Aryl-substituted DDR1 degradation agent as well as preparation method and application thereof

Abstract

The invention provides an aryl-substituted DDR1 degradation agent as well as a pharmaceutical composition, a preparation method and application of the aryl-substituted DDR1 degradation agent. Specifically, the invention provides a DDR1 degradation agent with a structure as shown in a formula (I), and the compound is a protein kinase degradation agent and can efficiently and selectively degrade DDR1 protein and inhibit proliferation, migration and invasion of various tumor cells. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of chemical medicine, and specifically relates to a class of aryl-substituted DDR1 degrading agents, their preparation methods and applications. Background Art

[0002] Protein kinases are key regulatory molecules of cell functions and constitute one of the largest and most functionally diverse gene families. Protein kinases guide the activities, localization and overall functions of many proteins through phosphorylation of substrate proteins and are involved in almost all cellular activities. Abnormalities in the expression, activation, localization, etc. of protein kinases are closely related to the occurrence and development of various diseases and are important driving factors for various diseases such as tumors and inflammation. As of December 31, 2020, the FDA has approved a total of 62 kinase inhibitor drugs for marketing. Research has found that the non-kinase functions of proteins play important roles in diseases such as tumors. The non-kinase functions of kinases such as DDR1, CDK6, FAK, EGFR, PIPK3, PDK1, BRAF, CRAF, CHK2, ZAP70, AKT, Aurora A, etc. have been reported in the literature. Therefore, simply inhibiting the activity of kinases cannot completely inhibit the non-kinase functions of kinases, thus bringing potential adverse effects such as low efficacy and drug resistance. Therefore, developing protein degrading agents is expected to comprehensively inhibit the enzymatic activity and non-kinase functions of kinases and exert a potent therapeutic effect. The protein degrading agents based on the PROTAC principle are currently the most successful and mature protein degradation strategies and have been successfully used for the development of degrading agents for multiple kinases and other targets.

[0003] ATTEC specifically refers to a class of small molecule compounds that can specifically recognize and induce the degradation of target proteins; the molecular structure consists of three parts: a target protein recognition ligand, a Linker and an LC3 recognition ligand. The advantage of ATTEC is that it can not only effectively inhibit the kinase activity of the target protein, but also rapidly degrade and remove the target protein. In theory, only a catalytic amount of the drug is required to degrade almost all proteins (including membrane proteins) in cells, so it has high safety, drug resistance and broad application prospects. At present, degrading agents for target proteins such as NAMPT have been successfully developed, and ATTEC belongs to one of the small molecule degrading agents. Research on a large number of degrading agents reported currently shows that they can not only treat the proliferation of gene-driven tumors but also overcome inhibitor resistance.

[0004] Discoidin domain receptor protein 1 (DDR1) belongs to the members of the receptor tyrosine kinase family (RTKs). It plays biological functions after being activated by ligands such as collagen. DDRs are divided into DDR1 and DDR2. DDR1 contains a total of five subtypes: a, b, c, d, and e. There is a DS domain (Discoidin domain) and a DS-like domain (discoidin-like domain) at its N-terminus. As a member of the RTKs protein family, DDR1 has an extracellular juxtamembrane domain (EJM), a transmembrane domain (TM), an intracellular juxtamembrane domain (IJM), and a kinase domain (KD) unique to protein kinases. The DS domain is the main structural difference between DDR1 and other RTKs proteins. DDR1 binds to various types of triple-helix collagens such as type I, II, III, and V through the DS domain and recognizes the GVMGVO peptide motif of collagen, and finally autophosphorylates to activate itself, rather than general RTKs proteins being activated by recognizing growth factor ligands. DDR1 is significantly different from other RTKs proteins due to its unique ECD, and its specific structure is also reflected in its distribution at the cellular and tissue levels. The DS domain of DDR1 plays an important function. TM4SF1 activates DDR1 to regulate the invasion-metastasis cascade reaction through non-classical DDR1 signals, and reactivates the self-renewal and metastasis of tumor stem cells by activating STAT3 in the stroma of target organs. The extracellular domain (ECD) of DDR1 in tumor cells mediates the orderly arrangement of collagen fibers in the extracellular matrix, which can effectively induce immune rejection effects, resulting in the escape of tumor cells. These studies suggest that the non-kinase catalytic function of DDR1 plays a key role in the occurrence and development of tumors. Using the lysosomal autophagy-targeting tethered chimera (ATTEC) technology and novel degradation warheads to induce the degradation of DDR1, while inhibiting its kinase function and non-kinase function, has great potential in the study of the biological function of DDR1 and disease treatment, and has attracted increasing interest from scientists in recent years. However, the existing DDR1 degraders have low selectivity and cannot meet clinical needs. Therefore, there is an urgent need for a class of highly efficient and highly selective DDR1 degraders. Summary of the Invention

[0005] To solve the above problems, the present invention provides a class of polysubstituted benzene ring compounds, which can be used as DDR1 degraders. This class of compounds can effectively and highly selectively degrade DDR1 protein kinase and inhibit the proliferation, migration, and invasion of various tumor cells.

[0006] In the first aspect of the present invention, there is provided a compound having the structure shown in formula (I), its pharmaceutically acceptable salt, stereoisomer or prodrug,

[0007]

[0008] Among them, the Linker does not exist or is

[0009] Among them, R1, R2, R3, R4, R5, R6 are the same or different, and each independently is selected from the following group of structures: chemical bond, CH2, C=O, O, NH;

[0010] Among them, n is 0, 1, 2, 3, 4, 5 or 6;

[0011] A is an LC3 protein ligand molecule or an unsaturated enone warhead molecule selected from the following group:

[0012]

[0013] Among them, R L is selected from the following group: hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C2 alkyl, halo-C1-C2 alkoxy.

[0014] In a preferred example, the Linker does not exist, or the Linker is

[0015] Among them, R1 is selected from the following group: chemical bond, -C(O)-;

[0016] R6 is selected from the following group: NH, -C(O)-;

[0017] R2, R3, R4, R5 are the same or different, and each independently is selected from the following group of structures: chemical bond, CH2, C=O, O, NH; among them, n is 0, 1, 2, 3, 4, 5 or 6.

[0018] In a preferred example, the Linker does not exist, or the Linker is selected from the following group:

[0019] Among them, n1, n2, n3, n4 each independently is selected from the following group: 1, 2, 3, 4, 5, 6, 7, 8 or 9.

[0020] In a preferred example, the R L is selected from the following group: hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, fluoro-C1-C2 alkyl, fluoro-C1-C2 alkoxy.

[0021] In a preferred example, the R L is selected from the following group: H, Cl, Br, F, CH3, CH2CH3, OCH3, OCH2CH3, CF3, OCF3.

[0022] In a preferred embodiment, the compound is selected from the group consisting of:

[0023]

[0024]

[0025]

[0026] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising

[0027] (1) a compound as described in the first aspect of the present invention, its pharmaceutically acceptable salt, its stereoisomer or its prodrug as an active ingredient; and

[0028] optionally (2) a pharmaceutically acceptable carrier.

[0029] In a third aspect of the present invention, there is provided the use of a compound as described in the first aspect of the present invention, its pharmaceutically acceptable salt, its stereoisomer or its prodrug, or a pharmaceutical composition as described in the second aspect of the present invention, for the preparation of a protein kinase degrader of DDR1.

[0030] In a fourth aspect of the present invention, there is provided the use of a compound as described in the first aspect of the present invention, its pharmaceutically acceptable salt, its stereoisomer or its prodrug, or a pharmaceutical composition as described in the second aspect of the present invention, for the preparation of a drug for preventing and / or treating a disease mediated by DDR1 receptor tyrosine protein kinase.

[0031] In a preferred embodiment, the diseases mediated by DDR1 receptor tyrosine protein kinase are selected from the group consisting of: prostate cancer, breast cancer, uterine cancer, ovarian cancer, non-small cell lung cancer, small cell lung cancer, Ewing's sarcoma, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumor, colon cancer, rectal cancer, glioma.

[0032] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated here one by one. Detailed Description of the Invention

[0033] The inventors have conducted extensive and in-depth research and unexpectedly found poly-substituted benzene ring compounds. A series of biological activity tests were carried out on them, and it was found that they have excellent DDR1 inhibitory performance. The present invention was completed on this basis.

[0034] Term

[0035] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by those skilled in the art to which this invention belongs. The terms used in the specification of this invention are for the purpose of describing specific embodiments only and are not intended to limit this invention.

[0036] The terms "comprising" and "having" and any variations thereof in this invention are intended to cover non-exclusive inclusion. For example, a process, method, apparatus, product or device that includes a series of steps is not limited to the listed steps or modules, but optionally further includes steps not listed, or optionally further includes other steps inherent to these processes, methods, products or devices.

[0037] As mentioned in this invention, "plurality" means two or more. "And / or" describes the associative relationship of associated objects and indicates that three relationships can exist. For example, A and / or B can represent: A exists alone, A and B exist simultaneously, and B exists alone. The character " / " generally represents an "or" relationship between the associated objects before and after.

[0038] In the compounds described in this invention, when any variable (such as R 10 、R 11 etc.) appears more than once in any component, its definition for each appearance is independent of the definition of each other appearance. Similarly, combinations of substituents and variables are allowed, provided that such combinations render the compound stable. The line extending from a substituent into a ring system indicates that the indicated bond can be attached to any ring atom capable of being substituted. If the ring system is polycyclic, it means that this bond is only attached to any suitable carbon atom of the adjacent ring. It is to be understood that those of ordinary skill in the art can select the substituents and substitution patterns of the compounds of this invention to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by the techniques of the art and the methods set forth below. If a substituent is itself substituted by more than one group, it is to be understood that these groups can be on the same carbon atom or different carbon atoms, provided that the structure is stable.

[0039] As used herein, the term "alkyl" is intended to include branched and straight-chain saturated hydrocarbon groups having a specific number of carbon atoms. For example, the definition of "C1-C8 alkyl" for "C1-C8" includes groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in a straight chain or branched chain.

[0040] As used herein, the term "alkoxy" refers to a group having an alkyl-oxy structure. For example, "C1-C6 alkoxy" refers to a straight-chain or branched-chain alkoxy having 1-6 carbon atoms, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc.

[0041] As used herein, the term "haloalkyl" represents an alkyl group in which one or more hydrogen atoms are replaced by halogen, where the definition of alkyl is as described above.

[0042] As used herein, the term "haloalkoxy" represents an alkoxy group in which one or more hydrogen atoms are replaced by halogen, where the definition of alkoxy is as described above.

[0043] As will be understood by those skilled in the art, "halogen" as used herein means including F, Cl, Br and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halogenated" means being replaced by an atom selected from F, Cl, Br, and I.

[0044] Unless otherwise specified as "substituted or unsubstituted", the groups described in the present invention can be substituted by substituents selected from the following group: halogen, nitrile group, nitro group, hydroxyl group, amino group, C1-C6 alkyl-amino group, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo C1-C6 alkyl, halo C2-C6 alkenyl, halo C2-C6 alkynyl, halo C1-C6 alkoxy, allyl group, benzyl group, C6-C 12 aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 cycloalkyl-carbonyl, C1-C6 alkyl-sulfonyl, etc.

