 8.33(s, 1H), 8.30(s, 1H), 7.80(d, J = 8.0 Hz, 1H), 7.74(d, J = 9.0 Hz, 3H), 7.60(t, J = 7.8 Hz, 1H), 7.52(s, 1H), 7.41(d, J = 8.2 Hz, 1H), 7.33(d, J = 8.3 Hz, 1H), 7.10(d, J = 14.9 Hz, 2H), 7.00(s, 1H), 6.91(s, 1H), 5.08(dd, J = 12.8, 5.3 Hz, 1H), 4.68(d, J = 20.1 Hz, 1H), 4.53(d, J = 35.4 Hz, 1H), 4.10(d, J = 16.2 Hz, 1H), 3.98(d, J = 14.4 Hz, 1H), 3.84(s, 2H), 3.60(dd, J = 25.9, 11.9 Hz, 1H), 2.89(t, J = 14.3 Hz, 1H), 2.67(s, 1H), 2.61(s, 1H), 2.55(d, J = 8.1 Hz, 2H), 2.03(d, J = 11.4 Hz, 1H), 1.63(s, 1H). MS(ESI): m / z 821.18[M + H] + 。

[0222] YUA2: Yellow solid. 1 H NMR(400 MHz, DMSO-d6) δ 11.63(s, 1H), 11.07(s, 1H), 9.66(s, 1H), 8.69(d, J = 8.6 Hz, 1H), 8.33(s, 1H), 8.28(s, 1H), 7.81(d, J = 7.8 Hz, 1H), 7.72(d, J = 10.2 Hz, 3H), 7.61–7.51(m, 2H), 7.37–7.28(m, 2H), 7.14(s, 2H), 7.03(d, J = 7.1 Hz, 1H), 6.73(s, 1H), 5.03(dd, J = 12.9, 5.3 Hz, 1H), 4.50(d, J = 52.7 Hz, 1H), 4.30(d, J = 65.1 Hz, 1H), 3.87–3.73(m, 3H), 3.62–3.50(m, 3H), 2.88(d, J = 18.7 Hz, 1H), 2.58(d, J = 16.3 Hz, 4H), 2.42–2.32(m, 1H), 1.99(s, 1H), 1.54(s, 1H). MS(ESI): m / z 835.20[M + H] + 。

[0223] YUA3: Yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 11.08 (s, 1H), 9.67 (s, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 8.28 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 8.6 Hz, 3H), 7.54 (dt, J = 23.4, 7.8 Hz, 2H), 7.32 (d, J = 9.4 Hz, 2H), 7.18–7.08 (m, 2H), 7.02 (s, 1H), 6.67 (s, 1H), 5.09–5.00 (m, 1H), 4.49 (d, J = 55.2 Hz, 1H), 4.28 (d, J = 63.4 Hz, 1H), 3.89 (d, J = 12.1 Hz, 1H), 3.72 (d, J = 15.9 Hz, 2H), 3.51 (s, 2H), 2.88 (dd, J = 17.3, 11.8 Hz, 1H), 2.58 (d, J = 16.3 Hz, 4H), 2.32–2.12 (m, 2H), 2.03 (s, 1H), 1.80 (s, 2H), 1.54 (s, 1H). MS (ESI): m / z 849.21 [M+H] + 。

[0224] YUA4: Yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 11.08 (s, 1H), 9.66 (s, 1H), 8.68 (d, J = 8.6 Hz, 1H), 8.32 (s, 1H), 8.28 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.9 Hz, 3H), 7.53 (t, J = 8.0 Hz, 2H), 7.37 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.14 (t, J = 7.3 Hz, 1H), 7.10–6.96 (m, 2H), 6.57 (s, 1H), 5.04 (d, J = 10.6 Hz, 1H), 4.49 (d, J = 53.4 Hz, 1H), 4.25 (d, J = 62.9 Hz, 1H), 3.99–3.83 (m, 2H), 3.71 (d, J = 14.8 Hz, 2H), 2.93–2.82 (m, 2H), 2.57 (d, J = 17.5 Hz, 4H), 2.28–2.07 (m, 2H), 2.01 (d, J = 13.0 Hz, 1H), 1.57 (d, J = 19.3 Hz, 5H). MS (ESI): m / z 863.23 [M+H] + 。

[0225] YUA5: Yellow solid.1 1H NMR (400 MHz, DMSO-d6) δ 11.66–11.59 (m, 1H), 11.09 (s, 1H), 9.66 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 8.4 Hz, 3H), 7.58–7.50 (m, 2H), 7.38 (s, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.11–7.04 (m, 1H), 7.01 (s, 1H), 6.52 (d, J = 22.0 Hz, 1H), 5.03 (s, 1H), 4.49 (d, J = 52.9 Hz, 1H), 4.25 (d, J = 62.7 Hz, 1H), 3.90 (s, 1H), 3.67 (d, J = 30.8 Hz, 2H), 2.86 (d, J = 14.8 Hz, 1H), 2.57 (t, J = 13.4 Hz, 4H), 2.20–2.00 (m, 3H), 1.54 (s, 6H), 1.35 (d, J = 6.6 Hz, 3H). MS (ESI): m / z 877.24 [M+H] + 。

[0226] YUA6: Yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 11.08 (s, 1H), 9.67 (s, 1H), 8.68 (d, J = 8.3 Hz, 1H), 8.30 (d, J = 14.7 Hz, 2H), 7.81 (d, J = 7.8 Hz, 1H), 7.74 (s, 3H), 7.59–7.49 (m, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.11–7.03 (m, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.50 (d, J = 18.3 Hz, 1H), 5.04 (d, J = 9.8 Hz, 1H), 4.48 (d, J = 54.1 Hz, 1H), 4.24 (d, J = 63.1 Hz, 1H), 3.89 (d, J = 14.5 Hz, 1H), 3.65 (dd, J = 23.5, 13.1 Hz, 2H), 3.24 (s, 2H), 2.92–2.81 (m, 1H), 2.58 (d, J = 17.1 Hz, 4H), 2.14–1.95 (m, 3H), 1.52 (s, 6H), 1.34 (d, J = 7.5 Hz, 3H). MS (ESI): m / z 891.26 [M+H]+ .

[0227] YUA7: Yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.63 (d, J=8.7Hz, 1H), 11.09 (s,

[0228] 1H),9.67(s,1H),8.68(s,1H),8.31(s,1H),8.29(s,1H),7.81(d,J=7.8Hz,1H),7.74(s,3H),7.57–7.50(m,2H),7.37(d,J=8 .1Hz,1H),7.30(d,J=8.2Hz,1H),7.14(t,J=7.6Hz,1H),7.10–7.02(m,1H),7.00(d,J=7.3Hz,1H),6.49(s,1H),5.04(dd,J=1 2.9,5.3Hz,1H),4.48(d,J=52.5Hz,1H),4.24(d,J=62.5Hz,1H),3.89(d,J=17.9Hz,1H),3.68(d,J=16.7Hz,2H),3.26(s,2H) ,2.88(td,J=15.7,5.1Hz,1H),2.58(d,J=17.0Hz,4H),2.02(d,J=12.9Hz,3H),1.52(s,6H),1.38–1.28(m,5H).MS(ESI):m / z 905.27[M+H] + .

[0229] YUA8: Yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.64 (d, J=13.7Hz, 1H), 11.08

[0230] (s,1H), 9.68(s,1H), 8.68(s,1H), 8.32(s,1H), 8.29(s,1H), 7.82(d, J = 7.8Hz,1H), 7.75(s,3H), 7.54(q, J = 8.3Hz,2H), 7.37(d, J = 8.2Hz,1H), 7.30(d, J = 8.2Hz,1H), 7.17–7.11(m,1H), 7.05(d, J = 10.0Hz,1H), 7.00(d, J = 7.0Hz,1H), 6.49(s,1H), 5.04(dd, J = 12.8,5.3Hz,1H), 4.48(d, J = 53.5Hz,1H), 4.24(d, J = 62.4Hz,1H), 3.89(d, J = 17.7Hz,1H), 3.67(q, J = 16.9Hz,2H), 3.25(s,2H), 2.88(ddd, J = 17.4,13.8,5.3Hz,1H), 2.62–2.51(m,4H), 2.16–1.97(m,3H), 1.52(s,6H), 1.28(s,7H). MS(ESI): m / z 919.29[M + H] + 。

[0231] YUA9: Yellow solid. 1 H NMR(400MHz, DMSO-d6) δ 11.64(d, J = 16.2Hz,1H), 11.09

[0232] (s,1H), 9.68(s,1H), 8.69(s,1H), 8.30(d, J = 10.0Hz,2H), 7.82(d, J = 7.9Hz,1H), 7.74(d, J = 8.2Hz,3H), 7.58–7.50(m,2H), 7.37(d, J = 8.1Hz,1H), 7.30(d, J = 8.3Hz,1H), 7.14(t, J = 7.5Hz,1H), 7.03(dd, J = 21.1,7.7Hz,2H), 6.49(s,1H), 5.04(dd, J = 12.9,5.4Hz,1H), 4.48(d, J = 52.7Hz,1H), 4.24(d, J = 62.5Hz,1H), 3.93(s,1H), 3.67(q, J = 16.1Hz,2H), 3.25(s,2H), 2.88(ddd, J = 17.3,13.9,5.4Hz,1H), 2.57(t, J = 13.4Hz,4H), 2.19–1.97(m,3H), 1.52(s,6H), 1.26(dd, J = 15.8,12.2Hz,9H). MS(ESI): m / z 933.30[M + H]+ .

[0233] YUA10: Yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),11.08(s,1H),9.67(s,1H),8.68(s,1H),8.31(s,2H),7.82(d,J=7.8Hz,1H),7.75(d,J=8.5Hz,3H),7. 58–7.54(m,1H),7.53(d,J=6.7Hz,1H),7.36(d,J=7.9Hz,1H),7.30(d,J=8.2Hz,1H),7.13(t,J=7.5Hz,1H),7.05(d,J=8.7Hz,1H),7.00(d,J =7.0Hz,1H),6.49(s,1H),5.04(dd,J=12.9,5.4Hz,1H),4.48(d,J=51.9Hz,1H),4.24(d,J=62.3Hz,1H),3.93(s,1H),3.67(d,J=16.2Hz,2H) ,3.25(s,2H),2.88(ddd,J=17.4,14.0,5.4Hz,1H),2.58(dd,J=20.4,6.1Hz,4H),2.12–1.95(m,3H),1.52(s,6H),1.26(s,11H).MS(ESI):m / z 947.32[M+H] + .

