Compound for targeted degradation of ALK protein as well as preparation method and application of compound

Abstract

The invention provides a compound for targeted degradation of ALK protein as well as a preparation method and application thereof, belongs to the field of biological medicines, and particularly relates to a compound as shown in a formula (I), a stereoisomer, a tautomer, an isotope label, nitrogen oxide, a solvate, a polymorphic substance, a metabolite, ester, pharmaceutically acceptable salt or prodrug or a pharmaceutical composition thereof. The compound can be used for preparing anti-tumor drugs, is high in oral availability and capable of penetrating the brain, has high-specificity ALK degradation property, and overcomes the problem of drug resistance. # imgabs0 # formula (I)

Description

Technical Field

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

[0002] Anaplastic lymphoma kinase (ALK) is a transmembrane protein tyrosine kinase that belongs to the insulin receptor kinase subfamily. It was first discovered in anaplastic large cell lymphoma (ALCL) with a nucleophosmin (NPM)-ALK fusion form, a subtype of T-cell non-Hodgkin lymphoma that is often associated with chromosomal translocations. Since then, many cancers have been found to be associated with 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, ALK gene amplification 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, in part because its levels in normal adult tissues are low, which is thought to reduce the chance of off-target toxicity caused by ALK inhibitors. Therefore, therapeutic strategies that inhibit ALK kinase activity are thought to produce fewer side effects. To date, the U.S. Food and Drug Administration (FDA) has approved five 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 sustained 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 the inability to clear abnormal proteins leads to drug resistance, which has become a major obstacle to clinical efficacy. Resistance to ALK inhibition remains a severe challenge. Therefore, there is an urgent need to develop new ALK drugs and alternative targeted ALK approaches to overcome new strategies for 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. Unfortunately, the ALK degraders reported so far generally have limitations such as low specificity, poor oral anti-tumor efficacy in vivo, and poor brain penetration, which cannot generate clinical value. It is urgent to develop ALK degraders with high oral availability, brain penetration, and high specificity. Summary of the invention

[0005] In order to improve the above technical problems, the present invention provides a B CRBN -Z 3 -PTM structured compound, its stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug, wherein B CRBN Z is the part that can bind to the ubiquitin enzyme CRBN. 3 is a linker moiety, PTM is a moiety capable of binding to kinase ALK; CRBN -Z 3 The compound of -PTM structure is a compound represented by the following formula (I) or formula (I');

[0006]

[0007] Formula (I)

[0008]

[0009] Formula (I')

[0010] in or It is a part that can bind to the ubiquitin enzyme CRBN;

[0011] In formula (I),

[0012] Y is selected from O, S;

[0013] Z 1 is selected from CH or N;

[0014] Z 2 Selected from single bond, CH 2 , O, S, NR 1 , NHCO;

[0015] A is selected from unsubstituted or optionally substituted with 1, 2, 3, or 4 R s1 Substituted with the following groups: aryl, heteroaryl, , or ;

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

[0017] Each R s1 are the same or different and are independently selected from the following groups: hydrogen, deuterium, halogen, nitro, cyano, hydroxyl, amino, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Halogenated alkoxy, C 1 -C 6 Alkylcarbonylamino, C 1 -C 6 Alkylcarbonyl, C 1 -C 6 Alkoxycarbonyl, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkylsulfinyl or C 1 -C 6 Alkylthio;

[0018] U is selected from CH or N;

[0019] X is selected from CH 2 , O, S, NR 1 ;

[0020] R 1 are independently selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, -CH 2 -C(=O)-R s3 、-C(=O)-R s3 、-CH(R')-OC(=O)-R s3、-CH 2 -OP(=O)(OR s3 ) 2 、-C(=O)O-CH(R')-OC(=O)-R s3 ; R', R s3 are the same or different and are independently selected from hydrogen, C 1 -C 6 Alkyl, 6-20 membered aryl, 5-20 membered heteroaryl;

[0021] Z 4 is selected from CH, C=O or C=S, and when Z 4 When selected from C=O or C=S, is a single bond, when Z 4 When selected from CH, is a double bond; optionally, X, U and adjacent carbon atoms therebetween form a condensed ring structure;

[0022] Z 3 For covalent bonds or C 1 -C 10 Alkyl, the C 1 -C 10 Any carbon atom in the alkyl group may be optionally replaced by NH, O, S or substituted by an oxo (=O) group;

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

[0024] The condition is that when A is selected from When Z 3 is -C(=O)-;

[0025] In formula (I'), Z 1 Select from N; R 1 , Z 2 , Z 3 , Y, PTM and ring A are as defined above.

[0026] According to an embodiment of the present invention, R 1 are independently selected from hydrogen, C 1 -C 3 alkyl;

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

[0028] According to an embodiment of the present invention, Z 2 Selected from single bond, CH 2 , O, S, NH, NCH 3 , NHCO;

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

[0030] Optionally, X forms a fused ring structure with the carbon atoms at positions 1 and 2, such as a fused benzene ring;

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

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

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

[0034] According to an embodiment of the present invention, each R s1 are the same or different and are independently selected from the following groups: hydrogen, deuterium, fluorine, chlorine, bromine, nitro, cyano, hydroxyl, amino, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Fluoroalkoxy, C 1 -C 3 Chloroalkoxy, C 1 -C 3 Alkylcarbonylamino, C 1 -C 3 Alkylcarbonyl, C 1 -C 3 Alkoxycarbonyl, C 1 -C 3 Alkylsulfonyl, C 1 -C 3 Alkylsulfinyl or C 1 -C 3 Alkylthio;

[0035] According to an embodiment of the present invention, A is selected from the following structures, wherein R s1 With the same definition as 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, Z 4 Selected from C=O or C=S, is a single bond, or Z 4 Selected from CH, is a double bond;

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

[0041] According to an embodiment of the present invention, Z 3 Selected from single bond, -C(=O)-, -C 1 -C 6 Alkyl-C(=O)-, -C(=O)-C 1 -C 6 Alkyl-, -NH-C(=O)-, -C(=O)-NH-C 1 -C 6 Alkyl-C(=O)-;

[0042] According to an embodiment of the present invention, Z 3 Selected from single bond, -C(=O)-, -C 1 -C 3 Alkyl-C(=O)-, -C(=O)-C 1 -C 3 Alkyl-, -NH-C(=O)-, -C(=O)-NH-C 1 -C 3 Alkyl-C(=O)-;

[0043] According to an embodiment of the present invention, Z 3 Selected from single bond, -C(=O)-, -CH 2 -C(=O)-、-C(=O)- CH 2 -、-NH-C(=O)-、-C(=O)-NH-CH 2 -C(=O)-;

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

[0045] , , , , , , , , ;

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

[0047] , , , , , , , , , , ;

[0048] L is selected from C 1 -C6 Alkylene, -C 1 -C 6 Alkylcarbonyl-;

[0049] T is selected from di-C 1 -C 6 Alkylphosphine oxide group, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkylsulfinyl;

[0050] R 2 To R 15 Selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, oxo, -C 1 -C 6 Alkyl-phenyl, C 1 -C 6 Alkoxy-C(O)-, C 1 -C 6 Alkylamino-C(O)-, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, hydroxyl C 1 -C 6 alkyl;

[0051] K is selected from C 1 -C 3 Alkylene, NH;

[0052] R S2 Selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy.

[0053] According to an embodiment of the present invention, PTM is selected from the following structures, wherein L, R 2 To R 15 , K, R S2 With the same definition as above:

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

[0055] According to an embodiment of the present invention, L is selected from C1 -C 3 Alkylene, -C 1 -C 3 Alkylcarbonyl-;

[0056] According to an embodiment of the present invention, T is selected from di-C 1 -C 3 Alkylphosphine oxide, C 1 -C 3 Alkylsulfonyl, C 1 -C 3 Alkylsulfinyl;

[0057] According to an embodiment of the present invention, R 2 To R 15 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, C 1 -C 3 Alkyl, oxo, -C 1 -C 3 Alkyl-phenyl, C 1 -C 3 Alkoxy-C(O)-, C 1 -C 3 Alkylamino-C(O)-, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, hydroxyl C 1 -C 3 alkyl;

[0058] According to an embodiment of the present invention, K is selected from C 1 -C 2 Alkylene;

[0059] According to an embodiment of the present invention, R S2 Selected from hydrogen, fluorine, chlorine, bromine, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy;

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

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

[0062] Wherein 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 Z 3 The right end is connected to the group fragment in the PTM, and it can also be connected to the adjacent structure in the opposite direction of the writing format, that is, the right end is connected to Z 3 The left end is connected to the group fragment in the PTM.

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

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

[0065] Wherein 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, or can be connected to the adjacent structure 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 an embodiment of the present invention, J is selected from the following structures:

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

[0068] Wherein 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, or can be connected to the adjacent structure 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 an embodiment of the present invention, the compound represented by formula (I), its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs;

[0070]

[0071] Formula (I)

[0072] in,

[0073] Y is selected from O, S;

[0074] Z 1 is selected from CH or N;

[0075] Z 2 Selected from single bond, CH 2 , O, S, NR 1 , NHCO;

[0076] A is selected from unsubstituted or optionally substituted with 1, 2, 3, or 4 R s1 Substituted from the following groups: phenyl, naphthyl, pyridine, indazole, quinoline, quinolizine, pyridazine, pyrazine, naphthyridinone, benzimidazole, benzopyrazole, benzisoxazole, imidazopyridine, triazolopyridine, pyrazolopyridine, benzopyrazole,

[0077] , , , , ;

[0078] Each R s1are the same or different and are independently selected from the following groups: hydrogen, deuterium, halogen, nitro, cyano, hydroxyl, amino, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Halogenated alkoxy, C 1 -C 6 Alkylcarbonylamino, C 1 -C 6 Alkylcarbonyl, C 1 -C 6 Alkoxycarbonyl, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkylsulfinyl or C 1 -C 6 Alkylthio;

[0079] U is selected from CH or N;

[0080] X is selected from CH 2 , O, S, NR 1 ;

[0081] R 1 are independently selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, -CH 2 -C(=O)-R s3 、-C(=O)-R s3 、-CH(R')-OC(=O)-R s3 、-CH 2 -OP(=O)(OR s3 ) 2 、-C(=O)O-CH(R')-OC(=O)-R s3 ; R', R s3 are the same or different and are independently selected from hydrogen, C 1 -C 6 Alkyl, 6-20 membered aryl, 5-20 membered heteroaryl;

[0082] Optionally, X forms a fused ring structure with the carbon atoms at positions 1 and 2, such as a fused benzene ring;

[0083] Z 3 Selected from single bond, -C(=O)-, -C 1 -C 6 Alkyl-C(=O)-, -C(=O)-C 1 -C 6 Alkyl-, -NH-C(=O)-, -C(=O)-NH- C 1 -C 6 Alkyl-C(=O)-;

[0084] The PTM is selected from the following structures:

[0085] , , , ;

[0086] Among them, J, T, R S2 Has the same definition as above;

[0087] The condition is that when A is selected from When Z 3 It is -C(=O)-.

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

[0089]

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

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

[0092]

[0093] wherein, Z is COOH or CH 2 COOH, R 1 , Z 1 , Z 2 , Z 3 , Y, PTM and ring A have the definitions as described above, and R has the same definition as R 1 described above; or, when R is a protecting group, Scheme 1 further includes a process of deprotecting to prepare a compound of formula (I) in which R 1 is hydrogen;

[0094] Or, Scheme 2: A compound represented by formula (II-2) reacts with a reactant PTM-(C=O)-Cl to obtain a compound represented by formula (I);

[0095]

[0096] wherein, R 1 , Z 1 , Z 2 , Z 3 , Y, PTM and ring A have the definitions as described above, and R has the same definition as R 1 described above; or, when R is a protecting group, Scheme 2 further includes a process of deprotecting to prepare a compound of formula (I) in which R 1 is hydrogen;

[0097] Or, Scheme 3: A compound represented by formula (III-1) or formula (III-2) or formula (III-3) reacts with a reactant to obtain a compound represented by formula (I);

[0098] ; or

[0099] ; or

[0100]

[0101] wherein, the reactant is or or ;

[0102] wherein, R 1 -R 9 , Z 1 , Z 2 , Z 3 , Y, R S2 , T, K, PTM and ring A have the definitions as described above;

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

[0104] ;

[0105] Among them, the reactants are , , , , , or ;

[0106] Among them, R 1 -R 9 , Z 1 , Z 2 , Z 3 , Y, R S2 , T, K, PTM and Ring A are as defined above;

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

[0108]

[0109] Among them, R 10 -R 13 , R 1 , Z 1 , Z 2 , Z 3 , Y, PTM and ring A are as defined above, L' is selected from C 1 -C 5 Alkyl-CHO or C 1 -C 5 Alkyl-COOH.

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

[0111] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound of 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 composition of the present invention can be prepared into a dosage form suitable for administration by methods known in the art.

[0116] When used as a drug, the compounds of the present invention can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical field, and they can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. It can be administered topically (e.g., transdermally, skin, eye and mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizers; intratracheal, intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. It can be administered parenterally in a single bolus form, or it can be administered by, for example, a continuous infusion pump. Topically administered pharmaceutical compositions and preparations can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, water, powders or oily bases, thickeners, etc. may be necessary or required.

[0117] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. The formulation may also contain: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners and flavoring agents. The composition of the present invention may be formulated using methods known in the art to provide an immediate release, sustained release or delayed release of the active ingredient after administration to the patient.

[0118] The tablets or pills of the present invention may be coated or compounded to obtain dosage forms that provide the advantage of prolonged action. For example, the tablet or pill contains an inner dose and an outer dose component, the latter being a film-coated form of the former. The two components may be isolated by an enteric layer that is used to prevent disintegration in the stomach so that the inner component passes intact through the duodenum or is delayed in release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids and such materials as shellac, cetyl alcohol, and cellulose acetate.

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

[0120] Compositions for inhalation or insufflation include solutions and suspensions, powders dissolved in pharmaceutically acceptable water or organic solvents or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In certain embodiments, the composition is administered by oral or nasal respiratory route to achieve local or systemic effect. The composition may be aerosolized by the use of an inert gas. The aerosolized solution may be inhaled directly from the aerosolizing device, or the aerosolizing device may be connected to a mask curtain or an intermittent positive pressure breathing machine. The solution, suspension or powder composition may be administered orally or by a device that delivers the formulation in an appropriate manner through the nose.

[0121] The amount of compound or composition administered to a patient is not fixed and depends on the drug being administered, the purpose of administration, such as prevention or treatment; the patient's condition, the mode of administration, etc. In therapeutic applications, a patient already suffering from a disease may be administered a composition in an amount sufficient to cure or at least partially suppress the symptoms of the disease and its complications. The effective dose will 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 patient's age, weight and general condition.

[0122] The present invention also provides a method for inhibiting ALK and / or mutated ALK, comprising administering to a subject in need thereof an effective amount of a compound of formula I of the present invention, its stereoisomers, tautomers, isotope labels, nitrogen 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 kinase plays a role, comprising administering to a subject in need thereof an effective amount of a compound of formula I of the present invention, its stereoisomers, tautomers, isotope labels, nitrogen 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 ALK targeted therapy.

[0125] The present invention also provides a method for inhibiting tumor cell proliferation in vitro or in vivo, which comprises contacting tumor cells with an effective amount of the compound of formula I of the present invention, its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions 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 as shown in Formula I, its stereoisomers, tautomers, isotope labels, nitrogen 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 conditions 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, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition thereof.

[0128] The present invention also provides the use of the compound of formula I, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or pharmaceutical compositions thereof in the preparation of a drug, wherein the drug is selected from any one of the following:

[0129] (1) The drug is a drug used to inhibit ALK kinase activity, or the drug is an ALK kinase inhibitor;

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

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

[0132] (4) The drug is capable of treating or preventing cancer in a subject identified as requiring inhibition of mutated ALK to treat or prevent cancer;

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

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

[0135] In some embodiments, the cancer is, for example, lung cancer; lymphoma; inflammatory myofibroblastic tumor; colorectal cancer; glioma; astrocytoblastoma; ovarian cancer; bone marrow disease; transplant-related cancer; neutropenia; leukemia; Unverheit syndrome; bronchogenic 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; 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's lymphoma; anaplastic lymphoma; anaplastic large cell lymphoma; CD20 positive lymphoma; primary lymphoma; B-cell lymphoma; relapsed B-cell non-Hodgkin's lymphoma; relapsed diffuse large B-cell lymphoma; relapsed mediastinal (thymic) large B-cell lymphoma; primary mediastinal (thymic) large B-cell lymphoma; relapsed transformed non-Hodgkin's lymphoma; refractory B-cell non-Hodgkin's lymphoma; refractory diffuse large B-cell lymphoma; refractory primary mediastinal (thymic) large B-cell lymphoma; refractory transformed non-Hodgkin's 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 myeloid leukemia; B-cell chronic lymphocytic leukemia; Ongwericht syndrome; bronchogenic 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 tumors; 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 / primitive neuroectodermal tumors (Ewing / PNETs); leiomyosarcoma; tumors resistant to ALK-targeted drugs; or tumors or diseases that depend on the ALK protein.

[0137] In some embodiments, the cancer is selected from the group consisting of: non-small cell lung cancer that is positive for anaplastic lymphoma kinase (ALK) mutation; lung cancer that is resistant to ALK targeted drugs; lymphoma that is resistant to ALK targeted drugs; or the following tumors, cancers, or diseases that depend 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 cancer, 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) of the present invention, its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs or pharmaceutical compositions thereof can be used to prepare anti-tumor drugs, which have high oral availability, can penetrate the brain, have highly specific ALK degradation properties, and overcome the problem of drug resistance.

[0141] Definition and explanation of terms

[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 arbitrarily combined and combined with each other. The group definitions and compound structures after such combination and combination shall fall within the scope recorded in the specification of this application.

[0143] In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds. When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH 2 O is equivalent to OCH 2 .

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

[0145] The term "a 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" refers to fluorine, chlorine, bromine and iodine.

[0148] The term "C 1 -C 10 "Alkyl" is understood to mean preferably a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 10 carbon atoms. For example, "C 1 -C 6The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, 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, or the like or isomers thereof.

[0149] The term "aryl" is understood to preferably mean a monovalent aromatic or partially aromatic monocyclic or bicyclic (such as fused, bridged, or spiro) hydrocarbon ring having 6 to 20 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together, also referred to as "C 6 -C 20 The term "6-10 membered aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic or bicyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms, in particular a ring having 6 carbon atoms ("C 6 aryl), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, it may be substituted at the ortho, para or meta position.

[0150] The term "heteroaryl" is understood to include 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, also noted as "5-20 membered heteroaryl", preferably "5- or 6-membered heteroaryl". The term "5- to 10-membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9, 10 ring atoms, in particular 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, in each case, may additionally be benzo-fused. The heteroaryl may be selected from "5- or 6-membered heteroaryl", i.e. including 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 group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolyl, quinazolinyl, isoquinolyl, quinoxalinyl, etc.; or isothiazolopyrimidinyl, imidazopyridinyl, azinyl, indolizinyl, purinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, triazolopyridinyl, pyrazolopyridinyl, etc.

[0151] Unless otherwise specified, heteroaryl includes all possible isomeric forms thereof, such as positional isomers thereof. 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-mentioned term "alkyl" such as "C 1- C 6 The definition of "alkyl" also applies to compounds containing "C 1- C 6 Other terms for "alkyl", such as the term "C 1- C 6 Alkoxy", "C 1- C 6 Haloalkyl", "C 1- C 6 Haloalkoxy", "C 1 -C 6 Alkoxycarbonyl", "C 1 -C 6 Alkylcarbonyl", "C 1 -C 4 Alkylsulfonyl", "C 1 -C 4Alkylsulfinyl", "C 1 -C 4 "Alkylthio" etc.

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

[0154] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like.

[0155] The term "tautomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

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

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

[0158] The term "solvate" refers to an association formed by one or more solvent molecules and the compounds 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 formed by a solvent molecule that is water.

[0159] The term "metabolite" refers to a product obtained by the metabolism of a specific compound or its salt in vivo. The metabolite of a compound can be identified by techniques known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of the compound, including metabolites produced by contacting the compound of the present invention with a mammal for a period of time.

[0160] The term "ester" refers to an in vivo hydrolyzable ester formed by a compound containing a hydroxyl or carboxyl group. Such an ester is, for example, a pharmaceutically acceptable ester that is hydrolyzed in the human or animal body to produce the parent alcohol or acid. The compound of formula (I) of the present invention contains a carboxyl group and can form an in vivo hydrolyzable ester with a suitable group, such groups include, but are 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, and most preferably humans.

[0162] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: for example, inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: for example, alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. DETAILED DESCRIPTION

[0163] The technical solution 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 exemplary illustrations and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included in the scope of protection intended by the present disclosure.