[0045] Active ingredient

[0046] The present invention includes the free form of the compound of formula (I), as well as its pharmaceutically acceptable salts, its stereoisomers and its prodrug molecules. The term "free form" refers to the compound in a non-salt form. The pharmaceutically acceptable salts included not only include the exemplary salts of the specific compounds described herein, but also include the typical pharmaceutically acceptable salts of all free forms of the compounds of formula (I) or formula (II). The free form of the specific salt of the compound can be separated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base such as dilute aqueous NaOH solution, dilute aqueous potassium carbonate solution, dilute aqueous ammonia and dilute aqueous sodium bicarbonate solution. The free form is somewhat different from its respective salt form in certain physical properties such as solubility in polar solvents, but for the purpose of the invention, such acid salts and base salts are equivalent to their respective free forms in other pharmaceutical aspects.

[0047] The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess amount of an inorganic or organic acid in the desired salt form in a suitable solvent or a combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0048] Thus, the pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by reacting basic compounds of the present invention with inorganic or organic acids. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and also include salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, trifluoroacetic acid, etc.

[0049] If the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, said bases including salts of primary amines, secondary amines and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, aminoglucose, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0050] Berg et al., "Pharmaceutical Salts" J. Pharm. Sci. ’1977:66:1-19 describes in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

[0051] Unless otherwise specified, the structural formulas described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are all within the scope of the present invention.

[0052] As used herein, the term "tautomer" refers to structural isomers of different energies that can interconvert across a low energy barrier. For example, proton tautomers (i.e., prototropy) include interconversion via proton migration, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion via reorganization of some of the bonding electrons.

[0053] As used herein, the term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0054] As used herein, the term "hydrate" refers to a complex formed by coordination of a compound of the present invention with water.

[0055] The compound of the present invention can also be in the form of a prodrug. As used herein, the term "prodrug" refers to a compound that produces an active compound when metabolized (e.g., in vivo or in vitro). In some embodiments, the prodrug can be inactive, or have an activity lower than that of the free drug, but can provide favorable processing, administration or metabolic characteristics. The exemplary prodrug moiety of the present invention can be connected to the free drug by the hydroxyl, amino, phosphate or thiophosphate backbone of nucleotides, and can include ester, carbamate, carbonyl, thioester, amide, isocyanate, urea, thiourea or other physiologically acceptable metabolically unstable parts. In some embodiments, the prodrug is activated by enzymatic hydrolysis.

[0056] The present disclosure also includes isotopically labeled compounds that are identical to compounds of formula (I) (including compounds of formula (II)), but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of suitable isotopes for inclusion in the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to, 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 31 P. 35 S. 18 F and 36 Cl. With heavier isotopes (such as deuterium, i.e. 2H) Substitution may provide certain therapeutic advantages due to higher metabolic stability, such as a longer in vivo half-life or lower dose requirements, and may thus be preferred in certain cases. The compounds described can bind to positron-emitting isotopes for medical imaging and positron emission tomography (PET) studies to determine the distribution of receptors. Suitable positron-emitting isotopes that can be incorporated into the compounds of formula (I) or (II) are 11 C, 13 N, 15 O and 18 F. Isotope-labeled compounds of formula (I) or (II) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriate isotope-labeled reagents in place of non-isotope-labeled reagents.

[0057] The compounds disclosed herein can exist in solvated and non-solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention is intended to cover both solvated and non-solvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in crystalline form.

[0058] Pharmaceutical Compositions and Methods of Administration

[0059] Since the compounds of the present invention are DDR1 protein degraders, the compounds and their pharmaceutically acceptable salts and other compound forms disclosed herein can be included in pharmaceutical compositions useful for treating, preventing, and alleviating diseases associated with DDR1 activity.

[0060] The pharmaceutical compositions of the present invention contain an effective amount, such as a safe and effective amount, of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier. "Effective amount" means an amount sufficient to elicit the desired biological response (e.g., treating a disorder). "Safe and effective amount" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 to 3000 mg (active dose range of 3 to 30 mg / kg) of the disclosed compound / dose, and more preferably contains 10 to 2000 mg of the compound of the present invention / dose. Preferably, "one dose" is a capsule or tablet.

[0061] "Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid fillers or gel substances suitable for human use, which must have sufficient purity and sufficiently low toxicity. "Compatibility" herein means that the components of the composition can be mixed with the compounds of the present disclosure and with each other without significantly reducing the efficacy of the compounds. Examples of the pharmaceutically acceptable carrier portion include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, and cellulose acetate), gelatin, talc, solid lubricants (such as stearic acid and magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil), polyols (propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers ( etc.), wetting agents (such as sodium lauryl sulfate, etc.), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, and pyrogen-free water.

[0062] There is no particular limitation on the administration route of the compounds or pharmaceutical compositions of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0063] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dibasic calcium phosphate, or is mixed with the following components: (a) fillers or fillers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxyethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, some complex silicates, and sodium carbonate; (e) retardant solvents, such as paraffin wax; (f) absorption promoters, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin; (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include buffering agents.

[0064] Solid dosage forms, such as tablets, dragees, capsules, pills, and granules, can be prepared from coating and encapsulating materials, such as enteric coatings and other materials well known in the art. They can contain opacifying agents, and the active compound or a compound that is released in a delayed manner in a part of the digestive tract in such compositions. Examples of the embedding components available are polymeric substances and waxes. If necessary, the active compound can also be in the form of microcapsules with one or more of the above excipients.

[0065] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0066] In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying agents and suspending agents, sweetening agents, flavoring agents and perfumes.

[0067] In addition to the active compound, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum monostearate and agar, or mixtures thereof.

[0068] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0069] Topical dosage forms of the compounds of the present invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed with a physiologically acceptable carrier and any preservatives, buffers or propellants (if required) under sterile conditions.

[0070] The compounds of the present disclosure can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0071] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is suitable for mammals (such as humans) that need treatment, wherein the dose is a dose considered pharmaceutically effective at the time of administration. The daily dose for a 60 kg human is generally 1-2000 mg, preferably 6-600 mg. Of course, the specific dose should also be determined by comprehensively considering factors such as the administration route and the health status of the patient, which are all within the capabilities of a skilled physician.

[0072] Uses and methods of treatment

[0073] As described above, the compounds of the present invention are DDR1 protein degraders, and thus the compounds or compositions containing the compounds can be used to treat, prevent and alleviate diseases associated with DDR1 activity or abnormal expression. In some embodiments, the use of the compounds of the present invention in the preparation of a medicament for preventing and / or treating diseases mediated by the DDR1 receptor tyrosine protein kinase is disclosed herein. In some embodiments, the compounds of the present invention for preventing and / or treating diseases mediated by the DDR1 receptor tyrosine kinase are disclosed herein. In some embodiments, a method for treating a disease mediated by the DDR1 receptor tyrosine kinase in a subject in need thereof is disclosed herein, comprising administering to the subject an effective amount of the compounds of the present invention. In some embodiments, diseases mediated by the DDR1 receptor tyrosine kinase include: prostate cancer, breast cancer, uterine cancer, ovarian cancer, non-small cell lung cancer, small cell lung cancer, Ewing's sarcoma, lung adenocarcinoma, squamous cell lung cancer, pancreatic cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumors, colon cancer, rectal cancer, glioma.

[0074] When used in the disclosed uses and methods, the disclosed compounds and compositions can be used in combination with other known therapies. As used herein, "combination" administration refers to delivering two (or more) different treatments to a subject during the course of a disorder in the subject, e.g., two or more treatments are administered after the subject has been diagnosed with a disorder and before the disorder has been cured or eliminated, or treatment has stopped for other reasons. In some embodiments, when the delivery of the second treatment begins, the delivery of one treatment is still ongoing, and thus there is overlap in administration. This is sometimes referred to herein as "simultaneous" or "co-parallel delivery". In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective due to combination administration. For example, the second treatment is more effective, e.g., the same effect can be seen with less of the second treatment compared to administering the second treatment without the first treatment, or the second treatment can alleviate symptoms to a greater extent, or for a similar situation observed with the first treatment. In some embodiments, the delivery is such that the reduction in symptoms or other parameters associated with the disorder is greater than that observed with one treatment delivered without the other treatment. The effects of the two treatments can be partially additive, fully additive, or greater than additive. The delivery can be such that the effect of the first treatment delivered is still detectable when the second treatment is delivered.

[0075] The compounds or compositions disclosed herein and at least one additional therapeutic agent can be administered simultaneously, in the same or separate compositions, or sequentially. For sequential administration, the compounds described herein can be administered first, followed by the additional agent, or the order of administration can be reversed.

[0076] In some embodiments, the compounds described herein are administered in combination with other therapeutic modalities, including surgery, radiation, transplantation (e.g., stem cell transplantation, bone marrow transplantation), chemotherapy, immunotherapy, cryotherapy, and / or thermotherapy. Such combination therapies may permit lower doses of the administered agent and / or other agents, thereby avoiding possible toxicities or complications associated with the various therapies.

[0077] In some embodiments, the compounds described herein are administered with at least one additional therapeutic agent, such as a chemotherapeutic agent. In certain embodiments, the compounds described herein are administered in combination with one or more additional chemotherapeutic agents. The chemotherapeutic agent may be a chemotherapeutic agent identified in the "A to Z List of Cancer Drugs" published by the National Cancer Institute of the United States.

[0078] The main advantages of the present invention are as follows:

[0079] 1. The degrader of discoidin domain receptor protein 1 (DDR1) provided by the present invention can effectively degrade the DDR1 protein kinase and can be used to prepare a drug for preventing or treating diseases mediated by the DDR1 protein kinase, such as prostate cancer, breast cancer, uterine cancer, ovarian cancer, non-small cell lung cancer, small cell lung cancer, Ewing sarcoma, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumors, colon cancer, rectal cancer, glioma, etc.

[0080] 2. The degrader of discoidin domain receptor protein 1 (DDR1) provided by the present invention has strong degradation activity.

[0081] 3. The degrader of discoidin domain receptor protein 1 (DDR1) provided by the present invention has high selectivity for protein kinase degradation.

[0082] For the experimental methods without specific conditions in the following examples of the present invention, they are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. All kinds of commonly used chemical reagents used in the examples are commercially available products.

[0083] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. For the experimental methods without specific conditions in the following examples, they are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0084] Example 1: Preparation of Compound YLJ-3-57

[0085]

[0086] Step 1: Preparation of Intermediate 11

[0087]

[0088] In a round-bottom flask, the anhydrous THF (30 mL) system of 3-nitro-5-(trifluoromethyl)benzoic acid (2.35 g, 10 mmol) was purged with argon three times, then BH3·THF (20 ml, 1 mol / L) was added. The temperature was raised to 65 °C. After the reaction was completed monitored by TLC, it was transferred to room temperature, quenched with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound 12 (yellow liquid, 2.17 g, yield 98%). 1 1H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 8.39 (s, 1H), 7.98 (s, 1H), 4.90 (s, 2H), 2.49 (br s, 1H).

[0089] Step 2: Preparation of Intermediate 12

[0090]

[0091] Under an ice bath, to a round-bottom flask, a CH2Cl2 (40 mL) solution of substrate 11 (2.21 g, 10 mmol) was added. Then carbon tetrabromide (6.63 g, 20 mmol) and triphenylphosphine (5.24 g, 20 mmol) were added in batches. After the addition was completed, the mixture was returned to room temperature. After two hours, when the reaction was completed monitored by TLC, it was quenched with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. It was purified by normal-phase chromatography on a silica gel column to obtain Intermediate 12 (yellow liquid, 2.0 g, 71%). 1H NMR (500 MHz, CDCl3) δ 8.45 (s, 1H), 8.42 (s, 1H), 7.98 (s, 1H), 4.70 (s, 2H).