[0234] YUA11: Yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.65 (d, J=19.0Hz, 1H), 11.09

[0235] (s, 1H), 9.68(s, 1H), 8.68(s, 1H), 8.32(s, 1H), 8.29(s, 1H), 7.82(d, J = 7.8 Hz, 1H), 7.74(s, 3H), 7.58–7.50(m, 2H), 7.36(d, J = 8.2 Hz, 1H), 7.30(d, J = 8.2 Hz, 1H), 7.14(t, J = 7.6 Hz, 1H), 7.05(d, J = 8.6 Hz, 1H), 7.01(d, J = 7.0 Hz, 1H), 6.49(s, 1H), 5.04(dd, J = 12.9, 5.4 Hz, 1H), 4.48(d, J = 52.0 Hz, 1H), 4.24(d, J = 62.0 Hz, 1H), 3.95(d, J = 13.4 Hz, 1H), 3.67(d, J = 15.3 Hz, 2H), 3.25(d, J = 7.1 Hz, 2H), 2.93–2.83(m, 1H), 2.58(dd, J = 20.5, 6.3 Hz, 4H), 2.03(s, 3H), 1.52(s, 6H), 1.25(s, 13H). MS(ESI): m / z 961.34[M+H] + .

[0236] YUA12: Yellowish green solid. 1 H NMR(400 MHz, DMSO-d6) δ 11.65(d, J = 15.5 Hz, 1H), 11.06(s, 1H), 9.69(s, 1H), 8.69(s, 1H), 8.32(s, 1H), 8.30(s, 1H), 7.82(d, J = 7.9 Hz, 1H), 7.76(s, 3H), 7.53(t, J = 8.7 Hz, 2H), 7.37(d, J = 8.2 Hz, 1H), 7.30(d, J = 8.3 Hz, 1H), 7.14(t, J = 7.5 Hz, 1H), 7.08(s, 1H), 6.92(s, 1H), 6.81(d, J = 8.5 Hz, 1H), 5.02(dd, J = 12.8, 5.4 Hz, 1H), 4.48(d, J = 53.6 Hz, 1H), 4.24(d, J = 62.8 Hz, 1H), 3.96–3.89(m, 1H), 3.67(d, J = 17.4 Hz, 2H), 3.49(d, J = 11.3 Hz, 1H), 3.12(s, 2H), 2.89–2.83(m, 1H), 2.61–2.52(m, 3H), 2.11–1.95(m, 3H), 1.52(s, 6H), 1.37–1.24(m, 9H). MS(ESI): m / z 933.30[M+H] + .

[0237] YUA13: Yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.65 (d, J=17.2Hz, 1H), 11.05

[0238] (s,1H),9.68(s,1H),8.69(s,1H),8.32(s,1H),8.29(s,1H),7.82(d,J=7.8Hz,1H),7.74(d,J=7.2Hz,3H),7.53(dd,J=10.8,7.8Hz, 2H),7.37(d,J=8.3Hz,1H),7.30(d,J=8.2Hz,1H),7.14(t,J=7.6Hz,1H),7.07(s,1H),6.93(d,J=2.1Hz,1H),6.81(d,J=8.5Hz,1H),5 .02(dd,J=12.9,5.4Hz,1H),4.48(d,J=52.7Hz,1H),4.24(d,J=62.3Hz,1H),3.94(s,1H),3.67(q,J=16.6Hz,2H),3.17(d,J=5.2Hz, 1H),3.11(s,2H),2.92–2.82(m,1H),2.61–2.52(m,3H),2.13–1.94(m,3H),1.59–1.40(m,6H),1.25(d,J=13.0Hz,11H).MS(ESI):m / z 947.32[M+H] + .

[0239] YUA14: Yellow-green solid. 1H NMR (400MHz, DMSO-d6) δ11.66(d,J=18.4Hz,1H),11.07(s,1H),9.70(s,1H),8.69(s,1H),8.32(s,1H),8.30(s,1H),7.82(d,J=7.8Hz,1H),7. 76(s,3H),7.54(dd,J=8.3,3.6Hz,2H),7.36(d,J=8.3Hz,1H),7.30(d,J=8.3Hz,1H),7.14(t,J=7.6Hz,1H),7.08(s,1H),6.93(d,J=2.1Hz,1H) ,6.82(d,J=8.4Hz,1H),5.03(dd,J=12.9,5.4Hz,1H),4.48(d,J=52.5Hz,1H),4.24(d,J=62.1Hz,1H),3.91(d,J=14.0Hz,1H),3.67(d,J=14.7H z,2H),3.49(d,J=11.6Hz,1H),3.11(s,2H),2.92–2.83(m,1H),2.61–2.53(m,3H),2.09–1.96(m,3H),1.52(s,6H),1.25(s,13H).MS(ESI):m / z 961.34[M+H] + .

[0240] Example 8. Preparation of compounds YUB1-YUB2, YUB5-YUB16

[0241]

[0242] Different ω-bromo fatty acids or brominated polyethylene glycol carboxylic acids (1.3 eq) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (1 eq) were placed in a double-necked flask under vacuum and argon protection. The mixture was dissolved in ultra-dry DMF, and DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF were added with stirring at room temperature. The mixture was stirred overnight at room temperature. After the reaction was detected by TLC, the reaction was quenched. The mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined and washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain a white solid. Take the white solid obtained in the previous step (1.3 eq), YUA-M1 (1 eq), sodium iodide (0.2 eq), and potassium carbonate (2 eq) and dissolve them in DMSO. React at 80 °C for 4 h. After the reaction is completed, the reaction is quenched by TLC. Extract with ethyl acetate three times (50 mL * 3). Combine the organic phases and wash successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). Dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain the final product by column chromatography.

[0243] YUB1: Off-white solid. 1 H NMR(400MHz,DMSO-d6)δ11.65(s,1H),9.74(d,J=24.2Hz,1H),8.98(s,1H),8.70(s,1H),8.43–8.27(m,3H) ,7.82(d,J=8.0Hz,1H),7.75(s,3H),7.53(s,1H),7.42(d,J=4.9Hz,3H),7.37(d,J=8.1Hz,4H),7.15(s,1H) ,5.13(s,1H),4.90(s,1H),4.52(s,1H),4.44(s,1H),4.28(s,1H),3.63(d,J=27.3Hz,4H),3.51(s,1H),2.4 5(d,J=2.0Hz,3H),2.03(s,2H),1.78(s,1H),1.36(d,J=7.8Hz,4H),0.94(s,9H).MS(ESI):m / z992.32[M+H] + .

[0244] YUB2: Off-white solid. 11H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.67 (s, 1H), 8.98 (s, 1H), 8.70 (s, 1H), 8.34 (dd, J = 19.8, 12.9 Hz, 4H), 7.82 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 7.7 Hz, 3H), 7.53 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 4.4 Hz, 4H), 7.15 (t, J = 7.6 Hz, 1H), 5.10 (s, 1H), 4.91 (t, J = 7.0 Hz, 1H), 4.52 (d, J = 9.4 Hz, 1H), 4.43 (t, J = 8.2 Hz, 1H), 4.28 (s, 1H), 3.71 (dd, J = 22.8, 11.8 Hz, 2H), 3.60 (s, 4H), 3.46 (d, J = 20.2 Hz, 1H), 2.63 (s, 2H), 2.45 (s, 3H), 2.35 (d, J = 18.4 Hz, 2H), 2.20 (d, J = 7.6 Hz, 1H), 2.02 (s, 1H), 1.80 (s, 1H), 1.51–1.47 (m, 1H), 1.39 (d, J = 7.3 Hz, 4H), 0.96 (s, 9H). MS (ESI): m / z 1006.34 [M+H] + .

[0245] YUB5: Milky white solid. 11H NMR (400 MHz, DMSO-d6) δ 11.65 (d, J = 5.8 Hz, 1H), 9.73 (d, J = 24.5 Hz, 1H), 8.98 (s, 1H), 8.69 (d, J = 8.5 Hz, 1H), 8.39–8.29 (m, 3H), 7.82 (d, J = 7.8 Hz, 1H), 7.79–7.73 (m, 4H), 7.52 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.39–7.31 (m, 4H), 7.17–7.12 (m, 1H), 5.11 (s, 1H), 4.91 (t, J = 7.2 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.1 Hz, 1H), 4.27 (s, 1H), 3.77 (s, 1H), 3.60 (s, 2H), 2.89 (s, 1H), 2.45 (s, 3H), 2.33 (s, 1H), 2.25 (d, J = 30.4 Hz, 2H), 2.10 (s, 2H), 2.01 (t, J = 10.3 Hz, 2H), 1.90 (s, 1H), 1.79 (s, 1H), 1.46 (s, 3H), 1.37 (d, J = 7.1 Hz, 4H), 0.92 (s, 9H). MS (ESI): m / z 1048.39 [M+H] + .

[0246] YUB6: Pale beige solid. 11H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.66 (s, 1H), 8.98 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.40–8.28 (m, 3H), 7.83–7.80 (m, 1H), 7.75 (t, J = 8.7 Hz, 4H), 7.51 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.40–7.36 (m, 4H), 7.14 (t, J = 7.6 Hz, 1H), 5.11 (d, J = 3.4 Hz, 1H), 4.91 (t, J = 7.2 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.58 (d, J = 17.9 Hz, 7H), 3.41 (s, 1H), 2.45 (s, 3H), 2.35 (s, 3H), 2.25 (dt, J = 15.2, 8.0 Hz, 1H), 2.12 (q, J = 6.8 Hz, 1H), 2.02 (d, J = 11.3 Hz, 1H), 1.79 (ddd, J = 12.9, 8.4, 4.5 Hz, 1H), 1.46 (d, J = 8.0 Hz, 2H), 1.37 (d, J = 7.1 Hz, 3H), 1.30–1.28 (m, 3H), 0.93 (s, 9H). MS (ESI): m / z 1062.40 [M+H] + 。

[0247] YUB7: Pale beige solid. 11H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.67 (s, 1H), 8.98 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.40–8.29 (m, 3H), 7.82 (d, J = 7.7 Hz, 1H), 7.76 (dd, J = 15.1, 8.5 Hz, 4H), 7.51 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.40–7.36 (m, 4H), 7.13 (t, J = 7.6 Hz, 1H), 5.12 (s, 1H), 4.91 (t, J = 7.2 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.58 (d, J = 18.4 Hz, 7H), 3.41 (s, 1H), 2.45 (s, 3H), 2.36 (s, 3H), 2.25 (dt, J = 14.5, 7.7 Hz, 1H), 2.11 (q, J = 7.0 Hz, 1H), 2.02 (d, J = 10.6 Hz, 1H), 1.79 (ddd, J = 12.9, 8.4, 4.6 Hz, 1H), 1.47–1.44 (m, 2H), 1.37 (d, J = 7.0 Hz, 3H), 1.28 (s, 5H), 0.93 (s, 9H). MS (ESI): m / z 1076.42 [M+H] + .

