4-carboxyamino isoindoline-1,3-dione compounds, methods of making, pharmaceutical compositions, and uses thereof

Abstract

A 4-carboxyamino isoindoline-1,3-dione compound represented by formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate (e.g. hydrate) thereof, or a clathrate thereof, or a racemate thereof, or an isotopically-labeled material thereof, or a nitroxide thereof; and pharmaceutical compositions and uses thereof. The compound has good anti-multiple myeloma activity, and can effectively treat and / or prevent the growth of multiple myeloma.

Description

Technical Field

[0001] This invention provides a 4-carbonylaminoisoindoline-1,3-dione compound, its preparation method, a pharmaceutical composition containing the compound, and its uses. Background Technology

[0002] Multiple myeloma (MM) is a malignant tumor caused by the abnormal proliferation of plasma cells. It is the second leading cause of hematologic disorders in many countries and remains incurable, with a 5-year relative survival rate of only about 40%. Common symptoms of MM include "CRAB" (calcium elevation), renal insufficiency, anemia, bone disease, and related manifestations such as secondary amyloidosis. Significant progress has been made in the treatment of MM over the past decade. Proteasome inhibitors (PIs), such as bortezomib, and immunomodulatory drugs (IMiDs), such as thalidomide or lenalidomide, are commonly used as first-line treatments. With the application of second-generation PIs (carfilzomib, esazomib), novel immunomodulatory drugs (pomalidomide), histone deacetylase inhibitors (pabistat), monoclonal antibodies (erlotuzumab and daratumumab), and other groups of drugs, patients' long-term survival and quality of life have been significantly improved, making the treatment prospects for MM both complex and encouraging.

[0003] Pomalidomide (trade name POMALYST) is a third-generation IMiD following thalidomide and lenalidomide, with a potency approximately 100 times that of thalidomide and 10 times that of lenalidomide. The mechanism of action of pomalidomide is not fully elucidated. CRBN has been shown to be a direct target of pomalidomide. Upon binding to CRBN, pomalidomide alters the substrate specificity of CRBN, leading to the recruitment of IKZF1 and IKZF3 to the CRBN-coupled E3 protein ligase, where they are ubiquitinated and degraded by the proteasome. Downregulation of IKZF1 / 3 further induces downregulation of IRF4 and MYC, two important proteins for myeloma proliferation and survival. Pomalidomide also has direct anti-proliferative and pro-apoptotic effects on plasma cells and possesses anti-angiogenic, anti-inflammatory, and immunomodulatory effects (increasing T and NK cell activity and inhibiting regulatory T cells). Therefore, pomalidomide exerts its antitumor activity through a pleiotropic mechanism of action. In patients with relapsed / refractory multiple myeloma (RRMM), pomalidomide induced a durable response of 12 months, compared to a median overall survival of 9 months and a progression-free survival (PFS) of only 5 months in this population. In several phase II studies, pomalidomide plus low-dose dexamethasone was effective in patients with advanced disease that was refractory to lenalidomide, bortezomib, or both. Furthermore, pomalidomide's use was further expanded with the approval of Kaposi's sarcoma treatment in 2020.

[0004] Despite the increasing availability of treatment options, almost all MM patients eventually relapse. The most common mechanism associated with IMiD resistance is the lack and mutation of CRBN. Hematologic toxicity, pneumonia, and fatigue are the most common adverse events associated with pomalidomide (Reference: Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target. Blood, (2016).). As MM progresses, the expression level of L-amino acid transome (LAT1) protein increases significantly. Moreover, the LAT1 inhibitor JPH-203 causes death in both IMiD-sensitive and resistant MM cell lines (Reference: The IMiD target CRBN determines HSP90 activity toward transmembrane proteins essential in multiple myeloma. Molecular Cell (2021).), suggesting that LAT1 is worthy of being considered as a therapeutic target for IMiD-resistant / refractory MM patients.

[0005] Furthermore, pomalidomide is a poorly soluble drug. Its solubility in purified water, pH 6.8 phosphate buffer, pH 4.5 acetate buffer, and 0.1 mol / L hydrochloric acid was determined to be 17.8, 17.0, 18.7, and 18.9 μg / mL, respectively. The low solubility of pomalidomide not only increases the difficulty of formulation processing but also limits the dissolution and absorption of the active ingredient in the gastrointestinal tract, thus affecting oral bioavailability. Summary of the Invention

[0006] This invention aims to provide a 4-carbonylaminoisoindoline-1,3-dione compound having the structure shown in formula (I), or an optical isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof (e.g., a hydrate thereof), an inclusion compound thereof, a racemic mixture thereof, an isotope label thereof, or a nitrogen oxide thereof. This invention also relates to methods for preparing the above-described compounds, pharmaceutical combinations thereof, and use in medicaments for treating, preventing, or managing multiple myeloma using such compounds.

[0007]

[0008] in:

[0009] A is selected from -O-, -S-, or -NH-;

[0010] Q is selected from substituted alkylene groups or alkylene arylene groups;

[0011] R1 is selected from -H, alkyl, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NHR4, -C(O)NR4R4';

[0012] R2 is selected from -H, optionally substituted alkyl, alkenyl, alkenylalkylene, ynyl, ynylalkylene, aryl, arylalkylene, heteroaryl, heteroarylalkylene;

[0013] R3 is selected from H, hydroxyl, alkyl, alkenyl, alkenylalkylene, alkynyl, alkynylalkylene, arylalkylene, heteroarylalkylene, alkylene-OC(O)R4, alkylene-OC(O)OR4, alkylene-OC(O)NHR4, alkylene-OC(O)NR4R4', or -OR4;

[0014] Each R4 and R4' may be the same or different, and each is independently selected from hydrogen, alkyl, alkenyl, alkenylalkylene, ynyl, ynylalkylene, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alicyclic, optionally substituted alicyclic, optionally substituted arylalkylene or optionally substituted heteroarylalkylene; or R4 and R4' form an optionally substituted 3-7 membered ring;

[0015] The term "optionally substituted" means substituted by one or more substituents, wherein the substituents of "optionally substituted alkylene", "optionally substituted alicyclic", "optionally substituted aliheterocyclic", "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted arylalkylene", and "optionally substituted heteroarylalkylene" are each independently selected from hydroxyl, amino, carboxyl, halogen, nitro, cyano, alkyl, alkoxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy, heteroaryloxy, cycloalkyl, aliheterocyclic, cycloalkyloxy, heterocycloalkyloxy, arylalkoxy, heteroarylalkoxy, alkanoyloxy, alkanoyloxymethyl, alkanoyloxy, or alkanoyloxy.

[0016] Optionally, the alkyl portion of "alkyl", "alkoxy", "arylalkoxy", "heteroarylalkoxy", "alkanoyloxymethyl", "alkoxyloxy", and "alkanoyloxy" is each independently C10. 1-20 Straight-chain or branched alkyl groups, optionally C10, are used. 1-17 Straight-chain or branched alkyl groups, optionally C10, are used. 1-10 Straight-chain or branched alkyl groups, optionally C10, are used. 1-8 Straight-chain or branched alkyl groups, optionally C10, are used. 1-6 Straight-chain or branched alkyl groups, optionally C10, are used. 1-4 Straight-chain or branched alkyl groups, optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl, dodecyl, pentadecyl, or hexadecyl.

[0017] Optionally, the alkylene moiety in "alkylene", "alkylene arylene", "alkenyl alkylene", "alkynyl alkylene", "aryl alkylene", "heteroaryl alkylene", "alkylene-OC(O)R4", "alkylene-OC(O)OR4", "alkylene-OC(O)NHR4" or "alkylene-OC(O)NR4R4'" is each independently C 1-20 Straight-chain or branched alkylene, optionally C 1-17 Straight-chain or branched alkylene, optionally C 1-10 Straight-chain or branched alkylene, optionally C 1-8 Straight-chain or branched alkylene, optionally C 1-6 Straight-chain or branched alkylene, optionally C 1-3The linear or branched alkylene group may optionally be methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, tert-butylene, sec-butylene, n-pentylene, isopentylene, neopentylene, tert-pentylene, n-hexylene, isohexylene, n-octylene, n-nonylene, n-decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, or hexadecylene.

[0018] Optionally, the cycloalkyl portion in "cycloalkyloxy" and "cycloalkyl" is C 3-8 The cycloalkyl group may optionally be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0019] The alkenyl moiety in "alkenyl" and "alkenyl alkylene" is each independently a C2-C bond containing one or more double bonds. 20 Straight-chain or branched alkenyl groups, optionally C2-C 15 Straight-chain or branched alkenyl groups, optionally C2-C 10 Straight-chain or branched alkenyl groups, optionally C2-C8 straight-chain or branched alkenyl groups, optionally C2-C6 straight-chain or branched alkenyl groups, optionally C2-C4 straight-chain or branched alkenyl groups;

[0020] The alkynyl group in "alkynyl" and "alkynyl alkylene" is each independently a C2-C group containing one or more triple bonds. 20 Straight-chain or branched alkynyl groups, optionally C2-C 15 Straight-chain or branched alkynyl groups, optionally C2-C 10 The alkynyl group is either straight-chain or branched, optionally C2-C8, optionally C2-C6, or optionally C2-C4.

