Benzo six-membered heterocyclic amide compound, pharmaceutical composition and application of benzo six-membered heterocyclic amide compound

Abstract

The invention discloses a benzo six-membered heterocyclic amide compound, a pharmaceutical composition and application of the benzo six-membered heterocyclic amide compound, and particularly provides a compound shown in a formula (I) or pharmaceutically acceptable salt of the compound. The compound provided by the invention has excellent positive allosteric regulation activity on an M4 receptor, has better pharmacodynamic / pharmacokinetic performance, and can be used for treating diseases and obstacles mediated by the M4 receptor. # imgabs0 #

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a benzo six-membered heterocyclic amide compound, a pharmaceutical composition and application thereof. Background Art

[0002] M receptors (Muscarinic receptors) are class I GPCRs, consisting of seven transmembrane segments, one of which is the extracellular N-terminus, one is the intracellular C-terminus, and there is a large intracellular segment between helix 5 and helix 6. The M receptor was first cloned and sequenced by Kubo et al. in 1986 and is encoded by the CHRM1 to CHRM5 genes, which produce five functionally divided subtypes, M1-M5. Among them, M4 is widely expressed in the striatum, caudate nucleus, and putamen, and is co-expressed with dopamine receptors in striatal projection neurons, where it regulates dopamine release and inhibits dopamine D1 receptor function. M4 has become a promising target for the treatment of cognitive and behavioral deficits in neurodegenerative and neuropsychiatric diseases.

[0003] M receptor positive allosteric modulations (PAMs) are a class of allosteric agonists that do not directly activate receptors. They increase the affinity of receptors for acetylcholine at the orthosteric binding site by binding to the allosteric site, thereby enhancing the receptor's response to acetylcholine. In addition, M receptor allosteric agonists do not cause receptor downregulation, probably because they do not bind to the same site as classical agonists. This advantage can effectively avoid receptor desensitization that is easily caused by classical agonists (Xie Kankan et al., Research Progress on Muscarinic Receptor Expression in Schizophrenia, Neurological Diseases and Mental Health, 2021, Vol. 21, No. 5). High subtype single selective M receptor PAMs have attracted much attention because they can avoid the adverse effects of activation of surrounding mAChRs. At present, PAMs targeting various subtypes of M receptors, especially PAMs targeting M4 receptors, have shown potential for anti-psychotic and cognitive improvement in preclinical studies (Gould RW, et al., Neuropharmacology, 2018, 128: 492-502.).

[0004] Extensive studies have shown that the regulation of M4 receptors has the potential to treat negative symptoms and cognitive impairment associated with schizophrenia. Currently, there are many compounds in the clinical research stage. Representative ones include Emraclidine (CVL-231) and NBI-1117568, which are already in clinical phase II, and NS-136, which has recently entered clinical phase I. In addition, Vanderbilt University has been committed to the research and development of M4 receptor PAMs since 2013. In the past decade, it has successively launched a variety of PAMs active molecules targeting M4 receptors, such as VU0467154, VU0152099, VU0152100, etc., but they are currently in the preclinical research stage; the patent applications for selective positive allosteric modulators of M4 receptors that have been disclosed include WO2018002760A1, WO2018234953A1, WO 2018112312 A1, WO2013126856A1, WO2014035829A1, WO2017223290A1, WO2019113179A1, WO2018035444A1, WO2023064588A1, WO2023141511A1, WO2024088408A1, etc.

[0005] In summary, although there is sufficient literature and drug development information to prove that PAMs targeting the M4 receptor may provide a new treatment approach for cognitive and behavioral deficits in neurodegenerative and neuropsychiatric diseases, no PAMs targeting the M4 receptor have been successfully marketed. Therefore, there is still a wide demand in this field for selective positive allosteric modulators of the M4 receptor with high subtype selectivity, good efficacy and high safety. Summary of the invention

[0006] The present invention provides a benzo six-membered heterocyclic amide compound and a pharmaceutical composition containing the compound and its use. The compound of the present invention has excellent positive allosteric regulation activity on M4 receptors, has better pharmacodynamics / pharmacokinetic properties, and can be used to treat diseases and disorders mediated by M4 receptors.

[0007] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0008]

[0009] wherein ring A is selected from phenyl and pyridyl;

[0010] X 1 and X 2 Independently selected from N and CR 4 , and stipulate that X 1 and X 2Not N simultaneously;

[0011] L 1 Selected from C 3-6 Cycloalkylidene and 4-6 membered heterocycloalkylidene, wherein the C 3-6 Cycloalkylidene and 4-6 membered heterocycloalkylidene are each independently optionally substituted by 1, 2 or 3 R a ; In the 4-6 membered heterocycloalkylidene, the heteroatom is N and the number of heteroatoms is 1;

[0012] R 1 Are each independently selected from H, cyano, halogen and C 1-6 Halogenated alkyl;

[0013] R 2 Is selected from halogen and C 1-6 Alkyl;

[0014] R 3 Is selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and NR b R c ;

[0015] R 4 Is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and NR b R c ;

[0016] n is 0, 1, 2, 3 or 4;

[0017] R a Are each independently H, hydroxy, halogen and C 1-6 Alkyl;

[0018] R b And R c Are each independently selected from hydrogen and C 1-3 Alkyl, or, wherein R b And R c Together with the nitrogen atom to which they are attached form a 4-6 membered saturated heterocycle; In the 4-6 membered saturated heterocycle, the heteroatom is N and the number of heteroatoms is 1.

[0019] In certain preferred embodiments of the present invention, some groups of the compound of formula (I) or its pharmaceutically acceptable salt are defined as follows, and the groups not mentioned are the same as those described in any aspect of the present invention (abbreviated as "in some embodiments").

[0020] In some embodiments, R 1 , R 2 , R 3 , R 4 and R a wherein the halogen is independently fluorine, chlorine, bromine or iodine; preferably fluorine or chlorine.

[0021] In some embodiments, R 2 , R 3 , R 4 and R a In the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl, more preferably methyl.

[0022] In some embodiments, R 1 , R 3 and R 4 In the C 1-6 Haloalkyl is independently C substituted with one or more halogens. 1-3 Alkyl groups, such as -CH 2 F, -CH 2 Cl, -CHF 2 , -CHCl 2 , -CCl 3 , -CF 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CF 3 or -CF 2 CF 3 .

[0023] In some embodiments, R 3 and R 4 In the C 1-6 The alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy.

[0024] In some embodiments, R 3 and R 4 In the C 1-6 The alkylthio group is independently methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio or tert-butylthio, preferably methylthio.

[0025] In some embodiments, L 1 In the C 3-6The cycloalkylene group is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene.

[0026] In some embodiments, L 1 In the example, the 4-6 membered heterocycloalkylene group may be an azetidinylene group (e.g. ), pyrrolidinyl ( ) or piperidinyl ( ), preferably azetidinylene.

[0027] In some embodiments, R b and R c In the C 1-3 Alkyl groups are independently methyl, ethyl, n-propyl or isopropyl.

[0028] In some embodiments, when R b and R c When the 4- to 6-membered saturated heterocyclic ring is formed together with the nitrogen atom to which it is connected, the 4- to 6-membered saturated heterocyclic ring is azetidine, pyrrolidine or piperidine.

[0029] In some embodiments, Ring A is selected from phenyl and pyridinyl;

[0030] X 1 and X 2 Independently for CR 4 ;

[0031] L 1 is a 4-6 membered heterocycloalkylene group, wherein the heteroatom is N and the number of heteroatoms is 1;

[0032] R 1 are each independently selected from halogen and C 1-6 Haloalkyl;

[0033] R 2 Selected from halogen and C 1-6 alkyl;

[0034] R 3 Selected from C 1-6 alkyl;

[0035] R 4 Select from H or C 1-6 alkyl;

[0036] n is 1 or 2.

[0037] In some embodiments, Ring A is selected from phenyl and pyridinyl;

[0038] X 1 and X 2 Independently for CR 4 ;

[0039] L 1 is a 4-6 membered heterocycloalkylene group, wherein the heteroatom is N and the number of heteroatoms is 1;

[0040] R 1 are each independently selected from halogen and C 1-6 Haloalkyl;

[0041] R 2 is selected from halogen;

[0042] R 3 Selected from C 1-6 alkyl;

[0043] R 4 Select from H or C 1-6 alkyl;

[0044] n is 1 or 2.

[0045] In some embodiments, ring A is pyridyl, for example or (The bond indicates the location of attachment to the rest of the molecule).

[0046] In some embodiments, X 1 and X 2 Independently for CR 4 ; R 4 H or C 1-6 alkyl.

[0047] In some embodiments, X 1 and X 2 Independently for CR 4 ; R 4 H or C 1-3 alkyl.

[0048] In some embodiments, X 1 and X 2 Independently for CR 4 ; R 4 It is H or methyl.

[0049] In some embodiments, X 1 and X 2 For CH.

[0050] In some embodiments, X 1 CR 4 ; R 4 C 1-6 Alkyl; X 2 For CH.

[0051] In some embodiments, X 1 CR4 ; R 4 C 1-3 Alkyl; X 2 For CH.

[0052] In some embodiments, X 1 CR 4 ; R 4 is methyl; X 2 For CH.

[0053] In some embodiments, R 1 are each independently selected from H, halogen and C 1-6 Halogenated alkyl.

[0054] In some embodiments, R 3 C 1-6 alkyl.

[0055] In some embodiments, R 3 It is methyl.

[0056] In some embodiments, Ring A is phenyl; in other embodiments, Ring A is pyridinyl.

[0057] In some embodiments, X 1 CR 4 , X 2 CR 4 In other embodiments, X 1 N, X 2 CR 4 In other embodiments, X 1 CR 4 , X 2 is N.

[0058] In some embodiments, X 1 CR 4 , X 2 For CH.

[0059] In some embodiments, L 1 C 3-6 Cycloalkylene; in some embodiments, L 1 It is a 4-6 membered heterocycloalkylene group, wherein the heteroatom is N and the number of the heteroatom is 1.

[0060] In some embodiments, L 1 It is azetidinylene.

[0061] In some embodiments, R 1 are independently H; in other embodiments, R 1are independently cyano; in other embodiments, R 1 are independently halogen; in other embodiments, R 1 Independently for C 1-6 Halogenated alkyl.

[0062] In some embodiments, R 1 independently selected from fluorine, chlorine and CF 3 .

[0063] In some embodiments, n is 0; in other embodiments, n is 1; in other embodiments, n is 2; in other embodiments, n is 3; in other embodiments, n is 4.

[0064] In some embodiments, n is selected from 1, 2, and 3, such as 1 and 2.

[0065] In some embodiments, R 2 is halogen; in other embodiments, R 2 C 1-3 alkyl.

[0066] In some embodiments, R 2 is selected from fluorine, chlorine, bromine, iodine and methyl.

[0067] In some embodiments, R 2 Selected from fluorine and chlorine.

[0068] In some embodiments, R 3 Selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio and NR b R c .

[0069] In some embodiments, R 3 Selected from C 1-3 alkyl.

[0070] In some embodiments, R 3 is selected from methyl, ethyl, n-propyl and isopropyl; further preferably, R 3 Selected from methyl and ethyl.

[0071] In some embodiments, R 4 Selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio and NR b R c .

[0072] In some embodiments, R4 Selected from H and C 1-3 alkyl.

[0073] In some embodiments, R 4 Selected from H and methyl.

[0074] In some embodiments, R a Each is independently H.

[0075] In some embodiments, R b and R c are each independently selected from hydrogen, methyl and ethyl; in other embodiments, R b and R c Together with the nitrogen atom to which it is attached it forms an azetidine, pyrrolidine or piperidine.

[0076] In some embodiments, X 1 and X 2 Independently for CR 4 , R 4 It is H or methyl.

[0077] In some embodiments, L 1 for , where the N atom is connected to ring A.

[0078] In some embodiments, R 1 Each independently selected from H, -F, -Cl or -CF 3 .

[0079] In some embodiments, R 2 is selected from methyl, -F or -Cl.

[0080] In some embodiments, R 2 It is -F or -Cl.

[0081] In some embodiments, R 3 Selected from methyl or ethyl.

[0082] In some embodiments, the structural unit Selected from , , , , , , , , , , , , , , , , , , and Preferably, the structural unit Selected from , , and .

[0083] In some embodiments, the structural unit Selected from , , , , , , , , , , , , , , , , , Preferably, the structural unit Selected from , , and .

[0084] In some embodiments, the structural unit Selected from , , , , , , , , , and Preferably, the structural unit Selected from , , , , and Preferably, the structural unit Selected from , and .

[0085] In some embodiments, the present invention provides a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of the formula (II):

[0086]

[0087] Among them, R 1 , R 2 , R 3 , R 4 , Ring A and n are as defined above.

[0088] Preferably,

[0089] Structural unit Selected from , , and , further preferably, the structural unit Selected from and .

[0090] R 2 is selected from fluorine, chlorine, bromine and iodine; preferably, R 2 is selected from fluorine and chlorine;

[0091] R 3 C 1-3 Alkyl; further preferably, R 3 is selected from methyl and ethyl;

[0092] R 4 Selected from hydrogen and C 1-3 Alkyl; further preferably, R 4 is selected from hydrogen and methyl.

[0093] In some embodiments, the compound represented by formula (I) is any of the following compounds:

[0094]

[0095]

[0096]

[0097] .

[0098] In some embodiments, the compound represented by formula (I) is any of the following compounds:

[0099] .

[0100] In some embodiments, the compound represented by formula (I) is any of the following compounds:

[0101] .

[0102] The present invention also provides a method for preparing the compound represented by formula (I), the method comprising the following steps:

[0103] The intermediate (IA) or its salt and the intermediate (IB) undergo amide condensation reaction in the presence of an amide condensation agent to prepare a compound of formula (I):

[0104]

[0105] Here, the group R in formula (IA), formula (IB) and formula (I) 1 , n, ring A, L 1 , R 2 , R 3 , X 1 and X 2 is defined as above;

[0106] The amide condensation agent is a carbodiimide condensation agent, an onium salt condensation agent or an organic phosphorus condensation agent.

[0107] The reaction preparation conditions may be conventional conditions for such reactions in the art.

[0108] In some embodiments, the salt of the intermediate formula (IA) may be a trifluoroacetate salt.

[0109] In another aspect, the present invention also provides the intermediates described in the present invention.

[0110] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient. In a specific embodiment, the compound of formula (I) of the present invention is provided in a therapeutically effective amount. In a specific embodiment, the compound of formula (I) of the present invention is provided in a preventive effective amount.

[0111] In another aspect, the present invention provides a use of a compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing diseases and / or disorders mediated by the M4 receptor.

[0112] In some embodiments, the diseases and / or disorders mediated by the M4 receptor include but are not limited to: Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive disorders, depression, Parkinson's disease, Huntington's disease, movement disorders, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, cerebral amyloid angiopathy, dementia, stroke, pancreatitis, peripheral amyloidosis, diabetes, alcoholic liver disease, hepatitis or atherosclerosis.

[0113] In another aspect, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing a disease and / or disorder;

[0114] The diseases and / or disorders include, but are not limited to, Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive disorders, depression, Parkinson's disease, Huntington's disease, movement disorders, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, cerebral amyloid angiopathy, dementia, stroke, pancreatitis, peripheral amyloidosis, diabetes, alcoholic liver disease, hepatitis, or atherosclerosis.

[0115] In another aspect, the present invention provides a method for treating diseases and / or disorders mediated by M4 receptors, comprising the step of administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention to a subject in need thereof.

[0116] In some embodiments, the diseases and / or disorders mediated by the M4 receptor include but are not limited to: Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive disorders, depression, Parkinson's disease, Huntington's disease, movement disorders, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, cerebral amyloid angiopathy, dementia, stroke, pancreatitis, peripheral amyloidosis, diabetes, alcoholic liver disease, hepatitis or atherosclerosis.

[0117] The terms used to describe the present invention in this application are defined as follows. For a specific term, if the meaning defined in this application is inconsistent with the meaning generally understood by those skilled in the art, the meaning defined in this application shall prevail; if not defined in this application, it shall have the meaning generally understood by those skilled in the art.

[0118] In the present application, the names of compounds and their structural formulas are in correspondence. When the names of compounds are inconsistent with the structural formulas, the structural formulas shall prevail, or they may be inferred based on the specific circumstances of the present invention and the knowledge of those skilled in the art.

[0119] As used herein, numerical ranges such as 1-6, 1-3, and 3-6, etc., defined in substituents indicate integers within the range, such as 1-6 is 1, 2, 3, 4, 5, or 6.

[0120] "Cyano" refers to -CN.

[0121] "Hydroxy" refers to -OH.

[0122] "Halogen" refers to a fluorine, chlorine, bromine or iodine atom, preferably fluorine.

[0123] "Alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group.1-6 "Alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl and n-hexyl. The alkyl group in the present application is preferably C 1-3 alkyl.

[0124] "Cycloalkylene" refers to a group consisting of designated ring carbon atoms (e.g., C 3-6 ) is a saturated cyclic divalent hydrocarbon group. For example, "C 3-6 "Cycloalkylene" refers to a saturated cyclic divalent hydrocarbon group consisting of 3 to 6 ring carbon atoms. Exemplary cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene.