[0248] YUB8: Pale beige solid. 11H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.67 (s, 1H), 8.98 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.39–8.28 (m, 3H), 7.84–7.80 (m, 1H), 7.76 (dd, J = 14.1, 8.5 Hz, 4H), 7.51 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.40–7.36 (m, 4H), 7.13 (t, J = 7.5 Hz, 1H), 5.11 (d, J = 3.5 Hz, 1H), 4.91 (t, J = 7.3 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.67–3.52 (m, 7H), 3.41 (s, 1H), 3.29 (s, 4H), 2.45 (s, 3H), 2.36 (s, 3H), 2.25 (dt, J = 14.7, 7.7 Hz, 1H), 2.10 (dt, J = 14.0, 7.0 Hz, 1H), 2.01 (t, J = 10.0 Hz, 1H), 1.79 (ddd, J = 12.8, 8.5, 4.8 Hz, 1H), 1.47–1.45 (m, 2H), 1.37 (d, J = 7.0 Hz, 3H), 1.28 (d, J = 5.4 Hz, 7H), 0.93 (s, 9H). MS (ESI): m / z 1090.43 [M+H] + .

[0249] YUB9: Pale beige solid. 11H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.67 (s, 1H), 8.98 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.39–8.29 (m, 3H), 7.82 (d, J = 7.8 Hz, 1H), 7.76 (dd, J = 13.3, 8.7 Hz, 4H), 7.51 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 7.9 Hz, 4H), 7.13 (t, J = 7.6 Hz, 1H), 5.11 (s, 1H), 4.91 (t, J = 7.2 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.27 (s, 1H), 3.67–3.53 (m, 7H), 3.41 (d, J = 6.1 Hz, 1H), 3.29 (s, 4H), 2.45 (s, 3H), 2.35 (s, 3H), 2.25 (dd, J = 14.2, 7.3 Hz, 1H), 2.10 (dt, J = 14.2, 7.1 Hz, 1H), 2.01 (t, J = 9.0 Hz, 1H), 1.79 (ddd, J = 13.0, 8.6, 4.7 Hz, 1H), 1.46 (d, J = 8.4 Hz, 2H), 1.37 (d, J = 7.0 Hz, 3H), 1.29 (s, 9H), 0.93 (s, 9H). MS (ESI): m / z 1104.45 [M+H] + .

[0250] YUB10: Off-white solid. 11H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.67 (s, 1H), 8.98 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.41–8.29 (m, 3H), 7.82 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 7.3 Hz, 4H), 7.51 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.0 Hz, 4H), 7.13 (t, J = 7.6 Hz, 1H), 5.12 (s, 1H), 4.91 (t, J = 7.2 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.27 (s, 1H), 3.66–3.53 (m, 7H), 3.41 (s, 1H), 3.29 (s, 4H), 2.45 (s, 3H), 2.35 (s, 3H), 2.28–2.21 (m, 1H), 2.10 (q, J = 7.0 Hz, 1H), 2.01 (t, J = 10.3 Hz, 1H), 1.79 (ddd, J = 12.8, 8.3, 4.6 Hz, 1H), 1.46 (d, J = 8.1 Hz, 2H), 1.37 (d, J = 7.0 Hz, 3H), 1.28 (d, J = 5.1 Hz, 11H), 0.93 (s, 9H). MS (ESI): m / z 1118.46 [M+H] + .

[0251] YUB11: Off-white solid. 11H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 9.67 (s, 1H), 8.98 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.39–8.30 (m, 3H), 7.82 (dd, J = 7.9, 1.6 Hz, 1H), 7.79–7.73 (m, 4H), 7.53–7.49 (m, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.5 Hz, 4H), 7.13 (t, J = 7.6 Hz, 1H), 5.11 (d, J = 3.5 Hz, 1H), 4.91 (t, J = 7.3 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.30–4.26 (m, 1H), 3.66–3.54 (m, 7H), 3.41 (s, 1H), 3.29 (s, 4H), 2.45 (s, 3H), 2.35 (s, 3H), 2.28–2.21 (m, 1H), 2.13–2.07 (m, 1H), 2.04–1.98 (m, 1H), 1.79 (ddd, J = 12.8, 8.5, 4.7 Hz, 1H), 1.47–1.44 (m, 2H), 1.37 (d, J = 7.0 Hz, 3H), 1.30 (d, J = 7.7 Hz, 13H), 0.93 (s, 9H). MS (ESI): m / z 1132.48 [M+H] + .

[0252] YUB12: Off-white solid. 11H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 9.68 (s, 1H), 8.98 (s, 1H), 8.71 (d, J = 8.7 Hz, 1H), 8.41–8.32 (m, 3H), 7.83 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (t, J = 9.7 Hz, 4H), 7.51 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.4 Hz, 4H), 7.13 (t, J = 7.5 Hz, 1H), 5.13 (d, J = 3.5 Hz, 1H), 4.91 (t, J = 7.3 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.65–3.54 (m, 7H), 3.41 (s, 1H), 3.30 (s, 4H), 2.45 (s, 3H), 2.36 (s, 3H), 2.23 (dd, J = 12.0, 7.2 Hz, 1H), 2.10 (q, J = 6.9 Hz, 1H), 2.03 (d, J = 12.0 Hz, 1H), 1.79 (td, J = 8.4, 4.3 Hz, 1H), 1.47–1.44 (m, 2H), 1.37 (d, J = 7.0 Hz, 3H), 1.27 (dt, J = 15.7, 5.4 Hz, 15H), 0.93 (s, 9H). MS (ESI): m / z 1146.50 [M+H] + .

[0253] YUB13: Pale beige solid. 11H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 9.67 (s, 1H), 8.98 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.39–8.29 (m, 3H), 7.82 (d, J = 7.7 Hz, 1H), 7.76 (dd, J = 11.3, 8.8 Hz, 4H), 7.51 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.5 Hz, 4H), 7.13 (t, J = 7.5 Hz, 1H), 5.11 (s, 1H), 4.91 (t, J = 7.3 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.65–3.53 (m, 7H), 3.41 (s, 1H), 3.30 (s, 4H), 2.45 (s, 3H), 2.35 (s, 3H), 2.27–2.21 (m, 1H), 2.12–2.06 (m, 1H), 2.06–2.00 (m, 1H), 1.79 (ddd, J = 12.9, 8.5, 4.7 Hz, 1H), 1.45 (d, J = 8.4 Hz, 2H), 1.37 (d, J = 7.0 Hz, 3H), 1.32–1.22 (m, 17H), 0.93 (s, 9H). MS (ESI): m / z 1160.51 [M+H] + .

[0254] YUB14: Pale beige solid. 11H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.68 (s, 1H), 8.98 (s, 1H), 8.71 (d, J = 8.1 Hz, 1H), 8.40–8.31 (m, 3H), 7.87–7.81 (m, 2H), 7.75 (d, J = 7.9 Hz, 3H), 7.52 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.37 (dd, J = 8.2, 6.3 Hz, 4H), 7.14 (t, J = 7.2 Hz, 1H), 5.13 (s, 1H), 4.90 (t, J = 7.2 Hz, 1H), 4.51 (d, J = 9.1 Hz, 1H), 4.45–4.39 (m, 1H), 4.27 (s, 1H), 3.67 (t, J = 14.4 Hz, 2H), 3.60–3.51 (m, 7H), 3.44–3.37 (m, 4H), 2.45 (s, 3H), 2.39 (d, J = 6.6 Hz, 1H), 2.35–2.32 (m, 1H), 1.99 (d, J = 10.1 Hz, 1H), 1.79 (td, J = 8.2, 4.1 Hz, 1H), 1.46 (d, J = 8.6 Hz, 1H), 1.35 (dd, J = 6.8, 4.7 Hz, 5H), 0.91 (d, J = 4.8 Hz, 9H). MS (ESI): m / z 1052.36 [M+H] + .

[0255] YUB15: Off-white solid. 11H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.67 (s, 1H), 8.98 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.40–8.30 (m, 3H), 7.87–7.81 (m, 2H), 7.76–7.73 (m, 3H), 7.52 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.39 (t, J = 4.2 Hz, 4H), 7.14 (t, J = 7.6 Hz, 1H), 5.13 (s, 1H), 4.91 (t, J = 7.2 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.70 (t, J = 13.8 Hz, 2H), 3.61–3.54 (m, 7H), 3.49–3.40 (m, 9H), 2.55 (d, J = 6.1 Hz, 1H), 2.45 (s, 3H), 2.39 (d, J = 6.8 Hz, 1H), 2.34 (d, J = 14.7 Hz, 1H), 2.00 (d, J = 9.1 Hz, 1H), 1.82–1.76 (m, 1H), 1.46 (d, J = 8.4 Hz, 1H), 1.37 (d, J = 7.0 Hz, 3H), 0.93 (s, 9H). MS (ESI): m / z 1096.39 [M+H] + .

[0256] YUB16: Pale beige solid. 1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),9.67(s,1H),8.98(s,1H),8.71(d,J =8.6Hz,1H),8.40–8.30(m,3H),7.87–7.81(m,2H),7.76–7.73(m,3H),7.54 –7.50(m,1H),7.43(d,J=8.2Hz,2H),7.39(t,J=4.3Hz,4H),7.14(t,J=7.5H z,1H),5.13(s,1H),4.91(t,J=7.2Hz,1H),4.52(d,J=9.3Hz,1H),4.43(t,J =8.0Hz,1H),4.28(s,1H),3.70(t,J=13.7Hz,2H),3.63–3.54(m,8H),3.48– 3.43(m,12H),2.55(d,J=7.4Hz,1H),2.45(s,3H),2.40(d,J=6.8Hz,1H),2. 33(d,J=7.8Hz,1H),2.02(dd,J=13.6,8.0Hz,1H),1.79(td,J=8.5,4.5Hz,1 H),1.47(d,J=8.4Hz,1H),1.37(d,J=7.0Hz,3H),0.93(s,9H).MS(ESI):m / z 1140.42[M+H] + .

[0257] Example 9. Preparation of compounds X2VL8-X2VL11

[0258]

[0259] 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1.3 eq) and 4-((5-bromo-4-((2-carbamoylphenyl)amino)pyrimidin-2-yl)amino)benzoic acid (1 eq) were placed in a double-necked flask under vacuum and argon protection. The ester was dissolved in ultra-dry DMF. DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF were added under stirring at room temperature. The mixture was stirred at room temperature and reacted overnight. The reaction was quenched after TLC detection. The mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined and washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain a white solid. The white solid obtained in the previous step was dissolved in dichloromethane, and trifluoroacetic acid (V) was slowly added under stirring. DCM V TFA=10:3), react at room temperature for 30 min. After the reaction was complete as detected by TLC, the solvent was removed by rotary evaporation (dichloromethane was added multiple times and evaporated) to obtain X2VL-M1.

[0260] Different ω-bromo fatty acids (1.3 eq) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (1 eq) were placed in a double-necked flask under vacuum and argon protection. The mixture was dissolved in ultra-dry DMF, and DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF were added with stirring at room temperature. The mixture was stirred overnight at room temperature. After the reaction was detected by TLC, the reaction was quenched. The mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined and washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain a white solid. Take the white solid obtained in the previous step (1.3 eq), X2VL-M1 (1 eq), sodium iodide (0.2 eq), and potassium carbonate (2 eq) and dissolve them in DMSO. React at 80 °C for 4 h. After the reaction is completed, the reaction is quenched by TLC. Extract with ethyl acetate three times (50 mL * 3). Combine the organic phases and wash successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). Dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain the final product by column chromatography.