[0021] Alternatively, exemplary alkenyl and alkynyl groups include, but are not limited to, ethylene, propylene, butene, pentene, acetylene, and hexyne.

[0022] Optionally, the heterocyclic group in "aliphatic heterocyclic group" or "heterocyclic alkyloxy group" is a C group containing 1-3 heteroatoms selected from O, N, S, SO or SO2 on the ring. 3-8 (preferably C) 4-6 The alicyclic group may optionally be ethylene oxide, thiocyclic propane, aziroxycyclic propane, oxetane, thiocyclic butane, aziroxycyclic butane, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrroleyl, morpholinyl, piperidinyl, or piperazineyl.

[0023] Optionally, the aryl group in "aryl", "arylalkylene", "arylalkoxy", and "aryloxy" is a 6-10 membered monocyclic or bicyclic fused aromatic ring group; optionally, it is phenyl or naphthyl.

[0024] Optionally, the arylene group in "alkylene arylene" is a 6-10 membered monocyclic or bicyclic fused aromatic ring group; optionally, it is phenylene or naphthylene.

[0025] Optionally, the heteroaryl group in "heteroaryl", "heteroarylalkylene", "heteroaryloxy", and "heteroarylalkoxy" is independently a 5-10 member monocyclic or bicyclic fused heteroaryl ring group containing 1-3 heteroatoms selected from O, N, S, SO, or SO2. Optionally, it is pyrroleyl, pyrazolyl, pyridinyl, furanyl, imidazolyl, thiazolyl, oxazolyl, oxazolyl, oxazolyl, 1H-azazolyl, quinolinyl, isoquinolinyl, indolyl, pyrimidinyl, pyrazinyl, or triazolyl.

[0026] Optionally, R1 is selected from -H, or -(C=O)CH3, -(C=O)OC(CH3)3, -(C=O)OBn.

[0027] Optionally, R2 is selected from -H, methyl, ethyl, tert-butyl, allyl, propyne, or benzyl.

[0028] Optionally, R3 is selected from -H, -OH,

[0029]

[0030] Optionally, the amino acid moiety of the compound of formula (I) is in the D configuration or the L configuration.

[0031] Optionally, the compound of formula (I), or its optical isomer, or its pharmaceutically acceptable salt, or its solvate (e.g., hydrate), or its inclusion complex, or its racemate, or its isotopic label, or its nitride, is selected from the following compounds:

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052] Optionally, the present invention provides a pharmaceutical composition comprising a compound of formula (I) above, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (e.g., a hydrate thereof), or an inclusion compound thereof, or a racemic mixture thereof, or an isotope label thereof, or a nitrogen oxide thereof, and a pharmaceutically acceptable excipient.

[0053] Optionally, the pharmaceutically acceptable excipients are selected from: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, coating materials, or other excipients.

[0054] Optionally, the pharmaceutically acceptable excipients include fillers comprising one or more of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, dicalcium phosphate, calcium sulfate, calcium carbonate, and microcrystalline cellulose; binders comprising one or more of sucrose, starch, povidone, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene glycol, pharmaceutical grade ethanol, and water; and disintegrants comprising one or more of starch, crospovidone, crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and effervescent disintegrants.

[0055] Optionally, the pharmaceutical composition may be administered via: oral (e.g., oral cavity), sublingual, parenteral (e.g., intramuscular, intravenous, or subcutaneous), rectal (e.g., via suppository or lotion), transdermal (e.g., electroporation), or inhalation (e.g., aerosol), and in solid, liquid, or gaseous form, including tablets and suspensions. Administration may be performed as a single unit dose during continuous treatment or as a random single dose. The therapeutic composition may also be in the form of an oil emulsion or dispersant incorporating a lipophilic salt such as dihydroxynaphthyl acid, or as a biodegradable sustained-release composition for subcutaneous or intramuscular administration.

[0056] Optionally, the pharmaceutical composition can be formulated into dosage forms such as solid oral preparations, liquid oral preparations, and injections. The solid and liquid oral preparations include: tablets, dispersible tablets, sugar-coated tablets, granules, dry powders, capsules, syrups, and solutions. The injections include: small injections, large-volume infusions, and lyophilized powder injections.

[0057] In another aspect, the present invention provides the use of a compound of formula (I) above, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (e.g., a hydrate thereof), or an inclusion compound thereof, or a racemic mixture thereof, or an isotope-labeled thereof, or a nitrogen oxide thereof, or the above pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of hematologic disorders; preferably, the diseases are selected from hematologic malignancies and bone marrow cancers, acute leukemia, chronic leukemia, lymphoma, Kaposi's sarcoma, multiple myeloma, or myelodysplastic syndromes. The compounds provided by the present invention can be used to treat, prevent, or manage primary or metastatic tumors.

[0058] In another aspect, the present invention also provides a method for preparing a compound of formula (I) above, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (e.g., a hydrate thereof), or an inclusion compound thereof, or a racemic mixture thereof, or an isotope label thereof, or a nitrogen oxide intermediate thereof:

[0059] This includes obtaining formula (C) by passing compounds of formula (A) and (B) through step A:

[0060] Step A: Obtain formula (C) by substitution reaction of formula (A) and formula (B);

[0061] Optionally, formula (A) and formula (B) are reacted with a base catalyzed solution in a suitable solvent at an appropriate temperature to prepare formula (C) via a substitution reaction. Optionally, the base is potassium carbonate, cesium carbonate, sodium hydride, or lithium bis(trimethylsilylamine), etc.; optionally, the solvent is N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or N-methylpyrrolidone, etc.; optionally, the temperature is 0°C to 25°C.

[0062]

[0063] in,

[0064] In equations (B) and (C), R3 is as described in equation (I), but cannot be H, OR4;

[0065] In formula (B), B is selected from Cl, Br, I, OTs, and OMs;

[0066] Alternatively, the compound of formula (B) may be processed using one of the following methods (but not limited to) 1-8:

[0067] Method 1:

[0068]

[0069] 1) The carboxyl group is reacted with thionyl chloride under reflux to obtain acyl chloride; 2) Acyl chloride and paraformaldehyde are reacted under zinc chloride catalyst to obtain formula (B);

[0070] Or method 2:

[0071]

[0072] At room temperature, a saturated sodium bicarbonate solution and a catalytic amount of tetrabutylammonium bisulfate were added to a vigorously stirred dichloromethane acid solution, followed by the addition of chloromethyl chlorosulfonate. After the reaction was completed, the layers were separated, the organic phase was collected, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and purified by column chromatography to obtain formula (B).

[0073] Method 3:

[0074]

[0075] At 0°C, the corresponding secondary amine was added to a dichloromethane solution of chloromethyl chloroformate. After the reaction was complete, the mixture was filtered, the organic phase was washed with 1N hydrochloric acid, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain formula (B).

[0076] Or method 4:

[0077]

[0078] At 0°C, pyridine was added to a dichloromethane solution of chloromethyl chloroformate, followed by the corresponding alcohol. After the reaction was complete, the mixture was filtered, the organic phase was washed with 1N hydrochloric acid, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain formula (B).

[0079] Or method 5:

[0080] Chloromethyl reagent and sodium bromide (or potassium bromide) are refluxed in acetonitrile (or acetone). After the reaction is complete, the solvent is removed under reduced pressure, an organic solvent and water are added, the layers are separated, the organic phase is collected, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain the corresponding brominated form (B).

[0081] Or method 6:

[0082]

[0083] Chloromethyl reagent and sodium iodide (or potassium iodide) are refluxed in acetonitrile (or acetone). After the reaction is complete, the solvent is removed under reduced pressure, an organic solvent and water are added, the layers are separated, the organic phase is collected, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain the corresponding iodoform (B).

[0084] Method 7:

[0085]

[0086] Chloromethyl reagent and silver methanesulfonate were refluxed in acetonitrile. After the reaction was complete, the solvent was removed under reduced pressure, and an organic solvent and water were added. The mixture was separated into layers, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the corresponding methanesulfonyloxy-substituted formula (B).

[0087] Or method 8:

[0088]

[0089] Chloromethyl reagent and silver p-toluenesulfonate were refluxed in acetonitrile. After the reaction was complete, the solvent was removed under reduced pressure, and an organic solvent and water were added. The mixture was separated into layers, and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the corresponding p-benzenesulfonyloxy-substituted formula (B).

[0090] Each Y is selected from -R4, -OR4, -NHR4, NR4R4', where R4 and R4' are as described in equation (I).

[0091] Alternatively, equation (C) can be obtained through the reaction of step A':

[0092] Step A': S1 and S2 are condensed to obtain S3, then S3 is deprotected to obtain S4, and then S4 and S5 are ammonolycated under Lewis base catalysis to obtain S6, which is then reduced with iron powder to obtain R3, a compound of formula (C) selected from OR4.

