Compounds for Targeted Degradation of ALK Protein, Preparation Methods Thereof and Applications

Abstract

Provided is a compound for targeted degradation of ALK protein, its preparation method and application. The application field is the field of biopharmaceuticals. Specifically, it relates to a compound represented by formula (I), its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition thereof. It can be used for preparing anti-tumor drugs, has high oral bioavailability, can penetrate the brain, has high-specific ALK degradation properties, and overcomes the problem of drug resistance. Formula (I).

Description

Technical Field

[0001] The present invention belongs to the field of biopharmaceuticals, and particularly relates to a compound for targeted degradation of ALK protein, a preparation method thereof, and an application thereof. Background Art

[0002] Anaplastic lymphoma kinase (ALK) is a transmembrane protein tyrosine kinase belonging to the insulin receptor kinase subfamily. It was first discovered in anaplastic large cell lymphoma (ALCL) with a nucleophosmin (NPM)-ALK fusion form, which is a subtype of T-cell non-Hodgkin lymphoma and is usually associated with chromosomal translocation. Since then, many cancers have been successively found to be related to different forms of ALK fusion, including non-small cell lung cancer (NSCLC, EML4-ALK), inflammatory myofibroblastic tumor (IMT, TPM3-ALK), and diffuse large B-cell lymphoma (DLBCL, CLTC-ALK). In addition, gene amplification of ALK and wild-type ALK protein mutations have been reported in a variety of tumors (such as EML4-ALK fusion, F1174L mutation, etc.).

[0003] ALK has become an attractive therapeutic target, partly because its level in normal adult tissues is low, which is considered to reduce the chance of off-target toxicity caused by ALK inhibitors. Therefore, therapeutic strategies that inhibit ALK kinase activity are considered to produce fewer side effects. So far, the US Food and Drug Administration (FDA) has approved 5 ALK small molecule inhibitors, including the first-generation inhibitor Crizotinib, the second-generation inhibitors Alectinib, Ceritinib, and Brigatinib, and the third-generation inhibitor Lorlatinib for the treatment of ALK-positive NSCLC patients. To achieve continuous ALK inhibition, the inhibitor must bind to the ALK protein for a long time to reach binding saturation. During this process, off-target effects and kinase mutations may occur, and abnormal proteins cannot be cleared, resulting in drug resistance, which becomes a major obstacle to clinical efficacy. Drug resistance to ALK inhibition remains a severe challenge. Therefore, there is an urgent need to develop new ALK drugs and alternative ALK-targeted methods to overcome drug resistance.

[0004] Targeted protein degradation (TPD) technology mainly uses small molecules to induce ubiquitination of target proteins through the ubiquitin-proteasome system and then rapidly degrade pathogenic target proteins to produce therapeutic effects. TPD is expected to treat a variety of diseases, including cancer, infection, inflammation, and neurodegenerative diseases. Compared with small molecule inhibitors, degraders have many advantages, including enhanced selectivity, the ability to overcome drug resistance, targeting undruggable proteins, and eliminating the entire protein (rather than just inhibiting enzyme function). In recent years, with the continuous development of protein degradation technology, TPD has been widely used in the development of therapeutic drugs for various diseases, and some ALK protein degraders have been reported one after another. Unfortunately, the currently reported ALK degraders generally have limitations such as low specificity, poor oral in vivo anti-tumor efficacy, and inability to penetrate the brain, and cannot produce clinical value. There is an urgent need to develop ALK degraders with high oral bioavailability, brain penetration, and high specificity. Summary of the Invention

[0005] To solve the above technical problems, the present invention provides a compound having a B CRBN -Z3-PTM structure, its stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, wherein B CRBN is a moiety capable of binding to the ubiquitin enzyme CRBN, Z3 is a linking group moiety, and PTM is a moiety capable of binding to the kinase ALK; the compound having a B CRBN -Z3-PTM structure is a compound represented by the following formula (I) or formula (I');

[0006]

[0007] Formula (I)

[0008]

[0009] Formula (I')

[0010] Wherein or is a moiety capable of binding to the ubiquitin enzyme CRBN;

[0011] In formula (I),

[0012] Y is selected from O, S;

[0013] Z1 is selected from CH or N;

[0014] Z2 is selected from a single bond, CH2, O, S, NR1, NHCO;

[0015] A is selected from the following groups which are unsubstituted or optionally substituted by 1, 2, 3, or 4 R s1 substituents: aryl, heteroaryl, 、 or ;

[0016] wherein the aryl is a 6- to 20-membered aromatic ring; and wherein the heteroaryl is a 5- to 20-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S;

[0017] Each R s1 is the same or different and is independently selected from the group consisting of: hydrogen, deuterium, halogen, nitro, cyano, hydroxy, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylcarbonylamino, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, or C1-C6 alkylthio;

[0018] U is selected from CH or N;

[0019] X is selected from CH2, O, S, NR1;

[0020] R1 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CH2-C(=O)-R s3 , -C(=O)-R s3 , -CH(R’)-OC(=O)-R s3 , -CH2-OP(=O)(OR s3 )2, -C(=O)O-CH(R’)-O-C(=O)-R s3 ; R’ and R s3 are the same or different and are independently selected from hydrogen, C1-C6 alkyl, 6- to 20-membered aryl, 5- to 20-membered heteroaryl;

[0021] Z4 is selected from CH, C=O, or C=S, and when Z4 is selected from C=O or C=S, is a single bond, and when Z4 is selected from CH, is a double bond; optionally, X, U, and the adjacent carbon atoms therebetween form a fused ring structure;

[0022] Z3 is a covalent bond or C1-C 10 alkyl, and any carbon atom in the C1-C 10 alkyl may optionally be replaced by NH, O, S, or substituted by an oxo (=O) group;

[0023] PTM is selected from a small molecule compound or a derivative thereof that binds to the target protein ALK;

[0024] provided that when A is selected from When, Z3 is -C(=O)-;

[0025] In formula (I'), Z1 is selected from N; R1, Z2, Z3, Y, PTM and ring A have the definitions as described above.

[0026] According to an embodiment of the present invention, R1 is independently selected from hydrogen, C1-C3 alkyl;

[0027] According to an embodiment of the present invention, Y is selected from O;

[0028] According to an embodiment of the present invention, Z2 is selected from a single bond, CH2, O, S, NH, NCH3, NHCO;

[0029] According to an embodiment of the present invention, A is selected from the following groups which are unsubstituted or optionally substituted by 1, 2, 3, or 4 R s1 substituted: aryl, heteroaryl, , or ; wherein the aryl is a 6-10 membered aromatic ring; wherein the heteroaryl is a 5-10 membered aromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; wherein Z4, X, U have the same definitions as described above;

[0030] Optionally, X forms a fused ring structure between the 1-position and 2-position carbon atoms, such as a fused benzene ring;

[0031] According to an embodiment of the present invention, A is selected from the following groups which are unsubstituted or optionally substituted by 1, 2, 3, or 4 R s1 substituted: phenyl, naphthyl, pyridine, indazole, quinoline, quinazoline, pyridazine, pyrazine, naphthyridone, benzimidazole, benzopyrazole, benzisoxazole, imidazopyridine, triazolopyridine, pyrazolopyridine, benzopyrazole, , , , , ; wherein X, U have the same definitions as described above;

[0032] According to an embodiment of the present invention, A is selected from the following groups which are unsubstituted or optionally substituted by 1, 2, 3, or 4 R s1 substituted:

[0033] , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0034] According to an embodiment of the present invention, each R s1 is the same or different and is independently selected from the following groups: hydrogen, deuterium, fluorine, chlorine, bromine, nitro, cyano, hydroxyl, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 fluoroalkoxy, C1-C3 chloroalkoxy, C1-C3 alkylcarbonylamino, C1-C3 alkylcarbonyl, C1-C3 alkoxycarbonyl, C1-C3 alkylsulfonyl, C1-C3 alkylsulfinyl or C1-C3 alkylthio;

[0035] According to an embodiment of the present invention, A is selected from the following structures, where R s1 has the same definition as described above:

[0036] , , , , , , , , , , , , , , , , , , , , , , , ;

[0037] According to an embodiment of the present invention, A is selected from the following groups:

[0038] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0039] According to an embodiment of the present invention, Z4 is selected from C=O or C=S, is a single bond, or Z4 is selected from CH, is a double bond;

[0040] According to an embodiment of the present invention, a fused benzene ring is formed between X, U and the adjacent carbon atoms therebetween;

[0041] According to an embodiment of the present invention, Z3 is selected from a single bond, -C(=O)-, -C1-C6 alkyl-C(=O)-, -C(=O)-C1-C6 alkyl-, -NH-C(=O)-, -C(=O)-NH-C1-C6 alkyl-C(=O)-;

[0042] According to an embodiment of the present invention, Z3 is selected from a single bond, -C(=O)-, -C1-C3 alkyl-C(=O)-, -C(=O)-C1-C3 alkyl-, -NH-C(=O)-, -C(=O)-NH-C1-C3 alkyl-C(=O)-;

[0043] According to an embodiment of the present invention, Z3 is selected from a single bond, -C(=O)-, -CH2-C(=O)-, -C(=O)- CH2-, -NH-C(=O)-, -C(=O)-NH-CH2-C(=O)-;

[0044] According to an embodiment of the present invention, PTM is selected from the following structures:

[0045] 、 、 、 、 、 、 、 、 ;

[0046] wherein, J is selected from the following structures:

[0047] 、 、 、 、 、 、 、 、 、 、 ;

[0048] L is selected from C1-C6 alkylene, -C1-C6 alkylcarbonyl-;

[0049] T is selected from bis-C1-C6 alkylphosphine oxide group, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl;

[0050] R2 to R 15 is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, oxo, -C1-C6 alkyl-phenyl, C1-C6 alkoxy-C(O)-, C1-C6 alkylamino-C(O)-, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl;

[0051] K is selected from C1-C3 alkylene, NH;

[0052] R S2 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy.

[0053] According to an embodiment of the present invention, PTM is selected from the following structures, where L, R2 to R 15 , K, R S2 have the same definitions as described above:

[0054] , , , , , , , , , ;

[0055] According to an embodiment of the present invention, L is selected from C1-C3 alkylene, -C1-C3 alkylcarbonyl-;

[0056] According to an embodiment of the present invention, T is selected from di-C1-C3 alkylphosphine oxide, C1-C3 alkylsulfonyl, C1-C3 alkylsulfinyl;

[0057] According to an embodiment of the present invention, R2 to R 15 are selected from hydrogen, deuterium, fluorine, chlorine, bromine, C1-C3 alkyl, oxo, -C1-C3 alkyl-phenyl, C1-C3 alkoxy-C(O)-, C1-C3 alkylamino-C(O)-, C1-C3 haloalkyl, C1-C3 alkoxy, hydroxy C1-C3 alkyl;

[0058] According to an embodiment of the present invention, K is selected from C1-C2 alkylene;

[0059] According to an embodiment of the present invention, R S2 is selected from hydrogen, fluorine, chlorine, bromine, C1-C3 alkyl, C1-C3 alkoxy;

[0060] According to an embodiment of the present invention, J is selected from the following structures:

[0061] , , , , , , , , , , , , , , , , ;

[0062] Both ends of J can be connected to adjacent structures and can be connected to adjacent structures according to the writing format, that is, the left end is connected to Z3 and the right end is connected to the group fragment in PTM. It can also be connected to adjacent structures in the opposite direction of the writing format, that is, the right end is connected to Z3 and the left end is connected to the group fragment in PTM.

[0063] According to the embodiments of the present invention, J is selected from the following structures:

[0064] , , , , , , , , , , , , , , , , ;

[0065] Both ends of J can be connected to adjacent structures and can be connected to adjacent structures according to the writing format, that is, the left end is connected to Z3 and the right end is connected to the group fragment in PTM. It can also be connected to adjacent structures in the opposite direction of the writing format, that is, the right end is connected to Z3 and the left end is connected to the group fragment in PTM.

[0066] According to the embodiments of the present invention, J is selected from the following structures:

[0067] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0068] Both ends of the J can be connected to adjacent structures, and can be connected to adjacent structures according to the writing format, that is, the left end is connected to Z3, and the right end is connected to the group fragment in PTM. It can also be connected to adjacent structures in the opposite direction of the writing format, that is, the right end is connected to Z3, and the left end is connected to the group fragment in PTM.

[0069] According to the embodiments of the present invention, the compound represented by formula (I), its stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs;

[0070]

[0071] Formula (I)

[0072] Wherein,

[0073] Y is selected from O, S;

[0074] Z1 is selected from CH or N;

[0075] Z2 is selected from a single bond, CH2, O, S, NR1, NHCO;

[0076] A is selected from the following groups which are unsubstituted or optionally substituted by 1, 2, 3, or 4 R s1 substituted phenyl, naphthyl, pyridine, indazole, quinoline, quinazine, pyridazine, pyrazine, naphthyridone, benzimidazole, benzopyrazole, benzisoxazole, imidazopyridine, triazolopyridine, pyrazolopyridine, benzopyrazole,

[0077] , , , , ;

[0078] Each R s1Identical or different, and independently selected from the following groups: hydrogen, deuterium, halogen, nitro, cyano, hydroxyl, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylcarbonylamino, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl or C1-C6 alkylthio;

[0079] U is selected from CH or N;

[0080] X is selected from CH2, O, S, NR1;

[0081] R1 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CH2-C(=O)-R s3 , -C(=O)-R s3 , -CH(R’)-OC(=O)-R s3 , -CH2-OP(=O)(OR s3 )2, -C(=O)O-CH(R’)-O-C(=O)-R s3 ; R’, R s3 are identical or different, and independently selected from hydrogen, C1-C6 alkyl, 6-20-membered aryl, 5-20-membered heteroaryl;

[0082] Optionally, a fused ring structure is formed between X and the carbon atoms at the 1- and 2-positions, such as a fused benzene ring;

[0083] Z3 is selected from a single bond, -C(=O)-, -C1-C6 alkyl-C(=O)-, -C(=O)-C1-C6 alkyl-, -NH-C(=O)-, -C(=O)-NH-C1-C6 alkyl-C(=O)-;

[0084] PTM is selected from the following structures:

[0085] , , , ;

[0086] wherein J, T, R S2 have the same definitions as described above;

[0087] Provided that when A is selected from , Z3 is -C(=O)-.

[0088] According to an embodiment of the present invention, the compound is selected from the following compounds:

[0089]

[0090] The compound of general formula I of the present invention can be prepared according to the following methods:

[0091] Scheme 1: The compound shown in formula (II-1) reacts with the reactant PTM-H to obtain the compound shown in formula (I);

[0092]

[0093] wherein, Z is COOH or CH2COOH, R1, Z1, Z2, Z3, Y, PTM and ring A have the definitions as described above, and R has the same definition as R1 as described above; or, when R is a protecting group, the said Scheme 1 further includes a process of deprotecting to prepare the compound shown in formula (I) with R1 being hydrogen;

[0094] Or, Scheme 2: The compound shown in formula (II-2) reacts with the reactant PTM-(C=O)-Cl to obtain the compound shown in formula (I);

[0095]

[0096] wherein, R1, Z1, Z2, Z3, Y, PTM and ring A have the definitions as described above, and R has the same definition as R1 as described above; or, when R is a protecting group, the said Scheme 2 further includes a process of deprotecting to prepare the compound shown in formula (I) with R1 being hydrogen;

[0097] Or, Scheme 3: The compound shown in formula (III-1) or formula (III-2) or formula (III-3) reacts with the reactant to obtain the compound shown in formula (I);

[0098] ; or

[0099] ; or

[0100]

[0101] wherein, the reactant is or or ;

[0102] Among them, R1-R9, Z1, Z2, Z3, Y, R S2 , T, K, PTM, and ring A have the definitions as described above;

[0103] Alternatively, Scheme 4: The compound shown in formula (II-3) reacts with a reactant to obtain the compound shown in formula (I);

[0104] ;

[0105] Among them, the reactant is , , , , , or ;

[0106] Among them, R1-R9, Z1, Z2, Z3, Y, R S2 , T, K, PTM, and ring A have the definitions as described above;

[0107] Alternatively, Scheme 5: The compound shown in formula (II-4) reacts with the compound shown in formula (III-4) to obtain the compound shown in formula (I);

[0108]

[0109] Among them, R 10 -R 13 , R1, Z1, Z2, Z3, Y, PTM, and ring A have the definitions as described above, and L' is selected from C1-C5 alkyl-CHO or C1-C5 alkyl-COOH.

[0110] The general formula I' compound of the present invention can be prepared by referring to the method of the general formula I compound.

[0111] The present invention also provides a pharmaceutical composition, which comprises at least one of a therapeutically effective amount of the compound shown in formula I, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs.

[0112] According to an embodiment of the present invention, the pharmaceutical composition further comprises one, two, or more pharmaceutically acceptable carriers or excipients.

[0113] According to an embodiment of the present invention, the pharmaceutical composition further contains one or more additional therapeutic agents.

[0114] According to an embodiment of the present invention, the pharmaceutical composition further contains one or more additional drugs for treating or preventing cancer.

[0115] According to the present invention, the pharmaceutical compositions of the present invention can be made into dosage forms suitable for administration by methods known in the art.

[0116] When used as a medicine, the compounds of the present invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well-known in the pharmaceutical art and can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area being treated. They can be administered locally (e.g., transdermally, dermally, ophthalmically, and mucosally including intranasally, vaginally, and rectally), by the pulmonary route (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheally, intranasally), orally, or parenterally. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranially, e.g., intrathecally or intraventricularly. They can be administered parenterally in a single large dose form, or can be administered, for example, by means of a continuous perfusion pump. Medicinal compositions and preparations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, water, powder or oily bases, thickening agents, etc. may be necessary or desirable.

[0117] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The preparations can also contain: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweetening and flavoring agents. The compositions of the present invention can be formulated by using methods known in the art so as to provide a rapid-release, sustained-release, or delayed-release action of the active ingredient after administration to a patient.

[0118] The tablets or pills of the present invention can be coated or compounded to obtain dosage forms that provide the advantage of a long-acting effect. For example, the tablets or pills contain an inner dose and an outer dose component, the latter being in the form of a coating for the former. The two components can be separated by an enteric layer, which is used to prevent disintegration in the stomach so that the inner component can pass through the duodenum intact or be released slowly. A variety of substances can be used for such enteric layers or coating agents, and such substances include a variety of high molecular weight acids and mixtures of high molecular weight acids with such substances as shellac, cetyl alcohol, and cellulose acetate.

[0119] Liquid forms in which the compounds and compositions of the present invention can be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions; and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil; as well as elixirs and similar pharmaceutical vehicles.

[0120] Compositions for inhalation or insufflation include solutions, suspensions, and powders dissolved in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In certain embodiments, the composition is administered by the oral or nasal breathing route to achieve local or systemic effects. The composition can be atomized by using an inert gas. The atomized solution can be inhaled directly by an atomization device, or the atomization device can be connected to a face mask tent or an intermittent positive pressure ventilator. The solution, suspension, or powder composition can be administered orally or nasally by a device that delivers the formulation in an appropriate manner.

[0121] The amount of the compound or composition administered to a patient is not fixed and depends on the drug administered, the purpose of administration such as prophylaxis or treatment; the condition of the patient, the mode of administration, etc. In therapeutic applications, a patient suffering from a disease can be administered an amount of the composition sufficient to cure or at least partially inhibit the disease and the symptoms of its complications. The effective dose should depend on the disease state being treated and the judgment of the attending clinician, which depends on factors such as the severity of the disease, the age, weight, and general condition of the patient, etc.

[0122] The present invention also provides a method for inhibiting ALK and / or mutant ALK, comprising administering to a subject in need an effective amount of a compound of formula I as described in the present invention, its stereoisomers, tautomers, isotopically labeled compounds, N-oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition thereof.

[0123] The present invention also provides a method for treating or preventing a disease or disorder in which a kinase plays a role, comprising administering to a subject in need an effective amount of a compound of formula I as described in the present invention, its stereoisomers, tautomers, isotopically labeled compounds, N-oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition thereof.

[0124] In some embodiments, the disease or disorder is resistant to treatment targeted at ALK.

[0125] The present invention also provides a method for inhibiting tumor cell proliferation in vitro or in vivo, the method comprising contacting tumor cells with an effective amount of a compound of formula I as described in the present invention, its stereoisomers, tautomers, isotopically labeled compounds, N-oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition thereof.

[0126] The present invention also provides a method for treating or preventing cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula I, its stereoisomers, tautomers, isotopically labeled compounds, N-oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition thereof.

[0127] The present invention also provides a method for treating or preventing cancer-related diseases or disorders in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I of the present invention, its stereoisomers, tautomers, isotopically labeled compounds, nitroxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition thereof.

[0128] The present invention also provides the use of a compound of formula I, its stereoisomers, tautomers, isotopically labeled compounds, nitroxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or a pharmaceutical composition thereof in the preparation of a medicament selected from any one of the following:

[0129] (1) The medicament is a medicament for inhibiting ALK kinase activity, or the medicament is an ALK kinase inhibitor;

[0130] (2) The medicament is a medicament targeting ALK;

[0131] (3) The medicament is capable of treating or preventing a disease or disorder in which mutant ALK plays a role;

[0132] (4) The medicament is capable of treating or preventing cancer in a subject identified as in need of inhibiting mutant ALK for the treatment or prevention of cancer;

[0133] (5) The medicament is capable of treating or preventing a disease or disorder resistant to ALK-targeted therapy;

[0134] (6) The medicament is capable of treating or preventing cancer, preferably, wherein the cancer cells of the cancer contain mutant ALK;

[0135] In some embodiments, the cancer is, for example: lung cancer; lymphoma; inflammatory myofibroblastic tumor; colorectal cancer; glioma; astrocytoma; ovarian cancer; myeloid disease; transplantation-related cancer; neutropenia; leukemia; Unverricht-Lundborg syndrome; bronchial cancer; prostate cancer; breast cancer; thyroid cancer; pancreatic cancer; neuroblastoma; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; adenocarcinoma of the large intestine; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; melanoma; brain cancer; oral cancer; sarcoma; tumors resistant to targeted drugs; or tumors or diseases dependent on ALK protein.

[0136] In some embodiments, the cancer is selected from the group consisting of: small cell lung cancer; non-small cell lung cancer; diffuse large B-cell lymphoma; non-Hodgkin lymphoma; anaplastic lymphoma; anaplastic large cell lymphoma; CD20-positive lymphoma; primary lymphoma; B-cell lymphoma; recurrent B-cell non-Hodgkin lymphoma; recurrent diffuse large B-cell lymphoma; recurrent mediastinal (thymic) large B-cell lymphoma; primary mediastinal (thymic) large B-cell lymphoma; recurrent transformed non-Hodgkin lymphoma; refractory B-cell non-Hodgkin lymphoma; refractory diffuse large B-cell lymphoma; refractory primary mediastinal (thymic) large B-cell lymphoma; refractory transformed non-Hodgkin lymphoma; multiple myeloma; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; plasma cell myeloma; smoldering myeloma; smoldering multiple myeloma; myelofibrosis; acute myeloid leukemia (AML); anemia associated with leukemia; chronic myelogenous leukemia; B-cell chronic lymphocytic leukemia; Unverricht-Lundborg syndrome; bronchial carcinoma; prostate cancer; triple-negative breast cancer; sporadic breast cancer; patients with Cowden disease; thyroid cancer; pancreatic cancer; neuroblastoma; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; melanoma; brain cancer; oral cancer; rhabdomyosarcoma; various lipogenic tumors; Ewing sarcoma / primitive neuroectodermal tumors (Ewing / PNETs); leiomyosarcoma; tumors resistant to ALK-targeted drugs; or tumors or diseases dependent on ALK protein.

[0137] In some embodiments, the cancer is selected from the group consisting of: anaplastic lymphoma kinase (ALK)-mutated positive non-small cell lung cancer; lung cancer resistant to ALK-targeted drugs; lymphoma resistant to ALK-targeted drugs; or the following tumors, cancers or diseases dependent on ALK protein: lung cancer, lymphoma, inflammatory myofibroblastic tumor, colorectal cancer, glioma, astrocytoma, ovarian cancer, leukemia, breast cancer, thyroid cancer, neuroblastoma, extramedullary plasmacytoma, plasmacytoma, esophageal squamous cell carcinoma, renal cell carcinoma, bronchial carcinoma, prostate cancer, breast cancer, thyroid cancer, pancreatic cancer, neuroblastoma, extramedullary plasmacytoma, plasmacytoma, gastric cancer, gastrointestinal stromal tumor, esophageal cancer, colorectal adenocarcinoma, esophageal squamous cell carcinoma, liver cancer, renal cell carcinoma, bladder cancer, endometrial cancer, melanoma, brain cancer, oral cancer or sarcoma.

[0138] In some embodiments, the patient is a mammal, such as a human.

[0139] Beneficial effects

[0140] The compound represented by formula (I) according to the present invention, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, or their pharmaceutical compositions can be used to prepare anti-tumor drugs, which have high oral bioavailability, can penetrate the brain, have high-specific ALK degradation properties, and overcome the problem of drug resistance.

[0141] Term Definitions and Explanations

[0142] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be combined and combined arbitrarily with each other. The defined groups and compound structures after such combination and combination should fall within the scope recorded in the specification of this application.

[0143] In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when writing the structural formula from right to left. For example, CH2O is equivalent to OCH2.

[0144] The term "moiety capable of binding to the ubiquitin enzyme CRBN" refers to a small molecule ligand of the CRBN protease with ubiquitination function.

[0145] The term "moiety capable of binding to the kinase ALK" refers to a small molecule ligand of the ALK tyrosine kinase.

[0146] The term "ligand" refers to a substance that has the ability to recognize and bind to a target receptor protein.

[0147] The term "halogen" means fluorine, chlorine, bromine and iodine.

[0148] The term "C1-C 10 alkyl" should preferably be understood to represent a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1 to 10 carbon atoms. For example, "C1-C6 alkyl" represents straight-chain and branched-chain alkyls having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyls are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers.

[0149] The term "aryl" should be understood to preferably denote a monocyclic, bicyclic (such as fused, bridged, spiro) hydrocarbon ring that is monovalent aromatic or partially aromatic and has 6 to 20 carbon atoms. It can be a monoaromatic ring or multiple aromatic rings fused together, and is also denoted as "C6-C 20 aryl". The term "6- to 10-membered aryl" should be understood to denote a monovalent aromatic or partially aromatic monocyclic or bicyclic hydrocarbon ring having 6, 7, 8, 9, or 10 carbon atoms, particularly a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl. When the aryl is substituted, it can be mono-substituted or multi-substituted. And there is no restriction on the substitution site, for example, it can be ortho-substituted, para-substituted, or meta-substituted.

[0150] The term "heteroaryl" should be understood to include such monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems: having 5 to 20 ring atoms and containing 1 to 4 heteroatoms independently selected from N, O, and S, and is also denoted as "5- to 20-membered heteroaryl", preferably "5- or 6-membered heteroaryl". The term "5- to 10-membered heteroaryl" should be understood to include such monocyclic or bicyclic aromatic ring systems: having 5, 6, 7, 8, 9, 10 ring atoms, particularly 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 4, preferably 1 to 3 heteroatoms independently selected from N, O, and S; and, additionally, can be benzo-fused in each case. The heteroaryl can be selected from "5- or 6-membered heteroaryl", that is, including such monocyclic aromatic ring systems: having 5 to 6 ring atoms and containing 1 to 4 heteroatoms independently selected from N, O, and S. In particular, the heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, quinoxalinyl, etc.; or isothiazolopyrimidinyl, imidazopyridyl, azocinyl, indolizinyl, purinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, triazolopyridyl, pyrazolopyridyl, etc.

[0151] Unless otherwise specified, heteroaryl includes all possible isomeric forms thereof, such as positional isomers. Thus, for some illustrative non-limiting examples, pyridyl includes pyridin-2-yl, pyridin-3-yl, pyridin-4-yl; thienyl includes thien-2-yl, thien-3-yl.

[0152] The above definition of the term "alkyl", such as "C 1- C6 alkyl", also applies to other terms containing "C 1- C6 alkyl", such as the terms "C 1- C6 alkoxy", "C 1- C6 haloalkyl", "C 1- C6 haloalkoxy", "C1-C6 alkoxycarbonyl", "C1-C6 alkylcarbonyl", "C1-C4 alkylsulfonyl", "C1-C4 alkylsulfinyl", "C1-C4 alkylthio", etc.

[0153] The term "pharmaceutically acceptable salt" as used herein refers to a salt that retains the biological potency of the free acid and free base of the specified compound and has no adverse effects biologically or otherwise. The compounds of the present application also include pharmaceutically acceptable salts, such as nitrates, hydrochlorides, sulfates, or phosphates, etc. Pharmaceutically acceptable salts refer to converting the basic group in the parent compound into a salt form. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amine (ammonia) groups. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound, i.e., the basic group in the parent compound reacts with 1-4 equivalents of an acid in a solvent system.

[0154] The term "stereoisomer" refers to compounds that have the same chemical constitution but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, atropisomers, and so on.

[0155] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. A mixture of diastereomers can be separated by high-resolution analytical operations such as electrophoresis and chromatography, such as HPLC.

[0156] The term "isotope label" includes, but is not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, 35S, and 36Cl) labeled compounds of the present invention. Isotope-labeled compounds of the present invention can be used for the determination of the tissue distribution of the compounds, their prodrugs, and metabolites; preferred isotopes for such determinations include 3H and 14C. In addition, in some cases, substitution with heavier isotopes (e.g., deuterium (2H or D)) can provide increased metabolic stability, which provides therapeutic advantages such as increased in vivo half-life or reduced dose requirements. Isotope-labeled compounds of the present invention can generally be prepared by substituting non-isotope-labeled reagents with isotope-labeled reagents according to the methods described herein.

[0157] The term "nitrogen oxide" refers to the formation of N-oxides by oxidizing one or more nitrogen atoms when the compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocycles. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L.W. Deady (Syn.Comm.1977, 7,509-514), where, for example, in an inert solvent such as dichloromethane, the amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA).

[0158] The term "solvate" refers to an association formed by one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association where the solvent molecule is water.

[0159] The term "metabolite" refers to the product obtained by the metabolic action of a specific compound or its salt in the body. Metabolites of a compound can be identified by techniques well known in the art, and their activities can be characterized by experimental methods as described in the present invention. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds, including metabolites produced by bringing the compounds of the present invention into sufficient contact with a mammal for a period of time.

[0160] The term "ester" refers to an in vivo hydrolyzable ester formed from a compound containing a hydroxyl or carboxyl group. Such esters are, for example, pharmaceutically acceptable esters that hydrolyze in a human or animal body to produce the parent alcohol or acid. The compounds of formula (I) of the present invention contain a carboxyl group and can form in vivo hydrolyzable esters with appropriate groups, such groups including, but not limited to, alkyl, arylalkyl, etc.

[0161] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, most preferably humans.

[0162] The phrase "therapeutically effective amount" as used herein refers to the amount of an active compound or drug that a researcher, veterinarian, physician or other clinician is seeking to elicit a biological or medical response in a tissue, system, animal, individual or human, and it includes one or more of the following: (1) preventing a disease: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or manifested the pathology or symptoms of the disease. (2) inhibiting a disease: for example, inhibiting a disease, disorder or condition (i.e., preventing the further development of the pathology and / or symptoms) in an individual who is experiencing or manifesting the pathology or symptoms of the disease, disorder or condition. (3) alleviating a disease: for example, alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or manifesting the pathology or symptoms of the disease, disorder or condition. Detailed implementation manners

[0163] The technical solutions of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only for illustrative explanation of the present disclosure and should not be construed as limiting the protection scope of the present disclosure. All technologies implemented based on the above content of the present disclosure are covered within the scope of protection intended by the present disclosure.

[0164] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products or can be prepared by known methods.

[0165] Abbreviations in this application:

[0166] AcOH: acetic acid; AIBN: azobisisobutyronitrile; Boc: tert-butoxycarbonyl; Boc2O: di-tert-butyl dicarbonate; Br2: bromine; BTI: [bis(trifluoroacetoxy)iodo]benzene; CDI: N,N'-carbonyldiimidazole; CHCl3: chloroform; CO: carbon monoxide; CO2: carbon dioxide; (COCl2)3: triphosgene; Cs2CO3: cesium carbonate; CuCN: cuprous cyanide; CuI: cuprous iodide; DCM: dichloromethane; DIEA: N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMF: N,N-dimethylformamide; DMF-DMA: N,N-dimethylformamide dimethyl acetal; DMSO: dimethyl sulfoxide; DMSO-d6: deuterated dimethyl sulfoxide; EA: ethyl acetate; Et3N: triethylamine; EtOH: ethanol; h: hour; HATU: 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HCl: hydrochloric acid; 11H NMR: Proton Nuclear Magnetic Resonance; HNO3: Nitric Acid; i-PrOH: Isopropyl Alcohol; K2CO3: Potassium Carbonate; KHMDS: Potassium Bis(trimethylsilyl)amide; LCMS: Liquid Chromatography-Mass Spectrometry; LiOH: Lithium Hydroxide; MeCN: Acetonitrile; MeOH: Methanol; mol / L: Moles per Liter; MsOH: Methanesulfonic Acid; NaBH3CN: Sodium Cyanoborohydride; NaH: Sodium Hydride; NaHB(OAc)3: Sodium Triacetoxyborohydride; NaHCO3: Sodium Bicarbonate; NaOH: Sodium Hydroxide; NBS: N-Bromosuccinimide; n-BuLi: n-Butyllithium; NMI: N-Methylimidazole; NMP: N-Methylpyrrolidone; NIS: N-Iodosuccinimide; Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0); Pd / C: Palladium on Carbon; Pd(dppf)Cl2DCM: Dichloride(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) Dichloromethane Complex; Pd(OH)2 / C: Palladium(II) Hydroxide on Carbon; PE: Petroleum Ether; PMB: p-Methoxybenzyl; Q-Phos: 1,2,3,4,5-Pentaphenyl-1-(di-tert-butylphosphino)ferrocene; t-BuOK: Potassium tert-Butoxide; TCFH: N,N,N′,N′-Tetramethylchloroformamidinium Hexafluorophosphate; Tf2O: Trifluoromethanesulfonic Anhydride; TfOH: Trifluoromethanesulfonic Acid; TFA: Trifluoroacetic Acid; THF: Tetrahydrofuran; TsOH: p-Toluenesulfonic Acid; Urea: Urea; RuPhos: 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl; RuPhosPdG2: Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II); RuPhosPdG3: Methanesulfonate(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II); X-Phos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0167] Synthesis Example

[0168] Preparation of AJ10a:

[0169]

[0170] Preparation of AJ10a-1: AJ10a-0 (200 mg, 0.45 mmol) was dissolved in 15 mL of dioxane. Under stirring at room temperature, 1-Boc-4-(piperidin-4-yl)-piperazine (245 mg, 0.91 mmol), Pd2(dba)3 (42 mg, 0.05 mmol), X-Phos (32 mg, 0.05 mmol) and KHMDS (1.8 mL, 1.82 mmol) were added successively, and the mixture was protected with argon. The reaction mixture was heated to 80 °C and stirred for about 3 h. After the reaction was completed, the reaction system was cooled to room temperature, 15 mL of water was added to the reaction solution for quenching, and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. Column chromatography (PE / EA = 100 / 1 - 2 / 1) gave a pale yellow solid AJ10a-1 (216 mg, 82%).

[0171] Preparation of AJ10a-2: AJ10a-1 (200 mg, 0.34 mmol) was dissolved in 10 mL of DCM. 3 mL of TFA was added dropwise to the reaction system at room temperature, and the reaction was continued to stir for about 1 h. LCMS detection showed that the raw material had disappeared and the reaction was completed. The solvent DCM and excess TFA were removed by concentration under reduced pressure to obtain a pale yellow solid AJ10a-2 (157 mg, 95%).

[0172] Preparation of AJ10a: 2-(2,6-Dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindole-4-carboxylic acid (12 mg, 0.04 mmol) and AJ10a-2 (20 mg, 0.04 mmol) were dissolved in 8 mL of DMF. Under stirring at room temperature, Et3N (12 mg, 0.13 mmol) and HATU (15.8 mg, 0.04 mmol) were added successively, and the reaction was stirred for about 1 h. 10 mL of water was added to the reaction solution for quenching, and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. Purification by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 4) gave a white solid AJ10a (19 mg, 61%). 11H NMR (400 MHz, DMSO-d6) δ12.71 (s, 1H), 11.00 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.04 (s, 1H), 8.00(s, 1H), 7.83 (dd, J = 6.3, 2.4 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.61 (s,1H), 7.59 (d, J = 1.4 Hz, 1H), 7.33 (s, 1H), 5.15 (dd, J = 13.2, 5.1 Hz, 1H),4.46 (d, J = 17.7 Hz, 1H), 4.36 (d, J = 17.7 Hz, 1H), 3.67 (s, 2H), 3.44 (s,2H), 3.23 (d, J = 11.3 Hz, 4H), 2.89 (dd, J = 12.7, 5.5 Hz, 1H), 2.78 (d, J =11.5 Hz, 2H), 2.76- 2.72 (m, 1H), 2.70 (d, J = 7.5 Hz, 2H), 2.66-2.60 (m,2H), 2.59-2.56 (m, 1H), 2.46-2.41 (m, 1H), 2.02-1.98 (m, 1H), 1.93-1.84 (m,2H), 1.75 (s, 6H), 1.68-1.59 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z752.6 [M+H] + .

[0173] Preparation of AJ11:

[0174]

[0175] Preparation of AJ11-1: Dissolve 2-fluoro-4-bromonitrobenzene (2.0 g, 9.1 mmol) and methylamine hydrochloride (0.7 g, 10.9 mmol) in 30 mL of MeCN, add K2CO3 (2.5 g, 18.2 mmol), and stir the reaction at room temperature for 4 h. Concentrate under reduced pressure, dilute the reaction solution with 50 mL of water and extract with 20 mL of EA. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a pale yellow solid AJ11-1 (1.7 g, 80%).

