A benzo six-membered heterocyclic amide compound, pharmaceutical composition and application thereof

Abstract

The present invention discloses a benzo(6-membered) heterocyclic amide compound, a pharmaceutical composition, and its use. Specifically, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof is provided. The compound of the present invention exhibits excellent positive allosteric modulation of the M4 receptor, exhibits improved pharmacodynamics and pharmacokinetic properties, and can be used to treat diseases and disorders 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 applications thereof. Background Art

[0002] Muscarinic receptors (M 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 modulators (PAMs) are a class of allosteric agonists that do not directly activate the receptor. Instead, they bind to the allosteric site, increasing the receptor's affinity for acetylcholine at the orthosteric binding site, thereby enhancing the receptor's response to acetylcholine. Furthermore, M receptor allosteric agonists do not cause receptor downregulation, likely because they do not bind to the same site as classical agonists. This advantage effectively avoids the receptor desensitization that is often caused by classical agonists (Xie Kankan et al., Progress in Muscarinic Receptor Expression in Schizophrenia, Neurological Diseases and Mental Health, 2021, Vol. 21, No. 5). Highly subtype-specific M receptor PAMs have attracted considerable attention because they can avoid the adverse effects of activation of surrounding mAChRs. Currently, PAMs targeting various M receptor subtypes, particularly those targeting the M4 receptor, have shown potential in preclinical studies for antipsychotic and cognitive improvement (Gould RW, et al., Neuropharmacology, 2018, 128:492-502).

[0004] Extensive studies have shown that modulation of the M4 receptor has the potential to treat negative symptoms and cognitive impairment associated with schizophrenia. Currently, several compounds are in clinical research. Representative examples include Emraclidine (CVL-231) and NBI-1117568, which are already in Phase II clinical trials, and NS-136, which recently entered Phase I clinical trials. In addition, Vanderbilt University has been committed to the research and development of M4 receptor PAMs since 2013. In the past decade, it has launched a variety of active PAMs molecules targeting the M4 receptor, such as VU0467154, VU0152099, and VU0152100, but they are all currently in the preclinical research stage. Published patent applications for selective positive allosteric modulators of the M4 receptor include WO2018002760A1, WO2018234953A1, and 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 therapeutic approach for cognitive and behavioral deficits in neurodegenerative diseases and neuropsychiatric diseases, no PAMs targeting the M4 receptor have been successfully launched on the market. Therefore, there is still a widespread 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, a pharmaceutical composition containing the compound, and its use. The compound has excellent positive allosteric modulation activity on the M4 receptor, exhibits improved pharmacodynamics and pharmacokinetic properties, and can be used to treat diseases and disorders mediated by the M4 receptor.

[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 stipulates that X 1 and X 2Not all N at the same time;

[0011] 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 groups 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;

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

[0013] R 2 Selected from halogen and C 1-6 alkyl;

[0014] R 3 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 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 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 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 heteroatoms is 1.

[0019] In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to 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 by one or more halogens. 1-3 Alkyl, for example -CH2F, -CH2Cl, -CHF2, -CHCl2, -CCl3, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3.

[0023] In some embodiments, R 3 and R 4 In the C 1-6 Alkoxy 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 3-6 The cycloalkylene group is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene.

[0026] In some embodiments, L 1 In the embodiment, the 4-6 membered heterocycloalkylene group may be an azetidinyl group (e.g. ), pyrrolidinyl ( ) or piperidinylene ( ), 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 4-6 membered saturated heterocyclic ring is formed together with the nitrogen atom to which it is connected, the 4-6 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 alkyl halide;

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

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

[0035] R 4 Selected 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 alkyl halide;

[0041] R 2 selected from halogen;

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

[0043] R 4 Selected 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 point 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 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 CR 4 ; 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 a methyl group.

[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 1 are independently cyano; in other embodiments, R 1 are independently halogen; in other embodiments, R 1 Independently C 1-6 Halogenated alkyl.

[0062] In some embodiments, R 1 Independently selected from fluorine, chlorine and CF3.

[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, R 4 Selected from H and C 1-3 alkyl.

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

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

[0075] In some embodiments, Rb 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 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 is independently selected from H, -F, -Cl or -CF3.