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

[0165] Abbreviations used in this application:

[0166] AcOH: acetic acid; AIBN: azobisisobutyronitrile; Boc: tert-butyloxycarbonyl; Boc 2 O: di-tert-butyl dicarbonate; Br 2 : bromine; BTI: [bis(trifluoroacetyloxy)iodo]benzene; CDI: N,N'-carbonyldiimidazole; CHCl 3 : chloroform; CO: carbon monoxide; CO 2 : Carbon dioxide; (COCl 2 ) 3 : Triphosgene; Cs 2 CO 3 : 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-d 6 : deuterated dimethyl sulfoxide; EA: ethyl acetate; Et 3 N: triethylamine; EtOH: ethanol; h: hour; HATU: 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate; HCl: hydrochloric acid; 1H NMR: nuclear magnetic resonance; HNO 3 : nitric acid; i-PrOH: isopropanol; K 2 CO 3 : potassium carbonate; KHMDS: potassium bis(trimethylsilyl)amide; LCMS: liquid chromatography-mass spectrometry; LiOH: lithium hydroxide; MeCN: acetonitrile; MeOH: methanol; mol / L: mole / liter; MsOH: methanesulfonic acid; NaBH 3 CN: sodium cyanoborohydride; NaH: sodium hydride; NaHB(OAc) 3 : Sodium triacetoxyborohydride; NaHCO 3 : sodium bicarbonate; NaOH: sodium hydroxide; NBS: N-bromosuccinimide; n-BuLi: n-butyllithium; NMI: N-methylimidazole; NMP: N-methylpyrrolidone; NIS: N-iodosuccinimide; Pd 2 (dba) 3 : tris(dibenzylideneacetone)dipalladium; Pd / C: palladium on carbon; Pd(dppf)Cl 2 DCM: [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex; Pd(OH) 2 / C: palladium hydroxide on carbon; PE: petroleum ether; PMB: p-methoxybenzyl; Q-Phos: 1,2,3,4,5-pentylphenyl-1-(di-tert-butylphosphino)ferrocene; t-BuOK: potassium tert-butoxide; TCFH: N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate; Tf 2 O: 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'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II); RuPhosPdG3: methanesulfonic acid(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, and 1-Boc-4-(piperidin-4-yl)-piperazine (245 mg, 0.91 mmol), Pd 2 (dba) 3 (42mg, 0.05mmol), X-Phos (32mg, 0.05mmol) and KHMDS (1.8mL, 1.82mmol), and protected with argon. The mixed system was heated to 80℃ and stirred for about 3h. After the reaction was completed, the reaction system was cooled to room temperature, 15mL of water was added to the reaction solution for quenching, and 10mL of EA was added for extraction and 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, which was purified by column chromatography (PE / EA=100 / 1-2 / 1) to obtain a light yellow solid AJ10a-1 (216mg, 82%).

[0171] Preparation of AJ10a-2: AJ10a-1 (200 mg, 0.34 mmol) was dissolved in 10 mL DCM, 3 mL TFA was added dropwise to the reaction system at room temperature, and the reaction was continued with stirring for about 1 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. The solvent DCM and excess TFA were removed by concentration under reduced pressure to obtain a light 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 DMF, and Et 3 N (12mg, 0.13mmol) and HATU (15.8mg, 0.04mmol) were added and stirred for about 1h. 10mL of water was added to the reaction solution for quenching and 10mL of EA was added for extraction and 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. AJ10a (19mg, 61%) was purified by reverse phase preparation (MeCN / water = 1 / 100-1 / 4) to obtain a white solid. 1 H NMR (400 MHz, DMSO-d 6) 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: 2-Fluoro-4-bromonitrobenzene (2.0 g, 9.1 mmol) and methylamine hydrochloride (0.7 g, 10.9 mmol) were dissolved in 30 mL MeCN and K 2 CO 3 (2.5 g, 18.2 mmol), stirred at room temperature for 4 h. Concentrated under reduced pressure, 50 mL of water was added to the reaction solution for dilution and 20 mL of EA was added for extraction and 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 phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a light 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 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. 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 K 2 CO 3 (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 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 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 Pd 2 (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 70o C and stirred for 2 h. After the reaction was completed, saturated ammonium chloride solution was added to the reaction solution for quenching, EA was extracted, the organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by column chromatography (MeOH / DCM=1 / 100-1 / 40) to obtain an off-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 TfOH and 2 mL 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 DMF, and Et 3 N (6mg, 0.063mmol) and HATU (14mg, 0.038mmol), continue stirring the reaction for about 1h. Add 10mL of water to the reaction solution for quenching and add 10mL of EA for extraction and separation, and 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 by reverse phase preparation (MeCN / water=1 / 100-1 / 4) to obtain a white solid AJ11 (5mg, 20%). 1 HNMR (400 MHz, DMSO-d 6) 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 / z781.6 [M+H] + .

[0182] Preparation of AJ12:

[0183]

[0184] Preparation of AJ12-1: AJ11-1 (1.7 g, 7.4 mmol) and 1-Boc-piperazine (1.5 g, 8.1 mmol) were dissolved in 25 mL NMP, and DIEA (1.4 g, 11.0 mmol) was added at room temperature. The mixture was heated to 110 o C and stirred for about 4h. LCMS detection showed that the reaction was complete and then the temperature was lowered. 40mL of water was added to the reaction solution for quenching and 15mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phases were dried and concentrated with anhydrous sodium sulfate to obtain a pale yellow concentrate crude product. A pale yellow solid AJ12-1 (2.1g, 83%) was obtained by column chromatography (EA / PE=1 / 100-1 / 2).

[0185] Preparation of AJ12-2: AJ12-1 (2.1 g, 6.3 mmol) was dissolved in 30 mL THF solution, Pd / C (content 10%, 200 mg) was added, hydrogen was replaced three times, and the reaction was carried out at room temperature for 3 h. LCMS detected that the reaction was complete. The filter cake was filtered and rinsed twice with 10 mL THF. The combined filtrate was concentrated under reduced pressure to obtain a light yellow solid AJ12-2 (1.7 g, 90%).

[0186] Preparation of AJ12-3: AJ12-2 (1.7 g, 5.6 mmol) and CDI (1.1 g, 6.8 mmol) were dissolved in 30 mL of MeCN. o C and stirred for 3h, and MeCN was removed by rotary evaporation. 40mL of water was added to the reaction solution to quench it, and 15mL of EA was added to extract the liquid, 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 phases were dried and concentrated with anhydrous sodium sulfate to obtain a crude product. A light yellow solid AJ12-3 (1.4g, 78%) was obtained by column chromatography (EA / PE=1 / 100-1 / 1).

[0187] Preparation of AJ12-4: AJ12-3 (500 mg, 1.5 mmol) was dissolved in 10 mL THF and cooled to 0 o C and NaH (60%, 181 mg, 4.5 mmol) was added in batches under stirring. After about 30 minutes, 3-bromopiperidine-2,6-dione (434 mg, 2.3 mmol) was added. The reaction solution was heated to 60 o C for 2h. LCMS detected that the reaction was complete and cooled to room temperature. Slowly poured into 40mL ice water, and extracted with 15mL EA, 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 and concentrated with anhydrous sodium sulfate to obtain a light yellow crude product. Purification by column chromatography (EA / PE=1 / 10-2 / 1) gave a light yellow solid AJ12-4 (287mg, 43%).

[0188] Preparation of AJ12-5: AJ12-4 (287 mg, 0.65 mmol) was dissolved in 10 mL of DCM, and 2 mL of dioxane hydrochloride solution (4 M) was added under stirring at room temperature. The resulting solution was stirred at room temperature for 2 h, and the solvent was removed by concentration under reduced pressure to obtain a light yellow solid AJ12-5 (211 mg, 95%).

[0189] Preparation of AJ12: AJ12-5 (34 mg, 0.1 mmol) was dissolved in 4 mL DMF, AJ12-6 (53 mg, 0.13 mmol) and DIEA (13 mg, 0.1 mmol) were added under stirring at room temperature, stirred for about 1 h, and then NaBH 3 CN (13mg, 0.2mmol), continue stirring at room temperature for about 4h. Detection reaction is complete, add 10mL water to the reaction solution for quenching, add 10mL EA for extraction and separation, repeat extraction three times until extraction is complete. Combine organic phases and dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude concentrate. White solid product AJ12 (33mg, 45%) is obtained by column chromatography (MeOH / DCM=1 / 100-1 / 30). 1 H NMR (400MHz, DMSO-d 6 ) 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 DMF and K was added under stirring at room temperature. 2 CO 3 (92 mg, 0.67 mmol), the reaction system was slowly heated to 80 o C for about 6h. After the detection reaction is complete, it is cooled to room temperature, 10mL of water is added to the reaction solution for quenching and 10mL of EA is added for extraction and separation, and the extraction is repeated three times until the extraction is complete. The organic phases are combined and backwashed with saturated brine, the organic phase is 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) gives a yellow solid AJ12a-1 (115mg, 56%).

[0193] Preparation of AJ12a-2: AJ12a-1 (115mg, 0.18mmol) and zinc powder (60mg, 0.93mmol) were dissolved in 5mL DCM, and AcOH (55mg, 0.93mmol) was slowly added dropwise under stirring at room temperature and the reaction was continued for 1h. LCMS detection showed that the reaction was complete, 10mL of water was added to the reaction solution for quenching and 10mL of DCM was added for extraction and 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, and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (DCM / MeOH=100 / 1-20 / 1) gave a yellow solid AJ12a-2 (88mg, 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 DMF and NaHCO was added under stirring at room temperature. 3 (25 mg, 0.3 mmol), the reaction system was slowly heated to 100 o C reaction for about 18h. LCMS detection shows that the reaction is complete, and it is cooled to room temperature. 10mL of water is added to the reaction solution for quenching and 10mL of EA is added for extraction and separation. The extraction is repeated three times until the extraction is complete. The organic phases are combined and backwashed with saturated brine, the organic phase is 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) gives a yellow solid AJ12a (20mg, 19%). 1 H NMR (400 MHz, DMSO-d 6) 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 = 7.7Hz, 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: AJ11-1 (1.0 g, 4.4 mmol) was dissolved in 15 mL DMF, and then K 2 CO 3(1.2g, 8.7mmol) and 4-piperidone ethylene glycol acetal (630mg, 4.4mmol), the reaction solution was heated to 100℃ for 2h. LCMS detection showed that the raw materials had reacted completely. Cool to room temperature, add 20mL of water to the reaction solution for dilution and add 15mL of EA for extraction and separation, and 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 by column chromatography (EA / PE=1 / 100-1 / 1) to obtain a pink solid AJ12b-1 (1.17g, 97%).

[0198] Preparation of AJ12b-2: AJ12b-1 (1.2 g, 4 mmol) was dissolved in 20 mL THF, and 10% Pd / C (10%, 120 mg) was added under stirring at room temperature, replaced with hydrogen and continued to stir at room temperature for 3 h under hydrogen atmosphere. LCMS detection showed that AJ12b-1 was completely reacted. Pd-carbon was removed by vacuum filtration, and the palladium carbon was rinsed three times with 20 mL THF. The organic phases were combined and concentrated under reduced pressure to obtain a brown solid concentrated product AJ12b-2 (1.04 g, 99%).

[0199] Preparation of AJ12b-3: AJ12b-2 (500 mg, 1.90 mmol) was dissolved in 10 mL MeCN solution, CDI (920 mg, 5.70 mmol) was added under stirring at room temperature, and the temperature was raised to 80 o C and stirred for 2 h. After the reaction was complete, the reaction solution was cooled and 20 mL of water was added to precipitate solids, which were filtered under reduced pressure and the filter cake was dried to obtain a brown solid AJ12b-3 (540 mg, 99%).

[0200] Preparation of AJ12b-4: AJ12b-3 (540 mg, 1.9 mmol) was dissolved in 5 mL DMF, 3-bromopiperidine-2,6-dione (433.2 mg, 2.3 mmol) and NaH (60%, 228 mg, 5.7 mmol) were added under stirring at room temperature, and the mixture was heated to 70 o C stirring reaction for about 8h. LCMS detection shows that the raw material reaction is complete. After the reaction solution is cooled to room temperature, it is poured into 5mL dilute hydrochloric acid (2M) aqueous solution for quenching, and 10mL EA is added to extract the liquid, and the extraction is repeated three times until the extraction is complete. The organic phases are combined and backwashed with saturated brine, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. Purified by column chromatography (EA / PE=1 / 100-1 / 1) to obtain a brown solid AJ12b-4 (400mg, 53%).

[0201] Preparation of AJ12b-5: AJ12b-4 (400 mg, 0.99 mmol) was dissolved in 15 mL of DCM solution, and 2 mL of dioxane solution (4 M) of hydrochloric acid was added to the reaction solution under stirring at room temperature, and the reaction was stirred at room temperature for 1 h. LCMS detection showed that the raw material reaction was complete. The reaction solution was concentrated under reduced pressure and dried, and the residue was purified by column chromatography (EA / PE=1 / 100-1 / 1) to obtain a brown solid AJ12b-5 (60 mg, 17%).

[0202] Preparation of AJ12b: AJ12b-5 (60 mg, 0.17 mmol) was dissolved in 5 mL DMF, and then AJ12b-6 (69 mg, 0.17 mmol, prepared according to the preparation method of AJ10a-2) was added under stirring at room temperature and stirred at room temperature for 1 h. Then NaHCO was added to the reaction solution. 3 (29 mg, 0.34 mmol) and NaHB(OAc) 3 (72mg, 0.34mmol), and continue to stir the reaction for about 4h. Wait until LCMS detection shows that AJ12b-5 reacts completely. Add 10mL of water to the reaction solution for quenching and add 10mL of EA for extraction and separation, and 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 by column chromatography (MeOH / DCM=1 / 100-1 / 20) to obtain a white solid AJ12b (10mg, 8%). 1 H NMR (400 MHz, DMSO-d 6) 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: o C, AJ13-0 (2.1 g, 12.43 mmol) was dissolved in 20 mL CHCl 3 Bromine (0.64 mL, 12.43 mmol) was added dropwise over 5 minutes with sufficient stirring. After the addition was complete, the reaction solution was slowly warmed to room temperature and the reaction was continued for 6 hours. 20 mL of water was added to the reaction solution to quench it and 20 mL of CHCl 3 The extraction was repeated three times until the extraction was complete. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow-brown concentrate. A yellow solid AJ13-1 (2.9 g, 95%) was obtained by column chromatography (DCM / MeOH=100 / 1-30 / 1).

[0206] Preparation of AJ13-2: at -70 o C, AJ13-1 (600mg, 2.43mmol) was dissolved in 10mL dry THF, NaH (583mg, 24.29mmol) was added in batches under stirring and reacted at low temperature for 1h, and then 3-bromopiperidine-2,6-dione (1.4g, 7.29mmol) was added to continue the reaction for 4h. Warm to room temperature, add 50mL of water to the reaction solution to quench and add 20mLEA to extract and separate, and repeat the extraction three times until the extraction is complete. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (DCM / MeOH=100 / 1-30 / 1) gave AJ13-2 (500mg, 57%) as a white solid.

[0207] Preparation of AJ13-3: AJ13-2 (500 mg, 1.40 mmol) was dissolved in 20 mL THF solution, and Pd 2 (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), the reaction solution was slowly heated to 70 o C and stirred for 5 h. After the reaction was completed, saturated ammonium chloride solution was added to the reaction solution for quenching, EA was extracted, the organic phases were combined and collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to remove the solvent, and the concentrate was purified by column chromatography (MeOH / DCM=1 / 100-1 / 30) to obtain a 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. The solvent was removed by rotary evaporation and purified by reverse phase preparation (MeCN / water = 1 / 100-1 / 4) to give a 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, AJ13-5 was prepared according to the preparation method of AJ10a-2) were dissolved in 5 mL of DMF, and Et 3N (13mg, 0.133mmol) and HATU (20mg, 0.053mmol) were added, and the reaction was continued for about 1h. 8mL of water was added to the reaction solution to quench and 10mL of EA was added for extraction and 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. After reverse phase preparation (MeCN / water = 1 / 100-1 / 2), the white solid product AJ13 (12mg, 32%) was obtained. 1 H NMR (400 MHz, DMSO-d 6 ) 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 Boc2 O (1.2 g, 5.6 mmol) was dissolved in 20 mL of tert-butyl alcohol, and DMAP (46 mg, 0.38 mmol) was added under stirring at room temperature. The resulting solution was heated to 40 o C stirring reaction for about 8h. After the detection reaction is complete, it is cooled to room temperature, 20mL of water and 20mL of EA are added to the reaction solution for extraction and separation, and the extraction is repeated three times until the extraction is complete. The organic phases are combined and backwashed with saturated brine, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (PE / EA=100 / 1-10 / 1) gives AJ14-1 (750mg, 78%) as a white solid.

[0213] Preparation of AJ14-2: AJ14-1 (750 mg, 2.9 mmol) was dissolved in 10 mL THF solution, and 10% Pd / C (80 mg) was added under stirring at room temperature, and hydrogen was replaced. The mixture was stirred at room temperature for about 3 h under hydrogen atmosphere. The mixture was filtered under reduced pressure, and the filter cake was rinsed twice with 10 mL THF. The filtrates were combined and concentrated under reduced pressure to obtain a 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 DMF, and 3-bromopiperidine-2,6-dione (426 mg, 2.22 mmol) and NaHCO were added under stirring. 3 (236 mg, 2.22 mmol), the reaction solution was slowly heated to 100 o C stirring reaction for about 6h. After LCMS detection reaction is complete, add 20mL water to the reaction solution to quench and add 10mL EA to extract and separate, repeat extraction three times until extraction is complete. Combine organic phases and dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude concentrate. Purify by column chromatography (DCM / MeOH=100 / 1-50 / 1) to obtain yellow solid AJ14-3 (50mg, 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, and the resulting solution was stirred at room temperature for 2 h. The solvent was then removed by concentration under reduced pressure, and the concentrate was purified by reverse phase preparation (water / MeCN = 1 / 100-3 / 1) to obtain a 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 DMF, and Et 3N (8mg, 0.75mmol) and HATU (00mg, 0.027mmol), continue stirring reaction for about 1h.Then add 6mL water in reaction solution to quench and add 5mL EA to extract liquid, repeat extraction three times to complete extraction.Merge organic phase and backwash with saturated aqueous common salt, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure to obtain enriched crude product.Prepare through reverse phase (MeCN / water=1 / 100-1 / 2) purification to obtain white solid AJ14 (5mg, 27%). 1 HNMR (400 MHz, DMSO-d 6 ) 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 H 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] 1 H NMR (400 MHz, DMSO-d 6) 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 = 7.3Hz, 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] 1 H NMR (400 MHz, DMSO-d 6) 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] 1 H NMR (400 MHz, DMSO-d 6) 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] 1 H NMR (400 MHz, DMSO-d 6) 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, and K was added to the reaction solution under stirring at room temperature. 2 CO 3 (6.6g, 48mmol), then the reaction solution was heated to 90℃ and stirred for 2h. After the reaction was complete, it was cooled to room temperature, 30mL of water was added to the reaction solution to quench it, and 30mL of EA was added to extract the liquid, and the extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A light yellow solid AJ31-1 (1.9g, 28%) was obtained by column chromatography (PE / EA=100 / 1-10 / 1).

[0235] Preparation of AJ31-2: AJ31-1 (1.9 g, 6 mmol) was dissolved in 20 mL THF, and 10% Pd / C (0.2 g) was added under stirring at room temperature. The reaction system was placed under hydrogen conditions, heated to 40°C and stirred for 2 h. When the reaction was complete, the Pd / C was removed by vacuum filtration and the palladium carbon was washed. The filtrate was concentrated under reduced pressure to obtain a white solid AJ31-2 (1.5 g, 88%).

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

[0237] Preparation of AJ31-4: AJ31-3 (1.1 g, 3.4 mmol) and 3-bromopiperidine-2,6-dione (2 g, 10 mmol) were dissolved in 15 mL DMF, and Cs was added to the system under stirring at room temperature. 2 CO 3 (2.3g, 7mmol), then heated to 50℃ and stirred for 4h. After the reaction was complete, cooled to room temperature, 2mL of dilute hydrochloric acid (1M) was added to the reaction solution for quenching, and 20mL of water and 20mL 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 and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (DCM / MeOH=100 / 1-60 / 1) gave a yellow oily compound AJ31-4 (1.3g, 88%).

[0238] Preparation of AJ31-5: AJ31-4 (1.3 g, 3 mmol) was dissolved in 20 mL of DCM, and 5 mL of a dioxane solution (4 M) of hydrochloric acid 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 starting material had disappeared and the reaction was complete. The excess hydrochloric acid and solvent were removed by concentration under reduced pressure to obtain an 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 THF and 2 mL DMF. After stirring at room temperature for about 1 h, acetic acid (4.9 mg, 0.08 mmol) and NaHB(OAc) were added dropwise. 3(14 mg, 0.07 mmol), and continue stirring at room temperature for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. 2 mL of saturated NaHCO 3 The aqueous solution was quenched and 5 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and separation, and the extraction was repeated three times until the extraction was complete, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (DCM / MeOH=100 / 1-20 / 1) gave AJ31 (5 mg, 17%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) 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: AJ33-0 (6 g, 28 mmol) was dissolved in 50 mL DMF solvent and Cs 2 CO 3(27g, 83mmol) and 3-bromopiperidine-2,6-dione (11g, 56mmol), the reaction solution was stirred at room temperature for about 4h. After the reaction was completed, 50mL of water was added to the reaction solution for dilution and 50mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, and the organic phases were dried and concentrated with anhydrous sodium sulfate to obtain a crude concentrate. Purification by column chromatography (EA / PE=1 / 100-1 / 80) gave a white solid AJ33-1 (5.3g, 59%).

[0243] Preparation of AJ33-2: AJ33-1 (500 mg, 1.5 mmol) was dissolved in 15 mL THF solvent, stirred at room temperature and Pd was added under argon protection. 2 (dba) 3 (180mg, 0.2mmol), Q-Phos (145mg, 0.2mmol), 2-tert-butoxy-2-carbonylethylzinc bromide (6mL THF solution, 6mmol), the reaction solution was slowly heated to 70°C and stirred for 2h. After the reaction was completed, saturated aqueous ammonium chloride solution was added to the reaction solution for quenching, and 15mL water and 15mL EA were added for extraction. The organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the solvent. The residue was purified by column chromatography (MeOH / DCM=1 / 100-1 / 70) to obtain an off-white solid AJ33-2 (340mg, 62%).