[0176] Preparation of AJ11-2: Dissolve AJ11-1 (1.7 g, 7.4 mmol) in 25 mL of DCM. Add zinc powder (1.4 g, 22.2 mmol) all at once and slowly add AcOH (1.8 g, 29.6 mmol). Stir the mixed system at room temperature for about 2 h. Filter by suction, and wash the filter cake twice with 20 mL of DCM. Combine the filtrates and concentrate to obtain a crude light yellow concentrate. Obtain a light yellow solid AJ11-2 (0.9 g, 60%) by column chromatography (EA / PE = 1 / 100 - 1 / 1).

[0177] Preparation of AJ11-3: Dissolve AJ11-2 (0.9 g, 4.5 mmol) and CDI (0.9 g, 5.4 mmol) in 30 mL of MeCN. Stir the resulting solution at 80 o °C for 3 h. Cool down and quench the reaction by adding water. Rotavapor to remove MeCN. Add 20 mL of water and 15 mL of EA to the concentrated solution for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry and concentrate the organic phases with anhydrous sodium sulfate to obtain a crude light yellow concentrate. Obtain a light yellow solid AJ11-3 (0.7 g, 71%) by column chromatography (EA / PE = 1 / 100 - 1 / 2).

[0178] Preparation of AJ11-4: Dissolve AJ11-3 (700 mg, 3.1 mmol) in 20 mL of MeCN. Add K2CO3 (855 mg, 6.2 mmol) and 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (1.44 g, 4.6 mmol) under stirring at room temperature. Heat the reaction solution to 80 o °C and stir for 6 h. Wait for the reaction to be detected and completed, then cool to room temperature. Pour into 40 mL of ice water and perform extraction and liquid separation with 15 mL of EA. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry and concentrate the organic phases with anhydrous sodium sulfate to obtain a light yellow crude product. Obtain a light yellow solid AJ11-4 (566 mg, 40%) by column chromatography (EA / PE = 1 / 10 - 2 / 1).

[0179] Preparation of AJ11-5: Dissolve AJ11-4 (300 mg, 0.66 mmol) in 20 mL of THF solvent. Stir at room temperature and add Pd2(dba)3 (60 mg, 0.066 mmol), Q-Phos (46 mg, 0.066 mmol) and 2-tert-butoxy-2-carbonylethylzinc bromide (0.5 M, 6.6 mL, 3.3 mmol) under argon protection. Slowly heat the reaction system to 70 oStir the reaction for 2 h. After the reaction is completed, add saturated ammonium chloride solution to the reaction solution for quenching, extract with EA, collect the organic phase, wash it with saturated brine, dry it over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to remove the solvent, and purify the concentrate by column chromatography (MeOH / DCM = 1 / 100 - 1 / 40) to obtain a white solid AJ11-5 (146 mg, 45%).

[0180] Preparation of AJ11-6: AJ11-5 (146 mg, 0.3 mmol) was dissolved in a mixed solution of 1 mL of TfOH and 2 mL of TFA, and the resulting solution was reacted at room temperature for 3 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the concentrate was purified by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 4) to obtain a white solid AJ11-6 (28 mg, 30%).

[0181] Preparation of AJ11: AJ11-6 (10 mg, 0.032 mmol) and AJ10a-2 (16 mg, 0.033 mmol) were dissolved in 5 mL of DMF. Under stirring at room temperature, Et3N (6 mg, 0.063 mmol) and HATU (14 mg, 0.038 mmol) were added successively, and the reaction was continued for about 1 h. 10 mL of water was added to the reaction solution for quenching and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. It was purified by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 4) to obtain a white solid AJ11 (5 mg, 20%). 1HNMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 11.11 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.01 (d, J = 1.1 Hz, 1H), 7.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.34 (s, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 9.0 Hz, 1H), 5.36 (dd, J = 12.8, 5.3 Hz, 1H), 3.77 (s, 3H), 3.66 - 3.55 (m, 2H), 3.55 - 3.46 (m, 2H), 3.46 - 3.40 (m, 2H), 3.28 - 3.19 (m, 2H), 2.96 - 2.91 (m, 1H), 2.90 - 2.81 (m, 2H), 2.80 - 2.74 (m, 2H), 2.74 - 2.71 (m, 2H), 2.70 (d, J = 7.5 Hz, 2H), 2.67 - 2.65 (m, 1H), 2.61 - 2.57 (m, 1H), 2.48 - 2.43 (m, 1H), 2.04 - 1.99 (m, 1H), 1.98 - 1.86 (m, 2H), 1.75 (s, 6H), 1.70 - 1.58 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 781.6 [M+H] + .

[0182] Preparation of AJ12:

[0183]

[0184] Preparation of AJ12-1: Dissolve AJ11-1 (1.7 g, 7.4 mmol) and 1-Boc-piperazine (1.5 g, 8.1 mmol) in 25 mL of NMP, and add DIEA (1.4 g, 11.0 mmol) at room temperature. Heat the mixed system to 110 o °C and stir for about 4 h. After detecting complete reaction by LCMS, cool down, add 40 mL of water to the reaction solution for quenching and add 15 mL of EA for extraction and liquid separation. Repeat extraction three times until extraction is complete. Combine the organic phases and backwash with saturated brine. Dry and concentrate the organic phases with anhydrous sodium sulfate to obtain a crude light yellow concentrate. Purify by column chromatography (EA / PE = 1 / 100 - 1 / 2) to obtain a light yellow solid AJ12-1 (2.1 g, 83%).

[0185] Preparation of AJ12-2: Dissolve AJ12-1 (2.1 g, 6.3 mmol) in 30 mL of THF solution, add Pd / C (content 10%, 200 mg), displace with hydrogen three times, react at room temperature for 3 h, and detect by LCMS that the reaction is complete. Filter by suction, wash the filter cake twice with 10 mL of THF, and concentrate the combined filtrate under reduced pressure to obtain a pale yellow solid AJ12-2 (1.7 g, 90%).

[0186] Preparation of AJ12-3: Dissolve AJ12-2 (1.7 g, 5.6 mmol) and CDI (1.1 g, 6.8 mmol) in 30 mL of MeCN, and stir the resulting solution at 80 o °C for 3 h. Rotate and evaporate to remove MeCN. Add 40 mL of water to the reaction solution to quench and add 15 mL of EA for extraction and liquid separation. Repeat extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry and concentrate the organic phase with anhydrous sodium sulfate to obtain the crude product. Obtain a pale yellow solid AJ12-3 (1.4 g, 78%) by column chromatography (EA / PE = 1 / 100 - 1 / 1).

[0187] Preparation of AJ12-4: Dissolve AJ12-3 (500 mg, 1.5 mmol) in 10 mL of THF, cool to 0 o °C and add NaH (60%, 181 mg, 4.5 mmol) in batches under stirring. After about 30 minutes, add 3-bromopiperidine-2,6-dione (434 mg, 2.3 mmol), and heat the reaction solution to 60 o °C and react for 2 h. Detect by LCMS that the reaction is complete and cool to room temperature. Slowly pour into 40 mL of ice water and extract and separate with 15 mL of EA. Repeat extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry and concentrate the organic phase with anhydrous sodium sulfate to obtain a pale yellow crude product. Purify by column chromatography (EA / PE = 1 / 10 - 2 / 1) to obtain a pale yellow solid AJ12-4 (287 mg, 43%).

[0188] Preparation of AJ12-5: Dissolve AJ12-4 (287 mg, 0.65 mmol) in 10 mL of DCM, add 2 mL of hydrochloric acid dioxane solution (4 M) under stirring at room temperature, stir the resulting solution at room temperature for 2 h, and concentrate under reduced pressure to remove the solvent to obtain a pale yellow solid AJ12-5 (211 mg, 95%).

[0189] Preparation of AJ12: AJ12-5 (34 mg, 0.1 mmol) was dissolved in 4 mL of DMF. AJ12-6 (53 mg, 0.13 mmol) and DIEA (13 mg, 0.1 mmol) were added under stirring at room temperature. The mixture was stirred for about 1 h, then NaBH3CN (13 mg, 0.2 mmol) was added, and stirring was continued at room temperature for about 4 h. After detecting the completion of the reaction, 10 mL of water was added to the reaction solution for quenching, and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Column chromatography (MeOH / DCM = 1 / 100 - 1 / 30) gave the white solid product AJ12 (33 mg, 45%). 1 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 11.08 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.05 (s, 1H), 8.03 - 7.97 (m, 1H), 7.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.35 (s, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 5.30 (dd, J = 12.8, 5.3 Hz, 1H), 3.31 (s, 3H), 3.25 (d, J = 11.0 Hz, 2H), 3.12 (s, 4H), 2.94 - 2.85 (m, 1H), 2.80 (t, J = 11.3 Hz, 2H), 2.76 - 2.72 (m, 4H), 2.70 (d, J = 7.3 Hz, 2H), 2.68 - 2.65 (m, 1H), 2.64 - 2.60 (m, 1H), 2.47 - 2.42 (m, 1H), 2.03 - 1.98 (m, 1H), 1.98 - 1.89 (m, 2H), 1.76 (s, 6H), 1.71 - 1.61 (m, 2H), 1.29 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 739.6 [M+H] + .

[0190] Preparation of AJ12a:

[0191]

[0192] Preparation of AJ12a-1: AJ10a-2 (160 mg, 0.33 mmol) and 3,4-difluoronitrobenzene (79 mg, 0.50 mmol) were dissolved in 10 mL of DMF. K2CO3 (92 mg, 0.67 mmol) was added under stirring at room temperature, and the reaction system was slowly heated to 80 o °C and reacted for about 6 h. After detecting the completion of the reaction, the temperature was lowered to room temperature. 10 mL of water was added to the reaction solution for quenching and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (DCM / MeOH = 100 / 1 - 60 / 1) gave yellow solid AJ12a-1 (115 mg, 56%).

[0193] Preparation of AJ12a-2: AJ12a-1 (115 mg, 0.18 mmol) and zinc powder (60 mg, 0.93 mmol) were dissolved in 5 mL of DCM. AcOH (55 mg, 0.93 mmol) was slowly added dropwise under stirring at room temperature and the reaction continued for 1 h. LCMS detection showed the completion of the reaction. 10 mL of water was added to the reaction solution for quenching and 10 mL of DCM was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (DCM / MeOH = 100 / 1 - 20 / 1) gave yellow solid AJ12a-2 (88 mg, 81%).

[0194] Preparation of AJ12a: AJ12a-2 (88 mg, 0.15 mmol) and 3-bromopiperidine-2,6-dione (57 mg, 0.298 mmol) were dissolved in 5 mL of DMF. NaHCO3 (25 mg, 0.3 mmol) was added under stirring at room temperature, and the reaction system was slowly heated to 100 o °C and reacted for about 18 h. LCMS detection showed the completion of the reaction. The temperature was lowered to room temperature. 10 mL of water was added to the reaction solution for quenching and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (DCM / MeOH = 100 / 1 - 25 / 1) gave yellow solid AJ12a (20 mg, 19%). 11H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 10.79 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.35 (s, 1H), 6.84 (t, J = 9.3 Hz, 1H), 6.52 (dd, J = 15.0, 2.5 Hz, 1H), 6.43 (dd, J = 8.7, 2.4 Hz, 1H), 5.82 (d, J = 7.7 Hz, 1H), 4.32 - 4.21 (m, 1H), 3.24 (d, J = 11.2 Hz, 2H), 3.07 - 2.95 (m, 1H), 2.95 - 2.84 (m, 4H), 2.80 (d, J = 11.8 Hz, 2H), 2.75 - 2.73 (m, 1H), 2.71 (d, J = 7.4 Hz, 2H), 2.70 - 2.65 (m, 3H), 2.57 - 2.53 (m, 1H), 2.45 - 2.40 (m, 1H), 2.13 - 2.04 (m, 1H), 1.99 - 1.90 (m, 2H), 1.89 - 1.82 (m, 1H), 1.75 (s, 6H), 1.69 - 1.59 (m, 2H), 1.28 (t, J = 7.4 Hz, 3H). LCMS(ESI) m / z 702.6 [M+H] + .

[0195] Preparation of AJ12b:

[0196]

[0197] Preparation of AJ12b-1: Dissolve AJ11-1 (1.0 g, 4.4 mmol) in 15 mL of DMF, and then successively add K2CO3 (1.2 g, 8.7 mmol) and 4-piperidone ethylene glycol ketal (630 mg, 4.4 mmol) under stirring at room temperature. Heat the reaction solution to 100 °C and react for 2 h. LCMS detection shows that the raw materials have completely reacted. Cool to room temperature, add 20 mL of water to the reaction solution for dilution and add 15 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate it under reduced pressure to obtain the crude concentrate. Purify it by column chromatography (EA / PE = 1 / 100 - 1 / 1) to obtain pink solid AJ12b-1 (1.17 g, 97%).

[0198] Preparation of AJ12b-2: Dissolve AJ12b-1 (1.2 g, 4 mmol) in 20 mL of THF, add 10% Pd / C (10%, 120 mg) under stirring at room temperature, displace with hydrogen and continue to stir at room temperature in a hydrogen atmosphere for 3 h. LCMS detection shows that AJ12b-1 has completely reacted. Filter off the palladium carbon under reduced pressure and wash the palladium carbon three times with 20 mL of THF. Combine the organic phases and concentrate them under reduced pressure to obtain brown solid concentrated product AJ12b-2 (1.04 g, 99%).

[0199] Preparation of AJ12b-3: Dissolve AJ12b-2 (500 mg, 1.90 mmol) in 10 mL of MeCN solution, add CDI (920 mg, 5.70 mmol) under stirring at room temperature, and heat to 80 o °C and react for 2 h. After detection shows that the reaction is complete, cool the reaction solution and add 20 mL of water. Solids precipitate out. Filter under reduced pressure and dry the filter cake to obtain brown solid AJ12b-3 (540 mg, 99%).

[0200] Preparation of AJ12b-4: Dissolve AJ12b-3 (540 mg, 1.9 mmol) in 5 mL of DMF, add 3-bromopiperidine-2,6-dione (433.2 mg, 2.3 mmol) and NaH (60%, 228 mg, 5.7 mmol) under stirring at room temperature, and heat the mixed system to 70 oStir the reaction for about 8 h. LCMS detection shows that the raw material has completely reacted. After cooling the reaction solution to room temperature, pour it into 5 mL of dilute hydrochloric acid (2 M) aqueous solution for quenching, and add 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure to obtain the crude concentrate. Purify by column chromatography (EA / PE = 1 / 100 - 1 / 1) to obtain the brown solid AJ12b-4 (400 mg, 53%).

[0201] Preparation of AJ12b-5: Dissolve AJ12b-4 (400 mg, 0.99 mmol) in 15 mL of DCM solution. Add 2 mL of dioxane solution of hydrochloric acid (4 M) to the reaction solution under stirring at room temperature, and stir the reaction at room temperature for 1 h. LCMS detection shows that the raw material has completely reacted. Spin-dry the reaction solution by concentration under reduced pressure, and purify the residue by column chromatography (EA / PE = 1 / 100 - 1 / 1) to obtain the brown solid AJ12b-5 (60 mg, 17%).

[0202] Preparation of AJ12b: Dissolve AJ12b-5 (60 mg, 0.17 mmol) in 5 mL of DMF, then add AJ12b-6 (69 mg, 0.17 mmol, prepared according to the preparation method of AJ10a-2) under stirring at room temperature, and stir at room temperature for 1 h. Then add NaHCO3 (29 mg, 0.34 mmol) and NaHB(OAc)3 (72 mg, 0.34 mmol) to the reaction solution, and continue to stir the reaction for about 4 h. Wait until LCMS detection shows that AJ12b-5 has completely reacted. Add 10 mL of water to the reaction solution for quenching and add 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure to obtain the crude concentrate. Purify by column chromatography (MeOH / DCM = 1 / 100 - 1 / 20) to obtain the white solid AJ12b (10 mg, 8%). 11H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 11.22 (s,1H), 8.32 (d, J = 8.1 Hz, 1H), 8.06 (s, 1H), 8.00 (d, J = 1.1 Hz, 1H), 7.61(dd, J = 8.2, 1.4 Hz, 1H), 7.37 (s, 1H), 7.32 (s, 1H), 7.30 (d, J = 2.8 Hz,1H), 7.10 (s, 1H), 5.36 (dd, J = 12.9, 5.3 Hz, 1H), 4.41 (d, J = 12.5 Hz,1H), 4.08 (d, J = 12.8 Hz, 1H), 3.31 (s, 3H), 3.18 - 3.10 (m, 2 H), 3.10 - 2.96(m, 4H), 2.95 - 2.90 (m, 1H), 2.89 - 2.81 (m, 2H), 2.78 - 2.75 (m, 1H), 2.72 (d, J= 7.5 Hz, 2H), 2.71 - 2.66 (m, 2H), 2.66 - 2.56 (m, 2H), 2.19 - 2.11 (m, 1H), 2.01 - 1.84 (m, 2H), 1.76 (s, 6H), 1.43 - 1.34 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 739.6 [M+H] + .

[0203] Preparation of AJ13:

[0204]

[0205] Preparation of AJ13-1: At 0 o °C, dissolve AJ13-0 (2.1 g, 12.43 mmol) in 20 mL of CHCl3. While stirring well, add bromine (0.64 mL, 12.43 mmol) dropwise within five minutes. After the addition, slowly raise the reaction solution to room temperature and continue the reaction for 6 h. Add 20 mL of water to quench the reaction and extract with 20 mL of CHCl3. Repeat the extraction three times until the extraction is complete. Combine the organic phases and dry and concentrate over anhydrous sodium sulfate to obtain a crude yellow-brown concentrate. Purify by column chromatography (DCM / MeOH = 100 / 1 - 30 / 1) to obtain yellow solid AJ13-1 (2.9 g, 95%).

[0206] Preparation of AJ13-2: At -70 o °C, AJ13-1 (600 mg, 2.43 mmol) was dissolved in 10 mL of dry THF. Under stirring, NaH (583 mg, 24.29 mmol) was added in batches and the mixture was reacted at low temperature for 1 h. Then, 3-bromopiperidine-2,6-dione (1.4 g, 7.29 mmol) was added and the reaction continued for 4 h. The reaction mixture was warmed to room temperature, quenched with 50 mL of water, and extracted with 20 mL of EA. The extraction was repeated three times until complete. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 100 / 1 - 30 / 1) to obtain white solid AJ13-2 (500 mg, 57%).

[0207] Preparation of AJ13-3: AJ13-2 (500 mg, 1.40 mmol) was dissolved in 20 mL of THF solution. Under argon protection, Pd2(dba)3 (145 mg, 0.14 mmol), Q-Phos (46 mg, 0.21 mmol), and 2-tert-butoxy-2-carbonylethylzinc bromide (0.5 M, 14 mL, 7 mmol) were added successively. The reaction mixture was slowly heated to 70 o °C and stirred for 5 h. After the reaction was completed, the reaction mixture was quenched with saturated ammonium chloride solution, extracted with EA, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the solvent. The concentrate was purified by column chromatography (MeOH / DCM = 1 / 100 - 1 / 30) to obtain light yellow solid AJ13-3 (300 mg, 55%).

[0208] Preparation of AJ13-4: AJ13-3 (100 mg, 0.254 mmol) was dissolved in a mixed solvent of 5 mL of DCM and 2 mL of TFA. The resulting solution was reacted at room temperature for 2 h, and the solvent was removed by rotary evaporation. The residue was purified by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 4) to obtain white solid AJ13-4 (80 mg, 93%).

[0209] Preparation of AJ13: AJ13-4 (15 mg, 0.044 mmol) and AJ13-5 (21 mg, 0.044 mmol, prepared according to the preparation method of AJ10a-2) were dissolved in 5 mL of DMF. Et3N (13 mg, 0.133 mmol) and HATU (20 mg, 0.053 mmol) were added under stirring at room temperature, and the reaction continued for about 1 h. 8 mL of water was added to the reaction solution to quench the reaction, and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Purification by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 2) gave the white solid product AJ13 (12 mg, 32%). 1 H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 11.15 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 6.9 Hz, 1H), 8.04 (s, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.89 - 7.80 (m, 1H), 7.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.33 (d, J = 7.3 Hz, 2H), 7.10 (d, J = 7.3 Hz, 1H), 5.50 - 5.43 (m, 1H), 4.17 (s, 2H), 3.67 - 3.62 (m, 2H), 3.56 - 3.46 (m, 2H), 3.26 - 3.18 (m, 2H), 2.98 - 2.90 (m, 1H), 2.87 - 2.81 (m, 1H), 2.78 - 2.73 (m, 2H), 2.72 (d, J = 7.5 Hz, 2H), 2.68 - 2.66 (m, 1H), 2.64 - 2.62 (m, 2H), 2.56 - 2.53 (m, 2H), 2.47 - 2.41 (m, 1H), 2.14 - 2.07 (m, 1H), 1.94 - 1.83 (m, 2H), 1.75 (s, 6H), 1.69 - 1.58 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 802.6 [M+H] + .

[0210] Preparation of AJ14:

[0211]

[0212] Preparation of AJ14-1: AJ14-0 (750 mg, 3.77 mmol) and Boc2O (1.2 g, 5.6 mmol) were dissolved in 20 mL of tert-butanol. DMAP (46 mg, 0.38 mmol) was added under stirring at room temperature, and the resulting solution was heated to 40 o C and stirred for about 8 h. After detecting the completion of the reaction, the temperature was lowered to room temperature. 20 mL of water and 20 mL of EA were added to the reaction solution for extraction and liquid separation, and the extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine, and the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (PE / EA = 100 / 1 - 10 / 1) gave white solid AJ14-1 (750 mg, 78%).

[0213] Preparation of AJ14-2: AJ14-1 (750 mg, 2.9 mmol) was dissolved in 10 mL of THF solution. 10% Pd / C (80 mg) was added under stirring at room temperature, and the hydrogen was replaced. The reaction was stirred at room temperature in a hydrogen atmosphere for about 3 h. Filtration was carried out under reduced pressure, and the filter cake was washed twice with 10 mL of THF. The filtrates were combined and concentrated under reduced pressure to obtain light yellow solid AJ14-2 (650 mg, 98%).

[0214] Preparation of AJ14-3: AJ14-2 (250 mg, 1.11 mmol) was dissolved in 5 mL of DMF. 3-bromopiperidine-2,6-dione (426 mg, 2.22 mmol) and NaHCO3 (236 mg, 2.22 mmol) were added under stirring, and the reaction solution was slowly heated to 100 o C and stirred for about 6 h. After detecting the completion of the reaction by LCMS, 20 mL of water was added to the reaction solution to quench the reaction and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The combined organic phases were dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (DCM / MeOH = 100 / 1 - 50 / 1) gave yellow solid AJ14-3 (50 mg, 13%).

[0215] Preparation of AJ14-4: AJ14-3 (50 mg, 0.149 mmol) was dissolved in a mixed solvent of 2 mL of DCM and 1 mL of TFA. The resulting solution was stirred at room temperature for 2 h. Then the solvent was removed by concentration under reduced pressure, and the concentrate was purified by reverse-phase preparation (water / MeCN = 1 / 100 - 3 / 1) to obtain white solid AJ14-4 (35 mg, 85%).

[0216] Preparation of AJ14: AJ14-4 (7 mg, 0.025 mmol) and AJ10a-2 (12 mg, 0.025 mmol) were dissolved in 5 mL of DMF. Under stirring at room temperature, Et3N (8 mg, 0.75 mmol) and HATU (00 mg, 0.027 mmol) were added successively, and the reaction was continued with stirring for about 1 h. Then, 6 mL of water was added to the reaction solution to quench it, and 5 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Purification by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 2) gave white solid AJ14 (5 mg, 27%). 1 HNMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.82 (s, 1H), 8.32 (d, J = 8.2 Hz,1H), 8.04 (s, 1H), 8.00 (d, J = 1.3 Hz, 1H), 7.61 (dd, J = 8.2, 1.4 Hz, 1H),7.34 (s, 1H), 6.91 (t, J = 8.7 Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H), 6.44 (s,1H), 6.09 (d, J = 7.7 Hz, 1H), 4.38 - 4.28 (m, 1H), 3.53 (s, 2H), 3.51 - 3.45 (m,2H), 3.41 - 3.37 (m, 2H), 3.23 - 3.19 (m, 2H), 2.81 - 2.79 (m, 1H), 2.79 - 2.76 (m,1H), 2.74 - 2.72 (m, 1H), 2.70 (d, J = 7.5 Hz, 2H), 2.68 - 2.65 (m, 2H), 2.54 - 2.52 (m, 2H), 2.44 - 2.36 (m, 2H), 2.14 - 2.05 (m, 1H), 1.94 - 1.89 (m, 1H), 1.88 - 1.85 (m, 2H), 1.75 (s, 6H), 1.62 - 1.58 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 744.6 [M+H] + .

[0217] Preparation of AJ14a: AJ14a was prepared according to the preparation method of AJ14.

[0218]

[0219] 1 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 11.01 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 3.7 Hz, 1H), 6.97 - 6.92 (m, 1H), 6.90 (t, J = 4.8 Hz, 1H), 6.65 - 6.56 (m, 1H), 6.51 (t, J = 7.7 Hz, 1H), 5.75 (d, J = 7.7 Hz, 1H), 4.38 - 4.22 (m, 1H), 3.61 - 3.50 (m, 2H), 3.49 - 3.42 (m, 4H), 3.24 - 3.16 (m, 4H), 2.90 - 2.85 (m, 1H), 2.83 (d, J = 3.8 Hz, 1H), 2.80 - 2.73 (m, 2H), 2.74 - 2.71 (m, 1H), 2.71 - 2.67 (m, 2H), 2.67 - 2.59 (m, 1H), 2.57 - 2.53 (m, 1H), 2.44 - 2.42 (m, 1H), 2.15 - 2.09 (m, 1H), 1.89 - 1.83 (m, 2H), 1.74 (s, 6H), 1.64 - 1.57 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 726.6 [M+H] + .

[0220] Preparation of AJ20: AJ20 was prepared according to the preparation method of AJ12a.

[0221]

[0222] 11H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 10.78 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.44 (s, 1H), 6.86 (s, 1H), 6.84 (s, 1H), 6.67 (s, 1H), 6.65 (s, 1H), 5.45 (d, J = 7.3 Hz, 1H), 4.25 - 4.20 (m, 1H), 3.31 - 3.25 (m, 2H), 3.18 - 3.11 (m, 4H), 2.95 - 2.86 (m, 1H), 2.76 (q, J = 7.5 Hz, 2H), 2.70 - 2.68 (m, 1H), 2.59 - 2.52 (m, 1H), 2.49 - 2.40 (m, 1H), 2.13 - 2.08 (m, 1H), 2.04 - 1.95 (m, 1H), 1.78 (s, 6H), 1.29 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 601.5 [M+H] + .

[0223] Preparation of AJ24: AJ24 was prepared according to the preparation method of AJ12a.

[0224]

[0225] 11H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 10.78 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.01 (s, 1H), 7.63 - 7.59 (m, 1H), 7.48 - 7.41 (m, 1H), 7.35 (s, 1H), 6.91 (t, J = 8.6 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 6.62 (d, J = 8.6 Hz, 1H), 5.39 (d, J = 7.4 Hz, 1H), 4.22 - 4.19 (m, 1H), 3.24 - 3.22 (m, 2H), 3.12 - 3.09 (m, 2H), 2.98 - 2.94 (m, 2H), 2.90 - 2.85 (m, 1H), 2.81 (d, J = 11.8 Hz, 2H), 2.78 - 2.74 (m, 1H), 2.72 (d, J = 7.5 Hz, 2H), 2.69 - 2.65 (m, 3H), 2.61 - 2.55 (m, 1H), 2.44 - 2.40 (m, 1H), 2.12 - 2.09 (m, 1H), 1.98 - 1.91 (m, 2H), 1.86 - 1.80 (m, 1H), 1.75 (s, 6H), 1.69 - 1.59 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 684.5 [M+H] + .

[0226] Preparation of AJ26: AJ26 was prepared according to the preparation method of AJ12a.

[0227]

[0228] 11H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.82 (s, 1H), 8.36 (s,1H), 8.04 (s, 1H), 8.03 (s, 1H), 7.63 - 7.59 (m, 1H), 7.48 - 7.41 (m, 1H), 7.35(s, 1H), 6.91 (s, 1H), 6.62 (d, J = 8.6 Hz, 1H), 5.42 (d, J = 7.4 Hz, 1H),4.23 - 4.18 (m, 1H), 3.24 - 3.22 (m, 2H), 3.12 - 3.09 (m, 2H), 2.98 - 2.94 (m, 2H),2.90 - 2.85 (m, 1H), 2.81 (d, J = 11.8 Hz, 2H), 2.78 - 2.74 (m, 1H), 2.72 (d, J =7.5 Hz, 2H), 2.69 - 2.65 (m, 3H), 2.61 - 2.55 (m, 1H), 2.44 - 2.40 (m, 1H), 2.12 - 2.09 (m, 1H), 1.98 - 1.91 (m, 2H), 1.86 - 1.80 (m, 1H), 1.75 (s, 6H), 1.69 - 1.59(m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 685.5 [M+H] + .

[0229] Preparation of AJ27: AJ27 was prepared according to the preparation method of AJ12a.

[0230]

[0231] 11H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 10.81 (s, 1H), 8.36 (s,1H), 8.04 (s, 1H), 8.01 - 7.98 (m, 1H), 7.63 - 7.59 (m, 1H), 7.48 - 7.41 (m, 1H),7.18 (s, 1H), 6.91 (s, 1H), 6.62 (d, J = 8.6 Hz, 1H), 5.42 (d, J = 7.4 Hz,1H), 4.20 - 4.17 (m, 1H), 3.24 - 3.22 (m, 2H), 3.12 - 3.09 (m, 2H), 2.99 - 2.92 (m,2H), 2.90 - 2.85 (m, 1H), 2.81 (d, J = 11.8 Hz, 2H), 2.78 - 2.74 (m, 1H), 2.71(d, J = 7.5 Hz, 2H), 2.69 - 2.65 (m, 3H), 2.61 - 2.55 (m, 1H), 2.44 - 2.40 (m, 1H),2.12 - 2.09 (m, 1H), 1.99 - 1.90 (m, 2H), 1.87 - 1.81 (m, 1H), 1.75 (s, 6H), 1.69 - 1.59 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 685.5 [M+H] + .

[0232] Preparation of AJ31:

[0233]

[0234] Preparation of AJ31 - 1: AJ31 - 0 (3 g, 19 mmol) and N - Boc - piperazine (4.3 g, 23 mmol) were dissolved in 30 mL of DMF. K2CO3 (6.6 g, 48 mmol) was added to the reaction solution under stirring at room temperature. Then the reaction solution was heated to 90 °C and stirred for 2 h. After the reaction was complete, it was cooled to room temperature. 30 mL of water was added to quench the reaction and 30 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 100 / 1 - 10 / 1) to obtain a pale yellow solid AJ31 - 1 (1.9 g, 28%).

[0235] Preparation of AJ31-2: Dissolve AJ31-1 (1.9 g, 6 mmol) in 20 mL of THF. Add 10% Pd / C (0.2 g) under stirring at room temperature. Place the reaction system under hydrogen conditions and heat it up to 40 °C and stir for 2 h. After detecting the complete reaction, filter off Pd / C under reduced pressure and wash the palladium carbon. The filtrate is concentrated under reduced pressure to obtain white solid AJ31-2 (1.5 g, 88%).

[0236] Preparation of AJ31-3: Dissolve AJ31-2 (1.5 g, 5 mmol) in 15 mL of THF solution. Add CDI (1 g, 6 mmol) under stirring at room temperature. Heat the reaction system up to 70 °C and stir for 3 h. After the reaction is complete, cool it to room temperature. Concentrate the reaction solution under reduced pressure to obtain a crude product, which is purified by column chromatography (PE / EA = 100 / 1 - 2 / 1) to obtain white solid AJ31-3 (1.1 g, 69%).

[0237] Preparation of AJ31-4: Dissolve AJ31-3 (1.1 g, 3.4 mmol) and 3-bromopiperidine-2,6-dione (2 g, 10 mmol) in 15 mL of DMF. Add Cs2CO3 (2.3 g, 7 mmol) to the system under stirring at room temperature, and then heat it up to 50 °C and stir for 4 h. After the reaction is complete, cool it to room temperature. Quench the reaction solution by adding 2 mL of dilute hydrochloric acid (1 M), and add 20 mL of water and 20 mL of DCM / MeOH (10:1) for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. Purify it by column chromatography (DCM / MeOH = 100 / 1 - 60 / 1) to obtain yellow oily compound AJ31-4 (1.3 g, 88%).

[0238] Preparation of AJ31-5: Dissolve AJ31-4 (1.3 g, 3 mmol) in 20 mL of DCM. Dropwise add 5 mL of dioxane solution of hydrochloric acid (4 M) to the reaction system under stirring at room temperature and stir for 1 h. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Concentrate under reduced pressure to remove the excess hydrochloric acid and solvent to obtain off-white solid AJ31-5 (970 mg, 98%).

[0239] Preparation of AJ31: AJ31-5 (14 mg, 0.03 mmol) and AJ12-6 (15 mg, 0.04 mmol) were dissolved in a mixed solvent of 8 mL of THF and 2 mL of DMF. After stirring at room temperature for about 1 h, acetic acid (4.9 mg, 0.08 mmol) and NaHB(OAc)3 (14 mg, 0.07 mmol) were added dropwise, and the reaction was continued by stirring at room temperature for 2 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 2 mL of saturated NaHCO3 aqueous solution was added to the reaction solution to quench it, and 5 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification by column chromatography (DCM / MeOH = 100 / 1 - 20 / 1) gave white solid AJ31 (5 mg, 17%). 1 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 11.20 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.07 - 7.98 (m, 2H), 7.61 (dd, J = 8.2, 1.4 Hz, 1H), 7.35 (s, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.83 - 6.76 (m, 1H), 5.31 (dd, J = 12.8, 5.3 Hz, 1H), 3.28 - 3.21 (m, 2H), 3.14 - 3.10 (m, 4H), 2.85 - 2.82 (m, 1H), 2.81 - 2.75 (m, 2H), 2.78 - 2.75 (m, 1H), 2.72 (q, J = 7.4 Hz, 2H), 2.70 - 2.68 (m, 3H), 2.67 - 2.62 (m, 1H), 2.59 - 2.55 (m, 1H), 2.48 - 2.40 (m, 1H), 2.17 - 2.10 (m, 1H), 1.99 - 1.92 (m, 2H), 1.76 (s, 6H), 1.71 - 1.64 (m, 2H), 1.28 (t, J = 7.4 Hz, 3H). LCMS(ESI) m / z 726.6 [M+H] + .

[0240] Preparation of AJ33:

[0241]

[0242] Preparation of AJ33-1: Dissolve AJ33-0 (6 g, 28 mmol) in 50 mL of DMF solvent. Add Cs2CO3 (27 g, 83 mmol) and 3-bromopiperidine-2,6-dione (11 g, 56 mmol) under stirring at room temperature. Stir the reaction solution at room temperature for about 4 h. After detecting the completion of the reaction, add 50 mL of water to the reaction solution for dilution and then add 50 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate it to obtain a crude concentrate. Purify it by column chromatography (EA / PE = 1 / 100 - 1 / 80) to obtain white solid AJ33-1 (5.3 g, 59%).

[0243] Preparation of AJ33-2: Dissolve AJ33-1 (500 mg, 1.5 mmol) in 15 mL of THF solvent. Stir at room temperature and add Pd2(dba)3 (180 mg, 0.2 mmol) and Q-Phos (145 mg, 0.2 mmol) under argon protection. Then add 2-tert-butoxy-2-carbonylethylzinc bromide (6 mL THF solution, 6 mmol). Slowly heat the reaction solution to 70 °C and stir for 2 h. After the reaction is completed, quench the reaction solution with saturated ammonium chloride aqueous solution, add 15 mL of water and 15 mL of EA for extraction. Collect the organic phase, wash it with saturated brine, dry it with anhydrous sodium sulfate, filter it, concentrate the filtrate to remove the solvent, and purify the residue by column chromatography (MeOH / DCM = 1 / 100 - 1 / 70) to obtain off-white solid AJ33-2 (340 mg, 62%).

[0244] Preparation of AJ33-3: Dissolve AJ33-2 (340 mg, 1 mmol) in a mixed solution of DCM / TFA (10 mL, 2:1). Stir the obtained solution at room temperature for 1 h. Then concentrate it under reduced pressure to remove the solvent to obtain off-white solid AJ33-3 (260 mg, 90%).

[0245] Preparation of AJ33: Dissolve AJ33-3 (10 mg, 0.03 mmol) and AJ10a-2 (16 mg, 0.03 mmol) in 5 mL of DMF solution. Add Et3N (10 mg, 0.1 mmol) under stirring at room temperature and slowly dropwise add a DMF solution of HATU (15 mg, 0.040 mmol). Stir the reaction solution at room temperature for 30 minutes. Then add 10 mL of water to the reaction solution for quenching, precipitate a white solid, filter it under reduced pressure and dry the filter cake to obtain a crude white solid. Purify it by column chromatography (MeOH / DCM = 1 / 100 - 1 / 20) to obtain white solid AJ33 (19 mg, 76%). 11H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 11.24 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.95 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 8.2, 1.4 Hz, 1H), 7.34 (s, 1H), 5.40 (dd, J = 12.9, 5.4 Hz, 1H), 3.81 (s, 2H), 3.58 - 3.50 (m, 2H), 3.50 - 3.46 (m, 2H), 3.36 - 3.40 (m, 2H), 3.26 - 3.19 (m, 2H), 2.96 - 2.89 (m, 1H), 2.84 - 2.80 (m, 1H), 2.77 - 2.74 (m, 2H), 2.71 (q, J = 7.5 Hz, 2H), 2.67 - 2.65 (m, 1H), 2.62 - 2.58 (m, 1H), 2.50 - 2.47 (m, 1H), 2.46 - 2.40 (m, 1H), 2.24 - 2.16 (m, 1H), 1.93 - 1.85 (m, 2H), 1.75 (s, 6H), 1.69 - 1.58 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 769.6 [M+H] + .