[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 selected from fluorine and chlorine;

[0091] R 3 C 1-3 Alkyl; further preferably, R 3 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), 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 The definition of is 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) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient. In a specific embodiment, the compound of formula (I) is provided in a therapeutically effective amount. In a specific embodiment, the compound of formula (I) is provided in a prophylactically 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] Such diseases and / or disorders include, but are not limited to, Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive impairment, 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 following definitions are provided for the terms used to describe the present invention in this application. For specific terms, if the meaning defined in this application is inconsistent with the meaning commonly understood by those skilled in the art, the meaning defined in this application shall prevail. If no definition is provided in this application, the term shall have the meaning commonly understood by those skilled in the art.

[0118] The names of the compounds in this application correspond to their structural formulas. When the names of the compounds are inconsistent with the structural formulas, the structural formulas shall prevail, or the names of the compounds can 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 being 1, 2, 3, 4, 5, or 6.

[0120] "Cyano" refers to -CN.

[0121] "Hydroxyl" 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. For example, "C 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 this 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 bivalent cyclic group consisting of a specified number of ring atoms (e.g., 4-6 members) and a specified number of nitrogen-containing heteroatoms, attached to the remainder of the molecule through a carbon atom or heteroatom. Examples of 4-6 membered heterocycloalkylene groups include, but are not limited to, azetidinylene, pyrrolidinylene, and piperidinylene.

[0127] "Pharmaceutically acceptable salts" refer to pharmaceutically acceptable organic or inorganic salts, as defined above, of the compounds of the present invention, 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 "optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, the term "optionally substituted with one or more substituents" means that the atom may or may not be substituted. When substituted, it means that any one or more hydrogen atoms on the specified atom are replaced by a substituent.

[0129] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only 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 as appropriate.

[0131] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than the active pharmaceutical ingredient (API). These substances are generally categorized as excipients and additives. For details, see the Pharmacopoeia of the People's Republic of China (2020 Edition) and the Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0132] The term "treat" refers to eliminating the cause or alleviating the symptoms of a disease.

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

[0134] The term "patient" refers to any animal, typically a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.

[0135] Other features and advantages of the present application will be described in the following description, and in part will become apparent from the description, or will be understood by practicing the present application. Other advantages of the present application can be realized and obtained by the solutions described in the description.

[0136] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

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

[0138] The positive progress of the present invention is that, compared with the prior art, the present invention has one or more of the following beneficial effects:

[0139] The compounds provided herein exhibit excellent positive allosteric modulatory activity on the M4 receptor and can be used as M4 receptor positive allosteric modulators for the treatment and / or prevention of diseases and / or disorders mediated by the M4 receptor. Furthermore, experiments have shown that the compounds of the present invention also exhibit favorable pharmacodynamic and / or pharmacokinetic properties. DETAILED DESCRIPTION

[0140] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0141] The structures of the compounds were confirmed 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 deuterated dimethyl sulfoxide (DMSO-d₆) or deuterated chloroform (CDCl₃) solvents, with tetramethylsilane (TMS) as the internal standard.

[0142] LCMS was determined using Waters ACQUITY UPLC.

[0143] High-performance liquid chromatography (HPLC) was performed on 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 stated, the raw materials and reagents used in the following examples are commercially available, or can be synthesized using methods known in the art, or can be purchased from reagent companies such as Aladdin, Bidtec Pharmaceuticals, and WuXi AppTec.

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

[0148] Intermediates 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), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (929 mg, 1.49 mmol) were dissolved in toluene (50 mL) and heated to 90 o C. Stir for 24 hours. After cooling the reaction mixture to room temperature, it was quenched with water and extracted with ethyl acetate (50 mL x 3). 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. Purification by silica gel column chromatography afforded 1-2 (1.34 g, yield: 63%). LC-MS (ESI) m / z = 286.20 [M+H] + . 1 H NMR (400 MHz, CDCl3) 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 adjust the pH to 8. Repeated extraction with dichloromethane is performed. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude 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), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (502 mg, 0.81 mmol) were dissolved in toluene (40 mL) and heated to 90 o C. Stir for 18 hours. After cooling the reaction mixture to room temperature, it was quenched with water and extracted with ethyl acetate (40 mL x 3). 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. Purification by silica gel column chromatography afforded 2-2 (1.28 g, yield: 71%). LC-MS (ESI) m / z = 268.21 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) 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 adjust the pH to 8. Repeated extraction with dichloromethane is performed. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated 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), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (412 mg, 0.66 mmol) were dissolved in toluene (60 mL) and heated to 80 o C. Stir for 18 hours. After the reaction solution was cooled to room temperature, it was quenched with water and extracted with ethyl acetate (60 mL × 3). 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. Purification by silica gel column chromatography gave 3-2 (2.61 g, yield: 93%). 1 H NMR (400 MHz, CDCl3) 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 adjust the pH to 8, then repeatedly extract with dichloromethane. 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), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (424 mg, 0.68 mmol) were dissolved in toluene (60 mL) and heated to 90o C. Stir for 18 hours. After cooling the reaction mixture to room temperature, it was quenched with water and extracted with ethyl acetate (50 mL x 3). 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. Purification by silica gel column chromatography afforded 4-2 (1.65 g, yield: 68%). LC-MS (ESI) m / z = 268.22 [M+H] + . 1 H NMR (400 MHz, CDCl3) 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 adjust the pH to 8, then repeatedly extract with dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude intermediate 4-3.