[0244] Preparation of AJ33-3: AJ33-2 (340 mg, 1 mmol) was dissolved in a mixed solution of DCM / TFA (10 mL, 2:1), and the resulting solution was stirred at room temperature for 1 h. The solvent was then removed by concentration under reduced pressure to obtain an off-white solid AJ33-3 (260 mg, 90%).

[0245] Preparation of AJ33: AJ33-3 (10 mg, 0.03 mmol) and AJ10a-2 (16 mg, 0.03 mmol) were dissolved in 5 mL DMF solution and Et 3 N (10 mg, 0.1 mmol) and slowly dropwise add HATU (15 mg, 0.040 mmol) in DMF solution, and stir the reaction at room temperature for 30 minutes. Then add 10 mL of water to the reaction solution for quenching, precipitate a white solid, and filter under reduced pressure and dry the filter cake to obtain a white solid crude product. Purify by column chromatography (MeOH / DCM=1 / 100-1 / 20) to obtain a white solid AJ33 (19 mg, 76%). 1 H NMR (400 MHz, DMSO-d 6) 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 15 mL of DMF / water (20:1) mixed solution, and Et 3 N (470 mg, 4.6 mmol) and Pd(dppf)Cl 2 DCM (122 mg, 0.15 mmol), the reaction system was replaced with carbon monoxide, and the temperature was raised to 90°C for 3 h under a carbon monoxide environment. After the reaction was detected to be complete, the low-boiling solvent 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 in 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, and Et 3 N (11 mg, 0.11 mmol), then slowly dropwise add HATU (15 mg, 0.04 mmol) in DMF and react at room temperature for 30 minutes. Add 10 mL of water to the reaction solution for quenching, precipitate a white solid, filter under reduced pressure and dry the filter cake to obtain a crude product. Purify by column chromatography (MeOH / DCM=1 / 100-1 / 15) to obtain a white solid AJ33a (11 mg, 52%). 1 H NMR (400 MHz, DMSO-d 6 ) 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, and 1-Boc-piperazine (280 mg, 1.5 mmol), Cs 2 CO 3 (420mg, 1.3mmol), RuPhos (93mg, 0.2mmol) and RuPhosPdG3 (120mg, 0.15mmol), the system was heated to 100℃ under argon protection and continued to stir for 2h. After the reaction was detected to be complete, it was cooled to room temperature, 15mL of water was added to the reaction solution for dilution and 15mL of EA was added for extraction and 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 phases were 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 a white solid AJ33b-1 (580mg, 87%).

[0253] Preparation of AJ33b-2: AJ33b-1 (580 mg, 1.4 mmol) was dissolved in 15 mL of a mixed solution of DCM / TFA (3:1), and the reaction solution was stirred at room temperature for 1 h. The solvent was then removed by concentration under reduced pressure to obtain an 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 THF / DMF (10 mL / 1 mL) mixed solvent, and AcOH (2.4 mg, 0.04 mmol) and NaHB(OAc) were added under stirring at room temperature. 3 (20 mg, 0.09 mmol), and continue the reaction at room temperature for 3 h. Saturated NaHCO 3 The aqueous solution was adjusted to a near-neutral pH value, diluted with 15 mL of water and extracted with 10 mL of EA, and the extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, the organic phases were 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 AJ33b (17 mg, 77%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6) 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 DMF and K was added under stirring at room temperature. 2 CO 3 (980 mg, 7 mmol) and 3-bromopiperidine-2,6-dione (1 g, 5 mmol), and the mixture was heated to 100 o C and stirred at this temperature for about 1h. LCMS detection shows that the raw material is completely consumed, and then 15mL of water is added to the reaction solution for quenching and 15mL of EA is added for extraction and separation, and the extraction is repeated three times until the extraction is complete. The organic phases are combined and backwashed with saturated brine, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. A light red solid product AJ35-1 (260mg, 36%) is obtained by column chromatography (EA / PE=1 / 100-1 / 1).

[0258] Preparation of AJ35-2: AJ35-1 (260 mg, 0.8 mmol) was dissolved in 10 mL THF solution, and Pd 2 (dba) 3 (74mg, 0.08mmol), Q-Phos (58mg, 0.08mmol), 2-tert-butoxy-2-carbonylethylzinc bromide (4mL THF solution, 3mmol), the reaction solution was slowly heated to 70°C and stirred for 2h. After the reaction was completed, it was cooled to room temperature, and a saturated aqueous solution of ammonium chloride was added to the reaction solution for quenching, and EA was extracted three times, 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 residue was purified by column chromatography (EA / PE=1 / 100-1 / 1) to obtain an off-white solid AJ35-2 (150mg, 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 reaction was complete. The DCM and TFA in the reaction solution were then removed by vacuum concentration to obtain a light yellow solid AJ35-3 (120 mg, 95%).

[0260] Preparation of AJ35: AJ35-3 (20 mg, 0.07 mmol) was dissolved in 8 mL DMF, and AJ10a-2 (27 mg, 0.07 mmol) and Et 3 N (20 mg, 0.2 mmol) and HATU (25 mg, 0.07 mmol) were added, and the reaction was stirred 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. Solids were precipitated, and the filter cake was filtered and dried to obtain a brown crude product. Purification by reverse phase column chromatography (MeCN / water = 1 / 100-1 / 2) gave a white solid product AJ35 (5 mg, 15%). 1 H NMR (400 MHz, DMSO-d 6) 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 DMF, and Et 3 N (20 mg, 0.2 mmol) and HATU (25 mg, 0.07 mmol) were added and stirred for about 30 minutes. LCMS showed that the raw materials had been consumed. 10 mL of water was added to the reaction solution for dilution. Solids precipitated, and the filter cake was filtered under reduced pressure and dried to obtain a solid crude product. Purification by reverse phase column chromatography (MeCN / water = 1 / 100-1 / 2) gave a white solid product AJ35b (32 mg, 64%). 1H NMR (400 MHz, DMSO-d 6 ) 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: AJ36-0 (950 mg, 4.5 mmol) was dissolved in 20 mL THF and cooled to 0 oC and add NaH (60%, 320mg, 14mmol) in batches under stirring, stir the reaction at low temperature for 30 minutes, then add 3-bromopiperidine-2,6-dione (1.3g, 7mmol), the reaction solution slowly rises to room temperature and continues to stir the reaction for 2h. LCMS detection reaction is complete, the reaction solution is slowly poured into 20mL ice water, and 15mL EA is used to extract the liquid, and the extraction is repeated three times until the extraction is complete. The organic phases are combined and backwashed with saturated brine, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (EA / PE=1 / 10-2 / 1) gives a pale yellow solid AJ36-1 (600mg, 43%).

[0267] Preparation of AJ36-2: AJ36-1 (250 mg, 0.8 mmol) was dissolved in 15 mL THF solvent, stirred at room temperature and Pd 2 (dba) 3 (70 mg, 0.07 mmol), Q-Phos (23 mg, 0.1 mmol), 2-tert-butoxy-2-carbonylethylzinc bromide (0.5 M) (7 mL, 4 mmol), slowly heated to 70 o C and continue stirring the reaction for 5h. After the reaction is completed, saturated aqueous ammonium chloride solution is added to the reaction solution for quenching, and 10mL water and 10mL EA are added to extract the liquid, and the extraction is repeated three times until the extraction is complete. The organic phase is collected and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to remove the solvent. The concentrate is purified by column chromatography (MeOH / DCM=1 / 100-1 / 70) to obtain an off-white solid AJ36-2 (100mg, 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, and the resulting solution was stirred at room temperature for 2 h. The solvent was then removed by concentration under reduced pressure, and the white solid AJ36-3 (69 mg, 82%) was obtained by purification by reverse phase preparation (MeCN / water = 1 / 100-1 / 2).

[0269] Preparation of AJ36: AJ36-3 (10 mg, 0.03 mmol) and AJ10a-2 (15 mg, 0.03 mmol) were dissolved in 5 mL DMF, and Et 3N (7mg, 0.07mmol) and HATU (14mg, 0.03mmol), continue to stir at room temperature for about 1h. Then add 8mL water to the reaction solution for quenching and add 5mL EA for extraction and separation, repeat extraction three times until 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 by reverse phase preparation (MeCN / water=1 / 100-1 / 2) to obtain a white solid AJ36 (1mg, 4%). 1 H NMR (400 MHz, DMSO-d 6 ) 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 using 5-bromoindole as a raw material according to the preparation method of AJ36.

[0271]

[0272] 1 H 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, 1.4Hz, 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 DMF, and K 2 CO 3 (290 mg, 2 mmol), and the mixed system was heated to 120 oC and stirred the reaction at this temperature for about 4h. After the detection reaction is complete, it is cooled to room temperature, 10mL of water is added to the reaction solution for quenching and 10mL of EA is added for extraction and separation, and the extraction is repeated three times until the extraction is complete. The organic phases are combined and backwashed with saturated brine, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. AJ38-1 (170mg, 60%) is obtained as a pale yellow solid by column chromatography (EA / PE=1 / 100-1 / 5).

[0276] Preparation of AJ38-2: AJ10a-0 (100 mg, 0.2 mmol) and AJ38-1 (83 mg, 0.3 mmol) were dissolved in a mixed solvent of 10 mL 1,4-dioxane and 1 mL water, stirred and Pd(dppf)Cl was added in sequence under argon protection. 2 DCM (18 mg, 0.02 mmol), K 2 CO 3 (50 mg, 0.3 mmol), the reaction solution was slowly heated to 100 o C and continue to react for 3h. After the reaction is complete, cool to room temperature, add 10mL of water to the reaction solution to quench and add 10mL of EA to extract and separate, 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 a crude concentrate. Purify by column chromatography (EA / PE=1 / 100-1 / 5) to obtain a light yellow solid AJ38-2 (67mg, 63%).

[0277] Preparation of AJ38-3: AJ38-2 (67 mg, 0.3 mmol) was dissolved in a mixed solvent of 1 mL of dilute hydrochloric acid (2 M) and 5 mL of THF, and the reaction solution was heated to 65 o C stirring reaction for 8h. After the reaction was complete, the mixture was cooled to room temperature and 10mL of water and 10mL of EA were added to the reaction solution for extraction and 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 phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow concentrate AJ38-3 (25mg, 42%).

[0278] Preparation of AJ38: AJ38-3 (12 mg, 0.03 mmol) was dissolved in a mixed solvent of 3 mL THF and 1 mL DMF, and AJ12-5 (10 mg, 0.03 mmol) was added under stirring at room temperature and the reaction was continued for 1 h. Then AcOH (2 mg, 0.03 mmol) and NaHB(OAc) were added. 3 (8 mg, 0.04 mmol) and stirred at room temperature for about 6 h. After the reaction was complete, 10 mL of water was added to the reaction solution to quench it. Then saturated NaHCO 3The aqueous solution was adjusted to pH 7, and 6 mL of EA was added to extract the liquid, and 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 AJ38 (5 mg, 23%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) 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, 1.4Hz, 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: AJ39-0 (200 mg, 1.4 mmol) and 1-Boc-piperazine (260 mg, 1.4 mmol) were dissolved in 10 mL DMF and K was added under stirring at room temperature. 2 CO 3 (105 mg, 0.08 mmol), and the mixture was heated to 80 oC and continue stirring the reaction for about 4h. Then add 10mL water to the reaction solution for quenching and add 10mL EA for extraction and separation, and 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 by column chromatography (EA / PE=1 / 100-1 / 5) to obtain a light yellow solid AJ39-1 (280mg, 65%).

[0282] Preparation of AJ39-2: AJ39-1 (280 mg, 0.9 mmol) and zinc powder (180 mg, 3 mmol) were dissolved in 10 mL DCM, AcOH (220 mg, 3.7 mmol) was slowly added dropwise under stirring at room temperature, and the mixed system was stirred at room temperature for about 2 h. Then the mixture was filtered under reduced pressure, and the filter cake was rinsed twice with 10 mL DCM. The filtrates were combined and concentrated to obtain a crude concentrate. AJ39-2 (150 mg, 60%) was obtained as a pale yellow solid by column chromatography (EA / PE=1 / 100-1 / 1).

[0283] Preparation of AJ39-3: AJ39-2 (150 mg, 0.6 mmol) and 3-bromopiperidine-2,6-dione (160 mg, 0.8 mmol) were dissolved in 15 mL DMF and K was added under stirring at room temperature. 2 CO 3 (150 mg, 1 mmol), and the mixed system was heated to 80 o C and stirred for 4 h. After the reaction was completed, 10 mL of water was added to the reaction solution for quenching and 10 mL of EA was added for extraction and 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 phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. A light yellow solid AJ39-3 (103 mg, 48%) was obtained by column chromatography (EA / PE=1 / 100-2 / 1).

[0284] Preparation of AJ39-4: AJ39-3 (103 mg, 0.3 mmol) was dissolved in a mixed solvent of 1 mL TFA and 2 mL DCM, and the resulting solution was stirred at room temperature for 3 h. The solvent was then removed by concentration under reduced pressure to obtain a light yellow solid product AJ39-4 (73 mg, 95%).

[0285] Preparation of AJ39: AJ38-3 (12 mg, 0.03 mmol) was dissolved in 6 mL THF and 2 mL DMF, and AJ39-4 (8 mg, 0.03 mmol) was added under stirring at room temperature. After reacting at room temperature for 1 h, AcOH (2 mg, 0.03 mmol) and NaHB(OAc) were added. 3(8 mg, 0.04 mmol), and continue stirring at room temperature for about 4 h. After the reaction is completed, 10 mL of water is added to the reaction solution for quenching, and saturated NaHCO 3 The aqueous solution was adjusted to pH 7, and 10 mL of EA was added for extraction and separation, and the extraction was repeated three times until the extraction was complete. The combined organic phases were 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 AJ39 (3 mg, 15%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) 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: AJ40-0 (3 g, 17 mmol) and ethyl acrylate (3.5 g, 35 mmol) were dissolved in 40 mL of AcOH and K 2 CO 3 (7.2 g, 52 mmol), and then slowly heated the reaction system to 120 oC for 6h. After the reaction was complete, the mixture was cooled to room temperature, 40mL of water was added to the reaction solution to quench it, and 40mL of EA was added to extract and separate the liquids. The extraction was repeated three times until the extraction was complete. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. AJ40-1 (2.8g, 59%) was obtained as a yellow solid by column chromatography (PE / EA=100 / 1-10 / 1).

[0289] Preparation of AJ40-2: AJ40-1 (1g, 4mmol) was dissolved in a mixed solvent of 10mL THF and 2mL water, and LiOH (150mg, 4mmol) was added under stirring at room temperature and stirred for about 2h. After the reaction was complete, dilute hydrochloric acid (1M) was added to the reaction solution to adjust the pH to 6, and then 20mL water and 15mL EA were added for extraction and separation, and the extraction was repeated three times until the extraction was complete. The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure. The residue was purified by reverse phase preparation (MeCN / water = 1 / 100-1 / 2) to obtain a yellow solid AJ40-2 (600mg, 67%).

[0290] Preparation of AJ40-3: AJ40-2 (600 mg, 2.5 mmol) and urea (1.5 g, 25 mmol) were dissolved in 20 mL of AcOH and heated to 130 °C with stirring. o C for 24h. After the reaction was detected to be complete, the mixture was cooled to room temperature, quenched with 20mL of water and extracted with 20mL of EA, and the extraction was repeated three times until the extraction was complete. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by reverse phase preparation (MeCN / water = 1 / 100-1 / 2) to obtain a yellow solid AJ40-3 (120mg, 18%).

[0291] Preparation of AJ40-4: AJ40-3 (60 mg, 0.2 mmol) and zinc powder (72 mg, 1 mmol) were dissolved in 10 mL DCM, AcOH (71 mg, 1 mmol) was slowly added under stirring at room temperature, and the mixed system was stirred and reacted at room temperature for about 2 h. Then the mixture was filtered under reduced pressure, and the filter cake was rinsed twice with 10 mL DCM. The filtrate was combined and concentrated under reduced pressure to obtain a crude concentrate. AJ40-4 (45 mg, 85%) was obtained as a pale yellow solid by column chromatography (DCM / MeOH=100 / 1-50 / 1).

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

[0293] Preparation of AJ40: 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) under an ice-water bath, and the temperature of the reaction system was slowly raised to room temperature and continued to be heated to 50 o C stirring reaction 2h. After the detection reaction is complete, it is cooled to room temperature, 10mL water is added to the reaction solution for quenching and 10mL EA is added for extraction and separation, and the extraction is repeated three times until the extraction is complete. The organic phases are combined and backwashed with saturated brine, the organic phase is dried over anhydrous sodium sulfate, filtered under reduced pressure and the filtrate is concentrated to obtain a crude product. The concentrate is purified by reverse phase preparation (MeCN / water=1 / 100-1 / 2) to obtain a white solid AJ40 (3mg, 8%). 1 H NMR (400 MHz, DMSO-d 6 ) 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: AJ41-0 (630 mg, 3.7 mmol) and 1-Boc-4-(piperidin-4-yl)-piperazine (1 g, 3.7 mmol) were dissolved in 20 mL of DMF and K was added under stirring at room temperature. 2 CO 3 (1g, 7.4mmol), slowly heated to 80 o C and continue to react for 2h. After the detection reaction is complete, it is cooled to room temperature, 20mL of water is added to the reaction solution to quench it and 20mL of EA is added to extract and separate the liquids, and the extraction is repeated three times until the extraction is complete. The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (DCM / MeOH=100 / 1-30 / 1) gives a yellow solid AJ41-1 (1.45g, 94%).

[0297] Preparation of AJ41-2: AJ14-1 (1.45 g, 3.5 mmol) was dissolved in 20 mL MeOH, and 10% Pd / C (140 mg) was added. The mixture was replaced with hydrogen and reacted at room temperature for 3 h under a hydrogen atmosphere. After the reaction was complete, Pd / C was removed by vacuum filtration, and the Pd / C filter cake was washed with 10 mL THF. The filtrates were combined and concentrated under reduced pressure to obtain a light yellow compound AJ41-2 (1.3 g, 96%).

[0298] Preparation of AJ41-3: AJ41-2 (600 mg, 1.5 mmol) and (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (580 mg, 1.8 mmol) were dissolved in 15 mL i-PrOH, TsOH (290 mg, 1.5 mmol) was added under stirring at room temperature, and the temperature was slowly raised to 90°C. o C reaction 10h. After the detection reaction is complete, it is cooled to room temperature, 5% sodium hydroxide aqueous solution is added to the reaction solution to adjust pH=7, 15mL water and 15mL EA are added to extract and separate, and the extraction is repeated three times until the extraction is complete. The organic phases are combined and backwashed with saturated brine, the organic phase is dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude concentrate. Purification by column chromatography (DCM / MeOH=100 / 1-30 / 1) gives a yellow solid AJ41-3 (700mg, 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. The solvent was then removed by concentration under reduced pressure, and the product was purified by reverse phase preparation to obtain AJ41-4 (550 mg, 92%) as a white solid.

[0300] Preparation of AJ41: AJ41-4 (15 mg, 0.03 mmol) and AJ35-3 (8 mg, 0.03 mmol) were dissolved in 8 mL DMF and Et 3 N (5mg, 0.05mmol) and HATU (11mg, 0.03mmol) were added and stirred at room temperature for about 1h. Then 10mL of water was added to the reaction solution for quenching and 10mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. A white solid AJ41 (3mg, 13%) was obtained by reverse phase preparation (MeCN / water = 1 / 100-1 / 2). 1 H NMR (400 MHz, DMSO-d 6 ) 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: AJ41-0 (2 g, 12 mmol) and 4-piperidone ethylene glycol acetal (2 g, 14 mmol) were dissolved in 30 mL DMF, and K was added to the system under stirring at room temperature. 2 CO 3 (4g, 29mmol), then heated to 75℃ and stirred for 4h. After the reaction was detected to be complete, it was cooled to room temperature, 30mL of water was added to the reaction solution to quench it, and 40mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete, and 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. Purification by column chromatography (PE / EA=100 / 1-3 / 1) gave a white solid AJ44-1 (3.3g, 97%).

[0304] Preparation of AJ44-2: AJ44-1 (3.3 g, 11 mmol) was dissolved in 20 mL of THF solution, and 10% Pd / C (300 mg) was added under stirring at room temperature. The reaction was placed under hydrogen conditions and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered under reduced pressure to remove the catalyst. The filtrate was concentrated under reduced pressure to obtain an off-white solid AJ44-2 (2.9 g, 98%).

[0305] Preparation of AJ44-3: AJ44-2 (1g, 4mmol) and (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (1.4g, 5mmol) were dissolved in 15mL i-PrOH, TsOH (1.4g, 8mmol) was added under stirring at room temperature, and the reaction solution was heated to 80°C and continued to react for 5h. After the reaction was complete, it was cooled to room temperature, and 1mol / L NaOH aqueous solution was added dropwise to the reaction solution to make the pH of the reaction solution = 7~8, and 20mL water and 20mL DCM were added for extraction and separation. The extraction was repeated three times until the extraction was complete, and 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. Purification by column chromatography (DCM / MeOH=100 / 1-60 / 1) gave a yellow-green solid AJ44-3 (850mg, 42%).