[0246] Preparation of AJ33a:

[0247]

[0248] Preparation of AJ33a-1: AJ33-1 (500 mg, 1.5 mmol) was dissolved in a mixed solution of 15 mL of DMF / water (20:1). Et3N (470 mg, 4.6 mmol) and Pd(dppf)Cl2DCM (122 mg, 0.15 mmol) were added under stirring at room temperature. The reaction system was purged with carbon monoxide and heated to 90 °C in a carbon monoxide atmosphere for 3 h. After detecting the completion of the reaction, the low-boiling solvents and water were removed by concentration under reduced pressure to obtain a DMF solution containing AJ33a-1 (about 12 mL, 22 mg / mL), which was directly used for the next step.

[0249] Preparation of AJ33a: AJ33a-1 (11 mg, 0.04 mmol) and AJ10a-2 (18 mg, 0.04 mmol) were dissolved in 10 mL of DMF solvent. Under stirring at room temperature, Et3N (11 mg, 0.11 mmol) was added successively, and then a DMF solution of HATU (15 mg, 0.04 mmol) was slowly added dropwise and reacted at room temperature for 30 minutes. 10 mL of water was added to the reaction solution for quenching, and a white solid was precipitated. The crude product was obtained by suction filtration under reduced pressure and drying the filter cake. The white solid AJ33a (11 mg, 52%) was obtained by purification through column chromatography (MeOH / DCM = 1 / 100 - 1 / 15). 1 H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 11.24 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.95 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 8.2, 1.4 Hz, 1H), 7.34 (s, 1H), 5.40 (dd, J = 12.9, 5.4 Hz, 1H), 3.58 - 3.50 (m, 2H), 3.50 - 3.46 (m, 2H), 3.36 - 3.40 (m, 2H), 3.26 - 3.19 (m, 2H), 2.96 - 2.89 (m, 1H), 2.84 - 2.80 (m, 1H), 2.77 - 2.74 (m, 2H), 2.71 (q, J = 7.5 Hz, 2H), 2.67 - 2.65 (m, 1H), 2.62 - 2.58 (m, 1H), 2.50 - 2.47 (m, 1H), 2.46 - 2.40 (m, 1H), 2.24 - 2.16 (m, 1H), 1.93 - 1.85 (m, 2H), 1.75 (s, 6H), 1.69 - 1.58 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 755.6 [M+H] + .

[0250] Preparation of AJ33b:

[0251]

[0252] Preparation of AJ33b-1: AJ33-1 (500 mg, 1.5 mmol) was dissolved in 15 mL of 1,4-dioxane. Under stirring at room temperature, 1-Boc-piperazine (280 mg, 1.5 mmol), Cs2CO3 (420 mg, 1.3 mmol), RuPhos (93 mg, 0.2 mmol) and RuPhosPdG3 (120 mg, 0.15 mmol) were added successively. The system was heated to 100 °C under argon protection and stirred for another 2 h. After detecting the complete reaction, it was cooled to room temperature. 15 mL of water was added to the reaction solution for dilution, and then 15 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (EA / PE = 1 / 100 - 1 / 5) gave white solid AJ33b-1 (580 mg, 87%).

[0253] Preparation of AJ33b-2: AJ33b-1 (580 mg, 1.4 mmol) was dissolved in a mixed solution of 15 mL of DCM / TFA (3:1). The reaction solution was stirred at room temperature for 1 h. Then the solvent was removed by concentration under reduced pressure to obtain off-white solid AJ33b-2 (410 mg, 92%).

[0254] Preparation of AJ33b: AJ33b-2 (10 mg, 0.03 mmol) and AJ12-6 (15 mg, 0.04 mmol) were dissolved in a mixed solvent of THF / DMF (10 mL / 1 mL). Under stirring at room temperature, AcOH (2.4 mg, 0.04 mmol) and NaHB(OAc)3 (20 mg, 0.09 mmol) were added, and the reaction continued at room temperature for 3 h. Saturated aqueous NaHCO3 solution was added dropwise to the reaction solution to adjust the pH to nearly neutral. 15 mL of water was added for dilution, and then 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (MeOH / DCM = 1 / 100 - 1 / 15) gave white solid AJ33b (17 mg, 77%). 11H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 11.23 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.05 - 7.96 (m, 2H), 7.93 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.62 (dd, J = 8.2, 1.4 Hz, 1H), 7.36 (s, 1H), 5.40 (dd, J = 12.9, 5.4 Hz, 1H), 3.58 - 3.50 (m, 2H), 3.50 - 3.46 (m, 2H), 3.36 - 3.40 (m, 2H), 3.26 - 3.19 (m, 2H), 2.96 - 2.89 (m, 1H), 2.84 - 2.80 (m, 1H), 2.77 - 2.74 (m, 2H), 2.71 (q, J = 7.5 Hz, 2H), 2.67 - 2.65 (m, 1H), 2.62 - 2.58 (m, 1H), 2.50 - 2.47 (m, 1H), 2.46 - 2.40 (m, 1H), 2.24 - 2.16 (m, 1H), 1.92 - 1.86 (m, 2H), 1.75 (s, 6H), 1.70 - 1.59 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 727.6 [M+H] + .

[0255] Preparation of AJ35:

[0256]

[0257] Preparation of AJ35-1: AJ35-0 (520 mg, 2.4 mmol) was dissolved in 15 mL of DMF. K2CO3 (980 mg, 7 mmol) and 3-bromopiperidine-2,6-dione (1 g, 5 mmol) were added under stirring at room temperature. The mixed system was heated to 100 o °C and stirred at this temperature for about 1 h. LCMS detection showed that the raw materials were completely consumed. Then, 15 mL of water was added to the reaction solution for quenching and 15 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Column chromatography (EA / PE = 1 / 100 - 1 / 1) gave a light red solid product AJ35-1 (260 mg, 36%).

[0258] Preparation of AJ35-2: AJ35-1 (260 mg, 0.8 mmol) was dissolved in 10 mL of THF solution. Under stirring at room temperature and under argon protection, Pd2(dba)3 (74 mg, 0.08 mmol), Q-Phos (58 mg, 0.08 mmol), and 2-tert-butoxy-2-carbonylethylzinc bromide (4 mL of THF solution, 3 mmol) were successively added. The reaction solution was slowly heated to 70 °C and stirred for 2 h. After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride aqueous solution was added to the reaction solution for quenching. It was extracted three times with EA, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to remove the solvent, and the residue was purified by column chromatography (EA / PE = 1 / 100 - 1 / 1) to obtain a white solid AJ35-2 (150 mg, 52%).

[0259] Preparation of AJ35-3: AJ35-2 (150 mg, 0.4 mmol) was dissolved in 8 mL of DCM solvent. 3 mL of TFA was added to the reaction solution and stirred at room temperature for 2 h. LCMS detection showed that the raw material had completely reacted. Then, DCM and TFA in the reaction solution were removed by concentration under reduced pressure to obtain a pale yellow solid AJ35-3 (120 mg, 95%).

[0260] Preparation of AJ35: AJ35-3 (20 mg, 0.07 mmol) was dissolved in 8 mL of DMF. Under stirring at room temperature, AJ10a-2 (27 mg, 0.07 mmol), Et3N (20 mg, 0.2 mmol), and HATU (25 mg, 0.07 mmol) were added to the reaction solution. After stirring for 30 minutes, LCMS detection showed that the raw materials had been consumed. 10 mL of water was added to the reaction solution for quenching, and a solid precipitated. The solid was filtered and dried to obtain a brown crude product. It was purified by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 2) to obtain a white solid product AJ35 (5 mg, 15%). 11H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 11.23 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.02 - 7.98 (m, 1H), 7.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.33 (s, 1H), 7.27 (d, J = 1.5 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.11 - 7.04 (m, 1H), 5.37 (dd, J = 12.8, 5.2 Hz, 1H), 3.76 (s, 2H), 3.58 - 3.50 (m, 2H), 3.50 - 3.46 (m, 2H), 3.34 - 3.30 (m, 2H), 3.22 (d, J = 11.3 Hz, 2H), 2.95 - 2.84 (m, 1H), 2.84 - 2.78 (m, 1H), 2.77 - 2.73 (m, 2H), 2.71 (d, J = 7.5 Hz, 2H), 2.70 - 2.65 (m, 1H), 2.64 - 2.61 (m, 1H), 2.57 - 2.52 (m, 1H), 2.42 - 2.36 (m, 1H), 2.21 - 2.12 (m, 1H), 1.93 - 1.81 (m, 2H), 1.75 (s, 6H), 1.67 - 1.56 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 768.6 [M+H] + .

[0261] Preparation of AJ35b:

[0262]

[0263] Preparation of AJ35b: AJ35 - 3 (20 mg, 0.07 mmol) and AJ13 - 5 (32 mg, 0.07 mmol) were dissolved in 8 mL of DMF. Et3N (20 mg, 0.2 mmol) and HATU (25 mg, 0.07 mmol) were added to the reaction solution under stirring at room temperature, and the reaction was stirred for about 30 minutes. LCMS detection showed that the raw materials had been consumed. 10 mL of water was added to the reaction solution for dilution, and a solid precipitated. The solid crude product was obtained by suction filtration under reduced pressure and drying the filter cake. The white solid product AJ35b (32 mg, 64%) was obtained by purification through reverse - phase column chromatography (MeCN / water = 1 / 100 - 1 / 2). 11H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 11.23(s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.00 (d, J = 1.0 Hz, 1H),7.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.36 (s, 1H), 7.27 (d, J = 1.5 Hz, 1H), 7.20(d, J = 8.1 Hz, 1H), 7.11-7.04 (m, 1H), 5.37 (dd, J = 12.9, 5.3 Hz, 1H),4.43-4.36 (m, 1H), 4.07-3.99 (m, 1H), 3.77 (s, 2H), 3.10-3.01 (m, 1H), 3.02-2.91 (m, 4H), 2.91-2.83 (m, 1H), 2.79-2.72 (m, 1H), 2.71 (d, J = 7.5 Hz, 2H),2.69-2.62 (m, 4H), 2.62-2.57 (m, 1H), 2.56-2.52 (m, 1H), 2.47-2.45 (m, 1H),2.19-2.12 (m, 1H), 1.90-1.78 (m, 2H), 1.75 (s, 6H), 1.32-1.28 (m, 2H), 1.26(t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 768.6 [M+H] + .

[0264] Preparation of AJ36:

[0265]

[0266] Preparation of AJ36-1: Dissolve AJ36-0 (950 mg, 4.5 mmol) in 20 mL of THF and cool to 0 oC. NaH (60%, 320 mg, 14 mmol) was added portionwise under stirring conditions, and the reaction mixture was stirred at low temperature for 30 minutes. Then 3-bromopiperidine-2,6-dione (1.3 g, 7 mmol) was added, and the reaction solution was slowly warmed to room temperature and stirred for another 2 h. The reaction was monitored by LCMS until completion. The reaction solution was slowly poured into 20 mL of ice water, and extracted with 15 mL of EA. The extraction was repeated three times until complete. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. The crude product was purified by column chromatography (EA / PE = 1 / 10 - 2 / 1) to give a pale yellow solid AJ36-1 (600 mg, 43%).

[0267] Preparation of AJ36-2: AJ36-1 (250 mg, 0.8 mmol) was dissolved in 15 mL of THF solvent. The solution was stirred at room temperature and Pd2(dba)3 (70 mg, 0.07 mmol), Q-Phos (23 mg, 0.1 mmol), and 2-tert-butoxy-2-carbonylethylzinc bromide (0.5 M) (7 mL, 4 mmol) were added successively under argon protection. The temperature was slowly raised to 70 o C and the reaction was continued for 5 h. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution, and 10 mL of water and 10 mL of EA were added for extraction. The extraction was repeated three times until complete. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the solvent. The concentrate was purified by column chromatography (MeOH / DCM = 1 / 100 - 1 / 70) to give an off-white solid AJ36-2 (100 mg, 36%).

[0268] Preparation of AJ36-3: AJ36-2 (100 mg, 0.3 mmol) was dissolved in a mixed solvent of 10 mL of DCM and 1 mL of TFA. The resulting solution was stirred at room temperature for 2 h. Then the solvent was removed by concentration under reduced pressure, and the product was purified by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 2) to give a white solid AJ36-3 (69 mg, 82%).

[0269] Preparation of AJ36: AJ36-3 (10 mg, 0.03 mmol) and AJ10a-2 (15 mg, 0.03 mmol) were dissolved in 5 mL of DMF. Under stirring at room temperature, Et3N (7 mg, 0.07 mmol) and HATU (14 mg, 0.03 mmol) were added successively, and the reaction was continued by stirring at room temperature for about 1 h. Then, 8 mL of water was added to the reaction solution for quenching, and 5 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude concentrate. Purification by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 2) gave white solid AJ36 (1 mg, 4%). 1 H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 10.51 (s, 1H), 8.32 (d, J = 8.2 Hz,1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H),7.20 - 7.12 (m, 1H), 6.81 - 6.73 (m, 1H), 6.70 (d, J = 9.3 Hz, 1H), 5.32 - 5.30(m, 1H), 4.45 (d, J = 17.6 Hz, 1H), 4.35 (d, J = 17.7 Hz, 1H ), 3.80 (s, 2H),3.59 - 3.51 (m, 4H), 3.47 - 3.42 (m, 2 H), 3.25 - 3.18 (m, 2 H), 3.05 - 2.99 (m, 1H),2.93 - 2.88 (m, 2H), 2.81 - 2.77 (m, 1H), 2.77 - 2.74 (m, 2H), 2.71 - 2.66 (m, 2H),2.59 - 2.55 (m, 1H), 2.44 - 2.40 (m, 1H), 2.01 - 1.97 (m, 1H), 1.91 - 1.86 (m, 2H),1.75 (s, 6H), 1.65 - 1.60 (m, 2H), 1.28 (t, J = 7.6 Hz, 3H). LCMS(ESI) m / z766.6 [M+H] + .

[0270] Preparation of AJ37: AJ37 was prepared from 5-bromooxindole according to the preparation method of AJ36.

[0271]

[0272] 1 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.97 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.03 (s, 1H), 8.00 (d, J = 1.1 Hz, 1H), 7.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.33 (s, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.87 (s, 1H), 6.78 (dd, J = 11.1, 7.9 Hz, 1H), 5.32 - 5.30 (m, 1H), 4.45 (d, J = 17.6 Hz, 1H), 4.35 (d, J = 17.7 Hz, 1H), 3.63 (d, J = 7.4 Hz, 2H), 3.50 - 3.48 (m, 2H), 3.46 - 3.40 (m, 2H), 3.40 - 3.36 (m, 2H), 3.30 - 3.28 (m, 2H), 3.26 - 3.15 (m, 2H), 2.80 - 2.78 (m, 1H), 2.76 - 2.72 (m, 1H), 2.71 (d, J = 7.5 Hz, 2H), 2.70 - 2.63 (m, 1H), 2.59 - 2.55 (m, 1H), 2.46 - 2.40 (m, 1H), 2.40 - 2.36 (m, 1H), 2.01 - 1.90 (m, 1H), 1.88 - 1.79 (m, 2H), 1.74 (s, 6H), 1.62 - 1.52 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 766.6 [M + H] + .

[0273] Preparation of AJ38:

[0274]

[0275] Preparation of AJ38-1: AJ38-0 (200 mg, 1 mmol) and bromoacetaldehyde ethylene glycol acetal (190 mg, 1 mmol) were dissolved in 10 mL of DMF. K2CO3 (290 mg, 2 mmol) was added under stirring at room temperature, and the mixture was heated to 120 oC and stir the reaction at this temperature for about 4 h. After detecting the completion of the reaction, cool it to room temperature, add 10 mL of water to the reaction solution for quenching and add 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure to obtain the crude concentrate. Purify by column chromatography (EA / PE = 1 / 100 - 1 / 5) to obtain a pale yellow solid AJ38-1 (170 mg, 60%).

[0276] Preparation of AJ38-2: Dissolve AJ10a-0 (100 mg, 0.2 mmol) and AJ38-1 (83 mg, 0.3 mmol) in a mixed solvent of 10 mL of 1,4-dioxane and 1 mL of water, stir, and sequentially add Pd(dppf)Cl2DCM (18 mg, 0.02 mmol) and K2CO3 (50 mg, 0.3 mmol) under argon protection. Slowly heat the reaction solution to 100 o C and continue the reaction for 3 h. After detecting the completion of the reaction, cool it to room temperature, add 10 mL of water to the reaction solution for quenching and add 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and dry with anhydrous sodium sulfate. Concentrate under reduced pressure to obtain the crude concentrate. Purify by column chromatography (EA / PE = 1 / 100 - 1 / 5) to obtain a pale yellow solid AJ38-2 (67 mg, 63%).

[0277] Preparation of AJ38-3: Dissolve AJ38-2 (67 mg, 0.3 mmol) in a mixed solvent of 1 mL of dilute hydrochloric acid (2 M) and 5 mL of THF, and heat the reaction solution to 65 o C and stir the reaction for 8 h. Detect the completion of the reaction, cool it to room temperature, add 10 mL of water and 10 mL of EA to the reaction solution for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure to obtain a pale yellow concentrate AJ38-3 (25 mg, 42%).

[0278] Preparation of AJ38: AJ38-3 (12 mg, 0.03 mmol) was dissolved in a mixed solvent of 3 mL of THF and 1 mL of DMF. AJ12-5 (10 mg, 0.03 mmol) was added under stirring at room temperature, and the reaction continued for 1 h. Then, AcOH (2 mg, 0.03 mmol) and NaHB(OAc)3 (8 mg, 0.04 mmol) were added, and the reaction was stirred at room temperature for about 6 h. After detecting the completion of the reaction, 10 mL of water was added to quench the reaction. The pH value was adjusted to 7 with saturated aqueous NaHCO3 solution, and 6 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (MeOH / DCM = 1 / 100 - 1 / 30) gave white solid AJ38 (5 mg, 23%). 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 11.08 (s, 1H), 8.34 (d, J = 8.1 Hz, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 8.05 - 8.00 (m, 1H), 7.84 (d, J = 0.9 Hz, 1H), 7.79 (s, 1H), 7.63 (dd, J = 8.1, 1.4 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.63 (dd, J = 8.6, 2.3 Hz, 1H), 5.29 (dd, J = 12.8, 5.4 Hz, 1H), 4.36 (t, J = 6.4 Hz, 2H), 3.17 - 3.02 (m, 4H), 2.93 - 2.87 (m, 1H), 3.30 (s, 3H), 2.86 - 2.81 (m, 4H), 2.72 - 2.66 (m, 1H), 2.66 - 2.60 (m, 4H), 2.61 - 2.56 (m, 1H), 2.00 - 1.96 (m, 1H), 1.79 (s, 6H), 1.22 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 750.6 [M+H] + .

[0279] Preparation of AJ39:

[0280]

[0281] Preparation of AJ39-1: Dissolve AJ39-0 (200 mg, 1.4 mmol) and 1-Boc-piperazine (260 mg, 1.4 mmol) in 10 mL of DMF. Add K2CO3 (105 mg, 0.08 mmol) under stirring at room temperature. Heat the mixed system to 80 o °C and continue stirring for about 4 h. Then add 10 mL of water to the reaction solution to quench it and add 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude concentrate. Purify it by column chromatography (EA / PE = 1 / 100 - 1 / 5) to obtain a pale yellow solid AJ39-1 (280 mg, 65%).

[0282] Preparation of AJ39-2: Dissolve AJ39-1 (280 mg, 0.9 mmol) and zinc powder (180 mg, 3 mmol) in 10 mL of DCM. Slowly add AcOH (220 mg, 3.7 mmol) dropwise under stirring at room temperature. Stir the mixed system at room temperature for about 2 h. Then filter under reduced pressure, and wash the filter cake twice with 10 mL of DCM. Combine the filtrates and concentrate to obtain a crude concentrate. Purify it by column chromatography (EA / PE = 1 / 100 - 1 / 1) to obtain a pale yellow solid AJ39-2 (150 mg, 60%).

[0283] Preparation of AJ39-3: Dissolve AJ39-2 (150 mg, 0.6 mmol) and 3-bromopiperidine-2,6-dione (160 mg, 0.8 mmol) in 15 mL of DMF. Add K2CO3 (150 mg, 1 mmol) under stirring at room temperature. Heat the mixed system to 80 o °C and stir for 4 h. After detecting the completion of the reaction, add 10 mL of water to the reaction solution to quench it and add 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude concentrate. Obtain a pale yellow solid AJ39-3 (103 mg, 48%) by column chromatography (EA / PE = 1 / 100 - 2 / 1).

[0284] Preparation of AJ39-4: Dissolve AJ39-3 (103 mg, 0.3 mmol) in a mixed solvent of 1 mL of TFA and 2 mL of DCM. Stir the resulting solution at room temperature for 3 h. Then concentrate under reduced pressure to remove the solvent to obtain a pale yellow solid product AJ39-4 (73 mg, 95%).

[0285] Preparation of AJ39: Dissolve AJ38-3 (12 mg, 0.03 mmol) in 6 mL of THF and 2 mL of DMF. Add AJ39-4 (8 mg, 0.03 mmol) under stirring at room temperature. After reacting at room temperature for 1 h, add AcOH (2 mg, 0.03 mmol) and NaHB(OAc)3 (8 mg, 0.04 mmol), and continue stirring at room temperature for about 4 h. After detecting the completion of the reaction, add 10 mL of water to the reaction solution to quench it, adjust the pH value to 7 with saturated aqueous NaHCO3 solution, and add 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and dry them with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude concentrate. Purify it by column chromatography (MeOH / DCM = 1 / 100 - 1 / 30) to obtain white solid AJ39 (3 mg, 15%). 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 10.77 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 8.02 (t, J = 1.0 Hz, 1H), 7.81 (d, J = 17.6 Hz, 2H), 7.63 (dd, J = 8.2, 1.5 Hz, 1H), 6.75 (d, J = 8.7 Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 5.39 (d, J = 7.3 Hz, 1H), 4.34 (t, J = 6.3 Hz, 2H), 4.24 - 4.14 (m, 1H), 2.97 - 2.88 (m, 4H), 2.84 (d, J = 7.5 Hz, 2H), 2.82 - 2.78 (m, 2H), 2.77 - 2.71 (m, 1H), 2.65 - 2.56 (m, 4H), 2.56 - 2.52 (m, 1H), 2.14 - 2.05 (m, 1H), 1.88 - 1.82 (m, 1H), 1.79 (s, 6H), 1.22 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 695.6 [M+H] + .

[0286] Preparation of AJ40:

[0287]

[0288] Preparation of AJ40-1: Dissolve AJ40-0 (3 g, 17 mmol) and ethyl acrylate (3.5 g, 35 mmol) in 40 mL of AcOH. Add K2CO3 (7.2 g, 52 mmol) under stirring at room temperature, and then slowly heat the reaction system to 120 o °C and react for 6 h. After detecting the completion of the reaction, cool it to room temperature, add 40 mL of water to quench the reaction and add 40 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases, dry them with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude concentrate. Purify it by column chromatography (PE / EA = 100 / 1 - 10 / 1) to obtain yellow solid AJ40-1 (2.8 g, 59%).

[0289] Preparation of AJ40-2: Dissolve AJ40-1 (1 g, 4 mmol) in a mixed solvent of 10 mL of THF and 2 mL of water. Add LiOH (150 mg, 4 mmol) under stirring at room temperature and stir for about 2 h. After the reaction is complete, adjust the reaction solution to pH = 6 with dilute hydrochloric acid (1 M), then add 20 mL of water and 15 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases, dry them with anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and purify the residue by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 2) to obtain yellow solid AJ40-2 (600 mg, 67%).

[0290] Preparation of AJ40-3: Dissolve AJ40-2 (600 mg, 2.5 mmol) and urea (1.5 g, 25 mmol) in 20 mL of AcOH. Heat the mixture to 130 o °C under stirring and react for 24 h. After detecting the completion of the reaction, cool it to room temperature, add 20 mL of water to quench the reaction and add 20 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases, dry them with anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and purify it by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 2) to obtain yellow solid AJ40-3 (120 mg, 18%).

[0291] Preparation of AJ40-4: Dissolve AJ40-3 (60 mg, 0.2 mmol) and zinc powder (72 mg, 1 mmol) in 10 mL of DCM. Slowly add AcOH (71 mg, 1 mmol) under stirring at room temperature, and continue to stir the mixed system at room temperature for about 2 h. Then filter under reduced pressure, and wash the filter cake twice with 10 mL of DCM. Combine the filtrates and concentrate under reduced pressure to obtain the crude concentrate. Purify it by column chromatography (DCM / MeOH = 100 / 1 - 50 / 1) to obtain light yellow solid AJ40-4 (45 mg, 85%).

[0292] Preparation of AJ40-5: AJ10a-2 (50 mg, 0.1 mmol) and DIEA (27 mg, 0.2 mmol) were dissolved in 8 mL of DCM. Triphosgene (46 mg, 0.16 mmol) was slowly added under stirring at room temperature. The mixture was stirred at room temperature for about 2 h. After concentrating under reduced pressure to remove the solvent, it was directly used for the next step.

[0293] Preparation of AJ40: Under an ice-water bath, the AJ40-5 obtained in the previous step was added to a solution of AJ40-4 (20 mg, 0.08 mmol) and DIEA (20 mg, 0.17 mmol) in THF (8 mL). The temperature of the reaction system was slowly raised to room temperature and then further heated to 50 o °C and stirred for 2 h. After detecting that the reaction was complete, it was cooled to room temperature. 10 mL of water was added to the reaction solution for quenching and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was concentrated to obtain the crude product. The concentrate was purified by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 2) to obtain white solid AJ40 (3 mg, 8%). 1 1H NMR (400 MHz, DMSO-d6) δ12.70 (s, 1H), 10.52 (s, 1H), 8.94 (d, J = 4.3 Hz, 1H), 8.31 (d, J = 8.1 Hz,1H), 8.13 (s, 1H), 8.05 - 7.97 (m, 2H), 7.85 (dd, J = 9.1, 2.4 Hz, 1H), 7.67(d, J = 2.4 Hz, 1H), 7.60 (dd, J = 8.2, 1.4 Hz, 1H), 7.35 (s, 1H), 4.03 - 3.90(m, 2H), 3.85 - 3.73 (m, 2H), 3.26 - 3.18 (m, 2H), 3.16 - 3.08 (m, 2H), 2.84 - 2.78(m, 2H), 2.77 - 2.74 (m, 2H), 2.74 - 2.72 (m, 2H), 2.71 (d, J = 7.5 Hz, 2H),2.67 - 2.61 (m, 1H), 2.46 - 2.43 (m, 2H), 1.91 - 1.85 (m, 2H), 1.74 (s, 6H), 1.65 - 1.58 (m, 2H), 1.26 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 747.6 [M+H] + .

[0294] Preparation of AJ41:

[0295]

[0296] Preparation of AJ41-1: Dissolve AJ41-0 (630 mg, 3.7 mmol) and 1-Boc-4-(piperidin-4-yl)-piperazine (1 g, 3.7 mmol) in 20 mL of DMF. Add K2CO3 (1 g, 7.4 mmol) under stirring at room temperature, and slowly heat up to 80 o °C and continue the reaction for 2 h. After detecting the completion of the reaction, cool it to room temperature. Add 20 mL of water to quench the reaction and add 20 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases, dry them with anhydrous sodium sulfate, and concentrate them under reduced pressure to obtain the crude concentrate. Purify it by column chromatography (DCM / MeOH = 100 / 1 - 30 / 1) to obtain the yellow solid AJ41-1 (1.45 g, 94%).

[0297] Preparation of AJ41-2: Dissolve AJ14-1 (1.45 g, 3.5 mmol) in 20 mL of MeOH. Add 10% Pd / C (140 mg), displace the air with hydrogen and react at room temperature under a hydrogen atmosphere for 3 h. After the reaction is complete, filter off Pd / C under reduced pressure, and wash the Pd / C cake with 10 mL of THF. Combine the filtrates and concentrate them under reduced pressure to obtain the pale yellow compound AJ41-2 (1.3 g, 96%).

[0298] Preparation of AJ41-3: Dissolve AJ41-2 (600 mg, 1.5 mmol) and (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (580 mg, 1.8 mmol) in 15 mL of i-PrOH. Add TsOH (290 mg, 1.5 mmol) under stirring at room temperature, and slowly heat up to 90 o °C and react for 10 h. After detecting the completion of the reaction, cool it to room temperature. Adjust the pH of the reaction solution to 7 with 5% aqueous sodium hydroxide solution, add 15 mL of water and 15 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Wash the combined organic phases with saturated brine, dry the organic phases with anhydrous sodium sulfate, filter and concentrate the filtrate to obtain the crude concentrate. Purify it by column chromatography (DCM / MeOH = 100 / 1 - 30 / 1) to obtain the yellow solid AJ41-3 (700 mg, 68%).

[0299] Preparation of AJ41-4: AJ41-3 (700 mg, 1 mmol) was dissolved in a mixed solvent of 10 mL of DCM and 2 mL of TFA, and the resulting solution was stirred at room temperature for 2 h. Then the solvent was removed by concentration under reduced pressure, and the product was purified by preparative reverse-phase chromatography to obtain white solid AJ41-4 (550 mg, 92%).

[0300] Preparation of AJ41: AJ41-4 (15 mg, 0.03 mmol) and AJ35-3 (8 mg, 0.03 mmol) were dissolved in 8 mL of DMF. Et3N (5 mg, 0.05 mmol) and HATU (11 mg, 0.03 mmol) were added under stirring at room temperature, and the mixture was continuously stirred at room temperature for about 1 h. Then 10 mL of water was added to the reaction solution for quenching, and 10 mL of EA was added for extraction. The extraction was repeated three times until complete. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. The product was purified by preparative reverse-phase chromatography (MeCN / water = 1 / 100 - 1 / 2) to obtain white solid AJ41 (3 mg, 13%). 11H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 11.18 (s, 1H), 8.48 (s, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 7.56 - 7.49 (m, 1H), 7.41 - 7.30 (m, 2H), 7.26 (d, J = 1.5 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.12 - 7.08 (m, 1H), 7.06 (dd, J = 8.3, 1.2 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 6.47 (dd, J = 8.7, 2.5 Hz, 1H), 5.36 (dd, J = 12.9, 5.2 Hz, 1H), 3.76 (s, 3H), 3.75 - 3.66 (m, 4H), 3.53 - 3.49 (m, 2H), 3.48 - 3.44 (m, 2H), 3.32 - 3.30 (m, 2H), 2.94 - 2.88 (m, 1H), 2.75 - 2.69 (m, 1H), 2.68 - 2.66 (m, 2H), 2.65 - 2.63 (m, 2H), 2.48 - 2.45 (m, 1H), 2.41 - 2.34 (m, 1H), 2.18 - 2.14 (m, 1H), 1.87 - 1.80 (m, 2H), 1.78 (s, 3H), 1.74 (s, 3H), 1.58 - 1.48 (m, 2H). LCMS (ESI) m / z 856.6 [M+H] + .

[0301] Preparation of AJ44:

[0302]

[0303] Preparation of AJ44-1: Dissolve AJ41-0 (2 g, 12 mmol) and 4-piperidone ethylene glycol acetal (2 g, 14 mmol) in 30 mL of DMF. Add K2CO3 (4 g, 29 mmol) to the system under stirring at room temperature, and then heat the temperature to 75 °C and stir for 4 h. After detecting that the reaction is complete, cool to room temperature, add 30 mL of water to quench the reaction and add 40 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify by column chromatography (PE / EA = 100 / 1 - 3 / 1) to obtain white solid AJ44-1 (3.3 g, 97%).

[0304] Preparation of AJ44-2: Dissolve AJ44-1 (3.3 g, 11 mmol) in 20 mL of THF solution. Add 10% Pd / C (300 mg) under stirring at room temperature. Place the reaction under hydrogen conditions and stir at room temperature for 2 h. After detecting the end of the reaction, filter the reaction solution under reduced pressure to remove the catalyst. Concentrate the obtained filtrate under reduced pressure to obtain off-white solid AJ44-2 (2.9 g, 98%).

[0305] Preparation of AJ44-3: Dissolve AJ44-2 (1 g, 4 mmol) and (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (1.4 g, 5 mmol) in 15 mL of i-PrOH. Add TsOH (1.4 g, 8 mmol) under stirring at room temperature, and heat the reaction solution to 80 °C and continue the reaction for 5 h. After the reaction is complete, cool to room temperature, add 1 mol / L NaOH aqueous solution dropwise to make the pH of the reaction solution 7 - 8, and add 20 mL of water and 20 mL of DCM for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify by column chromatography (DCM / MeOH = 100 / 1 - 60 / 1) to obtain yellow-green solid AJ44-3 (850 mg, 42%).

[0306] Preparation of AJ44-4: AJ44-3 (380 mg, 0.7 mmol) was dissolved in a mixed solvent of 10 mL of AcOH and 4 mL of distilled water. The reaction solution was heated to 90 °C and stirred for 4 h under stirring. After the reaction was completed, the reaction solution was cooled to room temperature. 1 mol / L saturated NaHCO3 aqueous solution was added dropwise to the reaction solution to make the pH of the reaction solution 7-8, and 10 mL of DCM was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 2) to obtain a yellow solid AJ44-4 (280 mg, 81%).

[0307] Preparation of AJ44: AJ44-4 (20 mg, 0.04 mmol) and AJ12-5 (15 mg, 0.04 mmol) were dissolved in 8 mL of THF. After heating to 40 °C and stirring for about 1 h, AcOH (7.2 mg, 0.12 mmol) and NaHB(OAc)3 (25 mg, 0.12 mmol) were added and the reaction was continued under stirring for 2 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 2 mL of saturated NaHCO3 aqueous solution was added to the reaction solution to quench the reaction, and 5 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 100 / 1 - 15 / 1) to obtain a white solid AJ44 (6 mg, 20%). 11H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 11.07 (s, 1H), 8.49 (s, 1H), 8.09 (s, 1H), 8.07 (s, 1H), 7.57 - 7.50 (m, 1H), 7.40 - 0.32 (m, 2H), 7.12 - 7.07 (m, 1H), 6.94 (d, J = 8.6 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.67 - 6.60 (m, 2H), 6.49 (dd, J = 8.8, 2.3 Hz, 1H), 5.29 (dd, J = 12.9, 5.3 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 2H), 3.14 - 3.06 (m, 4H), 2.92 - 2.82 (m, 2H), 2.79 - 2.65 (m, 7H), 2.66 - 2.59 (m, 1H), 2.61 - 2.54 (m, 1H), 2.43 - 2.37 (m, 1H), 2.02 - 1.96 (m, 1H), 1.96 - 1.88 (m, 3H), 1.78 (s, 3H), 1.75 (s, 3H), 1.62 - 1.54 (m, 2H). LCMS(ESI) m / z 827.6 [M+H] + .

[0308] Preparation of AJ45:

[0309]

[0310] Preparation of AJ45: Dissolve AJ44-4 (20 mg, 0.04 mmol) in 5 mL of THF and 1 mL of DMF. Add AJ39-4 (12 mg, 0.04 mmol) under stirring at room temperature. After stirring at room temperature for 1 h, add AcOH (3 mg, 0.04 mmol) and NaHB(OAc)3 (15 mg, 0.06 mmol), and continue stirring at room temperature for about 6 h. Then add 10 mL of water to quench the reaction, adjust the pH to 7 with saturated aqueous NaHCO3 solution, and add 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude concentrate. Purify by column chromatography (MeOH / DCM = 1 / 100 - 1 / 30) to obtain white solid AJ45 (9 mg, 30%). 11H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.78 (s, 1H), 8.48 (s, 1H), 8.08 (s, 1H), 8.05 (d, J = 13.3 Hz, 1H), 7.53 (dd, J = 14.1, 7.8 Hz, 1H), 7.39 (s, 1H), 7.34 - 7.30 (m, 2H), 7.11 - 7.08 (m, 1H), 7.01 - 6.89 (m, 1H), 6.85 - 6.80 (m, 1H), 6.79 - 6.69 (m, 1H), 6.63 (d, J = 7.8 Hz, 1H), 6.62 - 6.54 (m, 1H), 6.49 (d, J = 8.6 Hz, 1H), 4.40 - 4.23 (m, 1H), 3.76 (s, 3H), 3.30 - 3.24 (m, 2H), 3.23 - 2.98 (m, 4H), 2.97 - 2.91 (m, 1H), 2.91 - 2.78 (m, 2H), 2.75 - 2.73 (m, 1H), 2.70 - 2.61 (m, 4H), 2.61 - 2.53 (m, 1H), 2.41 - 2.35 (m, 1H), 2.14 - 2.05 (m, 1H), 1.96 - 1.85 (m, 2H), 1.77 (s, 3H), 1.74 (s, 3H), 1.66 - 1.46 (m, 2H). LCMS(ESI) m / z 772.6 [M+H] + .

[0311] Preparation of AJ46:

[0312]

[0313] Preparation of AJ46: Dissolve AJ41-4 (15 mg, 0.03 mmol) and AJ33-3 (8 mg, 0.03 mmol) in 5 mL of DMF. Add Et3N (5 mg, 0.05 mmol) and HATU (11 mg, 0.03 mmol) under stirring at room temperature. After about 1 h, add 8 mL of water to quench the reaction mixture and extract with 5 mL of EA. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure to obtain the crude concentrate. Purify by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 2) to obtain white solid AJ46 (12 mg, 52%). 11H NMR (400 MHz, DMSO-d6) δ11.23 (s, 1H), 11.17 (s, 1H), 8.48 (s, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 7.95(d, J = 1.7 Hz, 1H), 7.64 (d, J = 1.7 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.41 - 7.30(m, 2H), 7.09 (t, J = 7.5 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 6.47 (dd, J =8.7, 2.5 Hz, 1H), 5.39 (dd, J = 12.9, 5.4 Hz, 1H), 3.80 (s, 2H), 3.76 (s,3H), 3.73 (s, 2H), 3.58 - 3.52 (m, 2H), 3.50 - 3.43 (m, 2H), 3.30 - 3.20 (m, 2H),2.98 - 2.90 (m, 1H), 2.81 - 2.76 (m, 1H), 2.70 (m, 1H), 2.67 (d, J = 7.5 Hz, 2H),2.59 - 2.52 (m, 2H), 2.44 - 2.36 (m, 1H), 2.23 - 2.16 (m, 1H), 1.90 - 1.81 (m, 2H),1.78 (s, 3H), 1.74 (s, 3H), 1.60 - 1.50 (m, 2H). LCMS(ESI) m / z 857.6 [M+H] + .