[0092] Step 3: Preparation of Intermediate 13

[0093]

[0094] In a 250 mL round-bottom flask, to the CH2Cl2 (60 mL) system of compound 12 (7.70 g, 27.1 mmol), N-Boc-piperazine (5.60 g, 29.8 mmol) and triethylamine (5.50 g, 7.6 mL, 54.2 mmol) were added successively. After completion, the mixture was stirred at room temperature for 6 h. The reaction was monitored by TLC, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel normal-phase chromatography to obtain the target intermediate 13 (yellow solid, 8.87 g, 84%). 1 1H NMR (500 MHz, CDCl3) δ 8.42 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 3.66 (s, 2H), 3.49 - 3.43 (m, 4H), 2.48 - 2.38 (m, 4H), 1.46 (s, 9H).

[0095] Step 4: Preparation of intermediate 14

[0096]

[0097] In a 250 mL round-bottom flask, palladium-carbon (760 mg) was added to the MeOH (45 mL) system of compound 13 (7.60 g, 19.5 mmol). The gas in the flask was replaced with hydrogen three times, and the mixture was stirred at room temperature overnight. After the reaction was monitored by TLC and completed, it was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the target intermediate 14 (6.20 g, 88% yield). 1 1H NMR (500 MHz, CDCl3) δ 6.92 (s, 1H), 6.81 (s, 1H), 6.78 (s, 1H), 3.46 (s, 2H), 3.44 - 3.39 (m, 4H), 2.42 - 2.32 (m, 4H), 1.44 (s, 9H).

[0098] Step 5: Preparation of intermediate 15

[0099]

[0100] In a 250 mL round-bottom flask, trimethyl(ethynyl)silane (21.5 g, 31 mL, 219 mmol), Pd(PPh3)2Cl2 (0.80 g, 1.1 mmol), CuI (0.25 g, 1.3 mmol), and Et3N (17.5 g, 24 mL, 173 mmol) were successively added to a CH3CN (100 mL) system of methyl 4-ethyl-3-iodobenzoate (16.3 g, 56.2 mmol). After completion, the gas was replaced with argon three times, and the temperature was raised to 60 °C, followed by stirring overnight. After the reaction was completed by TLC, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated and directly subjected to the next reaction. K2CO3 (24.0 g, 174 mmol) was added to a MeOH (150 mL) suspension containing the concentrate, and the mixture was stirred at room temperature for 30 minutes. The solvent was evacuated, and ethyl acetate and water were added to the residue for extraction. The organic layer was separated, and the combined organic phases were dried over Na2SO4 and concentrated. The obtained crude product was further purified by chromatography to give a white solid (7.0 g, 66%). 1 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 1.7 Hz, 1H), 7.93 (dd, J = 8.1, 1.8 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 3.90 (s, 2H), 3.28 (s, 1H), 2.87 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H). LC-MS: calcd for C 12 1H 13 O2 [M + H] + m / z, 188.5; found, 188.5.

[0101] Step 6: Preparation of Compound 16

[0102]

[0103] In a 250 mL round-bottom flask, 6-bromopyrazolo[1,5-a]pyrimidine (7.70 g, 39. 1 mmol), DIPEA (9.65 g, 13 mL, 74.6 mmol), Pd(PPh3)2Cl2 (2.74 g, 3.72 mmol), and CuI (0.57 g, 3.72 mmol) were successively added to a DMF (120 mL) system of 15 (7.0 g, 37.2 mmol). After the gas was replaced with argon three times, the temperature was raised to 80 °C, followed by stirring overnight. After the reaction was completed by TLC monitoring, ethyl acetate and water were added for extraction. The organic layer was separated, and the combined organic phases were dried over Na2SO4 and concentrated. The obtained crude product was further purified by chromatography to give the target product 16 (yellow solid, 6.8 g, 60%). 11H NMR (500 MHz, DMSO-d6) δ 9.59 - 9.55 (m, 1H), 8.70 (s, 1H), 8.33 (s, 1H), 8.10 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 6.85 - 6.81 (m, 1H), 3.87 (s, 3H), 2.94 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H). LC-MS: calcd for C 18 H 16 N3O2 [M + H] + m / z, 306.3; found, 306.3.

[0104] Step 7: Preparation of Compound 17

[0105]

[0106] In a 100 mL round-bottom flask, NaOH (3.00 g, 75 mmol) was added to a MeOH / H2O (150 mL, v / v 2:1) system of 16 (3.05 g, 10 mmol), and the mixture was stirred at 60 °C for 6 h. After TLC detection showed that the reaction was complete, the pH of the system was adjusted to 2, and a yellow solid precipitated. The target product 17 (yellow solid, 2.80 g, 96%) was obtained by filtration. 1 1H NMR (500 MHz, DMSO-d6) δ 13.10 (br s, 1H), 9.57 (dd, J = 2.0, 0.9 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.33 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 1.8 Hz, 1H), 7.92 (dd, J = 8.0, 1.8 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 6.84 (dd, J = 2.3, 0.8 Hz, 1H), 3.33 (s, 3H), 2.94 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H). LC-MS: calcd for C 17 H 14 N3O2 [M + H] + m / z, 292.3; found, 292.3.

[0107] Step 8: Preparation of Compound 18

[0108]

[0109] In a 100 mL round-bottom flask, 14 (2.50 g, 6.96 mmol), DIPEA (4.45 g, 6.0 mL, 34.4 mmol), and HATU (4.79 g, 12.6 mmol) were added to a system of 17 (2.00 g, 6.87 mmol) in DMF (45 mL). The gas was displaced with argon three times, the temperature was raised to 80 °C, and the mixture was stirred overnight. After monitoring the completion of the reaction by TLC, dichloromethane and water were added for extraction. The organic layer was separated, and the combined organic phases were dried over Na2SO4 and concentrated. The obtained crude product was further purified by chromatography to give the target product 18 (2.80 g, 65%). 1 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.59 (dd, J = 2.0, 0.8 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.23 - 8.19 (m, 2H), 8.04 (s, 1H), 7.99 (dd, J = 8.1, 1.9 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.38 (s, 1H), 6.86 - 6.84 (m, 1H), 3.58 (s, 2H), 3.33 - 3.29 (m, 4H), 2.96 (q, J = 7.5 Hz, 2H), 2.39 - 2.31 (m, 4H), 1.39 (s, 9H), 1.30 (t, J = 7.5 Hz, 3H). LC-MS: calcd for C 34 1H 36 F3N6O3 [M + H]+ m / z, 633.6; found, 633.6.

[0110]

[0111] Step 9: Preparation of Compound YLJ-3-57

[0112] In a 25 ml round-bottom flask, TFA (0.5 ml) was injected into a system of 18 (107 mg, 0.16 mmol) in CH2Cl2 (2 ml), and the reaction was carried out at room temperature for 2 h. After the reaction was completed by TLC detection, the solvent was dried by suction and directly used for the next step. The crude product was dissolved in DMF (2 ml), and 2-(2,6-dibromo-4-((5-iodo-2-oxoindoline-3-ylidene)methyl)phenoxy)acetic acid (92.3 mg, 0.16 mmol), DIPEA (62 mg, 84 μL, 0.48 mmol), and HATU (91.3 mg, 0.24 mmol) were added successively. The reaction was carried out at room temperature for 3 h. After the reaction was completed by TLC monitoring, dichloromethane and water were added for extraction, the organic layer was separated, the combined organic phases were dried over Na2SO4 and concentrated, and then further purified by chromatography to obtain the target product YLJ-3-57 (yellow foamy solid, 131 mg, 75%). 1 1H NMR (600 MHz, CDCl3) δ 8.87 - 8.81 (m, 1H), 8.57 - 8.53 (m, 1H), 8.43 - 8.29 (m, 3H), 8.21 - 8.16 (m, 1H), 8.05 - 8.01 (m, 1H), 7.97 - 7.91 (m, 1H), 7.91 - 7.88 (m, 1H), 7.87 - 7.76 (m, 2H), 7.75 - 7.56 (m, 1H), 7.55 - 7.49 (m, 1H), 7.42 - 7.37 (m, 2H), 7.24 - 7.21 (m, 1H), 6.78 - 6.73 (m, 1H), 6.67 - 6.60 (m, 1H), 4.79 - 4.66 (m, 2H), 3.80 - 3.68 (m, 4H), 3.65 - 3.56 (m, 2H), 2.98 - 2.86 (m, 2H), 2.62 - 2.48 (m, 4H), 1.36 - 1.30 (m, 3H). HRMS (ESI) for C46H36Br2F3IN7O4 [M + H]+: calcd 1092.0187, found 1092.0181.

[0113] Example 2: Preparation of Compound YLJ-3-40

[0114]

[0115] Step 1: Preparation of Intermediate 18b

[0116] In a 25 mL round-bottom flask, TFA (0.5 mL) was injected into a system of 18 (101 mg, 0.16 mmol) in CH2Cl2 (2 mL), and the reaction was carried out at room temperature for 2 h. After the reaction was completed by TLC detection, the solvent was dried by suction and directly used for the next step. The crude product was dissolved in DMF (2 mL), and Boc-glycine (28.0 mg, 0.16 mmol), DIPEA (62 mg, 84 μL, 0.48 mmol), and HATU (76.0 mg, 0.20 mmol) were added successively. After reacting at room temperature for 3 h and monitoring the reaction completion by TLC, dichloromethane and water were added for extraction, the organic layer was separated, the combined organic phases were dried over Na2SO4 and concentrated, and then further purified by chromatography to obtain the target product intermediate 18b (solid in yellow foam, 80.6 mg, 73%). 1 H NMR (500 MHz, CDCl3) δ 8.83 (d, J = 1.4 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 8.04 (d, J = 1.7 Hz, 1H), 7.91 (s, 1H), 7.87 (s, 1H), 7.85 (dd, J = 8.1, 1.8 Hz, 1H), 7.58 (s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 6.75 (d, J = 2.9 Hz, 1H), 4.03 - 3.96 (m, 2H), 3.70 - 3.63 (m, 2H), 3.57 (s, 2H), 3.42 - 3.37 (m, 2H), 2.99 - 2.94 (m, 2H), 2.48 - 2.43 (m, 4H), 1.44 (s, 9H), 1.37 - 1.34 (m, 3H). LC-MS: calcd for C 36 H 39 F3N7O4 [M + H] + m / z, 689.9; found, 689.9.

[0117] Step 2: Preparation of Compound YLJ-3-40

[0118]

[0119] The synthesis method was similar to Step 9 of Example 1.

[0120] 1H NMR (600 MHz, CDCl3) δ 8.85 - 8.80 (m, 1H), 8.59 (s, 1H), 8.55 - 8.51 (m, 1H), 8.49 - 8.41 (m, 2H), 8.19 - 8.16 (m, 1H), 8.06 - 8.03 (m, 1H), 8.03 - 7.96 (m, 2H), 7.90 - 7.84 (m, 2H), 7.84 - 7.74 (m, 1H), 7.72 - 7.69 (m, 1H), 7.52 - 7.46 (m, 1H), 7.40 - 7.34 (m, 2H), 7.19 (s, 1H), 6.77 - 6.72 (m, 1H), 6.68 - 6.61 (m, 1H), 4.65 - 4.53 (m, 2H), 4.24 - 4.18 (m, 2H), 3.74 - 3.63 (m, 2H), 3.58 (s, 2H), 3.51 - 3.42 (m, 2H), 2.97 - 2.89 (m, 2H), 2.54 - 2.40 (m, 4H), 1.34 - 1.30 (m, 3H). HRMS (ESI) for C48H39Br2F3IN8O5 [M + H]+: calcd 1149.0401, found 1149.0402.