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

[0307] Preparation of AJ44: AJ44-4 (20 mg, 0.04 mmol) and AJ12-5 (15 mg, 0.04 mmol) were dissolved in 8 mL THF, heated to 40 °C and stirred for about 1 h, then AcOH (7.2 mg, 0.12 mmol) and NaHB(OAc) were added. 3 (25 mg, 0.12 mmol) and continue stirring the reaction for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. 2 mL of saturated NaHCO 3 The reaction was quenched with aqueous solution and 5 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and separation, and the extraction was repeated three times until the extraction was complete, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (DCM / MeOH=100 / 1-15 / 1) gave AJ44 (6 mg, 20%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6)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-.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: AJ44-4 (20 mg, 0.04 mmol) was dissolved in 5 mL THF and 1 mL DMF, and AJ39-4 (12 mg, 0.04 mmol) was added under stirring at room temperature. After stirring at room temperature for 1 h, AcOH (3 mg, 0.04 mmol) and NaHB(OAc) were added. 3 (15 mg, 0.06 mmol), and the reaction was continued to stir at room temperature for about 6 h. Then 10 mL of water was added to the reaction solution for quenching, and saturated NaHCO 3 The aqueous solution was adjusted to pH 7, and 10 mL of EA was added for extraction and separation, and 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 AJ45 (9 mg, 30%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6) 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: AJ41-4 (15 mg, 0.03 mmol) and AJ33-3 (8 mg, 0.03 mmol) were dissolved in 5 mL DMF and Et 3 N (5mg, 0.05mmol) and HATU (11mg, 0.03mmol). After about 1h, 8mL of water was added to the reaction solution for quenching and 5mL of EA was added for extraction and 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. After reverse phase preparation (MeCN / water=1 / 100-1 / 2), white solid AJ46 (12mg, 52%) was obtained. 1 H 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 and K was added under stirring at room temperature. 2 CO 3 (1.8g, 13mmol) and ethyl bromoacetate (0.95g, 6mmol), the resulting reaction solution was reacted at 120°C for 2h. After the reaction was completed, the mixture was cooled to room temperature, 20mL of water was added to dilute the reaction solution, and 20mL of EA was added for extraction and separation. 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 over anhydrous sodium sulfate, filtered, and concentrated to obtain a light yellow solid AJ49-7-1 (0.76g, 53%).

[0317] Preparation of AJ49-7-2: AJ49-7-1 (200 mg, 0.7 mmol) was dissolved in a mixed solvent of 1,4-dioxane / water (10 mL / 0.5 mL), and K 2 CO 3 (250 mg, 1.8 mmol), AJ10a-0 (310 mg, 0.7 mmol) and Pd(dppf)Cl 2 DCM (58mg, 0.07mmol), the reaction solution was heated to 90°C under argon protection and the reaction was continued for 3h. LCMS detected that the reaction was complete, 10mL of water was added to the reaction solution for dilution and 10mL of EA was added for extraction and 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 phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. A pale yellow solid AJ49-7-2 (200mg, 60%) was obtained by column chromatography (MeOH / DCM=1 / 100-1 / 40).

[0318] Preparation of AJ49-7: AJ49-7-2 (200 mg, 0.4 mmol) was dissolved in 10 mL THF solution, and an aqueous solution of LiOH (48 mg, 0.9 mmol) was slowly added dropwise under stirring at room temperature, and the reaction solution was heated to 40°C and continued to react for 1 h. LCMS detected that the reaction was complete, the reaction solution was cooled to room temperature and a dilute aqueous hydrochloric acid solution (1 M) was slowly added dropwise to adjust the pH value to weak alkalinity, and a white solid precipitated. The filter cake was filtered under reduced pressure and dried to obtain an off-white solid AJ49-7 (150 mg, 80%).

[0319] Preparation of AJ49-1: Under ice bath, add 8mL concentrated sulfuric acid to AJ49-0 (1g, 9mmol), then slowly add 4mL 65% concentrated nitric acid to the reaction system, stir for 30 minutes, then slowly heat to 60°C and continue stirring for 2h. LCMS detected that the reaction was complete, the reaction solution was placed in an ice water bath to cool, then the reaction solution was slowly added dropwise to 20mL ice water for quenching, and the remaining acid in the reaction solution was neutralized with 10% ammonia water, and a large amount of white solid was precipitated, and the filter cake was filtered and dried to obtain AJ49-1 (430mg, 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 NMP, DIEA (1.1 g, 9 mmol) was added under stirring at room temperature, and 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 it, and 15 mL of EA was added to extract and separate the liquids. The extraction was repeated three times, the organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. AJ49-2 (800 mg, 98%) was obtained as a yellow solid by column chromatography (PE / EA=100 / 1-5 / 1).

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

[0322] Preparation of AJ49-4: AJ49-3 (700 mg, 2.4 mmol) was dissolved in 15 mL MeCN solution, CDI (770 mg, 4.8 mmol) was added under stirring at room temperature, and the reaction solution was heated to 85°C and stirred for 2 h. After the reaction was detected to be complete, the reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM / MeOH=100 / 1-80 / 1) to obtain a 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 DMF, and Cs was added to the system under stirring at room temperature. 2 CO 3 (940mg, 2.9mmol), the system was heated to 50℃ and stirred for 5h. After the reaction was detected to be complete, it was cooled to room temperature, 1mL of dilute hydrochloric acid (2M) was added to the reaction solution to quench, 10mL of water and 15mL of EA were added to the reaction solution to extract the liquid, and the extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. AJ49-5 (400mg, 95%) was obtained as a white solid by column chromatography (DCM / MeOH=100 / 1-60 / 1).

[0324] Preparation of AJ49-6: AJ49-5 (100 mg, 0.2 mmol) was dissolved in 8 mL DCM, 2 mL 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 starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure to obtain AJ49-6 (70 mg, 92%) as a white solid.

[0325] Preparation of AJ49:AJ49-6 (10mg, 0.03mmol) and AJ49-7 (15mg, 0.03mmol) were dissolved in 5mLDF, DIEA (11mg, 0.08mmol) was added dropwise to the system under stirring at room temperature, HATU (13mg, 0.03mmol) was added in batches after about 10 minutes, and the stirring reaction was continued at room temperature for 30 minutes. LCMS detection showed that the raw material had disappeared, and the reaction was completed. 5mL distilled water was slowly added to the reaction solution under stirring, and 10mL EA was added to extract the liquid, and the extraction was repeated three times until the extraction was complete, the organic phase was merged and backwashed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase column chromatography (MeCN / water=1 / 100-1 / 2) to obtain a white solid AJ49 (5mg, 22%). 1 HNMR (400 MHz, DMSO-d 6) 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 DMF, and Cs was added to the system under stirring at room temperature. 2 CO 3 (3.5g, 11mmol), the reaction solution was heated to 50℃ and stirred for 4h. After the reaction was complete, it was cooled to room temperature, 5mL of dilute hydrochloric acid (2M) was added to the reaction solution to quench, 20mL of water was added to the reaction solution, and 20mL of EA was added to extract and separate, and the extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (DCM / MeOH=100 / 1-60 / 1) gave a red solid AJ50-1 (420mg, 28%).

[0329] Preparation of AJ50-2: AJ50-1 (150 mg, 0.5 mmol) was dissolved in 10 mL THF, stirred at room temperature and Pd 2 (dba) 3 (80mg, 0.09mmol), Q-Phos (63mg, 0.09mmol) and 2-tert-butoxy-2-carbonylethylzinc bromide (2mL, 1.76mmol), slowly heated to 70℃ and stirred for 2h. After the reaction was completed, 5mL of saturated ammonium chloride aqueous solution was added to the reaction solution for quenching, 10mL of water and 10mL of EA were added to the reaction solution for extraction and 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 phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (PE / EA=100 / 1-20 / 1) gave AJ50-2 (140mg, 84%) as a white solid.

[0330] Preparation of AJ50-3: AJ50-2 (140 mg, 0.4 mmol) was dissolved in 8 mL DCM, 3 mL 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 starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure to obtain a brown solid AJ50-3 (100 mg, 84%).

[0331] Preparation of AJ50: AJ50-3 (14 mg, 0.03 mmol) and AJ10a-2 (17 mg, 0.03 mmol) were dissolved in 10 mL DMF, and Et 3 N (9mg, 0.09mmol), HATU (13mg, 0.03mmol) was added in batches after stirring for about 10 minutes, and the stirring reaction continued for 30 minutes at room temperature. LCMS detection showed that the raw material had disappeared, and the reaction was completed. Under stirring, 10mL water was slowly added to the reaction solution, and 10mL EA was added to extract the liquid, and the extraction was repeated three times to complete extraction, and the organic phase was merged and backwashed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase column chromatography (MeCN / water=1 / 100-1 / 2) to obtain a white solid AJ50 (5mg, 15%). 1 H NMR (400 MHz, DMSO-d 6) 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, 5.4Hz, 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: AJ53-0 (1 g, 4.4 mmol) was dissolved in 10 mL of 2 mol / L hydrochloric acid, heated to 55 °C with stirring for 10 minutes, and acrylic acid (480 mg, 6.6 mmol) was slowly added to the reaction solution, and then the temperature was raised to 100 °C and the reaction was continued with stirring for 4 hours. After the reaction was complete, it was cooled to room temperature, the reaction solution was slowly added to ice water to quench the reaction, and then saturated NaHCO was slowly added to the mixed system. 3 Aqueous solution was added to make the pH of the reaction solution 6.5-7. After a large amount of solid precipitated, it was filtered and the filter cake was dried to obtain a yellow crude product AJ53-1 (1.1 g, 83%).

[0335] Preparation of AJ53-2: AJ53-1 (1.1 g, 4 mmol) was dissolved in 11 mL of AcOH, urea (780 mg, 13 mmol) was added, and the mixture was heated to 120 °C with stirring for 5 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. After the reaction was complete, the mixture was cooled to room temperature and saturated NaHCO was slowly added dropwise to the reaction system. 3 Aqueous solution was added to make the pH of the reaction solution = 7-8. After a large amount of solid precipitated, it was filtered under reduced pressure and the filter cake was dried to obtain a yellow crude product AJ53-2 (490 mg, 41%).

[0336] Preparation of AJ53-3: AJ53-2 (150 mg, 0.5 mmol) was dissolved in 10 mL THF solution, stirred at room temperature and Pd was added under argon protection. 2 (dba) 3 (80mg, 0.09mmol), Q-Phos (63mg, 0.09mmol), 2-tert-butoxy-2-carbonylethylzinc bromide (2mL, 1.8mmol), slowly heated to 70℃ for 2h. After the reaction was completed, 3mL of saturated ammonium chloride aqueous solution was added to the reaction solution to quench, 10mL of water was added to the reaction solution, and 10mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (PE / EA=100 / 1-20 / 1) gave AJ53-3 (140mg, 84%) as a white solid.

[0337] Preparation of AJ53-4: AJ53-3 (140 mg, 0.4 mmol) was dissolved in 8 mL DCM, 3 mL 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 starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure to obtain AJ53-4 (110 mg, 93%) as a white solid.

[0338] Preparation of AJ53: AJ53-4 (10 mg, 0.03 mmol) and AJ10a-2 (15 mg, 0.03 mmol) were dissolved in 5 mL DMF, DIEA (10 mg, 0.08 mmol) and HATU (12 mg, 0.03 mmol) were added to the reaction system under stirring at room temperature, and the reaction was continued under stirring at room temperature for 30 minutes. LCMS detection showed that the raw material had disappeared and the reaction was complete. 8 mL of water was slowly added to the reaction solution under stirring, and a white solid was precipitated from the reaction solution. The filter cake was filtered 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 AJ53 (5 mg, 20%).1 H NMR (400 MHz, DMSO-d 6 ) 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: AJ53-2 (200 mg, 0.6 mmol) and N-Boc-piperazine (230 mg, 0.7 mmol) were dissolved in 15 mL of dioxane solution, stirred at room temperature and RuPhos (43 mg, 0.06 mmol), RuPhosPdG2 (190 mg, 0.3 mmol) and Cs 2 CO 3 (300 mg, 0.9 mmol), the reaction solution was slowly heated to 100 ° C and the reaction was continued for 4 h. After the reaction was completed, 10 mL of water was added to the reaction solution to quench and 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 and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A light yellow solid AJ54-1 (72 mg, 27%) was obtained by column chromatography (DCM / MeOH=100 / 1-60 / 1).

[0342] Preparation of AJ54-2: AJ54-1 (72 mg, 0.17 mmol) was dissolved in 5 mL DCM, 2 mL TFA was added dropwise to the reaction system at room temperature, and the reaction was stirred at room temperature for 1 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. 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 THF and 1 mL DMF, and AcOH (11 mg, 0.18 mmol) and NaHB(OAc) were added under stirring at room temperature. 3 (25 mg, 0.12 mmol), and continue stirring at room temperature for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. 2 mL of saturated NaHCO 3 The aqueous solution was quenched and 5 mL of water was added, 10 mL of DCM / MeOH (10: 1) was used for extraction and separation, 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 give a crude product. Purification by reverse phase column chromatography (MeCN / water = 1 / 100-1 / 2) gave AJ54 (9.2 mg, 21%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )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 NaHCO 3 aqueous solution 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 a pale yellow solid crude 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 NaHCO 3 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 a yellow solid crude 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 Pd 2 (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), heat up to 70 °C and react for 2 h. After detecting the completion of the reaction, quench the reaction solution with 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 extraction three times until 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 (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 DCM, 3 mL TFA was added dropwise to the reaction system at room temperature, and the reaction was stirred at room temperature for 1 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure to obtain an off-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 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 under stirring at room temperature for 30 minutes. LCMS detection showed that the raw material had disappeared and the reaction was complete. 8 mL of water was slowly added to the reaction solution under stirring, and a white solid precipitate was precipitated from the reaction solution. The filter cake was obtained by vacuum filtration, 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%). 1 H NMR (400 MHz, DMSO-d 6) 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 = 1.1Hz, 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] 1 H NMR (400 MHz, DMSO - d 6) 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 (300mg, 1.5mmol) and glycine tert-butyl ester (210mg, 1.6mmol) were dissolved in 10mL DMF, and DIEA (480mg, 3.7mmol) was added to the system in turn under stirring at room temperature. HATU (590mg, 1.6mmol) was added in batches after 10 minutes. After stirring the reaction at room temperature for 30 minutes, LCMS detection showed that the raw material had disappeared and the reaction was completed. 10mL of water was added to the reaction solution to quench, and 10mL of EA was added to extract the liquid, and the extraction was repeated three times until the extraction was complete, the organic phase was combined and backwashed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A light yellow oily compound AJ72-1 (300mg, 64%) was obtained by column chromatography (PE / EA=100 / 1-5 / 1).

[0357] Preparation of AJ72-2: AJ72-1 (300 mg, 1 mmol) was dissolved in 15 mL DMF, and N,N-dimethylethane-1,2-diamine (140 mg, 1.6 mmol) was added dropwise to the reaction solution under stirring at room temperature. 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 K were added in sequence. 2 CO 3 (330mg, 2.4mmol), heated to 100℃ and stirred for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, 15mL of water was added to the reaction solution to quench and 15mL of EA was added for extraction and 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 phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (DCM / MeOH=100 / 1-80 / 1) gave a yellow oily compound AJ72-2 (310mg, 69%).

[0358] Preparation of AJ72-3: AJ72-2 (50 mg, 0.11 mmol) was dissolved in 6 mL DCM, 2 mL TFA was added dropwise to the reaction system at room temperature, and the reaction was stirred at room temperature for 1 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. The 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 DMF, and DIEA (19 mg, 0.14 mmol) and HATU (19 mg, 0.05 mmol) were added to the system under stirring at room temperature. After stirring at room temperature for about 20 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 was precipitated from the reaction solution. The filter cake was obtained by vacuum filtration, 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 TFA and 1 mL TfOH were added to AJ72-4 (25 mg, 0.03 mmol), and the reaction system was heated to 80 °C for 2 h under stirring. LCMS detection showed that the starting material had disappeared and the reaction was complete. The reaction solution was cooled to room temperature, ice water was added to the reaction solution in an ice bath to quench, and saturated NaHCO 3 The reaction solution was adjusted to pH 7-8 with aqueous solution, 10 mL EA was added for extraction and 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 phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A white solid AJ72 (5 mg, 24%) was obtained by column chromatography (DCM / MeOH=100 / 1-15 / 1). 1 H NMR (400 MHz, DMSO-d 6) 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 (1g, 5mmol) and glycine tert-butyl ester (620mg, 5mmol) were dissolved in 20mL DMF, and DIEA (1.6g, 12mmol) was added dropwise to the reaction system under stirring at room temperature. HATU (1.9g, 5mmol) was added in batches after stirring for 10 minutes. After continuing to stir the reaction for 20 minutes, LCMS detection showed that the raw material had disappeared and the reaction was completed. 20mL of water was added to the reaction system to quench, and 20mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, and the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A light yellow oily compound AJ72a-1 (1g, 64%) was obtained by column chromatography (PE / EA=100 / 1-5 / 1).

[0364] Preparation of AJ72a-2: Compound AJ72a-1 (1 g, 3.2 mmol) was dissolved in 15 mL DMF, and N,N-dimethylethane-1,2-diamine (230 mg, 2.6 mmol) was added dropwise to the reaction solution under stirring at room temperature. After stirring for 5 minutes under argon protection, 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (930 mg, 4 mmol), CuI (600 mg, 3.2 mmol) and K were added in sequence. 2 CO 3 (1.1g, 8mmol), heated to 100℃ and stirred for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, 20mL of water was added to the reaction solution to quench and 20mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (DCM / MeOH=100 / 1-60 / 1) gave a yellow oily compound AJ72a-2 (800mg, 54%).

[0365] Preparation of AJ72a-3: AJ72a-2 (65 mg, 0.14 mmol) was dissolved in 6 mL DCM, and 2 mL 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 starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure to obtain a white compound AJ72a-3 (55 mg, 96%).

[0366] Preparation of AJ72a-4: AJ72a-3 (55 mg, 0.13 mmol) and AJ10a-2 (64 mg, 0.13 mmol) were dissolved in 5 mL DMF, and DIEA (52 mg, 0.4 mmol) and HATU (51 mg, 0.13 mmol) were added dropwise to the system under stirring at room temperature. After stirring at room temperature for 20 minutes, LCMS detection showed that the raw material had disappeared and the reaction was completed. 10 mL of water was slowly added to the reaction solution under stirring, and a white solid was precipitated from the reaction solution. The filter cake was filtered under reduced pressure and dried to obtain a filter cake, which was purified by reverse phase column chromatography (MeCN / water = 1 / 100-1 / 2) to obtain a 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 to 80 °C and react for 2 h under stirring. LCMS detection showed that the starting material had disappeared and the reaction was complete. The reaction solution was cooled to room temperature, ice water was added to the reaction solution in an ice bath, and saturated NaHCO 3The reaction solution was adjusted to pH 7-8 with aqueous solution, 10 mL EA was added for extraction and 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 phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A white solid AJ72a (15 mg, 18%) was obtained by reverse phase column chromatography (MeCN / water = 1 / 100-1 / 2). 1 H NMR (400 MHz, DMSO-d 6 ) 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: AJ76-0 (1g, 4mmol) was dissolved in 10mL NMP, and CuCN (720mg, 8mmol) was added to the reaction solution under stirring, and then the reaction solution was heated to 150°C and stirred for 2h. LCMS detection showed that the raw material reaction was complete, 30mL of water was added to the reaction solution for dilution and 30mL of EA was added for extraction and 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 phases were dried and concentrated with anhydrous sodium sulfate to obtain a crude product. Purification by column chromatography (EA / PE=1 / 100-1 / 5) gave a colorless oily product AJ76-1 (800mg, 98%).

[0371] Preparation of AJ76-2: AJ76-1 (800 mg, 4 mmol) was dissolved in 8 mL of TFA, and then 5 mL of concentrated sulfuric acid was added. The reaction solution was heated to 60 °C and reacted for 4 h under stirring. LCMS detection showed that the raw material was completely reacted. The TFA in the reaction solution was removed by vacuum concentration, and then saturated NaHCO was used under ice bath. 3 The pH value of the reaction system was adjusted to neutral with aqueous solution, and then 20 mL of water was added for dilution and 20 mL of EA was added for extraction and 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 and concentrated with anhydrous sodium sulfate to obtain a crude product. Purification by column chromatography (EA / PE=1 / 100-1 / 2) gave a colorless oily product AJ76-2 (650 mg, 78%).

[0372] Preparation of AJ76-3: AJ76-2 (650 mg, 3 mmol) was dissolved in 6 mL of toluene solution, and then DMF-DMA (440 mg, 3.7 mmol) was added. The reaction solution was heated to 120°C with stirring and reacted at this temperature for 2 h. LCMS detection showed that the raw material had been consumed. No purification was required and the reaction solution was directly used in the next step.

[0373] Preparation of AJ76-4: t-BuOK (520 mg, 4.6 mmol) was added to the reaction solution of AJ76-3, and the mixture was heated to 120°C and stirred for 12 h. LCMS detection showed that the reaction of the raw materials was complete. After the reaction solution was cooled to room temperature, 20 mL of water was added, and solid precipitated. The filter cake was filtered, washed, and dried to obtain a brown solid AJ76-4 (137 mg, 24%).

[0374] Preparation of AJ76-5: AJ76-4 (137 mg, 0.6 mmol) was dissolved in 5 mL DMF and K was added under stirring at room temperature. 2 CO 3(165 mg, 1.2 mmol) and tert-butyl 2-bromoacetate (120 mg, 0.7 mmol). The mixed system was heated to 60 o C and stirred the reaction at this temperature for about 2h. LCMS detection shows that the raw material reaction is complete, 15mL water is added to the reaction solution to quench and 10mL EA is added to extract the liquid, and the extraction is repeated three times until the extraction is complete. The organic phases are combined and backwashed with saturated brine, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (EA / PE=1 / 100-1 / 1) gives a brown solid AJ76-5 (200mg, 96%).