[0314] Preparation of AJ49:

[0315]

[0316] Preparation of AJ49-7-1: AJ49-7-0 (1 g, 5 mmol) was dissolved in 20 mL of DMF solvent. K2CO3 (1.8 g, 13 mmol) and ethyl bromoacetate (0.95 g, 6 mmol) were added under stirring at room temperature. The resulting reaction solution was reacted at 120 °C for 2 h. After detecting the completion of the reaction, it was cooled to room temperature. 20 mL of water was added to the reaction solution for dilution and 20 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried with anhydrous sodium sulfate, filtered by suction, and concentrated to obtain a pale yellow solid AJ49-7-1 (0.76 g, 53%).

[0317] Preparation of AJ49-7-2: Dissolve AJ49-7-1 (200 mg, 0.7 mmol) in a mixed solvent of 1,4-dioxane / water (10 mL / 0.5 mL). Under stirring at room temperature, add K2CO3 (250 mg, 1.8 mmol), AJ10a-0 (310 mg, 0.7 mmol) and Pd(dppf)Cl2DCM (58 mg, 0.07 mmol) successively. Under argon protection, heat the reaction solution to 90 °C and continue the reaction for 3 h. After detecting the completion of the reaction by LCMS, add 10 mL of water to dilute the reaction solution and extract it with 10 mL of EA for liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry the organic phases with anhydrous sodium sulfate and concentrate them under reduced pressure to obtain the crude concentrate. Purify it by column chromatography (MeOH / DCM = 1 / 100 - 1 / 40) to obtain a pale yellow solid AJ49-7-2 (200 mg, 60%).

[0318] Preparation of AJ49-7: Dissolve AJ49-7-2 (200 mg, 0.4 mmol) in 10 mL of THF solution. Under stirring at room temperature, slowly add dropwise an aqueous solution of LiOH (48 mg, 0.9 mmol). Heat the reaction solution to 40 °C and continue the reaction for 1 h. After detecting the completion of the reaction by LCMS, cool the reaction solution to room temperature and slowly add dropwise dilute hydrochloric acid aqueous solution (1 M) to adjust the pH value to weakly basic. White solid precipitates. Filter it under reduced pressure and dry the filter cake to obtain an off-white solid AJ49-7 (150 mg, 80%).

[0319] Preparation of AJ49-1: Under an ice bath, add 8 mL of concentrated sulfuric acid to AJ49-0 (1 g, 9 mmol), and then slowly add dropwise 4 mL of 65% concentrated nitric acid to the reaction system. After stirring for 30 minutes, slowly heat up to 60 °C and continue stirring for 2 h. After detecting the completion of the reaction by LCMS, cool the reaction solution in an ice bath, and then slowly add dropwise the reaction solution to 20 mL of ice water for quenching. Neutralize the remaining acid in the reaction solution with 10% ammonia water. Wait until a large amount of white solid precipitates, filter it and dry the filter cake to obtain AJ49-1 (430 mg, 31%).

[0320] Preparation of AJ49-2: AJ49-1 (430 mg, 3 mmol) and N-Boc-piperazine (2.1 g, 11 mmol) were dissolved in 20 mL of NMP. DIEA (1.1 g, 9 mmol) was added under stirring at room temperature. The reaction solution was heated to 130 °C and stirred for 2 h. After the reaction was complete, it was cooled to room temperature. 15 mL of water was added to the reaction solution to quench the reaction, and then 15 mL of EA was added for extraction and liquid separation. The extraction was repeated three times. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 100 / 1 - 5 / 1) to obtain yellow solid AJ49-2 (800 mg, 98%).

[0321] Preparation of AJ49-3: AJ49-2 (800 mg, 2.5 mmol) was dissolved in 15 mL of THF solution. 10% Pd / C (80 mg) was added under stirring at room temperature. The reaction was carried out under hydrogen conditions and stirred for 2 h. After detecting that the reaction was complete, the reaction solution was filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure to obtain yellow solid AJ49-3 (700 mg, 96%).

[0322] Preparation of AJ49-4: AJ49-3 (700 mg, 2.4 mmol) was dissolved in 15 mL of MeCN solution. CDI (770 mg, 4.8 mmol) was added under stirring at room temperature. The reaction solution was heated to 85 °C and stirred for 2 h. After detecting that the reaction was complete, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 100 / 1 - 80 / 1) to obtain red solid AJ49-4 (310 mg, 41%).

[0323] Preparation of AJ49-5: AJ49-4 (310 mg, 1 mmol) and 3-bromopiperidine-2,6-dione (560 mg, 2.9 mmol) were dissolved in 10 mL of DMF. Cs2CO3 (940 mg, 2.9 mmol) was added to the system under stirring at room temperature. The system was heated to 50 °C and stirred for 5 h. After detecting that the reaction was complete, it was cooled to room temperature. 1 mL of dilute hydrochloric acid (2 M) was added to the reaction solution to quench the reaction. 10 mL of water and 15 mL of EA were added to the reaction solution for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was obtained as white solid AJ49-5 (400 mg, 95%) by column chromatography (DCM / MeOH = 100 / 1 - 60 / 1).

[0324] Preparation of AJ49-6: AJ49-5 (100 mg, 0.2 mmol) was dissolved in8 mL of DCM. 2 mL of TFA was added dropwise to the reaction system under stirring at room temperature, and the reaction was stirred at room temperature for 1 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. Excess TFA and DCM were removed by concentration under reduced pressure to obtain white solid AJ49-6 (70 mg, 92%).

[0325] Preparation of AJ49: AJ49-6 (10 mg, 0.03 mmol) and AJ49-7 (15 mg, 0.03 mmol) were dissolved in 5 mL of DMF. DIEA (11 mg, 0.08 mmol) was added dropwise to the system under stirring at room temperature. HATU (13 mg, 0.03 mmol) was added in batches about 10 minutes later, and the reaction was continued to stir at room temperature for 30 minutes. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 5 mL of distilled water was slowly added to the reaction solution under stirring, and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 2) to obtain white solid AJ49 (5 mg, 22%). 1HNMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 11.21 (s, 1H), 8.34 (dd, J = 8.1, 0.7Hz, 1H), 8.12 (s, 1H), 8.07 (d, J = 0.9 Hz, 1H), 8.04 - 8.01 (m, 1H), 7.85 (d,J = 0.8 Hz, 1H), 7.83 (dd, J = 4.4, 1.6 Hz, 1H), 7.79 (d, J = 2.5 Hz, 1H),7.71 (d, J = 2.3 Hz, 1H), 7.63 (dd, J = 8.1, 1.4 Hz, 1H), 5.34 (dd, J = 12.9,5.4 Hz, 1H), 5.30 (s, 2H), 3.75 - 3.68 (m, 2H), 3.68 - 3.61 (m, 2H), 3.27 - 3.19(m, 2H), 3.19 - 3.11 (m, 2H), 2.99 - 2.91 (m, 1H), 2.84 (q, J = 7.5Hz, 2H), 2.80 - 2.71 (m, 1H), 2.69 - 2.63 (m, 1H), 2.22 - 2.15 (m, 1H), 1.80 (s, 6H), 1.23 (t, J= 7.5 Hz, 3H). LCMS(ESI) m / z 752.5 [M+H] + .

[0326] Preparation of AJ50:

[0327]

[0328] Preparation of AJ50-1: AJ50-0 (1 g, 4 mmol) and 3-bromopiperidine-2,6-dione (1.3 g, 7 mmol) were dissolved in 30 mL of DMF. Cs2CO3 (3.5 g, 11 mmol) was added to the system under stirring at room temperature. The reaction solution was heated to 50 °C and stirred for 4 h. After the reaction was complete, it was cooled to room temperature. 5 mL of dilute hydrochloric acid (2 M) was added to the reaction solution to quench it. 20 mL of water was added to the reaction solution, and 20 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. It was purified by column chromatography (DCM / MeOH = 100 / 1 - 60 / 1) to obtain the red solid AJ50-1 (420 mg, 28%).

[0329] Preparation of AJ50-2: Dissolve AJ50-1 (150 mg, 0.5 mmol) in 10 mL of THF. Stir at room temperature and sequentially add Pd2(dba)3 (80 mg, 0.09 mmol), Q-Phos (63 mg, 0.09 mmol) and 2-tert-butoxy-2-carbonylethylzinc bromide (2 mL, 1.76 mmol) under argon protection. Slowly heat up to 70 °C and stir for 2 h. After the reaction is completed, quench the reaction mixture by adding 5 mL of saturated ammonium chloride aqueous solution. Add 10 mL of water and 10 mL of EA to the reaction mixture for extraction and separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry the organic phases with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify by column chromatography (PE / EA = 100 / 1 - 20 / 1) to obtain white solid AJ50-2 (140 mg, 84%).

[0330] Preparation of AJ50-3: Dissolve AJ50-2 (140 mg, 0.4 mmol) in 8 mL of DCM. Dropwise add 3 mL of TFA to the reaction system under stirring at room temperature. Stir at room temperature for 1 h. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Concentrate under reduced pressure to remove the excess TFA and DCM to obtain brown solid AJ50-3 (100 mg, 84%).

[0331] Preparation of AJ50: Dissolve AJ50-3 (14 mg, 0.03 mmol) and AJ10a-2 (17 mg, 0.03 mmol) in 10 mL of DMF. Dropwise add Et3N (9 mg, 0.09 mmol) to the system under stirring at room temperature. After stirring for about 10 minutes, add HATU (13 mg, 0.03 mmol) in batches and continue to stir at room temperature for 30 minutes. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Slowly add 10 mL of water to the reaction mixture under stirring and add 10 mL of EA for extraction and separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry the organic phases with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 2) to obtain white solid AJ50 (5 mg, 15%). 11H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 11.19 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.03 (s, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.60 (dd, J = 8.1, 1.5 Hz, 1H), 7.54 (d, J = 1.3 Hz, 1H), 7.33 (s, 1H), 7.30 - 7.13 (m, 2H), 5.49 (dd, J = 12.9, 5.4 Hz, 1H), 3.75 (s, 2H), 3.53 (s, 2H), 3.49 - 3.48 (m, 2H), 3.32 - 3.30 (m, 2H), 3.24 - 3.22 (m, 2H), 2.95 - 2.87 (m, 1H), 2.82 - 2.78 (m, 1H), 2.78 - 2.72 (m, 2H), 2.71 (q, J = 7.5 Hz, 2H), 2.69 - 2.65 (m, 1H), 2.59 - 2.53 (m, 1H), 2.46 - 2.42 (m, 1H), 2.43 - 2.39 (m, 1H), 2.10 - 2.03 (m, 1H), 1.91 - 1.83 (m, 2H), 1.74 (s, 6H), 1.66 - 1.57 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS (ESI) m / z 784.5 [M+H] + .

[0332] Preparation of AJ53:

[0333]

[0334] Preparation of AJ53-1: Dissolve AJ53-0 (1 g, 4.4 mmol) in 10 mL of 2 mol / L hydrochloric acid, heat the solution to 55 °C with stirring and react for 10 minutes. Slowly add acrylic acid (480 mg, 6.6 mmol) dropwise to the reaction solution, then raise the temperature to 100 °C and continue stirring for 4 h. After the reaction is complete, cool to room temperature, slowly add the reaction solution to ice water to quench the reaction, and then slowly add saturated aqueous NaHCO3 solution to the mixed system to adjust the pH of the reaction solution to 6.5 - 7. When a large amount of solid precipitates, filter by suction and dry the filter cake to obtain yellow crude AJ53-1 (1.1 g, 83%).

[0335] Preparation of AJ53-2: Dissolve AJ53-1 (1.1 g, 4 mmol) in 11 mL of AcOH, add urea (780 mg, 13 mmol), and heat the mixture to 120 °C with stirring for 5 h. LCMS detection shows that the raw materials have disappeared and the reaction is completed. After the reaction is complete, cool the reaction mixture to room temperature, slowly add saturated aqueous NaHCO3 solution to the reaction system to adjust the pH of the reaction solution to 7-8. When a large amount of solid precipitates, filter under reduced pressure. The filter cake is dried to obtain yellow crude AJ53-2 (490 mg, 41%).

[0336] Preparation of AJ53-3: Dissolve AJ53-2 (150 mg, 0.5 mmol) in 10 mL of THF solution, stir at room temperature, and add Pd2(dba)3 (80 mg, 0.09 mmol), Q-Phos (63 mg, 0.09 mmol), and 2-tert-butoxy-2-carbonylethylzinc bromide (2 mL, 1.8 mmol) under argon protection. Slowly heat the mixture to 70 °C and react for 2 h. After the reaction is completed, quench the reaction mixture by adding 3 mL of saturated aqueous ammonium chloride solution. Add 10 mL of water and 10 mL of EA to the reaction mixture for extraction and separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry the organic phases with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by column chromatography (PE / EA = 100 / 1 - 20 / 1) to obtain white solid AJ53-3 (140 mg, 84%).

[0337] Preparation of AJ53-4: Dissolve AJ53-3 (140 mg, 0.4 mmol) in 8 mL of DCM, and slowly add 3 mL of TFA dropwise to the reaction system with stirring at room temperature. Continue to stir the reaction mixture at room temperature for 1 h. LCMS detection shows that the raw materials have disappeared and the reaction is completed. Concentrate under reduced pressure to remove excess TFA and DCM to obtain white solid AJ53-4 (110 mg, 93%).

[0338] Preparation of AJ53: Dissolve AJ53-4 (10 mg, 0.03 mmol) and AJ10a-2 (15 mg, 0.03 mmol) in 5 mL of DMF, add DIEA (10 mg, 0.08 mmol) and HATU (12 mg, 0.03 mmol) to the reaction system with stirring at room temperature, and continue to stir the reaction mixture at room temperature for 30 minutes. LCMS detection shows that the raw materials have disappeared and the reaction is completed. Slowly add 8 mL of water to the reaction mixture with stirring. A white solid precipitates from the reaction solution. Filter to obtain the filter cake. Purify the filter cake by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 2) to obtain white solid AJ53 (5 mg, 20%). 11H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 10.56 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.59 (t, J = 8.9 Hz, 2H), 7.43 (s, 1H), 7.33 (s, 1H), 7.00 (d, J = 8.5 Hz, 1H), 3.97 (s, 3H), 3.92 (t, J = 6.7 Hz, 2H), 3.87 (s, 2H), 3.53 (d, J = 14.9 Hz, 4H), 3.21 (d, J = 11.3 Hz, 4H), 2.82 - 2.80 (m, 1H), 2.79 - 2.75 (m, 2H), 2.73 - 2.71 (m, 2H), 2.70 (q, J = 7.5 Hz, 2H), 2.43 - 2.40 (m, 2H), 1.88 - 1.85 (m, 2H), 1.74 (s, 6H), 1.63 - 1.58 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 766.6 [M+H] + .

[0339] Preparation of AJ54:

[0340]

[0341] Preparation of AJ54-1: Dissolve AJ53-2 (200 mg, 0.6 mmol) and N-Boc-piperazine (230 mg, 0.7 mmol) in 15 mL of dioxane solution, stir at room temperature and successively add RuPhos (43 mg, 0.06 mmol), RuPhosPdG2 (190 mg, 0.3 mmol) and Cs2CO3 (300 mg, 0.9 mmol) under argon protection. Slowly heat the reaction solution to 100 °C and continue the reaction for 4 h. After the reaction is completed, add 10 mL of water to quench the reaction and add 15 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify by column chromatography (DCM / MeOH = 100 / 1 - 60 / 1) to obtain a pale yellow solid AJ54-1 (72 mg, 27%).

[0342] Preparation of AJ54-2: AJ54-1 (72 mg, 0.17 mmol) was dissolved in 5 mL of DCM. At room temperature, 2 mL of TFA was added dropwise to the reaction system, and the reaction was stirred at room temperature for 1 h. LCMS detection showed that the raw material had disappeared and the reaction was completed. The excess TFA and DCM were removed by concentration under reduced pressure to obtain a brown solid AJ54-2 (50 mg, 91%).

[0343] Preparation of AJ54: AJ54-2 (20 mg, 0.06 mmol) and AJ12-6 (25 mg, 0.06 mmol) were dissolved in a mixed solvent of 5 mL of THF and 1 mL of DMF. Under stirring at room temperature, AcOH (11 mg, 0.18 mmol) and NaHB(OAc)3 (25 mg, 0.12 mmol) were added, and the reaction was continued to stir at room temperature for 2 h. LCMS detection showed that the raw material had disappeared and the reaction was completed. 2 mL of saturated aqueous NaHCO3 solution was added to the reaction solution to quench the reaction, and 5 mL of water was added. Extraction and liquid separation were carried out with 10 mL of DCM / MeOH (10:1), and the extraction was repeated three times until the extraction was complete. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 2) gave a white solid AJ54 (9.2 mg, 21%). 1 H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.52 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.59 (t, J = 8.9 Hz, 2H), 7.43 (s, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.23 (s, 1H), 3.95 (s, 3H), 3.71 (s, 2H), 3.53 (d, J = 14.9 Hz, 4H), 3.21 (d, J = 11.3 Hz, 4H), 2.82 - 2.80 (m, 1H), 2.79 - 2.75 (m, 2H), 2.74 - 2.73 (m, 2H), 2.72 (q, J = 7.5 Hz, 2H), 2.47 - 2.43 (m, 2H), 1.93 - 1.87 (m, 2H), 1.75 (s, 6H), 1.69 - 1.60 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 724.6 [M+H] + .

[0344] Preparation of AJ67:

[0345]

[0346] Preparation of AJ67-1: Dissolve AJ67-0 (300 mg, 1.4 mmol) in 3 mL of 2 mol / L dilute hydrochloric acid, heat up to 55 °C with stirring for about 10 minutes, slowly add acrylic acid (150 mg, 2 mmol) dropwise to the reaction solution, and heat up the reaction solution to 80 °C and continue stirring for 4 h. After the reaction is complete, cool to room temperature, add ice-water mixture to the reaction solution, and dropwise add saturated NaHCO3 aqueous solution to the reaction system to make the pH of the reaction solution 6.5 - 7. Wait until a large amount of solid precipitates, filter under reduced pressure, and dry the filter cake to obtain the crude product of light yellow solid AJ67-1 (200 mg, 50%).

[0347] Preparation of AJ67-2: Dissolve AJ67-1 (200 mg, 0.7 mmol) in 2 mL of acetic acid, add urea (140 mg, 2.4 mmol) under stirring at room temperature, heat up the system to 120 °C and stir for 5 h. LCMS detection shows that the raw materials have disappeared. Cool the reaction system to room temperature, and slowly add saturated NaHCO3 aqueous solution dropwise to the reaction solution under ice bath to make the pH of the reaction solution 7 - 8. Wait until a large amount of solid precipitates, filter under reduced pressure, and dry the filter cake to obtain the crude product of yellow solid AJ67-2 (180 mg, 83%).

[0348] Preparation of AJ67-3: Dissolve AJ67-2 (180 mg, 0.6 mmol) in 15 mL of THF, stir at room temperature and sequentially add Pd2(dba)3 (100 mg, 0.11 mmol), Q-Phos (80 mg, 0.11 mmol), 2-tert-butoxy-2-carbonylethylzinc bromide (3 mL, 2.2 mmol) under argon protection, heat up to 70 °C and react for 2 h. After detecting that the reaction is complete, quench the reaction solution by adding 2 mL of saturated ammonium chloride aqueous solution, add 10 mL of water to the reaction solution, and add 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify by column chromatography (PE / EA = 100 / 1 - 10 / 1) to obtain white solid AJ67-3 (190 mg, 95%).

[0349] Preparation of AJ67-4: AJ67-3 (190 mg, 0.5 mmol) was dissolved in 8 mL of DCM, and 3 mL of TFA was added dropwise to the reaction system at room temperature. The reaction mixture was stirred at room temperature for 1 h. LCMS detection showed that the raw material had disappeared and the reaction was completed. Excess TFA and DCM were removed by concentration under reduced pressure to obtain a grayish-white solid AJ67-4 (130 mg, 81%).

[0350] Preparation of AJ67: AJ67-4 (10 mg, 0.03 mmol) and AJ10a-2 (16 mg, 0.03 mmol) were dissolved in 5 mL of DMF. DIEA (11 mg, 0.08 mmol) and HATU (13 mg, 0.03 mmol) were added to the system under stirring at room temperature, and the reaction was continued by stirring at room temperature for 30 minutes. LCMS detection showed that the raw material had disappeared and the reaction was completed. 8 mL of water was slowly added to the reaction solution under stirring, and a white solid precipitate was formed in the reaction solution. The reaction solution was filtered under reduced pressure to obtain a filter cake, and the filter cake was purified by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 2) to obtain a white solid AJ67 (12 mg, 48%). 11H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 10.46 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.03 (s, 1H), 8.00 (d, J = 1.1 Hz, 1H), 7.90 (s, 1H), 7.88 (s, 1H), 7.84 - 7.79 (m, 1H), 7.60 (dd, J = 8.2, 1.4 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.47 - 7.42 (m, 1H), 7.33 (s, 1H), 3.91 (d, J = 7.2 Hz, 2H), 3.90 - 3.84 (m, 1H), 3.69 - 3.62 (m, 1H), 3.56 (s, 2H), 3.52 (s, 2H), 3.21 (d, J = 11.2 Hz, 2H), 3.05 - 2.89 (m, 2H), 2.80 - 2.74 (m, 2H), 2.74 - 2.71 (m, 1H), 2.71 - 2.67 (m, 2H), 2.68 - 2.62 (m, 1H), 2.59 - 2.52 (m, 1H), 2.45 - 2.37 (m, 2H), 1.88 - 1.85 (m, 2H), 1.74 (s, 6H), 1.65 - 1.55 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 762.5 [M+H] + .

[0351] Preparation of AJ71: AJ71 was prepared from 3-iodo-8-aminoquinoline as the raw material according to the preparation method of AJ67.

[0352]

[0353] 11H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 10.41 (s, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 1.4 Hz, 1H), 7.96 (dd, J = 8.3, 1.6 Hz, 1H), 7.71 (dd, J = 7.3, 1.6 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.62 - 7.59 (m, 1H), 7.33 (s, 1H), 3.99 (s, 2H), 3.88 - 3.83 (m, 2H), 3.63 - 3.57 (m, 2H), 3.54 - 3.49 (m, 2H), 3.25 - 3.18 (m, 2H), 2.84 - 2.81 (m, 2H), 2.80 - 2.77 (m, 2H), 2.75 - 2.72 (m, 1H), 2.69 (d, J = 7.6 Hz, 2H), 2.62 - 2.58 (m, 2H), 2.55 - 2.53 (m, 2H), 1.93 - 1.84 (m, 2H), 1.76 (s, 6H), 1.67 - 1.58 (m, 2H), 1.27 (t, J = 7.6 Hz, 3H). LCMS(ESI) m / z 763.5 [M+H] + .

[0354] Preparation of AJ72:

[0355]

[0356] Preparation of AJ72-1: AJ72-0 (300 mg, 1.5 mmol) and tert-butyl glycinate (210 mg, 1.6 mmol) were dissolved in 10 mL of DMF. Under stirring at room temperature, DIEA (480 mg, 3.7 mmol) was added dropwise to the system successively. After 10 minutes, HATU (590 mg, 1.6 mmol) was added in batches. After stirring at room temperature for 30 minutes, LCMS detection showed that the raw materials had disappeared and the reaction was completed. 10 mL of water was added to the reaction solution to quench it, and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 100 / 1 - 5 / 1) to obtain a pale yellow oily compound AJ72-1 (300 mg, 64%).

[0357] Preparation of AJ72-2: AJ72-1 (300 mg, 1 mmol) was dissolved in 15 mL of DMF. Under stirring at room temperature, N,N-dimethylethane-1,2-diamine (140 mg, 1.6 mmol) was added dropwise to the reaction solution. After stirring for 5 minutes under argon protection, 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (280 mg, 1.2 mmol), CuI (360 mg, 1.9 mmol) and K2CO3 (330 mg, 2.4 mmol) were added successively. The temperature was raised to 100 °C and the reaction was stirred for 3 h. After the reaction was detected to be completed, the reaction solution was cooled to room temperature. 15 mL of water was added to the reaction solution to quench it and 15 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 100 / 1 - 80 / 1) to obtain a yellow oily compound AJ72-2 (310 mg, 69%).

[0358] Preparation of AJ72-3: AJ72-2 (50 mg, 0.11 mmol) was dissolved in 6 mL of DCM. At room temperature, 2 mL of TFA was added dropwise to the reaction system. The reaction was stirred at room temperature for 1 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. Excess TFA and DCM were removed by concentration under reduced pressure to obtain an off-white solid AJ72-3 (40 mg, 91%).

[0359] Preparation of AJ72-4: AJ72-3 (20 mg, 0.05 mmol) and AJ10a-2 (23 mg, 0.05 mmol) were dissolved in 5 mL of DMF. Under stirring at room temperature, DIEA (19 mg, 0.14 mmol) and HATU (19 mg, 0.05 mmol) were added to the system. After stirring at room temperature for about 20 minutes, LCMS detection showed that the raw materials had disappeared and the reaction was completed. 8 mL of water was slowly added to the reaction solution under stirring, and a white solid precipitated from the reaction solution. The reaction solution was filtered under reduced pressure to obtain a filter cake, and the filter cake was purified by reverse-phase column chromatography (water / MeCN) to obtain a white solid AJ72-4 (25 mg, 60%).

[0360] Preparation of AJ72: 1 mL of TFA and 1 mL of TfOH were added to AJ72-4 (25 mg, 0.03 mmol), and the reaction system was heated to 80 °C under stirring for 2 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. The reaction solution was cooled to room temperature, quenched with ice water under an ice bath, and the pH of the reaction solution was adjusted to 7-8 with saturated NaHCO3 aqueous solution. 10 mL of EA was added for extraction and liquid separation, and the extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. It was purified by column chromatography (DCM / MeOH = 100 / 1 - 15 / 1) to obtain a white solid AJ72 (5 mg, 24%). 11H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.73(s, 1H), 9.32 (s, 1H), 8.87 (s, 1H), 8.62 (t, J = 8.5 Hz, 1H), 8.32 (d, J =8.1 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.63 (d, J = 8.7 Hz,1H), 7.51 (t, J = 7.9 Hz, 1H), 4.25-4.21 (m, 4H), 3.56-3.49 (m, 4H), 3.30 (m,4H), 2.83-2.80 (m, 1H), 2.79-2.77 (m, 2H), 2.76-2.73 (m,, 1H), 2.71 (d, J =7.4 Hz, 2H), 2.68-2.64 (m, 1H), 2.62-2.58 (m, 2H), 1.92-1.88 (m, 2H), 1.75(s, 6H), 1.69-1.60 (m, 2H), 1.27 (d, J = 7.5 Hz, 3H). LCMS(ESI) m / z 757.6 [M+H] + .

[0361] Preparation of AJ72a:

[0362]

[0363] Preparation of AJ72a-1: AJ72a-0 (1 g, 5 mmol) and tert-butyl glycinate (620 mg, 5 mmol) were dissolved in 20 mL of DMF. DIEA (1.6 g, 12 mmol) was added dropwise to the reaction system under stirring at room temperature. After stirring for 10 minutes, HATU (1.9 g, 5 mmol) was added in batches, and the reaction was continued for 20 minutes. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 20 mL of water was added to the reaction system to quench the reaction, and 20 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 100 / 1 - 5 / 1) to obtain a pale yellow oily compound AJ72a-1 (1 g, 64%).

[0364] Preparation of AJ72a-2: Dissolve compound AJ72a-1 (1 g, 3.2 mmol) in 15 mL of DMF. While stirring at room temperature, add N,N-dimethylethane-1,2-diamine (230 mg, 2.6 mmol) dropwise to the reaction solution. After stirring the reaction for 5 minutes under argon protection, successively add 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (930 mg, 4 mmol), CuI (600 mg, 3.2 mmol) and K2CO3 (1.1 g, 8 mmol), and heat the temperature to 100 °C and stir the reaction for 3 h. After detecting the completion of the reaction, cool the reaction solution to room temperature, add 20 mL of water to quench the reaction and add 20 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify by column chromatography (DCM / MeOH = 100 / 1 - 60 / 1) to obtain the yellow oily compound AJ72a-2 (800 mg, 54%).

[0365] Preparation of AJ72a-3: Dissolve AJ72a-2 (65 mg, 0.14 mmol) in 6 mL of DCM. While stirring at room temperature, add 2 mL of TFA dropwise to the reaction system and stir the reaction at room temperature for 1 h. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Concentrate under reduced pressure to remove the excess TFA and DCM to obtain the white compound AJ72a-3 (55 mg, 96%).

[0366] Preparation of AJ72a-4: Dissolve AJ72a-3 (55 mg, 0.13 mmol) and AJ10a-2 (64 mg, 0.13 mmol) in 5 mL of DMF. While stirring at room temperature, successively add DIEA (52 mg, 0.4 mmol) and HATU (51 mg, 0.13 mmol) dropwise to the system. After stirring the reaction at room temperature for 20 minutes, LCMS detection shows that the raw materials have disappeared and the reaction is complete. Slowly add 10 mL of water to the reaction solution while stirring. A white solid precipitates from the reaction solution. Filter under reduced pressure and dry to obtain the filter cake. Purify the filter cake by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 2) to obtain the brown solid AJ72a-4 (100 mg, 86%).

[0367] Preparation of AJ72a: Add 2 mL of TFA and 2 mL of TfOH to AJ72a-4 (100 mg, 0.11 mmol), heat the mixture to 80 °C under stirring and react for 2 h. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Cool the reaction solution to room temperature, add ice water to quench the reaction under an ice bath, adjust the pH of the reaction solution to 7 - 8 with saturated NaHCO3 aqueous solution, add 10 mL of EA for extraction and liquid separation, repeat the extraction three times until the extraction is complete, combine the organic phases, wash them with saturated brine, dry the organic phases with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify it by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 2) to obtain white solid AJ72a (15 mg, 18%). 1 H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 10.59(s, 1H), 9.05 (s, 1H), 8.89 - 8.86 (m, 1H), 8.75 (d, J = 2.5 Hz, 1H), 8.33 (d,J = 8.2 Hz, 1H), 8.19 - 8.16 (m, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.61 (dd, J =8.2, 1.4 Hz, 1H), 7.35 (s, 1H), 4.19 (d, J = 5.8 Hz, 2H), 3.91 (t, J = 6.6Hz, 2H), 3.58 - 3.49 (m, 4H), 3.27 - 3.21 (m, 4H), 2.88 - 2.83 (m, 1H), 2.79 - 2.76(m, 2H), 2.75 - 2.73 (m, 1H), 2.72 (d, J = 7.4 Hz, 2H), 2.71 - 2.67 (m, 1H),2.64 - 2.56 (m, 2H), 1.94 - 1.85 (m, 2H), 1.75 (s, 6H), 1.69 - 1.61 (m, 2H), 1.28(t, J = 7.4 Hz, 3H). LCMS(ESI) m / z 756.5 [M+H] + .

[0368] Preparation of AJ76:

[0369]

[0370] Preparation of AJ76-1: Dissolve AJ76-0 (1 g, 4 mmol) in 10 mL of NMP. While stirring, add CuCN (720 mg, 8 mmol) to the reaction solution, and then heat the reaction solution to 150 °C and stir for 2 h. LCMS detection shows that the raw material has completely reacted. Add 30 mL of water to the reaction solution for dilution and 30 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry and concentrate the organic phases with anhydrous sodium sulfate to obtain the crude product. Purify it by column chromatography (EA / PE = 1 / 100 - 1 / 5) to obtain the colorless oily product AJ76-1 (800 mg, 98%).

[0371] Preparation of AJ76-2: Dissolve AJ76-1 (800 mg, 4 mmol) in 8 mL of TFA, then add 5 mL of concentrated sulfuric acid. While stirring, heat the reaction solution to 60 °C and react for 4 h. LCMS detection shows that the raw material has completely reacted. Concentrate the reaction solution under reduced pressure to remove TFA. Then, adjust the pH value of the reaction system to neutral with saturated aqueous NaHCO3 solution under ice bath. Add 20 mL of water for dilution and 20 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry and concentrate the organic phases with anhydrous sodium sulfate to obtain the crude product. Purify it by column chromatography (EA / PE = 1 / 100 - 1 / 2) to obtain the colorless oily product AJ76-2 (650 mg, 78%).

[0372] Preparation of AJ76-3: Dissolve AJ76-2 (650 mg, 3 mmol) in 6 mL of toluene solution, then add DMF-DMA (440 mg, 3.7 mmol). While stirring, heat the reaction solution to 120 °C and react at this temperature for 2 h. LCMS detection shows that the raw material has been consumed. No purification is required, and the reaction solution is directly used for the next step.

[0373] Preparation of AJ76-4: Add t-BuOK (520 mg, 4.6 mmol) to the reaction solution of AJ76-3, and heat it to 120 °C and stir for 12 h. LCMS detection shows that the raw material has completely reacted. After cooling the reaction solution to room temperature, add 20 mL of water, and a solid precipitate will form. Filter, wash, and dry the filter cake to obtain the brown solid AJ76-4 (137 mg, 24%).

[0374] Preparation of AJ76-5: Dissolve AJ76-4 (137 mg, 0.6 mmol) in 5 mL of DMF. While stirring at room temperature, add K2CO3 (165 mg, 1.2 mmol) and tert-butyl 2-bromoacetate (120 mg, 0.7 mmol). Heat the mixed system to 60 oC and stir the reaction at this temperature for about 2 h. LCMS detection shows that the raw material has completely reacted. Add 15 mL of water to the reaction solution for quenching and add 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure to obtain the crude concentrate. Purify by column chromatography (EA / PE = 1 / 100 - 1 / 1) to obtain the brown solid AJ76-5 (200 mg, 96%).

[0375] Preparation of AJ76-6: Dissolve CuI (280 mg, 1.5 mmol) in DMF, then add N,N-dimethylethane-1,2-diamine (104 mg, 1.2 mmol), K2CO3 (244 mg, 1.8 mmol), 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (204 mg, 0.7 mmol) and AJ76-5 (200 mg, 0.6 mmol). After replacing the mixed system with argon, heat it up to 100 o C and stir the reaction under this condition for about 1 h. LCMS detection shows that AJ76-5 has completely reacted. Cool to room temperature and add 15 mL of water to the reaction solution for quenching, add 15 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure to obtain the crude concentrate. Purify by column chromatography (EA / PE = 1 / 100 - 1 / 1) to obtain the brown solid product AJ76-6 (36 mg, 12.4%).

[0376] Preparation of AJ76-7: Dissolve AJ76-6 (36 mg, 0.07 mmol) in 6 mL of DCM solution. Add 2 mL of TFA to the reaction solution under stirring at room temperature and continue the reaction for 1 h under stirring at room temperature. LCMS detection shows that the raw material has completely reacted. Rotate the reaction solution to dryness by concentration under reduced pressure to obtain the brown solid AJ76-7 (30 mg, 95%).

[0377] Preparation of AJ76-8: Dissolve AJ76-7 (30 mg, 0.07 mmol) in 6 mL of DMF. Add AJ10a-2 (33 mg, 0.07 mmol), DIEA (27 mg, 0.2 mmol) and HATU (32 mg, 0.08 mmol) to the reaction solution in sequence under stirring at room temperature. Stir the reaction mixture at room temperature for 20 minutes. LCMS detection shows that the raw material has completely reacted. Add 10 mL of water to the reaction solution, and a solid precipitate appears. Filter by suction and rotate to dryness by concentration under reduced pressure to obtain the crude concentrate. Purify by column chromatography (MeOH / DCM = 1 / 100 - 1 / 30) to obtain AJ76-8 (25 mg, 65%).

[0378] Preparation of AJ76: AJ76-8 (25 mg, 0.03 mmol) was dissolved in 1 mL of TFA solution. 1 mL of TfOH was added under stirring at room temperature, and the reaction mixture was stirred at room temperature for 2 h. LCMS detection showed that the raw material had completely reacted. The pH value of the reaction solution was adjusted to neutral with saturated aqueous NaHCO3 under ice bath. 10 mL of water and 10 mL of EA were added for extraction and liquid separation, and the extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude concentrate. It was purified by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 5) to obtain white solid AJ76 (5 mg, 40%). 1 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 10.59 (s, 1H), 9.29 (s, 1H), 8.77 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.35 (s, 1H), 6.65 (d, J = 7.4 Hz, 1H), 4.96 (s, 2H), 3.73 - 3.62 (m, 2H), 3.58 - 3.56 (m, 2H), 3.52 - 3.47 (m, 2H), 3.25 - 3.22 (m, 2H), 2.95 - 2.90 (m, 2H), 2.85 - 2.77 (m, 2H), 2.77 - 2.74 (m, 1H), 2.74 - 2.70 (m, 2H), 2.69 - 2.64 (m, 2H), 2.59 - 2.54 (m, 2H), 1.97 - 1.89 (m, 2H), 1.75 (s, 6H), 1.70 - 1.62 (m, 2H), 1.29 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 780.5 [M+H] + .

[0379] Preparation of AJ78:

[0380]

[0381] Preparation of AJ78-1: AJ78-0 (1.0 g, 5 mmol) was dissolved in 10 mL of MeCN. CDI (1.6 g, 10 mmol) was added under stirring at room temperature, and the reaction solution was heated to 80 oC and stir the reaction for about 1 h under this condition. LCMS detection shows that the raw material has completely reacted. After cooling the reaction solution to room temperature, add 15 mL of water, and a solid precipitate will form. Filter by suction, wash, and dry the filter cake to obtain a brown solid AJ78-1 (1.0 g, 87%).