[0121] Example 3: Preparation of Compound YLJ - 3 - 41

[0122]

[0123] The synthesis method is similar to that of Example 2.

[0124] 1 1H NMR (600 MHz, CDCl3) δ 8.86 - 8.80 (m, 1H), 8.56 - 8.51 (m, 1H), 8.50 - 8.46 (m, 3H), 8.44 (s, 1H), 8.21 - 8.15 (m, 1H), 8.06 - 8.01 (m, 1H), 7.97 - 7.82 (m, 3H), 7.77 - 7.70 (m, 1H), 7.54 - 7.47 (m, 1H), 7.42 - 7.35 (m, 2H), 7.24 - 7.18 (m, 1H), 6.77 - 6.72 (m, 1H), 6.68 - 6.59 (m, 1H), 4.60 - 4.48 (m, 2H), 3.71 - 3.62 (m, 2H), 3.58 (s, 2H), 3.52 - 3.43 (m, 4H), 2.97 - 2.88 (m, 2H), 2.51 - 2.39 (m, 6H), 2.04 - 1.93 (m, 2H), 1.34 - 1.30 (m, 3H). HRMS (ESI) for C 50 H 43Br2F3IN8O5[M+H]+ + :calcd 1177.0714,found 1177.0711.

[0125] Example 4: Preparation of Compound YLJ-3-42

[0126]

[0127] The synthesis method is similar to that of Example 2.

[0128] 1H NMR(600MHz,CDCl3)δ8.85-8.79(m,1H),8.73-8.57(m,2H),8.55-8.50(m,1H),8.44(s,1H),8.19-8.15(m,1H),8.06-8.03(m,1H),7.94-7.88(m,2H),7.87-7.83(m,1H),7.82-7.74(m,1H),7.72-7.70(m,1H),7.52-7.47(m,1H),7.40-7.34(m,2H),7.20(s,1H),7.07-7.02(m,1H),6.76-6.73(m,1H),6.64(dd,J=27.5,8.2Hz,1H),4.60-4.48(m,2H),3.66-3.60(m,2H),3.56(s,2H),3.51-3.45(m,2H),3.44-3.38(m,2H),2.94-2.89(m,2H),2.49-2.39(m,4H),2.37-2.29(m,2H),1.71-1.58(m,4H),1.47-1.39(m,2H),1.34-1.29(m,3H).HRMS(ESI)for C52H47Br2F3IN8O5[M+H]+:calcd 1205.1027,found1205.1025.

[0129] Example 5: Preparation of Compound YLJ-3-44

[0130]

[0131] The synthesis method refers to Example 2.

[0132] 11H NMR (600 MHz, CDCl3) δ 8.94 - 8.69 (m, 3H), 8.53 - 8.49 (m, 1H), 8.44 (s, 1H), 8.20 - 8.13 (m, 1H), 8.09 - 8.02 (m, 1H), 7.97 - 7.90 (m, 2H), 7.88 - 7.84 (m, 1H), 7.83 - 7.73 (m, 1H), 7.72 - 7.52 (m, 1H), 7.52 - 7.46 (m, 1H), 7.40 - 7.32 (m, 2H), 7.21 - 7.17 (m, 1H), 7.02 - 6.96 (m, 1H), 6.77 - 6.71 (m, 1H), 6.70 - 6.57 (m, 1H), 4.60 - 4.45 (m, 2H), 3.68 - 3.59 (m, 2H), 3.55 (s, 2H), 3.50 - 3.44 (m, 2H), 3.42 - 3.34 (m, 2H), 2.95 - 2.86 (m, 2H), 2.49 - 2.37 (m, 4H), 2.34 - 2.26 (m, 2H), 1.64 - 1.54 (m, 4H), 1.42 - 1.27 (m, 9H). HRMS (ESI) for C 54 H 51 Br2F3IN8O5 [M + H] + : calcd 1233.1340, found 1233.1338.

[0133] Example 6: Preparation of Compound YLJ - 3 - 63

[0134]

[0135] The synthesis method was referred to Example 2.

[0136] 11H NMR (600 MHz, CDCl3) δ 8.87 - 8.76 (m, 1H), 8.67 (s, 0.6H), 8.56 - 8.49 (m, 1H), 8.47 - 8.40 (m, 1H), 8.37 (s, 1H), 8.33 (s, 0.4H), 8.20 - 8.16 (m, 1H), 8.06 - 8.01 (m, 1H), 7.95 - 7.89 (m, 1H), 7.87 - 7.83 (m, 2H), 7.82 - 7.67 (m, 2H), 7.57 - 7.32 (m, 4.4H), 7.19 (s, 0.6H), 6.76 (s, 1H), 6.68 - 6.57 (m, 1H), 4.55 (d, J=51.2 Hz, 2H), 4.21 (d, J=14.1 Hz, 2H), 3.75 - 3.60 (m, 6H), 3.56 - 3.48 (m, 4H), 2.97 - 2.87 (m, 2H), 2.52 - 2.38 (m, 4H), 1.35 - 1.29 (m, 3H). HRMS (ESI) for C 50 H 43 Br2F3IN8O6 [M + H] + : calcd 1193.0664, found 1193.0675.

[0137] Example 7: Preparation of Compound YLJ - 3 - 64

[0138]

[0139] The synthesis method was referred to Example 2.

[0140] 1 1H NMR (600 MHz, CDCl3) δ 8.88 - 8.84 (m, 1H), 8.74 - 8.61 (m, 1H), 8.57 - 8.52 (m, 1H), 8.46 - 8.42 (m, 1H), 8.21 - 8.17 (m, 1H), 8.12 - 8.00 (m, 2H), 7.93 - 7.87 (m, 1H), 7.84 - 7.74 (m, 3H), 7.74 - 7.54 (m, 1H), 7.54 - 7.50 (m, 1H), 7.44 - 7.36 (m, 3H), 6.77 - 6.74 (m, 1H), 6.67 - 6.58 (m, 1H), 4.59 - 4.47 (m, 2H), 4.22 - 4.16 (m, 2H), 3.73 - 3.59 (m, 10H), 3.58 - 3.45 (m, 4H), 2.98 - 2.90 (m, 2H), 2.53 - 2.36 (m, 4H), 1.34 - 1.31 (m, 3H). HRMS (ESI) for C 52 H47 Br2F3IN8O7[M+H] + : Calculated 1237.0926, found 1237.0930.

[0141] Example 8: Preparation of Compound YLJ-3-67

[0142]

[0143] The synthesis method was referred to Example 2.

[0144] 1 H NMR (600 MHz, CDCl3) δ 8.88 - 8.83 (m, 1H), 8.71 - 8.58 (m, 1H), 8.57 - 8.51 (m, 1H), 8.45 - 8.42 (m, 1H), 8.21 - 8.16 (m, 1H), 8.12 - 8.05 (m, 1H), 8.06 - 8.03 (m, 1H), 7.93 - 7.86 (m, 1H), 7.86 - 7.81 (m, 1H), 7.80 - 7.74 (m, 2H), 7.75 - 7.49 (m, 2H), 7.45 - 7.36 (m, 3H), 6.78 - 6.74 (m, 1H), 6.67 - 6.59 (m, 1H), 4.61 - 4.46 (m, 2H), 4.21 - 4.16 (m, 2H), 3.72 - 3.59 (m, 12H), 3.56 - 3.47 (m, 4H), 2.99 - 2.89 (m, 2H), 2.50 - 2.44 (m, 2H), 2.43 - 2.36 (m, 2H), 2.03 - 1.99 (m, 2H), 1.35 - 1.31 (m, 3H). HRMS (ESI) for C 54 H 51 Br2F3IN8O8[M+H] + : Calculated 1281.1188, found 1281.1179.

[0145] Example 9: Preparation of Compound LLC0266

[0146]

[0147] Step 1: Preparation of Compound 18c.

[0148]

[0149] In a 25 mL round-bottom flask, TFA (0.5 mL) was injected into a system of 18 (60.0 mg, 0.095 mmol) in CH2Cl2 (2 mL), and the reaction was carried out at room temperature for 2 h. After the reaction was completed by TLC detection, the solvent was dried by suction and directly used for the next step. The crude product was dissolved in DMF (2 mL), and tert-butyl bromoacetate (22.2 mg, 0.114 mmol), K2CO3 (26.2 mg, 0.190 mmol), and KI (15.7 mg, 0.0948 mmol) were added in sequence. Then, the temperature was raised to 70 °C and stirred overnight. After the reaction was completed monitored by TLC, dichloromethane and water were added for extraction. The organic layer was separated, and the combined organic phases were dried over Na2SO4 and concentrated, and then further purified by chromatography to obtain the target product 18c (yellow foamy solid, 45.4 mg, 74%). 1 H NMR (500 MHz, CDCl3) δ 8.85 - 8.82 (m, 1H), 8.56 (d, J = 1.7 Hz, 1H), 8.29 (br, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.97 (s, 1H), 7.85 (dd, J = 8.0, 2.0 Hz, 1H), 7.80 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 6.77 - 6.73 (m, 1H), 3.57 (s, 2H), 3.11 (s, 2H), 2.98 - 2.93 (m, 2H), 2.70 - 2.59 (m, 4H), 2.58 - 2.50 (m, 4H), 1.45 (s, 9H), 1.34 (t, J = 7.6 Hz, 3H). LC-MS: calcd for C 35 H 38 F3N6O3 [M + H] + m / z, 647.6; found, 647.6.

[0150] Step 2: Preparation of compound LLC0266

[0151]

[0152] In a 25 mL round-bottom flask, tert-butyl (R)-(3-(N-(1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylpropyl)-4-methylbenzamido)propyl)carbamate (43.3 mg, 0.0702 mmol) and 18c (45.4 mg, 0.0702 mmol) were dissolved in 2.0 mL of CH2Cl2. TFA (0.5 mL) was added to the above solution via syringe. The mixture was stirred at room temperature for 2 h. After the TLC reaction was completed, the solvent was removed by vacuum. The crude product was dissolved in a small amount of DMF (2.0 mL) and Et3N (21.3 mg, 30 μL, 0.211 mmol) and HATU (40.0 mg, 0.105 mmol) were added. The mixture was stirred at room temperature for 3 h. After the reaction was monitored by TLC and completed, CH2Cl2 and H2O were added for extraction. The organic phases were combined, dried over Na2SO4, filtered and concentrated. Further purification by chromatography gave the target product LLC0266 (yellow foamy solid, 57.4 mg, 75%). 1 H NMR(600MHz,DMSO-d6)δ10.60(s,1H),9.58(dd,J=2.0,0.9Hz,1H),8.71(d,J=2.1Hz,1H),8.35(d,J=2.3Hz,1H),8.21(s,1H),8.20(d,J=6.6Hz,1H),8.18(s,1H),8.04(s,1H),7.99(dd,J=8.1,1.9Hz,1H),7.81(d,J=1.9Hz,1H),7.62(dd,J=8.6,2.0Hz,1H),7.56(d,J=8.2Hz,1H),7.37-7.33(m,3H),7.32-7.26(m,2H),7.25-7.22(m,2H),7.19(s,5H),6.85(dd,J=2.3,0.8Hz,1H),5.87(d,J=16.4Hz,1H),5.52(d,J=10.6Hz,1H),5.04(d,J=16.4Hz,1H),3.56(s,2H),3.27-3.18(m,2H),2.97(q,J=7.5Hz,2H),2.74-2.65(m,2H),2.64-2.58(m,2H),2.48-2.30(m,9H),2.29(s,3H),2.01-1.95(m,1H),1.30(t,J=7.5Hz,3H),0.88-0.80(m,4H),0.44(d,J=6.2Hz,3H).HRMS(ESI)forC 61 H 61 ClF3N10 O4[M+H] + :calcd 1089.4512,found 1089.4516.