[0176] Intermediate 5-3

[0177] Synthesis route:

[0178]

[0179] first step

[0180] Under 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 (391 mg, 0.43 momol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (789 mg, 1.28 mmol) were dissolved in toluene (60 mL) and heated to 90 oC. Stir for 18 hours. After cooling the reaction mixture to room temperature, it was quenched with water and extracted with ethyl acetate (60 mL x 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. Purification by silica gel column chromatography afforded 5-2 (1.86 g, yield: 72%). LC-MS (ESI) m / z = 302.19 [M+H] + .

[0181] Step 2

[0182] Dissolve 5-2 (1.86 g, 6.18 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 adjust the pH to 8, then repeatedly extract with dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude intermediate 5-3.

[0183] Intermediate 6-3

[0184] Synthesis route:

[0185]

[0186] first step

[0187] Under 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 (379 mg, 0.41 momol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (773 mg, 1.24 mmol) were dissolved in toluene (50 mL) and heated to 90 o C. Stir for 18 hours. After cooling the reaction mixture to room temperature, it was quenched with water and extracted with ethyl acetate (50 mL x 3). 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. Purification by silica gel column chromatography afforded 6-2 (1.77 g, yield: 75%). LC-MS (ESI) m / z = 229.17 [M+H-tBu] + . 1H NMR (400 MHz, CDCl3) 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 adjust the pH to 8, then repeatedly extract with dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude 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), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (680 mg, 1.09 mmol) were dissolved in toluene (50 mL) and heated to 90 o C. Stir for 24 hours. After cooling the reaction mixture to room temperature, it was quenched with water and extracted with ethyl acetate (50 mL x 3). 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. Purification by silica gel column chromatography afforded 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 adjust the pH to 8, then repeatedly extract with dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude 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), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (378 mg, 0.61 mmol) were dissolved in toluene (50 mL) and heated to 90 o C. Stir for 18 hours. After cooling the reaction mixture to room temperature, it was quenched with water and extracted with ethyl acetate (50 mL x 3). 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. Purification by silica gel column chromatography afforded 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 adjust the pH to 8, then repeatedly extract with dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude 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. The mixture was reacted at 120 °C for 45 minutes, and then B-1 (1.10 g, 13.11 mmol) was 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 heated to 50 C. o After beating for 1 hour, the mixture was 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-d6) 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. The mixture was reacted at 120 °C for 45 minutes, and then B-2 (1.62 g, 18.36 mmol) was 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 heated to 50 C. o After beating for 1 hour, the mixture was 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-d6) 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. The mixture was reacted at 120 °C for 45 minutes, and then B-3 (1.97 g, 20.10 mmol) was 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 heated to 50 C. 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. The mixture was reacted at 120 °C for 45 minutes, and then B-1 (1.63 g, 19.34 mmol) was 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 heated to 50 C. o After beating for 1 hour, the mixture was 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-d6) 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. The mixture was reacted at 120 °C for 45 minutes, and then B-2 (1.53 g, 17.41 mmol) was 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 heated to 50 C. o After beating for 1 hour, the mixture was 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. The mixture was reacted at 120 °C for 45 minutes, and then B-3 (2.37 g, 24.18 mmol) was 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 heated to 50 C. o After beating for 1 hour, the mixture was filtered and dried to obtain intermediate 10-4 (3.12 g, yield: 83%). LC-MS (ESI) m / z = 234.23 [M+H] + . 1H NMR (400 MHz, DMSO-d6) 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. The mixture was reacted at 120 °C for 45 minutes, and then B-1 (1.40 g, 16.67 mmol) was 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 heated to 50 C. o After beating for 1 hour, the mixture was 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-d6) 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 the mixture was reacted at 120 °C for 45 minutes. B-2 (2.01 g, 22.82 mmol) was then added to the test tube. 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 heated to 50 C. o After beating for 1 hour, the mixture was 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-d6) 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. The mixture was reacted at 120 °C for 45 minutes, and then B-3 (2.63 g, 26.79 mmol) was 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 heated to 50 C. o After beating for 1 hour, the mixture was 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-d6) 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), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (513 mg, 0.82 mmol) were dissolved in toluene (60 mL) and heated to 80 o C. Stir for 18 hours. After the reaction solution was cooled to room temperature, it was quenched with water and extracted with ethyl acetate (60 mL × 3). 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. Purification by silica gel column chromatography gave 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 adjust the pH of the reaction solution to approximately 11. Repeated extraction with dichloromethane is performed. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude 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 heated to 80 oC. Stir for 12 hours. After the reaction solution was cooled to room temperature, it was quenched with water and extracted with ethyl acetate (60 mL × 3). 