[0382] Preparation of AJ78-2: Dissolve AJ78-1 (1.0 g, 4 mmol) in 20 mL of DMF, and add K2CO3 (900 mg, 6.5 mmol) and 3-bromopiperidine-2,6-dione (1 g, 5 mmol) under stirring at room temperature. Heat the mixed system to 100 o C and stir the reaction for about 1 h at this temperature. LCMS detection shows that the raw materials have been consumed. Cool the reaction system to room temperature and add 20 mL of water to quench it. Add 20 mL of EA for extraction and liquid separation, and repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phases with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude concentrate. Purify by column chromatography (EA / PE = 1 / 100 - 1 / 1) to obtain a light red solid AJ78-2 (630 mg, 52%).

[0383] Preparation of AJ78-3: Dissolve compound AJ78-2 (400 mg, 1.2 mmol) in 15 mL of THF solvent, stir at room temperature, and successively add Pd2(dba)3 (214 mg, 0.23 mmol), Q-Phos (209 mg, 0.23 mmol), and 2-tert-butoxy-2-carbonylethylzinc bromide (12 mL, 12 mmol) under argon protection. Slowly heat the reaction system to 70 °C and stir the reaction for 2 h. After LCMS detection shows that the reaction is complete, add saturated ammonium chloride aqueous solution to the reaction solution to quench it, extract with EA, collect the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate. Purify the residue by column chromatography (MeOH / DCM = 1 / 100 - 1 / 80) to obtain an off-white solid AJ78-3 (320 mg, 72%).

[0384] Preparation of AJ78-4: Dissolve AJ78-3 (320 mg, 0.85 mmol) in 10 mL of DCM, and add 3 mL of TFA to the reaction solution under stirring at room temperature. After stirring at room temperature for 20 minutes, LCMS detection shows that the raw materials have completely reacted. Remove DCM and TFA in the reaction solution by concentration under reduced pressure to obtain a pale yellow solid AJ78-4 (255 mg, 93%).

[0385] Preparation of AJ78: AJ78-4 (255 mg, 0.8 mmol) was dissolved in 15 mL of DMF. Under stirring at room temperature, AJ10a-2 (380 mg, 0.8 mmol), DIEA (296 mg, 2.3 mmol) and HATU (332 mg, 0.9 mmol) were successively added to the reaction solution. After stirring for about 30 minutes, LCMS detection showed that the raw materials had completely reacted. 10 mL of water was added to the reaction solution, and a solid precipitate was formed. The solid was filtered, washed and dried to obtain the crude product. The crude product was purified by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 3) to obtain white solid AJ78 (117 mg, 19%). 1 H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 11.22 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.00 (d, J = 1.1 Hz, 1H), 7.60 (dd, J = 8.2, 1.4 Hz, 1H), 7.34 (s, 1H), 7.32 (d, J = 1.5 Hz, 1H), 7.30 (d, J = 5.0 Hz, 1H), 5.36 (dd, J = 12.9, 5.3 Hz, 1H), 3.76 (s, 2H), 3.62 - 3.52 (m, 2H), 3.52 - 3.41 (m, 2H), 3.23 (d, J = 11.1 Hz, 2H), 2.95 - 2.82 (m, 1H), 2.82 - 2.80 (m, 1H), 2.78 - 2.74 (m, 2H), 2.72 (d, J = 7.5 Hz, 2H), 2.71 - 2.66 (m, 1H), 2.64 - 2.62 (m, 1H), 2.61 - 2.57 (m, 2H), 2.54 - 2.52 (m, 1H), 2.48 - 2.39 (m, 1H), 2.20 - 2.10 (m, 1H), 1.95 - 1.83 (m, 2H), 1.75 (s, 6H), 1.69 - 1.54 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 786.4 [M+H] + .

[0386] Preparation of AJ78b:

[0387]

[0388] Preparation of AJ78b: AJ13-5 (20 mg, 0.04 mmol) and AJ78-4 (13 mg, 0.04 mmol) were dissolved in 5 mL of DMF. Under stirring at room temperature, DIEA (10 mg, 0.08 mmol) and HATU (17 mg, 0.05 mmol) were added successively. After stirring at room temperature for about 20 minutes, 10 mL of water was added to the reaction solution for quenching, and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Purification by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 3) gave white solid AJ78b (15 mg, 48%). 1 HNMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 11.22 (s, 1H), 8.32 (d, J = 8.1 Hz,1H), 8.06 (s, 1H), 8.00 (d, J = 1.1 Hz, 1H), 7.61 (dd, J = 8.2, 1.4 Hz, 1H),7.37 (s, 1H), 7.32 (s, 1H), 7.30 (d, J = 2.8 Hz, 1H), 5.36 (dd, J = 12.9, 5.3Hz, 1H), 4.41 (d, J = 12.5 Hz, 1H), 4.08 (d, J = 12.8 Hz, 1H), 3.78 (s, 2H),3.18 - 3.10 (m, 2 H), 3.10 - 2.96 (m, 4H), 2.95 - 2.90 (m, 1H), 2.89 - 2.81 (m, 2H),2.78 - 2.75 (m, 1H), 2.72 (d, J = 7.5 Hz, 2H), 2.71 - 2.66 (m, 2H), 2.66 - 2.56 (m,2H), 2.19 - 2.11 (m, 1H), 2.01 - 1.84 (m, 2H), 1.76 (s, 6H), 1.54 - 1.47 (m, 1H),1.43 - 1.34 (m, 1H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 786.4 [M+H] + .

[0389] Preparation of AJ78i:

[0390]

[0391] Preparation of AJ78i-1: AJ78i-0 (1 g, 5 mmol) was dissolved in 20 mL of DMSO solvent. Under stirring at room temperature and under argon protection, N-benzyloxycarbonyl-3,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (2 g, 6 mmol) and CuI (96 mg, 0.5 mmol) were successively added. The reaction system was heated to 60 °C and reacted for 8 h. After the reaction was detected to be complete by LCMS, it was cooled to room temperature. 30 mL of water was added to the reaction system for dilution, and 30 mL of DCM / MeOH (10:1) was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. It was purified by column chromatography (MeOH / DCM = 1 / 100 - 1 / 20) to obtain white solid AJ78i-1 (1.2 g, 58%).

[0392] Preparation of AJ78i-2: AJ78i-1 (500 mg, 1.2 mmol) was dissolved in DCM / MeOH (20 mL, 1:1) solution. Catalytic amount of 10% Pd / C (50 mg) was added, and the system was purged with hydrogen. The reaction was carried out at room temperature in a hydrogen atmosphere for 3 h. After the reaction was detected to be complete by LCMS, it was filtered under reduced pressure. The filter cake was washed twice with 10 mL of 1,4-dioxane. The filtrates were combined and concentrated under reduced pressure to obtain a crude concentrate. It was purified by column chromatography (EA / PE = 1 / 100 - 1 / 5) to obtain light yellow solid AJ78i-2 (330 g, 97%).

[0393] Preparation of AJ78i-3: AJ78i-2 (150 mg, 0.5 mmol) was dissolved in DMF (10 mL) solution. Under stirring at room temperature, AJ10a-0 (230 mg, 0.5 mmol), KHMDS (320 mg, 0.16 mmol), Pd2(dba)3(49 mg, 0.05 mmol), and X-Phos (25 mg, 0.05 mmol) were successively added. The system was purged with argon. The reaction solution was heated to 70 °C and reacted for 3 h. After the reaction was completed as detected by LCMS, it was cooled to room temperature. 20 mL of water was added to the reaction solution for dilution, and 20 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. It was purified by column chromatography (MeOH / DCM = 1 / 100 - 1 / 40) to obtain off-white solid AJ78i-3 (100 mg, 32%).

[0394] Preparation of AJ78i-4: AJ78i-3 (100 mg, 0.17 mmol) was dissolved in a mixed solution of DCM / TFA (10 mL, 3:1). The resulting solution was stirred at room temperature for 1 h, and the solvent was removed by concentration under reduced pressure to obtain a white solid AJ78i-4 (70 mg, 84%).

[0395] Preparation of AJ78i: AJ78i-4 (20 mg, 0.04 mmol) and AJ78-4 (13 mg, 0.04 mmol) were dissolved in 5 mL of DMF solvent. Et3N (12 mg, 0.12 mmol) was added under stirring at room temperature, and a DMF solution of HATU (15 mg, 0.04 mmol) was slowly added dropwise, and the reaction was continued to stir at room temperature for 30 minutes. Then 10 mL of water was added to the reaction solution for quenching, and a white precipitate was formed. The crude product was obtained by suction filtration and washing. The white solid AJ78i (10 mg, 32%) was obtained by purification by column chromatography (MeOH / DCM = 1 / 100 - 1 / 15). 1 H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 11.22 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.05 (s, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.61 (dd, J = 8.2, 1.4 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J = 4.9 Hz, 1H), 7.32 - 7.27 (m, 1H), 5.36 (dd, J = 12.9, 5.4 Hz, 1H), 4.54 - 4.45 (m, 1H), 4.28 (s, 1H), 4.06 (s, 1H), 3.83 (s, 2H), 3.81 - 3.76 (m, 1H), 3.71 - 3.63 (m, 1H), 3.53 - 3.45 (m, 1H), 3.42 - 3.35 (m, 1H), 3.27 - 3.21 (m, 2H), 2.98 - 2.82 (m, 3H), 2.79 - 2.74 (m, 2H), 2.74 - 2.69 (m, 1H), 2.68 - 2.65 (m, 1H), 2.21 - 2.12 (m, 1H), 1.97 - 1.87 (m, 2H), 1.76 (s, 6H), 1.73 - 1.65 (m, 2H), 1.29 (t, J = 7.4 Hz, 3H). LCMS(ESI) m / z800.4 [M+H] + .

[0396] Preparation of AJ79:

[0397]

[0398] Preparation of AJ79: Dissolve AJ79-1 (20 mg, 0.06 mmol, prepared according to the preparation method of AJ78-4) and AJ10a-2 (30 mg, 0.06 mmol) in 6 mL of DMF. Add DIEA (16 mg, 0.12 mmol) and HATU (26 mg, 0.07 mmol) under stirring at room temperature. After reacting for about 30 minutes, add 10 mL of water to the reaction solution to quench the reaction and add 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry and concentrate the organic phase with anhydrous sodium sulfate to obtain a crude concentrate. Purify it by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 2) to obtain white solid AJ79 (5 mg, 10%). 1 H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 11.25 (s, 1H), 8.32(d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.60 (dd, J = 8.1, 1.4 Hz,1H), 7.33 (s, 1H), 7.18 (d, J = 1.3 Hz, 1H), 7.04 (d, J = 11.9 Hz, 1H), 5.42(dd, J = 17.9, 9.9 Hz, 1H), 3.78 (s, 2H), 3.56 - 3.51 (m, 2H), 3.50 - 3.46 (m,2H), 3.26 - 3.19 (m, 2H), 3.08 - 2.89 (m, 2H), 2.86 - 2.78 (m, 1H), 2.78 - 2.74 (m,2H), 2.72 (d, J = 7.5 Hz, 2H), 2H), 2.69 - 2.61 (m, 2H), 2.54 (t, J = 1.9 Hz,2H), 2.45 - 2.39 (m, 1H), 2.30 - 2.25 (m, 1H), 1.92 - 1.84 (m, 2H), 1.75 (s, 6H),1.66 - 1.57 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 786.5 [M+H] + .

[0399] Preparation of AJ79b:

[0400]

[0401] Preparation of AJ79b: Dissolve AJ79-1 (20 mg, 0.06 mmol) and AJ13-5 (30 mg, 0.06 mmol) in 8 mL of DMF. Add DIEA (16 mg, 0.12 mmol) and HATU (26 mg, 0.068 mmol) under stirring at room temperature. After stirring for 20 minutes, add 10 mL of water for quenching and 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate to obtain the crude product. Obtain the white solid AJ79b (25 mg, 50%) through reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 2). 1 H NMR (400 MHz, DMSO-d6) δ12.71 (s, 1H), 11.25 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.04 (s, 1H), 8.01 - 7.97 (m, 1H), 7.60 (dd, J = 8.1, 1.4 Hz, 1H), 7.36 (s, 1H), 7.19 (s, 1H), 7.05 (d, J = 11.8 Hz, 1H), 5.43 (dd, J = 12.9, 5.3 Hz, 1H), 4.39 (d, J = 12.7 Hz, 1H), 4.03 (d, J = 12.6 Hz, 1H), 3.79 (d, J = 3.0 Hz, 2H), 3.12 - 3.04 (m, 1H), 3.04 - 2.88 (m, 5H), 2.78 - 2.73 (m, 1H), 2.72 (d, J = 7.5 Hz, 2H), 2.70 - 2.64 (m, 3H), 2.63 (d, J = 4.6 Hz, 1H), 2.61 - 2.56 (m, 1H), 2.55 - 2.52 (m, 1H), 2.49 - 2.44 (m, 1H), 2.30 - 2.26 (m, 1H), 1.89 - 1.78 (m, 2H), 1.75 (s, 6H), 1.44 - 1.30 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 786.5 [M+H] + .

[0402] Preparation of AJ80:

[0403]

[0404] Preparation of AJ80-1: Dissolve AJ80-0 (2 g, 16 mmol) in 30 mL of MeCN solvent. Add CDI (5.2 g, 32 mmol) under stirring at room temperature. Heat the resulting solution to 85 °C and stir for 2 h. After detecting the completion of the reaction by LCMS, cool it to room temperature and concentrate it under reduced pressure to remove MeCN. Then, add 50 mL of water dropwise with stirring. A large amount of white solid precipitates. Filter it under reduced pressure. Wash the solid with a mixed solvent of EA / PE (1:5), filter it, and dry the filter cake to obtain white solid AJ80-1 (1.8 g, 71%).

[0405] Preparation of AJ80-2: Dissolve AJ80-1 (1.8 g, 12 mmol) in 30 mL of DMF. Cool the system to 0 °C in an ice-water bath under stirring and slowly add a DMF solution of NBS (2.1 g, 12 mmol). Let the reaction system slowly warm up to room temperature and continue the reaction for 0.5 h. After detecting the completion of the reaction by LCMS, add 50 mL of water to dilute the reaction solution and add 30 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry the organic phases with anhydrous sodium sulfate, filter, and concentrate to obtain a pale yellow solid AJ80-2 (2.3 g, 82%).

[0406] Preparation of AJ80-3: Dissolve AJ80-2 (1 g, 4.3 mmol) in 20 mL of DMF solution. Add Cs2CO3 (2.8 g, 8.7 mmol) and 3-bromopiperidine-2,6-dione (1.2 g, 6.5 mmol) under stirring at room temperature. Stir the reaction solution at room temperature for about 6 h. After detecting the completion of the reaction by LCMS, add 30 mL of water to dilute the reaction solution and add 20 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry and concentrate the organic phases to obtain a crude concentrate. Purify it by column chromatography (EA / PE = 1 / 100 - 1 / 5) to obtain a pale yellow solid AJ80-3 (940 mg, 64%).

[0407] Preparation of AJ80-4: Dissolve AJ80-3 (20 mg, 0.64 mmol) in 10 mL of THF, stir at room temperature and add Pd2(dba)3 (88 mg, 0.1 mmol), Q-Phos (69 mg, 0.1 mmol) and 2-tert-butoxy-2-carbonylethylzinc bromide (2.6 mL, 2.6 mmol) under argon protection. Slowly heat up to 70 °C and stir the reaction for 2 h. After detecting the completion of the reaction, quench with saturated aqueous ammonium chloride solution, extract with EA, collect the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to remove the solvent, and purify the residue by column chromatography (MeOH / DCM = 1 / 100 - 1 / 50) to obtain a white solid AJ80-4 (240 mg, 98%).

[0408] Preparation of AJ80-5: Dissolve AJ80-4 (240 mg, 0.6 mmol) in a mixed solution of DCM / TFA (10 mL, 3:1), stir the resulting solution at room temperature for 1 h, and then concentrate under reduced pressure to remove the solvent to obtain a white solid AJ80-5 (200 mg, 98%).

[0409] Preparation of AJ80: Dissolve AJ80-5 (24 mg, 0.08 mmol) and AJ10-2 (36 mg, 0.08 mmol) in 5 mL of DMF solution, add DIEA (28 mg, 0.22 mmol) under stirring at room temperature, and slowly dropwise add a DMF solution of HATU (30 mg, 0.08 mmol). After detecting the completion of the reaction, quench the reaction solution with 10 mL of water, add 10 mL of EA for extraction and liquid separation, repeat the extraction three times until the extraction is complete, combine the organic phases, backwash with saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain the crude product. Purify by column chromatography (EA / PE = 1 / 100 - 1 / 1) to obtain a white solid AJ80 (25 mg, 43%). 1HNMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 11.24 (s, 1H), 8.32 (d, J = 8.2 Hz,1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.60 (dd, J = 8.1, 1.4 Hz, 1H), 7.34 (s,1H), 7.14 - 7.03 (m, 2H), 5.40 (dd, J = 13.0, 5.2 Hz, 1H), 3.82 (s, 2H), 3.62 - 3.55 (m, 2H), 3.52 - 3.46 (m, 2H), 3.27 - 3.20 (m, 2H), 2.95 - 2.87 (m, 1H), 2.87 - 2.77 (m, 2H), 2.76 - 2.73 (m, 1H), 2.72 (d, J = 7.5 Hz, 2H), 2.70 - 2.66 (m, 1H),2.66 - 2.62 (m, 1H), 2.62 - 2.56 (m, 2H), 2.56 - 2.54 (m, 1H), 2.46 - 2.42 (m, 1H),2.22 - 2.16 (m, 1H), 1.95 - 1.85 (m, 2H), 1.75 (s, 6H), 1.70 - 1.60 (m, 2H), 1.28(t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 786.5 [M+H] + .

[0410] Preparation of AJ81: AJ81 was prepared according to the preparation method of AJ31.

[0411]

[0412] 11H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 11.18 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 6.6 Hz, 1H), 8.00 (d, J = 1.1 Hz, 1H), 7.60 (dd, J = 8.1, 1.4 Hz, 1H), 7.34 (d, J = 11.6 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 5.32 (dd, J = 13.0, 5.4 Hz, 1H), 3.26 - 3.23 (m, 2H), 3.14 - 3.08 (m, 1H), 3.01 - 2.96 (m, 3H), 2.90 - 2.85 (m, 1H), 2.84 - 2.79 (m, 2H), 2.77 - 2.74 (m, 1H), 2.73 - 2.69 (m, 4H), 2.68 - 2.64 (m, 2H), 2.46 - 2.41 (m, 1H), 2.25 - 2.20 (m, 1H), 2.15 - 2.11 (m, 1H), 1.97 - 1.92 (mm, 2H), 1.76 (s, 6H), 1.70 - 1.60 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 744.5 [M+H] + .

[0413] Preparation of AJ82: AJ82 was prepared according to the preparation method of AJ31.

[0414]

[0415] 11H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 11.18 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 6.6 Hz, 1H), 8.00 (s, 1H), 7.60 (dd, J = 8.1, 1.4 Hz, 1H), 7.34 (d, J = 11.6 Hz, 2H), 7.15 - 7.10 (m, 1H), 5.34 (dd, J = 13.0, 5.4 Hz, 1H), 3.26 - 3.23 (m, 2H), 3.14 - 3.08 (m, 1H), 3.01 - 2.96 (m, 3H), 2.90 - 2.85 (m, 1H), 2.84 - 2.79 (m, 2H), 2.77 - 2.74 (m, 1H), 2.73 - 2.69 (m, 4H), 2.68 - 2.64 (m, 2H), 2.46 - 2.41 (m, 1H), 2.25 - 2.20 (m, 1H), 2.15 - 2.11 (m, 1H), 2.00 - 1.93 (mm, 2H), 1.76 (s, 6H), 1.70 - 1.61 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 744.5 [M+H] + .

[0416] Preparation of AJ83: AJ83 was prepared according to the preparation method of AJ31.

[0417]

[0418] 11H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 11.19 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.05 (d, J = 6.2 Hz, 1H), 8.00 (s, 1H), 7.60 (dd, J = 8.1, 1.5 Hz, 1H), 7.36 (d, J = 6.7 Hz, 1H), 7.08 - 6.99 (m, 1H), 6.91 (t, J = 8.2 Hz, 1H), 5.36 (dd, J = 12.8, 5.7 Hz, 1H), 3.64 - 3.48 (m, 2H), 3.26 - 3.21 (m, 1H), 3.14 - 3.09 (m, 1H), 3.04 - 2.96 (m, 2H), 2.92 - 2.87 (m, 1H), 2.86 - 2.78 (m, 2H), 2.78 - 2.75 (m, 1H), 2.76 - 2.74 (m, 2H), 2.72 (d, J = 7.5 Hz, 2H), 2.68 - 2.61 (m, 2H), 2.47 - 2.42 (m, 1H), 2.30 - 2.22 (m, 1H), 2.15 - 2.11 (m, 1H) 2.01 - 1.85 (m, 2H), 1.76 (s, 6H), 1.70 - 1.51 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 744.5 [M+H] + .

[0419] Preparation of AJ87: AJ87 was prepared according to the preparation method of AJ12.

[0420]

[0421] 11H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 10.99 (s, 1H), 8.32 (d, J =8.1 Hz, 1H), 8.02 (d, J = 17.2 Hz, 1H), 7.60 (dd, J = 8.1, 1.5 Hz, 1H), 7.35(s, 1H), 6.89 (s, 1H), 6.72 (s, 1H), 6.47 (s, 1H), 5.36 (dd, J = 12.8, 5.7Hz, 1H), 3.64-3.59 (m, 2H), 3.52-3.48 (m, 2H), 3.23 (s, 3H), 3.16-3.13 (m,2H), 3.01-2.91 (m, 2H), 2.87-2.86 (m, 1H), 2.85-2.82 (m, 2H), 2.80-2.79 (m,1H), 2.78-2.75(m, 1H), 2.73-2.69 (m, 2H), 2.65 -2.61 (m, 1H), 2.54-2.52 (m,1H), 2.46-2.41 (m, 1H), 2.11-2.07 (m, 1H), 2.01-1.97 (m, 2H), 1.75 (s, 6H),1.52-1.47 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H). LCMS(ESI) m / z 757.5 [M+H] + .

[0422] Preparation of AJ88: AJ88 was prepared according to the preparation method of AJ12.

[0423]

[0424] 11H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 11.08 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.05 (s, 1H), 8.00 (d, J = 1.0 Hz, 1H), 7.61 (dd, J = 8.2, 1.4 Hz, 1H), 7.35 (s, 1H), 7.15 (d, J = 12.1 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 5.31 (dd, J = 12.7, 5.4 Hz, 1H), 3.40 (s, 3H), 3.28 - 3.20 (m, 2H), 3.09 - 2.94 (m, 4H), 2.92 - 2.86 (m, 1H), 2.86 - 2.79 (m, 2H), 2.74 - 2.67 (m, 6H), 2.67 - 2.65 (m, 1H), 2.63 - 2.57 (m, 1H), 2.47 - 2.42 (m, 1H), 2.02 - 1.99 (m, 1H), 1.98 - 1.91 (m, 2H), 1.75 (s, 6H), 1.70 - 1.61 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 757.5 [M+H] + .

[0425] Preparation of AJ89: AJ89 was prepared according to the preparation method of AJ12.

[0426]

[0427] 11H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 11.11 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.60 (dd, J = 8.0, 1.4 Hz, 1H), 7.35 (s, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.74 (t, J = 8.2 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 3.48 (d, J = 1.8 Hz, 3H), 3.28 - 3.20 (m, 2H), 3.04 - 2.97 (m, 4H), 2.95 - 2.90 (m, 1H), 2.88 - 2.79 (m, 2H), 2.79 - 2.68 (m, 6H), 2.68 - 2.64 (m, 1H), 2.64 - 2.57 (m, 1H), 2.46 - 2.40 (m, 1H), 2.05 - 1.99 (m, 1H), 1.99 - 1.88 (m, 2H), 1.75 (s, 6H), 1.69 - 1.57 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 757.5 [M+H] + .

[0428] Preparation of AJ90:

[0429]

[0430] Preparation of AJ90-1: AJ90-0 (1 g, 5.6 mmol) and N-Boc-piperazine (1.1 g, 5.9 mmol) were dissolved in 15 mL of DMF. K2CO3 (1.5 g, 11 mmol) was added under stirring at room temperature, and then the reaction system was heated to 85 °C and stirred for 2 h. After the reaction was complete, it was cooled to room temperature. 15 mL of water was added to the reaction solution to quench the reaction, and 20 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (PE / EA = 100 / 1 - 20 / 1) gave a pale yellow solid AJ90-1 (1.8 g, 93%).

[0431] Preparation of AJ90-2: Dissolve AJ90-1 (500 mg, 1.4 mmol) in 10 mL of THF solution, add the catalyst Pd / C (palladium content is 10%, 50 mg), place the reaction under hydrogen conditions, and stir the reaction at room temperature for 2 h. After detecting the end of the reaction, filter the reaction solution under reduced pressure, and concentrate the obtained filtrate under reduced pressure to obtain a grayish-white solid AJ90-2 (430 mg, 94%).

[0432] Preparation of AJ90-3: Dissolve AJ90-2 (430 mg, 1.4 mmol) and 2,6-bis(benzyloxy)-3-bromopyridine (610 mg, 1.6 mmol) in 15 mL of dioxane, stir at room temperature and add Pd2(dba)3 (130 mg, 0.14 mmol), X-Phos (65 mg, 0.14 mmol), Cs2CO3 (890 mg, 2.7 mmol) under argon protection, slowly heat up to 100 °C and stir the reaction for 6 h. After detecting the completion of the reaction, cool to room temperature, add 10 mL of water to quench the reaction solution and add 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Obtain a white solid AJ90-3 (700 mg, 84%) by column chromatography (PE / EA = 100 / 1 - 10 / 1).

[0433] Preparation of AJ90-4: Dissolve AJ90-3 (250 mg, 0.4 mmol) in 10 mL of dioxane, add the catalyst Pd(OH)2 / C (Pd(OH)2 content is 20%, 30 mg) under stirring at room temperature, place the reaction system under hydrogen conditions, and stir at room temperature for 4 h. After detecting the end of the reaction, filter the reaction solution under reduced pressure and wash the filter cake. Concentrate the obtained filtrate under reduced pressure to obtain the crude product. Obtain a white solid AJ90-4 (142 mg, 80%) by column chromatography (PE / EA = 100 / 1 - 1 / 1).

[0434] Preparation of AJ90-5: Dissolve AJ90-4 (120 mg, 0.3 mmol) in 5 mL of DCM, add a 1,4-dioxane solution (4 M) of 2 mL of hydrochloric acid dropwise to the reaction system under stirring at room temperature, slowly heat up the reaction system to 40 °C and stir the reaction for 30 minutes. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Concentrate under reduced pressure to remove the excess hydrochloric acid solution and DCM to obtain a grayish-white solid AJ90-5 (85 mg, 93%).

[0435] Preparation of AJ90: AJ90-5 (20 mg, 0.06 mmol) and AJ12-6 (25 mg, 0.06 mmol) were dissolved in a mixed solvent of 5 mL of THF and 1 mL of DMF. After stirring at room temperature for 1 h, AcOH (11 mg, 0.18 mmol) was added dropwise, and NaHB(OAc)3 (26 mg, 0.12 mmol) was added. The reaction was continued with stirring for 2 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 2 mL of saturated NaHCO3 aqueous solution was added to the reaction solution to quench the reaction, and 5 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The white solid AJ90 (18 mg, 41%) was obtained by column chromatography (DCM / MeOH = 100 / 1 - 20 / 1). 1 1H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 10.82 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.04 (s, 1H), 8.00 (d, J = 1.1 Hz, 1H), 7.60 (dd, J = 8.2, 1.4 Hz, 1H), 7.35 (s, 1H), 6.34 (s, 1H), 6.31 (s, 1H), 6.26 (d, J = 7.9 Hz, 1H), 4.40 - 4.23 (m, 1H), 3.23 (d, J = 11.2 Hz, 2H), 2.99 (s, 4H), 2.80 (d, J = 12.0 Hz, 2H), 2.77 - 2.73 (m, 1H), 2.70 (q, J = 7.5 Hz, 2H), 2.63 (s, 4H), 2.56 - 2.51 (m, 1H), 2.44 - 2.39 (m, 1H), 2.09 - 2.03 (m, 1H), 1.96 - 1.89 (m, 2H), 1.89 - 1.83 (m, 1H), 1.75 (s, 6H), 1.69 - 1.62 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 720.5 [M+H] + .

[0436] Preparation of AJ90b:

[0437]

[0438] Preparation of AJ90b-1: AJ90b-0 (500 mg, 2.8 mmol) and 4-piperidone ethylene acetal (440 mg, 3 mmol) were dissolved in 15 mL of DMF. Under stirring at room temperature, K2CO3 (970 mg, 7 mmol) was added to the system, and then the reaction system was heated to 80 °C and stirred for 2 h. After detecting that the reaction was complete, it was cooled to room temperature. 10 mL of water was added to the reaction solution to quench the reaction, and 15 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (PE / EA = 100 / 1 - 20 / 1) gave a pale yellow solid AJ90b-1 (800 mg, 94%).

[0439] Preparation of AJ90b-2: AJ90b-1 (400 mg, 1.3 mmol) was dissolved in 10 mL of THF solution. Under stirring at room temperature, a catalytic amount of Pd / C (Pd content was 10%, 20 mg) was added, and the reaction was placed under hydrogen conditions and stirred at room temperature for 2 h. After detecting the end of the reaction, the reaction solution was filtered under reduced pressure and the filter cake was washed several times. The filtrate was concentrated under reduced pressure to obtain an off-white solid AJ90b-2 (350 mg, 97%).

[0440] Preparation of AJ90b-3: AJ90b-2 (350 mg, 1.3 mmol) and 2,6-bis(benzyloxy)-3-bromopyridine (576 mg, 1.56 mmol) were dissolved in 15 mL of dioxane. Under stirring at room temperature and under argon protection, Pd2(dba)3 (237 mg, 0.26 mmol), X-Phos (247 mg, 0.52 mmol) and Cs2CO3 (842 mg, 2.6 mmol) were added. Then the reaction system was slowly heated to 100 °C and stirred for 2 h. After the reaction was completed, it was cooled to room temperature. 10 mL of water was added to the reaction solution to quench the reaction, and 15 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (PE / EA = 100 / 1 - 10 / 1) gave a white solid AJ90b-3 (690 mg, 96%).

[0441] Preparation of AJ90b-4: AJ90b-3 (250 mg, 0.45 mmol) was dissolved in 10 mL of dioxane. Pd(OH)2 / C (with 20% Pd(OH)2 content, 25 mg) was added. The reaction was placed under hydrogen conditions and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was dried, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 100 / 1 - 20 / 1) to obtain white solid AJ90b-4 (163 mg, 96%).

[0442] Preparation of AJ90b-5: AJ90b-4 (163 mg, 0.43 mmol) was dissolved in 10 mL of THF. 2 mL of hydrochloric acid solution (6 M) was added dropwise to the reaction system at room temperature, and the temperature was slowly raised to 50 °C and stirred for about 40 minutes under stirring conditions. LCMS detection showed that the raw materials had disappeared and the reaction was completed. The reaction was cooled to room temperature, and ice water was added to quench the reaction solution in an ice bath. The pH of the reaction solution was adjusted to 7 - 8 with saturated NaHCO3 aqueous solution. 15 mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 100 / 1 - 80 / 1) to obtain yellowish-green solid AJ90b-5 (80 mg, 55%).

[0443] Preparation of AJ90b: AJ90b-5 (17 mg, 0.05 mmol) and AJ12b-6 (20 mg, 0.05 mmol) were dissolved in a mixed solvent of 5 mL of THF and 1 mL of DMF. After stirring at room temperature for 1 h, AcOH (9 mg, 0.15 mmol) and NaHB(OAc)3 (21 mg, 0.10 mmol) were added, and the reaction was continued to stir for 2 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 2 mL of saturated NaHCO3 solution was added to quench the reaction solution, and 5 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 100 / 1 - 30 / 1) to obtain white solid AJ90b (8 mg, 22%). 11H NMR (400 MHz, DMSO-d6) δ12.71 (s, 1H), 10.83 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.04 (s, 1H), 8.00(d, J = 1.1 Hz, 1H), 7.60 (dd, J = 8.2, 1.4 Hz, 1H), 7.35 (s, 1H), 6.34 (s,1H), 6.31 (s, 1H), 6.26 (d, J = 7.9 Hz, 1H), 4.38-4.21 (m, 1H), 4.19-4.16 (m,1H), 4.09-4.00 (m, 1H), 3.25-3.22 (m, 2H), 3.01-2.97 (m, 4H), 2.84-2.80 (m,1H), 2.79-2.76 (m, 1H), 2.76-2.74 (m, 1H), 2.72 (d, J = 7.5 Hz, 2H), 2.69-2.67 (m, 1H), 2.66-2.63 (m, 2H), 2.62-2.60 (m, 1H), 2.59-2.54 (m, 1H), 2.44-2.39 (m, 1H), 2.10-2.04 (m, 1H), 1.96-1.89 (m, 2H), 1.89-1.83 (m, 1H), 1.75(s, 6H), 1.44-1.30 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 720.5 [M+H] + .

[0444] Preparation of AJ90-8D:

[0445]

[0446] Preparation of AJ90-8D-1: Dissolve 3,4,5-trifluoronitrobenzene (570 mg, 3 mmol) in 20 mL of MeCN, add Et3N (610 mg, 6 mmol) and AJ90-8D-0 (560 mg, 4 mmol) under stirring at room temperature, and continue stirring the reaction at room temperature for 2 h. LCMS detection showed that the raw materials had completely reacted. The crude product of AJ90-8D-1 obtained from the reaction solution was directly used for the next step without purification.

[0447] Preparation of AJ90-8D-2: Add Boc2O (1.3 g, 6 mmol) to the crude reaction solution of AJ90-8D-1, and stir the reaction at room temperature for 30 minutes. LCMS detection shows that all the raw materials have reacted. Add 15 mL of water to the reaction solution, and extract and separate it with 15 mL of EA. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash them with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate it under reduced pressure to obtain a crude light yellow concentrate. Obtain the light yellow oily product AJ90-8D-2 (800 mg, 73%) by column chromatography (EA / PE = 1 / 100 - 1 / 5).

[0448] Preparation of AJ90-8D-3: Dissolve AJ90-8D-2 (800 mg, 2.3 mmol) in 15 mL of THF, add Pd / C (10% content, 80 mg) under stirring at room temperature, replace the reaction system with hydrogen, and continue to stir the reaction solution at room temperature for 2 h. LCMS detection shows that the raw materials have been consumed. Filter off the palladium carbon in the reaction solution, wash the palladium carbon three times with EA and DCM, combine the organic phases, and concentrate them under reduced pressure to obtain the yellow concentrated product AJ90-8D-3 (730 mg, 99%).

[0449] Preparation of AJ90-8D-4: Dissolve AJ90-8D-3 (300 mg, 0.9 mmol) and 2,6-bis(benzyloxy)-3-bromopyridine (520 mg, 1.4 mmol) in 10 mL of dioxane solution, then sequentially add Cs2CO3 (610 mg, 1.9 mmol), Pd2(dba)3 (128 mg, 0.14 mmol) and X-Phos (11 mg, 0.23 mmol) under stirring at room temperature. Heat the reaction system to 100 °C under argon protection and stir the reaction for 1 h. LCMS detection shows that the raw materials have been consumed. Cool the reaction solution to room temperature, add 10 mL of water and 15 mL of DCM / MeOH (10:1) and extract three times until the extraction is complete. Combine the organic phases and backwash them with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate it under reduced pressure to obtain a crude brown concentrate. Obtain the light yellow oily product AJ90-8D-4 (450 mg, 78%) by column chromatography (PE / EA = 100 / 1 - 10 / 1).

[0450] Preparation of AJ90-8D-5: Dissolve AJ90-8D-4 (450 mg, 0.74 mmol) in 10 mL of dioxane. Add Pd(OH)2 / C (20% content, 45 mg) under stirring at room temperature. Replace with hydrogen, and heat the reaction solution to 40 °C in a hydrogen atmosphere and stir for 2 h. LCMS detection shows that the raw material has been consumed. Filter off Pd(OH)2 / C in the reaction solution and wash it three times with EA and DCM. Combine the organic phases, and concentrate the filtrate under reduced pressure to obtain a yellow concentrated product AJ90-8D-5 (320 mg, 99%).

[0451] Preparation of AJ90-8D-6: Dissolve AJ90-8D-5 (320 mg, 0.74 mmol) in 10 mL of DCM solution. Add a 1,4-dioxane solution of hydrochloric acid (4 M, 2 mL) to the reaction solution under stirring at room temperature, and continue to stir at room temperature for 1 h. LCMS detection shows that the raw material is completely consumed. Concentrate the reaction solution under reduced pressure to obtain a light green solid AJ90-8D-6 (245 mg, 99%).

[0452] Preparation of AJ90-8D: Dissolve AJ90-8D-6 (100 mg, 0.3 mmol) in a mixed solvent of 5 mL of THF and DMF (4:1). Add AJ12-6 (100 mg, 0.24 mmol) and NaHCO3 (50 mg, 0.6 mmol) under stirring at room temperature, and heat the reaction solution to 45 °C and stir for 10 minutes. Then add NaHB(OAc)3 (85 mg, 0.4 mmol), and continue to stir for 2 h. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Add 2 mL of saturated aqueous NaHCO3 solution to quench the reaction solution, add 5 mL of water, and extract with 10 mL of DCM / MeOH (10:1) three times until the extraction is complete. Combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. Obtain a white solid product AJ90-8D (36 mg, 17%) by column chromatography (DCM / MeOH = 100 / 1 - 30 / 1). 11H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.83(s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.64-7.57 (m,1H), 7.35 (s, 1H), 6.35 (s, 1H), 6.32 (s, 1H), 6.27 (d, J = 7.8 Hz, 1H),4.38-4.27 (m, 1H), 3.24 (d, J = 10.9 Hz, 2H), 2.86-2.77 (m, 1H), 2.77-2.73(m, 1H), 2.71 (d, J = 7.5 Hz, 2H), 2.69-2.65 (m, 1H), 2.61-2.56 (m, 1H),2.45-2.39 (m, 1H), 2.12-2.03 (m, 1H), 1.96-1.87 (m, 2H), 1.88-1.82 (m, 1H),1.75 (s, 6H), 1.69-1.58 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z728.6 [M+H] + .