[0153] Example 10: Preparation of Compound LLC0284

[0154]

[0155] The synthesis method was referred to Example 9.

[0156] 1H NMR(600MHz,DMSO-d6)δ10.61(s,1H),9.58(dd,J=2.1,0.9Hz,1H),8.71(d,J=2.1Hz,1H),8.35(d,J=2.3Hz,1H),8.23(d,J=8.6Hz,1H),8.21(d,J=1.9Hz,1H),8.16 - 8.06(m,2H),7.99(dd,J=8.0,1.9Hz,1H),7.82 - 7.78(m,1H),7.68 - 7.63(m,1H),7.56(d,J=8.1Hz,1H),7.44 - 7.37(m,4H),7.38 - 7.27(m,6H),7.26 - 7.19(m,1H),6.85(dd,J=2.3,0.8Hz,1H),5.87(d,J=16.3Hz,1H),5.52(d,J=10.5Hz,1H),5.04(d,J=16.2Hz,1H),3.51(s,2H),3.27 - 3.17(m,2H),3.06 - 2.81(m,5H),2.75 - 2.66(m,1H),2.49 - 2.34(m,10H),2.33(s,3H),1.93 - 1.77(m,1H),1.73 - 1.43(m,1H),1.30(t,J=7.5Hz,3H),1.28 - 1.25(m,2H),0.88(d,J=6.7Hz,3H),0.84 - 0.77(m,1H),0.46(d,J=6.3Hz,3H).HRMS(ESI)for C63H65ClF3N10O4[M+H]+:calcd 1117.4825,found 1117.4822.

[0157] Example 11: Preparation of Compound LLC0285

[0158]

[0159] The synthesis method was referred to Example 9

[0160] 11H NMR(600 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.58 (dd, J = 2.1, 0.9 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.21 (d, J = 1.9 Hz, 1H), 8.18 - 8.07 (m, 2H), 7.99 (dd, J = 8.0, 1.9 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.6, 2.0 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.43 - 7.39 (m, 1H), 7.38 - 7.28 (m, 4H), 7.27 - 7.18 (m, 6H), 6.85 (dd, J = 2.3, 0.8 Hz, 1H), 5.87 (d, J = 16.2 Hz, 1H), 5.53 (d, J = 10.5 Hz, 1H), 5.04 (d, J = 16.3 Hz, 1H), 3.51 (s, 2H), 3.26 - 3.18 (m, 2H), 3.08 - 2.87 (m, 5H), 2.76 - 2.67 (m, 1H), 2.50 - 2.35 (m, 10H), 2.33 (s, 3H), 1.84 - 1.70 (m, 2H), 1.60 - 1.42 (m, 2H), 1.35 - 1.28 (m, 5H), 1.17 - 1.10 (m, 2H), 0.89 (d, J = 6.8 Hz, 3H), 0.85 - 0.78 (m, 1H), 0.47 (d, J = 6.2 Hz, 3H). HRMS(ESI) for C 65 H 69 ClF3N 10 O4[M + H] + : calcd 1145.5138, found 1145.5146.

[0161] Example 12: Preparation of Compound LLC0286

[0162]

[0163] The synthetic method was referred to Example 9.

[0164] 11H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.57 (dd, J = 2.0, 0.8 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.24 - 8.20 (m, 2H), 8.19 (s, 1H), 8.03 (s, 1H), 7.99 (dd, J = 8.0, 1.9 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.6, 2.0 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.38 - 7.26 (m, 5H), 7.22 (p, J = 7.9 Hz, 6H), 6.85 (dd, J = 2.3, 0.7 Hz, 1H), 5.86 (d, J = 16.2 Hz, 1H), 5.52 (d, J = 10.6 Hz, 1H), 5.04 (d, J = 16.4 Hz, 1H), 3.60 - 3.53 (m, 2H), 3.51 (s, 2H), 3.25 - 3.19 (m, 2H), 2.96 (q, J = 7.5 Hz, 2H), 2.91 - 2.78 (m, 1H), 2.75 - 2.66 (m, 1H), 2.48 - 2.35 (m, 8H), 2.32 (s, 3H), 2.26 - 2.17 (m, 2H), 1.81 - 1.69 (m, 2H), 1.44 - 1.33 (m, 2H), 1.32 - 1.27 (m, 5H), 1.22 - 1.17 (m, 4H), 1.15 - 1.08 (m, 2H), 0.88 (d, J = 6.7 Hz, 3H), 0.86 - 0.79 (m, 1H), 0.46 (d, J = 6.2 Hz, 3H). HRMS (ESI) for C 67 H 73 ClF3N 10 O4[M + H] + : calcd 1173.5451, found 1173.5448.

[0165] Example 13: Preparation of Compound LLC0287

[0166]

[0167] The synthesis method was referred to Example 9.

[0168] 11H NMR (600 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.59 - 9.57 (m, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.24 - 8.20 (m, 2H), 8.18 (s, 1H), 8.04 (s, 1H), 7.99 (dd, J = 8.0, 1.8 Hz, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.65 (dd, J = 8.6, 2.0 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.41 - 7.26 (m, 5H), 7.26 - 7.18 (m, 6H), 6.87 - 6.84 (m, 1H), 5.87 (d, J = 16.3 Hz, 1H), 5.53 (d, J = 10.6 Hz, 1H), 5.04 (d, J = 16.3 Hz, 1H), 3.62 - 3.53 (m, 2H), 3.51 (s, 2H), 3.25 - 3.19 (m, 2H), 2.96 (q, J = 7.5 Hz, 2H), 2.90 - 2.79 (m, 1H), 2.75 - 2.67 (m, 1H), 2.49 - 2.34 (m, 10H), 2.32 (s, 3H), 1.81 - 1.69 (m, 2H), 1.50 - 1.36 (m, 2H), 1.34 - 1.27 (m, 5H), 1.24 - 1.16 (m, 8H), 1.15 - 1.07 (m, 2H), 0.88 (d, J = 6.7 Hz, 3H), 0.86 - 0.80 (m, 1H), 0.46 (d, J = 6.2 Hz, 3H). HRMS (ESI) for C 69 H 77 ClF3N 10 O4[M + H] + : calcd 1201.5764, found 1201.5773.

[0169] Example 14: Preparation of Compound LLC0355

[0170]

[0171] The synthesis method is referred to Example 9

[0172] 11H NMR(600MHz, DMSO-d6) δ 10.60 (s, 1H), 9.57 (dd, J = 2.0, 0.9 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.23 - 8.20 (m, 2H), 8.16 (s, 1H), 8.05 (s, 1H), 7.99 (dd, J = 8.0, 1.9 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 8.6, 2.1 Hz, 1H), 7.57 - 7.52 (m, 2H), 7.37 - 7.32 (m, 3H), 7.31 - 7.26 (m, 1H), 7.25 - 7.22 (m, 2H), 7.22 - 7.18 (m, 4H), 6.85 (dd, J = 2.3, 0.8 Hz, 1H), 5.87 (d, J = 16.2 Hz, 1H), 5.52 (d, J = 10.6 Hz, 1H), 5.03 (d, J = 16.2 Hz, 1H), 3.66 - 3.59 (m, 2H), 3.58 - 3.52 (m, 2H), 3.50 (s, 2H), 3.47 - 3.38 (m, 2H), 3.29 - 3.20 (m, 2H), 2.97 (q, J = 7.5 Hz, 2H), 2.74 - 2.66 (m, 1H), 2.65 - 2.53 (m, 3H), 2.49 - 2.32 (m, 8H), 2.31 (s, 3H), 1.30 (t, J = 7.5 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H), 0.85 - 0.80 (m, 1H), 0.44 (d, J = 6.3 Hz, 3H). HRMS(ESI) for C 63 H 65 ClF3N 10 O5[M + H] + : calcd 1133.4775, found 1133.4772.

[0173] Example 15: Preparation of Compound LLC0357

[0174]

[0175] The synthetic method was referred to Example 9.

[0176] 1H NMR (600 MHz, DMSO-d6) δ 10.59 (s, 1H), 9.57 (dd, J = 2.0, 0.9 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.21 (dd, J = 5.2, 3.3 Hz, 2H), 8.18 (s, 1H), 8.03 (s, 1H), 7.99 (dd, J = 8.1, 1.9 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.63 (dd, J = 8.6, 2.1 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.37 - 7.33 (m, 3H), 7.32 - 7.27 (m, 2H), 7.25 - 7.22 (m, 2H), 7.22 - 7.18 (m, 4H), 6.85 (dd, J = 2.3, 0.8 Hz, 1H), 5.87 (d, J = 16.3 Hz, 1H), 5.52 (d, J = 10.5 Hz, 1H), 5.03 (d, J = 16.3 Hz, 1H), 3.64 - 3.60 (m, 2H), 3.53 (s, 2H), 3.52 - 3.49 (m, 2H), 3.49 - 3.44 (m, 4H), 3.42 - 3.38 (m, 2H), 3.27 - 3.18 (m, 2H), 2.96 (q, J = 7.5 Hz, 2H), 2.75 - 2.66 (m, 1H), 2.65 - 2.53 (m, 3H), 2.49 - 2.32 (m, 8H), 2.31 (s, 3H), 1.30 (t, J = 7.5 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H), 0.85 - 0.82 (m, 1H), 0.46 (d, J = 6.3 Hz, 3H). HRMS (ESI) for C6H69ClF3N10O6 [M + H]+: calcd 1177.5037, found 1177.5033.

[0177] Example 16: Preparation of Compound LLC0373

[0178]

[0179] The synthesis method was referred to Example 9.

[0180] 1H NMR (600 MHz, DMSO-d6) δ 10.59 (s, 1H), 9.58 - 9.56 (m, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.23 - 8.20 (m, 2H), 8.17 (s, 1H), 8.04 (s, 1H), 7.99 (dd, J = 8.0, 1.9 Hz, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.64 (dd, J = 8.6, 2.0 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.37 - 7.33 (m, 3H), 7.32 - 7.27 (m, 2H), 7.25 - 7.23 (m, 2H), 7.22 - 7.19 (m, 4H), 6.86 - 6.84 (m, 1H), 5.87 (d, J = 16.3 Hz, 1H), 5.52 (d, J = 10.5 Hz, 1H), 5.03 (d, J = 16.2 Hz, 1H), 3.63 - 3.60 (m, 2H), 3.59 - 3.53 (m, 2H), 3.52 - 3.43 (m, 10H), 3.42 - 3.38 (m, 2H), 3.27 - 3.21 (m, 2H), 2.96 (q, J = 7.5 Hz, 2H), 2.74 - 2.67 (m, 1H), 2.64 - 2.53 (m, 3H), 2.50 - 2.33 (m, 8H), 2.31 (s, 3H), 1.30 (t, J = 7.5 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H), 0.86 - 0.81 (m, 1H), 0.46 (d, J = 6.3 Hz, 3H). HRMS (ESI) for C67H73ClF3N10O7 [M + H]+: calcd 1221.5299, found 1221.5303.