[0375] Preparation of AJ76-6: CuI (280 mg, 1.5 mmol) was dissolved in DMF, and then N, N-dimethylethane-1,2-diamine (104 mg, 1.2 mmol) and K 2 CO 3 (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). The mixed system was replaced with argon and heated to 100 o C and stirred the reaction under this condition for about 1h. LCMS detection showed that AJ76-5 had reacted completely, cooled to room temperature and added 15mL of water to the reaction solution for quenching, added 15mL of EA for extraction and separation, and repeated extraction three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (EA / PE=1 / 100-1 / 1) gave a brown solid product AJ76-6 (36mg, 12.4%).

[0376] Preparation of AJ76-7: AJ76-6 (36 mg, 0.07 mmol) was dissolved in 6 mL of DCM solution, 2 mL of TFA was added to the reaction solution under stirring at room temperature, and the reaction was continued for 1 h under stirring at room temperature. LCMS detection showed that the raw material was completely reacted, and the reaction solution was concentrated under reduced pressure and dried to obtain a brown solid AJ76-7 (30 mg, 95%).

[0377] Preparation of AJ76-8: AJ76-7 (30 mg, 0.07 mmol) was dissolved in 6 mL DMF, and AJ10a-2 (33 mg, 0.07 mmol), DIEA (27 mg, 0.2 mmol) and HATU (32 mg, 0.08 mmol) were added to the reaction solution in sequence under stirring at room temperature. The reaction mixture was stirred at room temperature for 20 minutes, and LCMS detection showed that the raw material reaction was complete. 10 mL of water was added to the reaction solution, and solid precipitated, filtered, and concentrated under reduced pressure to obtain a crude concentrate. AJ76-8 (25 mg, 65%) was obtained by column chromatography (MeOH / DCM=1 / 100-1 / 30).

[0378] Preparation of AJ76: AJ76-8 (25 mg, 0.03 mmol) was dissolved in 1 mL of TFA solution, and 1 mL of TfOH was added under stirring at room temperature. The reaction mixture was stirred at room temperature for 2 h. LCMS detection showed that the raw material was completely reacted. The reaction mixture was heated to 40 °C with saturated NaHCO under ice bath. 3 The aqueous solution was used to adjust the pH value of the reaction solution to neutral, and 10 mL of water and 10 mL of EA were added for extraction and 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, and concentrated under reduced pressure to obtain a crude concentrate. AJ76 (5 mg, 40%) was purified by reverse phase column chromatography (MeCN / water = 1 / 100-1 / 5) to obtain a white solid. 1 H NMR (400 MHz, DMSO-d 6) 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 MeCN, CDI (1.6 g, 10 mmol) was added under stirring at room temperature, and the reaction solution was heated to 80 o C and stirred under this condition for about 1 h. LCMS detection showed that the raw material reaction was complete, and the reaction solution was cooled to room temperature and 15 mL of water was added, and solid precipitated. The filter cake was filtered, rinsed, and dried to obtain a brown solid AJ78-1 (1.0 g, 87%).

[0382] Preparation of AJ78-2: AJ78-1 (1.0 g, 4 mmol) was dissolved in 20 mL DMF and K was added under stirring at room temperature. 2 CO 3 (900 mg, 6.5 mmol) and 3-bromopiperidine-2,6-dione (1 g, 5 mmol). The mixture was heated to 100 oC and stirred at this temperature for about 1h. LCMS detection showed that the raw materials had been consumed. The reaction system was cooled to room temperature and 20mL of water was added for quenching. 20mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete. The organic phases were combined and backwashed with saturated brine. The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. A light red solid AJ78-2 (630mg, 52%) was obtained by column chromatography (EA / PE=1 / 100-1 / 1).

[0383] Preparation of AJ78-3: Compound AJ78-2 (400 mg, 1.2 mmol) was dissolved in 15 mL THF solvent, stirred at room temperature and Pd 2 (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), the reaction system was slowly heated to 70 ° C and stirred for 2 h. After the reaction was completed by LCMS, saturated ammonium chloride aqueous solution was added to the reaction solution for quenching, extracted with EA, the organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified 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: AJ78-3 (320 mg, 0.85 mmol) was dissolved in 10 mL of DCM, 3 mL of TFA was added to the reaction solution under stirring at room temperature, and the reaction was stirred at room temperature for 20 minutes. LCMS detection showed that the raw material had reacted completely. The DCM and TFA in the reaction solution were removed by vacuum concentration to obtain a light yellow solid AJ78-4 (255 mg, 93%).

[0385] Preparation of AJ78: AJ78-4 (255 mg, 0.8 mmol) was dissolved in 15 mL DMF, and AJ10a-2 (380 mg, 0.8 mmol), DIEA (296 mg, 2.3 mmol) and HATU (332 mg, 0.9 mmol) were added to the reaction solution in sequence under stirring at room temperature. After stirring the reaction for about 30 minutes, LCMS detection showed that the raw material reaction was complete. 10 mL of water was added to the reaction solution, and solid precipitated. The filter cake was filtered, washed and dried to obtain a crude product. AJ78 (117 mg, 19%) was obtained as a white solid by reverse phase column chromatography (MeCN / water = 1 / 100-1 / 3). 1 H NMR (400 MHz, DMSO-d 6) 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 = 5.0Hz, 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 (20mg, 0.04mmol) and AJ78-4 (13mg, 0.04mmol) were dissolved in 5mL DMF, and DIEA (10mg, 0.08mmol) and HATU (17mg, 0.05mmol) were added successively under stirring at room temperature. The reaction was stirred at room temperature for about 20 minutes. 10mL of water was added to the reaction solution for quenching and 10mL of EA was added for extraction and 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. AJ78b (15mg, 48%) was obtained by purification through reverse phase preparation (MeCN / water=1 / 100-1 / 3) as a white solid. 1HNMR (400 MHz, DMSO-d 6 ) 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 (1g, 5mmol) was dissolved in 20mL DMSO solvent, stirred at room temperature and N-benzyloxycarbonyl-3,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (2g, 6mmol) and CuI (96mg, 0.5mmol) were added in sequence under argon protection, and the reaction system was heated to 60°C for 8h. After the reaction was complete by LCMS detection, it was cooled to room temperature, 30mL of water was added to the reaction system for dilution and 30mL of DCM / MeOH (10:1) was added for extraction and 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 phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. AJ78i-1 (1.2g, 58%) was obtained by column chromatography (MeOH / DCM=1 / 100-1 / 20).

[0392] Preparation of AJ78i-2: AJ78i-1 (500 mg, 1.2 mmol) was dissolved in DCM / MeOH (20 mL, 1:1) solution, and Pd / C (50 mg) with a catalytic content of 10% was added, and hydrogen was replaced, and the reaction was carried out at room temperature in a hydrogen environment for 3 h. LCMS detected that the reaction was complete, and the filter cake was filtered under reduced pressure. The filter cake was rinsed twice with 10 mL of 1,4-dioxane, and the filtrate was combined and concentrated under reduced pressure to obtain a crude concentrate. AJ78i-2 (330 g, 97%) was obtained by column chromatography (EA / PE=1 / 100-1 / 5) to obtain a 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), and AJ10a-0 (230 mg, 0.5 mmol), KHMDS (320 mg, 0.16 mmol), Pd 2 (dba) 3 (49mg, 0.05mmol), X-Phos (25mg, 0.05mmol), argon replacement, the reaction solution was heated to 70℃ for 3h. LCMS detected that the reaction was complete, cooled to room temperature, 20mL of water was added to the reaction solution for dilution and 20mL of EA was added for extraction and 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 phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude concentrate. Purification by column chromatography (MeOH / DCM=1 / 100-1 / 40) gave an off-white solid AJ78i-3 (100mg, 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 an off-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 DMF solvent and Et 3 N (12 mg, 0.12 mmol), and slowly dropwise add HATU (15 mg, 0.04 mmol) in DMF solution and continue stirring the reaction at room temperature for 30 minutes. Then add 10 mL of water to the reaction solution for quenching, a white precipitate is generated, and the white solid crude product is obtained by suction filtration. Purification by column chromatography (MeOH / DCM=1 / 100-1 / 15) gives AJ78i (10 mg, 32%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) 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: AJ79-1 (20 mg, 0.06 mmol, AJ79-1 was prepared according to the preparation method of AJ78-4), AJ10a-2 (30 mg, 0.06 mmol) was dissolved in 6 mL DMF, and DIEA (16 mg, 0.12 mmol) and HATU (26 mg, 0.07 mmol) were added under stirring at room temperature. After about 30 minutes of reaction, 10 mL of water was added to the reaction solution for quenching and 10 mL of EA was added for extraction and 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 phases were dried and concentrated with anhydrous sodium sulfate to obtain a crude concentrate. AJ79 (5 mg, 10%) was obtained as a white solid after reverse phase preparation (MeCN / water = 1 / 100-1 / 2). 1 H NMR (400 MHz, DMSO-d 6 ) 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: AJ79-1 (20mg, 0.06mmol), AJ13-5 (30mg, 0.06mmol) were dissolved in 8mL DMF, DIEA (16mg, 0.12mmol) and HATU (26mg, 0.068mmol) were added under stirring at room temperature, and the reaction was stirred for 20 minutes before adding 10mL water for quenching and adding 10mL EA for extraction and 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 over anhydrous sodium sulfate and concentrated to give a crude product. AJ79b (25mg, 50%) was obtained as a white solid by reverse phase preparation (MeCN / water=1 / 100-1 / 2). 1 H NMR (400 MHz, DMSO-d 6) 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 = 12.7Hz, 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: AJ80-0 (2 g, 16 mmol) was dissolved in 30 mL MeCN solvent, and CDI (5.2 g, 32 mmol) was added under stirring at room temperature. The resulting solution was heated to 85°C and stirred for 2 h. LCMS detected that the reaction was complete, and the mixture was cooled to room temperature and concentrated under reduced pressure to remove MeCN. Then 50 mL of water was added under stirring, and a large amount of white solid precipitated. The solid was filtered under reduced pressure, and the solid was washed with a mixed solvent of EA / PE (1:5). The filter cake was filtered and dried to obtain a white solid AJ80-1 (1.8 g, 71%).

[0405] Preparation of AJ80-2: AJ80-1 (1.8 g, 12 mmol) was dissolved in 30 mL DMF, and the system was placed in an ice-water bath at 0 °C under stirring. A DMF solution of NBS (2.1 g, 12 mmol) was slowly added dropwise, and the reaction system was slowly warmed to room temperature and continued to react for 0.5 h. LCMS detected that the reaction was complete, 50 mL of water was added to the reaction solution for dilution and 30 mL of EA was added for extraction and 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 phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a light yellow solid AJ80-2 (2.3 g, 82%).

[0406] Preparation of AJ80-3: AJ80-2 (1 g, 4.3 mmol) was dissolved in 20 mL DMF solution and Cs 2 CO 3 (2.8g, 8.7mmol) and 3-bromopiperidine-2,6-dione (1.2g, 6.5mmol), the reaction solution was stirred at room temperature for about 6h. LCMS detected that the reaction was complete, 30mL of water was added to the reaction solution for dilution and 20mL of EA was added for extraction and 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 phases were dried and concentrated with anhydrous sodium sulfate to obtain a crude concentrate. A pale yellow solid AJ80-3 (940mg, 64%) was obtained by column chromatography (EA / PE=1 / 100-1 / 5).

[0407] Preparation of AJ80-4: AJ80-3 (20 mg, 0.64 mmol) was dissolved in 10 mL THF, stirred at room temperature and Pd was added under argon protection. 2 (dba) 3 (88mg, 0.1mmol), Q-Phos (69mg, 0.1mmol) and 2-tert-butoxy-2-carbonylethylzinc bromide (2.6mL, 2.6mmol), slowly heated to 70℃ and stirred for 2h. After the reaction was completed, saturated ammonium chloride aqueous solution was added for quenching, EA was extracted, 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 / 50) to obtain an off-white solid AJ80-4 (240mg, 98%).

[0408] Preparation of AJ80-5: AJ80-4 (240 mg, 0.6 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 then concentrated under reduced pressure to remove the solvent to obtain an off-white solid AJ80-5 (200 mg, 98%).

[0409] Preparation of AJ80: AJ80-5 (24 mg, 0.08 mmol) and AJ10-2 (36 mg, 0.08 mmol) were dissolved in 5 mL DMF solution, DIEA (28 mg, 0.22 mmol) was added under stirring at room temperature, and a DMF solution of HATU (30 mg, 0.08 mmol) was slowly added dropwise. After the reaction was completed, 10 mL of water was added to the reaction solution for quenching, and 10 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 and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. AJ80 (25 mg, 43%) was obtained as a white solid by column chromatography (EA / PE=1 / 100-1 / 1). 1 HNMR (400 MHz, DMSO-d 6 ) 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] 1 H NMR (400 MHz, DMSO-d 6 ) 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] 1 H NMR (400 MHz, DMSO-d 6) 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, 1.4Hz, 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] 1 H NMR (400 MHz, DMSO-d 6) 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, 1.5Hz, 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 / z744.5 [M+H] + .

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

[0420]

[0421] 1 H NMR (400 MHz, DMSO-d 6) 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] 1 H NMR (400 MHz, DMSO-d 6) 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, 1.4Hz, 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] 1 H NMR (400 MHz, DMSO-d 6) 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 / z757.5 [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 DMF, and K 2 CO 3 (1.5g, 11mmol), then the reaction system was heated to 85℃ and stirred for 2h. After the reaction was complete, it was cooled to room temperature, 15mL of water was added to the reaction solution to quench it, and 20mL of EA was added to extract and separate the liquids. The extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A pale yellow solid AJ90-1 (1.8g, 93%) was obtained by column chromatography (PE / EA=100 / 1-20 / 1).

[0431] Preparation of AJ90-2: AJ90-1 (500 mg, 1.4 mmol) was dissolved in 10 mL THF solution, and a catalyst Pd / C (10% palladium content, 50 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 filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain an off-white solid AJ90-2 (430 mg, 94%).

[0432] Preparation of AJ90-3: AJ90-2 (430 mg, 1.4 mmol) and 2,6-bis(benzyloxy)-3-bromopyridine (610 mg, 1.6 mmol) were dissolved in 15 mL of dioxane, stirred at room temperature and Pd was added under argon protection. 2 (dba) 3 (130mg,0.14mmol), X-Phos (65mg,0.14mmol), Cs 2 CO 3 (890mg, 2.7mmol), slowly heated to 100℃ and stirred for 6h. After the reaction was completed, it was cooled to room temperature, 10mL of water was added to the reaction solution to quench it and 10mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. AJ90-3 (700mg, 84%) was obtained as a white solid by column chromatography (PE / EA=100 / 1-10 / 1).

[0433] Preparation of AJ90-4: AJ90-3 (250 mg, 0.4 mmol) was dissolved in 10 mL of dioxane and the catalyst Pd(OH) was added under stirring at room temperature. 2 / C (Pd(OH) 2 The reaction system was placed under hydrogen conditions and stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was filtered under reduced pressure and the filter cake was washed. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (PE / EA=100 / 1-1 / 1) to obtain a white solid AJ90-4 (142 mg, 80%).

[0434] Preparation of AJ90-5: AJ90-4 (120 mg, 0.3 mmol) was dissolved in 5 mL of DCM, and 2 mL of a 1,4-dioxane solution (4 M) of hydrochloric acid was added dropwise to the reaction system under stirring at room temperature, and the reaction system was slowly heated to 40°C and stirred for 30 minutes. LCMS detection showed that the raw material had disappeared and the reaction was complete. The excess hydrochloric acid solution and DCM were removed by concentration under reduced pressure to obtain an off-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 THF and 1 mL DMF. After stirring at room temperature for 1 h, AcOH (11 mg, 0.18 mmol) was added dropwise, and NaHB(OAc) was added. 3 (26 mg, 0.12 mmol), continue stirring and react for 2 h. LCMS detection shows that the starting material has disappeared and the reaction is complete. Add 2 mL of saturated NaHCO 3 The aqueous solution was quenched and 5 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and separation, and the extraction was repeated three times until the extraction was complete, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A white solid AJ90 (18 mg, 41%) was obtained by column chromatography (DCM / MeOH=100 / 1-20 / 1). 1 H NMR (400 MHz, DMSO-d 6 ) 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 glycol acetal (440 mg, 3 mmol) were dissolved in 15 mL DMF, and K was added to the system under stirring at room temperature. 2 CO 3 (970mg, 7mmol), then the reaction system was heated to 80℃ and stirred for 2h. After the reaction was detected to be complete, it was cooled to room temperature, 10mL of water was added to the reaction solution to quench it, and 15mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A pale yellow solid AJ90b-1 (800mg, 94%) was obtained by column chromatography (PE / EA=100 / 1-20 / 1).

[0439] Preparation of AJ90b-2: AJ90b-1 (400 mg, 1.3 mmol) was dissolved in 10 mL THF solution, and a catalytic amount of Pd / C (Pd content of 10%, 20 mg) was added under stirring at room temperature, and the reaction was placed under hydrogen conditions and continued to stir at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered under reduced pressure and the filter cake was rinsed several times to obtain the filtrate under reduced pressure and concentrated 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, stirred at room temperature and Pd was added under argon protection. 2 (dba) 3 (237 mg, 0.26 mmol), X-Phos (247 mg, 0.52 mmol) and Cs 2 CO 3 (842mg, 2.6mmol), then slowly heated the reaction system to 100℃ and stirred for 2h. After the reaction was completed, cooled to room temperature, 10mL of water was added to the reaction solution to quench and 15mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. AJ90b-3 (690mg, 96%) was obtained as a white solid by column chromatography (PE / EA=100 / 1-10 / 1).

[0441] Preparation of AJ90b-4: AJ90b-3 (250 mg, 0.45 mmol) was dissolved in 10 mL of dioxane and Pd(OH) was added.2 / C (Pd(OH) 2 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 a crude product, which was then purified by column chromatography (DCM / MeOH=100 / 1-20 / 1) to obtain a white solid AJ90b-4 (163 mg, 96%).

[0442] Preparation of AJ90b-5: AJ90b-4 (163 mg, 0.43 mmol) was dissolved in 10 mL 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 with stirring for about 40 minutes. LCMS detection showed that the starting material had disappeared and the reaction was complete. The reaction was cooled to room temperature and ice water was added to the reaction solution in an ice bath to quench the reaction and saturated NaHCO 3 The reaction solution was adjusted to pH 7-8 with aqueous solution, 15 mL EA was added for extraction and 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 phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A yellow-green solid AJ90b-5 (80 mg, 55%) was obtained by column chromatography (DCM / MeOH=100 / 1-80 / 1).

[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 THF and 1 mL DMF, stirred at room temperature for 1 h, and then AcOH (9 mg, 0.15 mmol) and NaHB(OAc) were added. 3 (21 mg, 0.10 mmol), continue stirring and react for 2 h. LCMS detection shows that the starting material has disappeared and the reaction is complete. Add 2 mL of saturated NaHCO 3 The solution was quenched and 5 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and separation, and the extraction was repeated three times until the extraction was complete, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A white solid AJ90b (8 mg, 22%) was obtained by column chromatography (DCM / MeOH=100 / 1-30 / 1). 1 H NMR (400 MHz, DMSO-d 6) 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: 3,4,5-trifluoronitrobenzene (570 mg, 3 mmol) was dissolved in 20 mL MeCN, and Et 3 N (610 mg, 6 mmol) and AJ90-8D-0 (560 mg, 4 mmol) were added, and the reaction was continued under stirring at room temperature for 2 h. LCMS detection showed that the raw materials had reacted completely, and the crude AJ90-8D-1 obtained from the reaction solution was directly carried out to the next step without purification.

[0447] Preparation of AJ90-8D-2: Add Boc to the crude reaction solution of AJ90-8D-1 2O (1.3 g, 6 mmol) was stirred at room temperature for 30 minutes. LCMS detected that all the raw materials had reacted. 15 mL of water was added to the reaction solution, and extraction and liquid separation were carried out with 15 mL of EA. 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 light yellow concentrate. Through column chromatography (EA / PE = 1 / 100 - 1 / 5), a light yellow oily product AJ90 - 8D - 2 (800 mg, 73%) was obtained.

[0448] Preparation of AJ90 - 8D - 3: AJ90 - 8D - 2 (800 mg, 2.3 mmol) was dissolved in 15 mL of THF. Pd / C (10% content, 80 mg) was added under stirring at room temperature. The reaction system was purged with hydrogen, and the reaction solution was continuously stirred at room temperature for 2 h. LCMS detection showed that the raw materials had been consumed. The palladium carbon in the reaction solution was filtered off by suction, and the palladium carbon was washed three times with EA and DCM. The organic phases were combined and concentrated under reduced pressure to obtain a yellow concentrated product AJ90 - 8D - 3 (730 mg, 99%).

[0449] Preparation of AJ90 - 8D - 4: AJ90 - 8D - 3 (300 mg, 0.9 mmol) and 2,6 - bis(benzyloxy) - 3 - bromopyridine (520 mg, 1.4 mmol) were dissolved in 10 mL of dioxane solution. Then, Cs 2 CO 3 (610 mg, 1.9 mmol), Pd 2 (dba) 3 (128 mg, 0.14 mmol) and X - Phos (11 mg, 0.23 mmol) were added successively under stirring at room temperature. The reaction system was heated to 100 °C under argon protection and stirred for 1 h. LCMS detection showed that the raw materials had been consumed. The reaction solution was cooled to room temperature, and 10 mL of water and 15 mL of DCM / MeOH (10:1) were added for extraction three times until 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 brown concentrate. Through column chromatography (PE / EA = 100 / 1 - 10 / 1), a light yellow oily product AJ90 - 8D - 4 (450 mg, 78%) was obtained.