[0093]

[0094] This also includes obtaining formula (E) from compounds (C) and (D) via step B:

[0095] Step B: Acylation reaction of formulas (C) and (D) yields formula (E).

[0096] Optionally, formulas (C) and (D) are dissolved in a solvent and reacted under heating conditions to obtain formula (E); optionally, the solvent is tetrahydrofuran, or N,N-dimethylformamide, or N-methylpyrrolidone, or 2-methyltetrahydrofuran; optionally, the temperature is 45℃-90℃.

[0097]

[0098] In equations (C) and (E), R3 is defined as described in equation (I) above;

[0099] Alternatively, it may also include obtaining formula (G) from compounds of formula (C) and (F) via step C:

[0100] Step C: Formula (C) and formula (F) are prepared by acylation reaction to obtain formula (G);

[0101] Optionally, the synthesis method of formula (G) is as follows: formula (C) and formula (F) are reacted in a suitable solvent, and after the reaction is completed, the mixture is concentrated under reduced pressure to obtain formula (G); optionally, the solvent is dichloromethane, acetonitrile, tetrahydrofuran, etc.; optionally, the temperature is -20℃ to 50℃.

[0102]

[0103] In equations (C) and (G), R3 is defined as described in equation (I);

[0104] Alternatively, it may include obtaining formula (J) from compounds of formula (C) and formula (H) via step D:

[0105] Step D: Combine formula (C) and formula (H) through a condensation reaction to obtain formula (J);

[0106] Optionally, formula (C) and formula (H) are dispersed in a suitable solvent and reacted under heating conditions. After the reaction is completed, the mixture is directly evaporated to dryness to obtain formula (J). Optionally, the solvent is dichloromethane, acetonitrile, tetrahydrofuran, or dichloroethane, etc. Optionally, the temperature is 45℃-90℃.

[0107]

[0108] In equations (C) and (J), R3 is defined as described in equation (I);

[0109] This also includes reacting formula (E), formula (G), or formula (J) with formula (L) under base catalysis via nucleophilic substitution and optional deprotection reaction to obtain formula (I), as in the following synthetic step E:

[0110] Step E:

[0111] Optionally, the synthesis method of formula (I) is as follows: formula (E or G or J) is reacted with formula (L) in a suitable solvent, and after the reaction is completed, the mixture is concentrated under reduced pressure to obtain formula (I); optionally, the solvent is selected from dichloromethane, acetonitrile, N,N-dimethylformamide or tetrahydrofuran; optionally, the temperature is -20℃ to 50℃.

[0112]

[0113] in:

[0114] In formula (L), C is selected from any one of the groups -OH, -SH, and -NH2;

[0115] R5 is Cl.

[0116] Optionally, when R1 is Boc and R2 is H, -CH3, -CH2CH3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH(CH3)2, -CH2CH2OH, or -CH2CHOHCH2OH, the following methods can be used for deprotection:

[0117]

[0118] Disperse formula (M) in a suitable solvent, then deprotect it, precipitate a solid, filter it, and obtain formula (N) in the form of a salt; optionally, the solvent is ethyl acetate, or dioxane, or dichloromethane, or dichloroethane, etc.; optionally, the acid used for deprotection is hydrogen chloride, or hydrogen bromide, or sulfuric acid, or trifluoroacetic acid, or nitric acid, or phosphoric acid, or methanesulfonic acid, or p-toluenesulfonic acid, etc.; optionally, the temperature is 0-50℃.

[0119] Optionally, when R1 is Cbz and R2 is H, -CH3, -CH2CH3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH(CH3)2, -CH2CH2OH, or -CH2CHOHCH2OH, the following methods may be used for deprotection.

[0120]

[0121] Formula (O) is dispersed in a suitable solvent and reduced by palladium carbon hydrogen to obtain formula (N) in its free state. The free compound can also be obtained by dispersing the salt form of formula (N) in a suitable solvent (by adding an equivalent amount of base); optionally, the solvent is methanol, ethanol, isopropanol, or dioxane, etc.

[0122] In this invention, the compound of formula (I) or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its inclusion complex, or its racemate, or its isotopic label, or its nitride, or pharmaceutical compositions thereof, may be used in combination with one or more other pharmacologically active compounds (“second active compounds”) for use in medicaments for the prevention and / or treatment of hematologic disorders or conditions.

[0123] The compounds provided by this invention can be used to treat hematologic disorders. Preferably, the disorders are selected from blood cancers and bone marrow cancers, such as multiple myeloma, and acute and chronic leukemias, such as lymphoblastic leukemia, chronic myeloid leukemia, myeloid leukemia, lymphocytic leukemia, myeloid leukemia, adult T-cell leukemia, Kaposi's sarcoma, nuclear acute myeloid leukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell tumor, and low-grade follicular lymphoma. The compounds provided by this invention can be used to treat, prevent, or manage primary, metastatic, refractory, or chemotherapy- and radiotherapy-resistant tumors.

[0124] Multiple myeloma refers to hematological disorders characterized by malignant plasma cells, including the following conditions: monoclonal gammopathy of undetermined significance (MGUS); low-risk, intermediate-risk, and high-risk multiple myeloma; newly diagnosed multiple myeloma (including low-risk, intermediate-risk, and high-risk newly diagnosed multiple myeloma); transplant-suitable and transplant-unsuitable multiple myeloma; stagnant (indolent) multiple myeloma (including low-risk, intermediate-risk, and high-risk stagnant multiple myeloma); relapsed multiple myeloma; refractory and resistant multiple myeloma; active multiple myeloma; solitary plasmacytoma; extramedullary plasmacytoma; plasma cell leukemia; central nervous system multiple myeloma; light chain myeloma; non-secreting myeloma; immunoglobulin D myeloma; immunoglobulin E myeloma. Myeloma; and multiple myeloma characterized by genetic abnormalities such as: cyclin D translocation (e.g., t(11;14)(q13;q32); t(6;14)(q21;q32); t(12;14)(p13;q32) or t(6;20);); MMSET translocation (e.g., t(4;14)(p16;q32)); MAF translocation (e.g., t(14;16)(q32;q32); t(20;22); t(16;22)(q11;q13) or t(14;20)(q32;q11)); or other chromosomal factors (e.g., deletion of 17p13 or chromosome 13; del(17 / 17p), non-hyperdiploidy and increase (1q)).

[0125] As used herein, unless otherwise stated, the term "treatment" refers to the reduction or lessening of the severity of symptoms associated with the treated disease or condition, such as multiple myeloma. The term "prevention" includes suppressing symptoms of a specific disease or condition, such as multiple myeloma. The term "relapse" refers to a recurrence of myeloma cells and / or a decrease in normal cells in a patient who has been in remission after treatment for multiple myeloma. The terms "refractory and resistant" refer to the presence of residual myeloma cells and / or a decrease in normal cells in the bone marrow of a patient, even after intensive treatment.

[0126] The second active ingredient that can be used in the methods and compositions described herein can be a macromolecule (e.g., a protein), a small molecule (e.g., a synthetic inorganic, organometallic, or organic molecule), or a cell therapy (e.g., CAR cells). Specific examples of the second active ingredient include one or more of the following substances: melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, brobitutuzumab, proteasome inhibitors (e.g., bortezomib, carfilzomib, esazozomib, opozomib, or marizomib), histone deacetylase inhibitors (e.g., pabistat, ACY241), and BET inhibitors (e.g., GSK778).

[0127] The compounds of this invention can exist in isotopic tracer or enrichment form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. The isotopes can be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 C1 and 125 I. Compounds containing other isotopes of these and / or other atoms are within the scope of this invention.

[0128] As used herein, the term "optical isomer" refers to substances with identical molecular structures and similar physicochemical properties, but different optical rotations. This includes mixtures of optical isomers in any proportion. Compounds of formula (I) may contain one or more asymmetric carbon atoms, and may exist as optically pure enantiomers, such as mixtures of enantiomers of racemic compounds, optically pure diastereomers, mixtures of diastereomers, racemic compounds of diastereomers, or mixtures of racemic compounds of diastereomers. Optically active forms can be obtained, for example, by resolution of racemic compounds, by asymmetric synthesis, or by asymmetric chromatography (chromatography using chiral adsorbents or eluents). This invention includes all such forms.