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. Purification by silica gel column chromatography gave 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 adjust the pH of the reaction solution to approximately 11. Repeated extraction with dichloromethane is performed. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude 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), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (452 ​​mg, 0.73 mmol) were dissolved in toluene (60 mL) and heated to 90 o C. Stir for 18 hours. After the reaction solution was cooled to room temperature, it was quenched with water and extracted with ethyl acetate (60 mL × 3). 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. Purification by silica gel column chromatography gave 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 adjust the pH to approximately 11, then repeatedly extract with dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude 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), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (460 mg, 0.74 mmol) were dissolved in toluene (60 mL) and heated to 85 o C. Stir for 18 hours. After the reaction solution was cooled to room temperature, it was quenched with water and extracted with ethyl acetate (60 mL × 3). 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. Purification by silica gel column chromatography gave 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 adjust the pH of the reaction solution to approximately 11. Repeated extraction with dichloromethane is performed. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude 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), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (579 mg, 0.93 mmol) were dissolved in toluene (60 mL) and heated to 80 oC. Stir for 18 hours. After the reaction solution was cooled to room temperature, it was quenched with water and extracted with ethyl acetate (60 mL × 3). 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. Purification by silica gel column chromatography gave 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 adjust the pH of the reaction solution to approximately 11. Repeated extraction with dichloromethane is performed. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude 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 heated to 90 o C. Stir for 18 hours. After the reaction solution was cooled to room temperature, it was quenched with water and extracted with ethyl acetate (60 mL × 3). 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. Purification by silica gel column chromatography gave 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 adjust the pH to approximately 11, then repeatedly extract with dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude 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), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (425 mg, 0.68 mmol) were dissolved in toluene (60 mL) and heated to 90 o C. Stir for 18 hours. After the reaction solution was cooled to room temperature, it was quenched with water and extracted with ethyl acetate (60 mL × 3). 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. Purification by silica gel column chromatography gave 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 adjust the pH of the reaction solution to approximately 11. Repeated extraction with dichloromethane is performed. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude 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 heated to 80 oC. Stir for 18 hours. After the reaction solution was cooled to room temperature, it was quenched with water and extracted with ethyl acetate (60 mL × 3). 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. Purification by silica gel column chromatography gave 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 adjust the pH of the reaction mixture to approximately 11. Repeated extraction with dichloromethane is performed. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude 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), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (836 mg, 1.34 mmol) were dissolved in toluene (60 mL) and heated to 80 o C. Stir for 18 hours. After the reaction solution was cooled to room temperature, it was quenched with water and extracted with ethyl acetate (60 mL × 3). 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. Purification by silica gel column chromatography gave 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 adjust the pH of the reaction mixture to approximately 11. Repeated extraction with dichloromethane is performed. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude 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), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (530 mg, 0.85 mmol) were dissolved in toluene (60 mL) and heated to 90 o C. Stir for 18 hours. After the reaction solution was cooled to room temperature, it was quenched with water and extracted with ethyl acetate (60 mL × 3). 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. Purification by silica gel column chromatography gave 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 adjust the pH of the reaction mixture to approximately 11. Repeated extraction with dichloromethane is performed. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude 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. Intermediate 2-3 (144 mg, 0.86 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 1 (214 mg, 71% yield). 1H 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. Intermediate 4-3 (144 mg, 0.86 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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. This was purified by silica gel column chromatography to afford 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). 13C 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. Intermediate 5-3 (157 mg, 0.78 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 3 (249 mg, 83% yield). 1 H NMR (400 MHz, DMSO-d6) 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). 13C NMR (100 MHz, DMSO-d6) 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. Intermediate 7-3 (151 mg, 0.82 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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. This was purified by silica gel column chromatography to afford compound 4 (253 mg, yield: 84%). 1 H NMR (400 MHz, DMSO-d6) 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). 13C NMR (100 MHz, DMSO-d6) 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. Intermediate 1-3 (152 mg, 0.82 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford 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). 