[0125] "Alkoxy" refers to a group -OR, where R is an alkyl group as defined above. 1-3 Specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy and isopropoxy.

[0126] "Heterocycloalkylene" refers to a saturated divalent cyclic group with a specified number of ring atoms (e.g., 4-6 members) and a specified number of nitrogen-containing heteroatoms, which is connected to the rest of the molecule through a carbon atom or a heteroatom. Examples of 4-6 membered heterocycloalkylene include, but are not limited to, azetidinylene, pyrrolidinylene, piperidinylene, etc.

[0127] "Pharmaceutically acceptable salts" refer to pharmaceutically acceptable organic or inorganic salts of the compounds of the invention as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts, which may be formed in the presence of acidic protons capable of reacting with inorganic or organic bases.

[0128] The term "optional" or "optionally" means that the event or situation described subsequently may but need not occur, and the description includes instances where the event or situation occurs and instances where the event or situation does not occur. For example: the term "optionally substituted with one or more substituents" means that it may or may not be substituted. When substituted, it means that any one or more hydrogen atoms on a particular atom are replaced by a substituent.

[0129] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted with 1 - 2 Rs, the group may optionally be substituted with up to two Rs, and the R in each case has independent options. In addition, combinations of substituents and / or their variants are only permitted if such combinations result in stable compounds.

[0130] The term "therapeutically effective amount" refers to an amount administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art according to the circumstances.

[0131] The term "pharmaceutical excipient" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, and is generally divided into two major categories: excipients and additives. For details, see "Pharmacopoeia of the People's Republic of China (2020 Edition)", Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0132] The term "treatment" refers to eliminating the cause or alleviating the symptoms.

[0133] The term "prevention" refers to reducing the risk of developing a disease.

[0134] The term "patient" refers to any animal in need of treatment or prevention of a disease, usually a mammal, such as a human. Mammals include but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0135] Other features and advantages of the present application will be described in the subsequent specification, and will, in part, be apparent from the specification or understood by implementing the present application. Other advantages of the present application can be achieved and obtained through the solutions described in the specification.

[0136] On the basis of not violating the common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0137] The reagents and raw materials used in the present invention are all commercially available.

[0138] The positive and progressive effects of the present invention are as follows: Compared with the prior art, the present invention has one or more of the following beneficial effects:

[0139] The compounds provided by the present invention have excellent positive allosteric regulatory activity on M4 receptors, and can be used as M4 receptor positive allosteric modulators for treating and / or preventing diseases and / or disorders mediated by M4 receptors. In addition, experiments have shown that the compounds of the present invention also have good pharmacodynamic and / or pharmacokinetic effects. DETAILED DESCRIPTION

[0140] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0141] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6. NMR measurements were performed using a Bruker Avance Neo 400 MHz NMR spectrometer in a solvent of deuterated dimethyl sulfoxide (DMSO-d 6 ) or deuterated chloroform (CDCl 3 ), with tetramethylsilane (TMS) as the internal standard).

[0142] LCMS was determined using Waters ACQUITY UPLC.

[0143] High performance liquid chromatography (HPLC) was measured by a Thermo UltiMate 3000 liquid chromatograph using a VenusilASB C18 (4.6*250mm, 5µm) column.

[0144] The thin layer chromatography silica gel plate used was West Asia Reagent GF254 silica gel plate.

[0145] Column chromatography used 200-300 mesh silica gel from Qingdao Ocean Chemical Co., Ltd. as the carrier.

[0146] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products, or can be synthesized by methods known in the art, or can be purchased from reagent companies such as Aladdin, Bidex Pharmaceuticals, and WuXi AppTec.

[0147] This application uses the following abbreviations: 1 H NMR: hydrogen nuclear magnetic resonance; 13 C NMR: carbon nuclear magnetic resonance; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0148] Intermediate 1-3

[0149] Synthesis route:

[0150]

[0151] first step

[0152] Under nitrogen atmosphere, 1-1 (1.80 g, 7.47 mmol), A-1 (1.41 g, 8.22 mmol), cesium carbonate (7.28 g, 22.41 mmol), tris(dibenzylideneacetone)dipalladium (684 mg, 0.75 momol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (929 mg, 1.49 mmol) were dissolved in toluene (50 mL) and the mixture was heated to 90 °C. o C and stirred for 24 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 1-2 (1.34 g, yield: 63%). LC-MS (ESI) m / z=286.20 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ7.61 (d, J = 5.6 Hz, 1H), 6.17 (t, J = 5.7 Hz, 1H), 5.12 (s, 1H), 4.64 (s,1H), 4.48 - 4.44 (m, 2H), 4.00 - 3.96 (m, 2H), 1.47 (s, 9H).

[0153] Step 2

[0154] Dissolve 1-2 (1.34 g, 4.70 mmol) in dichloromethane (15 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 2 hours. Add saturated sodium bicarbonate aqueous solution to the reaction solution to adjust the pH to 8, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 1-3.

[0155] Intermediate 2-3

[0156] Synthesis route:

[0157]

[0158] first step

[0159] Under nitrogen atmosphere, 2-1 (1.50 g, 6.73 mmol), A-1 (1.27 g, 7.40 mmol), cesium carbonate (6.56 g, 20.19 mmol), tris(dibenzylideneacetone)dipalladium (246 mg, 0.27 momol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (502 mg, 0.81 mmol) were dissolved in toluene (40 mL) and the mixture was heated to 90 °C. o C and stirred for 18 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (40 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 2-2 (1.28 g, yield: 71%). LC-MS (ESI) m / z=268.21 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ8.13 (d, J = 4.5 Hz, 1H), 8.00 (dd, J = 5.4, 0.9 Hz, 1H), 7.59 (d, J = 7.3Hz, 1H), 6.49 (dd, J = 8.3, 5.4 Hz, 1H), 4.46 - 4.41 (m, 1H), 4.30 - 4.26 (m,2H), 3.89 - 3.85 (m, 2H), 1.39 (s, 9H).

[0160] Step 2

[0161] Dissolve 2-2 (1.28 g, 4.79 mmol) in dichloromethane (12 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 2 hours. Add saturated sodium bicarbonate aqueous solution to the reaction solution to adjust the pH to 8, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 2-3.

[0162] Intermediate 3-3

[0163] Synthesis route:

[0164]

[0165] first step

[0166] Under nitrogen atmosphere, 3-1 (2.01 g, 8.85 mmol), A-1 (1.67 g, 9.74 mmol), sodium tert-butoxide (1.19 g, 12.39 mmol), tris(dibenzylideneacetone)dipalladium (202 mg, 0.22 momol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (412 mg, 0.66 mmol) were dissolved in toluene (60 mL) and the mixture was heated to 80 °C. o C and stirred for 18 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (60 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 3-2 (2.61 g, yield: 93%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.28 (d, J = 5.8 Hz, 1H), 6.57(s, 1H), 6.33 (d, J = 5.5 Hz, 1H), 5.30 (d, J = 7.8 Hz, 1H), 4.67 (s, 1H),4.33 - 4.29 (m, 2H), 3.84 - 3.81 (m, 2H), 1.45 (s, 9H).

[0167] Step 2

[0168] Dissolve 3-2 (2.61 g, 8.23 ​​mmol) in dichloromethane (25 mL), add trifluoroacetic acid (8 mL), and stir at room temperature for 2 hours. Add saturated sodium bicarbonate aqueous solution to the reaction solution to adjust the pH to 8, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 3-3.

[0169] Intermediate 4-3

[0170] Synthesis route:

[0171]

[0172] first step

[0173] Under nitrogen atmosphere, 4-1 (1.60 g, 9.09 mmol), A-1 (1.72 g, 10.00 mmol), sodium tert-butoxide (1.22 g, 12.73 mmol), tris(dibenzylideneacetone)dipalladium (208 mg, 0.23 momol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (424 mg, 0.68 mmol) were dissolved in toluene (60 mL) and the mixture was heated to 90 °C. o C and stirred for 18 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 4-2 (1.65 g, yield: 68%). LC-MS (ESI) m / z=268.22 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ7.84 (d, J = 5.8 Hz, 1H), 6.15 - 6.13 (m, 1H), 5.78 (d, J = 1.9 Hz, 1H), 5.19(s, 1H), 4.67 (s, 1H), 4.31 - 4.27 (m, 2H), 3.80 - 3.77 (m, 2H), 1.47 (s, 9H).

[0174] Step 2

[0175] Dissolve 4-2 (1.65 g, 6.18 mmol) in dichloromethane (15 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 2 hours. Add saturated sodium bicarbonate aqueous solution to the reaction solution to adjust the pH to 8, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 4-3.

[0176] Intermediate 5-3

[0177] Synthesis route:

[0178]

[0179] first step

[0180] Under a nitrogen atmosphere, 5-1 (2.20 g, 8.56 mmol), A-1 (1.62 g, 9.42 mmol), sodium tert-butoxide (1.15 g, 11.98 mmol), tris(dibenzylideneacetone)dipalladium(0) (391 mg, 0.43 momol), and 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (789 mg, 1.28 mmol) were dissolved in toluene (60 mL), and the temperature was raised to 90 o °C and stirred for 18 hours. After the reaction solution was cooled to room temperature, it was quenched with water, extracted with ethyl acetate (60 mL × 3), the organic phases were combined, washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 5-2 (1.86 g, yield: 72%). LC-MS (ESI) m / z = 302.19 [M+H] + .

[0181] The second step

[0182] 5-2 (1.86 g, 6.18 mmol) was dissolved in dichloromethane (18 mL), trifluoroacetic acid (6 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate, extracted repeatedly with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of intermediate 5-3.

[0183] Intermediate 6-3

[0184] Synthetic route:

[0185]

[0186] The first step

[0187] Under a nitrogen atmosphere, 6-1 (1.60 g, 8.29 mmol), A-1 (1.57 g, 9.12 mmol), cesium carbonate (8.08 g, 24.87 mmol), tris(dibenzylideneacetone)dipalladium(0) (379 mg, 0.41 momol), and 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (773 mg, 1.24 mmol) were dissolved in toluene (50 mL), and the temperature was raised to 90 oC and stirred for 18 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 6-2 (1.77 g, yield: 75%). LC-MS (ESI) m / z=229.17 [M+H-tBu] + . 1 H NMR (400 MHz, CDCl 3 ) δ6.82 - 6.86 (m, 1H), 6.60 - 6.53 (m, 1H), 6.24 - 6.19 (m, 1H), 5.05 (s, 1H), 4.61 (s, 1H), 4.35 - 4.31 (m, 2H), 3.76 - 3.73 (m, 2H), 1.43 (s, 9H).

[0188] Step 2

[0189] Dissolve 6-2 (1.77 g, 6.23 mmol) in dichloromethane (18 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 2 hours. Add saturated sodium bicarbonate aqueous solution to the reaction solution to adjust the pH to 8, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 6-3.

[0190] Intermediate 7-3

[0191] Synthesis route:

[0192]

[0193] first step

[0194] Under nitrogen atmosphere, 7-1 (1.40 g, 7.29 mmol), A-1 (1.38 g, 8.00 mmol), sodium tert-butoxide (979 mg, 10.20 mmol), tris(dibenzylideneacetone)dipalladium (334 mg, 0.36 momol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (680 mg, 1.09 mmol) were dissolved in toluene (50 mL) and the mixture was heated to 90 °C. oC and stirred for 24 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 7-2 (1.51 g, yield: 73%). LC-MS (ESI) m / z=284.21 [M+H] + .

[0195] Step 2

[0196] Dissolve 7-2 (1.51 g, 5.34 mmol) in dichloromethane (15 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 2 hours. Add saturated sodium bicarbonate aqueous solution to the reaction solution to adjust the pH to 8, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 7-3.

[0197] Intermediate 8-3

[0198] Synthesis route:

[0199]

[0200] first step

[0201] Under nitrogen atmosphere, 8-1 (1.50 g, 6.76 mmol), A-1 (1.28 g, 7.44 mmol), cesium carbonate (6.59 g, 20.28 mmol), tris(dibenzylideneacetone)dipalladium (186 mg, 0.20 momol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (378 mg, 0.61 mmol) were dissolved in toluene (50 mL) and the mixture was heated to 90 °C. o C and stirred for 18 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 8-2 (1.62 g, yield: 90%). LC-MS (ESI) m / z=211.18 [M+H-tBu] + .

[0202] Step 2

[0203] Dissolve 8-2 (1.62 g, 6.09 mmol) in dichloromethane (15 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 2 hours. Add saturated sodium bicarbonate aqueous solution to the reaction solution to adjust the pH to 8, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 8-3.

[0204] Intermediate 9-2

[0205] Synthesis route:

[0206]

[0207] Compound 9-1 (1.50 g, 8.74 mmol) was added to a test tube, followed by 8 mL of 6 mol / L hydrochloric acid, and reacted at 120 °C for 45 minutes. B-1 (1.10 g, 13.11 mmol) was then added at 110 °C. o C for 24 hours. After the reaction solution was cooled to room temperature, the pH value of the system was adjusted to about 5 with a saturated sodium carbonate aqueous solution. After the solid was precipitated, it was filtered and dried. The filtrate was extracted three times with ethyl acetate and concentrated under reduced pressure to obtain a portion of the crude product, which was combined with the filter cake. The filter cake was added with 50 mL of ethyl acetate and the temperature was raised to 50 o C was slurried for 1 hour, filtered and dried to obtain intermediate 9-2 (1.71 g, yield: 83%). LC-MS (ESI) m / z = 236.16 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.54 (s, 1H), 8.32 (s, 1H), 7.40 (s, 1H), 2.67 (d, J = 11.0 Hz, 6H).

[0208] Intermediate 9-3

[0209] Synthesis route:

[0210]

[0211] Compound 9-1 (2.10 g, 12.24 mmol) was added to a test tube, followed by 8 mL of 6 mol / L hydrochloric acid, and reacted at 120 °C for 45 minutes. B-2 (1.62 g, 18.36 mmol) was then added at 110 °C. oC for 24 hours. After the reaction solution was cooled to room temperature, the pH value of the system was adjusted to about 5 with a saturated sodium carbonate aqueous solution. After the solid was precipitated, it was filtered and dried. The filtrate was extracted three times with ethyl acetate and concentrated under reduced pressure to obtain a portion of the crude product, which was combined with the filter cake. The filter cake was added with 50 mL of ethyl acetate and the temperature was raised to 50 o C was slurried for 1 hour, filtered and dried to obtain intermediate 9-3 (2.12 g, yield: 78%). LC-MS (ESI) m / z = 222.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.96 (d, J = 4.3 Hz, 1H), 8.64 (d, J = 1.8 Hz, 1H), 8.28 (d, J = 1.7 Hz, 1H), 7.59 (d, J = 4.3 Hz, 1H), 2.77(s, 3H).

[0212] Intermediate 9-4

[0213] Synthesis route:

[0214]

[0215] Compound 9-1 (2.30 g, 13.40 mmol) was added to a test tube, followed by 8 mL of 6 mol / L hydrochloric acid, and reacted at 120 °C for 45 minutes. B-3 (1.97 g, 20.10 mmol) was then added at 110 °C. o C for 24 hours. After the reaction solution was cooled to room temperature, the pH value of the system was adjusted to about 5 with a saturated sodium carbonate aqueous solution. After the solid was precipitated, it was filtered and dried. The filtrate was extracted three times with ethyl acetate and concentrated under reduced pressure to obtain a portion of the crude product, which was combined with the filter cake. The filter cake was added with 50 mL of ethyl acetate and the temperature was raised to 50 o C was slurried for 1 hour, filtered and dried to obtain intermediate 9-4 (2.71 g, yield: 81%).

[0216] Intermediate 10-2

[0217] Synthesis route:

[0218]

[0219] Compound 10-1 (2.50 g, 16.12 mmol) was added to a test tube, followed by 8 mL of 6 mol / L hydrochloric acid, and reacted at 120 °C for 45 minutes. B-1 (1.63 g, 19.34 mmol) was then added at 110 °C. oC for 24 hours. After the reaction solution was cooled to room temperature, the pH value of the system was adjusted to about 5 with a saturated sodium carbonate aqueous solution. After the solid was precipitated, it was filtered and dried. The filtrate was extracted three times with ethyl acetate and concentrated under reduced pressure to obtain a portion of the crude product, which was combined with the filter cake. The filter cake was added with 50 mL of ethyl acetate and the temperature was raised to 50 o C was slurried for 1 hour, filtered and dried to obtain intermediate 10-2 (2.90 g, yield: 82%). LC-MS (ESI) m / z = 220.18 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.44 - 8.43 (m, 1H), 7.87 (dd, J= 11.2, 1.7 Hz, 1H), 7.47 (d, J = 1.1 Hz, 1H), 2.70 (d, J = 1.0 Hz, 3H), 2.66(s, 3H).