[0450] Preparation of AJ90 - 8D - 5: AJ90 - 8D - 4 (450 mg, 0.74 mmol) was dissolved in 10 mL of dioxane. Pd(OH) 2 / C (20% content, 45 mg) was added under stirring at room temperature. The reaction system was purged with hydrogen, and the reaction solution was heated to 40 °C in a hydrogen environment and stirred for 2 h. LCMS detection showed that the raw materials had been consumed. The Pd(OH) in the reaction solution2 / C was removed by suction and washed three times with EA and DCM, the organic phases were combined, and the filtrate was concentrated under reduced pressure to obtain a yellow concentrated product AJ90-8D-5 (320 mg, 99%).

[0451] Preparation of AJ90-8D-6: AJ90-8D-5 (320 mg, 0.74 mmol) was dissolved in 10 mL of DCM solution, and a 1,4-dioxane solution of hydrochloric acid (4 M, 2 mL) was added to the reaction solution 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 was completely consumed. The reaction solution was concentrated under reduced pressure to obtain a light green solid AJ90-8D-6 (245 mg, 99%).

[0452] Preparation of AJ90-8D: AJ90-8D-6 (100 mg, 0.3 mmol) was dissolved in 5 mL of a mixed solvent of THF and DMF (4:1), and AJ12-6 (100 mg, 0.24 mmol) and NaHCO were added under stirring at room temperature. 3 (50 mg, 0.6 mmol), and the reaction solution was heated to 45°C and stirred for 10 minutes, then NaHB(OAc) was added 3 (85 mg, 0.4 mmol), continue stirring and react for 2 h. LCMS detection shows that the starting material has disappeared and the reaction is complete. Add 2 mL of saturated NaHCO 3 The aqueous solution was quenched and 5 mL of water was added, 10 mL of DCM / MeOH (10:1) was used for extraction and separation, and the extraction was repeated three times until the extraction was complete, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. A white solid product AJ90-8D (36 mg, 17%) was obtained by column chromatography (DCM / MeOH=100 / 1-30 / 1). 1 H NMR (400 MHz, DMSO-d 6) 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] 1 H NMR (400 MHz, DMSO-d 6) 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, 1.4Hz, 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] 1 H NMR (400 MHz, DMSO-d 6) 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, 1.4Hz, 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: AJ93-0 (1 g, 4 mmol) and NBS (1 g, 6 mmol) were dissolved in 30 mL CHCl 3 The mixture was stirred and slowly heated to reflux, AIBN (66 mg, 0.04 mmol) was added and the reaction was continued for 3 h. After the reaction was complete, 20 mL of water was added to the reaction solution to quench the mixture and 20 mL of CHCl 3 The extraction was repeated three times until the extraction was complete. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow concentrate crude product. A 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: AJ93-1 (1.2 g, 3.6 mmol) and 3-amino-2,6-piperidinedione (770 mg, 6 mmol) were dissolved in 15 mL of DMF. DIEA (900 mg, 7 mmol) was added under stirring at room temperature, and the reaction system was slowly heated to 75 o °C and continued to react for 3 h. After detecting that the reaction was complete, 20 mL of water was added to the reaction solution to quench it, and 30 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 over anhydrous sodium sulfate and concentrated to obtain a crude black concentrate. Column chromatography (DCM / MeOH = 100 / 1 - 50 / 1) gave white solid AJ93-2 (1.1 g, 91%).

[0463] Preparation of AJ93-3: Under the condition of -78 o °C, AJ93-2 (260 mg, 0.77 mmol) was dissolved in 15 mL of dry THF. n-BuLi (1.5 mL, 1.5 mmol) was slowly added dropwise under stirring and continued to react for 1 h. Then, under the condition of -78 o °C, CO 2 was introduced into the reaction system for about 30 minutes, and then slowly warmed to room temperature. After detecting that the reaction was complete by LCMS, 10 mL of saturated ammonium chloride solution 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 the extraction was complete. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude concentrate. Column chromatography (DCM / MeOH = 100 / 1 - 10 / 1) gave white solid AJ93-3 (110 mg, 50%).

[0464] Preparation of AJ93: AJ93-3 (30 mg, 0.01 mmol) and AJ10a-2 (48 mg, 0.01 mmol) were dissolved in 5 mL of DMF. TCFH (28 mg, 0.01 mmol) and NMI (16 mg, 0.02 mmol) were added under stirring at room temperature, and the reaction system was slowly heated to 80 o °C and reacted for 3 h. After detecting that the reaction was complete, 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 the extraction was complete. The combined organic phases were backwashed with saturated brine, and the organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a crude product. Purification by reverse-phase preparation (MeCN / water = 1 / 100 - 1 / 2) gave white solid AJ93 (24 mg, 32%). 1 H NMR (400 MHz, DMSO-d 6) 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 = 20.1Hz, 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] 1 H NMR (400 MHz, DMSO-d 6) 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] 1 H NMR (400 MHz, DMSO-d 6) 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 DCM, and Tf was slowly added dropwise under ice-salt bath and stirring. 2 O (3g, 10.7mmol) and continue stirring the reaction for 1h. After the detection reaction is completed, 20mL of water is added to the reaction solution to quench and 20mL of DCM is added for extraction and separation. The extraction is repeated three times until the extraction is complete, the organic phases are combined and backwashed with saturated brine, the organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. AJ96-1 (2.28g, 72%) was obtained as a yellow solid by column chromatography (PE / EA=100 / 1-40 / 1).

[0474] Preparation of AJ96-2: Dissolve AJ96-1 (500 mg, 1.4 mmol) in 15 mL of dioxane. Under stirring at room temperature, sequentially add 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (400 mg, 1.7 mmol), Pd 2 (dba) 3 (260 mg, 0.3 mmol), X-Phos (270 mg, 0.6 mmol) and Cs 2 CO 3 (910 mg, 2.8 mmol). Under argon protection, heat the mixed system to 80 °C and stir the reaction at this temperature for about 2 h. After detecting the completion of the reaction, cool the reaction system to room temperature, concentrate under reduced pressure to obtain the crude product, and purify it by column chromatography (DCM / MeOH = 100 / 1 - 50 / 1) to obtain white solid AJ96-2 (610 mg, 99%).

[0475] Preparation of AJ96-3: Dissolve AJ96-2 (330 mg, 0.76 mmol) in 15 mL of THF solution. Under stirring at room temperature and under argon protection, sequentially add Pd 2 (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). Slowly raise the reaction system to 70 °C and stir the reaction for 2 h. After the reaction is completed, quench the reaction solution by adding 2 mL of saturated ammonium chloride aqueous solution. 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 phases with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Obtain colorless transparent oily compound AJ96-3 (176 mg, 49%) by column chromatography (DCM / MeOH = 100 / 1 - 60 / 1).

[0476] Preparation of AJ96-4: Dissolve AJ96-3 (176 mg, 0.37 mmol) in 5 mL of DCM. Under stirring at room temperature, add 3 mL of TFA to the reaction system and stir the reaction at room temperature 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 TFA and DCM 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 DMF, and DIEA (31 mg, 0.24 mmol) and HATU (38 mg, 0.1 mmol) were added to the system under stirring at room temperature. 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 to precipitate a white solid precipitate, which was filtered 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: Add 1 mL of TFA and 1 mL of TfOH to AJ96-5 (40 mg, 0.05 mmol), slowly raise the temperature to 40 °C and continue stirring for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. In an ice bath, ice water was added to the reaction solution to quench and saturated NaHCO 3 The reaction solution was adjusted to pH 7-8 with aqueous solution to precipitate a white solid, which was filtered and dried to obtain a crude product. A white solid AJ96 (15 mg, 43%) was obtained after reverse phase column chromatography (MeCN / water = 1 / 100-1 / 2). 1 HNMR (400 MHz, DMSO-d 6) 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, 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 N 8 O 4 , Measured value: 763.5 [M+H] + .

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

[0480]

[0481] 1 H NMR (400 MHz, DMSO-d 6) 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 / z763.5 [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, stirred at room temperature and added with RuPhos (29 mg, 0.06 mmol), RuPhosPdG2 (196 mg, 0.25 mmol) and t-BuOK (106 mg, 0.94 mmol) under argon protection, and 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 and 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 and backwashed with saturated brine, and the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. AJ98-1 (163 mg, 61%) was obtained as a white solid by column chromatography (DCM / MeOH=100 / 1-60 / 1).

[0485] Preparation of AJ98-2: AJ98-1 (163 mg, 0.38 mmol) was dissolved in 5 mL DCM, 3 mL 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 starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure to obtain a 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 THF and 1 mL DMF, stirred at room temperature for 1 h, and then AcOH (11 mg, 0.19 mmol) and NaHB(OAc) were added dropwise. 3 (26 mg, 0.12 mmol), continue stirring the reaction for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. Add 5 mL of saturated NaHCO 3 The reaction was quenched with aqueous solution and 10 mL of DCM / MeOH (10:1) was added for extraction and separation. The extraction was repeated three times until the extraction was complete, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A white solid AJ98 (12 mg, 26%) was obtained by column chromatography (DCM / MeOH=100 / 1-20 / 1). 1 H NMR (400 MHz, DMSO-d 6) 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 acetal (90 mg, 0.63 mmol) were dissolved in 15 mL of dioxane, stirred at room temperature and added RuPhos (29 mg, 0.06 mmol), RuPhosPdG2 (196 mg, 0.25 mmol) and t-BuOK (106 mg, 0.94 mmol) in sequence under argon protection, and slowly heated to 100 ° C for 4 h. After the reaction was completed, 10 mL of water was added to the reaction solution to quench and 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 and backwashed with saturated brine, and the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. AJ98b-1 (110 mg, 46%) was obtained as a white solid by column chromatography (DCM / MeOH=100 / 1-80 / 1).

[0490] Preparation of AJ98b-2: AJ98b-1 (110 mg, 0.29 mmol) was dissolved in 10 mL THF, and 5 mL of hydrochloric acid solution (6 M) was added dropwise to the reaction system under stirring at room temperature, and the temperature was slowly raised to 50 °C and stirred for 40 minutes. LCMS detection showed that the starting material had disappeared and the reaction was complete. In an ice bath, ice water was added to the reaction solution to quench and saturated NaHCO 3 The reaction solution was adjusted to pH 7-8 with aqueous solution, 10 mL EA was added for extraction and 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 phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A pale yellow solid AJ98b-2 (50 mg, 51%) was obtained by column chromatography (DCM / MeOH=100 / 1-60 / 1).

[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 THF and 1 mL DMF. After stirring at room temperature for 1 h, AcOH (16 mg, 0.27 mmol) and NaHB(OAc) were added. 3 (38 mg, 0.18 mmol) and continue stirring the reaction for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. 2 mL of saturated NaHCO 3 The reaction was quenched with aqueous 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, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. AJ98b (3 mg, 5%) was obtained as a white solid by column chromatography (DCM / MeOH=100 / 1-30 / 1). 1 H NMR (400 MHz, DMSO-d 6) 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, 2 H),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 / z720.4 [M+H] + .

[0492] Preparation of AJ106:

[0493]

[0494] Preparation of AJ106-1: AJ106-0 (800 mg, 4 mmol) was dissolved in 10 mL THF, 3-bromopiperidine-2.6-dione (940 mg, 4.9 mmol) and t-BuOK (910 mg, 8 mmol) were added successively under stirring at room temperature, and the reaction system was slowly heated to 70 o C reaction 4h. After the reaction is completed, cool to room temperature and adjust pH=7 with dilute hydrochloric acid (1M), add 10mL water and 10mL EA to the reaction solution for extraction and separation, and repeat 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. Prepared by reverse phase (water / MeCN), AJ106-1 (350mg, 28%) as a white solid was obtained.

[0495] Preparation of AJ106-2: AJ106-1 (350 mg, 1.1 mmol) was dissolved in 10 mL of ultra-dry THF solvent, stirred at room temperature and Pd 2 (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), the reaction system was slowly heated to 70 o C and stirred for 2 h. After the reaction was completed, the mixture was cooled to room temperature and saturated ammonium chloride solution was added to the reaction solution for quenching, extracted 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 (DCM / MeOH=100 / 1-50 / 1) to obtain an off-white solid AJ106-2 (120 mg, 31%).

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

[0497] Preparation of AJ106: AJ106-3 (15mg, 0.05mmol) and AJ10a-2 (15mg, 0.05mmol) were dissolved in 5mL DMF, and DIEA (13mg, 0.1mmol) and HATU (22mg, 0.06mmol) were added under stirring at room temperature. After continuing to stir at room temperature for about 30 minutes, 6mL of water was added to the reaction solution for quenching and 6mL of EA was added for extraction and 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 over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a pale yellow concentrate crude product. AJ106 (20mg, 51%) was obtained as a white solid after reverse phase preparation (MeCN / water=1 / 100-1 / 2). 1 H NMR (400 MHz, DMSO-d 6) 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),2.86-8.80 (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] 1 H NMR (400 MHz, DMSO-d 6) 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: Dissolve AJ110-0 (1 g, 4.7 mmol) in 15 mL of DMF. Add acrylamide (1 g, 14 mmol) and Cs 2 CO 3 (2.3 g, 7 mmol) to the solution under stirring at room temperature. Slowly heat the reaction system to 100 °C and stir for 8 h. After detecting the completion of the reaction, cool to room temperature. Add 15 mL of water and 15 mL of DCM / MeOH (10:1) 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 phases with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by column chromatography (DCM / MeOH = 100 / 1 - 30 / 1) to obtain white solid AJ110-1 (355 mg, 27%).

[0504] Preparation of AJ110-2: AJ110-1 (355 mg, 1.2 mmol) was dissolved in 10 mL MeCN, CDI (310 mg, 1.9 mmol) was added under stirring at room temperature, and the reaction system was heated to 85 ° C and stirred for 2 h. After the reaction was detected to be complete, it was cooled to room temperature, and 10 mL of water and 15 mL of EA were added to the reaction solution for extraction and separation. The extraction was repeated three times until the extraction was complete, and 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. AJ110-2 (200 mg, 52%) was obtained as a white solid by column chromatography (PE / EA=100 / 1-2 / 1).

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

[0506] Preparation of AJ110-4: AJ110-3 (214 mg, 0.62 mmol) was dissolved in 10 mL DCM, 2 mL 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 starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure to obtain a 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 DMF, DIEA (28 mg, 0.22 mmol) and HATU (33 mg, 0.09 mmol) were added dropwise to the system under stirring at room temperature, and the reaction was stirred at room temperature for 30 minutes. LCMS detection showed that the raw material had disappeared and the reaction was complete. 10 mL of water was slowly added to the reaction solution under stirring to precipitate a white solid, and 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-d 6 ) 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-d 6 ) 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 temperature to 100 °C and stir for 2 h. After detecting that the reaction is complete, cool 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 cake under reduced pressure and dry it to obtain a dark green solid AJ112 - 1 (1.6 g, 98%).

[0514] Preparation of AJ112 - 2: N,N ’-Dimethylethane-1,2-diamine (60 mg, 0.7 mmol) was dissolved in 10 mL DMF, stirred at room temperature and under argon protection, 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 Cs 2 CO 3 (1.6g, 5mmol), the reaction system was heated to 100℃ and stirred for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, 10mL of water was added to the reaction solution to quench and 15mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A light yellow solid AJ112-2 (264mg, 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, stirred at room temperature and Pd 2 (dba) 3 (85mg, 0.09mmol), Q-Phos (66mg, 0.09mmol), 2-tert-butoxy-2-carbonylethylzinc bromide (5mL THF solution, 3mmol), slowly heat the reaction system to 70℃ and stir for 1h. After the reaction is completed, the mixture is cooled to room temperature and 5mL saturated ammonium chloride solution is added to the reaction solution for quenching. Then 10mL water and 10mL EA are added to the reaction solution for extraction and separation. The extraction is repeated three times until the extraction is complete. The organic phases are combined and backwashed with saturated brine. The organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A colorless and transparent oily compound AJ112-3 (167mg, 58%) is 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 DCM, 2 mL 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 starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure to obtain a 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, and DIEA (20 mg, 0.15 mmol) and HATU (23 mg, 0.06 mmol) were added to the system under stirring at room temperature, and the reaction was continued under stirring for 30 minutes at room temperature. LCMS detection showed that the raw material 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 from the reaction solution. The filter cake was obtained by vacuum filtration, 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 TFA and 1 mL TfOH, heated to 40 °C and stirred for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete and cooled to room temperature. In an ice bath, ice water was added to the reaction solution to quench the reaction and saturated NaHCO 3 The reaction solution was adjusted to pH 7-8 with aqueous solution, filtered, and the filter cake was dried to obtain a crude product. A white solid AJ112 (15 mg, 35%) was obtained by purification by reverse phase column chromatography (MeCN / water = 1 / 100-1 / 2). 1 H NMR (400 MHz, DMSO-d 6) 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] 1 H NMR (400 MHz, DMSO-d 6) 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, 1.6Hz, 1H), 4.45 - 4.37 (m, 1H), 4.10 - 4.02 (m, 1H), 3.83 (s, 2H), 3.79 (t, J = 6.7Hz, 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 CHCl 3 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 crude concentrate, 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 ’ -dimethyl - ethane - 1,2 - diamine (16 mg, 1.8 mmol), K2 CO 3 (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). The mixed system was replaced with argon and heated to 100 o C and continue stirring the reaction under this condition for about 1h. LCMS detection shows that AJ113-1 reacts completely, drops to room temperature and adds 15mL water and 15mL EA to the reaction solution for extraction and separation, and repeats extraction three times until extraction is complete. Combine the organic phases and backwash with saturated brine, and the organic phase is dried and concentrated with anhydrous sodium sulfate to obtain a brownish yellow concentrate crude product. AJ113-2 (240mg, 60%) is obtained as a brown solid by column chromatography (EA / PE=1 / 100-1 / 1).

[0526] Preparation of AJ113-3: AJ113-2 (240 mg, 0.56 mmol) was dissolved in 15 mL of ultra-dry THF, stirred at room temperature and Pd 2 (dba) 3 (51mg, 0.06mmol), Q-Phos (39mg, 0.06mmol), 2-tert-butoxy-2-carbonylethylzinc bromide (71mg, 0.28mmol), the reaction system was slowly heated to 70°C and stirred for 2h. After the reaction was completed, the temperature was cooled to room temperature and 5mL of saturated ammonium chloride solution was added to the reaction solution for quenching, and 20mL of EA was used for extraction three times until the extraction was complete. The organic phase was collected and 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 off-white solid target product AJ113-3 (130mg, 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 was continued for 1 h. LCMS detection showed that AJ113-3 had reacted completely. The reaction solution was concentrated under reduced pressure and dried to obtain a light red solid AJ113-4 (85 mg, 75%).

[0528] Preparation of AJ113-5: AJ113-4 (20 mg, 0.05 mmol) was dissolved in 8 mL DMF, and AJ10a-2 (24 mg, 0.05 mmol), DIEA (18 mg, 0.14 mmol) and HATU (20 mg, 0.05 mmol) were added to the reaction solution in sequence under stirring at room temperature, and the reaction was stirred at room temperature for about 30 minutes. LCMS detection showed that AJ113-4 reacted completely. 10 mL of water was added to the reaction solution, and a solid precipitated. The filter cake was dried by suction to obtain a brown crude product. AJ113-5 (30 mg, 72%) was obtained as a white solid by column chromatography (DCM / MeOH=100 / 1-20 / 1).

[0529] Preparation of AJ113: AJ113-5 (30 mg, 0.034 mmol) was dissolved in 1 mL of TFA solution, 1 mL of TfOH was added under stirring at room temperature, and then the reaction mixture was heated to 40 o C and stirred for 2 h. LCMS showed that AJ113-5 was completely reacted, and then cooled to room temperature and saturated NaHCO 3 The aqueous solution was used to adjust the pH of the reaction solution to neutral, and then 10 mL of water and 10 mL of EA were added for extraction and 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 over anhydrous sodium sulfate and concentrated to obtain a light brown concentrate crude product. A white solid AJ113 (10 mg, 40%) was obtained after reverse phase column chromatography (MeCN / water = 1 / 100-1 / 1). 1 H NMR (400 MHz, DMSO-d 6) 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] 1 H NMR (400 MHz, DMSO-d 6) 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: Dissolve AJ114 - 0 (1 g, 5 mmol) in 15 mL of MeCN. Add NIS (1.3 g, 6 mmol) under stirring at room temperature and continue stirring at room temperature for 2 h. After detecting the completion of the reaction, concentrate under reduced pressure and purify 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. Add N,N’ - dimethylethane - 1,2 - diamine (46 mg, 0.5 mmol) to the reaction solution under stirring at room temperature. 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), Cs 2 CO 3(1.3g, 3.9mmol), heated to 100℃ and stirred for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, 10mL of water was added to the reaction solution to quench and 15mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A light yellow solid AJ114-2 (440mg, 66%) was obtained by column chromatography (PE / EA=100 / 1-2 / 1).

[0537] Preparation of AJ114-3: AJ114-2 (300 mg, 0.7 mmol) was dissolved in 10 mL of ultra-dry THF solution, stirred at room temperature and Pd was added under argon protection. 2 (dba) 3 (96mg, 0.11mmol), Q-Phos (75mg, 0.11mmol), 2-tert-butoxy-2-carbonylethylzinc bromide (6mL, 3.6mmol), slowly heat the reaction system to 70℃ and stir for 2h. After the reaction is completed, 2mL saturated ammonium chloride solution is added to the reaction solution for quenching, and then 10mL water and 10mL EA are added to the reaction solution for extraction and separation. The extraction is repeated three times until the extraction is complete, the organic phases are combined and backwashed with saturated brine, the organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. AJ114-3 (300mg, 92%) is obtained as a white solid by column chromatography (DCM / MeOH=100 / 1-60 / 1).