13C 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. Intermediate 4-3 (142 mg, 0.85 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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. This was purified by silica gel column chromatography to afford 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). 13C 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. Intermediate 2-3 (142 mg, 0.85 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 7 (217 mg, yield: 72%). 1H 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. Intermediate 7-3 (149 mg, 0.81 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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. This was purified by silica gel column chromatography to afford 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. Intermediate 1-3 (142 mg, 0.77 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 9 (282 mg, 94% yield). 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-d6) 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. Intermediate 7-3 (144 mg, 0.78 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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. This was purified by silica gel column chromatography to afford compound 10 (260 mg, yield: 86%). 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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. Intermediate 2-3 (135 mg, 0.81 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford 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. Intermediate 8-3 (134 mg, 0.81 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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. This was purified by silica gel column chromatography to afford compound 12 (234 mg, yield: 78%). 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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. Intermediate 4-3 (135 mg, 0.81 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford 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. Intermediate 3-3 (158 mg, 0.73 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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. This was purified by silica gel column chromatography to afford 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. Intermediate 2-3 (137 mg, 0.82 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 15 (236 mg, 79% yield). 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. Intermediate 6-3 (145 mg, 0.79 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 16 (250 mg, 83% yield). 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. Intermediate 7-3 (147 mg, 0.80 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford 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. Intermediate 4-3 (137 mg, 0.82 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 18 (263 mg, 88% yield). 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. Intermediate 7-3 (139 mg, 0.76 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 19 (246 mg, 82% yield). 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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. Intermediate 2-3 (132 mg, 0.79 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 20 (251 mg, 84% yield). 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. Intermediate 5-3 (147 mg, 0.73 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 21 (265 mg, yield: 88%). 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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. Intermediate 4-3 (132 mg, 0.79 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 22 (242 mg, 81% yield). 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 stirred at room temperature for 15 minutes. Intermediate 7-3 (144 mg, 0.78 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 23 (270 mg, 90% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J = 6.8Hz, 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 CNMR (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] Synthesis 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. Intermediate 2-3 (137 mg, 0.82 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 24 (269 mg, 89% yield). 1 H NMR (400 MHz, DMSO-d6) 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 = 2.71 (s, 3H), 2.65 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) 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. Intermediate 5-3 (137 mg, 0.74 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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. This was purified by silica gel column chromatography to afford compound 25 (251 mg, 84% yield). 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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] 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 stirred at room temperature for 15 minutes. Intermediate 1-3 (144 mg, 0.78 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 26 (256 mg, 85% yield). 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-d6) 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. Intermediate 4-3 (132 mg, 0.79 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 27 (263 mg, 87% yield). 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. Intermediate 7-3 (138 mg, 0.75 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford 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. Intermediate 5-3 (145 mg, 0.72 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 29 (258 mg, 86% yield). 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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. Intermediate 1-3 (139 mg, 0.75 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 30 (255 mg, 85% yield). 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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. Intermediate 2-3 (132 mg, 0.79 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 31 (260 mg, yield: 86%). 1 H 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). 13C 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. Intermediate 1-3 (137 mg, 0.74 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 32 (256 mg, 86% yield). 1 H NMR (400 MHz, DMSO-d6) 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). 13C 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. Intermediate 4-3 (137 mg, 0.74 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 33 (270 mg, 90% yield). 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). 13C 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. Intermediate 2-3 (137 mg, 0.74 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 34 (243 mg, 81% yield). 