[0220] Intermediate 10-3

[0221] Synthesis route:

[0222]

[0223] Compound 10-1 (1.80 g, 11.61 mmol) was added to a test tube, followed by 8 mL of 6 mol / L hydrochloric acid, and reacted at 120 °C for 45 minutes. B-2 (1.53 g, 17.41 mmol) was then added at 110 °C. o C for 24 hours. After the reaction solution was cooled to room temperature, the pH value of the system was adjusted to about 5 with a saturated sodium carbonate aqueous solution. After the solid was precipitated, it was filtered and dried. The filtrate was extracted three times with ethyl acetate and concentrated under reduced pressure to obtain a portion of the crude product, which was combined with the filter cake. The filter cake was added with 50 mL of ethyl acetate and the temperature was raised to 50 o C was slurried for 1 hour, filtered and dried to obtain intermediate 10-3 (1.81 g, yield: 76%). LC-MS (ESI) m / z = 206.17 [M+H] + .

[0224] Intermediate 10-4

[0225] Synthesis route:

[0226]

[0227] Compound 10-1 (2.50 g, 16.12 mmol) was added to a test tube, followed by 8 mL of 6 mol / L hydrochloric acid, and reacted at 120 °C for 45 minutes. B-3 (2.37 g, 24.18 mmol) was then added at 110 °C. o C for 24 hours. After the reaction solution was cooled to room temperature, the pH value of the system was adjusted to about 5 with a saturated sodium carbonate aqueous solution. After the solid was precipitated, it was filtered and dried. The filtrate was extracted three times with ethyl acetate and concentrated under reduced pressure to obtain a portion of the crude product, which was combined with the filter cake. The filter cake was added with 50 mL of ethyl acetate and the temperature was raised to 50 o C was slurried for 1 hour, filtered and dried to obtain intermediate 10-4 (3.12 g, yield: 83%). LC-MS (ESI) m / z = 234.23 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.49 (d, J = 1.7 Hz, 1H), 7.87 (dd, J = 11.1, 1.7 Hz, 1H), 7.48 (s, 1H), 3.12 (q, J = 7.5 Hz, 2H), 2.69 (s,3H), 1.33 (t, J = 7.5 Hz, 3H).

[0228] Intermediate 11-2

[0229] Synthesis route:

[0230]

[0231] Compound 11-1 (2.10 g, 13.89 mmol) was added to a test tube, followed by 8 mL of 6 mol / L hydrochloric acid, and reacted at 120 °C for 45 minutes. B-1 (1.40 g, 16.67 mmol) was then added at 110 °C. o C for 24 hours. After the reaction solution was cooled to room temperature, the pH value of the system was adjusted to about 5 with a saturated sodium carbonate aqueous solution. After the solid was precipitated, it was filtered and dried. The filtrate was extracted three times with ethyl acetate and concentrated under reduced pressure to obtain a portion of the crude product, which was combined with the filter cake. The filter cake was added with 50 mL of ethyl acetate and the temperature was raised to 50 o C was slurried for 1 hour, filtered and dried to obtain intermediate 11-2 (2.45 g, yield: 82%). LC-MS (ESI) m / z = 216.21 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6) δ 8.48 (d, J = 1.8 Hz, 1H), 8.04 (s, 1H), 7.36 (s, 1H), 2.71 (s, 3H), 2.68 (s, 3H), 2.65 (s, 3H).

[0232] Intermediate 11-3

[0233] Synthesis route:

[0234]

[0235] Compound 11-1 (2.30 g, 15.21 mmol) was added to a test tube, followed by 8 mL of 6 mol / L hydrochloric acid, and reacted at 120 °C for 45 minutes. B-2 (2.01 g, 22.82 mmol) was then added at 110 °C. o C for 24 hours. After the reaction solution was cooled to room temperature, the pH value of the system was adjusted to about 5 with a saturated sodium carbonate aqueous solution. After the solid was precipitated, it was filtered and dried. The filtrate was extracted three times with ethyl acetate and concentrated under reduced pressure to obtain a portion of the crude product, which was combined with the filter cake. The filter cake was added with 50 mL of ethyl acetate and the temperature was raised to 50 o C was slurried for 1 hour, filtered and dried to obtain intermediate 11-3 (2.60 g, yield: 85%). LC-MS (ESI) m / z = 202.17 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.87 (d, J = 4.3 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.08 (s, 1H), 7.48 (d, J = 4.3 Hz, 1H), 2.74 (d, J = 4.4Hz, 6H).

[0236] Intermediate 11-4

[0237] Synthesis route:

[0238]

[0239] Compound 11-1 (2.70 g, 17.86 mmol) was added to a test tube, followed by 8 mL of 6 mol / L hydrochloric acid, and reacted at 120 °C for 45 minutes. B-3 (2.63 g, 26.79 mmol) was then added at 110 °C. oC for 24 hours. After the reaction solution was cooled to room temperature, the pH value of the system was adjusted to about 5 with a saturated sodium carbonate aqueous solution. After the solid was precipitated, it was filtered and dried. The filtrate was extracted three times with ethyl acetate and concentrated under reduced pressure to obtain a portion of the crude product, which was combined with the filter cake. The filter cake was added with 50 mL of ethyl acetate and the temperature was raised to 50 o C was slurried for 1 hour, filtered and dried to obtain intermediate 11-4 (3.28 g, yield: 80%). LC-MS (ESI) m / z = 230.18 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (d, J = 2.0 Hz, 1H), 8.03(s, 1H), 7.37 (s, 1H), 3.10 (q, J = 7.5 Hz, 2H), 2.72 (s, 3H), 2.67 (s, 3H),1.32 (t, J = 7.5 Hz, 3H).

[0240] Intermediate 13-3

[0241] Synthesis route:

[0242]

[0243] first step

[0244] Under nitrogen atmosphere, 13-1 (2.12 g, 8.24 mmol), A-1 (1.56 g, 9.06 mmol), sodium tert-butoxide (1.11 g, 11.53 mmol), tris(dibenzylideneacetone)dipalladium (377 mg, 0.41 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (513 mg, 0.82 mmol) were dissolved in toluene (60 mL) and the mixture was heated to 80 °C. o C and stirred for 18 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (60 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 13-2 (2.04 g, yield: 82%).

[0245] Step 2

[0246] Dissolve 13-2 (2.04 g, 6.75 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (7 mL), and stir at room temperature for 2 hours. Add 5% sodium hydroxide solution to the reaction solution to adjust the pH to about 11, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 13-3.

[0247] Intermediate 14-3

[0248] Synthesis route:

[0249]

[0250] first step

[0251] Under nitrogen atmosphere, 14-1 (1.78 g, 7.44 mmol), A-1 (1.41 g, 8.18 mmol), sodium tert-butoxide (1.00 g, 10.41 mmol), tris(dibenzylideneacetone)dipalladium (170 mg, 0.19 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (347 mg, 0.56 mmol) were dissolved in toluene (60 mL) and the mixture was heated to 80 °C. o C and stirred for 12 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (60 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 14-2 (1.50 g, yield: 71%).

[0252] Step 2

[0253] Dissolve 14-2 (1.50 g, 5.28 mmol) in dichloromethane (15 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 2 hours. Add 5% sodium hydroxide solution to the reaction solution to adjust the pH to about 11, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 14-3.

[0254] Intermediate 15-3

[0255] Synthesis route:

[0256]

[0257] first step

[0258] Under nitrogen atmosphere, 15-1 (1.40 g, 7.25 mmol), A-1 (1.37 g, 7.98 mmol), cesium carbonate (7.09 g, 21.76 mmol), tris(dibenzylideneacetone)dipalladium (199 mg, 0.22 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (452 ​​mg, 0.73 mmol) were dissolved in toluene (60 mL) and the mixture was heated to 90 °C. o C and stirred for 18 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (60 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 15-2 (1.44 g, yield: 70%).

[0259] Step 2

[0260] Dissolve 15-2 (1.44 g, 5.08 mmol) in dichloromethane (15 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 2 hours. Add 5% sodium hydroxide solution to the reaction solution to adjust the pH to about 11, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 15-3.

[0261] Intermediate 16-3

[0262] Synthesis route:

[0263]

[0264] first step

[0265] Under nitrogen atmosphere, 16-1 (1.67 g, 7.39 mmol), A-1 (1.40 g, 8.13 mmol), cesium carbonate (7.22 g, 22.17 mmol), tris(dibenzylideneacetone)dipalladium (338 mg, 0.37 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (460 mg, 0.74 mmol) were dissolved in toluene (60 mL) and the mixture was heated to 85 ℃. o C and stirred for 18 hours. After the reaction solution was cooled to room temperature, it was quenched with water, extracted with ethyl acetate (60 mL×3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 16-2 (1.78 g, yield: 76%).

[0266] Step 2

[0267] Dissolve 16-2 (1.78 g, 5.62 mmol) in dichloromethane (18 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 2 hours. Add 5% sodium hydroxide solution to the reaction solution to adjust the pH to about 11, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 16-3.

[0268] Intermediate 17-3

[0269] Synthesis route:

[0270]

[0271] first step

[0272] Under nitrogen atmosphere, 17-1 (2.10 g, 9.29 mmol), A-1 (1.76 g, 10.22 mmol), cesium carbonate (9.08 g, 27.88 mmol), tris(dibenzylideneacetone)dipalladium (425 mg, 0.46 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (579 mg, 0.93 mmol) were dissolved in toluene (60 mL) and the mixture was heated to 80 °C. o C and stirred for 18 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (60 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 17-2 (2.06 g, yield: 70%).

[0273] Step 2

[0274] Dissolve 17-2 (2.06 g, 6.5 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (7 mL), and stir at room temperature for 2 hours. Add 5% sodium hydroxide solution to the reaction solution to adjust the pH to about 11, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 17-3.

[0275] Intermediate 18-3

[0276] Synthesis route:

[0277]

[0278] first step

[0279] Under nitrogen atmosphere, 18-1 (2.16 g, 10.32 mmol), A-1 (1.95 g, 11.35 mmol), cesium carbonate (10.08 g, 30.95 mmol), tris(dibenzylideneacetone)dipalladium (472 mg, 0.52 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (642 mg, 1.03 mmol) were dissolved in toluene (60 mL) and the mixture was heated to 90 °C. o C and stirred for 18 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (60 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 18-2 (2.54 g, yield: 82%).

[0280] Step 2

[0281] Dissolve 18-2 (2.54 g, 8.46 mmol) in dichloromethane (25 mL), add trifluoroacetic acid (8 mL), and stir at room temperature for 2 hours. Add 5% sodium hydroxide solution to the reaction solution to adjust the pH to about 11, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 18-3.

[0282] Intermediate 19-3

[0283] Synthesis route:

[0284]

[0285] first step

[0286] Under nitrogen atmosphere, 19-1 (1.87 g, 6.83 mmol), A-1 (1.29 g, 7.51 mmol), cesium carbonate (6.67 g, 20.48 mmol), tris(dibenzylideneacetone)dipalladium (313 mg, 0.34 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (425 mg, 0.68 mmol) were dissolved in toluene (60 mL) and the mixture was heated to 90 °C. o C and stirred for 18 hours. After the reaction solution was cooled to room temperature, it was quenched with water, extracted with ethyl acetate (60 mL×3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 19-2 (1.63 g, yield: 75%).

[0287] Step 2

[0288] Dissolve 19-2 (1.63 g, 5.12 mmol) in dichloromethane (15 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 2 hours. Add 5% sodium hydroxide solution to the reaction solution to adjust the pH to about 11, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 19-3.

[0289] Intermediate 20-3

[0290] Synthesis route:

[0291]

[0292] first step

[0293] Under nitrogen atmosphere, 20-1 (1.65 g, 6.35 mmol), A-1 (1.20 g, 6.98 mmol), cesium carbonate (6.20 g, 19.04 mmol), tris(dibenzylideneacetone)dipalladium (291 mg, 0.32 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (395 mg, 0.63 mmol) were dissolved in toluene (60 mL) and the mixture was heated to 80 °C. o C and stirred for 18 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (60 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 20-2 (1.58 g, yield: 71%).

[0294] Step 2

[0295] Dissolve 20-2 (1.58 g, 4.51 mmol) in dichloromethane (15 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 2 hours. Add 5% sodium hydroxide solution to the reaction solution to adjust the pH to about 11, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 20-3.

[0296] Intermediate 21-3

[0297] Synthesis route:

[0298]

[0299] first step

[0300] Under nitrogen atmosphere, 21-1 (2.35 g, 13.43 mmol), A-1 (2.54 g, 14.77 mmol), cesium carbonate (13.13 g, 40.29 mmol), tris(dibenzylideneacetone)dipalladium (615 mg, 0.67 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (836 mg, 1.34 mmol) were dissolved in toluene (60 mL) and the mixture was heated to 80 °C. o C and stirred for 18 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (60 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 21-2 (2.61 g, yield: 73%).

[0301] Step 2

[0302] Dissolve 21-2 (2.61 g, 9.80 mmol) in dichloromethane (25 mL), add trifluoroacetic acid (8 mL), and stir at room temperature for 2 hours. Add 5% sodium hydroxide solution to the reaction solution to adjust the pH to about 11, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 21-3.

[0303] Intermediate 22-3

[0304] Synthesis route:

[0305]

[0306] first step

[0307] Under nitrogen atmosphere, 22-1 (2.21 g, 9.09 mmol), A-1 (1.61 g, 9.37 mmol), cesium carbonate (8.32 g, 25.55 mmol), tris(dibenzylideneacetone)dipalladium (390 mg, 0.43 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (530 mg, 0.85 mmol) were dissolved in toluene (60 mL) and the mixture was heated to 90 °C. o C and stirred for 18 hours. After the reaction solution was cooled to room temperature, water was added to quench, and ethyl acetate (60 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain 22-2 (2.09 g, yield: 70%).

[0308] Step 2

[0309] Dissolve 22-2 (2.09 g, 5.96 mmol) in dichloromethane (21 mL), add trifluoroacetic acid (7 mL), and stir at room temperature for 2 hours. Add 5% sodium hydroxide solution to the reaction solution to adjust the pH to about 11, add dichloromethane to extract repeatedly, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product of intermediate 22-3.

[0310] Compound 1

[0311] Synthesis route:

[0312]

[0313] Intermediate 11-3 (173 mg, 0.86 mmol) and HATU (392 mg, 1.03 mmol) were dissolved in dichloromethane (6 mL), triethylamine (261 mg, 2.58 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 2-3 (144 mg, 0.86 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 1 (214 mg, yield: 71%). 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J = 7.0Hz, 1H), 8.85 (d, J = 4.3 Hz, 1H), 8.49 (s, 1H), 8.21 (d, J = 4.8 Hz, 1H), 8.07 (s, 2H), 7.46 (d, J = 4.4 Hz, 1H), 6.62 - 6.59 (m, 1H), 4.99 - 4.91 (m,1H), 4.52 - 4.47 (m, 2H), 4.19 - 4.16 (m, 2H), 2.76 (s, 6H).

[0314] Compound 2

[0315] Synthesis route:

[0316]

[0317] Intermediate 11-3 (173 mg, 0.86 mmol) and HATU (392 mg, 1.03 mmol) were dissolved in dichloromethane (6 mL), triethylamine (261 mg, 2.58 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 4-3 (144 mg, 0.86 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 2 (247 mg, yield: 82%). 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (d, J = 7.0Hz, 1H), 8.85 (d, J = 4.3 Hz, 1H), 8.49 (d, J = 1.4 Hz, 1H), 8.08 (s, 1H),7.81 (d, J = 5.8 Hz, 1H), 7.46 (d, J = 4.4, Hz, 1H), 6.39 - 6.37 (m, 1H), 6.08 (d, J = 2.0 Hz, 1H), 5.00 - 4.92 (m, 1H), 4.38 - 4.34 (m, 2H), 4.03 -4.00 (m, 2H), 2.75 (s, 6H). 13 C NMR (100 MHz, DMSO-d6) δ 166.4, 165.1 (d, J =227.1 Hz), 159.3 (d, J = 11.7 Hz), 151.1, 148.1, 147.3 (d, J = 19.5 Hz), 146.2, 137.6, 131.1, 127.9, 127.4, 123.0, 122.5, 105.6 (d, J = 2.6 Hz), 89.4 (d, J = 42.5 Hz), 58.42, 40.9, 19.0, 18.7.

[0318] Compound 3

[0319] Synthesis route:

[0320]

[0321] Intermediate 11-3 (157 mg, 0.78 mmol) and HATU (356 mg, 0.94 mmol) were dissolved in dichloromethane (5 mL), triethylamine (236 mg, 2.34 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 5-3 (157 mg, 0.78 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 3 (249 mg, yield: 83%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.29 (d, J = 6.7 Hz, 1H), 8.85 (d, J = 4.3 Hz, 1H), 8.48 (s, 1H), 8.07 (s, 1H), 7.84 (d, J = 5.4Hz, 1H), 7.46 (d, J = 4.2 Hz, 1H), 6.59 (t, J = 6.1 Hz, 1H), 4.97 - 4.89 (m,1H), 4.54 - 4.50 (m, 2H), 4.22 - 4.19 (m, 2H), 2.76 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.4, 151.1, 148.1, 146.2, 145.3 (d, J = 8.9 Hz), 144.9 (d, J =6.0 Hz), 143.1 (d, J = 249.9 Hz), 137.7, 137.3 (d, J = 15.8 Hz), 131.1, 127.8, 127.4, 123.0, 122.5, 109.8 (d, J = 2.5 Hz), 60.2, 41.5 (d, J = 2.6Hz), 19.0, 18.7.