[0261] X2VL8: Off-white solid. 11H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.68 (s, 1H), 8.98 (s, 1H), 8.69 (d, J = 8.6 Hz, 1H), 8.40–8.29 (m, 3H), 7.82 (d, J = 7.8 Hz, 1H), 7.79–7.71 (m, 4H), 7.51 (t, J = 7.9 Hz, 1H), 7.44–7.37 (m, 4H), 7.29 (d, J = 8.2 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 5.12 (s, 1H), 4.91 (t, J = 7.2 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.60 (d, J = 4.6 Hz, 2H), 3.51 (s, 2H), 2.45 (s, 3H), 2.29 (s, 4H), 2.23 (q, J = 8.0 Hz, 4H), 2.14–2.02 (m, 2H), 2.00 (d, J = 9.0 Hz, 1H), 1.79 (ddd, J = 12.9, 8.6, 4.7 Hz, 1H), 1.51–1.43 (m, 8H), 1.40–1.36 (m, 7H), 1.24 (s, 8H), 0.93 (s, 9H). MS (ESI): m / z 1146.50 [M+H] + .

[0262] X2VL9: Pale beige solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.68 (s, 1H), 8.98 (s, 1H), 8.69 (d, J = 8.6 Hz, 1H), 8.40–8.30 (m, 3H), 7.82 (dd, J = 7.9, 1.6 Hz, 1H), 7.79–7.71 (m, 4H), 7.53–7.48 (m, 1H), 7.44–7.37 (m, 4H), 7.30–7.27 (m, 2H), 7.14 (t, J = 7.6 Hz, 1H), 5.12 (s, 1H), 4.91 (t, J = 7.2 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.27 (s, 1H), 3.60 (d, J = 5.2 Hz, 2H), 3.51 (s, 2H), 2.45 (s, 3H), 2.34 (s, 4H), 2.31–2.20 (m, 4H), 2.15–2.02 (m, 2H), 2.00 (d, J = 9.3 Hz, 1H), 1.79 (ddd, J = 12.8, 8.4, 4.6 Hz, 1H), 1.49 (s, 8H),

[0263] –1.36(m,7H),1.24(s,10H),0.93(s,9H).MS(ESI):m / z 1160.51[M+H] + .

[0264] X2VL10: Off-white solid. 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),9.69(s,1H),8.98(s,1H),8.69(d,J=8.7Hz,1H),8.40–8.31(m,3H),7.83(dd,J=7.9,1.6Hz,1H),7.75(dd,J=19 .9,8.8Hz,4H),7.53–7.48(m,1H),7.40(d,J=13.2Hz,4H),7.29(d,J=8.4H z,2H),7.14(t,J=7.6Hz,1H),5.12(s,1H),4.91(t,J=7.2Hz,1H),4.51(d,J =9.3Hz,1H),4.42(t,J=8.0Hz,1H),4.28(s,1H),3.60(t,J=4.0Hz,2H),3. 51(s,2H),2.45(s,3H),2.30(d,J=7.0Hz,4H),2.28–2.20(m,4H),2.14–2.0 2(m,2H),2.02–1.97(m,1H),1.79(ddd,J=12.8,8.4,4.7Hz,1H),1.48(d,J= 5.9Hz,8H),1.39(d,J=6.5Hz,7H),1.23(s,12H),0.93(s,9H).MS(ESI):m / z 1174.53[M+H] + .

[0265] X2VL11: Off-white solid. 1H NMR (400MHz, DMSO-d6) δ11.64(s,1H),9.69(s,1H),8.98(s,1H),8.69(d,J=8.6Hz,1H),8.40–8.30(m,3H),7.82(dd,J=7.9,1.6Hz,1H),7.75(dd,J=1 8.3,8.9Hz,4H),7.54–7.48(m,1H),7.44–7.37(m,4H),7.29(d,J=8.4Hz,2 H),7.17–7.12(m,1H),5.12(d,J=3.6Hz,1H),4.91(t,J=7.2Hz,1H),4.51( d,J=9.3Hz,1H),4.42(t,J=8.0Hz,1H),4.28(s,1H),3.62–3.57(m,2H),3. 51(s,2H),2.45(s,3H),2.26(dd,J=14.2,7.4Hz,1H),2.13–2.08(m,1H),2 .08–1.97(m,2H),1.80(td,J=8.4,4.3Hz,1H),1.62–1.47(m,8H),1.45(s, 7H),1.37(d,J=7.0Hz,3H),1.27–1.21(m,18H),0.93(s,9H).MS(ESI):m / z 1188.54[M+H] + .

[0266] Example 10. Preparation of compounds X3VL8-X3VL11

[0267]

[0268] 2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.3 eq) and 4-((5-bromo-4-((2-carbamoylphenyl)amino)pyrimidin-2-yl)amino)benzoic acid (1 eq) were placed in a double-necked flask under vacuum and argon protection. The ester was dissolved in ultra-dry DMF. DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF were added under stirring at room temperature. The mixture was stirred at room temperature and reacted overnight. After the reaction was detected by TLC, the reaction was quenched. The mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined and washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain a white solid. The white solid obtained in the previous step was dissolved in dichloromethane, and trifluoroacetic acid (V...) was slowly added under stirring. DCM V TFA=10:3), reacted at room temperature for 30 min. After the reaction was complete as detected by TLC, the solvent was removed by rotary evaporation (dichloromethane was added multiple times and evaporated) to obtain X3VL-M1.

[0269] Different ω-bromo fatty acids (1.3 eq) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (1 eq) were placed in a double-necked flask under vacuum and argon protection. The mixture was dissolved in ultra-dry DMF, and DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF were added with stirring at room temperature. The mixture was stirred overnight at room temperature. After the reaction was detected by TLC, the reaction was quenched. The mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined and washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain a white solid. Take the white solid obtained in the previous step (1.3 eq), X3VL-M1 (1 eq), sodium iodide (0.2 eq), and potassium carbonate (2 eq) and dissolve them in DMSO. React at 80 °C for 4 h. After the reaction is completed, the reaction is quenched by TLC. Extract with ethyl acetate three times (50 mL * 3). Combine the organic phases and wash successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). Dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain the final product by column chromatography.

[0270] X3VL8: Off-white solid. 11H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.69 (s, 1H), 8.98 (s, 1H), 8.69 (d, J = 8.5 Hz, 1H), 8.41–8.29 (m, 3H), 7.82 (d, J = 7.9 Hz, 1H), 7.75 (dd, J = 19.1, 9.0 Hz, 4H), 7.51 (t, J = 7.8 Hz, 1H), 7.44–7.36 (m, 4H), 7.29 (d, J = 8.3 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 5.12 (s, 1H), 4.91 (t, J = 7.2 Hz, 1H), 4.51 (d, J = 9.4 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.60 (d, J = 4.9 Hz, 2H), 3.51 (s, 1H), 2.45 (s, 3H), 2.29–2.20 (m, 2H), 2.14–2.06 (m, 2H), 2.00 (d, J = 9.7 Hz, 1H), 1.78 (td, J = 8.2, 4.2 Hz, 1H), 1.59 (t, J = 6.8 Hz, 2H), 1.48 (s, 6H), 1.41–1.35 (m, 7H), 1.24 (d, J = 4.8 Hz, 13H), 0.93 (s, 9H). MS (ESI): m / z 1132.48 [M+H] + .

[0271] X3VL9: Pale beige solid. 11H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.68 (s, 1H), 8.98 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.39–8.28 (m, 3H), 7.82 (dd, J = 7.9, 1.6 Hz, 1H), 7.79–7.71 (m, 4H), 7.51 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.44–7.36 (m, 4H), 7.31–7.27 (m, 2H), 7.15 (td, J = 7.6, 1.2 Hz, 1H), 5.10 (d, J = 3.4 Hz, 1H), 4.92 (q, J = 7.0 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.1 Hz, 1H), 4.28 (s, 1H), 3.60 (t, J = 3.8 Hz, 2H), 3.51 (s, 1H), 2.45 (s, 3H), 2.25 (dt, J = 14.8, 7.6 Hz, 2H), 2.14–2.02 (m, 2H), 1.99 (dd, J = 6.8, 3.4 Hz, 1H), 1.78 (td, J = 8.4, 4.2 Hz, 1H), 1.65 (s, 2H), 1.58–1.40 (m, 10H), 1.37 (d, J = 7.0 Hz, 3H), 1.25 (dd, J = 6.2, 3.5 Hz, 15H), 0.93 (s, 9H). MS (ESI): m / z 1146.50 [M+H] + 。

[0272] X3VL10: Pale beige solid. 11H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.69 (s, 1H), 8.98 (s, 1H), 8.68 (d, J = 8.5 Hz, 1H), 8.40–8.29 (m, 3H), 7.82 (dd, J = 8.0, 1.6 Hz, 1H), 7.75 (dd, J = 18.4, 8.8 Hz, 4H), 7.51 (t, J = 7.9 Hz, 1H), 7.44–7.36 (m, 4H), 7.29 (d, J = 8.4 Hz, 2H), 7.15 (t, J = 7.6 Hz, 1H), 5.11 (s, 1H), 4.91 (t, J = 7.2 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.27 (s, 1H), 3.60 (d, J = 5.4 Hz, 2H), 3.51 (s, 1H), 2.45 (s, 3H), 2.25 (dt, J = 14.9, 7.8 Hz, 2H), 2.08 (dq, J = 16.3, 8.1 Hz, 2H), 2.00 (d, J = 9.7 Hz, 1H), 1.78 (td, J = 8.3, 4.1 Hz, 1H), 1.63 (s, 2H), 1.58–1.40 (m, 10H), 1.37 (d, J = 7.0 Hz, 3H), 1.28–1.21 (m, 17H), 0.93 (s, 9H). MS (ESI): m / z 1160.51 [M+H] + .

[0273] X3VL11: Off-white solid. 1H NMR (400MHz, DMSO-d6) δ11.63(s,1H),9.68(s,1H),8.98(s,1H),8.68(d,J=8.5 Hz,1H),8.39–8.29(m,3H),7.82(dd,J=7.9,1.6Hz,1H),7.79–7.72(m,4H),7.5 3–7.49(m,1H),7.44–7.36(m,4H),7.30–7.27(m,2H),7.14(td,J=7.5,1.2Hz,1 H),5.11(d,J=3.5Hz,1H),4.91(t,J=7.3Hz,1H),4.51(d,J=9.3Hz,1H),4.42(t ,J=8.0Hz,1H),4.27(s,1H),3.60(d,J=4.6Hz,2H),3.51(s,1H),2.45(s,3H),2 .36(d,J=11.6Hz,4H),2.28–2.21(m,1H),2.10(q,J=6.8Hz,1H),2.03–1.98(m, 1H),1.78(td,J=8.3,4.2Hz,1H),1.61(t,J=6.9Hz,2H),1.49(dq,J=14.4,7.3H z,8H),1.37(d,J=7.0Hz,3H),1.24(d,J=4.3Hz,19H),0.93(s,9H).MS(ESI):m / z 1174.53 [M+H] + .