[0129] As used herein, the term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids, including both inorganic and organic acid salts. Examples include, but are not limited to, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfonic acid, phosphoric acid, carbonic acid, nitric acid, hydrogen sulfate, methanesulfonic acid, hydroxyethanesulfonic acid, tartaric acid, formic acid, acetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, trifluoroacetic acid, pyruvic acid, cinnamic acid, lauric acid, salicylic acid, citric acid, succinic acid, fumaric acid, benzoic acid, anthranilic acid, 2-(4-hydroxybenzoyl)benzoic acid, and benzene. Sulfonic acid, ethanesulfonic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, phenylacetic acid, ascorbic acid, alginic acid, furoic acid, stearic acid, mucilage, mandelic acid, malic acid, pyric acid, pantothenic acid, camphor sulfonic acid, gluconic acid, glutamic acid, glucuronic acid, galacturonic acid, glycidic acid, lactic acid, malic acid, maleic acid, aspartic acid, thiocyanate, glucohepanoic acid, glycerophosphate, sulfosalicylic acid, hemisulfonic acid, oxalic acid, malonic acid, picric acid, etc.

[0130] As used herein, the term "solvent" refers to a compound of a stoichiometric or non-stoichiometric solvent that is further bound by non-covalent intermolecular forces. For example, when the solvent is water, the solvate is a hydrate.

[0131] Abbreviations

[0132] DCM: Dichloromethane

[0133] DCE: Dichloroethane

[0134] ACN: Acetonitrile

[0135] THF: Tetrahydrofuran

[0136] 2-MeTHF: 2-Methyltetrahydrofuran

[0137] DMSO: Dimethyl sulfoxide

[0138] DMF: N,N-dimethylformamide

[0139] DIPEA: N,N-Diisopropylethylamine

[0140] NMP: N-methylpyrrolidone

[0141] DMAC: N,N-Dimethylacetamide

[0142] LiHMDS: Lithium bis(trimethylsilyl)aminobis(TBS): Tert-butyldimethylsilyl

[0143] LAT1: L-amino acid transfection 1

[0144] RPMI-8226: Human multiple myeloma cells

[0145] NCI-H929: Human myeloma cells Attached Figure Description

[0146] Figure 1 The expression of LAT1 in different cells.

[0147] Figure 2 The trend of tumor volume change in mice in the RPMI-8226 model (n=7).

[0148] Figure 3 The trend of tumor volume change in mice in the NCI-H929 model (n=7). Detailed Implementation

[0149] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Where multiple definitions exist for terms used herein, this section shall prevail unless otherwise stated.

[0150] The embodiments of the present invention are described in detail below, but the provided embodiments do not limit the present invention in any way.

[0151] Example

[0152] General synthesis method 1: Synthesize using steps C and E above.

[0153] 1. Disperse formula (C) (1.0 equivalent) and formula (F) (0.33 equivalent) in acetonitrile, stir at 45°C for 1 h, cool to room temperature, add toluene, stir for 1 h, and filter to obtain a grayish-white solid.

[0154] 2. Disperse the solid obtained in step 1 and formula (L) (1.0 equivalent) (purchased or self-made) in DCM. Add DIPEA (1.1 equivalent) dropwise under low temperature stirring. Stir the reaction until the starting material disappears. Add DCM and wash the mixture sequentially with saturated sodium bisulfate aqueous solution, water, and saturated sodium chloride aqueous solution. Collect the organic phase, dry it with anhydrous sodium sulfate, filter it, evaporate it to dryness under reduced pressure, and purify it by silica gel column chromatography to obtain the product.

[0155] 3. Dissolve the product obtained in step 2 above in DCM and dioxane, then pass hydrogen chloride gas through it or carry out a deprotection reaction at room temperature using methanesulfonic acid, sulfuric acid, phosphoric acid, etc. After the reaction is complete, filter, wash with DCM and dry.

[0156] The synthesis method of formula (L) is as follows: Boc-tyrosine (1.0 equivalent), cesium carbonate (0.5 equivalent), and iodoethane, or 1-iodobutane, or 1-iodohexane, or isopropyl iodine, or TBS-protected hydroxyethyl iodine, or 4-(iodomethyl)-2,2-dimethyl-1,3-dioxocyclopentane (1.1 equivalent) are dispersed in DMF, stirred overnight at room temperature, extracted, and column chromatography is performed to obtain the product of formula (L).

[0157] Example 1: Preparation of Compound 6

[0158]

[0159] The hydrochloride was prepared using general synthesis method 1, yielding a white solid with a yield of 81.63%.

[0160] 1 H NMR (400MHz, DMSO-d6) δ11.18 (s, 1H), 9.68 (s, 1H), 8.69 (s, 3H), 8.18 (d, J=8.3Hz, 1 H), 7.95-7.83 (m, 1H), 7.68 (d, J=7.1Hz, 1H), 7.33 (d, J=8.6Hz, 2H), 7.25 (d, J=8.6Hz , 2H), 5.17 (dd, J=12.8, 5.4Hz, 1H), 4.31 (t, J=6.5Hz, 1H), 3.70 (s, 3H), 3.18 (qd, J= 14.2, 6.5Hz, 2H), 2.97-2.85 (m, 1H), 2.67-2.52 (m, 2H), 2.08 (dd, J=9.1, 3.6Hz, 1H).

[0161] General synthesis method 2: Synthesis using steps B and E.

[0162] Formula (C) (1.0 equivalent) and Formula (D) (1.5 equivalent) were dispersed in tetrahydrofuran and stirred under reflux for 12 h. After evaporation under reduced pressure, Formula (L) and DIPEA (1.1 equivalent) dissolved in DMF were added. After stirring at room temperature for 1 h, the crude product was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The crude product was then evaporated under reduced pressure and purified by silica gel column chromatography.

[0163] Example 2: Preparation of Compound 8

[0164]

[0165] The sample was prepared using general synthesis method 2, yielding a white solid with a yield of 75.75%.

[0166] 1 H NMR (600MHz, DMSO-d6) δ12.90 (s, 1H), 11.13 (s, 1H), 10.06 (s, 1H), 8.31 (d, J=8.0Hz, 1H ), 8.16 (d, J = 8.4Hz, 1H), 7.87-7.83 (m, 1H), 7.66 (d, J = 7.3Hz, 1H), 5.14 (dd, J = 12.9, 5.4 Hz, 1H), 4.43 (dt, J=5.2, 3.2Hz, 1H), 3.44 (dd, J=13.8, 5.0Hz, 1H), 3.15 (dd, J=13.8, 8.4 Hz, 1H), 2.94-2.85 (m, 1H), 2.64-2.51 (m, 2H), 2.09-2.02 (m, 1H), 1.85 (d, J=0.8Hz, 3H).

[0167] Example 3: Preparation of Compound 11

[0168]

[0169] The hydrochloride was prepared using general synthesis method 1, yielding a white solid with a yield of 52.13%.

[0170] 1 H NMR (600MHz, DMSO-d6) δ11.16 (s, 1H), 9.66 (s, 1H), 8.29 (s, 3H), 8.18 (d, J=8.4H z, 1H), 7.93-7.86 (m, 1H), 7.68 (d, J=7.2Hz, 1H), 7.34 (d, J=8.6Hz, 2H), 7.25 (d, J=8.6Hz, 2H), 5.17 (dd, J=12.9, 5.4Hz, 1H), 4.13 (d, J=6.2Hz, 1H), 3.16-3.06 (m , 2H), 2.91 (ddd, J=17.1, 14.0, 5.4Hz, 1H), 2.65-2.52 (m, 2H), 2.11-2.01 (m, 1H).

[0171] Example 4: Preparation of Compound 12

[0172]

[0173] The methanesulfonate was prepared using general synthesis method 1, and was obtained as an off-white solid with a yield of 51.27%.

[0174] 1H NMR (400MHz, DMSO-d6) δ11.17 (s, 1H), 9.67 (s, 1H), 8.41 (s, 3H), 8.18 (d, J=8. 4Hz, 1H), 7.99-7.82 (m, 1H), 7.68 (d, J=7.2Hz, 1H), 7.28 (dd, J=19.7, 8.7Hz, 4H ), 5.17 (dd, J=12.7, 5.4Hz, 1H), 4.36 (t, J=6.6Hz, 1H), 3.71 (s, 3H), 3.22-3.02 (m, 2H), 2.97-2.84 (m, 1H), 2.69-2.52 (m, 2H), 2.31 (s, 3H), 2.13-2.02 (m, 1H).

[0175] Example 5: Preparation of Compound 13

[0176]

[0177] The sulfate was prepared using general synthesis method 1, and was obtained as a white solid with a yield of 54.72%.

[0178] 1 H NMR (400MHz, DMSO-d6) δ11.17 (s, 1H), 9.67 (s, 1H), 8.53 (s, 3H), 8.18 (d, J=8.3 Hz, 1H), 7.95-7.86 (m, 1H), 7.68 (d, J=7.2Hz, 1H), 7.28 (dd, J=19.2, 8.7Hz, 4H), 5.17 (dd, J=12.8, 5.4Hz, 1H), 4.33 (t, J=6.6Hz, 1H), 3.71 (s, 3H), 3.11 (d, J=6.5 Hz, 2H), 2.96-2.86 (m, 1H), 2.66 (d, J=12.1Hz, 2H), 2.08 (dd, J=9.1, 3.7Hz, 1H).

[0179] Example 6: Preparation of Compound 14

[0180]

[0181] The phosphate was prepared using general synthesis method 1, and the phosphate was obtained as a white solid with a yield of 76.58%.