[0322] Compound 4

[0323] Synthesis route:

[0324]

[0325] Intermediate 11-3 (165 mg, 0.82 mmol) and HATU (374 mg, 0.98 mmol) were dissolved in dichloromethane (5 mL), triethylamine (248 mg, 2.46 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 7-3 (151 mg, 0.82 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 4 (253 mg, yield: 84%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.27 (d, J = 6.8 Hz, 1H), 8.85 (d, J = 4.3 Hz, 1H), 8.49 (d, J = 1.4 Hz, 1H), 8.18 (s, 1H), 8.12(d, J = 5.6 Hz, 1H), 8.08 (s, 1H), 7.47 (d, J = 4.3 Hz, 1H), 6.55 (d, J = 5.6Hz, 1H), 4.93 - 4.85 (m, 1H), 4.61 - 4.57 (m, 2H), 4.25 - 4.21 (m, 2H), 2.76(s, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.4, 151.4, 151.1, 149.5, 148.2, 148.1,146.2, 137.6, 131.1, 127.8, 127.4, 123.0, 122.5, 115.4, 109.2, 60.4, 41.0,19.0,18.7.

[0326] Compound 5

[0327] Synthesis route:

[0328]

[0329] Intermediate 11-3 (165 mg, 0.82 mmol) and HATU (374 mg, 0.98 mmol) were dissolved in dichloromethane (5 mL), triethylamine (248 mg, 2.46 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 1-3 (152 mg, 0.82 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 5 (238 mg, yield: 79%). 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J = 6.8Hz, 1H), 8.83 (d, J = 4.3 Hz, 1H), 8.48 (d, J = 1.4 Hz, 1H), 8.07 (s, 1H),7.64 (d, J = 5.6 Hz, 1H), 7.44 (d, J = 4.3 Hz, 1H), 6.51 (t, J = 5.9 Hz, 1H), 4.99 - 4.90 (m, 1H), 4.54 - 4.50 (m, 2H), 4.23 - 4.20 (m, 2H), 2.75 (s, 6H). 13 C NMR (100 MHz, DMSO-d6) δ 166.4, 152.5 (dd, J = 226.6, 11.1 Hz), 151.1,148.1, 146.8 (dd, J = 5.7, 5.9 Hz), 146.1, 141.5 (dd, J = 18.1, 6.5 Hz),137.6, 133.3 (dd, J = 247.7, 31.4 Hz), 131.0, 127.8, 127.4, 123.0, 122.5,108.8, 60.3, 41.5 (d, J = 1.8 Hz), 19.0, 18.7.

[0330] Compound 6

[0331] Synthesis route:

[0332]

[0333] Intermediate 10-3 (174 mg, 0.85 mmol) and HATU (388 mg, 1.02 mmol) were dissolved in dichloromethane (5 mL), triethylamine (258 mg, 2.55 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 4-3 (142 mg, 0.85 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 6 (235 mg, yield: 78%). 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J = 6.9Hz, 1H), 8.87 (d, J = 4.3 Hz, 1H), 8.47 (d, J = 0.8 Hz, 1H), 7.98 (dd, J =11.6, 1.7 Hz, 1H), 7.80 (d, J = 5.8 Hz, 1H), 7.55 (dd, J = 4.4, 1.1 Hz, 1H), 6.39 - 6.36 (m, 1H), 6.08 (d, J = 1.9 Hz, 1H), 4.99 - 4.91 (m, 1H), 4.38 -4.34 (m, 2H), 4.03 - 4.00 (m, 2H), 2.77 (d, J = 1.0 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.1 (d, J = 227.1 Hz), 165.1 (d, J = 2.1 Hz), 159.2 (d, J = 11.8Hz), 156.6, 152.4, 147.3 (d, J = 19.4 Hz), 146.4 (d, J = 2.6 Hz), 139.2 (d, J= 11.8 Hz), 131.6 (d, J = 7.0 Hz), 129.3 (d, J = 2.1 Hz), 124.2, 120.5 (d, J= 4.2 Hz), 112.1 (d, J = 20.8 Hz), 105.6 (d, J = 2.4 Hz), 89.4 (d, J = 42.6Hz), 58.3, 41.0, 19.0.

[0334] Compound 7

[0335] Synthesis route:

[0336]

[0337] Intermediate 10-3 (174 mg, 0.85 mmol) and HATU (388 mg, 1.02 mmol) were dissolved in dichloromethane (5 mL), triethylamine (258 mg, 2.55 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 2-3 (142 mg, 0.85 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 7 (217 mg, yield: 72%). 1 H NMR (400 MHz, DMSO-d6) δ 9.38 (d, J = 6.9Hz, 1H), 8.88 (d, J = 4.3 Hz, 1H), 8.48 (s, 1H), 8.17 (d, J = 4.5 Hz, 1H), 8.04 (d, J = 5.4 Hz, 1H), 7.99 (d, J = 11.6, 1.2 Hz, 1H), 7.57 (d, J = 4.3Hz, 1H), 6.60 - 6.56 (m, 1H), 4.97 - 4.89 (m, 1H), 4.49 - 4.44 (m, 2H), 4.16- 4.12 (m, 2H), 2.77 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.1, 157.9 (d, J =254.9 Hz), 152.4, 149.4 (d, J = 249.8 Hz), 146.5 (d, J = 4.3 Hz), 146.4 (d, J= 2.5 Hz), 144.0 (d, J = 8.6 Hz), 139.2 (d, J = 11.7 Hz), 136.8 (d, J = 19.9Hz), 131.6 (d, J = 7.3 Hz), 129.3 (d, J = 2.2 Hz), 124.2, 120.5 (d, J = 4.3Hz), 112.1 (d, J = 20.7 Hz), 109.4, 60.0, 41.7 (d, J = 2.2 Hz), 19.0.

[0338] Compound 8

[0339] Synthesis route:

[0340]

[0341] Intermediate 10-3 (167 mg, 0.81 mmol) and HATU (369 mg, 0.97 mmol) were dissolved in dichloromethane (5 mL), triethylamine (245 mg, 2.43 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 7-3 (149 mg, 0.81 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 8 (249 mg, yield: 83%). 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (d, J = 6.8Hz, 1H), 8.88 (d, J = 4.3 Hz, 1H), 8.49 (s, 1H), 8.18 (s, 1H), 8.12 (d, J =5.6 Hz, 1H), 7.99 (dd, J = 11.5, 1.3 Hz, 1H), 7.57 (d, J = 4.3 Hz, 1H), 6.55(d, J = 5.6 Hz, 1H), 4.92 - 4.84 (m, 1H), 4.61 - 4.57 (m, 2H), 4.25 - 4.22(m, 2H), 2.78 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.1, 157.9 (d, J = 254.9Hz), 152.4, 151.4, 149.4, 148.1, 146.4 (d, J = 2.5 Hz), 139.2 (d, J = 11.9Hz), 131.6 (d, J = 7.0 Hz), 129.3 (d, J = 2.1 Hz), 124.2, 120.5 (d, J = 4.3Hz), 112.2, 112.0, 109.2, 60.3, 41.1, 19.0.

[0342] Compound 9

[0343] Synthesis route:

[0344]

[0345] Intermediate 9-3 (171 mg, 0.77 mmol) and HATU (351 mg, 0.92 mmol) were dissolved in dichloromethane (5 mL), triethylamine (233 mg, 2.31 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 1-3 (142 mg, 0.77 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 9 (282 mg, yield: 94%). 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (d, J = 6.7Hz, 1H), 8.92 (d, J = 4.3 Hz, 1H), 8.60 (d, J = 1.7 Hz, 1H), 8.36 (d, J = 1.7Hz, 1H), 7.63 (d, J = 5.6 Hz, 1H), 7.56 (d, J = 4.3 Hz, 1H), 6.51 (t, J = 5.9Hz, 1H), 4.97 - 4.89 (m, 1H), 4.55 - 4.50 (m, 2H), 4.23 - 4.20 (m, 2H), 2.77(s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 164.9, 152.8, 152.5 (dd, J = 226.5, 11.2Hz), 147.0, 146.8 (dd, J = 6.0, 6.0 Hz), 145.0, 141.5 (dd, J = 18.0, 6.7 Hz), 133.8, 133.3 (dd, J = 247.8, 31.5 Hz), 131.5, 128.9, 127.8, 124.1, 124.0,108.8, 60.2, 41.7 (d, J = 1.8 Hz), 19.0.

[0346] Compound 10

[0347] Synthesis route:

[0348]

[0349] Intermediate 9-3 (173 mg, 0.78 mmol) and HATU (356 mg, 0.94 mmol) were dissolved in dichloromethane (5 mL), triethylamine (236 mg, 2.34 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 7-3 (144 mg, 0.78 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 10 (260 mg, yield: 86%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.41 (d, J = 6.8Hz, 1H), 8.94 (d, J = 4.0 Hz, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.0Hz, 1H), 8.18 (s, 1H), 8.12 (d, J = 5.2 Hz, 1H), 7.58 (d, J = 4.4 Hz, 1H), 6.55 (d, J = 5.6 Hz, 1H), 4.92 - 4.84 (m, 1H), 4.61 - 4.57 (m, 2H), 4.25 -4.21 (m, 2H), 2.79 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.0, 152.8, 151.4,149.6, 148.3, 147.0, 145.0, 133.8, 131.6, 128.9, 127.9, 124.2, 124.1, 115.4,109.2, 60.3, 41.1, 19.0.

[0350] Compound 11

[0351] Synthesis route:

[0352]

[0353] Intermediate 9-3 (180 mg, 0.81 mmol) and HATU (369 mg, 0.97 mmol) were dissolved in dichloromethane (5 mL), triethylamine (245 mg, 2.43 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 2-3 (135 mg, 0.81 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 11 (237 mg, yield: 79%). 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (d, J = 6.8Hz, 1H), 8.94 (d, J = 4.4 Hz, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.38 (d, J = 1.8Hz, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.58 (d, J = 4.3 Hz, 1H), 6.61 - 6.58(m, 1H), 4.98 - 4.89 (m, 1H), 4.50 - 4.47 (m, 2H), 4.17 - 4.14 (m, 2H), 2.79 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 164.9, 152.8, 149.4 (d, J = 242.5 Hz), 147.0, 146.1 (d, J = 4.0 Hz), 145.0, 144.2 (d, J = 8.6 Hz), 136.4 (d, J =20.5 Hz), 133.8, 131.6, 128.9, 127.8, 124.2, 124.1, 109.4, 60.0, 41.7 (d, J =2.3 Hz), 19.0.

[0354] Compound 12

[0355] Synthesis route:

[0356]

[0357] Intermediate 9-3 (180 mg, 0.81 mmol) and HATU (369 mg, 0.97 mmol) were dissolved in dichloromethane (5 mL), triethylamine (245 mg, 2.43 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 8-3 (134 mg, 0.81 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 12 (234 mg, yield: 78%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.34 (d, J = 6.9Hz, 1H), 8.90 (d, J = 4.3 Hz, 1H), 8.59 (d, J = 1.7 Hz, 1H), 8.35 (d, J = 1.7Hz, 1H), 7.53 (d, J = 4.3 Hz, 1H), 7.09 - 7.01 (m, 2H), 6.76 - 6.71 (m, 1H), 6.64 - 6.59 (m, 1H), 4.93 - 4.85 (m, 1H), 4.32 - 4.28 (m, 2H), 3.96 - 3.92(m, 2H), 2.76 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 164.9, 152.7, 152.2 (d, J =239.2 Hz), 147.0, 144.9, 139.8 (d, J = 10.7 Hz), 133.7, 131.6, 128.8, 127.9,125.1 (d, J = 3.1 Hz), 124.1, 124.0, 119.2 (d, J = 6.6 Hz), 115.9 (d, J =18.5 Hz), 115.3 (d, J = 4.2 Hz), 60.4 (d, J = 2.0 Hz), 41.8 (d, J = 2.4 Hz), 19.0.

[0358] Compound 13

[0359] Synthesis route:

[0360]

[0361] Intermediate 9-3 (180 mg, 0.81 mmol) and HATU (369 mg, 0.97 mmol) were dissolved in dichloromethane (5 mL), triethylamine (245 mg, 2.43 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 4-3 (135 mg, 0.81 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 13 (246 mg, yield: 82%). 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (d, J = 6.9Hz, 1H), 8.93 (d, J = 4.4 Hz, 1H), 8.61 (d, J = 1.9 Hz, 1H), 8.37 (d, J = 1.8Hz, 1H), 7.80 (d, J = 5.7 Hz, 1H), 7.57 (d, J = 4.3 Hz, 1H), 6.39 - 6.37 (m,1H), 6.08 (d, J = 1.9 Hz, 1H), 4.99 - 4.91 (m, 1H), 4.38 - 4.34 (m, 2H), 4.03- 4.00 (m, 2H), 2.78 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.1 (d, J = 228.4Hz), 165.0, 159.3 (d, J = 11.7 Hz), 152.8, 147.3 (d, J = 19.4 Hz), 147.1,145.0, 133.8, 131.5, 128.9, 127.8, 124.2, 124.1, 105.6, 89.4 (d, J = 42.7Hz), 58.3, 41.0, 19.0.

[0362] Compound 14

[0363] Synthesis route:

[0364]

[0365] Intermediate 11-2 (157 mg, 0.73 mmol) and HATU (333 mg, 0.88 mmol) were dissolved in dichloromethane (4 mL), triethylamine (251 mg, 2.49 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 3-3 (158 mg, 0.73 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 14 (236 mg, yield: %). 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J = 7.2 Hz,1H), 8.42 (d, J = 1.2 Hz, 1H), 8.27 (d, J = 5.6 Hz, 1H), 8.02 (s, 1H), 7.35(s, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.63 (dd, J = 5.6, 2.4 Hz, 1H), 5.02 -4.93 (m, 1H), 4.43 - 4.39 (m, 2H), 4.07 - 4.04 (m, 2H), 2.71 (d, J = 8.4 Hz, 6H), 2.64 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 166.5, 159.5, 155.8, 150.0,147.8, 147.4 (q, J = 33.1 Hz), 145.9, 136.8, 130.2, 127.8, 125.7, 123.6, 122.4 (q, J = 272.0 Hz), 122.3, 108.6, 103.0, 58.4, 40.8, 25.7, 18.9, 18.7.

[0366] Compound 15

[0367] Synthesis route:

[0368]

[0369] Intermediate 11-2 (176 mg, 0.82 mmol) and HATU (374 mg, 0.98 mmol) were dissolved in dichloromethane (5 mL), triethylamine (248 mg, 2.46 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 2-3 (137 mg, 0.82 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 15 (236 mg, yield: 79%). 1 H NMR (400 MHz, DMSO-d6) δ 9.30 (d, J = 6.9Hz, 1H), 8.45 (s, 1H), 8.17 (d, J = 4.5 Hz, 1H), 8.05 - 8.04 (m, 2H), 7.35(s, 1H), 6.59 - 6.56 (m, 1H), 4.96 - 4.89 (m, 1H), 4.48 - 4.43 (m, 2H), 4.17- 4.13 (m, 2H), 2.71 (d, J = 5.0 Hz, 6H), 2.64 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 166.5, 159.5, 149.4 (d, J = 242.3 Hz), 147.9, 146.5 (d, J = 4.2 Hz), 145.9, 144.1 (d, J = 8.7 Hz), 136.8 (d, J = 20.1 Hz), 136.7, 130.2, 127.9,125.7, 123.6, 122.3, 109.4, 60.1, 41.5, 25.7, 18.9, 18.6.

[0370] Compound 16

[0371] Synthesis route:

[0372]

[0373] Intermediate 11-2 (170 mg, 0.79 mmol) and HATU (360 mg, 0.95 mmol) were dissolved in dichloromethane (5 mL), triethylamine (239 mg, 2.37 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 6-3 (145 mg, 0.79 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 16 (250 mg, yield: 83%). 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (d, J = 6.9Hz, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.05 (s, 1H), 7.35 (s, 1H), 7.05 - 6.99(m, 1H), 6.75 - 6.69 (m, 1H), 6.44 (t, J = 8.2 Hz, 1H), 4.95 - 4.87 (m, 1H), 4.36 - 4.32(m, 2H), 4.05 - 4.01 (m, 2H), 2.71 (d, J = 1.8 Hz, 6H), 2.64 (s,3H). 13 C NMR (100 MHz, DMSO-d6) δ 166.4, 159.4, 151.0 (dd, J = 241.0, 11.0 Hz), 147.8, 146.0, 141.6 (dd, J = 6.0, 4.0 Hz), 140.1 (dd, J = 239.0, 14.0 Hz)136.7, 130.2, 128.0, 124.8 (dd, J = 9.0, 4.0 Hz), 125.7, 123.5, 122.4, 110.7,106.3 (d, J = 17.3 Hz), 60.6, 41.7, 25.7, 19.0, 18.6.