[0274] Example 11. Preparation of compounds X4VL8-X4VL11

[0275]

[0276] 1-(tert-butoxycarbonyl)azacyclobutane-2-carboxylic acid (1.3 eq) and ((2-((4-(3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)benzamide (1 eq) were placed in a double-necked flask, evacuated, and protected with argon. The mixture was dissolved in ultra-dry DMF, and DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF were added under stirring at room temperature. The mixture was stirred overnight at room temperature. After the reaction was detected by TLC, the reaction was quenched, and the mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined and washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain a white solid. The white solid obtained in the previous step was dissolved in dichloromethane, and trifluoroacetic acid (V) was slowly added under stirring. DCM VTFA =10:3), reacted at room temperature for 30 min. After the reaction was complete as detected by TLC, the solvent was removed by rotary evaporation (dichloromethane was added multiple times and evaporated) to obtain X4VL-M1.

[0277] Different ω-bromo fatty acids (1.3 eq) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (1 eq) were placed in a double-necked flask under vacuum and argon protection. The mixture was dissolved in ultra-dry DMF, and DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF were added with stirring at room temperature. The mixture was stirred overnight at room temperature. After the reaction was detected by TLC, the reaction was quenched. The mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined and washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain a white solid. Take the white solid obtained in the previous step (1.3 eq), X4VL-M1 (1 eq), sodium iodide (0.2 eq), and potassium carbonate (2 eq) and dissolve them in DMSO. React at 80 °C for 4 h. After the reaction is completed, the reaction is quenched by TLC. Extract with ethyl acetate three times (50 mL * 3). Combine the organic phases and wash successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). Dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain the final product by column chromatography.

[0278] X4VL8: Off-white solid. 11H NMR (400 MHz, DMSO-d6) δ 11.65 (d, J = 10.5 Hz, 1H), 9.70 (d, J = 3.9 Hz, 1H), 8.98 (s, 1H), 8.69 (d, J = 8.6 Hz, 1H), 8.41–8.29 (m, 3H), 7.83 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.1 Hz, 4H), 7.52 (s, 1H), 7.40 (d, J = 13.8 Hz, 4H), 7.33 (d, J = 10.0 Hz, 2H), 7.14 (t, J = 7.6 Hz, 1H), 5.12 (d, J = 3.5 Hz, 1H), 4.91 (t, J = 7.2 Hz, 1H), 4.68 (d, J = 18.5 Hz, 1H), 4.51 (d, J = 9.4 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.30–4.25 (m, 1H), 4.21 (d, J = 14.0 Hz, 1H), 3.90 (dt, J = 23.9, 12.8 Hz, 1H), 3.69 (d, J = 13.8 Hz, 2H), 3.60 (d, J = 4.7 Hz, 2H), 3.51 (s, 1H), 2.65–2.58 (m, 1H), 2.45 (s, 3H), 2.21 (d, J = 7.7 Hz, 2H), 2.12 (dd, J = 8.1, 3.7 Hz, 2H), 2.01 (dd, J = 11.3, 7.1 Hz, 2H), 1.79 (ddd, J = 12.8, 8.4, 4.7 Hz, 1H), 1.57 (s, 2H), 1.46 (s, 2H), 1.37 (d, J = 7.0 Hz, 3H), 1.30–1.15 (m, 13H), 0.92 (s, 9H). MS (ESI): m / z 1173.47 [M+H] + .

[0279] X4VL9: Pale beige solid. 11H NMR (400 MHz, DMSO-d6) δ 11.65 (d, J = 12.1 Hz, 1H), 9.70 (s, 1H), 8.98 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.41–8.27 (m, 3H), 7.82 (d, J = 7.9 Hz, 1H), 7.75 (s, 4H), 7.52 (s, 1H), 7.40 (d, J = 14.1 Hz, 4H), 7.33 (d, J = 9.5 Hz, 2H), 7.14 (t, J = 7.6 Hz, 1H), 5.11 (d, J = 3.3 Hz, 1H), 4.91 (p, J = 7.1 Hz, 1H), 4.68 (d, J = 18.1 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.27 (s, 1H), 4.21 (d, J = 13.6 Hz, 1H), 3.98–3.84 (m, 1H), 3.70 (t, J = 12.4 Hz, 2H), 3.60 (d, J = 4.7 Hz, 2H), 3.51 (s, 1H), 2.60 (d, J = 15.6 Hz, 1H), 2.45 (s, 3H), 2.21 (d, J = 7.6 Hz, 2H), 2.14–2.06 (m, 2H), 2.05–1.97 (m, 2H), 1.79 (ddd, J = 12.9, 8.4, 4.6 Hz, 1H), 1.57 (d, J = 9.0 Hz, 2H), 1.49–1.41 (m, 2H), 1.37 (d, J = 7.0 Hz, 3H), 1.31–1.12 (m, 15H), 0.93 (s, 9H). MS (ESI): m / z 1187.49 [M+H] + .

[0280] X4VL10: Pale beige solid. 11H NMR (400 MHz, DMSO-d6) δ 11.66 (d, J = 14.7 Hz, 1H), 9.69 (s, 1H), 8.98 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.40–8.28 (m, 3H), 7.82 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 10.2 Hz, 4H), 7.52 (s, 1H), 7.40 (d, J = 14.1 Hz, 4H), 7.32 (d, J = 11.4 Hz, 2H), 7.14 (t, J = 7.6 Hz, 1H), 5.11 (s, 1H), 4.91 (p, J = 7.1 Hz, 1H), 4.68 (d, J = 21.6 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.27 (s, 1H), 4.21 (d, J = 13.8 Hz, 1H), 3.96–3.84 (m, 1H), 3.70 (t, J = 15.0 Hz, 2H), 3.60 (d, J = 4.4 Hz, 2H), 3.51 (s, 1H), 2.62 (d, J = 10.3 Hz, 1H), 2.45 (s, 3H), 2.21 (d, J = 8.6 Hz, 2H), 2.11 (d, J = 8.6 Hz, 2H), 2.01 (t, J = 10.0 Hz, 2H), 1.79 (ddd, J = 12.9, 8.5, 4.7 Hz, 1H), 1.57 (d, J = 10.8 Hz, 2H), 1.46 (d, J = 7.7 Hz, 2H), 1.37 (d, J = 7.0 Hz, 3H), 1.29–1.11 (m, 17H), 0.93 (s, 9H). MS (ESI): m / z 1201.50 [M+H] + .

[0281] X4VL11: Off-white solid. 1H NMR(400MHz,DMSO-d6)δ11.67(d,J=17.5Hz,1H),9.70(s,1H),8.98(s,1H),8.69(s,1H),8.4 1–8.31(m,3H),7.83(d,J=7.8Hz,1H),7.76(d,J=10.0Hz,4H),7.52(d,J=7.1Hz,1H),7.40(d, J=13.5Hz,4H),7.33(d,J=8.9Hz,2H),7.14(t,J=7.6Hz,1H),5.13(d,J=3.5Hz,1H),4.91(p,J =7.1Hz,1H),4.69(d,J=25.3Hz,1H),4.51(d,J=9.3Hz,1H),4.42(t,J=8.0Hz,1H),4.28(s,1H ),4.20(d,J=14.5Hz,1H),3.97(dd,J=33.0,18.0Hz,1H),3.72(d,J=20.0Hz,2H),3.60(d,J= 4.8Hz,2H),3.51(s,1H),2.62(d,J=11.3Hz,1H),2.45(s,3H),2.21(d,J=7.5Hz,2H),2.10(t, J=7.2Hz,2H),2.01(t,J=10.9Hz,2H),1.79(ddd,J=12.8,8.4,4.6Hz,1H),1.61–1.49(m,2H), 1.48–1.41(m,2H),1.37(d,J=7.0Hz,3H),1.20(t,J=17.3Hz,19H),0.93(s,9H).MS(ESI):m / z 1215.52[M+H] + .

[0282] Example 12. Preparation of compounds X1V1L9, X1V2L9, and X1V3L9

[0283]

[0284] (s)-[1-(4-bromo-phenyl)-ethyl]-tert-butyl carbamate (1 eq), different five-membered aromatic heterocycles (R1) (2 eq), palladium acetate (0.1 eq), and potassium acetate (2 eq) were placed in a double-necked flask, evacuated, and protected with argon. The mixture was dissolved in ultra-dry DMF and reacted at 120 °C for 6 h. After the reaction was detected by TLC, the reaction was quenched, and the mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined and washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain a 1 d of off-white solid. The 1 d of off-white solid obtained in the previous step was dissolved in dichloromethane, and trifluoroacetic acid (V) was slowly added with stirring. DCM V TFA =10:3), reacted at room temperature for 30 min. After the reaction was complete as detected by TLC, the solvent was removed by rotary evaporation (dichloromethane was added multiple times and evaporated) to give an oily compound 2d.

[0285] Boc-L-hydroxyproline (1.3 eq) and oily compound 2d (1 eq) were placed in a double-necked flask, evacuated, and protected with argon. The mixture was dissolved in ultra-dry DMF, and DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF were added under stirring at room temperature. The mixture was stirred overnight at room temperature. After TLC detection, the reaction was quenched, and the mixture was extracted three times with ethyl acetate (50 mL * 3). The combined organic phases were washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain a milky white solid 3d. The milky white solid 3d obtained in the previous step was dissolved in dichloromethane, and trifluoroacetic acid (V...) was slowly added under stirring. DCM V TFA =10:3), reacted at room temperature for 30 min. After the reaction was complete as detected by TLC, the solvent was removed by rotary evaporation (dichloromethane was added multiple times and evaporated) to give an oily compound 4d.

[0286] A Boc-β-substituted-β-aminopropionic acid derivative (1.3 eq) and an oily compound 4d (1 eq) were placed in a double-necked flask under vacuum and argon protection. The mixture was dissolved in ultra-dry DMF, and DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF were added with stirring at room temperature. The mixture was stirred overnight at room temperature. After TLC detection, the reaction was quenched, and the mixture was extracted three times (50 mL * 3) with ethyl acetate. The combined organic phases were washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain a milky white solid 5d. The milky white solid 5d obtained in the previous step was dissolved in dichloromethane, and trifluoroacetic acid (V...) was slowly added with stirring. DCM V TFA=10:3), reacted at room temperature for 30 min. After the reaction was complete as detected by TLC, the solvent was removed by rotary evaporation (dichloromethane was added multiple times and evaporated) to give an oily compound 6d.