[0182] 1H NMR (400MHz, DMSO-d6) δ11.17 (s, 1H), 9.67 (s, 1H), 8.53 (s, 3H), 8.18 (d, J=8.3 Hz, 1H), 7.95-7.86 (m, 1H), 7.68 (d, J=7.2Hz, 1H), 7.28 (dd, J=19.2, 8.7Hz, 4H), 5.17 (dd, J=12.8, 5.4Hz, 1H), 4.33 (t, J=6.6Hz, 1H), 3.71 (s, 3H), 3.11 (d, J=6.5 Hz, 2H), 2.96-2.86 (m, 1H), 2.66 (d, J=12.1Hz, 2H), 2.08 (dd, J=9.1, 3.7Hz, 1H).

[0183] General Synthesis Method 3:

[0184] The synthesis is carried out using steps A, B, and E.

[0185] Step 1: Preparation of chloromethyl reagent

[0186] (1) At room temperature, saturated sodium bicarbonate and tetrabutylammonium bisulfate (0.1 equivalent) and chloromethyl chlorosulfonate (1.2 equivalent) were added to a DCM solution of benzoic acid, or substituted benzoic acid, or n-decanoic acid, or n-dodecanoic acid, or n-tetradecanoic acid (1.0 equivalent) under vigorous stirring. After the reaction was completed, the layers were separated, the organic phase was collected, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and purified by column chromatography to obtain formula (B).

[0187] (2) Dissolve morpholine, or dimethylamine, or diethylamine (1.0 equivalent), DIPEA and DMAP in DCM, cool to 0°C, slowly add chloromethyl chloroformate (1.1 equivalent) to DCM, react at room temperature for 1.5 h, add DCM, extract with 1N hydrochloric acid and saturated brine, dry with anhydrous sodium sulfate, and distill under reduced pressure to obtain formula (B).

[0188] Step Two:

[0189] Formula (A) (1.0 equivalent), Formula (B) (1.2 equivalent) (purchased or homemade), and cesium carbonate (1.2 equivalent) were added to DMF and stirred at 0°C to 25°C for 3 hours. Ethyl acetate was added, and the organic phase was washed successively with saturated ammonium chloride aqueous solution, water, and saturated sodium chloride aqueous solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The filtrate was purified by silica gel column chromatography to obtain formula (C).

[0190] Formula (C) (1.0 equivalent) and Formula (D) (1.5 equivalent) were dispersed in tetrahydrofuran and stirred under reflux for 12 h. After evaporation under reduced pressure, Formula (L) and DIPEA (1.1 equivalent) dissolved in DMF were added. After stirring at room temperature for 1 h, the crude product was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The crude product was then evaporated under reduced pressure and purified by silica gel column chromatography.

[0191] Step 3:

[0192] The above product was dispersed in ethyl acetate, and then deprotected at room temperature by passing hydrogen chloride gas or methanesulfonic acid, sulfuric acid, phosphoric acid, etc. After the reaction was complete, it was filtered, washed with ethyl acetate and n-heptane, and dried at 50°C.

[0193] Example 7: Preparation of Compound 15

[0194]

[0195] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 52.16%.

[0196] 1 H NMR (600MHz, DMSO-d6) δ9.63 (s, 1H), 8.19 (d, J = 8.3Hz, 1H), 8.01-7.87 (1n, 3H), 7.67 (d d, J=12.9, 7.2Hz, 2H), 7.54 (t, J=7.8Hz, 2H), 7.34 (d, J=8.5Hz, 2H), 7.22 (d, J=8.5Hz, 2 H), 5.94 (dd, J=26.1, 9.6Hz, 2H), 5.40 (dd, J=13.0, 5.4Hz, 1H), 3.97 (s, 1H), 3.19-3.02 (m, 3H), 2.90 (dd, J=13.6, 2.9Hz, 1H), 2.66 (dd, J=13.3, 4.4Hz, 1H), 2.23-2.10 (m, 1H).

[0197] Example 8: Preparation of Compound 16

[0198]

[0199] The hydrochloride was prepared using general synthesis method 1, yielding an off-white solid with a yield of 97.53%.

[0200] 1H NMR (600MHz, DMSO-d6) δ 11.16 (s, 1H), 10.09 (s, 1H), 9.10 (s, 1H), 8.62 (d, J = 8.6Hz, 1H), 7.79 (t, J = 7.9Hz, 1H), 7.50 (d, J = 7.2Hz, 1H), 7.45 ( d, J=8.4Hz, 2H), 7.21 (d, J=8.4Hz, 2H), 5.15 (dd, J=12.8, 5.4Hz, 1H), 3.98 (s, 1H), 3.11-2.87 (m, 3H), 2.66-2.52 (m, 2H), 2.13-2.05 (m, 1H).

[0201] Example 9: Preparation of Compound 17

[0202]

[0203] The hydrochloride was prepared using general synthesis method 3, yielding a yellow solid with a yield of 78.94%.

[0204] 1 H NMR (600MHz, DMSO-d6) δ9.65 (s, 1H), 8.59 (s, 3H), 8.19 (d, J=8.4Hz, 1H), 8.00-7.92 (m, 2H), 7.92-7.8 7 (m, 1H), 7.67 (dd, J=16.5, 7.4Hz, 2H), 7.54 (t, J=7.8Hz, 2H), 7.32 (d, J=8.5Hz, 2H), 7.24 (d, J=8.5Hz , 2H), 5.96 (d, J=9.6Hz, 1H), 5.92 (d, J=9.6Hz, 1H), 5.40 (dd, J=13.0, 5.4Hz, 1H), 4.30 (t, J=6.6Hz, 1H ), 3.70 (s, 3H), 3.25-3.03 (m, 3H), 2.90 (dd, J=13.6, 3.0Hz, 1H), 2.67-2.55 (m, 1H), 2.23-2.09 (m, 1H).

[0205] Example 10: Preparation of Compound 19

[0206]

[0207] The hydrochloride was prepared using general synthesis method 1, yielding a pale yellow solid with a yield of 68.59%.

[0208] 1H NMR (600MHz, DMSO-d6) δ11.15 (s, 1H), 9.10 (s, 1H), 8.72 (s, 3H), 8.35 (d, J=8.4Hz, 1H), 7.88 (dd, J=8.4, 7.4Hz, 1H), 7.63 (d, J=7. 3Hz, 1H), 5.15 (dd, J=12.9, 5.4Hz, 1H), 4.64-4.50 (m, 3H), 3.80 (s, 3H), 2.94-2.86 (m, 1H), 2.64-2.51 (m, 2H), 2.11-2.02 (m, 1H).

[0209] Example 11: Preparation of Compound 20

[0210]

[0211] The hydrochloride was prepared using general synthesis method 1, yielding a white solid with a yield of 58.71%.

[0212] 1 H NMR (600MHz, DMSO-d6) δ11.16 (s, 1H), 9.07 (s, 1H), 8.88 (s, 3H), 8.37 (dd, J=8 .5, 3.9Hz, 1H), 7.90-7.81 (m, 1H), 7.62 (dd, J=7.3, 1.5Hz, 1H), 5.34-5.24 (m, 1H), 5.15 (ddd, J=12.9, 5.3, 3.5Hz, 1H), 4.42 (t, J=3.5Hz, 1H), 3.77 (s, 3H), 2 .96-2.84(m, 1H), 2.65-2.51(m, 2H), 2.13-2.04(m, 1H), 1.45(d, J=6.7Hz, 3H).

[0213] Example 12: Preparation of Compound 21

[0214]

[0215] The hydrochloride was prepared using general synthesis method 1, and was obtained as a white solid with a yield of 68.56%.

[0216] 1H NMR (600MHz, DMSO-d6) δ11.16 (s, 1H), 9.03 (s, 1H), 8.58 (s, 2H), 8.42-8.3 7(m, 1H), 8.04-7.80(m, 1H), 7.61(dd, J=7.3, 1.1Hz, 1H), 5.38-5.27(m, 1H ), 5.16-5.11(m, 1H), 4.22(s, 1H), 2.94-2.85(m, 1H), 2.61(d, J=17.0Hz, 1 H), 2.53-2.46 (m, 1H), 2.08 (dd, J=11.2, 6.0Hz, 1H), 1.44 (d, J=6.6Hz, 3H).

[0217] Example 13: Preparation of Compound 22

[0218]

[0219] The hydrochloride was prepared using general synthesis method 1, yielding a pale yellow solid with a yield of 97.71%.

[0220] 1 H NMR (600MHz, DMSO-d6) δ11.14 (s, 1H), 8.12 (d, J=8.4Hz, 1H), 7.87 (dd, J=8.2, 7.4Hz, 1H), 7.70 (d, J=7.3Hz, 1H), 5.14 (dd, J=1 2.9, 5.4Hz, 1H), 4.15 (s, 1H), 3.53-3.49 (m, 1H), 3.42-3.37 (m, 1H), 2.94-2.85 (m, 1H), 2.64-2.53 (m, 2H), 2.09-2.01 (m, 1H).