[0374] Compound 17

[0375] Synthesis route:

[0376]

[0377] Intermediate 11-2 (172 mg, 0.80 mmol) and HATU (365 mg, 0.96 mmol) were dissolved in dichloromethane (5 mL), triethylamine (242 mg, 2.40 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 7-3 (147 mg, 0.80 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 17 (232 mg, yield: 76%). 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (d, J = 6.8Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 8.03 (s, 1H), 7.36 (s, 1H), 6.55 (d, J = 5.6 Hz, 1H), 4.92 - 4.84 (m, 1H), 4.61 - 4.57 (m, 2H), 4.24 - 4.21 (m, 2H), 2.72 (d, J = 6.6 Hz, 6H), 2.65 (s,3H). 13 C NMR (100 MHz, DMSO-d6) δ 166.5, 159.5, 151.5, 149.4, 148.1, 147.8,145.9, 136.7, 130.2, 127.9, 125.7, 123.6, 122.3, 109.2, 60.4, 40.9, 25.7,18.9, 18.7, 9.1.

[0378] Compound 18

[0379] Synthesis route:

[0380]

[0381] Intermediate 11-2 (176 mg, 0.82 mmol) and HATU (374 mg, 0.98 mmol) were dissolved in dichloromethane (5 mL), triethylamine (248 mg, 2.46 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 4-3 (137 mg, 0.82 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 18 (263 mg, yield: 88%). 1 H NMR (400 MHz, DMSO-d6) δ 9.26 (d, J = 7.0Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (d, J = 5.8 Hz, 1H), 7.36 (s, 1H), 6.40 - 6.37 (m, 1H), 6.08 (d, J = 2.0 Hz, 1H), 5.00 - 4.91 (m,1H), 4.37 - 4.33 (m, 2H), 4.03 - 4.00 (m, 2H), 2.72 (d, J = 6.7 Hz, 6H), 2.65(s, 3H). 13 C NMR (100 MHz, DMSO) δ 166.5, 165.3 (d, J = 227.0 Hz), 159.5, 159.3 (d, J = 11.7 Hz), 147.8, 147.3 (d, J = 19.6 Hz), 145.9, 136.7, 130.2, 127.9,125.7, 123.6, 122.3, 105.5, 89.3 (d, J = 45.3 Hz), 58.43, 40.8, 25.7, 18.9,18.7.

[0382] Compound 19

[0383] Synthesis route:

[0384]

[0385] Intermediate 11-4 (174 mg, 0.76 mmol) and HATU (347 mg, 0.912 mmol) were dissolved in dichloromethane (4 mL), triethylamine (230 mg, 2.28 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 7-3 (139 mg, 0.76 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 19 (246 mg, yield: 82%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.21 (d, J = 6.8Hz, 1H), 8.47 (s, 1H), 8.18 (s, 1H), 8.11 (d, J = 5.5 Hz, 1H), 8.04 (s, 1H), 7.36 (s, 1H), 6.55 (d, J = 5.5 Hz, 1H), 4.93 - 4.84 (m, 1H), 4.60 - 4.56 (m,2H), 4.24 - 4.20 (m, 2H), 3.13 (q, J = 7.4 Hz, 2H), 2.73 (s, 3H), 2.67 (s,3H), 1.34 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.5, 159.6,151.4, 151.3, 149.7, 148.4, 148.0, 136.9, 130.2, 127.7, 124.8, 121.7, 121.5,115.5, 109.2, 60.4, 40.9, 25.8, 24.7, 18.8, 14.6.

[0386] Compound 20

[0387] Synthesis route:

[0388]

[0389] Intermediate 11-4 (181 mg, 0.79 mmol) and HATU (360 mg, 0.95 mmol) were dissolved in dichloromethane (5 mL), triethylamine (239 mg, 2.37 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 2-3 (132 mg, 0.79 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 20 (251 mg, yield: 84%). 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (d, J = 6.9Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.18 (d, J = 4.6 Hz, 1H), 8.06 - 8.03 (m,2H), 7.36 (s, 1H), 6.60 - 6.57 (m, 1H), 4.98 - 4.90 (m, 1H), 4.49 - 4.44 (m,2H), 4.17 - 4.12 (m, 2H), 3.13 (q, J = 7.2 Hz, 2H), 2.73 (s, 3H), 2.67 (s,3H), 1.34 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 166.5, 159.7,151.3, 149.5 (d, J = 237.9 Hz), 146.1 (d, J = 6.1 Hz), 144.2 (d, J = 8.2 Hz), 148.1, 136.9, 136.5 (d, J = 18,9 Hz), 130.2, 127.7, 124.8, 121.7, 121.5,109.4, 60.1, 41.6 (d, J = 2.3 Hz), 25.8, 24.7, 18.7, 14.6.

[0390] Compound 21

[0391] Synthesis route:

[0392]

[0393] Intermediate 11-4 (167 mg, 0.73 mmol) and HATU (333 mg, 0.88 mmol) were dissolved in dichloromethane (4 mL), triethylamine (221 mg, 2.19 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 5-3 (147 mg, 0.73 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 21 (265 mg, yield: 88%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.23 - 9.19 (m,1H), 8.45 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.85 - 7.81 (m, 1H),7.34 (d, J = 8.4 Hz, 1H), 6.61 - 6.56 (m, 1H), 4.93 - 4.89 (m, 1H), 4.56 -4.43 (m, 2H), 4.21 - 4.18 (m, 2H), 3.12 (t, J = 8.1 Hz, 2H), 2.72 - 2.64 (m,6H), 1.35 - 1.29 (m, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.5, 159.7, 151.2,148.1, 145.3 (d, J = 9.0 Hz), 144.9 (d, J = 6.0 Hz), 143.1 (d, J = 248.3 Hz), 137.3 (d, J = 15.7 Hz), 136.9, 130.2, 127.7, 124.8, 121.7, 121.5, 109.8 (d, J= 2.4 Hz), 60.3, 41.4 (d, J= 2.6 Hz), 25.8, 24.7, 18.7, 14.6.

[0394] Compound 22

[0395] Synthesis route:

[0396]

[0397] Intermediate 11-4 (181 mg, 0.79 mmol) and HATU (360 mg, 0.95 mmol) were dissolved in dichloromethane (5 mL), triethylamine (239 mg, 2.37 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 4-3 (132 mg, 0.79 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 22 (242 mg, yield: 81%). 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.80 (s, 1H), 8.47 (s, 1H), 8.04 (s, 1H), 7.36 (s, 1H), 6.38 (s, 1H), 6.08 (s, 1H), 4.98 - 4.93 (m, 1H), 4.37 - 4.33 (m, 2H), 4.03 - 4.00 (m, 2H), 3.12 -3.10 (m, 2H), 2.70 (d, J = 23.0 Hz, 6H), 1.34 (t, J = 7.5 Hz, 3H). 13 C NMR (100MHz, DMSO-d6) δ 166.5, 165.1 (d, J = 226.8 Hz), 159.7, 159.3 (d, J = 11.5Hz), 151.3, 148.0, 147.3 (d, J = 19.0 Hz), 136.9, 130.2, 127.8, 124.8, 121.7,121.5, 105.6, 89.4 (d, J = 42.9 Hz), 58.4, 40.9, 25.8, 24.7, 18.7, 14.6.

[0398] Compound 23

[0399] Synthesis route:

[0400]

[0401] Intermediate 10-2 (171 mg, 0.78 mmol) and HATU (356 mg, 0.94 mmol) were dissolved in dichloromethane (5 mL). Triethylamine (236 mg, 2.34 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Then Intermediate 7-3 (144 mg, 0.78 mmol) was added, and stirring was continued for 4 hours. After the reaction was completed, the mixture was diluted with water (30 mL) and extracted with dichloromethane (30×3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography to obtain Compound 23 (270 mg, yield: 90%). 1 H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J = 6.8 Hz, 1H), 8.42 (s, 1H), 8.17 (s, 1H), 8.11 (d, J = 5.6 Hz, 1H), 7.94 (dd, J = 11.6, 0.8 Hz, 1H), 7.45 (s, 1H), 6.54 (d, J = 5.6 Hz, 1H), 4.91 - 4.82 (m, 1H), 4.59 - 4.55 (m, 2H), 4.22 - 4.20 (m, 2H), 2.72 (s, 3H), 2.65 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.2, 161.3, 157.4 (d, J = 254.0 Hz), 151.4, 149.6, 148.3, 146.1 (d, J = 2.4 Hz), 138.9 (d, J = 11.4 Hz), 130.7 (d, J = 7.1 Hz), 127.8 (d, J = 2.5 Hz), 124.8, 120.2 (d, J = 4.0 Hz), 115.5, 112.2 (d, J = 20.9 Hz), 109.2, 60.3, 41.1, 25.4, 18.9.

[0402] Compound 24

[0403] Synthetic route:

[0404]

[0405] Intermediate 10-2 (180 mg, 0.78 mmol) and HATU (374 mg, 0.98 mmol) were dissolved in dichloromethane (5 mL), triethylamine (248 mg, 2.46 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 2-3 (137 mg, 0.82 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 24 (269 mg, yield: 89%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.33 (d, J = 6.8Hz, 1H), 8.41 (d, J = 0.8 Hz, 1H), 8.24 (d, J = 4.9 Hz, 1H), 8.07 (d, J = 5.6Hz, 1H), 7.94 (dd, J = 11.6, 1.6 Hz, 1H), 7.44 (s, 1H), 6.62 (dd, J = 8.3,5.6 Hz, 1H), 4.97 - 4.89 (m, 1H), 4.54 - 4.49 (m, 2H), 4.21 - 4.18 (m, 2H), 2.71 (s, 3H), 2.65 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 165.2 (d, J = 2.2 Hz), 161.2, 157.5 (d, J = 253.9 Hz), 149.0 (d, J = 244.7 Hz), 146.0 (d, J = 2.7Hz), 145.1 (d, J = 3.7 Hz), 144.6 (d, J = 8.7 Hz), 138.9 (d, J = 11.5 Hz), 135.3 (d, J = 22.1 Hz), 130.6 (d, J = 7.1 Hz), 127.8 (d, J = 2.4 Hz), 124.8, 120.2 (d, J = 4.0 Hz), 112.1 (d, J = 20.9 Hz), 109.2, 60.1, 41.7 (d, J = 2.3Hz), 25.4, 18.9.

[0406] Compound 25

[0407] Synthesis route:

[0408]

[0409] Intermediate 10-2 (162 mg, 0.74 mmol) and HATU (337 mg, 0.89 mmol) were dissolved in dichloromethane (4 mL), triethylamine (224 mg, 2.22 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 5-3 (137 mg, 0.74 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 25 (251 mg, yield: 84%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.34 (d, J = 6.7Hz, 1H), 8.43 (s, 1H), 7.94 (dd, J = 11.6, 1.4 Hz, 1H), 7.85 (d, J = 5.5 Hz,1H), 7.47 (s, 1H), 6.62 - 6.59 (m, 1H), 4.95 - 4.87 (m, 1H), 4.55 - 4.51 (m,2H), 4.22 - 4.19 (m, 2H), 2.73 (s, 3H), 2.66 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.3, 161.2, 157.5 (d, J = 252.3 Hz), 146.0 (d, J = 2.7 Hz), 145.3 (d,J = 9.0 Hz), 144.9 (d, J = 6.1 Hz), 143.1 (d, J = 248.3 Hz), 138.9 (d, J =11.3 Hz), 137.3 (d, J = 15.6 Hz), 130.7 (d, J = 6.9 Hz), 127.8 (d, J = 2.5Hz), 124.8, 120.2 (d, J = 4.2 Hz), 112.2 (d, J = 20.9 Hz), 109.8 (d, J = 2.4Hz), 60.2, 41.6 (d, J = 2.5 Hz), 25.4, 18.9.

[0410] Compound 26

[0411] Synthesis route:

[0412]

[0413] Dissolve intermediate 10-2 (171 mg, 0.78 mmol) and HATU (356 mg, 0.94 mmol) in dichloromethane (5 mL), add triethylamine (236 mg, 2.34 mmol), stir at room temperature for 15 minutes, then add intermediate 1-3 (144 mg, 0.78 mmol) and continue stirring for 4 hours. After the reaction is completed, dilute with water (30 mL), extract with dichloromethane (30×3 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product containing the target compound. Purify by silica gel column chromatography to obtain compound 26 (256 mg, yield: 85%). 1 H NMR (400 MHz, DMSO-d6) δ 9.33 - 9.32 (m, 1H), 8.39 (s, 1H), 7.94 - 7.90 (m, 1H), 7.64 - 7.62 (m, 1H), 7.42 - 7.41 (m, 1H), 6.52 - 6.49 (m, 1H), 4.93 - 4.89 (m, 1H), 4.54 - 4.92 (m, 2H), 4.22 - 4.19 (m, 2H), 2.70 - 2.63 (m, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.2, 161.2, 157.5 (d, J = 253.8 Hz), 152.5 (dd, J = 226.4, 11.3 Hz), 146.8 (dd, J = 6.0, 6.0 Hz), 146.0 (d, J = 2.2 Hz), 141.5 (dd, J = 18.0, 6.6 Hz), 138.9 (d, J = 11.3 Hz), 133.3 (dd, J = 247.5, 31.6 Hz), 130.6 (d, J = 7.2 Hz), 127.7, 124.7, 120.2 (d, J = 4.0 Hz), 112.1 (d, J = 20.8 Hz), 108.8, 60.2, 41.6, 25.4, 18.9.

[0414] Compound 27

[0415] Synthesis route:

[0416]

[0417] Intermediate 10-4 (184 mg, 0.79 mmol) and HATU (360 mg, 0.95 mmol) were dissolved in dichloromethane (5 mL), triethylamine (239 mg, 2.37 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 4-3 (132 mg, 0.79 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 27 (263 mg, yield: 87%). 1 H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 7.0Hz, 1H), 8.45 (s, 1H), 7.94 (dd, J = 11.6, 1.7 Hz, 1H), 7.80 (d, J = 5.7 Hz,1H), 7.45 (s, 1H), 6.39 - 6.36 (m, 1H), 6.08 (d, J = 1.9 Hz, 1H), 4.98 - 4.90(m, 1H), 4.37 - 4.33 (m, 2H), 4.03 - 4.00 (m, 2H), 3.13 (q, J = 7.6 Hz, 2H),2.67 (s, 3H), 1.33 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.3 (d,J = 2.0 Hz), 165.1 (d, J = 227.1 Hz), 161.5 (d, J = 0.9 Hz), 159.2 (d, J =11.9 Hz), 158.9, 156.3, 151.3, 147.3 (d, J = 19.7 Hz), 130.7 (d, J = 7.1 Hz), 126.9, 122.8, 119.6 (d, J = 3.8 Hz), 112.0 (d, J = 20.7 Hz), 105.6 (d, J =2.2 Hz), 89.4 (d, J = 42.2 Hz), 58.3, 41.0, 25.6, 24.8, 14.3.

[0418] Compound 28

[0419] Synthesis route:

[0420]

[0421] Intermediate 10-4 (175 mg, 0.75 mmol) and HATU (342 mg, 0.90 mmol) were dissolved in dichloromethane (4 mL), triethylamine (227 mg, 2.25 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 7-3 (138 mg, 0.75 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 28 (245 mg, yield: 82%). 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (d, J = 6.7Hz, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 8.12 (d, J = 5.7 Hz, 1H), 7.95 (dd, J =11.6, 1.7 Hz, 1H), 7.47 (s, 1H), 6.57 (d, J = 5.7 Hz, 1H), 4.91 - 4.83 (m,1H), 4.62 - 4.58 (m, 2H), 4.27 - 4.23 (m, 2H), 3.15 (q, J = 7.5 Hz, 2H), 2.68(s, 3H), 1.34 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.3, 161.5,157.6 (d, J = 247.8 Hz), 151.5, 151.3, 148.9, 147.6, 139.1 (d, J = 8.7 Hz), 130.7 (d, J = 7.0 Hz), 126.9 (d, J = 2.3 Hz), 122.8, 119.7 (d, J = 4.2 Hz), 112.1, 111.9, 109.1, 60.3, 41.1, 25.6, 24.8, 14.3.

[0422] Compound 29

[0423] Synthesis route:

[0424]

[0425] Intermediate 10-4 (168 mg, 0.72 mmol) and HATU (328 mg, 0.86 mmol) were dissolved in dichloromethane (4 mL), triethylamine (218 mg, 2.16 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 5-3 (145 mg, 0.72 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 29 (258 mg, yield: 86%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.33 (d, J = 6.7Hz, 1H), 8.45 (s, 1H), 7.94 (dd, J = 11.6, 1.6 Hz, 1H), 7.84 (d, J = 5.5 Hz,1H), 7.45 (s, 1H), 6.59 (dd, J = 6.6, 5.6 Hz, 1H), 4.96 - 4.87 (m, 1H), 4.54- 4.50 (m, 2H), 4.22 - 4.19 (m, 2H), 3.14 (q, J = 7.5 Hz, 2H), 2.68 (s, 3H),1.34 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.2 (d, J = 2.1 Hz),161.4, 157.6 (d, J = 254.0 Hz), 151.3 (d, J = 2.4 Hz), 145.3 (d, J = 9.1 Hz),144.9 (d, J = 6.0 Hz), 143.1 (d, J = 250.1 Hz), 139.1 (d, J = 11.1 Hz), 137.4(d, J = 15.7 Hz), 130.7 (d, J = 7.1 Hz), 126.9 (d, J = 2.4 Hz), 122.8, 119.7(d, J = 4.0 Hz), 112.0 (d, J = 20.9 Hz), 109.8 (d, J = 2.5 Hz), 60.1, 41.6 (d, J = 2.4 Hz), 25.6, 24.8, 14.3.