[0181] Example 17: Preparation of Compound LLC0477

[0182]

[0183] The synthetic method was referred to Step 9 of Example 1.

[0184] 1H NMR(600MHz,Chloroform-d)δ8.88 - 8.78(m,1H),8.59 - 8.51(m,1H),8.27(s,1H),8.20 - 8.16(m,1H),8.09 - 8.04(m,1H),8.03 - 7.99(m,2H),7.96 - 7.89(m,3H),7.89 - 7.82(m,1H),7.48 - 7.42(m,1H),7.41 - 7.39(m,1H),7.38(s,1H),7.00 - 6.92(m,2H),6.79 - 6.73(m,1H),3.88(s,3H),3.79(s,2H),3.72 - 3.66(m,2H),3.65 - 3.59(m,2H),2.94(q,J=7.6Hz,2H),2.65 - 2.43(m,4H),1.34(t,J=7.6Hz,3H).HRMS(ESI)for C40H36F3N6O3[M + H]+,calcd:721.2745;found,721.2745.

[0185] Example 18: Preparation of Compound YLJ - 2 - 51

[0186]

[0187] The synthesis method refers to Step 9 of Example 1.

[0188] 1H NMR(600MHz,Chloroform-d)δ8.89 - 8.78(m,1H),8.59 - 8.52(m,1H),8.49(s,1H),8.23 - 8.15(m,1H),8.12 - 8.04(m,1H),8.02 - 7.98(m,2H),7.96 - 7.94(m,1H),7.92 - 7.90(m,1H),7.89 - 7.87(m,1H),7.87 - 7.84(m,1H),7.63 - 7.56(m,1H),7.52 - 7.44(m,3H),7.39 - 7.33(m,2H),6.76 - 6.73(m,1H),3.79 - 3.72(m,2H),3.68 - 3.62(m,2H),3.58(s,2H),2.92(q,J=7.6Hz,2H),2.85 - 2.76(m,1H),2.52 - 2.46(m,3H),1.32(t,J=7.6,2.0Hz,3H).HRMS(ESI)for C 39 H 34 F3N6O3[M + H]+,calcd: ,691.2639;found,691.2639.

[0189] Example 19: Preparation of Compound YLJ-2-52

[0190]

[0191] The synthesis method refers to Step 9 of Example 1.

[0192] 1 H NMR(600MHz,Chloroform-d)δ8.87-8.82(m,1H),8.59-8.54(m,1H),8.21-8.17(m,1H),8.05-8.04(m,2H),7.99-7.95(m,2H),7.94-7.92(m,1H),7.90-7.87(m,1H),7.85(s,1H),7.52-7.45(m,3H),7.43-7.41(m,1H),7.40-7.35(m,1H),6.79-6.74(m,1H),3.81-3.75(m,2H),3.70-3.63(m,2H),3.61(s,2H),2.96(q,2H),2.59-2.42(m,3H),1.35(t,J=7.6Hz,3H).HRMS(ESI)for C 39 H 33 ClF3N6O3[M+H] + ,calcd:725.2249,found:725.2249.

[0193] Example 20: Preparation of Compound YLJ-2-57

[0194]

[0195] The synthesis method refers to Step 9 of Example  1.

[0196] 1H NMR (600 MHz, Chloroform-d) δ 8.88 - 8.73 (m, 1H), 8.60 (s, 1H), 8.56 - 8.51 (m, 1H), 8.23 - 8.14 (m, 1H), 8.09 - 8.02 (m, 1H), 7.99 - 7.93 (m, 1H), 7.94 - 7.87 (m, 4H), 7.88 - 7.83 (m, 1H), 7.48 - 7.40 (m, 1H), 7.39 - 7.31 (m, 2H), 7.31 - 7.26 (m, 2H), 6.76 - 6.72 (m, 1H), 3.80 - 3.70 (m, 2H), 3.66 - 3.59 (m, 2H), 3.57 (s, 2H), 2.91 (q, J=7.6 Hz, 2H), 2.53 - 2.45 (m, 4H), 2.40 (s, 2H), 1.31 (t, J=7.6 Hz, 3H). HRMS(ESI) for C 40 H 36 F3N6O3[M + H] + , calcd: 705.2796; found, 705.2796.

[0197] Example 21: Preparation of Compound YLJ - 3 - 7

[0198]

[0199] The synthesis method refers to Step 9 of Example 1.

[0200] 1H NMR (600 MHz, Chloroform-d) δ 8.89 - 8.82 (m, 1H), 8.59 - 8.54 (m, 1H), 8.21 - 8.17 (m, 1H), 8.15 - 8.10 (m, 2H), 8.06 - 8.02 (m, 1H), 7.98 (s, 1H), 7.94 (s, 1H), 7.93 - 7.89 (m, 1H), 7.87 - 7.83 (m, 2H), 7.80 - 7.75 (m, 2H), 7.56 - 7.50 (m, 1H), 7.45 - 7.42 (m, 1H), 7.40 (s, 1H), 6.79 - 6.75 (m, 1H), 3.82 - 3.75 (m, 2H), 3.70 - 3.65 (m, 2H), 3.61 (s, 2H), 2.97 (q, J=7.6 Hz, 2H), 2.57 - 2.49 (m, 4H), 1.35 (t, J=7.6 Hz, 3H). HRMS(ESI) for C 40 H 33 F6N6O3[M + H] +, calcd: 759.2513; found, 759.2913.

[0201] Example 22: Preparation of Compound YLJ-3-22

[0202]

[0203] The synthesis method refers to Step 9 of Example 1.

[0204] 1H NMR(600MHz,Chloroform-d)δ8.87-8.80(m,1H),8.58-8.53(m,1H),8.27(s,1H),8.22-8.16(m,3H),8.06-8.02(m,1H),7.98-7.94(m,1H),7.94-7.90(m,1H),7.88-7.83(m,3H),7.68-7.63(m,1H),7.56-7.52(m,1H),7.43-7.40(m,1H),7.40-7.35(m,1H),6.81-6.73(m,1H),3.81-3.75(m,2H),3.70-3.64(m,2H),3.60(s,2H),2.95(q,2H),2.58-2.41(m,4H),1.34(t,J=7.5Hz,3H).HRMS(ESI)for C 40 H 33 F6N6O3[M+H]+,calcd:759.2513;found,759.2513.

[0205] Example 23: Preparation of Compound YLJ-3-23

[0206]

[0207] The synthesis method refers to Step 9 of Example 1.

[0208] 1H NMR(600MHz,Chloroform-d)δ8.89 - 8.82(m,1H),8.61 - 8.54(m,1H),8.22 - 8.16(m,1H),8.06 - 8.01(m,1H),7.98(s,1H),7.91(s,1H),7.85 - 7.83(m,2H),7.77 - 7.74(m,1H),7.66 - 7.60(m,2H),7.51 - 7.47(m,1H),7.43(d,J=8.1Hz,1H),7.39(s,1H),7.32 - 7.29(m,1H),7.15 - 7.10(m,1H),6.79 - 6.75(m,1H),3.79 - 3.70(m,2H),3.60(s,2H),3.57 - 3.52(m,2H),2.97(q,J=7.6Hz,2H),2.55 - 2.44(m,4H),1.36(t,J=7.6Hz,3H).HRMS(ESI)for C41H37F6N6O4[M+CH3OH+H]+,calcd:759.2513;found,759.2913.

[0209] Example 24: Preparation of Compound YLJ - 3 - 28

[0210]

[0211] The synthesis method refers to Step 9 of Example 1.

[0212] 1 1H NMR(600MHz,Chloroform-d)δ8.86 - 8.81(m,1H),8.57 - 8.53(m,1H),8.20(s,1H),8.20 - 8.17(m,1H),8.08 - 8.02(m,3H),7.96 - 7.92(m,1H),7.92 - 7.87(m,1H),7.87 - 7.83(m,2H),7.51 - 7.45(m,1H),7.43 - 7.38(m,1H),7.39(s,1H),7.19 - 7.14(m,2H),6.77 - 6.74(m,1H),3.80 - 3.73(m,2H),3.70 - 3.63(m,2H),3.60(s,2H),2.95(q,J=7.6Hz,2H),2.56 - 2.48(m,4H),1.34(t,J=7.6Hz,3H).HRMS(ESI)for C 39 H 33 F4N6O4[M+H] +, calcd: 709.2545; found, 709.2545.

[0213] Example 25: Preparation of Compound YLJ-3-29

[0214]

[0215] The synthesis method refers to Step 9 of Example 1.

[0216] 1 H NMR (600 MHz, Chloroform-d) δ 8.87 - 8.81 (m, 1H), 8.59 - 8.54 (m, 1H), 8.22 - 8.17 (m, 1H), 8.15 (s, 1H), 8.05 - 8.03 (m, 1H), 7.95 - 7.92 (m, 1H), 7.89 - 7.83 (m, 3H), 7.82 - 7.78 (m, 1H), 7.73 - 7.68 (m, 1H), 7.51 - 7.47 (m, 2H), 7.43 - 7.40 (m, 1H), 7.39 (s, 1H), 7.33 - 7.29 (m, 1H), 6.77 - 6.74 (m, 1H), 3.81 - 3.74 (m, 2H), 3.69 - 3.63 (m, 2H), 3.60 (s, 2H), 2.95 (q, J = 7.6 Hz, 2H), 2.55 - 2.49 (m, 4H), 1.34 (t, J = 7.6 Hz, 3H). HRMS (ESI) for C 39 H 33 F4N6O4 [M + H] + , calcd: 709.2545; found, 709.2545.

[0217] Example 26: Preparation of Compound YLJ-3-30

[0218]

[0219] The synthesis method refers to Step 9 of Example 1.

[0220] 11H NMR (600 MHz, Chloroform-d) δ 8.86 - 8.82 (m, 1H), 8.58 - 8.54 (m, 1H), 8.21 - 8.17 (m, 1H), 8.13 (s, 1H), 8.07 - 8.02 (m, 1H), 7.94 - 7.90 (m, 1H), 7.88 - 7.79 (m, 3H), 7.78 - 7.67 (m, 1H), 7.61 - 7.53 (m, 1H), 7.46 - 7.35 (m, 3H), 7.29 - 7.22 (m, 1H), 7.19 - 7.11 (m, 1H), 6.78 - 6.74 (m, 1H), 3.78 - 3.73 (m, 2H), 3.67 - 3.62 (m, 2H), 3.60 (s, 2H), 2.96 (q, J=7.6 Hz, 2H), 2.56 - 2.47 (m, 4H), 1.35 (t, J=7.6 Hz, 3H). HRMS(ESI) for C 39 H 33 F4N6O4[M + H] + , calcd: 709.2545; found, 709.2545.

[0221] Example 27: Preparation of Compound YLJ - 3 - 32

[0222]

[0223] The synthesis method refers to Step 9 of Example 1.