[0453] Preparation of AJ91: AJ91 was prepared according to the preparation method of AJ90.

[0454]

[0455] 11H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 10.81 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.60 (dd, J = 8.1, 1.4 Hz, 1H), 7.35 (s, 1H), 6.80 - 6.75 (m, 1H), 6.75 - 6.71 (m, 1H), 6.62 - 6.58 (m, 1H), 5.11 - 5.04 (m, 1H), 4.30 - 4.24 (m, 1H), 3.28 - 3.20 (m, 2H), 3.06 - 2.92 (m, 4H), 2.84 - 2.80 (m, 2H), 2.76 - 2.73 (m, 1H), 2.72 (d, J = 7.5 Hz, 2H), 2.70 - 2.68 (m, 2H), 2.68 - 2.65 (m, 2H), 2.61 - 2.53 (m, 1H), 2.45 - 2.37 (m, 1H), 2.13 - 2.05 (m, 1H), 2.00 (dd, J = 12.5, 4.5 Hz, 1H), 1.96 - 1.87 (m, 2H), 1.75 (s, 6H), 1.68 - 1.60 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 702.6 [M+H] + .

[0456] Preparation of AJ92: AJ92 was prepared according to the preparation method of AJ90.

[0457]

[0458] 11H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.81 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 6.3 Hz, 1H), 8.00 (s, 1H), 7.60 (dd, J = 8.2, 1.4 Hz, 1H), 7.36 (d, J = 6.6 Hz, 1H), 6.85 (dd, J = 13.2, 8.0 Hz, 1H), 6.74 (dd, J = 14.4, 8.4 Hz, 1H), 5.50 (d, J = 8.4 Hz, 1H), 4.43 - 4.29 (m, 1H), 3.25 - 3.20 (m, 2H), 2.93 - 2.88 (m, 4H), 2.84 - 2.80 (m, 1H), 2.78 - 2.76 (m, 1H), 2.75 - 2.73 (m, 1H), 2.71 (d, J = 7.4 Hz, 2H), 2.69 - 2.65 (m, 4H), 2.59 - 2.54 (m, 1H), 2.44 - 2.37 (m, 1H), 2.10 - 2.01 (m, 2H), 1.96 - 1.88 (m, 2H), 1.75 (s, 6H), 1.70 - 1.59 (m, 2H), 1.29 (d, J = 7.4 Hz, 3H). LCMS(ESI) m / z 720.5 [M+H] + .

[0459] Preparation of AJ93:

[0460]

[0461] Preparation of AJ93-1: Dissolve AJ93-0 (1 g, 4 mmol) and NBS (1 g, 6 mmol) in 30 mL of CHCl3, slowly heat up to reflux under stirring, add AIBN (66 mg, 0.04 mmol), and continue the reflux reaction for 3 h. After detecting the completion of the reaction, add 20 mL of water to quench the reaction mixture and extract with 20 mL of CHCl3. Repeat the extraction three times until the extraction is complete. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product of pale yellow concentrate. The transparent oily product AJ93-1 (1.2 g, 90%) was obtained by column chromatography (PE / EA = 100 / 1 - 80 / 1).

[0462] Preparation of AJ93-2: Dissolve AJ93-1 (1.2 g, 3.6 mmol) and 3-amino-2,6-piperidinedione (770 mg, 6 mmol) in 15 mL of DMF. Add DIEA (900 mg, 7 mmol) under stirring at room temperature. Slowly heat the reaction system to 75 o °C and continue the reaction for 3 h. After detecting that the reaction is complete, add 20 mL of water to the reaction solution to quench it and add 30 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases, dry them with anhydrous sodium sulfate, and concentrate to obtain a crude black concentrate. Obtain white solid AJ93-2 (1.1 g, 91%) by column chromatography (DCM / MeOH = 100 / 1 - 50 / 1).

[0463] Preparation of AJ93-3: Under the condition of -78 o °C, dissolve AJ93-2 (260 mg, 0.77 mmol) in 15 mL of dry THF. Slowly dropwise add n-BuLi (1.5 mL, 1.5 mmol) under stirring and continue the reaction for 1 h. Then, keep the temperature at -78 o °C and introduce CO2 into the reaction system for about 30 minutes, and then slowly raise the temperature to room temperature. Detect that the reaction is complete by LCMS. Add 10 mL of saturated ammonium chloride solution to the reaction solution to quench it and add 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases, dry them with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude concentrate. Obtain white solid AJ93-3 (110 mg, 50%) by column chromatography (DCM / MeOH = 100 / 1 - 10 / 1).

[0464] Preparation of AJ93: Dissolve AJ93-3 (30 mg, 0.01 mmol) and AJ10a-2 (48 mg, 0.01 mmol) in 5 mL of DMF. Add TCFH (28 mg, 0.01 mmol) and NMI (16 mg, 0.02 mmol) under stirring at room temperature. Slowly raise the temperature of the reaction system to 80 o °C and react for 3 h. After detecting that the reaction is complete, add 10 mL of water to the reaction solution to quench it and add 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry and concentrate the organic phases with anhydrous sodium sulfate to obtain a crude product. Purify it by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 2) to obtain white solid AJ93 (24 mg, 32%). 11H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 10.99 (s, 1H), 8.31 (dd, J = 7.8, 3.3 Hz, 1H), 8.05 - 7.95 (m, 1H), 7.67 - 7.56 (m, 1H), 7.52 (d, J = 20.1 Hz, 1H), 7.33 (s, 1H), 7.21 (s, 1H), 6.77 (d, J = 89.0 Hz, 1H), 5.32 (dd, J = 13.2, 5.2 Hz, 1H), 4.73 (d, J = 17.7 Hz, 1H), 4.44 (d, J = 17.6 Hz, 1H), 3.88 - 3.55 (m, 2H), 3.25 - 3.21 (m, 2H), 3.18 - 3.15 (m, 2H), 3.11 - 2.99 (m, 2H), 2.97 - 2.92 (m, 1H), 2.88 - 2.84 (m, 2H), 2.82 - 2.79 (m, 1H), 2.76 - 2.72 (m, 1H), 2.72 (d, J = 7.5 Hz, 2H), 2.58 - 2.54 (m, 1H), 2.47 - 2.44 (m, 1H), 2.42 - 2.38 (m, 1H), 2.18 - 2.15 (m, 1H), 1.97 - 1.86 (m, 2H), 1.74 (s, 6H), 1.67 - 1.55 (m, 2H), 1.13 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 770.6 [M+H] + .

[0465] Preparation of AJ94: AJ94 was prepared according to the preparation method of AJ93.

[0466]

[0467] 11H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 11.02 (s, 1H), 8.31 (d, J =8.2 Hz, 1H), 8.03 (s, 1H), 8.00 (d, J = 1.3 Hz, 1H), 7.65 (dd, J = 7.5, 2.4Hz, 1H), 7.59 (td, J = 9.8, 9.0, 1.9 Hz, 2H), 7.33 (s, 1H), 5.15 (dd, J =13.2, 5.2 Hz, 1H), 4.42 (d, J = 17.7 Hz, 1H), 4.33 (d, J = 17.6 Hz, 1H),3.75-3.59 (m, 2H), 3.32-3.28 (m, 2H), 3.26-3.17 (m, 2H), 2.99-2.83 (m, 2H),2.83-2.79 (m, 1H), 2.76-2.73 (m, 1H), 2.72 (q, J = 7.5 Hz, 2H), 2.65-2.59 (m,2H), 2.59-2.53 (m, 2H), 2.49-2.45 (m, 1H), 2.45-2.41 (m, 1H), 2.05-1.97 (m,1H), 1.95-1.82 (m, 2H), 1.74 (s, 6H), 1.68-1.55 (m, 2H), 1.27 (t, J = 7.5 Hz,3H). LCMS(ESI) m / z 770.6 [M+H] + .

[0468] Preparation of AJ95: AJ95 was prepared according to the preparation method of AJ93.

[0469]

[0470] 11H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 11.02 (s, 1H), 8.34 - 8.29(m, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.68 (dd, J = 8.4, 4.5 Hz, 1H), 7.60(dd, J = 8.1, 1.4 Hz, 1H), 7.44 - 7.37 (m, 1H), 7.33 (s, 1H), 5.11 (dd, J =13.1, 5.1 Hz, 1H), 4.47 (d, J = 18.3 Hz, 1H), 4.37 (d, J = 18.2 Hz, 1H),3.71 - 3.62 (m, 2H), 3.31 - 3.27 (m, 2H), 3.27 - 3.17 (m, 2H), 2.98 - 2.84 (m, 2H),2.84 - 2.79 (m, 1H), 2.79 - 2.75 (m, 1H), 2.72 (q, J = 7.5 Hz, 2H), 2.67 - 2.59 (m,2H), 2.59 - 2.53 (m, 2H), 2.47 - 2.43 (m, 1H), 2.43 - 2.37 (m, 1H), 2.02 - 1.96 (m,1H), 1.94 - 1.83 (m, 2H), 1.75 (s, 6H), 1.70 - 1.59 (m, 2H), 1.27 (t, J = 7.5 Hz,3H). LCMS(ESI) m / z 770.6 [M+H] + .

[0471] Preparation of AJ96:

[0472]

[0473] Preparation of AJ96-1: Pyridine (2.1 g, 26.8 mmol) and 4-hydroxy-7-bromoquinoline (AJ96-0, 2 g, 8.9 mmol) were dissolved in 30 mL of DCM. Under an ice-salt bath and with stirring, Tf2O (3 g, 10.7 mmol) was slowly added dropwise and the reaction was continued with stirring for 1 h. After detecting the end of the reaction, 20 mL of water was added to the reaction solution to quench it, and 20 mL of DCM was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (PE / EA = 100 / 1 - 40 / 1) gave yellow solid AJ96-1 (2.28 g, 72%).

[0474] Preparation of AJ96-2: AJ96-1 (500 mg, 1.4 mmol) was dissolved in 15 mL of dioxane. Under stirring at room temperature, 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (400 mg, 1.7 mmol), Pd2(dba)3 (260 mg, 0.3 mmol), X-Phos (270 mg, 0.6 mmol) and Cs2CO3 (910 mg, 2.8 mmol) were successively added. The mixed system was heated to 80 °C under argon protection and stirred at this temperature for about 2 h. After detecting the completion of the reaction, the reaction system was cooled to room temperature and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (DCM / MeOH = 100 / 1 - 50 / 1) to obtain white solid AJ96-2 (610 mg, 99%).

[0475] Preparation of AJ96-3: AJ96-2 (330 mg, 0.76 mmol) was dissolved in 15 mL of THF solution. Under stirring at room temperature and under argon protection, Pd2(dba)3 (104 mg, 0.11 mmol), Q-Phos (81 mg, 0.11 mmol) and 2-tert-butoxy-2-carbonylethylzinc bromide (9 mL THF solution, 3.6 mmol) were successively added. The reaction system was slowly heated to 70 °C and stirred for 2 h. After the reaction was completed, 2 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. 10 mL of water and 10 mL of EA were added to the reaction solution for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (DCM / MeOH = 100 / 1 - 60 / 1) gave colorless transparent oily compound AJ96-3 (176 mg, 49%).

[0476] Preparation of AJ96-4: AJ96-3 (176 mg, 0.37 mmol) was dissolved in 5 mL of DCM. Under stirring at room temperature, 3 mL of TFA was added to the reaction system and stirred at room temperature for 30 minutes. LCMS detection showed that the raw material had disappeared and the reaction was complete. Excess TFA and DCM were removed by concentration under reduced pressure to obtain brown compound AJ96-4 (133 mg, 86%).

[0477] Preparation of AJ96-5: AJ96-4 (40 mg, 0.1 mmol) and AJ10a-2 (48 mg, 0.1 mmol) were dissolved in 5 mL of DMF. Under stirring at room temperature, DIEA (31 mg, 0.24 mmol) and HATU (38 mg, 0.1 mmol) were added to the system. After stirring at room temperature for 30 minutes, LCMS detection showed that the raw materials had disappeared and the reaction was completed. 10 mL of water was slowly added to the reaction solution under stirring, and a white solid precipitate was formed. The precipitate was filtered by suction to obtain a filter cake, and the filter cake was dried to obtain a white solid AJ96-5 (81 mg, 96%).

[0478] Preparation of AJ96: 1 mL of TFA and 1 mL of TfOH were added to AJ96-5 (40 mg, 0.05 mmol). The temperature was slowly raised to 40 °C under stirring and the reaction was continued for 2 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. Under an ice bath, ice water was added to the reaction solution for quenching and the pH of the reaction solution was adjusted to 7-8 with saturated aqueous NaHCO3 solution. A white solid precipitate was formed, filtered by suction, and the filter cake was dried to obtain a crude product. A white solid AJ96 (15 mg, 43%) was obtained by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 2). 1HNMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.62 (s, 1H), 8.94 (d, J = 4.6 Hz,1H), 8.32 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 13.8 Hz, 2H), 7.95 (d, J = 8.6Hz, 1H), 7.94 - 7.90 (m, 1H), 7.61 (dd, J = 8.2, 1.4 Hz, 1H), 7.54 - 7.47 (m,2H), 7.33 (s, 1H), 4.08 - 4.01 (m, 1H), 4.00 (s, 2H), 3.72 - 3.67 (m, 1H), 3.62 - 3.55 (m, 2H), 3.55 - 3.46 (m, 2H), 3.27 - 3.17 (m, 2H), 3.06 - 2.97 (m, 1H), 2.79 - 2.78 (m, 1H), 2.76 - 2.72 (m, 2H), 2.71 (d, J = 7.5 Hz, 2H), 2.68 - 2.65 (m, 1H),2.57 - 2.53 (m, 3H), 2.45 - 2.38 (m, 1H), 1.91 - 1.85 (m, 2H), 1.75 (s, 6H), 1.64 - 1.58 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). Molecular formula: C 45 H 46 N8O4, Measured value: 763.5 [M+H] + .

[0479] Preparation of AJ97: AJ97 was prepared according to the preparation method of AJ96.

[0480]

[0481] 11H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.62 (s, 1H), 8.94 (d, J = 4.7 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.04 (s, 1H), 8.01 (d, J = 1.2 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.54 - 7.49 (m, 2H), 7.36 (s, 1H), 4.44 (d, J = 12.8 Hz, 1H), 4.14 - 4.02 (m, 2H), 4.01 (s, 2H), 3.73 - 3.66 (m, 1H), 3.12 - 3.05 (m, 1H), 3.05 - 3.00 (m, 1H), 2.99 - 2.94 (m, 4H), 2.78 - 2.73 (m, 1H), 2.72 (d, J = 7.5 Hz, 2H), 2.68 - 2.63 (m, 4H), 2.62 - 2.60 (m, 1H), 2.56 - 2.53 (m, 1H), 1.85 - 1.79 (m, 2H), 1.75 (s, 6H), 1.37 - 1.29 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 763.5 [M+H] + .

[0482] Preparation of AJ98:

[0483]

[0484] Preparation of AJ98-1: AJ67-2 (200 mg, 0.63 mmol) and N-Boc-piperazine (117 mg, 0.63 mmol) were dissolved in 10 mL of dioxane solution. The mixture was stirred at room temperature and RuPhos (29 mg, 0.06 mmol), RuPhosPdG2 (196 mg, 0.25 mmol) and t-BuOK (106 mg, 0.94 mmol) were added under argon protection. The reaction solution was slowly heated to 100 °C and stirred for 4 h. After the reaction was completed, 10 mL of water was added to the reaction solution to quench it, and 15 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (DCM / MeOH = 100 / 1 - 60 / 1) gave white solid AJ98-1 (163 mg, 61%).

[0485] Preparation of AJ98-2: AJ98-1 (163 mg, 0.38 mmol) was dissolved in 5 mL of DCM. 3 mL of TFA was added dropwise to the reaction system under stirring at room temperature, and the reaction was continued for 1 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. Excess TFA and DCM were removed by concentration under reduced pressure to obtain white compound AJ98-2 (110 mg, 88%).

[0486] Preparation of AJ98: AJ98-2 (20 mg, 0.06 mmol) and AJ12-6 (25 mg, 0.06 mmol) were dissolved in a mixed solvent of 5 mL of THF and 1 mL of DMF. After stirring at room temperature for 1 h, AcOH (11 mg, 0.19 mmol) and NaHB(OAc)3 (26 mg, 0.12 mmol) were added dropwise, and the reaction was continued for 2 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 5 mL of saturated NaHCO3 aqueous solution was added to the reaction solution to quench the reaction, and 10 mL of DCM / MeOH (10:1) was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (DCM / MeOH = 100 / 1 - 20 / 1) gave white solid AJ98 (12 mg, 26%). 11H NMR (400 MHz, DMSO-d6) δ12.71 (s, 1H), 10.42 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 8.00(d, J = 1.2 Hz, 1H), 7.79-7.70 (m, 2H), 7.64-7.57 (m, 1H), 7.43 (t, J = 7.9Hz, 2H), 7.36 (s, 1H), 7.25 (d, J = 6.8 Hz, 2H), 3.91-3.83 (m, 1H), 3.67-3.60(m, 1H), 3.29-3.19 (m, 4H), 3.01-2.88 (m, 1H), 2.87-2.79 (m, 2H), 2.79-2.77(m, 2H), 2.76-2.75 (m, 2H), 2.74-2.72 (m, 2H), 2.71 (d, J = 7.5 Hz, 2H),2.69-2.62 (m, 1H), 2.46-2.41 (m, 1H), 1.99-1.92 (m, 2H), 1.76 (s, 6H), 1.72-1.61 (m, 2H), 1.29 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 720.4 [M+H] + .

[0487] Preparation of AJ98b:

[0488]

[0489] Preparation of AJ98b-1: AJ67-2 (200 mg, 0.63 mmol) and 4-piperidone ethylene glycol ketal (90 mg, 0.63 mmol) were dissolved in 15 mL of dioxane. The mixture was stirred at room temperature and under argon protection, and RuPhos (29 mg, 0.06 mmol), RuPhosPdG2 (196 mg, 0.25 mmol) and t-BuOK (106 mg, 0.94 mmol) were added successively. The temperature was slowly raised to 100 °C and the reaction was carried out for 4 h. After the reaction was completed, 10 mL of water was added to quench the reaction, and 15 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (DCM / MeOH = 100 / 1 - 80 / 1) gave white solid AJ98b-1 (110 mg, 46%).

[0490] Preparation of AJ98b-2: AJ98b-1 (110 mg, 0.29 mmol) was dissolved in 10 mL of THF. While stirring at room temperature, 5 mL of hydrochloric acid solution (6 M) was added dropwise to the reaction system, and the temperature was slowly raised to 50 °C and stirred for 40 minutes. LCMS detection showed that the raw material had disappeared and the reaction was completed. Under an ice bath, ice water was added to the reaction solution to quench it, and the pH of the reaction solution was adjusted to 7 - 8 with saturated aqueous NaHCO3 solution. 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (DCM / MeOH = 100 / 1 - 60 / 1) gave a pale yellow solid AJ98b-2 (50 mg, 51%).

[0491] Preparation of AJ98b: AJ98b-2 (30 mg, 0.09 mmol) and AJ12b-6 (35 mg, 0.09 mmol) were dissolved in a mixed solvent of 5 mL of THF and 1 mL of DMF. After stirring at room temperature for 1 h, AcOH (16 mg, 0.27 mmol) and NaHB(OAc)3 (38 mg, 0.18 mmol) were added and stirring was continued for 2 h. LCMS detection showed that the raw material had disappeared and the reaction was completed. 2 mL of saturated aqueous NaHCO3 solution was added to the reaction solution to quench the reaction, then 5 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (DCM / MeOH = 100 / 1 - 30 / 1) gave a white solid AJ98b (3 mg, 5%). 11H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 10.43 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.73 (t, J = 9.2 Hz, 2H), 7.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.38 (s, 1H), 7.28 (s, 1H), 7.24 (d, J = 7.3 Hz, 1H), 3.95 - 3.89 (m, 2H), 3.88 - 3.80 (m, 1H), 3.67 - 3.60 (m, 1H), 3.04 - 2.97 (m, 4H), 2.95 - 2.89 (m, 1H), 2.87 - 2.78 (m, 2H), 2.78 - 2.74 (m, 2H), 2.74 - 2.72 (m, 2H), 2.68 (d, J = 7.5 Hz, 2H) 2.66 - 2.62 (m, 1H), 2.58 - 2.52 (m, 1H), 2.01 - 1.91 (m, 2H), 1.75 (s, 6H), 1.67 - 1.65 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 720.4 [M+H] + .

[0492] Preparation of AJ106:

[0493]

[0494] Preparation of AJ106 - 1: AJ106 - 0 (800 mg, 4 mmol) was dissolved in 10 mL of THF. Under stirring at room temperature, 3 - bromopiperidine - 2,6 - dione (940 mg, 4.9 mmol) and t - BuOK (910 mg, 8 mmol) were added successively. The reaction system was slowly heated to 70 o °C and reacted for 4 h. After the reaction was completed, it was cooled to room temperature and the pH was adjusted to 7 with dilute hydrochloric acid (1 M). 10 mL of water and 10 mL of EA were added to the reaction solution for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and back - washed with saturated brine. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Through reverse - phase preparation (water / MeCN), white solid AJ106 - 1 (350 mg, 28%) was obtained.

[0495] Preparation of AJ106-2: Dissolve AJ106-1 (350 mg, 1.1 mmol) in 10 mL of ultra-dry THF solvent, stir at room temperature and successively add Pd2(dba)3 (104 mg, 0.1 mmol), Q-Phos (120 mg, 0.17 mmol), 2-tert-butoxy-2-carbonylethylzinc bromide (0.5 M THF solution, 9.7 mL, 1.7 mmol) under argon protection. Slowly heat the reaction system to 70 o C and stir the reaction for 2 h. After the reaction is completed, cool to room temperature and quench the reaction solution by adding saturated ammonium chloride solution. Extract with EA, collect the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to remove the solvent, and purify the residue by column chromatography (DCM / MeOH = 100 / 1 - 50 / 1) to obtain a white solid AJ106-2 (120 mg, 31%).

[0496] Preparation of AJ106-3: Dissolve AJ106-2 (120 mg, 0.35 mmol) in a mixed solution of 10 mL of DCM and 2 mL of TFA. Stir the resulting solution at room temperature for 2 h, concentrate under reduced pressure to remove the solvent, and purify by reverse-phase preparation (water / MeCN = 100 / 1 - 3 / 1) to obtain a white solid AJ106-3 (90 mg, 90%).

[0497] Preparation of AJ106: Dissolve AJ106-3 (15 mg, 0.05 mmol) and AJ10a-2 (15 mg, 0.05 mmol) in 5 mL of DMF. Add DIEA (13 mg, 0.1 mmol) and HATU (22 mg, 0.06 mmol) under stirring at room temperature. Continue to stir the reaction at room temperature for about 30 minutes, then quench the reaction solution by adding 6 mL of water and extract with 6 mL of EA. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude yellowish concentrate. Purify by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 2) to obtain a white solid AJ106 (20 mg, 51%). 11H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 11.21 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.63 - 7.53 (m, 2H), 7.49 - 7.39 (m, 1H), 7.32 (s, 1H), 7.12 (dd, J = 14.7, 8.4 Hz, 1H), 5.69 (dd, J = 12.5, 5.5 Hz, 1H), 3.82 (s, 2H), 3.57 - 3.45 (m, 4H), 3.22 - 3.19 (m, 2H), 2.96 - 2.88 (m, 1H), 2.86 - 2.80 (m, 1H), 2.78 - 2.76 (m, 1H), 2.75 - 2.71 (m, 2H), 2.70 (d, J = 7.5 Hz, 2H), 2.68 - 2.66 (m, 1H), 2.56 - 2.52 (m, 1H), 2.46 - 2.39 (m, 2H), 2.39 - 2.34 (m, 1H), 2.26 - 2.19 (m, 1H), 1.88 - 1.81 (m, 2H), 1.74 (s, 6H), 1.64 - 1.54 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 751.5 [M+H] + .

[0498] Preparation of AJ106b: AJ106b was prepared according to the preparation method of compound AJ106.

[0499]

[0500] 11H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 11.21 (s, 1H), 8.32 (d, J =8.2 Hz, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.65-7.61 (m, 1H),7.61-7.53 (m, 1H), 7.41 (s, 1H), 7.35 (d, J = 2.7 Hz, 1H), 7.13 (dd, J =13.4, 8.2 Hz, 1H), 5.74-5.64 (m, 1H), 4.43 (d, J = 12.3 Hz, 1H), 4.09-4.00(m, 1H), 3.83 (s, 2H), 3.08-2.87 (m, 6H), 2.86-2.78 (m, 1H), 2.78-2.72 (m,1H), 2.72 (d, J = 7.5 Hz, 2H), 2.67-2.58 (m, 4H), 2.58-2.53 (m, 1H), 2.47-2.44 (m, 1H), 2.27-2.17 (m, 1H), 1.86-1.78 (m, 2H), 1.74 (s, 6H), 1.71-1.64(m, 2H), 1.26 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 751.5 [M+H] + .

[0501] Preparation of AJ110:

[0502]

[0503] Preparation of AJ110-1: AJ110-0 (1 g, 4.7 mmol) was dissolved in 15 mL of DMF. Acrylamide (1 g, 14 mmol) and Cs2CO3 (2.3 g, 7 mmol) were added under stirring at room temperature. The reaction system was slowly heated to 100 °C and stirred for 8 h. After detecting the completion of the reaction, it was cooled to room temperature. 15 mL of water and 15 mL of DCM / MeOH (10:1) were added to the reaction solution for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. White solid AJ110-1 (355 mg, 27%) was obtained by column chromatography (DCM / MeOH = 100 / 1 - 30 / 1).

[0504] Preparation of AJ110-2: AJ110-1 (355 mg, 1.2 mmol) was dissolved in 10 mL of MeCN. CDI (310 mg, 1.9 mmol) was added under stirring at room temperature. The reaction system was heated to 85 °C and stirred for 2 h. After detecting the completion of the reaction, it was cooled to room temperature. 10 mL of water and 15 mL of EA were added to the reaction solution for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (PE / EA = 100 / 1 - 2 / 1) gave white solid AJ110-2 (200 mg, 52%).

[0505] Preparation of AJ110-3: AJ110-2 (200 mg, 0.65 mmol) was dissolved in 10 mL of ultra-dry THF solution. Pd2(dba)3 (89 mg, 0.1 mmol) and Q-Phos (69 mg, 0.1 mmol) were added under stirring at room temperature under argon protection. 2-tert-butoxy-2-carbonylethylzinc bromide (4 mL of THF solution, 2.4 mmol) was added. The reaction system was heated to 70 °C and stirred for 2 h. After detecting the completion of the reaction, it was cooled to room temperature and 5 mL of saturated ammonium chloride solution was added to the reaction solution for quenching. Then 10 mL of water and 10 mL of EA were added to the reaction solution for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (DCM / MeOH = 100 / 1 - 80 / 1) gave white solid AJ110-3 (214 mg, 96%).

[0506] Preparation of AJ110-4: AJ110-3 (214 mg, 0.62 mmol) was dissolved in 10 mL of DCM. 2 mL of TFA was added dropwise to the reaction system under stirring at room temperature, and stirring was continued at room temperature for 1 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. Excess TFA and DCM were removed by concentration under reduced pressure to obtain yellow solid AJ110-4 (164 mg, 91%).

[0507] Preparation of AJ110: AJ110-4 (25 mg, 0.09 mmol) and AJ10-2 (46 mg, 0.1 mmol) were dissolved in 8 mL of DMF. Under stirring at room temperature, DIEA (28 mg, 0.22 mmol) and HATU (33 mg, 0.09 mmol) were added dropwise to the system, and the reaction was stirred at room temperature for 30 minutes. LCMS detection showed that the raw materials had disappeared and the reaction was complete. 10 mL of water was slowly added to the reaction solution under stirring, and a white solid was precipitated. The filter cake was obtained by vacuum filtration and purified by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 2) to obtain a white solid AJ110 (40 mg, 62%). 1 H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 10.91 (s,1H), 8.31 (d, J = 8.1 Hz, 1H), 8.03 (s, 1H), 8.00 (d, J = 1.1 Hz, 1H), 7.76(d, J = 8.3 Hz, 1H), 7.60 (dd, J = 8.2, 1.4 Hz, 1H), 7.57 (s, 1H), 7.33 (s,1H), 7.24 (dd, J = 8.5, 1.3 Hz, 1H), 4.07 (t, J = 6.6 Hz, 2H), 3.92 (s, 2H),3.61 - 3.52 (m, 2H), 3.52 - 3.46 (m, 2H), 3.21 (d, J = 11.1 Hz, 2H), 2.83 - 2.78(m, 2H), 2.78 - 2.74 (m, 2H), 2.72 (d, J = 7.5 Hz, 2H), 2.68 - 2.65 (m, 1H),2.56 - 2.55 (m, 2H), 2.47 - 2.42 (m, 1H), 2.42 - 2.33 (m, 1H), 1.91 - 1.83 (m, 2H),1.74 (s, 6H), 1.63 - 1.59 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z753.4 [M+H] + .

[0508] Preparation of AJ110b: AJ110b was prepared according to the preparation method of AJ110.

[0509]

[0510] 11H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 10.91 (s, 1H), 8.31 (d, J =8.2 Hz, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.61 (dd,J = 8.1, 1.4 Hz, 1H), 7.57 (s, 1H), 7.36 (s, 1H), 7.28-7.21 (m, 1H), 4.41 (d,J = 12.5 Hz, 1H), 4.07 (t, J = 6.5 Hz, 2H), 4.05-3.98 (m, 1H), 3.93 (s, 2H),3.09-3.01 (m, 1H), 3.01-2.90 (m, 4H), 2.79 (t, J = 6.6 Hz, 2H), 2.71 (d, J =7.4 Hz, 2H), 2.69-2.62 (m, 4H), 2.62-2.59 (m, 1H), 2.56-2.54 (m, 1H), 1.86-1.78 (m, 2H), 1.75 (s, 6H), 1.34-1.27 (m, 2H), 1.25 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 753.4 [M+H] + .

[0511] Preparation of AJ112:

[0512]

[0513] Preparation of AJ112-1: Dissolve AJ112-0 (1 g, 5 mmol) in 15 mL of DMF. Add NIS (1.4 g, 6 mmol) under stirring at room temperature, and then heat the mixture to 100 °C and stir for 2 h. After detecting that the reaction is complete, cool it to room temperature. Slowly add 15 mL of water to the reaction solution under stirring. A white solid precipitates from the reaction solution. Filter the precipitate under reduced pressure to obtain a filter cake. After drying, a dark green solid AJ112-1 (1.6 g, 98%) is obtained.

[0514] Preparation of AJ112-2: N,N ’-Dimethylethane-1,2-diamine (60 mg, 0.7 mmol) was dissolved in 10 mL of DMF. The reaction solution was stirred at room temperature and CuI (260 mg, 1.4 mmol), AJ112-1 (660 mg, 2 mmol), 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (420 mg, 1.8 mmol) and Cs2CO3 (1.6 g, 5 mmol) were successively added to the reaction solution under argon protection. The reaction system was heated to 100 °C and stirred for 3 h. After detecting the completion of the reaction, the reaction solution was cooled to room temperature, 10 mL of water was added to quench the reaction, and 15 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The pale yellow solid AJ112-2 (264 mg, 30%) was obtained by column chromatography (DCM / MeOH = 100 / 1 - 30 / 1).

[0515] Preparation of AJ112-3: AJ112-2 (264 mg, 0.6 mmol) was dissolved in 10 mL of ultra-dry THF solution. The reaction solution was stirred at room temperature and Pd2(dba)3 (85 mg, 0.09 mmol), Q-Phos (66 mg, 0.09 mmol), 2-tert-butoxy-2-carbonylethylzinc bromide (5 mL THF solution, 3 mmol) were successively added under argon protection. The reaction system was slowly heated to 70 °C and stirred for 1 h. After detecting the completion of the reaction, it was cooled to room temperature and 5 mL of saturated ammonium chloride solution was added to quench the reaction. Then 10 mL of water and 10 mL of EA were added to the reaction solution for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The colorless transparent oily compound AJ112-3 (167 mg, 58%) was obtained by column chromatography (DCM / MeOH = 100 / 1 - 40 / 1).

[0516] Preparation of AJ112-4: AJ112-3 (167 mg, 0.36 mmol) was dissolved in 5 mL of DCM. 2 mL of TFA was added dropwise to the reaction system under stirring at room temperature, and stirring was continued at room temperature for 1 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. Excess TFA and DCM were removed by concentration under reduced pressure to obtain the white compound AJ112-4 (120 mg, 82%).

[0517] Preparation of AJ112-5: AJ112-4 (25 mg, 0.06 mmol) and AJ10a-2 (32 mg, 0.07 mmol) were dissolved in 5 mL of DMF. Under stirring at room temperature, DIEA (20 mg, 0.15 mmol) and HATU (23 mg, 0.06 mmol) were added to the system, and the reaction was continued to stir for 30 minutes at room temperature. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 10 mL of water was slowly added to the reaction solution under stirring, and a white solid precipitated from the reaction solution. The filter cake was obtained by suction filtration under reduced pressure, and the filter cake was dried to obtain a white solid AJ112-5 (50 mg, 94%).

[0518] Preparation of AJ112: AJ112-5 (50 mg, 0.06 mmol) was added to a mixed solution of 1 mL of TFA and 1 mL of TfOH, and the temperature was raised to 40 °C and stirred for 2 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed and cooled to room temperature. Under an ice bath, ice water was added to the reaction solution to quench the reaction and the pH of the reaction solution was adjusted to 7-8 with saturated NaHCO3 aqueous solution, and suction filtration was carried out. The filter cake was dried to obtain the crude product. Purification by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 2) gave a white solid AJ112 (15 mg, 35%). 11H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 10.68 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H), 8.23 (d, J = 6.9 Hz, 1H), 8.03 (s, 1H), 8.00 (d, J = 1.3 Hz, 1H), 7.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.51 (s, 1H), 7.42 (s, 1H), 7.33 (s, 1H), 6.83 (dd, J = 6.8, 1.5 Hz, 1H), 3.85 - 3.74 (m, 4H), 3.62 - 3.53 (m, 2H), 3.53 - 3.44 (m, 2H), 3.26 - 3.18 (m, 2H), 2.88 - 2.80 (m, 2H), 2.81 - 2.74 (m, 2H), 2.72 (d, J = 7.5 Hz, 2H), 2.67 - 2.62 (m, 1H), 2.59 - 2.53 (m, 2H), 2.47 - 2.35 (m, 2H), 1.92 - 1.84 (m, 2H), 1.74 (s, 6H), 1.69 - 1.58 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 752.4 [M+H] + .

[0519] Preparation of AJ112b: AJ112b was prepared according to the preparation method of AJ112.

[0520]

[0521] 11H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 10.68 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.23 (d, J = 7.0 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.51 (s, 1H), 7.42 (s, 1H), 7.36 (s, 1H), 6.83 (dd, J = 7.1, 1.6 Hz, 1H), 4.45 - 4.37 (m, 1H), 4.10 - 4.02 (m, 1H), 3.83 (s, 2H), 3.79 (t, J = 6.7 Hz, 2H), 3.11 - 3.03 (m, 1H), 3.02 - 2.92 (m, 4H), 2.87 - 2.76 (m, 2H), 2.72 (d, J = 7.5 Hz, 2H), 2.71 - 2.65 (m, 4H), 2.65 - 2.62 (m, 1H), 2.55 - 2.52 (m, 1H), 1.89 - 1.79 (m, 2H), 1.75 (s, 6H), 1.42 - 1.29 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 752.4 [M+H] + .

[0522] Preparation of AJ113:

[0523]

[0524] Preparation of AJ113-1: Dissolve 7-bromo-[1,2,4]triazolo[4,3-a]pyridine (AJ113-0, 600 mg, 3 mmol) in 20 mL of CHCl3, and then add NIS (1 g, 4.5 mmol) to the reaction solution under stirring at room temperature. Heat the reaction system to 60 o °C and react for 1 h. LCMS detection shows that the raw material is completely consumed. Concentrate under reduced pressure to remove the solvent to obtain a light red solid concentrated crude product, and obtain a red solid AJ113-1 (825 mg, 84%) by column chromatography (EA / PE = 1 / 100 - 1 / 10).

[0525] Preparation of AJ113-2: Suspend CuI (35 mg, 1.8 mmol) in 15 mL of DMF, and successively add N,N ’-Dimethylethane-1,2-diamine (16 mg, 1.8 mmol), K2CO3 (256 mg, 1.8 mmol), 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (240 mg, 1 mmol) and AJ113-1 (300 mg, 0.9 mmol). After the mixed system was purged with argon, it was heated to 100 o °C and stirred at this condition for about 1 h. LCMS detection showed that the reaction of AJ113-1 was complete. It was cooled to room temperature and 15 mL of water and 15 mL of EA were added to the reaction solution for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude yellowish-brown concentrate. Column chromatography (EA / PE = 1 / 100 - 1 / 1) gave a brown solid AJ113-2 (240 mg, 60%).