[0426] Compound 30

[0427] Synthesis route:

[0428]

[0429] Intermediate 10-4 (175 mg, 0.75 mmol) and HATU (342 mg, 0.90 mmol) were dissolved in dichloromethane (4 mL), triethylamine (227 mg, 2.25 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 1-3 (139 mg, 0.75 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 30 (255 mg, yield: 85%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.33 (d, J = 6.8Hz, 1H), 8.44 (s, 1H), 7.94 (d, J = 11.5 Hz, 1H), 7.64 (d, J = 5.6 Hz, 1H), 7.44 (s, 1H), 6.52 (t, J = 5.9 Hz, 1H), 4.95 - 4.90 (m, 1H), 4.54 - 4.50 (m,2H), 4.23 - 4.20 (m, 2H), 3.13 (q, J = 7.5 Hz, 2H), 2.67 (s, 3H), 1.34 (t, J= 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO-d 6) δ 165.2, 161.4, 157.6 (d, J = 253.9Hz), 152.5 (dd, J = 225.3, 11.0 Hz), 151.2 (d, J = 2.3 Hz), 146.8 (dd, J =5.8, 6.0 Hz), 141.5 (dd, J = 18.4, 6.5 Hz), 139.1 (d, J = 11.3 Hz), 133.3 (dd, J = 247.9, 31.1 Hz), 130.7 (d, J = 7.1 Hz), 126.9, 122.7, 119.6 (d, J =4.1 Hz), 112.0 (d, J = 20.9 Hz), 108.9, 60.2, 41.7, 25.5, 24.8, 14.3.

[0430] Compound 31

[0431] Synthesis route:

[0432]

[0433] Intermediate 10-4 (184 mg, 0.79 mmol) and HATU (360 mg, 0.95 mmol) were dissolved in dichloromethane (5 mL), triethylamine (239 mg, 2.37 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 2-3 (132 mg, 0.79 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 31 (260 mg, yield: 86%). 1H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J = 6.8Hz, 1H), 8.46 (d, J = 1.8 Hz, 1H), 8.17 (d, J = 4.5 Hz, 1H), 8.04 (d, J = 5.4Hz, 1H), 7.95 (dd, J = 11.6, 1.7 Hz, 1H), 7.46 (s, 1H), 6.60 - 6.56 (m, 1H), 4.97 - 4.88 (m, 1H), 4.48 - 4.44 (m, 2H), 4.16 - 4.12 (m, 2H), 3.14 (q, J =7.5 Hz, 2H), 2.68 (s, 3H), 1.34 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6)δ 165.2, 161.4, 157.6 (d, J = 252.5 Hz), 151.3 (d, J = 2.3 Hz), 149.4 (d, J =244.4 Hz), 146.5 (d, J = 4.3 Hz), 144.0 (d, J = 8.5 Hz), 139.1 (d, J = 11.4Hz), 136.8 (d, J = 20.0 Hz), 130.7 (d, J = 7.0 Hz), 126.9, 122.8, 119.7 (d, J= 4.1 Hz), 112.0 (d, J = 21.0 Hz), 109.4 (d, J = 2.3 Hz), 60.0, 41.7, 25.6,24.8, 14.3.

[0434] Compound 32

[0435] Synthesis route:

[0436]

[0437] Intermediate 9-2 (174 mg, 0.74 mmol) and HATU (338 mg, 0.89 mmol) were dissolved in dichloromethane (4 mL), triethylamine (224 mg, 2.22 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 1-3 (137 mg, 0.74 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 32 (256 mg, yield: 86%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.84 (d, J = 6.6Hz, 1H), 8.71 (d, J = 1.8 Hz, 1H), 8.36 (d, J = 1.7 Hz, 1H), 7.62 (d, J = 5.6Hz, 1H), 7.47 (s, 1H), 6.52 - 6.47 (m, 1H), 4.96 - 4.87 (m, 1H), 4.52 - 4.47(m, 2H), 4.33 - 4.29 (m, 2H), 2.76 (s, 3H), 2.68 (s, 3H). 13 C NMR (100 MHz, DMSO) δ 165.1, 161.7, 152.5 (dd, J = 225.4 Hz, 11.3 Hz), 147.4, 146.9 (dd, J= 5.9 Hz, 6.0 Hz), 144.4, 141.5 (dd, J = 18.1 Hz, 6.6 Hz), 133.2 (dd, J =246.1 Hz, 31.4 Hz), 132.5, 130.7, 128.1, 127.3, 124.8, 124.1, 108.9, 60.1, 41.7, 25.4, 19.1.

[0438] Compound 33

[0439] Synthesis route:

[0440]

[0441] Intermediate 9-2 (184 mg, 0.78 mmol) and HATU (356 mg, 0.94 mmol) were dissolved in dichloromethane (5 mL), triethylamine (236 mg, 2.34 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 4-3 (137 mg, 0.74 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 33 (270 mg, yield: 90%). 1 H NMR (400 MHz, DMSO-d6) δ 9.39 (d, J = 6.9Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.32 (d, J = 1.9 Hz, 1H), 7.80 (d, J = 5.7Hz, 1H), 7.45 (s, 1H), 6.38 (d, J = 5.8 Hz, 1H), 6.07 (d, J = 2.0 Hz, 1H), 4.99 - 4.90 (m, 1H), 4.37 - 4.33 (m, 2H), 4.03 - 3.99 (m, 2H), 2.72 (s, 3H), 2.67 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.1, 165.1 (d, J = 227.1 Hz), 161.8, 159.3 (d, J = 11.8 Hz), 147.3 (d, J = 19.6 Hz), 146.7, 144.8, 133.0,130.7, 127.8, 127.3, 124.8, 123.8, 105.6 (d, J = 2.4 Hz), 89.4 (d, J = 42.9Hz), 58.3, 41.0, 25.6, 18.9.

[0442] Compound 34

[0443] Synthesis route:

[0444]

[0445] Intermediate 9-2 (184 mg, 0.78 mmol) and HATU (356 mg, 0.94 mmol) were dissolved in dichloromethane (5 mL), triethylamine (236 mg, 2.34 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 2-3 (137 mg, 0.74 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 34 (243 mg, yield: 81%). 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (d, J = 6.9Hz, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.32 (d, J = 1.9 Hz, 1H), 8.17 (d, J = 4.5Hz, 1H), 8.04 (d, J = 5.4 Hz, 1H), 7.47 (s, 1H), 6.60 - 6.56 (m, 1H), 4.97 -4.88 (m, 1H), 4.49 - 4.44 (m, 2H), 4.15 - 4.12 (m, 2H), 2.74 (s, 3H), 2.68(s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.1, 161.8, 149.4 (d, J = 244.0 Hz), 146.7, 146.5 (d, J = 4.2 Hz), 144.8, 144.0 (d, J = 8.5 Hz), 136.8 (d, J =20.1 Hz), 133.0, 130.7, 127.8, 127.3, 124.8, 123.8, 109.4, 60.0, 41.7 (d, J =2.1 Hz), 25.6, 18.9.

[0446] Compound 35

[0447] Synthesis route:

[0448]

[0449] Intermediate 9-2 (177 mg, 0.75 mmol) and HATU (342 mg, 0.90 mmol) were dissolved in dichloromethane (4 mL), triethylamine (227 mg, 2.25 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 6-3 (138 mg, 0.75 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 35 (229 mg, yield: 76%). 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (d, J = 6.9Hz, 1H), 8.55 (s, 1H), 8.32 (s, 1H), 7.44 (s, 1H), 7.05 - 7.00 (m, 1H), 6.76- 6.69 (m, 1H), 6.44 (t, J = 8.0 Hz, 1H), 4.95 - 4.87 (m, 1H), 4.37 - 4.34(m, 2H), 4.03 - 3.99 (m, 2H), 2.72 (s, 3H), 2.66 (s, 3H). 13 CNMR (100 MHz, DMSO-d6) δ 164.9, 161.7, 151.1 (dd, J = 240.6, 10.1 Hz), 146.7, 144.7, 141.5 (dd, J = 7.4, 2.2 Hz), 140.1 (dd, J = 239.0, 14.0 Hz), 132.9, 130.7, 127.8,127.2, 124.8 (dd, J = 9.4, 4.3 Hz), 124.7, 123.7, 110.7, 106.4 (d, J = 17.8Hz), 60.5, 41.7, 25.6, 18.9.

[0450] Compound 36

[0451] Synthesis route:

[0452]

[0453] Intermediate 9-2 (186 mg, 0.79 mmol) and HATU (360 mg, 0.95 mmol) were dissolved in dichloromethane (5 mL), triethylamine (239 mg, 2.37 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 7-3 (145 mg, 0.79 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 36 (228 mg, yield: 72%). 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (d, J = 6.8Hz, 1H), 8.57 (d, J = 1.9 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 8.17 (s, 1H),8.11 (d, J = 5.6 Hz, 1H), 7.49 (s, 1H), 6.55 (d, J = 5.6 Hz, 1H), 4.90 - 4.85(m, 1H), 4.60 - 4.56 (m, 2H), 4.24 - 4.20 (m, 2H), 2.74 (d, J = 0.8 Hz, 3H), 2.69 (d, J = 4.4 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.1, 161.8, 151.4,149.7, 148.3, 146.7, 144.8, 133.0, 130.7, 127.8, 124.8, 123.8, 115.5, 109.2, 60.3, 41.1, 38.7, 25.6, 18.9.

[0454] Compound 37

[0455] Synthesis route:

[0456]

[0457] Intermediate 9-2 (170 mg, 0.72 mmol) and HATU (328 mg, 0.86 mmol) were dissolved in dichloromethane (4 mL), triethylamine (218 mg, 2.16 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 5-3 (145 mg, 0.72 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 37 (211 mg, yield: 70%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.38 (d, J = 6.7Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.32 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 5.5Hz, 1H), 7.46 (d, J = 1.1 Hz, 1H), 6.60 (dd, J = 6.7, 5.5 Hz, 1H), 4.96 -4.87 (m, 1H), 4.54 - 4.50 (m, 2H), 4.22 - 4.19 (m, 2H), 2.73 (s, 3H), 2.68(s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.1, 161.7, 146.6, 145.3 (d, J = 9.0Hz), 144.9 (d, J = 6.0 Hz), 144.8, 143.1 (d, J = 249.9 Hz), 137.3 (d, J =15.5 Hz), 133.0, 130.7, 127.8, 127.3, 124.8, 123.8, 109.8 (d, J = 2.4 Hz), 60.1, 41.6 (d, J = 2.4 Hz), 25.6, 18.9.

[0458] Compound 38

[0459] Synthesis route:

[0460]

[0461] Intermediate 9-4 (188 mg, 0.75 mmol) and HATU (342 mg, 0.90 mmol) were dissolved in dichloromethane (4 mL), triethylamine (227 mg, 2.25 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 2-3 (125 mg, 0.75 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 38 (242 mg, yield: 81%). 1 H NMR (400 MHz, DMSO-d6) δ 9.44 (d, J = 6.3Hz, 1H), 8.60 (d, J = 1.9 Hz, 1H), 8.57 (d, J = 6.8 Hz, 1H), 8.34 (d, J = 1.8Hz, 1H), 8.20 (d, J = 6.7 Hz, 1H), 7.49 (s, 1H), 6.88 - 6.84 (m, 1H), 4.99 -4.91 (m, 1H), 4.78 - 4.74 (m, 2H), 4.49 - 4.45 (m, 2H), 3.16 (q, J = 7.5 Hz,2H), 2.71 (s, 3H), 1.35 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ165.3, 162.1, 151.9, 147.4 (d, J = 237.0 Hz), 147.2 (d, J = 9.0 Hz), 145.0,139.0, 133.2, 130.6, 128.8 (d, J = 31.2 Hz), 127.6, 126.4, 123.3, 122.9,108.6 (d, J = 6.6 Hz), 60.4, 41.7 (d, J = 2.3 Hz), 25.7, 24.7, 14.5.

[0462] Compound 39

[0463] Synthesis route:

[0464]

[0465] Intermediate 9-4 (180 mg, 0.72 mmol) and HATU (328 mg, 0.86 mmol) were dissolved in dichloromethane (4 mL), triethylamine (218 mg, 2.16 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 7-3 (132 mg, 0.72 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 39 (251 mg, yield: 84%). 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (d, J = 6.7Hz, 1H), 8.66 (d, J = 1.8 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.17 (s, 1H),8.11 (d, J = 5.6 Hz, 1H), 7.46 (s, 1H), 6.53 (d, J = 5.6 Hz, 1H), 4.91 - 4.83(m, 1H), 4.58 - 4.54 (m, 2H), 4.28 - 4.25 (m, 2H), 3.17 (q, J = 7.5 Hz, 2H), 2.69 (s, 3H), 1.33 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.1,161.9, 152.0, 151.4, 149.7, 148.3, 144.9, 133.1, 130.7, 127.8, 126.4, 123.3,122.7, 115.5, 109.2, 60.2, 41.1, 25.7, 24.8, 14.5.

[0466] Compound 40

[0467] Synthesis route:

[0468]

[0469] Intermediate 9-4 (173 mg, 0.69 mmol) and HATU (315 mg, 0.83 mmol) were dissolved in dichloromethane (4 mL), triethylamine (209 mg, 2.07 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 5-3 (139 mg, 0.69 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 40 (269 mg, yield: 90%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.38 (d, J = 6.7Hz, 1H), 8.59 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 5.5Hz, 1H), 7.47 (s, 1H), 6.61 - 6.58 (m, 1H), 4.96 - 4.86 (m, 1H), 4.54 - 4.50(m, 2H), 4.22 - 4.19 (m, 2H), 3.16 (q, J = 7.5 Hz, 2H), 2.70 (s, 3H), 1.34(t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.0, 161.9, 151.9, 145.3(d, J = 8.9 Hz), 144.9, 144.9 (d, J = 20.9 Hz), 143.1 (d, J = 249.9 Hz), 137.3 (d, J = 15.6 Hz), 133.2, 130.7, 127.7, 126.4, 123.2, 122.7, 109.8, 60.1, 41.6 (d, J = 2.3 Hz), 25.7, 24.7, 14.4.

[0470] Compound 46

[0471] Synthesis route:

[0472]

[0473] Intermediate 10-3 (173 mg, 0.86 mmol) and HATU (392 mg, 1.03 mmol) were dissolved in dichloromethane (6 mL), triethylamine (261 mg, 2.58 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 13-3 (173 mg, 0.86 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 46 (217 mg, yield: 65%). 1 H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J = 6.8Hz, 1H), 8.87 (d, J = 4.4 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H), 7.99 - 7.95 (m,2H), 7.56 (d, J = 4.0 Hz, 1H), 6.60 (d, J = 6.8 Hz, 1H), 4.95 - 4.87 (m, 1H), 4.53 - 4.48 (m, 2H), 4.21 - 4.16 (m, 2H), 2.77 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.2 (d, J = 2.3 Hz), 157.9 (d, J = 253.4 Hz), 152.4, 148.9 (d, J =244.1 Hz), 146.5 (d, J = 2.5 Hz), 146.3, 145.9 (d, J = 10.6 Hz), 139.1 (d, J= 11.6 Hz), 135.9 (d, J = 23.4 Hz), 131.6 (d, J = 7.2 Hz), 129.3 (d, J = 2.2Hz), 124.2, 120.5 (d, J = 4.2 Hz), 112.1 (d, J = 20.7 Hz), 107.7 (d, J = 3.3Hz), 60.0, 41.6 (d, J = 2.4 Hz), 19.0.

[0474] Compound 47

[0475] Synthesis route:

[0476]

[0477] Intermediate 10-3 (189 mg, 0.92 mmol) and HATU (420 mg, 1.10 mmol) were dissolved in dichloromethane (6 mL), triethylamine (279 mg, 2.76 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 14-3 (169 mg, 0.92 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 47 (242 mg, yield: 71%). 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J = 7.0Hz, 1H), 8.87 (d, J = 4.3 Hz, 1H), 8.47 (s, 1H), 7.91 (d, J = 11.6, 1H), 7.93(d, J = 5.7 Hz, 1H), 7.56 (d, J = 4.4, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.43 -6.41 (m, 1H), 4.98 - 4.90 (m, 1H), 4.37 - 4.33 (m, 2H), 4.03 - 4.99 (m, 2H),2.76 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.2, 157.9 (d, J = 253.6 Hz), 157.1, 152.4, 151.2, 149.4, 146.5 (d, J = 2.6 Hz), 139.2 (d, J = 11.6 Hz), 131.6 (d, J = 7.0 Hz), 129.3, 124.2, 120.5 (d, J = 4.3 Hz), 112.1 (d, J =20.8 Hz), 106.3, 105.0, 58.20, 41.1, 19.0.