[0221] Example 14: Preparation of Compound 23

[0222]

[0223]

[0224] The hydrochloride was prepared using general synthesis method 1, yielding a yellow solid with a yield of 86.59%.

[0225] 1H NMR (600MHz, DMSO-d6) δ11.15 (s, 1H), 9.07 (s, 1H), 8.56 (s, 2H), 8.37 (dd, J=8.5, 3.3Hz, 1H), 7.88 (dd, J=8.3, 7.5Hz, 1H), 7.62 (d, J=7.3Hz, 1H), 5 .14(dd, J=12.9, 5.4Hz, 1H), 4.64-4.48(m, 2H), 4.38(s, 1H), 2.93-2.86( m, 1H), 2.64-2.59 (m, 1H), 2.52-2.51 (m, 1H), 2.08 (dd, J=7.2, 5.3Hz, 1H).

[0226] Example 15: Preparation of Compound 24

[0227]

[0228] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 33.83%.

[0229] 1 H NMR (600MHz, DMSO-d6) δ9.09 (s, 1H), 8.81 (s, 3H), 8.36 (d, J = 8.5Hz, 1H), 7.93 (d, J = 7.2Hz, 2H) , 7.91-7.86 (m, 1H), 7.70 (t, J=7.4Hz, 1H), 7.64 (d, J=7.3Hz, 1H), 7.55 (t, J=7.5Hz, 2H), 6.00- 5.83 (m, 2H), 5.39 (ddd, J=13.1, 5.3, 1.6Hz, 1H), 4.64-4.52 (m, 3H), 3.79 (d, J=4.3Hz, 3H), 3.1 9-3.01 (m, 1H), 2.90 (dd, J=14.2, 3.4Hz, 1H), 2.70-2.57 (m, 1H), 2.16 (dd, J=13.2, 7.7Hz, 1H).

[0230] Example 16: Preparation of Compound 25

[0231]

[0232] The hydrochloride was prepared using general synthesis method 1, yielding a white solid with a yield of 52.74%.

[0233] 1H NMR (400MHz, DMSO-d6) δ11.16 (s, 1H), 8.77 (s, 3H), 8.09 (d, J=8.3Hz, 1H), 7.94-7.77 (m, 1H), 7.71 (d, J=7.3Hz, 1H), 5.15 (dd, J=12.8, 5. 4Hz, 1H), 4.34 (t, J=5.6Hz, 1H), 3.75 (s, 3H), 3.49 (t, J=5.2Hz, 2H), 2.98-2.81 (m, 1H), 2.63 (dt, J=27.1, 5.4Hz, 2H), 2.10-2.00 (m, 1H).

[0234] Example 17: Preparation of Compound 26

[0235]

[0236] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 76.72%.

[0237] 1 H NMR (400MHz, DMSO-d6) δ9.05 (s, 1H), 8.69 (s, 3H), 8.38 (dd, J=8.4, 2.2Hz, 1H), 7.96-7.91 (m, 2 H), 7.91-7.85 (m, 1H), 7.72-7.66 (m, 1H), 7.64 (d, J=6.9Hz, 1H), 7.56 (t, J=7.7Hz, 2H), 5.98-5. 88(m, 2H), 5.42-5.24(m, 2H), 4.43(t, J=3.5Hz, 1H), 3.77(d, J=2.0Hz, 3H), 3.17-3.04(m, 1H), 2.90 (d, J=17.5Hz, 1H), 2.62 (dd, J=13.3, 4.3Hz, 1H), 2.25-2.10 (m, 1H), 1.43 (d, J=6.6Hz, 3H).

[0238] Example 18: Preparation of Compound 28

[0239]

[0240]

[0241] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 70.65%.

[0242] 1H NMR (600MHz, DMSO-d6) δ9.03 (s, 1H), 8.41 (d, J=8.5Hz, 1H), 7.98-7.91 (m, 2H), 7.91-7 .84 (m, 1H), 7.73-7.67 (m, 1H), 7.62 (dd, J=7.2, 2.0Hz, 1H), 7.56 (t, J=7.8Hz, 2H), 6.03 -5.75(m, 2H), 5.57-5.34(m, 1H), 5.36-5.28(m, 1H), 4.17(d, J=3.4Hz, 1H), 3.15-3.04( m, 1H), 2.97-2.85 (m, 1H), 2.73-2.56 (m, 1H), 2.21-2.12 (m, 1H), 1.45 (d, J=6.6Hz, 3H).

[0243] Example 19: Preparation of Compound 29

[0244]

[0245] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 64.56%.

[0246] 1 H NMR (600MHz, DMSO-d6) δ8.14 (d, J=8.3Hz, 1H), 7.97-7.91 (m, 2H), 7.90-7.86 (m, 1H), 7.73- 7.65 (m, 2H), 7.56 (t, J=7.7Hz, 2H), 5.96-5.86 (m, 2H), 5.39 (ddd, J=13.0, 5.4, 1.3Hz, 1H), 4.09 (t, J=5.3Hz, 1H), 3.56-3.46 (m, 1H), 3.41 (ddd, J=14.5, 6.3, 2.9Hz, 1H), 3.11 (ddd, J= 17.6, 14.0, 5.4Hz, 1H), 2.95-2.85 (m, 1H), 2.63 (qd, J=13.3, 4.4Hz, 1H), 2.20-2.12 (m, 1H).

[0247] Example 20: Preparation of Compound 30

[0248]

[0249] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 56.64%.

[0250] 1H NMR (600MHz, DMSO-d6) δ9.06 (s, 1H), 8.62 (s, 2H), 8.38 (dd, J=8.4, 3.2Hz, 1H), 7.93 (d, J=8.1Hz , 2H), 7.91-7.86 (m, 1H), 7.70 (t, J=7.4Hz, 1H), 7.63 (d, J=7.3Hz, 1H), 7.55 (t, J=7.2Hz, 2H), 6. 01-5.77 (m, 2H), 5.39 (ddd, J=13.1, 5.2, 2.8Hz, 1H), 4.62 (dt, J=11.5, 3.6Hz, 1H), 4.56-4.46 (m , 1H), 4.29(s, 1H), 3.15-3.02(m, lH), 2.95-2.82(m, lH), 2.69-2.57(m, 1H), 2.20-2.12(m, 1H).

[0251] Example 21: Preparation of compound 31

[0252]

[0253] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 64.32%. 1 H NMR (600MHz, DMSO-d6) δ9.65 (s, 1H), 8.61 (s, 3H), 8.20 (d, J=8.4Hz, 1H), 7.93-7.88 (m, 1H), 7.69 (d, J=7.3Hz, 1H), 7.32 (d, J=8.5Hz, 2H), 7.25 (d, J=8.5Hz, 2H), 5.68 (dd, J=27.8, 9.4Hz , 2H), 5.36 (dd, J=13.1, 5.4Hz, 1H), 4.78 (m, 1H), 4.32 (s, 1H), 3.70 (s, 3H), 3.22-3.03 (m, 3H ), 2.86 (dd, J=13.7, 2.8Hz, 1H), 2.62 (m, 1H), 2.17-2.11 (m, 1H), 1.22 (dd, J=6.2, 1.6Hz, 6H).

[0254] Example 22: Preparation of compound 32

[0255]

[0256] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 57.84%.

[0257] 1H NMR (400MHz, DMSO-d6) δ10.36 (s, 1H), 8.57 (s, 3H), 8.10 (d, J=8.2Hz, 1H), 7.92-7.86 (m, 1H), 7 .72 (d, J=7.4Hz, 1H), 5.67 (dd, J=21.2, 9.4Hz, 2H), 5.34 (dd, J=13.1, 5.3Hz, 1H), 4.78 (dt, J=12 .5, 6.2Hz, 1H), 4.38 (t, J=5.4Hz, 1H), 3.76 (s, 3H), 3.47 (m, 2H), 3.05 (dd, J=13.9, 5.0Hz, 1H), 2.85 (d, J=16.7Hz, 1H), 2.59 (dd, J=13.3, 4.1Hz, 1H), 2.15-2.08 (m, 1H), 1.22 (d, J=6.2Hz, 6H).

[0258] Example 23: Preparation of compound 33

[0259]

[0260] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 65.41%.

[0261] 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 8.50 (s, 3H), 8.39 (dd, J=8.5, 3.1Hz, 1H), 7 .93-7.86 (m, 1H), 7.63 (d, J=7.3Hz, 1H), 5.66 (m, 2H), 5.35 (dd, J=13.1, 4.1Hz, 1H ), 4.82-4.72(m, 1H), 4.63-4.45(m, 2H), 4.30(s, 1H), 3.11-3.01(m, 1H), 2.85(d, J=16.5Hz, 1H), 2.57 (d, J=14.1Hz, 1H), 2.17-2.10 (m, 1H), 1.23 (d, J=6.2Hz, 6H).