[0526] Preparation of AJ113-3: AJ113-2 (240 mg, 0.56 mmol) was dissolved in 15 mL of ultradry THF. It was stirred at room temperature and Pd2(dba)3 (51 mg, 0.06 mmol), Q-Phos (39 mg, 0.06 mmol), and 2-tert-butoxy-2-carbonylethylzinc bromide (71 mg, 0.28 mmol) were successively added under argon protection. The reaction system was slowly heated to 70 °C and stirred for 2 h. After the reaction was completed, it was cooled to room temperature and 5 mL of saturated ammonium chloride solution was added to the reaction solution for quenching. It was extracted three times with 20 mL of EA until the extraction was complete. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (MeOH / DCM = 1 / 100 - 1 / 80) to obtain the target product AJ113-3, a white solid (130 mg, 50%).

[0527] Preparation of AJ113-4: AJ113-3 (130 mg, 0.28 mmol) was dissolved in 5 mL of DCM solution. 2 mL of TFA was added to the reaction solution under stirring at room temperature and the reaction continued for 1 h. LCMS detection showed that the reaction of AJ113-3 was complete. The reaction solution was concentrated under reduced pressure to dryness to obtain a light red solid AJ113-4 (85 mg, 75%).

[0528] Preparation of AJ113-5: Dissolve AJ113-4 (20 mg, 0.05 mmol) in 8 mL of DMF. Under stirring at room temperature, sequentially add AJ10a-2 (24 mg, 0.05 mmol), DIEA (18 mg, 0.14 mmol) and HATU (20 mg, 0.05 mmol) to the reaction solution, and react for about 30 minutes under stirring at room temperature. LCMS detection shows that the reaction of AJ113-4 is complete. Add 10 mL of water to the reaction solution, and a solid precipitate appears. Filter the solid by suction and dry the filter cake to obtain a brown crude product. The white solid AJ113-5 (30 mg, 72%) is obtained by column chromatography (DCM / MeOH = 100 / 1 - 20 / 1).

[0529] Preparation of AJ113: Dissolve AJ113-5 (30 mg, 0.034 mmol) in 1 mL of TFA solution. Add 1 mL of TfOH under stirring at room temperature, and then heat the reaction mixture to 40 o C and stir for 2 h. LCMS detection shows that the reaction of AJ113-5 is complete. Then cool to room temperature and adjust the pH of the reaction solution to neutral with saturated aqueous NaHCO3 solution. Add 10 mL of water and 10 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry and concentrate the organic phases with anhydrous sodium sulfate to obtain a light brown crude concentrate. The white solid AJ113 (10 mg, 40%) is obtained by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 1). 11H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 10.91(s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.25 (s, 1 H), 8.06 (s, 1H), 8.02 (s, 1H),7.61 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.37 (s, 1H), 6.87 (d, J = 6.9 Hz,1H), 4.05-4.0 (m, 2H), 3.99-3.92 (m, 2H), 3.86 (s, 2H), 3.67-3.59 (m, 2H),3.55-3.48 (m, 2H), 2.93-2..89 (m, 1H), 2.86-2.77 (m, 3H), 2.73-2.70 (m, 2H),2.67-2.65 (m, 1H), 2.60-2.57 (m, 2H), 2.46-2.37 (m, 2H), 1.94-1.85 (m, 2H),1.85-1.62 (m, 6H), 1.56-1.53 (m, 2H), 1.17 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z753.5 [M+H] + .

[0530] Preparation of AJ113b: AJ113b was prepared according to the preparation method of AJ113.

[0531]

[0532] 11H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 10.90 (s, 1H), 8.31 (d, J =8.1 Hz, 1H), 8.23 (d, J = 7.0 Hz, 1H), 8.04 (s, 1H), 8.01 (s, 1H), 7.62 (s,1H), 7.60 - 7.58 (m, 1H), 7.37 (s, 1H), 6.88 (d, J = 7.5 Hz, 1H), 4.43 - 4.38 (m,1H), 4.09 - 4.03 (m, 1H), 3.97 (t, J = 6.6 Hz, 2H), 3.88 (s, 2H), 3.13 - 3.06 (m,1H), 3.05 - 2.90 (m, 4H), 2.84 - 2.80 (m, 2H), 2.77 - 2.73 (m, 1H), 2.73 - 2.63 (m,4H), 2.63 - 2.59 (m, 1H), 2.57 - 2.54 (m, 2H), 1.89 - 1.79 (m, 2H), 1.75 (s, 6H),1.40 - 1.33 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 753.5 [M+H] + .

[0533] Preparation of AJ114:

[0534]

[0535] Preparation of AJ114-1: AJ114-0 (1 g, 5 mmol) was dissolved in 15 mL of MeCN, and NIS (1.3 g, 6 mmol) was added under stirring at room temperature. Stirring was continued at room temperature for 2 h. After the reaction was detected to be complete, it was concentrated under reduced pressure and purified by column chromatography (PE / EA = 100 / 1 - 10 / 1) to obtain white solid AJ114-1 (1.18 g, 72%).

[0536] Preparation of AJ114-2: Suspend CuI (197 mg, 1 mmol) in 15 mL of dioxane. Under stirring at room temperature, add N,N'-dimethyl ethane-1,2-diamine (46 mg, 0.5 mmol) to the reaction solution. After stirring for 10 minutes under argon protection, successively add AJ114-1 (500 mg, 1.6 mmol), 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (310 mg, 1.3 mmol), and Cs2CO3 (1.3 g, 3.9 mmol). Heat the reaction mixture to 100 °C and stir for 3 h. After detecting the completion of the reaction, cool the reaction solution to room temperature, add 10 mL of water to quench the reaction and then add 15 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify it by column chromatography (PE / EA = 100 / 1 - 2 / 1) to obtain a pale yellow solid AJ114-2 (440 mg, 66%).

[0537] Preparation of AJ114-3: Dissolve AJ114-2 (300 mg, 0.7 mmol) in 10 mL of ultra-dry THF solution. Stir at room temperature and add Pd2(dba)3 (96 mg, 0.11 mmol) and Q-Phos (75 mg, 0.11 mmol) under argon protection. Then add 2-tert-butoxy-2-carbonylethylzinc bromide (6 mL, 3.6 mmol). Slowly heat the reaction system to 70 °C and stir for 2 h. After the reaction is completed, add 2 mL of saturated ammonium chloride solution to quench the reaction. Then add 10 mL of water and 10 mL of EA to the reaction solution for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Obtain a white solid AJ114-3 (300 mg, 92%) by column chromatography (DCM / MeOH = 100 / 1 - 60 / 1).

[0538] Preparation of AJ114-4: Dissolve AJ114-3 (300 mg, 0.65 mmol) in 5 mL of DCM. Dropwise add 2 mL of TFA to the reaction system under stirring at room temperature and stir for 1 h. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Concentrate under reduced pressure to remove the excess TFA and DCM to obtain a white compound AJ114-4 (240 mg, 91%).

[0539] Preparation of AJ114-5: AJ114-4 (20 mg, 0.05 mmol) and AJ10a-2 (21 mg, 0.04 mmol) were dissolved in 8 mL of DMF. Under stirring at room temperature, DIEA (14 mg, 0.11 mmol) and HATU (18 mg, 0.05 mmol) were added to the system, and the reaction was stirred at room temperature for 30 minutes. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 10 mL of water was slowly added to the reaction solution under stirring, and a white solid precipitated from the reaction solution. The reaction solution was filtered under reduced pressure and the filter cake was dried to obtain the crude product, which was purified by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 2) to obtain a white solid AJ114-5 (35 mg, 82%).

[0540] Preparation of AJ114: AJ114-5 (35 mg, 0.04 mmol) was dissolved in a mixed solution of 1 mL of TFA and 1 mL of TfOH. The temperature was raised to 40 °C under stirring and the reaction was continued for 2 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. Under an ice bath, ice water was added to the reaction solution for quenching and the pH of the reaction solution was adjusted to 7 - 8 with saturated aqueous NaHCO3 solution. The mixture was filtered, and the filter cake was dried to obtain the crude product. The yellow solid AJ114 (10 mg, 33%) was obtained through reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 1). 1 H NMR(400 MHz, DMSO-d6) δ 12.72 (s, 1H), 10.46 (s, 1H), 8.52 (s, 1H), 8.32 (d, J =8.1 Hz, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.99 (s, 1H), 7.63-7.57 (m, 1H),7.53 (d, J = 9.1 Hz, 1H), 7.34 (s, 1H), 7.14-7.07 (m, 1H), 3.83-3.73 (m, 4H),3.62-3.57 (m, 2H), 3.54-3.46 (m, 2H), 3.27-3.16 (m, 2H), 2.83-2.74 (m, 4H),2.72 (d, J = 7.5 Hz, 2H), 2.67-2.64 (m, 1H), 2.62-2.54 (m, 2H), 2.48-2.38 (m,2H), 1.92-1.85 (m, 2H), 1.75 (s, 6H), 1.64-1.60 (m, 2H), 1.27 (t, J = 7.5 Hz,3H). LCMS(ESI) m / z 752.5 [M+H] + .

[0541] Preparation of AJ114b: AJ114b was prepared according to the preparation method of AJ114.

[0542]

[0543] 1 H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 10.45 (s, 1H), 8.53 (s,1H), 8.32 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.01 (d, J = 1.2 Hz, 1H), 7.99(s, 1H), 7.61 (dd, J = 8.2, 1.4 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.36 (s, 1H),7.11 (dd, J = 9.2, 1.4 Hz, 1H), 4.42 - 4.39 (m, 1H), 4.11 - 4.07 (m, 1H), 3.81 - 3.74 (m, 4H), 3.12 - 3.05 (m, 1H), 3.02 - 2.95 (m, 4H), 2.79 - 2.75 (m, 2H), 2.72(d, J = 7.5 Hz, 2H), 2.71 - 2.66 (m, 1H), 2.65 - 2.60 (m, 1H), 2.56 - 2.53 (m, 1H),1.88 - 1.79 (m, 2H), 1.75 (s, 6H), 1.44 - 1.32 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H).LCMS(ESI) m / z 752.5 [M+H] + .

[0544] Preparation of AJ115:

[0545]

[0546] Preparation of AJ115 - 1: 2 - Nitro - 4 - chloro - 5 - bromophenol (AJ115 - 0, 2 g, 8 mmol) was dissolved in 30 mL of THF solution. Under stirring at room temperature, catalyst Pd / C (with a content of 10%, 200 mg) was added. The reaction was placed under hydrogen conditions and stirred at room temperature for 2 h. After detecting the end of the reaction, the reaction solution was filtered under reduced pressure to remove the catalyst, and the obtained filtrate was concentrated under reduced pressure to obtain white solid AJ115 - 1 (1.36 g, 77%).

[0547] Preparation of AJ115-2: AJ115-1 (1.36 g, 6 mmol) was dissolved in 15 mL of MeCN solution. CDI (2 g, 12 mmol) was added under stirring at room temperature. The reaction system was heated to 85 °C and stirred for 2 h. After the reaction was complete, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA = 100 / 1 - 4 / 1) to obtain yellow solid AJ115-2 (1.2 g, 79%).

[0548] Preparation of AJ115-3: AJ115-2 (350 mg, 1.4 mmol) and 3-bromopiperidine-2,6-dione (400 mg, 2 mmol) were dissolved in 10 mL of DMF. K2CO3 (480 mg, 3.5 mmol) was added to the system under stirring at room temperature, and then the temperature was raised to 100 °C and stirred for 2 h. After detecting the reaction was complete, it was cooled to room temperature. 10 mL of water was added to the reaction solution, and 15 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. It was purified by column chromatography (DCM / MeOH = 100 / 1 - 80 / 1) to obtain white solid AJ115-3 (210 mg, 41%).

[0549] Preparation of AJ115-4: AJ115-3 (210 mg, 0.6 mmol) was dissolved in 10 mL of ultra-dry THF solution. Under stirring at room temperature and under argon protection, Pd2(dba)3 (80 mg, 0.09 mmol), Q-Phos (62 mg, 0.09 mmol), and 2-tert-butoxy-2-carbonylethylzinc bromide (5 mL, 3 mmol) were added in sequence. Then the system was slowly heated to 70 °C and stirred for 2 h. After detecting the reaction was completed, 2 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. 10 mL of water was added to the reaction solution, and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. It was purified by column chromatography (DCM / MeOH = 100 / 1 - 60 / 1) to obtain white solid AJ115-4 (110 mg, 48%).

[0550] Preparation of AJ115-5: AJ115-4 (110 mg, 0.11 mmol) was dissolved in 8 mL of DCM. 2 mL of TFA was added dropwise to the reaction system under stirring at room temperature, and the reaction was continued under stirring at room temperature for 1 h. LCMS detection showed that the raw material had disappeared and the reaction was complete. Excess TFA and DCM were removed by concentration under reduced pressure to obtain white compound AJ115-5 (80 mg, 85%).

[0551] Preparation of AJ115: AJ115-5 (20 mg, 0.06 mmol) and AJ13-5 (26 mg, 0.05 mmol) were dissolved in 5 mL of DMF. Under stirring at room temperature, DIEA (14 mg, 0.11 mmol) and HATU (21 mg, 0.06 mmol) were added to the system, and the reaction was stirred at room temperature for 30 minutes. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 10 mL of water was slowly added to the reaction solution under stirring, and a white solid precipitated from the reaction solution. The filter cake was obtained by suction filtration under reduced pressure. The filter cake was purified by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 1) to obtain white solid AJ115 (15 mg, 32%). 1 1H NMR (400 MHz, DMSO-d6) δ 12.73(s, 1H), 11.23 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.00 (d, J =1.3 Hz, 1H), 7.61 (dd, J = 8.0, 1.4 Hz, 1H), 7.51 (s, 1H), 7.39 (s, 1H), 7.37(s, 1H), 5.39 (dd, J = 12.8, 5.4 Hz, 1H), 4.41-4.34 (m, 1H), 4.10-4.03 (m,1H), 3.85 (d, J = 3.6 Hz, 2H), 3.14-3.07 (m, 1H), 3.03-2.95 (m, 4H), 2.89-2.82 (m, 1H), 2.76-2.74 (m, 1H), 2.73-2.68 (m, 5H), 2.68-2.64 (m, 2H), 2.64-2.59 (m, 1H), 2.59-2.53 (m, 1H), 2.19-2.12 (m, 1H), 1.92-1.81 (m, 2H), 1.75(s, 6H), 1.52-1.38 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 802.5 [M+H] + .

[0552] Preparation of AJ119:

[0553]

[0554] Preparation of AJ119-1: AJ119-0 (50 mg, 0.23 mmol) and AJ12b-6 (92 mg, 0.23 mmol) were dissolved in a mixed solvent of 5 mL THF and 5 mL DMF. After stirring at room temperature for 10 minutes, AcOH (41 mg, 0.69 mmol) was added dropwise, and NaHB(OAc)3 (98 mg, 0.46 mmol) was added. Then the temperature was raised to 40 °C and the reaction was continued with stirring for 6 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 2 mL of saturated NaHCO3 aqueous solution was added to the reaction solution to quench the reaction, and 10 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 100 / 1 - 40 / 1) to obtain white solid AJ119-1 (26 mg, 19%).

[0555] Preparation of AJ119-2: AJ119-1 (26 mg, 0.04 mmol) was dissolved in 5 mL of DCM. 1 mL of TFA was added dropwise to the reaction system under stirring at room temperature, and the reaction was continued with stirring at room temperature for 1 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. Excess TFA and DCM were removed by concentration under reduced pressure to obtain light brown compound AJ119-2 (20 mg, 92%).

[0556] Preparation of AJ119: AJ119-2 (20 mg, 0.04 mmol) and AJ78-4 (14 mg, 0.04 mmol) were dissolved in 5 mL of DMF. Under stirring at room temperature, DIEA (10 mg, 0.08 mmol) and HATU (16 mg, 0.04 mmol) were added to the system, and the reaction was continued with stirring at room temperature for 30 minutes. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 10 mL of water was slowly added to the reaction solution under stirring, and a white solid precipitated from the reaction solution. The filter cake was obtained by suction filtration under reduced pressure, and the filter cake was purified by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 1) to obtain white solid AJ119 (10 mg, 31%). 11H NMR (400 MHz, DMSO-d6) δ 12.72(s, 1H), 11.23 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 8.01 (d, J =1.3 Hz, 1H), 7.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.39 (s, 1H), 7.32 (s, 1H),7.31-7.29 (m, 1H), 5.36 (dd, J = 12.8, 5.4 Hz, 1H), 4.93-4.79 (m, 1H), 4.80-4.64 (m, 1H), 4.63-4.49 (m, 1H), 4.47-4.35 (m, 1H), 4.29-4.07 (m, 2H), 3.81(d, J = 17.1 Hz, 2H), 3.22-3.16 (m, 1H), 3.03-2.97 (m, 3H), 2.92-2.87 (m,1H), 2.85-2.80 (m, 4H), 2.72 (d, J = 7.5 Hz, 2H), 2.68-2.65 (m, 1H), 2.65-2.57 (m, 1H), 2.18-2.14 (m, 1H), 1.91-1.83 (m, 1H), 1.76 (s, 6H), 1.67-1.56(m, 1H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 804.5 [M+H] + .

[0557] Preparation of AJ120: AJ120 was prepared according to the preparation method of AJ119.

[0558]

[0559] 11H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 11.23 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.61 (dd, J = 8.2, 1.4 Hz, 1H), 7.39 (s, 1H), 7.33 (s, 1H), 7.32 - 7.29 (m, 1H), 5.37 (dd, J = 12.8, 5.4 Hz, 1H), 4.61 - 4.52 (m, 1H), 4.51 - 4.42 (m, 1H), 4.37 - 4.28 (m, 1H), 4.20 - 4.10 (m, 1H), 3.84 (d, J = 9.7 Hz, 2H), 3.21 - 3.13 (m, 1H), 3.04 - 2.97 (m, 4H), 2.96 - 2.85 (m, 4H), 2.84 - 2.78 (m, 1H), 2.72 (d, J = 7.4 Hz, 2H), 2.70 - 2.65 (m, 1H), 2.65 - 2.59 (m, 1H), 2.19 - 2.10 (m, 1H), 1.98 - 1.83 (m, 2H), 1.76 (s, 6H), 1.27 (t, J = 7.4 Hz, 3H). LCMS(ESI) m / z 822.6 [M+H] + .

[0560] Preparation of AJ124:

[0561]

[0562] Preparation of AJ124-1: AJ124-0 (1 g, 5.8 mmol) and 1-Boc-4-(piperidin-4-yl)-piperazine (1.4 g, 5.3 mmol) were dissolved in 20 mL of DMF. K2CO3 (1.4 g, 10.6 mmol) was added under stirring at room temperature, and the system was heated to 75 °C and stirred for 2 h. LCMS detection showed that the raw materials had disappeared, and the reaction ended. The reaction system was cooled to room temperature, 20 mL of water was added to the reaction solution, and 20 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The colorless transparent oily compound AJ124-1 (2.42 g, 98%) was obtained by column chromatography (PE / EA = 100 / 1 - 40 / 1).

[0563] Preparation of AJ124-2: Dissolve AJ124-1 (1 g, 2.4 mmol) in 15 mL of THF solution, add a catalytic amount of Pd / C (with a content of 10%, 100 mg), place the reaction under hydrogen conditions, heat up to 40 °C and stir for 2 h. After detecting the end of the reaction, filter the reaction solution to remove Pd / C, and concentrate the filtrate under reduced pressure to obtain a yellow solid AJ124-2 (920 mg, 99%).

[0564] Preparation of AJ124-3: Dissolve AJ124-2 (500 mg, 1.3 mmol) and 3,5-dichloro-6-ethylpyrazinecarboxamide (253 mg, 1.2 mmol) in 15 mL of dioxane, add DIEA (413 mg, 3.2 mmol) under stirring at room temperature, heat the system to 110 °C and stir for 2 h. LCMS detection shows that the raw materials have disappeared and the reaction ends. Cool the reaction system to room temperature, concentrate under reduced pressure and perform column chromatography (DCM / MeOH = 100 / 1 - 60 / 1) to obtain a colorless transparent oily compound AJ124-3 (300 mg, 41%).

[0565] Preparation of AJ124-4: Dissolve AJ124-3 (300 mg, 0.5 mmol) and 4-aminotetrahydropyran (423 mg, 4.2 mmol) in 15 mL of NMP, heat up to 190 °C and stir for 2 h. LCMS detection shows that the raw materials have disappeared. Cool the reaction system to room temperature, add 15 mL of water and 15 mL of EA to the reaction solution for extraction and liquid separation, repeat the extraction three times until the extraction is complete, combine the organic phases and backwash with saturated brine, dry the organic phases with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Perform column chromatography (DCM / MeOH = 100 / 1 - 40 / 1) to obtain a colorless transparent oily compound AJ124-4 (300 mg, 90%).

[0566] Preparation of AJ124-5: Dissolve AJ124-4 (300 mg, 0.47 mmol) in 10 mL of DCM, add 3 mL of TFA dropwise to the reaction system under stirring at room temperature, and stir at room temperature for 1 h. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Concentrate under reduced pressure to remove the excess TFA and DCM to obtain a light brown compound AJ124-5 (200 mg, 79%).

[0567] Preparation of AJ124-6: AJ124-5 (12 mg, 0.02 mmol) and AJ112-4 (10 mg, 0.02 mmol) were dissolved in 5 mL of DMF. DIEA (6 mg, 0.04 mmol) and HATU (9 mg, 0.02 mmol) were added under stirring at room temperature, and the mixture was stirred at room temperature for 30 minutes. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 10 mL of water was slowly added to the reaction solution under stirring. A white solid precipitated from the reaction solution. The solid was obtained by suction filtration under reduced pressure, and after drying, a brown solid AJ124-6 (20 mg, 97%) was obtained.

[0568] Preparation of AJ124: AJ124-6 (20 mg, 0.02 mmol) was dissolved in a mixed solution of 1 mL of TFA and 1 mL of TfOH, and the temperature was raised to 40 °C and stirred for 2 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. The temperature was lowered to room temperature, and ice water was added to quench the reaction solution under an ice bath. The pH of the reaction solution was adjusted to 7 - 8 with saturated aqueous NaHCO3 solution. The solid was obtained by suction filtration, and the solid was dried to obtain the crude product. After reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 1), a yellow solid AJ124 (12 mg, 69%) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.68 (s, 1H), 8.27 (s, 2H), 7.54 (s, 1H), 7.46 - 7.43 (m, 1H), 7.33 - 7.22 (m, 2H), 7.01 (d, J = 2.3 Hz, 1H), 6.83 (s, 1H), 6.81 (d, J = 6.2 Hz, 2H), 4.17 - 4.01 (m, 2H), 3.97 - 3.88 (m, 2H), 3.81 (s, 3H), 3.80 - 3.74 (m, 2H), 3.54 (s, 2H), 3.48 (s, 2H), 3.38 (d, J = 2.3 Hz, 2H), 3.36 - 3.35 (m, 2H), 3.33 - 3.32 (m, 2H), 3.31 - 3.28 (m, 2H), 2.87 - 2.77 (m, 2H), 2.60 - 2.58 (m, 2H), 2.55 - 2.52 (m, 2H), 2.48 - 2.39 (m, 2H), 1.91 - 1.72 (m, 4H), 1.70 - 1.52 (m, 4H), 1.19 (t, J = 7.3 Hz, 3H). LCMS (ESI) m / z 809.5 [M+H] + .

[0569] Preparation of AJ124b: AJ124b was prepared according to the preparation method of AJ124.

[0570]

[0571] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (m, 1H), 10.68 (s, 1H), 8.23 (d, J =7.1 Hz, 1H), 7.55 (s, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 7.25 (s,1H), 7.15 - 7.13 (m, 1H), 7.03 (s, 1H), 6.83 (d, J = 6.9 Hz, 2H), 4.17 - 4.07 (m,2H), 3.96 - 3.89 (m, 2H), 3.85 - 3.81 (m, 3H), 3.81 - 3.75 (m, 2H), 3.64 - 3.53 (m,2H), 3.53 - 3.45 (m, 2H), 3.43 - 3.38 (m, 2H),3.32 - 3.28 (m, 2H), 3.19 - 3.13 (m,2H), 3.09 - 3.05 (m, 2H), 2.96 - 2.89 (m, 2H), 2.84 - 2.79 (m, 2H), 2.61 - 2.57 (m,2H), 2.55 - 2.54 (m, 1H), 2.45 - 2.42 (m, 1H), 1.91 - 1.75 (m, 4H), 1.71 - 1.61 (m,2H), 1.60 - 1.48 (m, 2H), 1.19 (t, J = 7.3 Hz, 3H). LCMS(ESI) m / z 809.5 [M+H] + .

[0572] Preparation of AJ125:

[0573]

[0574] Preparation of AJ125-1: AJ112-2 (643 mg, 1.5 mmol) was dissolved in a mixed solution of 15 mL of DMF / water (20:1). Et3N (470 mg, 4.5 mmol) and Pd(dppf)Cl2DCM (122 mg, 0.15 mmol) were added under stirring at room temperature. The reaction system was purged with carbon monoxide and heated to 90 °C in a carbon monoxide atmosphere for 3 h. After detecting the completion of the reaction, the low-boiling solvents and water were removed by concentration under reduced pressure to obtain a DMF solution containing AJ125-1 (about 15 mL, 20 mg / mL), which was directly used for the next step.

[0575] Preparation of AJ125-2: AJ124-5 (30 mg, 0.06 mmol) and AJ125-1 (24 mg, 0.06 mmol) were dissolved in 5 mL of DMF. DIEA (14 mg, 0.11 mmol) and HATU (22 mg, 0.06 mmol) were added to the system under stirring at room temperature, and the reaction was continued to stir at room temperature for 30 minutes. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 10 mL of water was slowly added to the reaction solution under stirring, and a white solid precipitated from the reaction solution. The reaction solution was filtered by suction under reduced pressure to obtain a filter cake, which was dried to obtain a brown solid AJ125-2 (40 mg, 78%).

[0576] Preparation of AJ125: AJ125-2 (40 mg, 0.04 mmol) was dissolved in a mixed solvent of 1 mL of TFA and 1 mL of TfOH. The reaction solution was heated to 40 °C and stirred for 2 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. The temperature was lowered to room temperature, and ice water was added to quench the reaction solution under an ice bath, and the pH of the reaction solution was adjusted to 7-8 with a saturated NaHCO3 aqueous solution. The mixture was filtered by suction, and the filter cake was dried to obtain a crude product. The crude product was purified by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 1) to obtain a yellow solid AJ125 (5 mg, 14%). 11H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 10.72 (s, 1H), 8.40 (d, J = 6.2 Hz, 1H), 7.68 (s, 1H), 7.54 (s, 2H), 7.32 - 7.21 (m, 2H), 7.06 - 6.97 (m, 2H), 6.82 (t, J = 8.1 Hz, 2H), 4.16 - 4.05 (m, 2H), 3.94 - 3.89 (m, 2H), 3.85 - 3.83 (m, 2H), 3.81 (s, 3H), 3.69 - 3.60 (m, 2H), 3.44 - 3.40 (m, 1H), 3.30 - 3.29 (m, 4H), 2.89 - 2.77 (m, 2H), 2.69 - 2.64 (m, 1H), 2.63 - 2.60 (s, 1H), 2.60 - 2.56 (m, 2H), 2.56 - 2.53 (m, 1H), 2.49 - 2.43 (m, 2H), 2.42 - 2.34 (m, 1H), 2.20 - 2.09 (m, 1H), 1.88 - 1.74 (m, 4H), 1.71 - 1.61 (m, 2H), 1.61 - 1.51 (m, 2H), 1.18 (t, J = 7.4 Hz, 3H). LCMS(ESI) m / z 795.5 [M+H] + .

[0577] Preparation of AJ125b: AJ125b was prepared according to the preparation method of AJ125.

[0578]

[0579] 11H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.73 (s, 1H), 8.45 (s,1H), 7.71 (d, J = 9.9 Hz, 1H), 7.57 (s, 1H), 7.37 (d, J = 12.3 Hz, 1H), 7.27(s, 1H), 7.12 (s, 1H), 7.09-6.96 (m, 2H), 6.87 (d, J = 14.1 Hz, 2H), 4.17-4.03 (m, 2H), 4.00-3.90 (m, 2H), 3.83 (s, 3H), 3.66-3.60 (m, 2H), 3.56-3.52(m, 1H), 3.50-3.46 (m, 2H), 3.26-3.18 (m, 2H), 3.08-2.98 (m, 2H), 2.93-2.89(m, 2H), 2.81-2.7m (m, 2H), 2.72-2.62 (m, 2H), 2.62-2.52 (m, 4H), 2.45-2.43(m, 1H), 1.91-1.81 (m, 2H), 1.81-1.71 (m, 2H), 1.71-1.60 (m, 2H), 1.60-1.44(m, 2H), 1.16 (t, J = 7.3 Hz, 3H). LCMS(ESI) m / z 795.5 [M+H] + .

[0580] Preparation of AJ126:

[0581]

[0582] Preparation of A-1: AJ124-0 (1 g, 5.84 mmol) and 4-piperidone ethylene acetal (920 mg, 6.43 mmol) were dissolved in 20 mL of DMF. K2CO3 (1.61 g, 11.69 mmol) was added under stirring at room temperature. The reaction system was heated to 75 °C and stirred for 2 h. LCMS detection showed that the raw materials had disappeared, and the reaction was completed. The reaction system was cooled to room temperature. 20 mL of water was added to the reaction solution, and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The colorless transparent oily compound A-1 (1.6 g, 93%) was obtained by column chromatography (PE / EA = 100 / 1 - 40 / 1).

[0583] Preparation of A-2: Dissolve A-1 (500 mg, 1.70 mmol) in 15 mL of THF solution, add a catalytic amount of 10% Pd / C (50 mg), place the reaction under hydrogen conditions, heat up to 40 °C and stir for 3 h. After detecting the end of the reaction, cool to room temperature, filter off palladium carbon under reduced pressure, and the obtained filtrate is concentrated under reduced pressure to obtain yellow solid A-2 (420 mg, 93%).

[0584] Preparation of A-3: Dissolve A-2 (420 mg, 1.59 mmol) and 3,5-dichloro-6-ethylpyrazinecarboxamide (314 mg, 1.43 mmol) in 20 mL of dioxane, add DIEA (513 mg, 3.98 mmol) under stirring at room temperature, heat the system up to 110 °C and stir for 4 h. LCMS detection shows that the raw materials have disappeared and the reaction ends. Cool the reaction system to room temperature, concentrate under reduced pressure to remove low-boiling solvents and perform column chromatography (PE / EA = 100 / 1 - 60 / 1) to obtain colorless transparent oily compound A-3 (500 mg, 70%).

[0585] Preparation of A-4: Dissolve A-3 (500 mg, 1.12 mmol) and 4-aminotetrahydropyran (904 mg, 8.95 mmol) in 10 mL of NMP, heat the reaction system up to 190 °C and stir for 2 h. LCMS detection shows that the raw materials have disappeared. Cool the system to room temperature, add 20 mL of water to the reaction solution and extract with 15 mL of EA, repeat the extraction three times until the extraction is complete, combine the organic phases and backwash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Perform column chromatography (DCM / MeOH = 100 / 1 - 70 / 1) to obtain colorless transparent oily compound A-4 (510 mg, 89%).

[0586] Preparation of A: Dissolve A-4 (510 mg, 1.00 mmol) in 10 mL of THF, add 5 mL of hydrochloric acid aqueous solution (6 M) dropwise to the reaction system under stirring at room temperature, heat the reaction system up to 50 °C and stir for about 1 h. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Under an ice bath, add ice water to quench the reaction solution and adjust the pH of the reaction solution to 7 - 8 with saturated NaHCO3 aqueous solution, add 10 mL of EA for extraction and separation, repeat the extraction three times until the extraction is complete, combine the organic phases and backwash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Perform column chromatography (DCM / MeOH = 100 / 1 - 60 / 1) to obtain white solid A (300 mg, 64%).

[0587] Preparation of AJ126-1: Dissolve AJ112-2 (500 mg, 1.2 mmol) in 15 mL of dioxane, stir at room temperature, and sequentially add N-Boc-piperazine (435 mg, 2.3 mmol), RuPhos (109 mg, 0.23 mmol), RuPhosPdG2 (727 mg, 0.93 mmol) and Cs2CO3 (761 mg, 2.34 mmol) under argon protection. Slowly heat the reaction system to 100 °C and stir for 2 h. After the reaction is completed, cool the reaction system to room temperature, concentrate under reduced pressure and obtain the transparent colorless oily compound AJ126-1 (540 mg, 86%) by column chromatography (DCM / MeOH = 100 / 1 - 30 / 1).

[0588] Preparation of AJ126-2: Dissolve AJ126-1 (540 mg, 1.01 mmol) in 10 mL of DCM, add 10 mL of TFA dropwise to the reaction system at room temperature, and stir at room temperature for 1 h. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Concentrate under reduced pressure to remove excess TFA and DCM to obtain the white compound AJ126-2 (425 mg, 97%).

[0589] Preparation of AJ126-3: Dissolve AJ126-2 (25 mg, 0.06 mmol) and compound A (30 mg, 0.06 mmol) in 10 mL of absolute ethanol, heat to 45 °C and stir for 1 h, then add AcOH (10 mg, 0.17 mmol) and NaHB(OAc)3 (37 mg, 0.17 mmol), and continue to stir for 2 h. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Cool to room temperature, add 2 mL of saturated NaHCO3 aqueous solution to quench the reaction solution, then add 5 mL of water and 10 mL of DCM / MeOH (10:1) for extraction and separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Obtain the white solid AJ126-3 (20 mg, 39%) by column chromatography (DCM / MeOH = 100 / 1 - 15 / 1).

[0590] Preparation of AJ126: Dissolve AJ126-3 (20 mg, 0.02 mmol) in a mixed solution of 1 mL of TFA and 1 mL of TfOH, heat to 40 °C and stir for 2 h. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Cool to room temperature, add ice water to quench the reaction solution in an ice bath and adjust the pH of the reaction solution to 7 - 8 with saturated NaHCO3 aqueous solution, filter by suction, and dry the filter cake to obtain the crude product. Obtain the white solid AJ126 (5 mg, 29%) by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 1).1 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.61 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.53 (s, 1H), 7.32 - 7.25 (m, 2H), 7.25 - 7.21 (m, 1H), 7.03 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.67 (s, 1H), 4.19 - 4.04 (m, 2H), 3.96 - 3.89 (m, 2H), 3.82 (s, 3H), 3.75 (t, J = 6.7 Hz, 2H), 3.38 (d, J = 10.3 Hz, 2H), 3.32 - 3.30 (m, 1H), 3.23 (s, 4H), 2.80 (t, J = 6.6 Hz, 2H), 2.74 - 2.65 (m, 4H), 2.60 (d, J = 7.2 Hz, 1H), 2.59 - 2.54 (m, 2H), 2.54 - 2.52 (m, 1H), 2.40 - 2.35 (m, 1H), 1.88 - 1.84 (m, 4H), 1.67 - 1.59 (m, 2H), 1.58 - 1.51 (m, 2H), 1.19 (t, J = 7.3 Hz, 3H). LCMS (ESI) m / z 767.5 [M+H] + .

[0591] Preparation of AJ126b:

[0592]

[0593] Preparation of B-1: Dissolve 2-fluoro-5-nitroanisole (1 g, 5.84 mmol) and N-Boc-piperazine (1.31 g, 7.01 mmol) in 20 mL of DMF. Add K2CO3 (1.61 g, 11.69 mmol) under stirring at room temperature, and heat the system to 75 °C and stir for 2 h. LCMS detection shows that the raw materials have disappeared and the reaction is completed. Cool the reaction system to room temperature, add 20 mL of water to the reaction solution and extract with 15 mL of EA. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Obtain the yellow solid B-1 (1.9 g, 96%) by column chromatography (PE / EA = 100 / 1 - 40 / 1).

[0594] Preparation of B-2: Dissolve B-1 (1.9 g, 5.64 mmol) in 15 mL of THF solution, add a catalytic amount of 10% Pd / C (200 mg), place the reaction under hydrogen atmosphere, heat to 40 °C and stir for 2 h. After detecting the completion of the reaction, cool the reaction solution to room temperature, filter off Pd / C under reduced pressure by suction, and concentrate the filtrate under reduced pressure to obtain the brown solid B-2 (1.7 g, 98%).

[0595] Preparation of B-3: Dissolve B-2 (860 mg, 2.80 mmol) and 3,5-dichloro-6-ethylpyrazinecarboxamide (555 mg, 2.52 mmol) in 20 mL of dioxane. Add DIEA (723 mg, 5.60 mmol) under stirring at room temperature, and heat the reaction system to 110 °C and stir for about 2 h. LCMS detection shows that the raw materials have disappeared and the reaction is completed. Cool the reaction system to room temperature, concentrate under reduced pressure and obtain the yellow transparent oily B-3 (700 mg, 51%) by column chromatography (PE / EA = 100 / 1 - 50 / 1).

[0596] Preparation of B-4: Dissolve B-3 (700 mg, 1.43 mmol) and 4-aminotetrahydropyran (866 mg, 8.57 mmol) in 10 mL of NMP. Heat the reaction system to 190 °C and stir for about 3 h. LCMS detection shows that the raw materials have disappeared and the reaction is completed. Cool the reaction system to room temperature, add 20 mL of water to the reaction solution and extract with 15 mL of EA. Repeat the extraction three times until the extraction is complete. Combine the organic phases and backwash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Obtain the yellow solid B-4 (614 mg, 77%) by column chromatography (DCM / MeOH = 100 / 1 - 80 / 1).

[0597] Preparation of B: Dissolve B-4 (300 mg, 0.54 mmol) in 10 mL of DCM. At room temperature, add 5 mL of TFA dropwise to the reaction system and stir the reaction at room temperature for about 1 h. LCMS detection shows that the raw material has disappeared and the reaction is complete. Concentrate under reduced pressure to remove the excess TFA and DCM to obtain white solid B (240 mg, 97%).