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). 13C 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. Intermediate 6-3 (138 mg, 0.75 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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. This was purified by silica gel column chromatography to afford 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). 13CNMR (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. Intermediate 7-3 (145 mg, 0.79 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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. This was purified by silica gel column chromatography to afford 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). 13C 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. Intermediate 5-3 (145 mg, 0.72 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 37 (211 mg, 70% yield). 1 H NMR (400 MHz, DMSO-d6) 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). 13C NMR (100 MHz, DMSO-d6) 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. Intermediate 2-3 (125 mg, 0.75 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 38 (242 mg, 81% yield). 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). 13C 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. Intermediate 7-3 (132 mg, 0.72 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 39 (251 mg, 84% yield). 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). 13C 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. Intermediate 5-3 (139 mg, 0.69 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 40 (269 mg, 90% yield). 1 H NMR (400 MHz, DMSO-d6) 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). 13C NMR (100 MHz, DMSO-d6) 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. Intermediate 13-3 (173 mg, 0.86 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 46 (217 mg, 65% yield). 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). 13C 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. Intermediate 14-3 (169 mg, 0.92 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 47 (242 mg, yield: 71%). 1H 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. Intermediate 15-3 (140 mg, 0.76 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 48 (178 mg, yield: 63%). 1H 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. Intermediate 16-3 (206 mg, 0.95 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford 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. Intermediate 17-3 (211 mg, 0.97 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with dichloromethane (30 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford 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. Intermediate 18-3 (158 mg, 0.79 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with dichloromethane (30 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford 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. Intermediate 19-3 (212 mg, 0.97 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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. This was purified by silica gel column chromatography to afford 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. Intermediate 20-3 (236 mg, 0.94 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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. This was purified by silica gel column chromatography to afford 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. Intermediate 21-3 (199 mg, 1.20 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with dichloromethane (30 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford 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. Intermediate 22-3 (193 mg, 0.77 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with dichloromethane (30 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford 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. The mixture was reacted at 120 °C for 45 minutes, and then B-1 (1.69 g, 20.15 mmol) was 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 saturated sodium carbonate aqueous solution. After the solid was precipitated, it was filtered and dried. The filtrate was extracted three times with EA 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 heated to 50°C. o C was slurried for 1 hour, filtered, and dried to obtain intermediate 12-2 (2.36 g, yield: 70%). 1H NMR (400 MHz, DMSO-d6) 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. Intermediate 1-3 (152 mg, 0.82 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound VU6009548 (229 mg, yield: 76%). 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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 reaction was carried out at 120 °C for 45 minutes. B-2 (2.70 g, 30.63 mmol) was then added and the mixture was stirred at 110 °C for 2 h. 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 saturated sodium carbonate aqueous solution. After the solid was precipitated, it was filtered and dried. The filtrate was extracted three times with EA 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 heated to 50°C. 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-d6) 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. Intermediate 6-3 (156 mg, 0.85 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with dichloromethane (30 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 41 (234 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6) 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-d6) 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. Intermediate 1-3 (157 mg, 0.85 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 42 (217 mg, 72% yield). 1 H NMR (400 MHz, DMSO-d6) 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-d6)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. Intermediate 6-3 (156 mg, 0.85 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 43 (207 mg, yield: 69%). 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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. Intermediate 6-3 (132 mg, 0.72 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with dichloromethane (30 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 44 (226 mg, 75% yield). 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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. Intermediate 4-3 (134 mg, 0.80 mmol) was then added and stirring continued for 4 hours. After completion of the reaction, 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 afford a crude product containing the target compound. This was purified by silica gel column chromatography to afford compound 45 (221 mg, 76% yield).