[0287] Different ω-bromofatty acids (1.3 eq) and an oily compound 6d (1 eq) were placed in a double-necked flask under vacuum and argon protection. The mixture was dissolved in ultra-dry DMF, and DIPEA (4.0 eq) and HATU (1.2 eq) dissolved in ultra-dry DMF were added with stirring at room temperature. The mixture was stirred overnight at room temperature. After the reaction was detected by TLC, the reaction was quenched, and the mixture was extracted three times with ethyl acetate (50 mL * 3). The combined organic phases were washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain a white solid 7d. The white solid 7d (1.3 eq), YUA-M1 (1 eq), sodium iodide (0.2 eq), and potassium carbonate (2 eq) obtained in the previous step were dissolved in DMSO and reacted at 80 °C for 4 h. After the reaction was detected by TLC, the reaction was quenched, and the product was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined and washed successively with saturated ammonium chloride (50 mL), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). The product was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the final product.

[0288] X1V1L9: Off-white solid. 11H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 9.68 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.39–8.30 (m, 3H), 7.82 (dd, J = 7.9, 1.6 Hz, 1H), 7.77 (dd, J = 16.9, 8.9 Hz, 4H), 7.53–7.49 (m, 1H), 7.39 (d, J = 2.9 Hz, 2H), 7.36 (d, J = 2.5 Hz, 4H), 7.13 (t, J = 7.6 Hz, 1H), 5.12 (d, J = 3.5 Hz, 1H), 4.90 (t, J = 7.3 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.41 (t, J = 8.0 Hz, 1H), 4.27 (s, 1H), 3.68–3.54 (m, 7H), 3.43 (s, 1H), 2.61 (s, 3H), 2.36 (s, 3H), 2.36–2.32 (m, 2H), 2.25 (dt, J = 14.7, 7.6 Hz, 2H), 2.12–2.07 (m, 1H), 2.03–1.99 (m, 1H), 1.81–1.76 (m, 1H), 1.50–1.44 (m, 3H), 1.36 (d, J = 7.0 Hz, 3H), 1.29 (d, J = 3.7 Hz, 12H), 0.93 (s, 9H). MS (ESI): m / z 1118.46 [M+H] + .

[0289] X1V2L9: Pale beige solid. 11H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 9.67 (s, 1H), 8.98 (s, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.39–8.30 (m, 3H), 7.97 (d, J = 8.6 Hz, 1H), 7.83 (dd, J = 7.9, 1.6 Hz, 1H), 7.76–7.73 (m, 3H), 7.53–7.49 (m, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.37 (t, J = 7.7 Hz, 4H), 7.13 (t, J = 7.6 Hz, 1H), 5.12 (s, 1H), 4.90 (t, J = 7.2 Hz, 1H), 4.44–4.41 (m, 1H), 4.41–4.38 (m, 1H), 4.28 (t, J = 3.8 Hz, 1H), 3.80 (dd, J = 22.3, 10.6 Hz, 2H), 3.65–3.54 (m, 7H), 3.41 (d, J = 5.5 Hz, 1H), 3.19 (dd, J = 15.4, 7.6 Hz, 2H), 2.45 (s, 3H), 2.36 (d, J = 6.2 Hz, 3H), 2.16 (ddd, J = 19.0, 12.9, 7.4 Hz, 2H), 2.10–2.00 (m, 2H), 1.90–1.84 (m, 1H), 1.80–1.74 (m, 1H), 1.65 (d, J = 13.5 Hz, 1H), 1.54 (d, J = 13.3 Hz, 1H), 1.47 (dd, J = 8.7, 5.4 Hz, 4H), 1.36 (d, J = 7.0 Hz, 3H), 1.29 (t, J = 4.5 Hz, 12H). MS (ESI): m / z 1132.44 [M+H] + 。

[0290] X1V3L9: Pale beige solid. 1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),9.67(s,1H),8.71(d,J=8.4Hz,1H),8 .39(d,J=7.8Hz,1H),8.32(d,J=4.8Hz,3H),7.82(dd,J=7.9,1.6Hz,1H),7.7 9–7.73(m,4H),7.55(d,J=8.3Hz,2H),7.53–7.49(m,1H),7.39(t,J=8.7Hz,4 H),7.15–7.11(m,1H),5.12(s,1H),4.90(t,J=7.2Hz,1H),4.51(d,J=9.3Hz, 1H),4.42(t,J=8.0Hz,1H),4.27(s,1H),3.59(tt,J=14.2,8.2Hz,7H),3.41 (s,1H),2.38(d,J=7.2Hz,2H),2.35(s,3H),2.28–2.21(m,1H),2.13–2.08(m ,1H),2.03–1.98(m,1H),1.78(ddd,J=12.8,8.4,4.7Hz,1H),1.46(d,J=8.2H z,2H),1.36(d,J=7.0Hz,3H),1.33–1.24(m,14H),0.93(s,9H).MS(ESI):m / z 1088.47[M+H] + .

[0291] Example 13. Preparation of compounds F1-F2, F4-F24

[0292]

[0293] 2,4-Dichloro-5-bromopyrimidine (1 eq), o-aminobenzamide (1.2 eq), and DIPEA (1.5 eq) were dissolved in IPA and reacted overnight at 90 °C. After the reaction was completed, the mixture was cooled, filtered, and washed with IPA to obtain the first-step intermediate.

[0294] Take the intermediate obtained in the first step (1 eq) and p-aminobenzoic acid / p-aminophenylacetic acid / 3-(4-aminophenyl)propionic acid / 4-(4-aminophenyl)butyric acid (2 eq), add sec-butanol (10 mL) and trifluoroacetic acid (TFA, 200 μL). The reaction mixture was stirred and heated overnight at 100 °C in a sealed tube. After the reaction was completed by TLC, it was cooled to room temperature, and a solid precipitated. The residue was collected by vacuum filtration and washed with sec-butanol. No further purification was required to obtain the second-step intermediate with different chain lengths.

[0295] Take the corresponding second-step intermediate (1 eq), HATU (1.3 eq), and DIPEA (2.6 eq), dissolve them in DMF (3 mL), and slowly add a DMF solution of the corresponding amine (1.5 eq). Stir overnight at room temperature. After the reaction is completed by TLC monitoring, add water (10 mL) to quench the reaction. A solid precipitates out. Collect the residue by vacuum filtration. Pulverize the residue with PE / EA = 1:1 (3 mL), filter again, and wash with PE / EA = 1:1 (2 mL × 2) to obtain the target compounds F1-F2, F4, and F6-F24.

[0296] Take the corresponding intermediate from step 2 (1 eq), DMAPO (0.025 eq), and carbazole (1 eq), add ultra-dry DMF and ultra-dry TEA (2 eq) under nitrogen protection, stir at room temperature for a period of time, add a DMF solution of di-tert-butyl dicarbonate (1.3 eq), stir at room temperature for 4 h, quench with water, extract with EA, combine the EA layers, extract with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure to remove solvent, and perform column chromatography on 200-300 mesh silica gel (DCM / MeOH = 20:1) to obtain compound F5.

[0297] F1: Off-white solid. 1 H NMR (400MHz, DMSO-d6) δ11.67(s,1H),9.75(s,1H),8.71(d,J=8.5Hz,1H),8.36(s,1H),8.32(s,1H),8.26(t,J=5.8Hz,1H),7.83 (dd,J=8.0,1.6Hz,1H),7.77(d,J=3.8Hz,5H),7.59–7.50(m,1H),7.22–7.13(m,1H),6.19(dd,J=5.7,3.0Hz,1H),6.05(dd,J=5. 8,2.9Hz,1H),3.00(dt,J=12.8,6.0Hz,1H),2.93(dd,J=8.5,5.9Hz,1H),2.81(s,1H),2.78(s,1H),2.35(d,J=11.4Hz,1H),1.80 (ddd,J=12.4,9.1,3.8Hz,1H),1.36–1.30(m,1H),1.22(d,J=8.1Hz,1H),0.56(dd,J=11.4,4.2Hz,1H).MS(ESI):m / z533.13[M+H] + .

[0298] F2: Off-white solid. 1H NMR (400MHz, DMSO-d6) δ11.67(s,1H),9.72(s,1H),8.72(d,J=8.5Hz,1H),8.35(s,1H),8.31(s,1H),7.82(dd,J=7.7,1.5Hz ,1H),7.79–7.67(m,5H),7.55(t,J=7.6Hz,1H),7.40(s,1H),7.17(t,J=7.6Hz,1H),2.07(s,9H),1.66(s,6H).MS(ESI):m / z 561.16[M+H] + .

[0299] F4: Off-white solid. 1 H NMR (400MHz, DMSO-d6) δ11.68(s,1H),9.83(s,1H),9.66(s,1H),8.72(d,J=8.5Hz,1H),8.43–8.31(m,2H),7.94–7.76(m,6H),7.59 (t,J=7.9Hz,1H),7.18(t,J=7.6Hz,1H),7.01(s,1H),2.92–2.81(m,4H),2.72(d,J=7.7Hz,4H),1.99(p,J=7.5Hz,4H).MS(ESI):m / z 583.15[M+H] + .

[0300] F5: Off-white solid. 1 H NMR (400MHz, DMSO-d6) δ11.70(s,1H),10.06(s,1H),8.70(d,J=8.4Hz,1H),8.41(s,1H),8.32(s,1H),8.27–8.20(m,2H),7.93(d,J=8.6Hz,2H),7.8 5(s,1H),7.82–7.75(m,2H),7.65(d,J=8.7Hz,2H),7.51–7.46(m,2H),7.4 3(d,J=6.1Hz,1H),7.42–7.37(m,3H),7.10(t,J=7.4Hz,1H).MS(ESI):m / z 577.10[M+H] + .

[0301] F6: Off-white solid. 1H NMR (400MHz, DMSO-d6) δ11.68(s,1H),9.80(s,1H),8.91(d,J=8.4Hz,1H),8.71(d,J=8.5Hz,1H),8.37(s,1H),8.32(s,1H),7.90(dd,J=8.2,3.7Hz,4 H),7.84–7.76(m,4H),7.58–7.50(m,3H),7.44(t,J=7.4Hz,2H),7.34(td, J=7.4,1.1Hz,2H),7.19–7.12(m,1H),6.31(d,J=8.3Hz,1H).MS(ESI):m / z 591.11[M+H] + .

[0302] F7: Pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.69 (s, 1H), 9.78 (d, J = 2.4Hz, 1H), 9.10 (dd, J = 9.0, 2.4Hz, 1H),8.73(d,J=8.5Hz,1H),8.38–8.35(m,1H),8.32(s,1H),7.88(dd,J=8.9,2.4Hz,2 H),7.85–7.76(m,4H),7.54(t,J=7.7Hz,1H),7.42–7.33(m,8H),7.28(dp,J=7.0,2.5 Hz,2H),7.17(t,J=8.1Hz,1H),6.43(dd,J=9.0,2.3Hz,1H).MS(ESI):m / z593.13[M+H] + .