[0598] Preparation of AJ126b-1: Dissolve AJ112-2 (500 mg, 1.17 mmol) in 10 mL of dioxane. Under argon protection, add 4-piperidone ethylene ketal (334 mg, 2.34 mmol), RuPhos (109 mg, 0.23 mmol), RuPhosPdG2 (727 mg, 0.93 mmol) and Cs2CO3 (761 mg, 2.34 mmol). Slowly heat the reaction system to 100 °C and stir the reaction for 2 h. After the reaction is completed, cool the reaction system to room temperature, concentrate under reduced pressure to remove the solvent, and obtain a transparent colorless oily compound AJ126b-1 (274 mg, 48%) by column chromatography (DCM / MeOH = 100 / 1 - 60 / 1).

[0599] Preparation of AJ126b-2: Dissolve AJ126b-1 (274 mg, 0.12 mmol) in 10 mL of THF. At room temperature, add 2.5 mL of 6 mol / L hydrochloric acid aqueous solution dropwise to the reaction system, and heat the reaction solution to 40 °C and stir the reaction for 1 h. LCMS detection shows that the raw material has disappeared and the reaction is complete. Cool to room temperature, add ice water to quench the reaction solution in an ice bath, adjust the pH of the reaction solution to 7 - 8 with saturated NaHCO3 aqueous solution, and perform extraction and liquid separation with DCM / MeOH (10:1). Repeat the extraction three times until the extraction is complete. Combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Obtain white compound AJ126b-2 (180 mg, 72%) by column chromatography (DCM / MeOH = 100 / 1 - 20 / 1).

[0600] Preparation of AJ126b-3: AJ126b-2 (50 mg, 0.11 mmol) and B (46 mg, 0.10 mmol) were dissolved in 6 mL of DMF. The mixture was slowly heated to 45 °C under stirring and reacted for 1 h. Then, AcOH (18 mg, 0.30 mmol) was added dropwise and NaHB(OAc)3 (64 mg, 0.30 mmol) was added. The reaction was continued under stirring for 2 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. 2 mL of saturated NaHCO3 aqueous solution was added to the reaction solution to quench the reaction, and 5 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 100 / 1 - 15 / 1) to obtain a pale yellow solid AJ126b-3 (25 mg, 25%).

[0601] Preparation of AJ126b: AJ126b-3 (25 mg, 0.03 mmol) was dissolved in a mixed solvent of 1 mL of TFA and 1 mL of TfOH. The mixture was heated to 40 °C under stirring and reacted for 2 h. LCMS detection showed that the raw materials had disappeared and the reaction was completed. The temperature was lowered to room temperature, and ice water was added to the reaction solution under an ice bath to quench the reaction. The pH of the reaction solution was adjusted to 7 - 8 with saturated NaHCO3 aqueous solution, and then filtered by suction. The filter cake was dried to obtain the crude product. The crude product was purified by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 1) to obtain a white solid AJ126b (5 mg, 23%). 11H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.60 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.55 – 7.51 (m, 1H), 7.30 – 7.25 (m, 2H), 7.23 (s, 1H), 7.02 (d, J = 2.3 Hz, 1H), 6.89 (dd, J = 7.7, 1.9 Hz, 1H), 6.81 (t, J = 8.8 Hz, 2H), 6.71 – 6.66 (m, 1H), 4.18 – 4.03 (m, 2H), 3.96 – 3.89 (m, 2H), 3.86 (d, J = 12.3 Hz, 2H), 3.81 (s, 3H), 3.75 (t, J = 6.7 Hz, 2H), 3.38 (d, J = 11.8 Hz, 2H), 3.31 (s, 1H), 2.93 (s, 4H), 2.79 – 2.72 (m, 2H), 2.66 (s, 4H), 2.58 (q, J = 7.4 Hz, 2H), 2.47 – 2.41 (m, 1H), 1.93 – 1.81 (m, 4H), 1.67 - 1.59 (m, 2H), 1.58 - 1.51 (m, 2H), 1.19 (t, J = 7.3 Hz, 3H). LCMS(ESI) m / z 767.5 [M+H] + .

[0602] Preparation of AJ127:

[0603]

[0604] Preparation of AJ127-1: AJ53-2 (80 mg, 0.25 mmol) was dissolved in 10 mL of dioxane, stirred at room temperature and successively added with N-Boc-piperazine (92 mg, 0.50 mmol), RuPhos (23 mg, 0.05 mmol), RuPhosPdG2 (155 mg, 0.20 mmol) and Cs2CO3 (162 mg, 0.50 mmol) under argon protection. The system was slowly heated to 100 °C and stirred for 2 h. After the reaction was completed, the reaction system was cooled to room temperature, the solvent was removed by reduced pressure concentration, and the colorless transparent oily compound AJ127-1 (50 mg, 84%) was obtained by column chromatography (DCM / MeOH = 100 / 1 - 60 / 1).

[0605] Preparation of AJ127-2: AJ127-1 (50 mg, 0.12 mmol) was dissolved in 10 mL of DCM. 2 mL of TFA was added dropwise to the reaction system under stirring at room temperature, and the reaction was continued to stir at room temperature for 1 h. LCMS detection showed that the raw material had disappeared and the reaction was completed. The excess TFA and DCM were removed by concentration under reduced pressure to obtain the white compound AJ127-2 (30 mg, 78%).

[0606] Preparation of AJ127: AJ127-2 (30 mg, 0.09 mmol) and A (47 mg, 0.10 mmol) were dissolved in a mixed solvent of 5 mL of THF and 1 mL of DMF. The reaction solution was heated to 45 °C and stirred for 1 h, then AcOH (16 mg, 0.27 mmol) was added dropwise, and NaHB(OAc)3 (58 mg, 0.27 mmol) was added and the reaction was continued to stir for 2 h. LCMS detection showed that the raw material had disappeared and the reaction was completed. The temperature was lowered to room temperature, 2 mL of saturated aqueous NaHCO3 solution was added to the reaction solution to quench the reaction, and 5 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The pale yellow solid AJ127 (16 mg, 22%) was obtained by column chromatography (DCM / MeOH = 100 / 1 - 15 / 1). 11H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.53 (s, 1H), 8.26 (s, 1H), 7.54 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.33 - 7.26 (m, 1H), 7.26 - 7.20 (m, 1H), 7.04 (s, 1H), 6.97 - 6.90 (m, 1H), 6.87 - 6.81 (m, 2H), 4.19 - 4.04 (m, 1H), 3.96 - 3.94 (m, 2H), 3.92 - 3.90 (m, 2H), 3.89 (s, 3H), 3.82 (s, 3H), 3.38 (d, J = 10.3 Hz, 2H), 3.32 - 3.30 (m, 4H), 2.95 - 2.93 (m, 2H), 2.93 - 2.90 (m, 2H), 2.74 - 2.65 (m, 4H), 2.60 (d, J = 7.2 Hz, 1H), 2.59 - 2.54 (m, 2H), 2.54 - 2.52 (m, 1H), 2.05 - 1.98 (m, 1H), 1.91 - 1.84 (m, 4H), 1.67 - 1.59 (m, 4H), 1.19 (t, J = 7.3 Hz, 3H). LCMS(ESI) m / z 781.5 [M+H] + .

[0607] Preparation of AJ128:

[0608]

[0609] Preparation of AJ128: Dissolve AJ124 - 5 (15 mg, 0.03 mmol) and AJ35 - 3 (9 mg, 0.03 mmol) in 5 mL of DMF. Under stirring at room temperature, add DIEA (7 mg, 0.06 mmol) and HATU (11 mg, 0.03 mmol) to the system, and continue stirring at room temperature for 30 minutes. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Slowly add 10 mL of water to the reaction solution under stirring. A white solid precipitates from the reaction solution. The crude product is obtained by suction filtration under reduced pressure and drying the filter cake, and is purified by reverse-phase column chromatography (MeCN / water = 1 / 100 - 1 / 1) to obtain a white solid AJ128 (10 mg, 43%). 11H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 11.02 (s, 1H), 7.54 (s, 1H), 7.30 - 7.28 (m, 1H), 7.26 (s, 1H), 7.25 - 7.22 (m, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 7.01 (d, J = 2.3 Hz, 1H), 6.81 (t, J = 8.3 Hz, 2H), 5.36 (dd, J = 12.8, 5.2 Hz, 1H), 4.15 - 4.07 (m, 1H), 3.96 - 3.92 (m, 1H), 3.92 - 3.87 (m, 1H), 3.80 (s, 3H), 3.75 (s, 2H), 3.55 - 3.48 (m, 2H), 3.48 - 3.43 (m, 2H), 3.39 (t, J = 3.0 Hz, 2H), 3.36 - 3.34 (m, 2H), 3.33 - 3.30 (m, 2H), 2.91 - 2.83 (m, 1H), 2.76 - 2.68 (m, 1H), 2.67 - 2.65 (m, 1H), 2.65 - 2.61 (m, 1H), 2.61 - 2.55 (m, 2H), 2.56 - 2.53 (m, 1H), 2.49 - 2.45 (m, 2H), 2.35 - 2.29 (m, 1H), 2.19 - 2.12 (m, 1H), 1.89 - 1.81 (m, 2H), 1.81 - 1.72 (m, 2H), 1.69 - 1.59 (m, 2H), 1.59 - 1.47 (m, 2H), 1.18 (t, J = 7.3 Hz, 3H). LCMS(ESI) m / z 825.5 [M+H] + .

[0610] Preparation of AJ128b:

[0611]

[0612] Preparation of AJ128b: AJ124b-5 (18 mg, 0.033 mmol) and AJ35-3 (10 mg, 0.033 mmol) were dissolved in 5 mL of DMF solution. DIEA (12.9 mg, 0.10 mmol) and HATU (13 mg, 0.033 mmol) were added under stirring at room temperature, and the reaction was stirred at room temperature for 30 minutes. After detecting the completion of the reaction, 10 mL of water was added to the reaction solution for quenching. The mixture was filtered by suction, and the filter cake was dried to obtain the crude white solid. The white solid AJ128b (15 mg, 54%) was obtained by column chromatography (MeOH / DCM = 1 / 100 - 1 / 20). 1 HNMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 11.02 (s, 1H), 7.54 (s, 1H), 7.27(dd, J = 9.3, 1.9 Hz, 2H), 7.24 (s, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.09-7.05(m, 1H), 7.02 (d, J = 2.3 Hz, 1H), 6.81 (s, 1H), 6.79 (s, 1H), 5.36 (dd, J =12.8, 5.2 Hz, 1H), 4.38 (d, J = 12.3 Hz, 1H), 4.16-4.07 (m, 1H), 4.01 (d, J =12.9 Hz, 1H), 3.92 (d, J = 11.2 Hz, 2H), 3.80 (s, 3H), 3.75 (s, 2H), 3.41-3.35 (m, 2H), 3.33-3.30 (m, 2H), 3.01 (t, J = 12.5 Hz, 1H), 2.95-2.84 (m,4H), 2.74-2.68 (m, 1H), 2.66 (s, 1H), 2.64-2.59 (m, 2H), 2.59 (s, 2H), 2.57-2.53 (m, 2H), 2.47-2.41 (m, 1H), 2.19-2.11 (m, 1H), 1.91-1.81 (m, 2H), 1.82-1.73 (m, 2H), 1.69-1.56 (m, 2H), 1.33-1.22 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H).LCMS(ESI) m / z 825.5 [M+H] + .

[0613] Preparation of AJ129:

[0614]

[0615] Preparation of AJ129: Dissolve AJ12-5 (29 mg, 0.086 mmol) in a mixed solution of 5 mL of THF and 1 mL of DMF. Add A (40 mg, 0.086 mmol) under stirring at room temperature and stir the reaction at room temperature for 30 minutes. Then, add dropwise AcOH (5 mg, 0.086 mmol) and add NaHB(OAc)3 (36 mg, 0.17 mmol) and continue stirring the reaction for 2 h. LCMS detection shows that the raw materials have disappeared and the reaction is complete. Add 2 mL of saturated aqueous NaHCO3 solution to the reaction solution to quench it, add 5 mL of water and 10 mL of DCM / MeOH (10:1) for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Obtain white solid AJ129 (24 mg, 35%) by column chromatography (DCM / MeOH = 100 / 1 - 20 / 1). 11H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 11.02 (s, 1H), 7.54 (s,1H), 7.30 - 7.28 (m, 1H), 7.26 (s, 1H), 7.25 - 7.22 (m, 1H), 7.19 (d, J = 8.2 Hz,1H), 7.09 - 7.06 (m, 1H), 7.01 (d, J = 2.3 Hz, 1H), 6.81 (t, J = 8.3 Hz, 2H),5.36 (dd, J = 12.8, 5.2 Hz, 1H), 4.15 - 4.07 (m, 1H), 3.96 - 3.92 (m, 1H), 3.92 - 3.87 (m, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.55 - 3.48 (m, 2H), 3.48 - 3.43 (m,2H), 3.41 - 3.38 (m, 2H), 3.36 - 3.34 (m, 2H), 3.33 - 3.30 (m, 2H), 2.95 - 2.84 (m,1H), 2.76 - 2.68 (m, 1H), 2.68 - 2.66 (m, 1H), 2.65 - 2.61 (m, 1H), 2.61 - 2.55 (m,2H), 2.56 - 2.53 (m, 1H), 2.49 - 2.45 (m, 2H), 2.35 - 2.29 (m, 1H), 2.19 - 2.12 (m,1H), 1.89 - 1.81 (m, 2H), 1.81 - 1.72 (m, 2H), 1.69 - 1.59 (m, 2H), 1.59 - 1.47 (m,2H), 1.19 (t, J = 7.3 Hz, 3H). LCMS(ESI) m / z 796.5 [M+H] + .

[0616] Preparation of AJ132:

[0617]

[0618] Preparation of AJ132 - 1: AJ132 - 0 (1 g, 4.9 mmol) was dissolved in 20 mL of EtOH, and an aqueous solution of chloroacetaldehyde (1.4 g, 7.3 mmol, 40%) was added under stirring, and the mixture was slowly heated to 90 under argon protection oReact for 4 h. After detecting the completion of the reaction, concentrate under reduced pressure to remove EtOH, add 10 mL of water for dilution and adjust the pH to 7 with saturated NaHCO3 solution. Solid precipitate appears. Filter by suction, and the filter cake is washed and dried to obtain AJ132-1 (1 g, 90%).

[0619] Preparation of AJ132-2: Dissolve AJ132-1 (1 g, 4.3 mmol) in 10 mL of DMF, add NIS (1.12 g, 6.5 mmol) under stirring, and stir the reaction at room temperature for 4 h. After detecting the completion of the reaction, filter by suction, and the filter cake is washed and dried to obtain the crude product, which is purified by column chromatography (PE / EA = 100 / 1 - 10 / 1) to obtain off-white solid AJ132-2 (1.4 g, 90%).

[0620] Preparation of AJ132-3: Under argon protection, dissolve N,N'-dimethylethylenediamine (30 mg, 0.34 mmol) in 15 mL of DMF, add CuI (97 mg, 0.51 mmol) and stir at room temperature for 10 minutes, then successively add AJ132-2 (500 mg, 1.41 mmol), 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (494 mg, 2.11 mmol) and K2CO3 (388 mg, 2.81 mmol). Slowly heat the reaction system to 90 o C and continue to react for 4 h. After detecting the complete reaction, cool to room temperature, add 15 mL of water to the reaction solution to quench and add 15 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases, dry with anhydrous sodium sulfate and concentrate to obtain the crude black concentrate, which is purified by column chromatography (DCM / MeOH = 100 / 1 - 50 / 1) to obtain white solid product AJ132-3 (80 mg, 12%).

[0621] Preparation of AJ132-4: Dissolve AJ132-3 (80 mg, 0.17 mmol) in 10 mL of THF solvent, stir at room temperature and successively add Pd2(dba)3 (32 mg, 0.035 mmol), Q-Phos (37 mg, 0.052 mmol) and 2-tert-butoxy-2-carbonylethylzinc bromide (0.5 M THF solution, 1.5 mL, 0.26 mmol) under argon protection. Slowly heat the reaction system to 70 o C and stir the reaction for 2 h. After the reaction is completed, cool to room temperature and add saturated ammonium chloride aqueous solution to the reaction solution to quench. Extract with EA, collect the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate to remove the solvent, and the residue is purified by column chromatography (DCM / MeOH = 100 / 1 - 50 / 1) to obtain off-white solid AJ132-4 (30 mg, 35%).

[0622] Preparation of AJ132-5: AJ132-4 (30 mg, 0.06 mmol) was dissolved in a mixed solvent of 5 mL of DCM and 1 mL of TFA. The resulting solution was stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative reverse phase chromatography (MeCN / water = 1 / 100 - 1 / 2) to obtain a white solid AJ132-5 (20 mg, 77%).

[0623] Preparation of AJ132-6: AJ132-5 (18 mg, 0.042 mmol) and AJ10a-2 (20 mg, 0.042 mmol) were dissolved in 10 mL of DMF. Under stirring at room temperature, DIEA (16 mg, 0.125 mmol) and HATU (16 mg, 0.042 mmol) were added, and the mixture was stirred at room temperature for about 1 h. After the reaction was completed as detected, 10 mL of water was added to the reaction solution to quench the reaction, and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a pale yellow crude concentrate. It was purified by preparative reverse phase chromatography (MeCN / water = 1 / 100 - 1 / 1) to obtain a white solid AJ132-6 (10 mg, 27%).

[0624] Preparation of AJ132: AJ132-6 (10 mg, 0.011 mmol) was dissolved in a mixed solvent of 1 mL of TFA and 1 mL of TfOH. The mixture was stirred at room temperature for about 3 h. After the reaction was completed as detected, the solvent was removed by concentration under reduced pressure. Water and saturated aqueous NaHCO3 solution were added to adjust the pH to 7 - 8, and a white precipitate was formed. The precipitate was filtered and dried to obtain a crude product, which was purified by preparative reverse phase chromatography (MeCN / water = 1 / 100 - 1 / 1) to obtain a white solid AJ132 (2 mg, 23%). 11H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.67 (s, 1H), 8.65 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.69 - 7.61 (m, 1H), 7.61 - 7.52 (m, 2H), 7.34 (s, 1H), 3.92 (d, J = 8.6 Hz, 2H), 3.81 (t, J = 6.8 Hz, 2H), 3.61 (s, 2H), 3.50 (s, 2H), 3.24 (d, J = 10.9 Hz, 2H), 2.88 - 2.80 (m, 2H), 2.78 (s, 1H), 2.76 - 2.73 (m, 1H), 2.70 (d, J = 7.5 Hz, 2H), 2.66 - 2.59 (m, 2H), 2.59 - 2.53 (m, 2H), 2.48 - 2.40 (m, 1H), 1.91 (d, J = 11.5 Hz, 2H), 1.75 (s, 6H), 1.70 - 1.60 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). LCMS(ESI) m / z 786.5 [M+H] + .

[0625] Preparation of AJ133:

[0626]

[0627] Preparation of AJ133-1: In a 100 mL sealed reaction flask, dissolve 4-bromo-2,5-difluoropyridine (2 g, 10.42 mmol) and ammonia water (10 mL) in an EtOH solution, seal it, heat the reaction solution to 100 °C and stir for 2 h. When it is detected by LCMS that the raw materials have been consumed, stop the reaction. After the reaction solution cools down, release the pressure, add 20 mL of water and 20 mL of EA for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry the organic phases with anhydrous sodium sulfate and concentrate them under reduced pressure to obtain a crude red concentrate. Through column chromatography (EA / PE = 1 / 100 - 1 / 1), a light red solid AJ133-1 (400 mg, 52.6%) is obtained.

[0628] Preparation of AJ133-2: AJ133-1 (460 mg, 2.42 mmol) was dissolved in 10 mL of EtOH, and then chloroacetaldehyde (285 mg, 3.63 mmol) was added to the reaction solution with stirring at room temperature under argon protection. The reaction system was heated to 60 °C and reacted at this temperature for 4 h. After the reaction was completed, the temperature was lowered to room temperature, and the pH value was adjusted to weakly alkaline with saturated aqueous NaHCO3 solution. Then 10 mL of water was added, and a solid precipitate was formed. The solid was filtered by suction and the filter cake was dried to obtain white solid AJ133-2 (311 mg, 60%).

[0629] Preparation of AJ133-3: AJ133-2 (311 mg, 1.45 mmol) was dissolved in 10 mL of DMF, and then NIS (488 mg, 2.17 mmol) was added to the reaction solution. The reaction solution was heated to 60 °C and reacted at this temperature for 2 h. LCMS detection showed that the raw material reaction was complete. After the reaction solution was cooled, 10 mL of water was added, and a solid precipitate was formed. The solid was filtered by suction under reduced pressure, and the filter cake was dried to obtain crude yellow concentrate solid AJ133-3 (490 mg, 98%).

[0630] Preparation of AJ133-4: CuI (224 mg, 1.17 mmol) was dissolved in 10 mL of DMF. Under stirring at room temperature, N,N ’ -dimethyl ethane-1,2-diamine (129 mg, 1.46 mmol), K2CO3 (122 mg, 0.88 mmol), AJ133-3 (110.5 mg, 0.47 mmol) and 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (197 mg, 0.58 mmol) were added in sequence. The mixed system was heated to 90 o °C under argon protection and stirred and reacted under this condition for about 2 h. LCMS detection showed that the raw material reaction was complete. 10 mL of water was added to the reaction solution for quenching and 10 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phase was dried and concentrated with anhydrous sodium sulfate to obtain a crude concentrate. Column chromatography (PE / EA = 100 / 1 - 2 / 1) was used to obtain light yellow oily solid AJ133-4 (210 mg, 80%).

[0631] Preparation of AJ133-5: AJ133-4 (210 mg, 0.469 mmol) was dissolved in 15 mL of THF solution. The solution was stirred at room temperature and Pd2(dba)3 (64.7 mg, 0.07 mmol), Q-Phos (50.1 mg, 0.07 mmol) and 2-tert-butoxy-2-carbonylethylzinc bromide (4.7 mL of THF solution, 2.35 mmol) were added under argon protection. The mixture was slowly heated to 70 °C and stirred for 2 h. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted three times with EA until the extraction was complete, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to remove the solvent, and the residue was purified by column chromatography (MeOH / DCM = 1 / 100 - 1 / 60) to obtain a white solid AJ133-5 (100 mg, 44.2%).

[0632] Preparation of AJ133-6: AJ133-5 (100 mg, 0.207 mmol) was dissolved in 8 mL of DCM solvent. 2 mL of TFA was added to the reaction solution with stirring at room temperature, and the mixture was stirred for 2 h. LCMS detection showed that the raw materials had completely reacted. Then, the reaction solution was concentrated under reduced pressure to remove DCM and TFA in the reaction solution, and a white solid AJ133-6 (78 mg, 88.6%) was obtained.

[0633] Preparation of AJ133-7: AJ133-6 (30 mg, 0.07 mmol) was dissolved in 5 mL of DMF. AJ10a-2 (27 mg, 0.056 mmol), DIEA (18.06 mg, 0.14 mmol) and HATU (29.4 mg, 0.077 mmol) were added to the reaction solution with stirring at room temperature, and the mixture was stirred at room temperature for about 30 minutes. LCMS detection showed that the raw materials had completely reacted. 10 mL of water was added to the reaction solution, and a solid precipitate formed. The solid was filtered by suction, and the filter cake was dried to obtain the crude product. The crude product was purified by column chromatography (MeOH / DCM = 1 / 100 - 1 / 30) to obtain a white solid AJ133-7 (25 mg, 40%).

[0634] Preparation of AJ133: AJ133-7 (25 mg, 0.027 mmol) was dissolved in a mixed solution of 1 mL of TFA and 1 mL of TfOH, and the reaction mixture was stirred at room temperature for 2 h. LCMS detection showed that the raw material reacted completely. Then, the pH value of the reaction solution was adjusted to neutral with saturated aqueous NaHCO3, and 10 mL of water and 10 mL of EA were added for extraction and liquid separation. The extraction was repeated three times until complete extraction. The organic phases were combined and backwashed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a light brown crude concentrate. Column chromatography (MeCN / water = 1 / 100 - 1 / 3) gave white solid AJ133 (5 mg, 25%). 1 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.67 (s, 1H), 8.58 (d, J = 5.1 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.57 (s, 1H), 7.50 (d, J = 6.7 Hz, 1H), 7.34 (s, 1H), 3.89 (s, 2H), 3.79 (t, J = 6.7 Hz, 2H), 3.59 (s, 2H), 3.50 (s, 2H), 3.24 (d, J = 10.9 Hz, 2H), 2.87 - 2.80 (m, 2H), 2.78 (s, 1H), 2.75 (d, J = 6.8 Hz, 1H), 2.70 (d, J = 7.5 Hz, 2H), 2.66 - 2.60 (m, 2H), 2.58 - 2.52 (m, 2H), 2.48 - 2.41 (m, 1H), 1.91 (d, J = 11.6 Hz, 2H), 1.75 (s, 6H), 1.71 - 1.61 (m, 2H), 1.28 (t, J = 7.4 Hz, 3H). LCMS(ESI) m / z 770.5 [M+H] + .

[0635] Preparation of AJ133b: AJ133b was prepared according to the preparation method of AJ133.

[0636]

[0637] 11H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 10.67 (s, 1H), 8.60 (s,1H), 8.32 (d, J = 8.2 Hz, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.62 (dd, J = 8.1,1.4 Hz, 1H), 7.58 (s, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 4.50-4.41 (m, 1H),4.20-4.11 (m, 1H), 3.96-3.90 (m, 2H), 3.85-3.76 (m, 2H), 3.23-3.17 (m, 1H),3.17-3.09 (m, 2H), 3.08-2.97 (m, 2H), 2.96 (s, 1H), 2.88-2.80 (m, 2H), 2.79-2.76 (m, 1H), 2.74 (d, J = 7.5 Hz, 2H), 2.72-2.69 (m, 1H), 2.67-2.65 (m, 1H),2.64-2.60 (m, 1H), 2.59-2.54 (m, 1H), 2.02-1.89 (m, 2H), 1.77 (s, 6H), 1.49(s, 2H), 1.28-1.26 (m, 3H). LCMS(ESI) m / z 770.5 [M+H] + .

[0638] Preparation of AJ134:

[0639]

[0640] Preparation of AJ134-1: In a 100 mL pressure-resistant reaction flask, dissolve 4-bromo-3-chloro-2-fluoropyridine (1 g, 4.78 mmol) in 15 mL of EtOH. While stirring at room temperature, add 10 mL of 25%-28% ammonia water to the reaction solution. After sealing, heat the reaction system to 100 °C and carry out the reaction in a sealed tube under stirring for 5 h. When the reaction is detected to be complete, cool it to room temperature, add 10 mL of water and 15 mL of EA to the reaction solution for extraction and liquid separation. Repeat the extraction three times until the extraction is complete. Combine the organic phases and wash them with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Obtain the colorless transparent oily compound AJ134-1 (900 mg, 91%) by column chromatography (PE / EA = 100 / 1 - 40 / 1).

[0641] Preparation of AJ134-2: AJ134-1 (900 mg, 4.34 mmol) was dissolved in 15 mL of EtOH. Chloroacetaldehyde (512 mg, 6.52 mmol) was added dropwise under stirring, and the mixture was heated to 80 °C and stirred for 2 h under argon protection. After the reaction was complete, it was cooled to room temperature, the solvent was removed by concentration under reduced pressure, and saturated aqueous NaHCO3 was added dropwise to the reaction solution in an ice bath to adjust the pH of the system to 7. A yellow precipitate was formed, filtered by suction, and the filter cake was washed and dried to obtain a yellow solid AJ134-2 (1 g, 99%).

[0642] Preparation of AJ134-3: AJ134-2 (500 mg, 2.17 mmol) was dissolved in 15 mL of MeCN. NIS (587 mg, 2.61 mmol) was added under stirring, and the mixture was stirred at room temperature for 1 h. After the reaction was complete, the crude product was obtained by concentration under reduced pressure and purified by column chromatography (PE / EA = 100 / 1 - 4 / 1) to obtain a white solid AJ134-3 (712 mg, 92%).

[0643] Preparation of AJ134-4: N,N'-Dimethylethane-1,2-diamine (29 mg, 0.33 mmol) was dissolved in 15 mL of DMF. CuI (127 mg, 0.67 mmol) was added to the reaction solution, and the mixture was stirred for 10 minutes under argon protection. Then, AJ134-3 (356 mg, 1.00 mmol), 3-(4-Methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (195 mg, 0.83 mmol), and Cs2CO3 (814 mg, 2.50 mmol) were added in sequence. The reaction system was heated to 80 °C and stirred for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, 10 mL of water was added to quench the reaction, and 15 mL of EA was added for extraction and liquid separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification by column chromatography (PE / EA = 100 / 1 - 2 / 1) gave a pale yellow solid AJ134-4 (200 mg, 43%).

[0644] Preparation of AJ134-5: Dissolve AJ134-4 (100 mg, 0.22 mmol) in 10 mL of THF solution, stir at room temperature and sequentially add Pd2(dba)3 (23 mg, 0.03 mmol), Q-Phos (30 mg, 0.03 mmol), and 2 mL of 2-tert-butoxy-2-carbonylethylzinc bromide (0.6 mol / L) under argon protection. Slowly heat the reaction system to ...

Claims

1. A compound represented by the following formula (I), its stereoisomers, isotopically labeled compounds, or pharmaceutically acceptable salts thereof; Formula (I) Wherein, Y is selected from O; Z1 is selected from CH or N; Z2 is selected from a single bond, CH2, NH, N(C1-C3 alkyl), NHCO; A is selected from the following groups which are unsubstituted or optionally substituted by 1, 2, 3, or 4 R s1 groups: phenyl, naphthyl, pyridine, indazole, quinoline, quinazine, pyridazine, pyrazine, naphthyridone, benzimidazole, benzopyrazole, benzisoxazole, imidazopyridine, triazolopyridine, pyrazolopyridine, benzopyrazole 、 、 ； Each R s1 which are the same or different and each independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, bromine, nitro, cyano, hydroxy, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 fluoroalkoxy, C1-C3 chloroalkoxy, C1-C3 alkylcarbonylamino, C1-C3 alkylcarbonyl, C1-C3 alkoxycarbonyl, C1-C3 alkylsulfonyl, C1-C3 alkylsulfinyl or C1-C3 alkylthio; U is selected from CH or N; X is selected from CH2, O, S, N(C1-C3 alkyl); R1 is selected from hydrogen; Optionally, a fused ring structure is formed between X and the carbon atoms at positions 1 and 2; Z3 is selected from a single bond, -C(=O)-, -CH2-C(=O)-, -NH-C(=O)-, -C(=O)-NH-CH2-C(=O)-; PTM is selected from the following structures: 、 、 ； J is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 ； L is selected from C1-C3 alkylene, -carbonyl C1-C3 alkyl-; T is selected from di-C1-C3 alkylphosphine oxide group, C1-C3 alkylsulfonyl group, C1-C3 alkylsulfinyl group; R2 to R 14 selected from hydrogen, deuterium, fluorine, chlorine, bromine, C1-C3 alkyl, oxo, -C1-C3 alkyl-phenyl, C1-C3 alkoxy-C(O)-, C1-C3 alkylamino-C(O)-, C1-C3 haloalkyl, C1-C3 alkoxy, hydroxy C1-C3 alkyl; K is selected from C1-C2 alkylene; R S2 selected from hydrogen, fluorine, chlorine, bromine, C1-C3 alkyl, C1-C3 alkoxy; Provided that when A is selected from Z3 is -C(=O)-.

2. The compound of formula (I) according to claim 1, its stereoisomers, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, wherein, A is selected from the following groups which are unsubstituted or optionally substituted by 1, 2, 3, or 4 Rs s1 substituted as follows: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； wherein R s1 has the definition in claim 1.

3. The compound of formula (I) according to claim 1, its stereoisomers, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, wherein, A is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； wherein R s1 has the definition in claim 1.

4. The compound of formula (I), its stereoisomers, isotopically labeled compounds, or pharmaceutically acceptable salts thereof according to claim 1, wherein, A is selected from the following groups: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 5. The compound of formula (I), its stereoisomers, isotopically labeled compounds, or pharmaceutically acceptable salts thereof according to claim 1, wherein, J is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 6. The compound of formula (I), its stereoisomers, isotopically labeled compounds, or pharmaceutically acceptable salts thereof according to claim 1, wherein, J is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 7. The compound of formula (I), its stereoisomers, isotopically labeled compounds, or pharmaceutically acceptable salts thereof according to claim 1, wherein, J is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 8. The compound of formula (I), its stereoisomers, isotope-labeled compounds, or pharmaceutically acceptable salts thereof according to claim 1, wherein, The compound is selected from the following structures: 。 9. A method for preparing the compound of formula (I) according to claim 1, its stereoisomers, isotopically labeled compounds, or pharmaceutically acceptable salts thereof: Scheme 1: The compound represented by formula (II-1) reacts with the reactant PTM-H to obtain the compound represented by formula (I); ； Among them, Z is COOH or CH2COOH, R1, Z1, Z2, Z3, Y, PTM and A have the definitions as described in claim 1, and R has the same definition as R1 in claim 1; or, when R is a protecting group, Scheme 1 further includes a process of deprotecting to obtain the compound of formula (I) with R1 being hydrogen; Or, Scheme 2: The compound represented by formula (II-2) reacts with the reactant PTM-(C=O)-Cl to obtain the compound represented by formula (I); ； Wherein, R1, Z1, Z2, Z3, Y, PTM and A have the definitions as described in claim 1, and R has the same definition as R1 in claim 1; or, when R is a protecting group, Scheme 2 further includes a process of deprotecting to obtain the compound of formula (I) with R1 being hydrogen; Or, Scheme 3: The compound represented by formula (III-1) or formula (III-2) or formula (III-3) reacts with the reactant to obtain the compound represented by formula (I); ; or ; or ； Among them, the reactants are or or ; wherein, R1-R9, Z1, Z2, Z3, Y, R S2 , T, K, PTM, and A have the definitions as described in claim 1; Or, Scheme 4: The compound represented by formula (II-3) reacts with the reactant to obtain the compound represented by formula (I); ; Among them, the reactants are , , , , , or ; wherein, R1-R9, Z1, Z2, Z3, Y, R S2 , T, K, PTM, and A have the definitions as described in claim 1; Or, Scheme 5: The compound represented by formula (II-4) reacts with the compound represented by formula (III-4) to obtain the compound represented by formula (I); ； wherein, R 10 -R 13 , R1, Z1, Z2, Z3, Y, PTM and A have the definitions as described in claim 1, and L’ is selected from C1-C2 alkyl-CHO or C1-C3 alkyl-COOH.

10. A pharmaceutical composition comprising at least one of a therapeutically effective amount of the compound of formula (I) according to claim 1, its stereoisomers, isotopically labeled compounds, or pharmaceutically acceptable salts thereof.

11. Use of the compound of formula (I) according to any one of claims 1-8, its stereoisomers, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 10, in the preparation of a medicament, wherein the medicament is selected from any one of the following: (1) The medicament is a medicament for inhibiting ALK kinase activity; (2) The medicament is a medicament targeting ALK; (3) The medicament is capable of treating or preventing a disease or disorder in which mutant ALK plays a role.

12. Use of the compound of formula (I) according to any one of claims 1-8, its stereoisomers, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 10, in the preparation of a medicament for treating or preventing cancer.

13. The use according to claim 12, wherein the cancer cells of the cancer comprise mutant ALK.

14. The use according to claim 12, wherein the cancer is: lung cancer; lymphoma; inflammatory myofibroblastic tumor; colorectal cancer; glioma; ovarian cancer; myeloid disease; transplantation-related cancer; neutropenia; leukemia; Unverricht-Lundborg syndrome; bronchial carcinoma; prostate cancer; breast cancer; thyroid cancer; pancreatic cancer; neuroblastoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; melanoma; brain cancer; oral cancer; sarcoma; tumors resistant to targeted drugs; or tumors or diseases dependent on ALK protein.

15. The use according to claim 12, wherein the cancer is selected from the group consisting of: small cell lung cancer; non-small cell lung cancer; diffuse large B-cell lymphoma; non-Hodgkin lymphoma; anaplastic lymphoma; anaplastic large cell lymphoma; CD20-positive lymphoma; B-cell lymphoma; recurrent B-cell non-Hodgkin lymphoma; recurrent diffuse large B-cell lymphoma; recurrent mediastinal large B-cell lymphoma; primary mediastinal large B-cell lymphoma; recurrent transformed non-Hodgkin lymphoma; refractory B-cell non-Hodgkin lymphoma; refractory diffuse large B-cell lymphoma; refractory primary mediastinal large B-cell lymphoma; refractory transformed non-Hodgkin lymphoma; multiple myeloma; myelodysplastic syndrome; previously treated myelodysplastic syndrome; plasmacytoma; smoldering myeloma; smoldering multiple myeloma; myelofibrosis; acute myeloid leukemia; anemia associated with leukemia; chronic myeloid leukemia; B-cell chronic lymphocytic leukemia; Unverricht-Lundborg syndrome; bronchial carcinoma; prostate cancer; triple-negative breast cancer; sporadic breast cancer; patients with Cowden disease; thyroid cancer; pancreatic cancer; neuroblastoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; melanoma; brain cancer; oral cancer; rhabdomyosarcoma; various adipose-derived tumors; Ewing sarcoma / peripheral primitive neuroectodermal tumor; leiomyosarcoma; tumors resistant to ALK-targeted drugs; or tumors or diseases dependent on ALK protein.

16. The use according to claim 12, wherein the cancer is selected from the group consisting of: anaplastic lymphoma kinase mutant-positive non-small cell lung cancer; lung cancer resistant to ALK-targeted drugs; lymphoma resistant to ALK-targeted drugs; or the following tumors, cancers or diseases dependent on ALK protein: lung cancer, lymphoma, inflammatory myofibroblastic tumor, colorectal cancer, glioma, ovarian cancer, leukemia, breast cancer, thyroid cancer, neuroblastoma, plasmacytoma, esophageal squamous cell carcinoma, renal cell carcinoma, bronchial carcinoma, prostate cancer, pancreatic cancer, gastric cancer, gastrointestinal stromal tumor, esophageal cancer, colorectal adenocarcinoma, liver cancer, bladder cancer, endometrial cancer, melanoma, brain cancer, oral cancer or sarcoma.

Images