[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 regulatory 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 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 plates, Greiner were 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 plan:

[0561] 1. Experimental Preparation

[0562] 1) Cell Preparation: Aspirate the medium from the 384-well plate; wash the cells with 3 mL of D-PBS (Dulbecco's Phosphate-Buffered Saline), then aspirate. Add 3 mL of trypsin-EDTA (ethylenediaminetetraacetic acid). Incubate at 37°C for 1-2 minutes. Monitor the progress of the enzymatic treatment using an inverted microscope. Gently tap the culture flask to dislodge the cells from the bottom. Add 3 mL of growth medium and thoroughly resuspend the cells with a pipette. Wash any remaining cells at the bottom and centrifuge at 1000 rpm for 5 minutes. Gently discard or aspirate the supernatant, taking care not to remove any cells. Resuspend the cells in 5-10 mL of growth medium and remove 1 mL for cell counting. Count the cells using a ViCell. Resuspend the cells in growth medium at a concentration of 10 x 10^5 cells / mL. Add 20 µL of the cell suspension (20K / well) to each well of the 384-well plate. Incubate the cells overnight at 37°C with 5% CO2.

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

[0564] 2. Experimental process:

[0565] 1) Compound Preparation: Prepare the test compounds (Example compounds and Comparative Example compound VU6009548 in Table 1 below) in DMSO to a 10 mM stock solution. Perform a 3-fold serial dilution of each compound into 10 concentrations in triplicate. Transfer 250 nL of compound to a 384-well compound plate using an ECHO pipetting system. Add 50 μL of assay buffer and shake 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 TM No washing with loading buffer is required. The final volume in the cell culture plate is 40 µL.

[0567] 3) Incubation: Incubate at 37°C, 5% CO2 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 material 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 compounds.

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

[0571] 7) Data processing and analysis: By plotting the signal value against the compound concentration, the compound EC was calculated 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 values ​​of the representative example compounds were 50 The results are summarized in Table 1 below.

[0578] Table 1

[0579]

[0580] Biological Example 2: Determination of the inhibitory effect of the compound of the present invention on MK-801-induced rapid activity behavior in mice

[0581] 1.1 Experimental Animals and Instruments: 17-19 g SPF-grade male ICR mice were purchased from Hunan Slake Jingda Laboratory Animal Co., Ltd.; the mouse open field test chamber and VisuTrack animal behavior analysis software were purchased from Shanghai Xinruan.

[0582] 1.2 Test samples and solvents

[0583] 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% normal saline (solvent).

[0584] Experimental methods:

[0585] Purchased SPF-grade male ICR mice were acclimated to the housing environment for 3 days. Prior to the experiment, the mice were placed in an open-field chamber for 2-3 hours to reduce their anxiety about the new environment. During the experiment, the animals were grouped by weight and randomly divided into a blank group, a model group, and a treatment group, with 10 mice per group. Detailed dosing information is shown in Table 2 below:

[0586] Table 2. Experimental groups and drug administration information

[0587]

[0588] Mice were dosed according to the grouping and dosing information described above. The drug-treated groups received the corresponding compound via intraperitoneal injection at the corresponding dose. The blank and model groups received the same volume of vehicle via intraperitoneal injection. All groups, except the blank group, received an intraperitoneal injection of MK-801 (0.3 mg / kg). The blank group also received an intraperitoneal injection of the same volume of saline. Fifteen minutes after dosing, the mice were immediately placed in an experimental chamber. Their movements (total distance traveled) were automatically recorded for 30 minutes using a camera and analyzed using VisuTrack animal behavior analysis software. Data were analyzed using GraphPad 9.0 after the experiment. All statistical analyses were performed using one-tailed analysis, with a statistical significance level of P ≤ 0.05. All indicators are expressed as mean ± standard error. The maximum possible effect (MPE%) (maximum possible effect percentage) was calculated based on the results.

[0589] MPE%= (Mean(model)-individual data) / (Mean(model)-Mean (sham))×100%.

[0590] Notes: ① Subtract the values ​​from the sham group to eliminate the influence of background noise. 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 from the drug-treated group. The experimental results are shown in Table 3 below:

[0591] Table 3. Inhibitory effects of the compounds of the present invention on MK-801-induced rapid activity in mice

[0592]

[0593] Note: *p<0.05, **p<0.01, ***p<0.001.

[0594] 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 MK-801-induced rapid movement behavior in mice.

[0595] Although the embodiments disclosed in this application are as described above, the contents described are merely embodiments adopted to facilitate understanding of this application and are not intended to limit this application. Any person skilled in the art to which this application belongs may make any modifications and changes in the form and details of the 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 by the attached claims.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: ； in, Structural unit Selected from and ; Structural unit Selected from and ; L 1 for , where the N atom is connected to ring A.

2. 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: 。 3. A method for preparing the compound of 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 structural units in formula (IA), formula (IB) and formula (I) 、 and group L 1 The definition of as claimed in claim 1; The amide condensation agent is a carbodiimide condensation agent, an onium salt condensation agent or an organic phosphorus condensation agent.

4. A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, and at least one pharmaceutical excipient.

5. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 4, in the preparation of a medicament for treating and / or preventing diseases and / or disorders mediated by M4 receptors; wherein the diseases and / or disorders mediated by M4 receptors are Alzheimer's disease, psychosis, cognitive impairment or Parkinson's disease.

6. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 4, in the preparation of a medicament for treating and / or preventing diseases and / or disorders mediated by M4 receptors; wherein the diseases and / or disorders mediated by M4 receptors are schizophrenia.

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