[0478] Compound 48

[0479] Synthesis route:

[0480]

[0481] Intermediate 10-3 (156 mg, 0.76 mmol) and HATU (347 mg, 0.91 mmol) were dissolved in dichloromethane (6 mL), triethylamine (231 mg, 2.28 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 15-3 (140 mg, 0.76 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 48 (178 mg, yield: 63%). 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J = 6.8Hz, 1H), 8.88 (d, J = 4.3 Hz, 1H), 8.49 (s, 1H), 8.01 - 7.96 (m, 1H), 7.57 -7.56 (m, 1H), 7.28 - 7.21 (m, 1H), 6.59 - 6.53 (s, 1H), 6.31 - 6.26 (m, 1H), 4.94 - 4.86 (m, 1H), 4.24 - 4.20 (m, 2H), 3.85 - 3.82 (m, 2H), 2.78 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.0, 157.9 (d, J = 253.3 Hz), 152.4, 150.4 (dd,J = 243.7, J = 12.8 Hz), 149.6 (d, J = 10.0 Hz), 146.4, 142.7 (dd, J = 232.4,J = 10.2 Hz), 139.2 (d, J = 11.7 Hz), 131.7 (d, J = 7.1 Hz), 129.3 (d, J =2.1 Hz), 124.1 , 120.5 (d, J = 4.2 Hz), 118.0 (d, J = 17.7 Hz), 112.2 (d, J =20.7 Hz), 107.8 (dd, J = 5.8, 2.8 Hz), 100.9 (d, J = 20.2 Hz), 59.5, 40.8,19.0.

[0482] Compound 49

[0483] Synthesis route:

[0484]

[0485] Intermediate 9-3 (211 mg, 0.95 mmol) and HATU (433 mg, 1.14 mmol) were dissolved in dichloromethane (6 mL), triethylamine (288 mg, 2.85 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 16-3 (206 mg, 0.95 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 49 (324 mg, yield: 81%). 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J = 7.0Hz, 1H), 8.94 (d, J = 4.4 Hz, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.38 (d, J = 1.8Hz, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.58 (d, J = 4.4 Hz, 1H), 7.20 (s, 1H), 5.01 - 4.95 (m, 1H), 4.43 - 4.39 (m 2H), 4.04 - 4.01 (m, 2H), 2.79 (s, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 164.9, 152.8, 147.2, 147.0, 145.0, 138.5, 134.0 (q,J = 4.4 Hz), 133.8, 131.6, 128.9, 127.8, 125.7 (q,J = 271.2 Hz), 125.6 (q, J = 31.5 Hz), 124.1 (d, J = 9.1 Hz), 114.3, 59.4, 41.5, 19.0.

[0486] Compound 50

[0487] Synthesis route:

[0488]

[0489] Intermediate 10-3 (199 mg, 0.97 mmol) and HATU (443 mg, 1.16 mmol) were dissolved in dichloromethane (6 mL), triethylamine (294 mg, 2.91 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 17-3 (211 mg, 0.97 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 50 (298 mg, yield: 76%). LC-MS (ESI) m / z=405.24 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J = 6.9 Hz, 1H), 8.87 (d, J = 4.4 Hz, 1H), 8.48 (s, 1H),8.00 - 7.79 (m, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 4.3 Hz, 1H), 7.01 (dd, J = 8.6, 2.7 Hz, 1H), 5.02 - 4.94 (m, 1H), 4.43 - 4.39 (m, 2H), 4.07 -4.04 (m, 2H), 2.77 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.1, 157.9 (d, J =254.9 Hz), 152.4, 149.0, 146.3 (d, J = 2.5 Hz), 139.2 (d, J = 11.7 Hz), 134.8(q, J = 33.9 Hz), 134.3, 131.6 (d, J = 7.1 Hz), 129.3 (d, J = 2.3 Hz), 123.1(q, J = 270.0 Hz), 124.1, 121.4 (d, J = 3.1 Hz), 120.5 (d, J = 4.2 Hz),117.9, 112.1 (d, J = 20.7 Hz), 59.0, 41.5, 19.0.

[0490] Compound 51

[0491] Synthesis route:

[0492]

[0493] Intermediate 10-3 (162 mg, 0.79 mmol) and HATU (360 mg, 0.95 mmol) were dissolved in dichloromethane (6 mL), triethylamine (240 mg, 2.37 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 18-3 (158 mg, 0.79 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 51 (193 mg, yield: 63%). LC-MS (ESI) m / z=388.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 7.0 Hz, 1H), 8.88 (d, J = 4.3 Hz, 1H), 8.49 (d, J =0.8 Hz, 1H), 8.01 - 7.98 (m, 1H), 7.58 -7.56 (m, 1H), 7.27 -7.22 (m, 1H), 6.68 - 6.66 (m, 1H), 6.50 - 6.46 (m, 1H), 4.95 - 4.86 (m, 1H), 4.25 - 4.21(m, 2H), 3.86 - 3.83 (m, 2H), 2.78 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.0,157.9 (d, J = 253.3 Hz), 152.4, 150.6 (d, J = 234.0 Hz), 149.6 (d, J = 1.8Hz), 146.4, 139.2 (d, J = 11.8 Hz), 131.7 (d, J = 7.1 Hz), 129.3 (d, J = 2.2Hz ), 124.2, 120.5 (d, J = 4.0 Hz), 120.1 (d, J = 18.4 Hz), 117.4 (d, J =21.8 Hz), 113.0, 112.2 (d, J = 20.8 Hz), 112.0 (d, J = 6.6 Hz), 59.5, 40.9,19.0.

[0494] Compound 52

[0495] Synthesis route:

[0496]

[0497] Intermediate 10-3 (199 mg, 0.97 mmol) and HATU (443 mg, 1.16 mmol) were dissolved in dichloromethane (6 mL), triethylamine (294 mg, 2.91 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 19-3 (212 mg, 0.97 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 52 (295 mg, yield: 75%). LC-MS (ESI) m / z=203.21 [M / 2+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.89 (d, J = 4.4 Hz, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.02 - 7.98 (m, 2H), 7.58 (d, J = 4.0 Hz, 1H), 6.59 (s, 1H), 4.87 (s, 1H), 4.66 - 4.62 (m, 2H), 4.31 - 4.27 (m, 2H), 2.86 - 2.79 (s, 3H). 13 C NMR (100MHz, DMSO-d6) δ 165.2 (dd, J = 2.0 Hz), 157.9 (d, J = 253.3 Hz), 152.8,152.4, 149.7, 149.1, 146.4 (d, J = 2.5 Hz), 139.2 (d, J = 11.7 Hz), 131.6 (d,J = 7.0 Hz), 129.3 (d, J = 2.2 Hz), 124.2, 120.5 (d, J = 4.1 Hz), 115.0,112.1 (d, J = 20.7 Hz), 107.5, 60.5, 41.0, 19.0.

[0498] Compound 53

[0499] Synthesis route:

[0500]

[0501] Intermediate 10-3 (193 mg, 0.94 mmol) and HATU (429 mg, 1.13 mmol) were dissolved in dichloromethane (6 mL), triethylamine (285 mg, 2.82 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 20-3 (236 mg, 0.94 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 53 (305 mg, yield: 74%). LC-MS (ESI) m / z=438.13 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.39 (d, J = 6.9 Hz, 1H), 8.89 (d, J = 4.3 Hz, 1H), 8.50 (d, J =1.8 Hz, 1H), 8.00 (d, J = 11.5, 1.7 Hz, 1H), 7.59 (d, J = 4.2 Hz, 1H), 6.76(s, 2H), 4.95 - 4.86 (m, 1H), 4.32 - 3.95 (m, 2H), 3.95 - 3.92 (m, 2H), 2.79(s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.1, 157.9 (d, J = 254.9 Hz), 152.4, 151.0, 146.4, 139.3, 133.6, 131.7, 129.4, 124.2, 120.6, 116.8, 112.3, 112.1,59.2, 40.8, 19.0.

[0502] Compound 54

[0503] Synthesis route:

[0504]

[0505] Intermediate 9-3 (266 mg, 1.20 mmol) and HATU (547 mg, 1.44 mmol) were dissolved in dichloromethane (6 mL), triethylamine (364 mg, 3.60 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 21-3 (199 mg, 1.20 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 54 (359 mg, yield: 81%). LC-MS (ESI) m / z=370.19[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 7.1 Hz, 1H), 8.92 (d, J = 4.3 Hz, 1H), 8.61 (d, J =1.9 Hz, 1H), 8.37 (d, J = 1.8 Hz, 1H), 7.56 - 7.55 (m, 1H), 7.12 - 6.92 (m,2H), 6.64 - 6.39 (m, 2H), 5.00 - 4.82 (m, 1H), 4.23 - 4.19 (m, 2H), 3.82 -3.79 (m, 2H), 2.84 - 2.70 (m, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 164.8, 155.8(d, J = 231.0 Hz), 152.7, 149.1, 147.0, 145.0, 133.8, 131.6, 128.9, 127.9,124.1 (d, J = 10.2 Hz), 115.8 (d, J = 22.1 Hz), 113.3, 113.2, 59.6, 41.0,18.9.

[0506] Compound 55

[0507] Synthesis route:

[0508]

[0509] Intermediate 10-3 (158 mg, 0.77 mmol) and HATU (351 mg, 0.92 mmol) were dissolved in dichloromethane (6 mL), triethylamine (234 mg, 2.31 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 22-3 (193 mg, 0.77 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 55 (256 mg, yield: 76%). LC-MS (ESI) m / z=438.13 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 7.0 Hz, 1H), 8.89 (d, J = 4.3 Hz, 1H), 8.50 (s, 1H), 8.00 (d, J = 11.6 Hz, 1H), 7.58 (d, J = 4.3 Hz, 1H), 7.49 (d, J = 8.6 Hz,1H), 6.83 (d, J = 2.8 Hz, 1H), 6.79 - 6.77 (m, 1H), 4.98 - 4.90 (m, 1H), 4.35- 4.32 (m, 2H), 3.96 - 3.92 (m, 2H), 2.78 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ165.1, 157.9 (d, J = 253.4 Hz), 152.3, 150.6, 146.4, 139.2 (d, J = 11.6 Hz), 132.4, 131.7 (d, J = 7.2 Hz), 129.3, 127.4 (d, J = 30.0 Hz), 124.2, 123.5 (d, J = 271.4 Hz), 120.5 (d, J = 4.0 Hz), 117.7, 116.7, 112.1 (d, J = 20.9 Hz), 110.2, 59.2, 40.9, 19.0.

[0510] The following compound was synthesized using a preparation method similar to that of Example 55:

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521] .

[0522] Comparative Example

[0523] Preparation and synthesis of comparative compound VU6009548 (compound 15t in Bioorganic & Medicinal Chemistry Letters (2017), 27(22), 4999-5001)

[0524] Synthesis route:

[0525]

[0526] first step:

[0527] Compound 12-1 (2.30 g, 16.79 mmol) was added to a test tube, followed by 8 mL of 6 mol / L hydrochloric acid, and reacted at 120 °C for 45 minutes. B-1 (1.69 g, 20.15 mmol) was then added at 110 °C. o C for 24 hours. After the reaction solution was cooled to room temperature, the pH value of the system was adjusted to about 5 with a saturated sodium carbonate aqueous solution. After the solid was precipitated, it was filtered and dried. The filtrate was extracted with EA three times and concentrated under reduced pressure to obtain a part of the crude product and combined with the filter cake. The filter cake was added with 50 mL of ethyl acetate and heated to 50 o C was slurried for 1 hour, filtered and dried to obtain intermediate 12-2 (2.36 g, yield: 70 %). 1 H NMR (400 MHz, DMSO-d 6) δ 8.63 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.36 (s, 1H), 2.69 (s, 3H), 2.63 (s, 3H).

[0528] Step 2

[0529] Intermediate 12-2 (165 mg, 0.82 mmol) and HATU (374 mg, 0.98 mmol) were dissolved in dichloromethane (5 mL), triethylamine (248 mg, 2.46 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 1-3 (152 mg, 0.82 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound VU6009548 (229 mg, yield: 76%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.32 (d,J = 6.8 Hz, 1H), 8.58 (d, J = 1.9 Hz, 1H), 8.15 (dd, J = 8.7, 2.0 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 5.6 Hz, 1H), 7.34 (s, 1H), 6.52 (t, J= 5.9 Hz, 1H), 5.04 – 4.85 (m, 1H), 4.59 – 4.45 (m, 2H), 4.30 – 4.16 (m, 2H), 2.71 (s, 3H), 2.62 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.3, 160.7, 152.5(dd, J = 226.6, 10.8 Hz), 148.9, 146.8 (t, J = 5.9 Hz), 145.7, 141.5 (dd, J =18.0, 6.6 Hz), 133.3 (dd, J = 247.6, 31.3 Hz), 130.7, 129.2, 127.9, 125.8, 124.4, 123.7, 108.8, 60.2, 41.6, 25.2, 18.6.

[0530] Intermediate 12-3

[0531] Synthesis route:

[0532]

[0533] Compound 12-1 (2.80 g, 20.42 mmol) was added to the reaction flask, followed by 15 mL of 6 mol / L hydrochloric acid, and the mixture was reacted at 120 °C for 45 minutes. B-2 (2.70 g, 30.63 mmol) was then added at 110 °C. o C for 24 hours. After the reaction solution was cooled to room temperature, the pH value of the system was adjusted to about 5 with a saturated sodium carbonate aqueous solution. After the solid was precipitated, it was filtered and dried. The filtrate was extracted with EA three times and concentrated under reduced pressure to obtain a part of the crude product and combined with the filter cake. The filter cake was added with 50 mL of ethyl acetate and heated to 50 o C was slurried for 1 hour, filtered and dried to obtain intermediate 12-3 (2.06 g, yield: 54 %). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.87 (d, J = 4.4 Hz, 1H), 8.71 (d, J = 1.7 Hz, 1H), 8.22 (dd,J = 8.7, 1.8 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 4.9 Hz, 1H),2.76 (s, 3H).

[0534] Compound 41

[0535] Synthesis route:

[0536]

[0537] 2-Methyl-6-quinolinecarboxylic acid (159 mg, 0.85 mmol) and HATU (396 mg, 1.02 mmol) were dissolved in dichloromethane (5 mL), triethylamine (258 mg, 2.55 mmol) was added and stirred at room temperature for 15 minutes, and intermediate 6-3 (156 mg, 0.85 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 41 (234 mg, yield: 78%). 1 H NMR (400 MHz, DMSO-d 6) δ 9.23 (d, J= 6.9 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.16 (dd,J = 8.8, 2.1 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.08 – 6.95 (m, 1H), 6.80 – 6.66 (m, 1H), 6.53 – 6.35 (m, 1H), 4.99 – 4.80(m, 1H), 4.42 – 4.26 (m, 2H), 4.05 – 3.93 (m, 2H), 2.68 (s, 3H). 13 C NMR (100MHz, DMSO-d 6 ) δ 166.2, 161.2, 151.1 (dd, J = 242.5, 10.4 Hz), 148.9, 141.6 (dd, J = 7.4, 2.2 Hz), 140.11 (dd, J = 240.6, 15.0 Hz), 129.8 (dd, J = 212.2,28.3 Hz), 128.7, 128.3, 128., 125.8, 124.8 (dd, J = 8.8, 4.0 Hz), 123.4,110.6 (dd, J = 5.0, 2.4 Hz), 106.27 (d, J = 17.4 Hz), 60.6, 41.7, 25.5.

[0538] Compound 42

[0539] Synthesis route:

[0540]

[0541] 2-Methyl-6-quinolinecarboxylic acid (159 mg, 0.85 mmol) and HATU (396 mg, 1.02 mmol) were dissolved in dichloromethane (5 mL), triethylamine (258 mg, 2.55 mmol) was added and stirred at room temperature for 15 minutes, and intermediate 1-3 (157 mg, 0.85 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 42 (217 mg, yield: 72%).1 H NMR (400 MHz, DMSO-d 6 ) δ 9.39 (d, J= 6.8 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.17 (dd,J = 8.8, 2.0 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 5.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 6.51 (t, J = 5.9 Hz, 1H), 5.01 – 4.84 (m, 1H), 4.55– 4.47 (m, 2H), 4.29 – 4.15 (m, 2H), 2.68 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 )δ 166.3, 161.2, 152.5 (dd, J = 225.4, 12.1 Hz), 148.9, 146.9 (t, J = 5.8 Hz), 141.5 (dd, J = 18.3, 6.6 Hz), 137.6, 134.3 (dd, J = 246.2, 10.6 Hz), 131.2, 128.7, 128.4, 128.1, 125.8, 123.5, 108.9, 60.2, 41.5, 25.5.

[0542] Compound 43

[0543] Synthesis route:

[0544]

[0545] Intermediate 12-3 (159 mg, 0.85 mmol) and HATU (396 mg, 1.02 mmol) were dissolved in dichloromethane (5 mL), triethylamine (258 mg, 2.55 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 6-3 (156 mg, 0.85 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 43 (207 mg, yield: 69%). 1 H NMR (400 MHz, DMSO-d 6) δ 9.31 (d, J = 6.9Hz, 1H), 8.82 (d, J = 4.3 Hz, 1H), 8.65 (d, J = 1.7 Hz, 1H), 8.21 (dd, J =8.8, 1.9 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 4.4, 1.1 Hz, 1H),7.06 – 6.97 (m, 1H), 6.76 – 6.66 (m, 1H), 6.43 (t, J = 8.2 Hz, 1H), 5.05 –4.82 (m, 1H), 4.45 – 4.29 (m, 2H), 4.10 – 3.95 (m, 2H), 2.76 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.1, 152.2, 150.6 (dd, J = 241.1, 10.3 Hz), 149.1,141.5 (dd, J = 7.5, 2.3 Hz), 140.0 (dd, J = 224.5, 14.7 Hz), 131.7, 130.0, 128.0, 127.5, 124.8 (dd, J = 8.9, 4.2 Hz), 124.6, 123.1, 110.6, 106.4, 60.6, 41.7, 18.7.