[0224] 1 1H NMR (600 MHz, Chloroform-d) δ 8.87 - 8.80 (m, 1H), 8.59 - 8.52 (m, 1H), 8.23 - 8.15 (m, 2H), 8.07 - 8.01 (m, 1H), 7.93 (s, 1H), 7.88 - 7.82 (m, 2H), 7.63 - 7.61 (m, 1H), 7.60 - 7.57 (m, 1H), 7.42 - 7.38 (m, 3H), 7.31 - 7.26 (m, 3H), 6.78 - 6.75 (m, 1H), 3.81 - 3.72 (m, 2H), 3.64 - 3.60 (m, 2H), 3.59 (s, 2H), 2.95 (q, J=7.6 Hz, 2H), 2.52 - 2.50 (m, 4H), 2.49 (s, 3H), 1.34 (t, J=7.6 Hz, 3H). HRMS(ESI) for C 40 H 35 F3N6O4[M + H] + , calcd: 705.2796; found, 705.2796.

[0225] Example 28: Preparation of Compound YLJ-3-72

[0226]

[0227] The synthesis method refers to Step 9 of Example 1.

[0228] 1H NMR(600MHz,Chloroform-d)δ8.86-8.82(m,1H),8.58-8.53(m,1H),8.23(s,1H),8.21-8.16(m,1H),8.06-7.99(m,3H),7.96(m,1H),7.93-7.91(m,1H),7.90-7.84(m,1H),7.60-7.58(m,1H),7.48-7.43(m,1H),7.42-7.33(m,2H),6.97-6.93(m,2H),6.77-6.73(m,1H),4.18-4.05(m,2H),3.84-3.73(m,2H),3.72-3.63(m,2H),3.59(s,1H),2.99-2.88(m,2H),2.56-2.46(m,4H),1.46-1.42(m,3H),1.35-1.32(m,3H).HRMS(ESI)forC 41 H 38 F3N6O4[M+H]+,calcd:735.2901;found,735.2901.

[0229] Example 29: Preparation of Compound YLJ-3-73

[0230]

[0231] The synthesis method refers to Step 9 of Example 1.

[0232] 11H NMR (600 MHz, Chloroform-d) δ 8.90 - 8.78 (m, 1H), 8.65 - 8.49 (m, 1H), 8.20 - 8.16 (m, 1H), 8.10 (s, 1H), 8.06 - 8.03 (m, 1H), 7.98 - 7.88 (m, 2H), 7.65 - 7.58 (m, 2H), 7.55 - 7.52 (m, 1H), 7.50 - 7.46 (m, 1H), 7.44 - 7.34 (m, 3H), 7.19 - 7.13 (m, 1H), 6.80 - 6.73 (m, 1H), 3.87 (s, 3H), 3.82 - 3.75 (m, 2H), 3.70 - 3.64 (m, 2H), 3.61 (s, 2H), 3.00 - 2.90 (m, 2H), 2.57 - 2.47 (m, 4H), 1.42 - 1.30 (m, 3H). HRMS(ESI) for C 40 H 36 F3N6O4[M + H] + , calcd: 721.2745; found, 721.2745.

[0233] Example 30: Preparation of Compound YLJ - 3 - 74

[0234]

[0235] The synthesis method was referred to Step 9 of Example 1.

[0236] 1 1H NMR (600 MHz, Chloroform-d) δ 8.87 - 8.82 (m, 1H), 8.58 - 8.53 (m, 1H), 8.20 (s, 1H), 8.19 - 8.14 (m, 1H), 8.08 - 8.03 (m, 1H), 8.01 - 7.94 (m, 3H), 7.93 - 7.91 (m, 1H), 7.89 - 7.84 (m, 1H), 7.62 - 7.58 (m, 1H), 7.49 - 7.44 (m, 1H), 7.42 - 7.35 (m, 2H), 7.35 - 7.29 (m, 2H), 6.77 - 6.74 (m, 1H), 3.87 - 3.74 (m, 2H), 3.69 - 3.64 (m, 2H), 3.60 (s, 2H), 2.98 - 2.89 (m, 2H), 2.75 - 2.68 (m, 2H), 2.55 - 2.48 (m, 4H), 1.36 - 1.31 (m, 3H), 1.28 - 1.25 (m, 3H). HRMS(ESI) for C 41 H 38 F3N6O3[M + H] +, calcd: 719.2952; found, 719.2952.

[0237] Example 31: Preparation of Compound YLJ-3-75

[0238]

[0239] The synthesis method refers to Step 9 of Example 1.

[0240] 1 H NMR (600 MHz, Chloroform-d) δ 8.87 - 8.81 (m, 1H), 8.60 - 8.53 (m, 1H), 8.21 - 8.18 (m, 1H), 8.16 (s, 1H), 8.06 - 8.03 (m, 1H), 7.93 - 7.90 (m, 1H), 7.89 (s, 1H), 7.87 - 7.84 (m, 1H), 7.78 - 7.73 (m, 1H), 7.70 - 7.65 (m, 1H), 7.52 - 7.47 (m, 1H), 7.42 - 7.40 (m, 1H), 7.39 (s, 1H), 7.34 - 7.30 (m, 1H), 7.04 - 7.00 (m, 1H), 6.99 - 6.94 (m, 1H), 6.78 - 6.74 (m, 1H), 3.90 (s, 3H), 3.78 - 3.73 (m, 2H), 3.69 - 3.63 (m, 2H), 3.60 (s, 2H), 2.95 (q, J = 7.6 Hz, 2H), 2.55 - 2.46 (m, 4H), 1.35 (t, J = 7.6 Hz, 3H). HRMS (ESI) for C 40 H 36 F3N6O4 [M + H] + , calcd: 721.2744; found, 721.2744.

[0241] Example 32: Preparation of Compound YLJ-3-98

[0242]

[0243] The synthesis method refers to Step 9 of Example 1.

[0244] 11H NMR (600 MHz, Chloroform-d) δ 8.87 - 8.81 (m, 1H), 8.58 - 8.53 (m, 1H), 8.20 - 8.17 (m, 1H), 8.15 (s, 1H), 8.10 - 8.06 (m, 2H), 8.06 - 8.03 (m, 1H), 7.98 - 7.93 (m, 1H), 7.92 - 7.88 (m, 1H), 7.87 - 7.83 (m, 1H), 7.61 - 7.59 (m, 1H), 7.52 - 7.48 (m, 1H), 7.43 - 7.36 (m, 2H), 7.35 - 7.30 (m, 2H), 6.77 - 6.73 (m, 1H), 3.83 - 3.75 (m, 2H), 3.69 - 3.64 (m, 2H), 3.61 (s, 2H), 2.94 (m, 2H), 2.57 - 2.47 (m, 4H), 1.34 (m, 3H). HRMS (ESI) for C 40 H 33 F6N6O4[M + H] + , calcd: 775.2462; found, 775.2462.

[0245] Example 33: Preparation of Compound YLJ - 4 - 2

[0246]

[0247] The synthesis method refers to Step 9 of Example 1.

[0248] 1 1H NMR (600 MHz, Chloroform-d) δ 8.83 - 8.74 (m, 1H), 8.53 - 8.47 (m, 1H), 8.15 - 8.08 (m, 1H), 8.00 - 7.94 (m, 1H), 7.88 (s, 1H), 7.85 (s, 1H), 7.84 - 7.80 (m, 3H), 7.80 - 7.75 (m, 2H), 7.62 - 7.59 (m, 1H), 7.58 - 7.56 (m, 1H), 7.45 - 7.40 (m, 1H), 7.40 - 7.35 (m, 1H), 7.33 (s, 1H), 6.72 - 6.67 (m, 1H), 3.74 - 3.69 (m, 2H), 3.62 - 3.58 (m, 3H), 3.54 (s, 2H), 2.90 (q, J = 7.6 Hz, 2H), 2.54 - 2.36 (m, 4H), 1.29 (t, J = 7.6 Hz, 3H). HRMS (ESI) for C 39 H 33 O3N6BrF3[M + H] +, calcd: 769.1744; found, 769.1744.

[0249] Example 34: Preparation of Compound YLJ-4-21

[0250]

[0251] The synthesis method refers to Step 9 of Example 1.

[0252] 1 H NMR (600 MHz, Chloroform-d) δ 8.90 - 8.80 (m, 1H), 8.59 - 8.53 (m, 1H), 8.21 - 8.16 (m, 1H), 8.12 (s, 1H), 8.06 - 8.02 (m, 1H), 8.01 - 7.97 (m, 1H), 7.95 - 7.92 (m, 1H), 7.88 - 7.80 (m, 3H), 7.62 - 7.59 (m, 1H), 7.50 - 7.45 (m, 4H), 7.45 - 7.34 (m, 4H), 6.78 - 6.74 (m, 1H), 3.82 - 3.74 (m, 2H), 3.71 - 3.64 (m, 2H), 3.61 (s, 1H), 2.94 (q, J = 7.6 Hz, 2H), 2.59 - 2.49 (m, 4H), 2.43 (s, 3H), 1.34 (t, J = 7.9 Hz, 3H). HRMS(ESI) for C 40 H 36 F3N6O3[M + H] + , calcd: 705.2796; found, 705.2796.

[0253] Example 35: Preparation of Compound YLJ-4-22

[0254]

[0255] The synthesis method refers to Step 9 of Example 1.

[0256] 11H NMR (600 MHz, Chloroform-d) δ 8.86 - 8.81 (m, 1H), 8.57 - 8.53 (m, 1H), 8.26 (s, 1H), 8.21 - 8.16 (m, 1H), 8.08 - 8.03 (m, 1H), 8.01 - 7.97 (m, 1H), 7.97 - 7.92 (m, 1H), 7.91 - 7.88 (m, 1H), 7.88 - 7.83 (m, 3H), 7.61 - 7.55 (m, 1H), 7.52 - 7.47 (m, 1H), 7.46 - 7.42 (m, 1H), 7.42 - 7.34 (m, 2H), 6.79 - 6.73 (m, 1H), 3.81 - 3.74 (m, 2H), 3.68 - 3.64 (m, 2H), 3.60 (s, 2H), 2.95 (q, J=7.6 Hz, 2H), 2.59 - 2.44 (m, 4H), 1.34 (t, J=7.6 Hz, 2H). HRMS(ESI) for C 39 H 33 ClF3N6O3 [M + H] + , calcd: 725.2249; found, 725.2249.

[0257] Example 36: Preparation of Compound YLJ - 4 - 23

[0258]

[0259] The synthesis method refers to Step 9 of Example 1.

[0260] 1 1H NMR (600 MHz, Chloroform-d) δ 8.84 - 8.81 (m, 1H), 8.57 - 8.52 (m, 1H), 8.39 (s, 1H), 8.20 - 8.14 (m, 1H), 8.06 - 8.03 (m, 1H), 7.96 - 7.92 (m, 1H), 7.88 - 7.83 (m, 2H), 7.59 - 7.46 (m, 2H), 7.46 - 7.42 (m, 2H), 7.40 - 7.33 (m, 3H), 7.26 - 7.22 (m, 1H), 6.77 - 6.72 (m, 1H), 3.75 - 3.71 (m, 2H), 3.62 - 3.59 (m, 2H), 3.58 (s, 2H), 2.94 (q, J=6.6, 5.8 Hz, 2H), 2.52 - 2.47 (m, 4H), 1.33 (t, J=7.6 Hz, 3H). HRMS(ESI) for C 39 H 33 ClF3N6O3 [M + H] +, calcd: 725.2249; found, 725.2249.

[0261] Example 37: Preparation of Compound YLJ-4-73

[0262]

[0263] The synthesis method refers to Step 9 of Example 1.