[0303] F8: White solid. 11H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.44 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 7.6 Hz, 2H), 8.01 (t, J = 5.6 Hz, 1H), 7.81 (dd, J = 7.9, 1.5 Hz, 1H), 7.76 (s, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.48 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 8.3 Hz, 2H), 7.14–7.07 (m, 1H), 6.14 (dd, J = 5.6, 3.0 Hz, 1H), 5.94 (dd, J = 5.6, 2.9 Hz, 1H), 3.34 (s, 2H), 2.83 (dt, J = 12.8, 6.1 Hz, 1H), 2.76 (s, 1H), 2.74 (s, 1H), 2.69–2.58 (m, 1H), 2.22–2.09 (m, 1H), 1.76 (ddd, J = 12.6, 9.2, 3.8 Hz, 1H), 1.30 (d, J = 8.1 Hz, 1H), 1.18 (d, J = 7.3 Hz, 1H), 0.45 (ddd, J = 11.4, 4.3, 2.4 Hz, 1H). MS (ESI): m / z 547.15 [M+H] + 。

[0304] F9: White solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.41 (s, 1H), 8.72 (d, J = 7.9 Hz, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 7.84–7.75 (m, 3H), 7.55 (d, J = 8.1 Hz, 2H), 7.50 (t, J = 7.9 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 8.5 Hz, 2H), 6.12 (dd, J = 5.7, 3.0 Hz, 1H), 5.92 (dd, J = 5.7, 2.9 Hz, 1H), 2.88–2.56 (m, 6H), 2.36 (q, J = 7.3 Hz, 2H), 2.11 (s, 1H), 1.72 (t, J = 3.0 Hz, 1H), 1.29–1.23 (m, 1H), 1.14 (d, J = 7.9 Hz, 1H), 0.41 (dt, J = 11.4, 3.9 Hz, 1H). MS (ESI): m / z 561.16 [M+H] + 。

[0305] F10: White solid. 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),9.42(s,1H),8.72(s,1H),8.30(s,1H),8.28(s,1H),7.85–7.79(m,2H),7.77(s,1H) ,7.56(d,J=8.1Hz,2H),7.52–7.44(m,1H),7.15–7.10(m,1H),7.10–7.05(m,2H),6.15(dd,J=5.7,3.0Hz,1H),5.96(dd,J=5 .7,2.9Hz,1H),2.86–2.72(m,3H),2.64(ddd,J=13.2,9.0,5.7Hz,1H),2.24–2.11(m,1H),2.08(t,J=7.3Hz,2H),1.77(ddt ,J=11.3,9.1,6.2Hz,3H),1.30(dt,J=6.7,2.2Hz,1H),1.21–1.17(m,1H),0.45(ddd,J=11.4,4.6,2.6Hz,1H).MS(ESI):m / z 575.18[M+H] + .

[0306] F11: White solid. 1 H NMR(400MHz,DMSO-d6)δ11.62(s,1H),9.43(s,1H),8.70(s,1H),8.30(s,1H ),8.28(s,1H),7.80(dd,J=7.9,1.5Hz,1H),7.76(s,1H),7.58–7.51(m,3H), 7.47(t,J=7.8Hz,1H),7.14(d,J=8.4Hz,2H),7.10(d,J=7.6Hz,1H),3.29(s, 2H),1.99(s,3H),1.93(d,J=2.9Hz,6H),1.61(t,J=3.0Hz,6H).MS(ESI):m / z 575.18[M+H] + .

[0307] F12: White solid. 1H NMR (400MHz, DMSO-d6) δ11.68(s,1H),9.76(s,1H),8.72(d,J=8.5Hz,1H),8.36(s,1H),8.33(s,1H),8.13(t,J=6.4Hz,1H),7.85–7.74(m ,6H),7.58–7.51(m,1H),7.20–7.12(m,1H),2.99(d,J=6.3Hz,2H),1.93(s,3H),1.63(q,J=12.1Hz,6H),1.53–1.45(m,6H).MS(ESI):m / z 575.18[M+H] + .

[0308] F13: White solid. 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),9.43(s,1H),8.71(s,1H),8.29(d,J=2.9Hz,1H), 8.28(s,1H),7.86–7.78(m,2H),7.76(s,1H),7.56(d,J=8.2Hz,2H),7.48(t,J=7.7Hz,1 H),7.18(d,J=8.2Hz,2H),7.15–7.08(m,1H),3.38(s,2H),2.77(d,J=6.3Hz,2H),1.89( s,3H),1.64(d,J=12.4Hz,3H),1.54(d,J=11.7Hz,3H),1.42–1.38(m,6H).MS(ESI):m / z 589.19[M+H] + .

[0309] F14: White solid. 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),9.41(s,1H),8.72(s,1H),8.29(d,J=13.6Hz,2H),7.84–7.74(m,2H),7.64(t,J=6.2Hz,1H),7.60–7. 48(m,3H),7.17–7.07(m,3H),2.82–2.71(m,4H),2.41(t,J=7.6Hz,2H),1.85(s,3H),1.64–1.47(m,6H),1.32(d,J=2.8Hz,6H).MS(ESI):m / z 603.21[M+H] + .

[0310] F15: White solid. 11H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.42 (s, 1H), 8.71 (s, 1H), 8.30 (s, 1H), 8.27 (s, 1H), 7.84–7.73 (m, 2H), 7.66 (d, J = 6.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.11 (dd, J = 18.3, 8.0 Hz, 3H), 2.76 (d, J = 6.2 Hz, 2H), 2.12 (t, J = 7.5 Hz, 2H), 1.91 (s, 3H), 1.79 (q, J = 7.8 Hz, 2H), 1.65 (d, J = 12.1 Hz, 3H), 1.57 (d, J = 12.0 Hz, 3H), 1.44–1.40 (m, 6H). MS (ESI): m / z 617.22 [M+H] + 。

[0311] F16: White solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 9.61 (s, 1H), 9.01 (d, J = 8.7 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 3.1 Hz, 2H), 7.81 (dd, J = 8.0, 1.6 Hz, 1H), 7.77 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.46–7.38 (m, 1H), 7.35–7.27 (m, 8H), 7.26–7.23 (m, 2H), 7.20 (d, J = 8.3 Hz, 2H), 7.15–7.07 (m, 1H), 6.12 (d, J = 8.6 Hz, 1H), 3.52 (s, 2H). MS (ESI): m / z 607.15 [M+H] +

[0312] F17: White solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 9.45 (s, 1H), 8.71 (t, J = 9.0 Hz, 2H), 8.29 (s, 2H), 7.81 (d, J = 7.9 Hz, 1H), 7.74 (s, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.29 (t, J = 7.4 Hz, 4H), 7.24–7.09 (m, 9H), 6.11 (d, J = 8.5 Hz, 1H), 2.81 (t, J = 7.6 Hz, 2H), 2.53 (d, J = 7.2 Hz, 2H). MS (ESI): m / z 621.16 [M+H]+

[0313] F18: Light brown solid. 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),9.90(s,1H),8.78(d,J=8.8Hz,1H),8.6 2–8.54(m,1H),8.35(s,2H),7.86–7.80(m,2H),7.48(d,J=8.2Hz,2H),7.48–7 .40(m,1H),7.37–7.19(m,10H),7.19–7.10(m,3H),6.15(d,J=8.7Hz,1H),2.5 4(t,J=7.6Hz,2H),2.25(t,J=7.4Hz,2H),1.83(p,J=7.5Hz,2H).MS(ESI):m / z 635.18[M+H] +

[0314] F19: Light brown solid. 1 H NMR(400MHz,DMSO-d6)δ11.65(s,1H),9.55(s,1H),9.49(s,1H),8.71(s,1H),8.30( d,J=4.4Hz,2H),7.80(d,J=8.1Hz,1H),7.77(s,1H),7.61(d,J=8.1Hz,2H),7.47(t, J=7.9Hz,1H),7.25(d,J=8.2Hz,2H),7.10(t,J=7.6Hz,1H),6.94(s,1H),3.55(s,2H ),2.80(t,J=7.4Hz,4H),2.63(t,J=7.4Hz,4H),1.94(p,J=7.4Hz,4H).MS(ESI):m / z 597.16[M+H] +

[0315] F20: Brown solid. 1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),9.59(s,1H),9.34(s,1H),8.68(s,1H),8.32 (d,J=8.3Hz,2H),7.87–7.77(m,2H),7.56(d,J=8.2Hz,2H),7.50–7.44(m,1H),7.1 9(d,J=8.4Hz,2H),7.11(t,J=7.5Hz,1H),6.91(s,1H),2.89(t,J=7.5Hz,2H),2.78 (t,J=7.4Hz,4H),2.59(td,J=7.7,2.4Hz,6H),1.92(p,J=7.4Hz,4H).MS(ESI):m / z 611.18[M+H] +

[0316] F21: Brown solid. 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),9.69(s,1H),9.35(s,1H),8.75–8.54(m,1H),8.33(d ,J=8.6Hz,2H),7.82(d,J=7.8Hz,2H),7.54(d,J=8.1Hz,2H),7.47(t,J=7.9Hz,1H),7.14(dd ,J=14.5,7.7Hz,3H),6.94(s,1H),2.81(t,J=7.4Hz,4H),2.68(t,J=7.4Hz,4H),2.61(t,J=7 .6Hz,2H),2.31(t,J=7.4Hz,2H),1.96(p,J=7.5Hz,4H),1.90(t,J=7.5Hz,2H).MS(ESI):m / z 625.19[M+H] +

[0317] F22: Pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),9.46(s,1H),8.72(dd,J=12.9,8.4Hz,2H),8 .30(s,2H),7.87(d,J=7.5Hz,2H),7.81(dd,J=7.9,1.6Hz,1H),7.75(s,1H),7.61( d,J=8.5Hz,2H),7.51–7.38(m,5H),7.32(t,J=7.4Hz,2H),7.23(d,J=8.5Hz,2H),7 .11(t,J=7.6Hz,1H),6.02(d,J=8.2Hz,1H),3.50(s,2H).MS(ESI):m / z605.13[M+H] +

[0318] F23: White solid. 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),9.44(s,1H),8.73(d,J=7.8Hz,1H),8.42(d,J=8.4Hz,1H) ,8.29(s,2H),7.82(d,J=7.6Hz,2H),7.80(d,J=7.7Hz,1H),7.74(s,1H),7.59(d,J=8.3Hz,2H), 7.49(t,J=7.9Hz,1H),7.39(t,J=7.4Hz,2H),7.34(d,J=7.4Hz,2H),7.26(t,J=7.4Hz,2H),7.15 (d,J=8.3Hz,2H),7.11(t,J=7.4Hz,1H),6.02(d,J=8.5Hz,1H),2.94–2.85(m,2H).MS(ESI):m / z 619.15[M+H] +

[0319] F24: White solid. 1H NMR (400MHz, DMSO-d6) δ11.87(s,1H),9.68(s,1H),8.64(d,J=8.3Hz,1H),8.46(d,J=8 .4Hz,1H),8.32(d,J=4.3Hz,2H),7.89–7.74(m,4H),7.50(dt,J=13.1,7.0Hz,4H),7.42 (t,J=7.4Hz,3H),7.33(t,J=7.4Hz,2H),7.15(dd,J=8.1,6.4Hz,3H),6.06(d,J=8.3Hz ,1H),2.60(t,J=7.6Hz,2H),2.25(t,J=7.3Hz,2H),1.91(p,J=7.4Hz,2H).MS(ESI):m / z 633.16[M+H] +

[0320] Example 14. Preparation of compound F3

[0321]

[0322] Take the intermediate (1 eq) obtained in the first step of Example 7 and 4-(1-adamantyl)aniline (2 eq), add 10 mL of sec-butanol and 200 μL of TFA, and react overnight at 100 °C under sealed conditions. A solid precipitates out. After cooling to room temperature, collect the residue by vacuum filtration and wash with sec-butanol; slurry the residue with methanol (5 mL), filter again, and wash with methanol to obtain the target compound F3, a white solid.