[0546] Compound 44

[0547] Synthesis route:

[0548]

[0549] 3-Bromoquinoline-6-carboxylic acid (181 mg, 0.72 mmol) and HATU (335 mg, 0.86 mmol) were dissolved in dichloromethane (5 mL), triethylamine (218 mg, 2.16 mmol) was added and stirred at room temperature for 15 minutes, and intermediate 6-3 (132 mg, 0.72 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 44 (226 mg, yield: 75%). 1 H NMR (400 MHz, DMSO-d 6) δ 9.32 (d, J =6.9 Hz, 1H), 9.01 (d, J = 2.4 Hz, 1H), 8.79 (d, J = 2.3 Hz, 1H), 8.50 (d, J =2.0 Hz, 1H), 8.23 ​​(dd, J = 8.8, 2.0 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.11 – 6.91 (m, 1H), 6.82 – 6.61 (m, 1H), 6.50 – 6.33 (m, 1H), 5.03 – 4.76 (m, 1H), 4.44 – 4.24 (m, 2H), 4.10 – 3.92 (m, 2H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.8,153.0, 150.6 (dd, J = 241.1, 10.4 Hz), 147.2, 141.5 (dd, J = 7.5, 2.2 Hz), 140.1 (dd, J = 239.4, 15.1 Hz), 138.8, 133.3, 129.4, 128.6, 128.3 (d, J =51.5 Hz), 124.7 (dd, J = 8.9, 4.2 Hz), 117.9, 110.6, 106.3 (d, J = 17.3 Hz), 60.5, 41.7.

[0550] Compound 45

[0551] Synthesis route:

[0552]

[0553] Intermediate 23-2 (172 mg, 0.80 mmol) and HATU (365 mg, 0.96 mmol) were dissolved in dichloromethane (6 mL), triethylamine (243 mg, 2.40 mmol) was added and stirred at room temperature for 15 minutes, and then intermediate 4-3 (134 mg, 0.80 mmol) was added and stirred for 4 hours. After the reaction was completed, it was diluted with water (30 mL), extracted with dichloromethane (30×3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography to obtain compound 45 (221 mg, yield: 76%).

[0554] 1 H NMR (400 MHz, DMSO-d6 ) δ 9.45 (d, J = 6.9 Hz, 1H), 8.66 (d, J = 1.9Hz, 1H), 8.17 (dd, J = 8.8, 2.0 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.80 (d, J= 5.7 Hz, 1H), 7.36 (s, 1H), 6.38 - 6.36 (m, 1H), 6.07 (d, J = 1.9 Hz, 1H), 4.99 - 4.91 (m, 1H), 4.36 - 4.32 (m, 2H), 4.07 - 4.03 (m, 2H), 3.15 (q, J =7.3 Hz, 2H), 2.64 (s, 3H), 1.34 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6)δ 166.4, 165.1 (d, J = 228.4 Hz), 160.9, 159.3 (d, J = 11.7 Hz), 151.1,149.1, 147.3 (d, J = 19.7 Hz), 130.8, 129.4, 127.9, 124.9, 123.9, 121.7,105.6, 89.4 (d, J = 42.8 Hz), 58.3, 41.0, 25.4, 24.5, 14.5.

[0555] Biological activity test

[0556] Biological Example 1: Testing of the positive allosteric regulation activity of the compounds of the present invention on the M4 receptor

[0557] Objective: To explore the allosteric regulatory effect of PAMs on the intracellular calcium ion release induced by acetylcholine activation of M4 receptor in CHO cells stably expressing M4.

[0558] Main experimental materials and sources:

[0559] CHO cells stably expressing M4; culture medium F12 gibco FBS was purchased from Ecosine Biotechnology Co., Ltd.; Geneticin was purchased from Thermo Fisher Scientific; Penicillin / Streptomycin was purchased from Thermo Fisher Scientific; Fluo-4 Direct was purchased from Thermo Fisher Scientific; 384-well plate, Greiner was purchased from Greiner Biotechnology Co., Ltd.; Vi-cell XR cell viability analyzer was purchased from Beckman Coulter); incubator was purchased from Thermo Fisher Scientific.

[0560] Experimental protocol:

[0561] 1. Experimental Preparation

[0562] 1) Cell preparation: Aspirate the culture medium in the 384-well plate; wash the cells with 3 mL D-PBS (Dole's phosphate buffered saline) and then aspirate; add 3 mL trypsin-EDTA (ethylenediaminetetraacetic acid). Incubate at 37°C for 1 to 2 minutes. Observe the progress of enzyme treatment under an inverted microscope; gently tap the culture bottle to peel off the cells from the bottom; add 3 mL growth medium, fully suspend the cells with a pipette, wash the remaining cells at the bottom, and centrifuge at 1000 rpm for 5 minutes; gently pour out or aspirate the supernatant, being careful not to aspirate the cells. Resuspend the cells with 5-10mL of culture medium and take out 1 mL for cell counting; count the cell concentration with ViCell. Suspend the cells in growth medium at a concentration of 10x10^5 / mL; add 20 µL of cell suspension (20K / well) to each well of the 384-well plate; place the cells in a 37°C, 5% CO 2 incubator overnight.

[0563] 2) FLIPR experiment preparation: Prepare Probenecid in FLIPR assay buffer; prepare 2x (8µM) Fluo-4 Direct TM No-Wash Loading Buffer (10 mL each).

[0564] 2. Experimental process:

[0565] 1) Compound preparation: The test compounds (the example compounds and comparative example compound VU6009548 in Table 1 below) were prepared into 10 mM compound stock solution with DMSO, and each compound was diluted 3-fold, 10 concentration gradients, and 3 parallels were set. Then, 250 nl of the compound was transferred to a 384-well compound plate using an ECHO pipetting system. 50 μL of experimental buffer was added and shaken for 15 minutes.

[0566] 2) Add Fluo-4: Remove the cell plate from the incubator, gently remove the culture medium, and use a pipette to add 20 μL of assay buffer and 20 μL of 2x Fluo-4 Direct to the 384-well cell culture plate. TM No washing with loading buffer is required. Final volume in cell culture plate is 40 µL.

[0567] 3) Incubation: 37°C, 5% CO 2 Incubate for 2 hours.

[0568] 4) Prepare the FLIPR: Remove the cell plate from the incubator and place it in the FLIPR. Place the compound plate and tip box in the FLIPR.

[0569] 5) For compound plates (agonist testing): run the protocol on FLIPRTETRA; transfer 10 µL of reference and compound from the compound plate to the cell plate; read the fluorescence signal; calculate the “Max-Min” from the first reading to the maximum allowed value. Calculate the EC for each cell line using FLIPR 20 Value; prepare 6×EC 20 concentration of agonist reference compound.

[0570] 6) For compound plate (PAM test): run protocol on FLIPRTETRA; transfer 10 µL of reference material and compounds from compound plate to cell plate; read fluorescence signal; transfer 6×EC from compound plate 20 Add the agonist reference substance to the cell plate; read the fluorescence signal; calculate the "Max-Min" from the first reading to the maximum allowed value.

[0571] 7) Data processing and analysis: Plot the signal value against the compound concentration and calculate the compound EC using the following GraphPad nonlinear fitting formula 50 :

[0572] Y=Bottom + (Top-Bottom) / (1+10^((LogEC 50 -X)*Hill Slope))

[0573] X: log value of compound concentration;

[0574] Y:Activation %

[0575] Hill Slope: Slope factor or Hill slope

[0576] Experimental results:

[0577] The compounds of the present invention were tested in the above assays. The EC 50The results are summarized in Table 1 below.

[0578] Table 1

[0579]

[0580] .

[0581] Biological Example 2: Determination of the inhibitory effect of the compounds of the present invention on MK-801-induced rapid activity behavior in mice

[0582] 1.1 Experimental animals and experimental instruments: 17-19 g SPF-grade male ICR mice were purchased from Hunan Slake Jingda Experimental Animal Co., Ltd.; the mouse open field test box and VisuTrack animal behavior analysis software were purchased from Shanghai Xinruan.

[0583] 1.2 Test samples and solvents

[0584] MK-801: 0.9% NaCl injection (solvent), purchased from Shanghai MacLean Biochemical Technology Co., Ltd.; Compound of this example: 5% DMSO+30% PEG-400+5% Tween-80+60% physiological saline (solvent).

[0585] Experimental methods:

[0586] The purchased SPF grade male ICR mice were adapted to the breeding environment for 3 days. Before the experiment, the mice were brought to the open field test box for 2-3 hours to reduce the animals' anxiety about the new environment. During the experiment, the animals were grouped according to their weight and randomly divided into a blank group, a model group, and a drug group, 10 per group. Detailed drug administration information is shown in Table 2 below:

[0587] Table 2. Experimental groups and drug administration information

[0588]

[0589] The mice were administrated according to the above grouping and administration information, wherein the administration group was intraperitoneally injected with the corresponding compound according to the corresponding administration dose, and the blank group and the model group were intraperitoneally injected with the same volume of solvent, and at the same time, except for the blank group, the other groups were intraperitoneally injected with MK-801 (0.3 mg / kg), and the blank group was intraperitoneally injected with the same volume of saline. 15 minutes after administration, the mice were immediately placed in the experimental box, and the activities of the mice in the experimental box (total movement distance) were automatically recorded by the camera for 30 minutes, and the recorded mouse activities were analyzed and processed using VisuTrack animal behavior analysis software. After the experiment, the experimental results were processed using the statistical software Graph Pad 9.0. All statistical analyses were performed using single-tail analysis, and the statistical level was set at P≤0.05. Each indicator was expressed as "mean ± standard error". MPE% (Maximum Possible Effect, recorded as a percentage) was calculated based on the results obtained.

[0590] MPE%= (Mean(model)-individual data) / (Mean(model)-Mean (sham))×100%.

[0591] Notes: ① Subtract the values ​​of the sham group to eliminate the influence of background noise on the experiment. ② Mean (model) represents the mean value of the model group; Mean (sham) represents the mean value of the blank control; Individual data: individual data of the drug administration group. The experimental results are shown in Table 3 below:

[0592] Table 3. Inhibitory effect of the compounds of the present invention on MK-801-induced rapid activity behavior in mice

[0593]

[0594] Note: *p<0.05, **p<0.01, ***p<0.001.

[0595] The above results show that a single intraperitoneal injection of 10 mg / kg of the representative compound of the present invention can significantly inhibit the rapid movement behavior of mice induced by MK-801.

[0596] Although the embodiments disclosed in this application are as above, the contents described are only embodiments adopted to facilitate understanding of this application and are not intended to limit this application. Any technician in the field to which this application belongs can make any modifications and changes in the form and details of implementation without departing from the spirit and scope disclosed in this application, but the scope of protection of this application shall still be based on the scope defined in the attached claims.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, Ring A is selected from phenyl and pyridyl; X 1 and X 2 Independently selected from N and CR 4 , and stipulate that X 1 and X 2 Not all are N; L 1 Selected from C 3-6 Cycloalkylene and 4-6 membered heterocycloalkylene, wherein the C 3-6 The cycloalkylene and 4-6 membered heterocycloalkylene are each independently optionally substituted by 1, 2 or 3 R a substituted; in the 4-6 membered heterocycloalkylene group, the heteroatom is N, and the number of heteroatoms is 1; R 1 are each independently selected from H, cyano, halogen and C 1-6 Haloalkyl; R 2 Selected from halogen and C 1-6 alkyl; R 3 Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and NR b R c ; R 4 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and NR b R c ; n is 0, 1, 2, 3 or 4; R a are independently H, hydroxyl, halogen and C 1-6 alkyl; R b and R c are each independently selected from hydrogen and C 1-3 Alkyl, or, wherein R b and R c Together with the nitrogen atom to which it is connected, it forms a 4-6 membered saturated heterocyclic ring; in the 4-6 membered saturated heterocyclic ring, the heteroatom is N, and the number of the heteroatom is 1.

2. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) R 1 , R 2 , R 3 , R 4 and R a wherein the halogen is independently fluorine, chlorine, bromine or iodine; (2) R 2 , R 3 , R 4 and R a In the C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; (3) R 1 , R 3 and R 4 In the C 1-6 Haloalkyl is independently C substituted with one or more halogens. 1-3 alkyl; (4) R 3 and R 4 In the C 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy; (5) R 3 and R 4 In the C 1-6 Alkylthio is independently methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio or tert-butylthio; (6) L 1 In the C 3-6 Cycloalkylene is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene; (7) L 1 wherein the 4-6 membered heterocycloalkylene group is azetidinylene, pyrrolidinylene or piperidinylene; (8) R b and R c In the C 1-3 Alkyl is independently methyl, ethyl, n-propyl or isopropyl; (9) When R b and R c When the 4- to 6-membered saturated heterocyclic ring is formed together with the nitrogen atom to which it is connected, the 4- to 6-membered saturated heterocyclic ring is azetidine, pyrrolidine or piperidine.

3. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: It meets one or more of the following conditions: (1) R 1 , R 2 , R 3 , R 4 and R a wherein the halogen is independently fluorine or chlorine; (2) R 2 , R 3 , R 4 and R a In the C 1-6 Alkyl is independently methyl or ethyl; (3) R 1 , R 3 and R 4 In the C 1-6 Haloalkyl is independently -CH2F, -CH2Cl, -CHF2, -CHCl2, -CCl3, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3; (4) R 3 and R 4 In the C 1-6 Alkoxy is independently methoxy; (5) R 3 and R 4 In the C 1-6 Alkylthio is independently methylthio; (6) L 1 In the above, the azetidinyl group is ; (7) L 1 wherein the pyrrolidylene is ; (8) L 1 In which the piperidinylene group is .

4. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets the following conditions: Ring A is selected from phenyl and pyridyl; X 1 and X 2 Independently for CR 4 ; L 1 is a 4-6 membered heterocycloalkylene group, wherein the heteroatom is N and the number of heteroatoms is 1; R 1 are each independently selected from halogen and C 1-6 Haloalkyl; R 2 Selected from halogen and C 1-6 alkyl; R 3 Selected from C 1-6 alkyl; R 4 Select from H or C 1-6 alkyl; n is 1, 2 or 3.

5. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) Ring A is pyridyl; (2) X 1 and X 2 Independently for CR 4 ; R 4 H or C 1-6 alkyl; (3) R 1 are each independently selected from H, halogen and C 1-6 Haloalkyl; (4) R 3 C 1-6 alkyl; (5) L 1 is a 4-6 membered heterocycloalkylene group, wherein the heteroatom is N and the number of heteroatoms is 1; (6) n is selected from 1, 2 and 3; (7) R 2 It is a halogen.

6. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) X 1 and X 2 Independently for CR 4 , R 4 is H or methyl; (2) L 1 for , where the N atom is connected to ring A; (3) R 1 Each independently selected from H, -F, -Cl or -CF3; (4) R 2 is selected from methyl, -F or -Cl; (5) R 3 Selected from methyl or ethyl.

7. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) Structural unit Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , and ; (2) Structural unit Selected from , , , , , , , , , and .

8. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) has the structural characteristics of formula (II): Among them, R 1 , R 2 , R 3 , R 4 , Ring A and n are as defined in claim 1.

9. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) is any of the following compounds: 。 10. The method for preparing the compound represented by formula (I) according to claim 1, comprising the following steps: The intermediate (IA) or its salt and the intermediate (IB) undergo amide condensation reaction in the presence of an amide condensation agent to prepare a compound of formula (I): in, The group R in formula (IA), formula (IB) and formula (I) 1 , n, ring A, L 1 , R 2 , R 3 , X 1 and X 2 The definition of as in claim 1; The amide condensation agent is a carbodiimide condensation agent, an onium salt condensation agent or an organic phosphorus condensation agent.

11. A pharmaceutical composition comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, and at least one pharmaceutical excipient.

12. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 11, in the preparation of a medicament for treating and / or preventing diseases and / or disorders mediated by M4 receptors.

13. The use of claim 12, wherein the disease and / or disorder mediated by the M4 receptor is Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorder, cognitive disorder, depression, Parkinson's disease, Huntington's disease, movement disorder, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, cerebral amyloid angiopathy, dementia, stroke, pancreatitis, peripheral amyloidosis, diabetes, alcoholic liver disease, hepatitis or atherosclerosis.

14. Use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 11, in the preparation of a medicament for treating and / or preventing a disease and / or disorder; The disease and / or disorder is Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorder, cognitive disorder, depression, Parkinson's disease, Huntington's disease, movement disorder, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, cerebral amyloid angiopathy, dementia, stroke, pancreatitis, peripheral amyloidosis, diabetes, alcoholic liver disease, hepatitis or atherosclerosis.

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