[0264] 1 H NMR (600 MHz, Chloroform-d) δ 8.85 - 8.81 (m, 1H), 8.57 - 8.53 (m, 1H), 8.25 (s, 1H), 8.20 - 8.16 (m, 1H), 8.06 - 8.02 (m, 1H), 7.94 - 7.91 (m, 1H), 7.88 - 7.82 (m, 2H), 7.71 - 7.66 (m, 1H), 7.60 - 7.56 (m, 1H), 7.51 - 7.45 (m, 1H), 7.44 - 7.37 (m, 3H), 7.36 - 7.29 (m, 2H), 6.79 - 6.71 (m, 1H), 3.76 - 3.72 (m, 2H), 3.62 - 3.60 (m, 2H), 3.59 (s, 2H), 2.95 (q, J = 7.6 Hz, 2H), 2.50 - 2.49 (m, 4H), 1.34 (t, J = 7.5 Hz, 3H). HRMS (ESI) for C 40 H 33 F6N6O4 [M + H] + , calcd: 775.2462; found, 775.2462.

[0265] Example 38: Preparation of Compound YLJ-4-74

[0266]

[0267] The synthesis method refers to Step 9 of Example 1.

[0268] 1H NMR(600MHz,Chloroform-d)δ8.88-8.83(m,1H),8.59-8.54(m,1H),8.22-8.17(m,1H),8.08(s,1H),8.06-8.0 2(m,1H),7.96-7.94(m,1H),7.94-7.93(m,1H),7.90-7.88(m,1H),7.87-7.84(m,3H),7.56-7.53(,,1H),7.51- 7.48(m,1H),7.47-7.46(m,1H),7.45-7.41(m,1H),7.40-7.37(m,1H),6.79-6.72(m,1H),3.81-3.76(m,2H),3 .69-3.64(m,2H),3.61(s,1H),2.96(q,J=7.6Hz,2H),,2.56-2.47(m,4H),1.35(t,J=7.6Hz,2H).HRMS(ESI)for C 40 H 33 F6N6O4[M+H] + ,calcd:775.2462; found,775.2462.

[0269] Example 39: Preparation of Compound YLJ-4-77

[0270]

[0271] The synthesis method refers to step 9 of Example 1.

[0272] 11H NMR (600 MHz, Chloroform-d) δ 8.85 - 8.80 (m, 1H), 8.57 - 8.52 (m, 1H), 8.38 (s, 1H), 8.21 - 8.15 (m, 1H), 8.08 - 8.02 (m, 1H), 7.94 - 7.87 (m, 2H), 7.87 - 7.83 (m, 1H), 7.84 - 7.79 (m, 1H), 7.72 - 7.63 (m, 1H), 7.50 - 7.43 (m, 1H), 7.41 - 7.33 (m, 2H), 7.33 - 7.26 (m, 1H), 7.03 - 6.96 (m, 1H), 6.97 - 6.89 (m, 1H), 6.78 - 6.72 (m, 1H), 4.12 (q, J = 7.0 Hz, 2H), 3.79 - 3.69 (m, 2H), 3.67 - 3.61 (m, 2H), 3.57 (s, 2H), 2.93 (q, J = 7.7 Hz, 2H), 2.52 - 2.44 (m, 4H), 1.45 (t, J = 7.0 Hz, 3H), 1.33 (t, J = 7.6 Hz, 3H). HRMS(ESI) for C 43 H 38 F3N6O4[M + H] + , calcd: 735.2901; found, 775.2901.

[0273] Example 40: Preparation of Compound YLJ - 4 - 80

[0274]

[0275] The synthesis method refers to Step 9 of Example 1.

[0276] 11H NMR (600 MHz, Chloroform-d) δ 8.84 - 8.81 (m, 1H), 8.56 - 8.53 (m, 1H), 8.37 (s, 1H), 8.20 - 8.16 (m, 1H), 8.06 - 8.02 (m, 1H), 7.96 - 7.92 (m, 1H), 7.90 - 7.86 (m, 2H), 7.86 - 7.55 (m, 1H), 7.60 - 7.55 (m, 1H), 7.52 - 7.49 (m, 1H), 7.47 - 7.43 (m, 1H), 7.40 - 7.35 (m, 3H), 7.16 - 7.10 (m, 1H), 6.77 - 6.73 (m, 1H), 4.07 (q, J = 7.0 Hz, 2H), 3.79 - 3.73 (m, 2H), 3.69 - 3.62 (m, 2H), 3.59 (s, 2H), 2.93 (q, J = 7.5 Hz, 2H), 2.54 - 2.47 (m, 4H), 1.42 (t, J = 7.0 Hz, 3H), 1.33 (t, J = 7.6 Hz, 3H). HRMS(ESI) for C 43 H 38 F3N6O4[M + H] + , calcd: 735.2901; found, 775.2901.

[0277] Example 41: Preparation of Compound YLJ - 4 - 82

[0278]

[0279] The synthesis method was referred to Step 9 of Example 1.

[0280] 1 1H NMR (600 MHz, Chloroform-d) δ 8.86 - 8.81 (m, 1H), 8.58 - 8.53 (m, 1H), 8.22 - 8.16 (m, 1H), 8.12 (s, 1H), 8.06 - 8.03 (m, 1H), 8.01 - 7.92 (m, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.87 - 7.82 (m, 3H), 7.50 - 7.43 (m, 2H), 7.43 - 7.34 (m, 3H), 6.78 - 6.74 (m, 1H), 3.81 - 3.75 (m, 2H), 3.69 - 3.65 (m, 2H), 3.61 (s, 2H), 2.95 (q, J = 7.8 Hz, 2H), 2.72 (q, J = 7.6 Hz, 2H), 2.58 - 2.48 (m, 4H), 1.34 (t, J = 7.5 Hz, 3H), 1.26 (t, J = 7.6 Hz, 3H). HRMS(ESI) for C41 H 38 F3N6O3[M+H] + ,calcd:719.2952;found,917.2952.

[0281] Example 42: Preparation of Compound YLJ-4-84

[0282]

[0283] The synthesis method refers to Step 9 of Example 1.

[0284] 1 H NMR(600MHz,Chloroform-d)δ8.85 - 8.78(m,1H),8.56 - 8.51(m,1H),8.47(s,1H),8.21 - 8.15(m,1H),8.07 - 8.03(m,1H),7.98 - 7.93(m,1H),7.88 - 7.81(m,2H),7.62 - 7.49(m,2H),7.45 - 7.39(m,1H),7.39 - 7.33(m,2H),7.32 - 7.27(m,1H),7.29 - 7.22(m,2H),6.78 - 6.71(m,1H),3.76 - 3.68(m,2H),3.61 - 3.56(m,2H),3.57(s,2H),2.93(q,J=7.8Hz,2H),2.81(q,J=7.5Hz,2H),2.52 - 2.44(m,4H),1.32(t,J=7.6Hz,3H),1.20(t,J=7.5Hz,3H).HRMS(ESI)for C 41 H 38 F3N6O3[M+H] + ,calcd:719.2952;found,917.2952.

[0285] Example 43: Test of the DDR1 Degradation Activity of Representative Compounds in NCI-H23 Cells

[0286] Experimental Method

[0287] The cell line NCI-H23 was commercially purchased. Detection was performed using conventional Western Blot (immunoblotting) as follows: The NCI-H23 cells were seeded at 2×10 5Cells were seeded at a density in 12-well cell culture plates and treated with the compound for the specified time. Then the cells were collected, lysed and denatured in 150 μl of SDS cell lysis buffer (62.5 mM Tris-HCl, pH 6.8, 2% w / v SDS, 10% glycerol, 50 mM DTT, 0.01% w / v bromophenol blue). Cell lysates containing 20 μg of protein were loaded onto 10% or 15% SDS-PAGE gels. Then the separated proteins were transferred to PVDF membranes. After blocking the membranes with 5% non-fat milk (dissolved in 1×TBS containing 0.1% Tween-20) at room temperature for 2 hours, they were incubated with the primary antibody overnight at 4°C, and then with the corresponding enzyme-labeled secondary antibody for 1 hour at room temperature. Finally, protein bands were visualized using an ECL Western blotting detection kit (Thermo Scientific) according to the manufacturer's instructions.

[0288] Experimental results

[0289] In the degradation activity test of the compounds, we found that the representative compounds such as YLJ-3-67, YLJ-3-30, YLJ-4-22, YLJ-3-57, etc. had a protein degradation rate of DDR1 reaching over 75%, and the compounds LLC0447, YLJ-3-28, YLJ-3-29 had a degradation rate of DDR1 protein reaching over 50%. Other series of compounds all had certain degradation activities.

[0290] Example 44: Study on the colony formation of non-small cell lung cancer cell NCI-H23 by compounds

[0291] Experimental method

[0292] NCI-H23 cells were counted and 500 cells were seeded in 6-well plates. Then the cells were treated with the compound at the specified concentration for 10 days. Then the cells were washed with PBS, fixed with methanol for 30 minutes, and stained with crystal violet at room temperature for 30 minutes. Then pictures were taken with a camera.

[0293] Experimental results

[0294] The results showed that the preferred compounds such as YLJ-3-67, YLJ-3-28, etc. could significantly inhibit the colony formation of NCI-H23 cells.

[0295] All documents mentioned in this invention are cited in this application as references, as if each document was cited separately as a reference. In addition, it should be understood that after reading the above teachings of this invention, those skilled in the art can make various changes or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A compound having a structure represented by formula (I), a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, in, Linker does not exist or is wherein R1, R2, R3, R4, R5, and R6 are the same or different and are each independently selected from the following structures: a chemical bond, CH2, C=O, O, and NH; Wherein, n is 0, 1, 2, 3, 4, 5 or 6; A is an LC3 protein ligand molecule or an unsaturated enone warhead molecule selected from the following group: 1) 2) 3) Among them, R L Selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C2 alkyl, halogenated C1-C2 alkoxy.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: The Linker does not exist, or the Linker is wherein R1 is selected from the group consisting of a chemical bond, -C(O)-; R6 is selected from the group consisting of NH, -C(O)-; R2, R3, R4, and R5 are the same or different and are each independently selected from the following group of structures: a chemical bond, CH2, C=O, O, or NH; wherein n is 0, 1, 2, 3, 4, 5, or 6.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: The linker does not exist, or the linker is selected from the following group: wherein n1, n2, n3, and n4 are each independently selected from the following group: 1, 2, 3, 4, 5, 6, 7, 8, or 9.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: The R L Selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, fluorinated C1-C2 alkyl, and fluorinated C1-C2 alkoxy.

5. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: The R L Selected from the group consisting of H, Cl, Br, F, CH3, CH2CH3, OCH3, OCH2CH3, CF3, OCF3.

6. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: The compound is selected from the group consisting of:

7. A pharmaceutical composition, characterized in that Include (1) a compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt, stereoisomer or prodrug thereof as an active ingredient; and Optional (2) a pharmaceutically acceptable carrier or excipient.

8. Use of the compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt, stereoisomer or prodrug, or the pharmaceutical composition according to claim 7, characterized in that: Used to prepare DDR1 tyrosine protein kinase degrader.

9. Use of the compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt, stereoisomer or prodrug, or the pharmaceutical composition according to claim 7, characterized in that: Used for preparing drugs for preventing and / or treating diseases mediated by DDR1 tyrosine protein kinase.

10. The use according to claim 9, characterized in that The disease mediated by DDR1 tyrosine protein kinase is selected from the following group: prostate cancer, breast cancer, uterine cancer, ovarian cancer, non-small cell lung cancer, small cell lung cancer, Ewing sarcoma, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumors, colon cancer, rectal cancer, glioma.

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