[0262] Example 24: Preparation of compound 34

[0263]

[0264] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 57.26%.

[0265] 1H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.84 (s, 3H), 8.37 (d, J=8.5Hz, 1H), 7.93-7.86 (m, 1 H), 7.64 (d, J=7.3Hz, 1H), 5.70 (d, J=9.4Hz, 1H), 5.64 (dd, J=9.4, 1.7Hz, 1H), 5.36 (dd, J= 13.0, 5.2Hz, 1H), 4.83-4.73(m, 1H), 4.64-4.53(m, 3H), 3.80(s, 3H), 3.13-3.02(m, 1H), 2 .89-2.81 (m, 1H), 2.57 (dd, J=13.5, 3.4Hz, 1H), 2.19-2.09 (m, 1H), 1.23 (d, J=6.2Hz, 6H).

[0266] Example 25: Preparation of compound 35

[0267]

[0268]

[0269] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 61.46%.

[0270] 1 H NMR (400MHz, DMSO-d6) δ9.64 (s, 1H), 8.19 (d, J = 8.3Hz, 1H), 7.95-7.85 (m, 1H), 7.69 ( d, J=7.2Hz, 1H), 7.25 (dd, J=28.6, 8.6Hz, 4H), 5.66 (dd, J=29.7, 9.4Hz, 2H), 5.34 (dd , J=13.0, 5.4Hz, 1H), 4.01 (t, J=6.4Hz, 1H), 3.66 (s, 3H), 3.54 (s, 4H), 3.31 (s, 4H), 3 .12-2.96 (m, 3H), 2.89-2.80 (m, 1H), 2.56 (dd, J=13.5, 4.5Hz, 1H), 2.19-2.09 (m, 1H).

[0271] Example 26: Preparation of compound 36

[0272]

[0273] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 63.58%.

[0274] 1H NMR (400MHz, DMSO-d6) δ10.37 (s, 1H), 8.50 (s, 3H), 8.13 (d, J=8.2Hz, 1H), 7.92-7.85 (m, 1H ), 7.72 (d, J=7.3Hz, 1H), 5.67 (dd, J=20.8, 9.4Hz, 2H), 5.35 (dd, J=13.1, 5.3Hz, 1H), 4.77 (d t, J=12.4, 6.2Hz, 1H), 4.24 (s, 1H), 3.54 (s, 4H), 3.47-3.38 (m, 4H), 3.13-3.02 (m, 1H), 2.8 5 (d, J=16.6Hz, 1H), 2.59 (dd, J=13.2, 4.3Hz, 1H), 2.16-2.08 (m, 1H), 1.22 (d, J=6.2Hz, 6H).

[0275] Example 27: Preparation of Compound 37

[0276]

[0277] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 59.27%.

[0278] 1 H NMR (400MHz, DMSO-d6) δ10.37 (s, 1H), 8.70 (s, 2H), 8.13-8.07 (m, 1H), 7.91-7.85 (m, 1H), 7.7 2(d, J=7.3Hz, 1H), 5.65 (dd, J=23.9, 9.4Hz, 2H), 5.32 (dd, J=13.0, 5.4Hz, 1H), 4.36 (t, J=5.6H z, 1H), 4.03 (q, J=7.1Hz, 1H), 3.75 (s, 3H), 3.54 (s, 4H), 3.48 (t, J=6.0Hz, 2H), 3.35-3.29 (m, 4 H), 3.06 (m, 1H), 2.84 (dd, J=13.8, 2.9Hz, 1H), 2.58-2.53 (m, 1H), 2.12 (dd, J=9.1, 3.8Hz, 1H).

[0279] Example 28: Preparation of compound 38

[0280]

[0281] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 69.36%.

[0282] 1H NMR (400MHz, DMSO-d6) δ8.33 (d, J=8.3Hz, 1H), 8.02-7.79 (m, 1H), 7.63 (d, J=7.1Hz, 1H), 5.65 (q, J=8.2, 6.7Hz, 2H), 5.32 (d, J=9.7Hz, 1H), 4.42 ( d, J=58.4Hz, 2H), 3.76 (s, 2H), 3.54 (s, 3H), 3.05 (s, 1H), 2.84 (d, J=16. 4Hz, 1H), 2.68 (m, 4H), 2.57 (m, 4H), 2.12 (s, 1H), 1.25 (d, J=14.4Hz, 2H).

[0283] Example 29: Preparation of compound 39

[0284]

[0285] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 62.36%.

[0286] 1 H NMR (400MHz, DMSO-d6) δ9.66 (s, 1H), 8.33 (s, 3H), 8.19 (d, J=8.4Hz, 1H), 7.93-7.8 7 (m, 1H), 7.69 (d, J=7.2Hz, 1H), 7.29 (dd, J=43.4, 8.6Hz, 4H), 5.66 (dd, J=29.8, 9. 4Hz, 2H), 5.34 (dd, J=13.0, 5.4Hz, 1H), 4.15 (t, J=6.3Hz, 1H), 3.54 (s, 4H), 3.31 (s , 4H), 3.18-3.01(m, 3H), 2.88-2.80(m, 1H), 2.60-2.55(m, 1H), 2.19-2.08(m, 1H).

[0287] Example 30: Preparation of Compound 40

[0288]

[0289] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 64.15%.

[0290] 1H NMR (400MHz, DMSO-d6) δ10.36 (s, 1H), 8.45 (s, 3H), 8.12 (d, J=8.4Hz, 1H), 7.93-7.85 (m, 1H), 7.72 (d, J=7.3Hz, 1H), 5.65 (m, 2H), 5.32 (dd .

[0291] Example 31: Preparation of compound 41

[0292]

[0293] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 58.26%.

[0294] 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 8.39 (d, J=8.5Hz, 1H), 7.93-7.86 (m, 1H), 7.63 (d, J=7.2Hz, 1H), 5.65 (dd, J=17.2, 9.9Hz, 2H), 5.32 (dd, J= 12.5, 4.7Hz, 1H), 4.65-4.45 (m, 2H), 4.25 (s, 1H), 3.81 (d, J=6.6Hz, 1H) , 3.54(s, 4H), 3.31-3.24(m, 4H), 3.04(m, 1H), 2.82(m, 1H), 2.15(m, 1H).

[0295] Example 32: Preparation of compound 42

[0296]

[0297] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 62.52%.

[0298] 1H NMR (400MHz, DMSO-d6) δ9.68 (s, 1H), 8.45 (s, 3H), 8.19 (d, J=8.4Hz, 1H), 7.94-7.88 (m, 1H), 7.69 (d, J=7.2Hz, 1H), 7.36 (d, J=8.6Hz, 2H), 7.25 (d, J=8.6Hz, 2H), 5.68 (dd, J=19.9, 9.4Hz, 2H), 5.37 (dd, J= 13.1, 5.3Hz, 1H), 4.78 (m, 1H), 4.17 (t, J=6.2Hz, 1H), 3.16 (d, J=6.1Hz, 2H), 3.13-3.00 (m, 1H), 2.86 ( dd, J=13.7, 2.8Hz, 1H), 2.61 (dd, J=13.3, 4.5Hz, 1H), 2.19-2.10 (m, 1H), 1.22 (dd, J=6.2, 0.9Hz.6H).

[0299] Example 33: Preparation of compound 43

[0300]

[0301] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 67.25%.

[0302] 1 H NMR (400MHz, DMSO-d6) δ9.66 (s, 1H), 8.52 (s, 3H), 8.18 (d, J=8.4Hz, 1H), 7.96-7 .87 (m, 1H), 7.69 (d, J=7.1Hz, 1H), 7.28 (dd, J=25.5, 8.6Hz, 4H), 5.70-5.62 (m, 2H ), 5.36 (dd, J=13.0, 5.4Hz, 1H), 4.34 (t, J=6.6Hz, 1H), 3.71 (s, 3H), 3.20-3.05 ( m, 3H), 2.90-2.82 (m, 1H), 2.59 (d, J=4.3Hz, 1H), 2.18-2.10 (m, 1H), 1.11 (s, 9H).

[0303] Example 34: Preparation of compound 44

[0304]

[0305] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 58.25%.

[0306] 1H NMR (400MHz, DMSO-d6) δ10.36 (s, 1H), 8.70 (s, 3H), 8.10 (d, J=8.3Hz, 1H), 7.88 (t, J=7.8Hz, 1H), 7.72 (d, J=7.3Hz, 1H), 5.65 (d, J=10.0Hz, 2H), 5.34 (dd, J=13.0, 5.3H z, 1H), 4.36 (t, J=5.4Hz, 1H), 3.76 (d, J=9.0Hz, 3H), 3.54-3.41 (m, 2H), 3.15-3.03 (m, 1H), 2.85 (d, J=16.7Hz, 1H), 2.61-2.55 (m, 1H), 2.17-2.07 (m, 1H), 1.11 (s, 9H).