[0538] Preparation of AJ114-4: AJ114-3 (300 mg, 0.65 mmol) was dissolved in 5 mL DCM, 2 mL 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 starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure 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, DIEA (14 mg, 0.11 mmol) and HATU (18 mg, 0.05 mmol) were added to the system under stirring at room temperature, and the reaction was stirred at room temperature for 30 minutes. LCMS detection showed that the raw material 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 from the reaction solution. The crude product was obtained by vacuum filtration and drying the filter cake, and 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 TFA and 1 mL TfOH, and the mixture was heated to 40 °C with stirring and continued to react for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. In an ice bath, ice water was added to the reaction solution to quench the mixture and saturated NaHCO 3 The reaction solution was adjusted to pH 7-8 with aqueous solution, filtered, and the filter cake was dried to obtain a crude product. A yellow solid AJ114 (10 mg, 33%) was obtained after reverse phase column chromatography (MeCN / water = 1 / 100-1 / 1). 1 H NMR (400 MHz, DMSO-d 6 ) 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-d 6) 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 THF solution, and the catalyst Pd / C (content of 10%, 200 mg) was added under stirring at room temperature, and the reaction was placed under hydrogen conditions and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered under reduced pressure to remove the catalyst, and the filtrate was concentrated under reduced pressure to obtain a 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 MeCN solution, CDI (2 g, 12 mmol) was added under stirring at room temperature, and the reaction system was heated to 85 ° C and stirred for 2 h. After the reaction was complete, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (PE / EA=100 / 1-4 / 1) to obtain a 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 DMF, and K was added to the system under stirring at room temperature. 2 CO 3 (480mg, 3.5mmol), then heated to 100℃ and stirred for 2h. After the reaction was detected to be complete, it was cooled to room temperature, 10mL of water was added to the reaction solution, and 15mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. AJ115-3 (210mg, 41%) was obtained as a white solid by column chromatography (DCM / MeOH=100 / 1-80 / 1).

[0549] Preparation of AJ115-4: AJ115-3 (210 mg, 0.6 mmol) was dissolved in 10 mL of ultra-dry THF solution, stirred at room temperature and Pd 2 (dba) 3 (80mg, 0.09mmol), Q-Phos (62mg, 0.09mmol), 2-tert-butoxy-2-carbonylethyl zinc bromide (5mL, 3mmol), then slowly heat the system to 70°C and stir for 2h. After the reaction is completed, 2mL of saturated ammonium chloride aqueous solution is added to the reaction solution for quenching, 10mL of water is added to the reaction solution, and 10mL of EA is added for extraction and separation. The extraction is repeated three times until the extraction is complete, the organic phases are combined and backwashed with saturated brine, the organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. AJ115-4 (110mg, 48%) is obtained as a white solid by column chromatography (DCM / MeOH=100 / 1-60 / 1).

[0550] Preparation of AJ115-5: AJ115-4 (110 mg, 0.11 mmol) was dissolved in 8 mL of DCM, and 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 starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure to obtain a 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 DMF, DIEA (14 mg, 0.11 mmol) and HATU (21 mg, 0.06 mmol) were added to the system under stirring at room temperature, and the reaction was stirred at room temperature for 30 minutes. LCMS detection showed that the raw material had disappeared and the reaction was completed. 10 mL of water was slowly added to the reaction solution under stirring, and a white solid was precipitated from the reaction solution. The filter cake was obtained by vacuum filtration, and the filter cake was purified by reverse phase column chromatography (MeCN / water = 1 / 100-1 / 1) to obtain a white solid AJ115 (15 mg, 32%). 1 H NMR (400 MHz, DMSO-d 6 ) 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, stirred at room temperature for 10 minutes, AcOH (41 mg, 0.69 mmol) was added dropwise, and NaHB(OAc) was added 3 (98 mg, 0.46 mmol), then heated to 40 °C and continued to stir for 6 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. 2 mL of saturated NaHCO 3 The aqueous solution was quenched and 10 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and separation, and the extraction was repeated three times until the extraction was complete, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (DCM / MeOH=100 / 1-40 / 1) gave AJ119-1 (26 mg, 19%) as a white solid.

[0555] Preparation of AJ119-2: AJ119-1 (26 mg, 0.04 mmol) was dissolved in 5 mL DCM, 1 mL 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 starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure to obtain a 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, DIEA (10 mg, 0.08 mmol) and HATU (16 mg, 0.04 mmol) were added to the system under stirring at room temperature, and the reaction was continued to stir for 30 minutes at room temperature. LCMS detection showed that the raw material 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 from the reaction solution. The filter cake was obtained by vacuum filtration, and the filter cake was purified by reverse phase column chromatography (MeCN / water = 1 / 100-1 / 1) to obtain a white solid AJ119 (10 mg, 31%). 1 H NMR (400 MHz, DMSO-d 6) 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] 1 H NMR (400 MHz, DMSO-d 6) 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, 1.4Hz, 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 DMF and K was added under stirring at room temperature. 2 CO 3 (1.4g, 10.6mmol), the system was heated to 75℃ and stirred for 2h. LCMS detection showed that the raw material had disappeared and the reaction was over. The reaction system was cooled to room temperature, 20mL of water and 20mL of EA were added to the reaction solution for extraction and 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 phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A colorless and transparent oily compound AJ124-1 (2.42g, 98%) was obtained by column chromatography (PE / EA=100 / 1-40 / 1).

[0563] Preparation of AJ124-2: AJ124-1 (1 g, 2.4 mmol) was dissolved in 15 mL THF solution, and a catalytic amount of Pd / C (content of 10%, 100 mg) was added. The reaction was placed under hydrogen conditions, heated to 40 ° C and stirred for 2 h. After the reaction was completed, the reaction solution was filtered to remove Pd / C, and the filtrate was concentrated under reduced pressure to obtain a yellow solid AJ124-2 (920 mg, 99%).

[0564] Preparation of AJ124-3: AJ124-2 (500 mg, 1.3 mmol) and 3,5-dichloro-6-ethylpyrazinecarboxamide (253 mg, 1.2 mmol) were dissolved in 15 mL of dioxane, DIEA (413 mg, 3.2 mmol) was added under stirring at room temperature, and the system was heated to 110 ° C and stirred for 2 h. LCMS detection showed that the raw material had disappeared and the reaction was completed. The reaction system was cooled to room temperature, concentrated under reduced pressure and column chromatography (DCM / MeOH=100 / 1-60 / 1) was used to obtain a colorless transparent oil compound AJ124-3 (300 mg, 41%).

[0565] Preparation of AJ124-4: AJ124-3 (300 mg, 0.5 mmol) and 4-aminotetrahydropyran (423 mg, 4.2 mmol) were dissolved in 15 mL NMP, heated to 190 ° C and stirred for 2 h. LCMS detection showed that the raw material had disappeared, and the reaction system was cooled to room temperature. 15 mL of water and 15 mL of EA were added to the reaction solution for extraction and separation. The extraction was repeated three times until the extraction was complete, and 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. A colorless and transparent oily compound AJ124-4 (300 mg, 90%) was obtained by column chromatography (DCM / MeOH=100 / 1-40 / 1).

[0566] Preparation of AJ124-5: AJ124-4 (300 mg, 0.47 mmol) was dissolved in 10 mL DCM, 3 mL 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 starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure 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 DMF, DIEA (6 mg, 0.04 mmol) and HATU (9 mg, 0.02 mmol) were added under stirring at room temperature, and the reaction was continued under stirring at room temperature for 30 minutes. LCMS detection showed that the raw material 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 from the reaction solution. The filter cake was obtained by vacuum filtration and dried to obtain a brown solid AJ124-6 (20 mg, 97%).

[0568] Preparation of AJ124: AJ124-6 (20 mg, 0.02 mmol) was dissolved in a mixed solution of 1 mL TFA and 1 mL TfOH, heated to 40 °C and stirred for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. Cool to room temperature, add ice water to the reaction solution in an ice bath, and quench with saturated NaHCO 3 The reaction solution was adjusted to pH 7-8 with aqueous solution, filtered, and the filter cake was dried to obtain a crude product. A yellow solid AJ124 (12 mg, 69%) was obtained after reverse phase column chromatography (MeCN / water = 1 / 100-1 / 1). 1 H NMR (400 MHz, DMSO-d 6) 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-d 6) 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 15 mL of DMF / water (20:1) mixed solution, and Et 3 N (470 mg, 4.5 mmol) and Pd(dppf)Cl 2 DCM (122 mg, 0.15 mmol), the reaction system was replaced with carbon monoxide, and the temperature was raised to 90°C for 3 h under a carbon monoxide environment. After the reaction was detected to be complete, the low-boiling solvent 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 in 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, and 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 under stirring for 30 minutes at room temperature. LCMS detection showed that the raw material had disappeared and the reaction was complete. 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 vacuum filtration and 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 TFA and 1 mL TfOH, and the reaction solution was heated to 40 °C and stirred for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. Cool to room temperature, add ice water to the reaction solution in an ice bath, and quench with saturated NaHCO 3 The reaction solution was adjusted to pH 7-8 with aqueous solution, filtered, and the filter cake was dried to obtain a crude product. A yellow solid AJ125 (5 mg, 14%) was obtained by purification by reverse phase column chromatography (MeCN / water = 1 / 100-1 / 1). 1 H NMR (400 MHz, DMSO-d 6) 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] 1 H NMR (400 MHz, DMSO-d 6) 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 glycol acetal (920 mg, 6.43 mmol) were dissolved in 20 mL DMF, and K 2 CO 3 (1.61g, 11.69mmol), the system was heated to 75℃ and stirred for 2h. LCMS detection showed that the raw material had disappeared and the reaction was over. The reaction system was cooled to room temperature, 20mL of water and 10mL of EA were added to the reaction solution for extraction and 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 phases were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Compound A-1 (1.6g, 93%) was obtained as a colorless and transparent oil by column chromatography (PE / EA=100 / 1-40 / 1).

[0583] Preparation of A-2: A-1 (500 mg, 1.70 mmol) was dissolved in 15 mL THF solution, and a catalytic amount of 10% Pd / C (50 mg) was added. The reaction was placed under hydrogen conditions, heated to 40°C and stirred for 3 hours. After the reaction was completed, the temperature was cooled to room temperature, and the palladium carbon was removed by vacuum filtration. The filtrate was concentrated under reduced pressure to obtain a yellow solid A-2 (420 mg, 93%).

[0584] Preparation of A-3: A-2 (420 mg, 1.59 mmol) and 3,5-dichloro-6-ethylpyrazinecarboxamide (314 mg, 1.43 mmol) were dissolved in 20 mL of dioxane, DIEA (513 mg, 3.98 mmol) was added under stirring at room temperature, and the system was heated to 110 ° C and stirred for 4 hours. LCMS detection showed that the raw material had disappeared and the reaction was completed. The reaction system was cooled to room temperature, concentrated under reduced pressure to remove the low boiling point solvent, and column chromatography (PE / EA=100 / 1-60 / 1) was used to obtain a colorless transparent oily compound A-3 (500 mg, 70%).

[0585] Preparation of A-4: A-3 (500 mg, 1.12 mmol) and 4-aminotetrahydropyran (904 mg, 8.95 mmol) were dissolved in 10 mL NMP, and the reaction system was heated to 190 ° C and stirred for 2 h. LCMS detection showed that the raw material had disappeared, and the system was cooled to room temperature. 20 mL of water and 15 mL of EA were added to the reaction solution for extraction and separation. The extraction was repeated three times until the extraction was complete, and 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. A colorless and transparent oily compound A-4 (510 mg, 89%) was obtained by column chromatography (DCM / MeOH=100 / 1-70 / 1).

[0586] Preparation of A: A-4 (510 mg, 1.00 mmol) was dissolved in 10 mL THF, and 5 mL of aqueous hydrochloric acid solution (6 M) was added dropwise to the reaction system under stirring at room temperature. The reaction system was heated to 50 °C and stirred for about 1 h. LCMS detection showed that the raw material had disappeared and the reaction was complete. In an ice bath, ice water was added to the reaction solution to quench and saturated NaHCO 3 The reaction solution was adjusted to pH 7-8 with aqueous solution, 10 mL EA was added for extraction and 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 phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A white solid A (300 mg, 64%) was obtained by column chromatography (DCM / MeOH=100 / 1-60 / 1).

[0587] Preparation of AJ126-1: AJ112-2 (500 mg, 1.2 mmol) was dissolved in 15 mL of dioxane, stirred at room temperature and N-Boc-piperazine (435 mg, 2.3 mmol), RuPhos (109 mg, 0.23 mmol), RuPhosPdG2 (727 mg, 0.93 mmol) and Cs were added in sequence under argon protection. 2 CO 3 (761 mg, 2.34 mmol), the reaction 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, concentrated under reduced pressure and subjected to column chromatography (DCM / MeOH=100 / 1-30 / 1) to obtain a transparent colorless oily compound AJ126-1 (540 mg, 86%).

[0588] Preparation of AJ126-2: AJ126-1 (540 mg, 1.01 mmol) was dissolved in 10 mL DCM, 10 mL TFA was added dropwise to the reaction system at room temperature, and stirred at room temperature for 1 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure to obtain a white compound AJ126-2 (425 mg, 97%).

[0589] Preparation of AJ126-3: AJ126-2 (25 mg, 0.06 mmol) and compound A (30 mg, 0.06 mmol) were dissolved in 10 mL of anhydrous ethanol, heated to 45 °C and stirred for 1 h, then AcOH (10 mg, 0.17 mmol) and NaHB(OAc) were added. 3 (37 mg, 0.17 mmol), continue stirring the reaction for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. Cool to room temperature and add 2 mL of saturated NaHCO 3 The aqueous solution was quenched, and then 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, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A white solid AJ126-3 (20 mg, 39%) was obtained by column chromatography (DCM / MeOH=100 / 1-15 / 1).

[0590] Preparation of AJ126: AJ126-3 (20 mg, 0.02 mmol) was dissolved in a mixed solution of 1 mL TFA and 1 mL TfOH, and the temperature was raised to 40 °C and stirred for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. Cool to room temperature, add ice water to the reaction solution in an ice bath, and quench with saturated NaHCO 3The reaction solution was adjusted to pH 7-8 with aqueous solution, filtered, and the filter cake was dried to obtain a crude product. A white solid AJ126 (5 mg, 29%) was obtained after reverse phase column chromatography (MeCN / water = 1 / 100-1 / 1). 1 H NMR (400 MHz, DMSO-d 6 ) 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 / z767.5 [M+H] + .

[0591] Preparation of AJ126b:

[0592]

[0593] Preparation of B-1: 2-Fluoro-5-nitroanisole (1 g, 5.84 mmol) and N-Boc-piperazine (1.31 g, 7.01 mmol) were dissolved in 20 mL DMF, and K was added under stirring at room temperature. 2 CO 3(1.61g, 11.69mmol), the system was heated to 75℃ and stirred for 2h. LCMS detection showed that the raw material had disappeared and the reaction was over. The reaction system was cooled to room temperature, 20mL of water and 15mL of EA were added to the reaction solution for extraction and 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 phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Yellow solid B-1 (1.9g, 96%) was obtained 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 THF solution, add a catalytic amount of 10% Pd / C (200 mg), place the reaction under hydrogen conditions, heat to 40 ° C and stir for 2 h. After the reaction is completed, cool the reaction solution to room temperature, remove Pd / C by vacuum filtration, and concentrate the filtrate under reduced pressure to obtain a 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, heat the reaction system to 110 ° C and stir for about 2 hours. LCMS detection shows that the raw material has disappeared and the reaction is over. The reaction system is cooled to room temperature, concentrated under reduced pressure and subjected to column chromatography (PE / EA=100 / 1-50 / 1) to obtain yellow transparent oil B-3 (700 mg, 51%).

[0596] Preparation of B-4: Dissolve B-3 (700 mg, 1.43 mmol) and 4-aminotetrahydropyran (866 mg, 8.57 mmol) in 10 mL NMP, heat the reaction system to 190 ° C and stir for about 3 hours. LCMS detection shows that the raw material has disappeared and the reaction is over. Cool the reaction system to room temperature, add 20 mL of water to the reaction solution and add 15 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 a crude product. Column chromatography (DCM / MeOH=100 / 1-80 / 1) gave a yellow solid B-4 (614 mg, 77%).

[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 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 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 glycol acetal (334 mg, 2.34 mmol), RuPhos (109 mg, 0.23 mmol), RuPhosPdG2 (727 mg, 0.93 mmol) and Cs 2 CO 3 (761 mg, 2.34 mmol). 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 to remove the solvent, and obtain 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 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 NaHCO 3 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: Dissolve AJ126b-2 (50 mg, 0.11 mmol) and B (46 mg, 0.10 mmol) in 6 mL of DMF. Slowly heat the reaction system to 45 °C and react for 1 h under stirring, then add AcOH (18 mg, 0.30 mmol) dropwise and add NaHB(OAc) 3 (64 mg, 0.30 mmol), and continue to stir and react for 2 h. LCMS detection shows that the raw material has disappeared and the reaction is complete. Add 2 mL of saturated NaHCO 3The aqueous solution was quenched and 5 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and separation, and the extraction was repeated three times until the extraction was complete, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A pale yellow solid AJ126b-3 (25 mg, 25%) was obtained by column chromatography (DCM / MeOH=100 / 1-15 / 1).

[0601] Preparation of AJ126b: AJ126b-3 (25 mg, 0.03 mmol) was dissolved in a mixed solvent of 1 mL TFA and 1 mL TfOH, and heated to 40 °C under stirring for 2 h. LCMS showed that the starting material had disappeared and the reaction was complete. Cool to room temperature, add ice water to the reaction solution in an ice bath, and quench with saturated NaHCO 3 The reaction solution was adjusted to pH 7-8 with aqueous solution, filtered, and the filter cake was dried to obtain a crude product. A white solid AJ126b (5 mg, 23%) was obtained after reverse phase column chromatography (MeCN / water = 1 / 100-1 / 1). 1 H NMR (400 MHz, DMSO-d 6 ) 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 N-Boc-piperazine (92 mg, 0.50 mmol), RuPhos (23 mg, 0.05 mmol), RuPhosPdG2 (155 mg, 0.20 mmol) and Cs were added in sequence under argon protection. 2 CO 3 (162 mg, 0.50 mmol), 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, concentrated under reduced pressure to remove the solvent, and subjected to column chromatography (DCM / MeOH=100 / 1-60 / 1) to obtain a colorless transparent oily compound AJ127-1 (50 mg, 84%).

[0605] Preparation of AJ127-2: AJ127-1 (50 mg, 0.12 mmol) was dissolved in 10 mL DCM, 2 mL 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 starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure to obtain a 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 THF and 1 mL DMF. The reaction solution was heated to 45 °C and stirred for 1 h. AcOH (16 mg, 0.27 mmol) was then added dropwise, and NaHB(OAc) was added. 3 (58 mg, 0.27 mmol) and continue stirring the reaction for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. Cool to room temperature and add 2 mL of saturated NaHCO 3 The aqueous solution was quenched and 5 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and separation, and the extraction was repeated three times until the extraction was complete, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A pale yellow solid AJ127 (16 mg, 22%) was obtained by column chromatography (DCM / MeOH=100 / 1-15 / 1). 1 H NMR (400 MHz, DMSO-d 6) 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: AJ124-5 (15 mg, 0.03 mmol) and AJ35-3 (9 mg, 0.03 mmol) were dissolved in 5 mL DMF, DIEA (7 mg, 0.06 mmol) and HATU (11 mg, 0.03 mmol) were added to the system under stirring at room temperature, and the reaction was continued at room temperature for 30 minutes. LCMS detection showed that the raw material 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 from the reaction solution. The crude product was obtained by vacuum filtration and drying the filter cake, and purified by reverse phase column chromatography (MeCN / water = 1 / 100-1 / 1) to obtain AJ128 (10 mg, 43%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6) 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 DMF solution, DIEA (12.9 mg, 0.10 mmol) and HATU (13 mg, 0.033 mmol) were added under stirring at room temperature and stirred at room temperature for 30 minutes. After the reaction was detected to be complete, 10 mL of water was added to the reaction solution for quenching, and the filter cake was filtered and dried to obtain a white solid crude product. AJ128b (15 mg, 54%) was obtained as a white solid by column chromatography (MeOH / DCM=1 / 100-1 / 20). 1 HNMR (400 MHz, DMSO-d 6 ) 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: AJ12-5 (29 mg, 0.086 mmol) was dissolved in a mixed solution of 5 mL THF and 1 mL DMF, A (40 mg, 0.086 mmol) was added under stirring at room temperature and stirred at room temperature for 30 minutes, then AcOH (5 mg, 0.086 mmol) was added dropwise, and NaHB(OAc) was added. 3 (36 mg, 0.17 mmol) and continue stirring the reaction for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. 2 mL of saturated NaHCO 3 The aqueous solution was quenched and 5 mL of water and 10 mL of DCM / MeOH (10:1) were added for extraction and separation, and the extraction was repeated three times until the extraction was complete, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A white solid AJ129 (24 mg, 35%) was obtained by column chromatography (DCM / MeOH=100 / 1-20 / 1). 1 H NMR (400 MHz, DMSO-d 6) 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 chloroacetaldehyde aqueous solution (1.4 g, 7.3 mmol, 40%) was added under stirring, and the mixture was slowly heated to 90°C under argon protection. o C for 4 h. After the reaction was completed, the EtOH was removed by concentration under reduced pressure, and 10 mL of water was added for dilution and saturated NaHCO 3The solution was adjusted to pH = 7, and a solid precipitate was precipitated. The filter cake was filtered and washed and dried to obtain AJ132-1 (1 g, 90%).