[0323] 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),10.16(s,1H),8.56(s,1H),8.41(s,1H),8.39(s,1H),7.90–7.82(m,2H),7.48(d,J=8.6Hz,2H),7.4 3(t,J=7.9Hz,1H),7.36–7.31(m,2H),7.22(t,J=7.6Hz,1H),2.09–2.05(m,3H),1.87(d,J=3.1Hz,6H),1.74(d,J=3.2Hz,6H).MS(ESI):m / z 518.16[M+H] + .

[0324] Example 15. Determination of the degradation activity of the pyrimidine compounds of the present invention against JNK.

[0325] (1) Reagents and materials: human bronchial epithelial cells (BEAS-2B), fenestrone (#22862-76-6, Aladdin, China), BCA protein concentration assay kit (#P0010, Beyotime, China).

[0326] (2) Experimental instruments: Western blot electrophoresis apparatus, e-BLOT exposure apparatus.

[0327] (3) Experimental methods: BEAS-2B cells in logarithmic growth phase were placed in 6 cm cell culture dishes and starved with serum-free medium for 24 hours. Through exploration of the treatment time and concentration of different degradation agents, JNK1 degradation agents of different concentrations were used for a certain period of time, followed by induction with 0.25 μM anisomycin for 1 hour to activate the JNK signaling pathway. After lysis with RIPA lysis buffer, the supernatant protein concentration was measured using a BCA protein concentration assay kit.

[0328] After denaturation, protein samples were separated by electrophoresis on a 10% SDS-PAGE gel and then transferred to a PVDF membrane. The PVDF membrane was then blocked with 5% skim milk for 1 hour, and the corresponding sample bands were incubated overnight at 4°C with their respective antibodies. Afterward, the samples were incubated with secondary antibody at room temperature for 1 hour. Following thorough washing, the samples were visualized using an e-BLOT instrument.

[0329] (4) Experimental Results

[0330] The bioactivity of the compounds described in this invention was determined through the above experiments. All compounds exhibited a certain degree of degradation activity against JNK1, as shown in the table below. Among them, the compounds designated as "A" for JNK1 degradation activity provided DC... 50 Value is DC 50 ≤0.01 μM; DC provided by compounds with activity specified as "B" 50 The value is 0.01 μM < DC 50 ≤0.1 μM; DC provided by compounds with activity specified as "C" 50 The value is 0.1 μM < DC 50 ≤1μM; DC provided by compounds with activity specified as "D" 50 The value is 1μM < DC 50 ≤10 μM; DC provided by compounds with activity specified as "E" 50 Value is DC 50 >10μM;

[0331]

[0332]

[0333] Example 16. Determination of the inhibitory activity of the compounds of the present invention on tumor cells.

[0334] (1) Reagents and materials: different tumor cell lines (including but not limited to human lung adenocarcinoma cells (A549), human cervical cancer cells (HeLa), human pancreatic cancer cells (SW1990), human pancreatic cancer cells (PANC-1), human orthotopic pancreatic adenocarcinoma cells (BxPC-3)), CellTiter-Glo (#G7573, Promega, USA).

[0335] (2) Experimental instruments: microplate shaker (Thermo, USA), Spark microplate reader (Tecan, Switzerland).

[0336] (3) Experimental methods:

[0337] Different cell lines were seeded at a density of 3000 cells / well in 80 μL of culture medium into 96-well plates (#3917, CORNING, USA). The next day, different concentrations of the test compound (20 μL, ≤1% DMSO) were added to each well, with three replicates for each treatment. The 96-well plates were then incubated at 37°C and 5% CO2 for 72 hours.

[0338] After equilibrating the 96-well plate and CellTiter-Glo assay reagent at room temperature for 10 min, add an equal volume of CellTiter-Glo reagent to each well, equal to the amount of culture medium. Incubate the cells on a plate shaker at 25°C for 20 min to stabilize the luminescence signal. Finally, quantitatively detect the luminescence signal using a Spark microplate reader.

[0339] (4) Experimental Results

[0340] The compounds of the present invention exhibited varying degrees of cell-inhibiting activity against different tumor cells, as determined by the methods described above.

[0341] Example 17. Toxicity experiment of the compound of the present invention on normal cells.

[0342] (1) Reagents and materials: normal cells (such as normal human lung epithelial cells (BEAS-2B)) and CellTiter-Glo (#G7573, Promega, USA).

[0343] (2) Experimental instruments: microplate shaker (Thermo, USA), Spark microplate reader (Tecan, Switzerland).

[0344] (3) Experimental methods:

[0345] BEAS-2B cells in logarithmic growth phase were seeded at a density of 800 cells / well in 20 μL of culture medium into 384-well plates (#3570, CORNING, USA). The next day, different compounds were diluted to different concentrations (5 μL, ≤1% DMSO), with three replicates for each treatment. The 384-well plates were then incubated at 37°C and 5% CO2 for 48 hours.

[0346] The 384-well plate and CellTiter-Glo assay reagent were equilibrated at room temperature for 10 min. Then, an equal volume of CellTiter-Glo reagent to the culture medium was added to each well. The cells were incubated on a plate shaker at 25°C for 20 min to stabilize the luminescence signal. Finally, the luminescence signal was quantitatively detected using a Spark microplate reader.

[0347] (4) Experimental Results

[0348] The compounds of the present invention exhibit acceptable toxicity to normal cells (such as BEAS-2B cells) as determined by the above methods, thus demonstrating suitable safety.

[0349] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of Formula 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, Formula 1 wherein JL represents a ligand that binds to a target protein JNK, D represents a ligand that binds to an E3 ubiquitin ligase or is a hydrophobic tag, and L represents a linker that connects the two ligands. JL is:

2. The compound according to claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, wherein wherein, alternatively, two adjacent R2s together with the carbon atoms to which they are attached form a 3-10 membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; R1is selected from: H, halo, cyano, optionally substituted C 1-10 alkyl, optionally substituted C 1-10 alkoxy, -C(O)R5; R2is selected from: H, hydroxy, optionally substituted C 1-10 alkyl, optionally substituted C 5-10 aryl, halogen, cyano, nitro, -C 0-6 -C(O)R5, -C 0-6 -OR6, -C 0-6 -N(R7)2, optionally substituted sulfonyl, optionally substituted phosphinyl, optionally substituted 5-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; x is 0, 1, 2, 3, 4, or 5; y is 0, 1, 2, 3, 4, or 5, as valency permits; A ring is selected from: C 5-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, C 3-10 cycloalkenyl, 3-10 membered heterocyclenyl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, 8-10 membered bicyclic aryl, or bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, 8-10 membered bicyclic carbocyclyl, or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; R3is selected from: H, hydroxyl, halogen, cyano, nitro, -C 0-6 -C(O)R5, -C 0-6 -OR6, -C 0-6 -N(R7)2, optionally substituted sulfonyl, optionally substituted C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 1-10 alkoxy, optionally substituted C 5-10 aryl or heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; R4 is H; 3. The compound of claim 2, or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: each R5is independently selected from the group consisting of: H, optionally substituted hydroxy, optionally substituted amino, optionally substituted C 1-10 alkyl, optionally substituted C 1-10 alkoxy, optionally substituted C 5-10 aryl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; each R6is independently selected from the group consisting of: H, optionally substituted C 1-3 acyl, optionally substituted C 1-10 alkyl, optionally substituted C 5-10 aryl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; each R7is independently selected from the group consisting of: H, optionally substituted C 1-3 acyl, optionally substituted C 1-10 alkyl, optionally substituted C 5-10 aryl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S. R1 is selected from the group consisting of H, halogen; x is 0, 1, 2, or 3; R2is selected from: H, hydroxyl, halogen, cyano, nitro, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, -C 0-6 -C(O)R5, -C 0-6 -OR6, -C 0-6 -N(R7)2; y is 0, 1, or 2, as valency permits; A ring is selected from: phenyl, 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, C 3-6 cycloalkyl, 5-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; R3is selected from: H, hydroxyl, halogen, cyano, nitro, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy; R4 is H; JL is: R5is independently selected from: H, hydroxyl, optionally substituted amino, optionally substituted C 1-6 alkoxy; R6is independently selected from: H, optionally substituted C 1-6 alkyl; R7is independently selected from: H, optionally substituted C 1-6 alkyl.

4. The compound of claim 3, or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein, L is a bond, -C(O)-, or selected from the group consisting of:

5. The compound according to claims 1-4, or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, L is a bond, or C 1-20 saturated or unsaturated hydrocarbon chain, wherein said C 1-20 one or more carbon atoms in the hydrocarbon chain can be independently replaced by -O-, -S-, -C(O)-, -S(O)2-, -N(R7)-, -N(R7)-C(O)-, -C(O)-N(R7)-, -O-C(O)-, -C(O)-O-, -N(R7)-S(O)2-, -S(O)2-N(R7)-, or, independently, by C 5-10 aryl, 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, C 3-10 cycloalkenyl, 3-10 membered heterocyclenyl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, 8-10 membered bicyclic aryl or bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, 8-10 membered bicyclic carbocyclyl or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, all of which can be optionally substituted when appropriate; each R7is independently selected from the group consisting of H, optionally substituted C 1-6 alkyl.

6. The compound of claim 5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein, D is a ligand that binds to CRBN, VHL, or RNF126.

7. The compound according to claims 1-4, or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, D is selected from the group consisting of:

8. The compound of claim 7, or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein, D is a hydrophobic tag. wherein R8is selected from the group consisting of: hydroxy, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkynyl, -O-aryl, 5-10 membered aryl, or heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; or, two R8together with the carbon atom to which they are attached form a 5-10 membered aryl or heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a 5-10 membered cycloalkyl, or a heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, or S.

9. The compound according to claims 1-4, or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, 11. A compound selected from the group consisting of:

10. The compound of claim 9, or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein, D is selected from the group consisting of: The pharmaceutical composition comprises a compound of any one of claims 1-11, or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier. Preferably, the compound is selected from the group consisting of:

12. A pharmaceutical composition, characterized by, 13. Use of a compound of any one of claims 1-11, or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a JNK degrader. ​

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