[0619] Preparation of AJ132-2: AJ132-1 (1 g, 4.3 mmol) was dissolved in 10 mL DMF, NIS (1.12 g, 6.5 mmol) was added under stirring, and the mixture was stirred at room temperature for 4 h. After the reaction was completed, the mixture was filtered, and the filter cake was washed and dried to obtain a crude product, which was purified by column chromatography (PE / EA=100 / 1-10 / 1) to obtain an off-white solid AJ132-2 (1.4 g, 90%).

[0620] Preparation of AJ132-3: Under argon protection, N,N'-dimethylethylenediamine (30 mg, 0.34 mmol) was dissolved in 15 mL DMF, CuI (97 mg, 0.51 mmol) was added and stirred at room temperature for 10 minutes, and then AJ132-2 (500 mg, 1.41 mmol), 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (494 mg, 2.11 mmol) and K were added in sequence. 2 CO 3 (388 mg, 2.81 mmol), the reaction system was slowly heated to 90 o C and continue to react for 4 hours. When the reaction is complete, 15 mL of water is added to the reaction solution after cooling to room temperature to quench and 15 mL of EA is added for extraction and separation, and the extraction is repeated three times until the extraction is complete. The combined organic phases are dried over anhydrous sodium sulfate and concentrated to obtain a black concentrate crude product, which is purified by column chromatography (DCM / MeOH=100 / 1-50 / 1) to obtain a white solid product AJ132-3 (80 mg, 12%).

[0621] Preparation of AJ132-4: AJ132-3 (80 mg, 0.17 mmol) was dissolved in 10 mL THF solvent, stirred at room temperature and Pd 2 (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), the reaction system was slowly heated to 70 o C and stirred for 2 h. After the reaction was completed, the mixture was cooled to room temperature and saturated aqueous ammonium chloride solution was added to the reaction solution for quenching, extracted with EA, the organic phase was collected and 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 (DCM / MeOH=100 / 1-50 / 1) to obtain an 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 DCM and 1 mL TFA, and the resulting solution was stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure, and the mixture was purified by reverse phase preparation (MeCN / water = 1 / 100-1 / 2) to obtain AJ132-5 (20 mg, 77%) as a white solid.

[0623] Preparation of AJ132-6: AJ132-5 (18mg, 0.042mmol), AJ10a-2 (20mg, 0.042mmol) were dissolved in 10mL DMF, DIEA (16mg, 0.125mmol) and HATU (16mg, 0.042mmol) were added under stirring at room temperature, and the reaction was continued under stirring at room temperature for about 1h. After the reaction was detected, 10mL of water was added to the reaction solution for quenching and 10mL of EA was added for extraction and 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, and concentrated under reduced pressure to obtain a pale yellow concentrate crude product. AJ132-6 (10mg, 27%) was obtained as a white solid after reverse phase preparation (MeCN / water = 1 / 100-1 / 1).

[0624] Preparation of AJ132: AJ132-6 (10 mg, 0.011 mmol) was dissolved in a mixed solvent of 1 mL TFA and 1 mL TfOH and reacted at room temperature for about 3 h under stirring. After the reaction was complete, the solvent was removed by vacuum concentration, and water and saturated NaHCO 3 The aqueous solution was adjusted to pH = 7-8, and a white precipitate was precipitated. The filter cake was filtered and dried to obtain a crude product, which was purified by reverse phase preparation (MeCN / water = 1 / 100-1 / 1) to obtain a white solid AJ132 (2 mg, 23%). 1 H NMR (400 MHz, DMSO-d 6) 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 = 7.5Hz, 3H). LCMS(ESI) m / z 786.5 [M+H] + .

[0625] Preparation of AJ133:

[0626]

[0627] Preparation of AJ133-1: In a 100mL sealed reaction bottle, 4-bromo-2,5-difluoropyridine (2g, 10.42mmol) and ammonia water (10mL) were dissolved in EtOH solution, sealed, and the reaction solution was heated to 100°C and stirred for 2h. The raw material was detected by LCMS to have been consumed, and the reaction was stopped. After the reaction solution was cooled, the pressure was removed, and 20mL of water and 20mL of EA were added for extraction and 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 red concentrate crude product. A light red solid AJ133-1 (400mg, 52.6%) was obtained by column chromatography (EA / PE=1 / 100-1 / 1).

[0628] Preparation of AJ133-2: AJ133-1 (460 mg, 2.42 mmol) was dissolved in 10 mL of EtOH, then stirred at room temperature and chloroacetaldehyde (285 mg, 3.63 mmol) was added to the reaction solution 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 cooled to room temperature and saturated NaHCO 3 The pH value of the aqueous solution was adjusted to be weakly alkaline, and then 10 mL of water was added to cause solid precipitation. The filter cake was filtered and dried to obtain a 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, and the reaction solution was heated to 60°C and reacted at this temperature for 2 h. LCMS detection showed that the raw material was completely reacted, and 10 mL of water was added after the reaction solution was cooled, and solid precipitated, which was filtered under reduced pressure, and the filter cake was dried to obtain a yellow condensed solid crude product AJ133-3 (490 mg, 98%).

[0630] Preparation of AJ133-4: CuI (224 mg, 1.17 mmol) was dissolved in 10 mL DMF, and N, N ’ -dimethylethane-1,2-diamine (129 mg, 1.46 mmol), K 2 CO 3 (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), the mixed system was heated to 90°C under argon protection. o C and stirred the reaction under this condition for about 2h. LCMS detection shows that the raw material reaction is complete, 10mL water is added to the reaction solution for quenching and 10mL EA is added for extraction and separation, and the extraction is repeated three times until the extraction is complete. The organic phases are combined and backwashed with saturated brine, and the organic phase is dried and concentrated with anhydrous sodium sulfate to obtain a crude concentrate. AJ133-4 (210mg, 80%) is obtained as a light yellow oily solid by column chromatography (PE / EA=100 / 1-2 / 1).

[0631] Preparation of AJ133-5: AJ133-4 (210 mg, 0.469 mmol) was dissolved in 15 mL THF solution, stirred at room temperature and Pd was added under argon protection. 2 (dba) 3(64.7mg, 0.07mmol), Q-Phos (50.1mg, 0.07mmol) and 2-tert-butoxy-2-carbonylethylzinc bromide (4.7mL THF solution, 2.35mmol), slowly heated to 70°C and stirred for 2h. After the reaction was completed, saturated aqueous ammonium chloride solution was added to the reaction solution for quenching, and EA was used for extraction three times until the extraction was complete. The organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the solvent. The residue was purified by column chromatography (MeOH / DCM=1 / 100-1 / 60) to obtain an off-white solid AJ133-5 (100mg, 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 under stirring at room temperature, and the reaction was continued for 2 h. LCMS detection showed that the raw material was completely reacted, and then the DCM and TFA in the reaction solution were removed by vacuum concentration to obtain AJ133-6 (78 mg, 88.6%) as a white solid.

[0633] Preparation of AJ133-7: AJ133-6 (30 mg, 0.07 mmol) was dissolved in 5 mL DMF, and 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 under stirring at room temperature, and the reaction was stirred at room temperature for about 30 minutes. LCMS detection showed that the raw material reaction was complete, 10 mL of water was added to the reaction solution, and solid precipitation was precipitated, filtered, and the filter cake was dried to obtain a crude product. Purification by column chromatography (MeOH / DCM=1 / 100-1 / 30) gave AJ133-7 (25 mg, 40%) as a white solid.

[0634] Preparation of AJ133: AJ133-7 (25 mg, 0.027 mmol) was dissolved in a mixed solution of 1 mL TFA and 1 mL TfOH, and the reaction mixture was stirred at room temperature for 2 h. LCMS detection showed that the raw material was completely reacted, and then saturated NaHCO 3 After the pH value of the reaction solution was adjusted to neutral with aqueous solution, 10 mL of water and 10 mL of EA were added for extraction and 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 over anhydrous sodium sulfate and concentrated to obtain a light brown concentrate crude product. AJ133 (5 mg, 25%) was obtained as a white solid by column chromatography (MeCN / water = 1 / 100-1 / 3). 1 H NMR (400MHz, DMSO-d 6) 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 = 7.5Hz, 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] 1 H NMR (400 MHz, DMSO-d 6) 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 100mL pressure-resistant reaction bottle, 4-bromo-3-chloro-2-fluoropyridine (1g, 4.78mmol) was dissolved in 15mL EtOH, and 10mL 25%-28% ammonia water was added to the reaction solution under stirring at room temperature. After sealing, the reaction system was heated to 100°C and the tube was sealed for reaction for 5h under stirring. After the reaction was detected to be complete, it was cooled to room temperature, and 10mL water and 15mL EA were added to the reaction solution for extraction and separation. The extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, and the organic phases were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A colorless and transparent oily compound AJ134-1 (900mg, 91%) was obtained 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, and chloroacetaldehyde (512 mg, 6.52 mmol) was added dropwise under stirring. The mixture was heated to 80 °C and stirred for 2 h under argon protection. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and saturated NaHCO was added dropwise to the reaction mixture under ice bath. 3 The aqueous solution made the system pH = 7, and a yellow precipitate was precipitated. After suction filtration, the filter cake was rinsed 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 MeCN, and 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 mixture was concentrated under reduced pressure to obtain a crude product, which was then 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 DMF, CuI (127 mg, 0.67 mmol) was added to the reaction solution, and after stirring for 10 minutes under argon protection, AJ134-3 (356 mg, 1.00 mmol), 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (195 mg, 0.83 mmol) and Cs 2 CO 3 (814mg, 2.50mmol), the reaction system was heated to 80℃ and stirred for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, 10mL of water was added to the reaction solution to quench the reaction and 15mL of EA was added for extraction and separation. The extraction was repeated three times until the extraction was complete, the organic phases were combined and backwashed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A pale yellow solid AJ134-4 (200mg, 43%) was obtained by column chromatography (PE / EA=100 / 1-2 / 1).

[0644] Preparation of AJ134-5: AJ134-4 (100 mg, 0.22 mmol) was dissolved in 10 mL THF solution, stirred at room temperature and Pd 2 (dba) 3(23mg, 0.03mmol), Q-Phos (30mg, 0.03mmol), 2mL 2-tert-butoxy-2-carbonylethylzinc bromide (0.6mol / L), slowly heat the reaction system to 70℃ and stir for 1h. After the reaction is completed, the reaction solution is cooled to room temperature, 1mL saturated ammonium chloride aqueous solution is added to the reaction solution for quenching, and then 10mL water and 10mL EA are added to the reaction solution for extraction and separation. The extraction is repeated three times until the extraction is complete, the organic phases are combined and backwashed with saturated brine, the organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. AJ134-5 (37mg, 34%) was obtained as a white solid by column chromatography (DCM / MeOH=100 / 1-60 / 1).

[0645] Preparation of AJ134-6: AJ134-5 (37 mg, 0.07 mmol) was dissolved in 5 mL DCM, 2 mL 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 starting material had disappeared and the reaction was complete. The excess TFA and DCM were removed by concentration under reduced pressure to obtain a light yellow compound AJ134-6 (29 mg, 88%).

[0646] Preparation of AJ134-7: AJ134-6 (29 mg, 0.06 mmol) and AJ10a-2 (29 mg, 0.06 mmol) were dissolved in 5 mL DMF, and DIEA (19 mg, 0.15 mmol) and HATU (24 mg, 0.06 mmol) were added to the system in sequence under stirring at room temperature, and the reaction was stirred at room temperature for 30 minutes. LCMS detection showed that the raw material 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 from the reaction solution. The filter cake was obtained by vacuum filtration, and the filter cake was dried to obtain a white solid AJ134-7 (55 mg, 93%).

[0647] Preparation of AJ134: AJ134-7 (55 mg, 0.05 mmol) was dissolved in a mixed solution of 1 mL TFA and 1 mL TfOH and stirred at room temperature for 2 h. LCMS detection showed that the starting material had disappeared and the reaction was complete. In an ice bath, ice water was added to the reaction solution to quench and saturated NaHCO 3 The reaction soluti...

Claims

1. A compound represented by the following formula (I), its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs; Formula (I) in, Y is selected from O, S; Z1 is selected from CH or N; Z2 is selected from a single bond, CH2, O, S, NR1, NHCO; A is selected from unsubstituted or optionally substituted with 1, 2, 3, or 4 R s1 Substituted with the following groups: aryl, heteroaryl, , or ; wherein the aryl group is a 6-20 membered aromatic ring; wherein the heteroaryl group is a 5-20 membered aromatic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; Each R s1 are the same or different and are independently selected from the following groups: 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; U is selected from CH or N; X is selected from CH2, O, S, NR1; 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')-OC(=O)-R s3 ; R', R s3 are the same or different and are independently selected from hydrogen, C1-C6 alkyl, 6-20 membered aryl, 5-20 membered heteroaryl; 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, when Z4 is selected from CH, is a double bond; optionally, X, U and adjacent carbon atoms therebetween form a condensed ring structure; Z3 is a covalent bond or C1-C 10 Alkyl, the C1-C 10 Any carbon atom in the alkyl group may be optionally replaced by NH, O, S or substituted by an oxo (=O) group; The PTM is selected from a small molecule compound or a derivative thereof that binds to the target protein ALK; The condition is that when A is selected from When Z3 is -C(=O)-.

2. The compound of formula (I) according to claim 1, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, wherein: R1 is independently selected from hydrogen, C1-C3 alkyl; Alternatively, Y is selected from O; Alternatively, Z2 is selected from a single bond, CH2, O, S, NH, NCH3, NHCO; Alternatively, 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)-; Alternatively, A is selected from unsubstituted or optionally substituted with 1, 2, 3, or 4 R s1 Substituted with the following groups: aryl, heteroaryl, , ,or ; wherein the aryl group is a 6-10 membered aromatic ring; wherein the heteroaryl group 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 definitions in claim 1; Optionally, X forms a fused ring structure with the carbon atoms at positions 1 and 2.

3. The compound of formula (I) according to claim 1, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from unsubstituted or optionally substituted with 1, 2, 3, or 4 R s1 Substituted from the following groups: phenyl, naphthyl, pyridine, indazole, quinoline, quinolizine, pyridazine, pyrazine, naphthyridinone, benzimidazole, benzopyrazole, benzisoxazole, imidazopyridine, triazolopyridine, pyrazolopyridine, benzopyrazole, , , , ,or ; wherein X and U have the definitions in claim 1.

4. The compound of formula (I) according to claim 1, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from unsubstituted or optionally substituted with 1, 2, 3, or 4 R s1 Substituted with the following groups: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； Where R s1 As defined in claim 1.

5. The compound of formula (I) according to claim 4, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, wherein: Each R s1 are the same or different and are 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.

6. The compound of formula (I) according to claim 1, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； Where R s1 As defined in claim 1.

7. The compound of formula (I) according to claim 1, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from the following groups: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 8. The compound of formula (I) according to claim 1, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, wherein: Z4 is selected from C=O or C=S, is a single bond, or, Z4 is selected from CH, is a double bond; Alternatively, X, U and adjacent carbon atoms therebetween form a fused benzene ring; Alternatively, 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)-.

9. The compound of formula (I) according to claim 1, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, wherein: Z3 is selected from a single bond, -C(=O)-, -CH2-C(=O)-, -C(=O)-CH2-, -NH-C(=O)-, -C(=O)-NH-CH2-C(=O)-.

10. The compound of formula (I) according to claim 1, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, wherein: The PTM is selected from the following structures: 、 、 、 、 、 、 、 、 ； Wherein, J is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 ； L is selected from C1-C6 alkylene, -C1-C6 alkylcarbonyl-; T is selected from di-C1-C6 alkylphosphine oxide, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl; R2 to R 15 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, hydroxyC1-C6 alkyl; K is selected from C1-C3 alkylene, NH; R S2 Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy.

11. The compound of formula (I) according to claim 10, its stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug, wherein: The PTM is selected from the following structures: 、 、 、 、 、 、 、 、 、 ； Among them, L, R2 to R 15 , K, R S2 As defined in claim 10.

12. The compound of formula (I) according to claim 10, its stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug, wherein: L is selected from C1-C3 alkylene, -C1-C3 alkylcarbonyl-; Alternatively, T is selected from di-C1-C3 alkylphosphine oxide, C1-C3 alkylsulfonyl, C1-C3 alkylsulfinyl; Alternatively, R2 to R 15 is 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, hydroxyC1-C3 alkyl; Alternatively, K is selected from C1-C2 alkylene; Or, R S2 Selected from hydrogen, fluorine, chlorine, bromine, C1-C3 alkyl, C1-C3 alkoxy.

13. The compound of formula (I) according to claim 10, its stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug, wherein: J is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 14. The compound of formula (I) according to claim 10, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, wherein: J is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 15. The compound of formula (I) according to claim 10, its stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug, wherein: J is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 16. The compound of formula (I) according to claim 10, its stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug, in, Y is selected from O; Z1 is selected from CH or N; Z2 is selected from a single bond, CH2, O, S, NR1, NHCO; A is selected from unsubstituted or optionally substituted with 1, 2, 3, or 4 R s1 Substituted from the following groups: phenyl, naphthyl, pyridine, indazole, quinoline, quinolizine, pyridazine, pyrazine, naphthyridinone, benzimidazole, benzopyrazole, benzisoxazole, imidazopyridine, triazolopyridine, pyrazolopyridine, benzopyrazole, 、 、 、 、 ； Each R s1 are the same or different and are independently selected from the following groups: 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; U is selected from CH or N; X is selected from CH2, O, S, NR1; R1 is selected from hydrogen; Optionally, X forms a fused ring structure with the carbon atoms at positions 1 and 2; 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)-; The PTM is selected from the following structures: 、 、 、 ； Among them, J, T, R S2 As defined in claim 10; The condition is that when A is selected from When Z3 is -C(=O)-.

17. The compound of formula (I) according to claim 1, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, wherein: The compound is selected from the following structures: 。 18. A method for preparing the compound of formula (I) according to claim 1, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs: Scheme 1: The compound represented by formula (II-1) reacts with the reactant PTM-H to obtain the compound represented by formula (I); in, 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 as described in claim 1; or, when R is a protecting group, the scheme 1 further comprises a process of removing the protecting group to prepare a compound represented by formula (I) wherein R1 is hydrogen; Alternatively, 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 as described in claim 1; or, when R is a protecting group, the scheme 2 further comprises a process of removing the protecting group to prepare a compound represented by formula (I) in which R1 is hydrogen; Alternatively, Scheme 3: The compound represented by formula (III-1) or formula (III-2) or formula (III-3) reacts with a reactant to obtain a compound represented by formula (I); ;or ;or ； Among them, the reactants are or or ; Among them, R1-R9, Z1, Z2, Z3, Y, R S2 , T, K, PTM and A have the definitions as in claim 1; Alternatively, Scheme 4: The compound represented by formula (II-3) reacts with the reactant to obtain a compound represented by formula (I); ; Among them, the reactants are , , , , , or ; Among them, R1-R9, Z1, Z2, Z3, Y, R S2 , T, K, PTM and A have the definitions as in claim 1; Alternatively, Scheme 5: The compound represented by formula (II-4) reacts with the compound represented by formula (III-4) to obtain a compound represented by formula (I); Among them, R 10 -R 13 , R1, Z1, Z2, Z3, Y, PTM and A have the meanings as defined in claim 1, and L' is selected from C1-C5 alkyl-CHO or C1-C5 alkyl-COOH.

19. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound of formula I according to claim 1, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs.

20. Use of the compound of formula I according to claim 1, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or the pharmaceutical composition according to claim 19 in the preparation of a drug, wherein the drug is selected from any one of the following: (1) The drug is a drug used to inhibit ALK kinase activity; (2) The drug is a drug targeting ALK; (3) The drug is capable of treating or preventing a disease or disorder in which mutant ALK plays a role.

21. Use of the compound of formula I according to claim 1, its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or the pharmaceutical composition according to claim 19 in the preparation of a medicament for treating or preventing cancer.

22. The use according to claim 21, wherein the cancer cells of the cancer comprise mutated ALK.

23. The use according to claim 21, wherein the cancer is: lung cancer; lymphoma; inflammatory myofibroblastic tumor; colorectal cancer; glioma; astrocytoblastoma; ovarian cancer; bone marrow disease; transplant-related cancer; neutropenia; leukemia; Unverheit syndrome; bronchogenic 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; sarcoma; tumors resistant to targeted drugs; or tumors or diseases dependent on ALK protein.

24. The use according to claim 21, 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's lymphoma; anaplastic lymphoma; anaplastic large cell lymphoma; CD20 positive lymphoma; primary lymphoma; B-cell lymphoma; relapsed B-cell non-Hodgkin's lymphoma; relapsed diffuse large B-cell lymphoma; relapsed mediastinal (thymic) large B-cell lymphoma; primary mediastinal (thymic) large B-cell lymphoma; relapsed transformed non-Hodgkin's lymphoma; refractory B-cell non-Hodgkin's lymphoma; refractory diffuse large B-cell lymphoma; refractory primary mediastinal (thymic) large B-cell lymphoma; refractory transformed non-Hodgkin's lymphoma; multiple myeloma; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome symptoms; plasma cell myeloma; smoldering myeloma; smoldering multiple myeloma; myelofibrosis; acute myeloid leukemia (AML); anemia associated with leukemia; chronic myeloid leukemia; B-cell chronic lymphocytic leukemia; Ongwericht syndrome; bronchogenic 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 tumors; 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 / primitive neuroectodermal tumors (Ewing / PNETs); leiomyosarcoma; tumors resistant to ALK-targeted drugs; or tumors or diseases that depend on the ALK protein.

25. The use according to claim 21, wherein the cancer is selected from the group consisting of: non-small cell lung cancer that is positive for anaplastic lymphoma kinase (ALK) mutation; lung cancer that is resistant to ALK targeted drugs; lymphoma that is resistant to ALK targeted drugs; or the following tumors, cancers or diseases that depend 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 cancer, 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.

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