[0307] Example 35: Preparation of compound 45

[0308]

[0309] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 49.25%.

[0310] 1 H NMR (400MHz, DMSO-d6) δ10.37 (s, 1H), 8.66 (s, 3H), 8.10 (d, J = 8.3Hz, 1H), 7.88 (t, J = 7.8Hz, 1H), 7.72 (d, J = 7.3Hz, 1H), 5.66 (s, 2H), 5.34 (dd, J = 12 .9, 5.3Hz, 1H), 4.38 (d, J=5.3Hz, 1H), 3.75 (s, 3H), 3.53-3.41 (m, 2H), 3. 14-3.03 (m, 1H), 2.85 (m, 1H), 2.59 (m1H), 2.17-2.07 (m, 1H), 1.11 (s, 9H).

[0311] Example 36: Preparation of Compound 46

[0312]

[0313] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 52.25%.

[0314] 1H NMR (400MHz, DMSO-d6) δ9.66 (s, 1H), 8.30 (s, 3H), 8.18 (d, J=8.3Hz, 1H), 7.93- 7.85 (m, 1H), 7.69 (d, J=7.1Hz, 1H), 7.29 (dd, J=40.7, 8.6Hz, 4H), 5.71-5.63 (m , 2H), 5.36 (dd, J=13.0, 5.4Hz, 1H), 4.14 (s, 1H), 3.20-3.03 (m, 3H), 2.87 (dd, J =12.2, 8.9Hz, 1H), 2.64-2.54 (m, 1H), 2.19-2.08 (m, 1H), 1.11 (d, J = 5.9Hz, 9H).

[0315] Example 37: Preparation of Compound 47

[0316]

[0317] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 52.62%.

[0318] 1 H NMR (400MHz, DMSO-d6) δ8.13 (d, J=8.4Hz, 1H), 7.91-7.84 (m, 1H), 7.71 (d, J=7.3Hz, 1H), 5.66 (s, 2H), 5.36-5.30 (m, 1H), 4.19 (s , 1H), 3.45 (dd, J=29.2, 5.5Hz, 2H), 3.14-3.02 (m, 1H), 2.90-2.8l (m, 1H), 2.62-2.55 (m, 1H), 2.13 (d, J=6.8Hz, 1H), 1.11 (s, 9H).

[0319] Example 38: Preparation of compound 48

[0320]

[0321] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 59.25%.

[0322] 1H NMR (400MHz, DMSO-d6) δ8.40 (d, J=8.5Hz, 1H), 7.88 (t, J=8.0Hz, 1H), 7.62 (d, J=7.2Hz, 1H), 5.65 (s, 2H), 5.34 (d, J=12.9Hz, 2H), 4. 58 (d, J=11.4Hz, 2H), 4.40 (s, 2H), 3.97 (s, 2H), 3.09 (t, J=14.5Hz, 2H), 2.85 (d, J=17.4Hz, 2H), 2.14 (s, 1H), 1.17 (d, J=50.1Hz, 9H).

[0323] Example 39: Preparation of compound 49

[0324]

[0325] The sample was prepared using general synthesis method 2 without deprotection to obtain a yellow solid with a yield of 48.15%.

[0326] 1 H NMR (400MHz, DMSO-d6) δ12.89 (s, 1H), 11.17 (s, 1H), 10.10 (s, 1H), 8.17 (d, J=8.3Hz, 1H), 7.86 (t, J=7 .9Hz, 1H), 7.67 (d, J=7.3Hz, 1H), 7.28 (d, J=8.4Hz, 1H), 5.15 (dd, J=12.8, 5.4Hz, 1H), 4.12 (dd, J=8.9, 4.6Hz, 1H), 4.08 (d, J=4.8Hz, 1H), 3.46 (dd, J=13.7, 4.5Hz, 1H), 3.09 (dd, J=13.2, 10.1Hz, 1H), 2.90 (d dd, J=16.8, 13.9, 5.3Hz, 1H), 2.58 (dd, J=25.0, 11.9Hz, 2H), 2.07 (dd, J=9.2, 3.7Hz, 1H), 1.38 (s, 9H).

[0327] Example 40: Preparation of Compound 50

[0328]

[0329] It was prepared by general synthesis method 2 without deprotection, yielding a yellow solid with a yield of 52.57%.

[0330] 1H NMR (400MHz, DMSO-d6) δ11.16 (s, 1H), 10.14 (s, 1H), 8.14 (d, J=8.2Hz, 1H), 7.90 -7.81 (m, 1H), 7.67 (d, J=7.0Hz, 1H), 7.44 (d, J=8.2Hz, 1H), 5.14 (dd, J=12.8, 5. 5Hz, 1H), 4.24-4.14 (m, 1H), 3.66 (s, 3H), 3.43 (dd, J=13.9, 4.8Hz, 2H), 3.14-3. 06(m, 1H), 2.95-2.85(m, 1H), 2.60(m, 1H), 2.11-2.02(m, 1H), 1.43-1.29(s, 9H).

[0331] Example 41: Preparation of Compound 51

[0332]

[0333] The sample was prepared using general synthesis method 2 without deprotection to obtain a yellow solid, with a yield of 45.14%.

[0334] 1 H NMR (400MHz, DMSO-d6) δ11.17 (s, 1H), 9.64 (s, 1H), 8.19 (d, J=8.3Hz, 1H), 7.9 3-7.86 (m, 1H), 7.67 (d, J = 6.8Hz, 1H), 7.30 (d, J = 8.5Hz, 2H), 7.18 (d, J = 8.5Hz , 2H), 5.17 (dd, J=12.8, 5.4Hz, 1H), 4.19 (td, J=8.5, 5.1Hz, 1H), 3.62 (s, 3H), 3.02(m, 1H), 2.91-2.84(m, 1H), 2.65-2.51(m, 3H), 2.08(m, 1H), 1.30(s, 9H).

[0335] Example 42: Preparation of compound 52

[0336]

[0337] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 62.63%.

[0338] 1H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 8.44 (s, 3H), 8.40-8.36 (m, 1H), 7.93-7.85 (m, 1H) , 7.64 (d, J = 7.3Hz, 1H), 7.62-7.53 (m, 2H), 7.16 (d, J = 8.3Hz, 1H), 7.02 (t, J = 7.6Hz, 1H) , 5.89-5.79 (m, 2H), 5.38 (m, 1H), 4.63-4.46 (m, 2H), 4.34 (s, 1H), 3.81 (d, J=1.1Hz, 3H) , 3.13-3.05 (m, 1H), 2.93-2.85 (m, 1H), 2.61 (dd, J=13.1, 4.1Hz, lH), 2.20-2.11 (m, lH).

[0339] Example 43: Preparation of compound 53

[0340]

[0341] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 35.36%.

[0342] 1 H NMR (400MHz, DMSO-d6) δ8.43 (s, 3H), 8.13 (d, J = 8.3Hz, 1H), 7.93-7.84 (m, 1H), 7.72 (d, J = 7.3 Hz, 1H), 7.63-7.54 (m, 2H), 7.16 (d, J=8.4Hz, 1H), 7.03 (t, J=7.5Hz, 1H), 5.84 (q, J=9.7Hz, 2H) , 5.37 (dd, J=12.7, 5.3Hz, 1H), 4.21 (t, J=5.3Hz, 1H), 3.82 (s, 3H), 3.55-3.41 (m, 2H), 3.10 (dd , J=21.7, 9.4Hz, 1H), 2.88 (d, J=17.5Hz, 1H), 2.62 (dd, J=13.1, 4.3Hz, 2H), 2.16-2.09 (m, 1H).

[0343] Example 44: Preparation of Compound 54

[0344]

[0345] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 52.37%.

[0346] 1H NMR (400MHz, DMSO-d6) δ13.92 (s, 1H), 9.68 (s, 1H), 8.40 (s, 3H), 8.19 (d, J=8.3Hz, 1H), 7.95-7.86 (m, 1H), 7.7 0 (d, J=7.3Hz, 1H), 7.61 (dd, J=7.7, 1.7Hz, 1H), 7.58-7.50 (m, 1H), 7.34 (d, J=8.6Hz, 2H), 7.25 (d, J=8.6Hz, 2H ), 7.15 (d, J=8.4Hz, 1H), 7.02 (t, J=7.5Hz, 1H), 5.85 (dd, J=16.6, 9.6Hz, 2H), 5.39 (dd, J=13.0, 5.4Hz, 1H), 4. 21 (s, 1H), 3.82 (s, 3H), 3.20-3.06 (m, 3H), 2.89 (dd, J=10.5, 6.0Hz, 1H), 2.72-2.57 (m, 1H), 2.22-2.11 (m, 1H).

[0347] Example 45: Preparation of compound 55

[0348]

[0349] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 61.25%.

[0350] 1 H NMR (400MHz, DMSO-d6) δ9.67 (s, 1H), 8.51 (s, 3H), 8.19 (d, J=8.4Hz, 1H), 7.93-7.86 (m, 1H), 7.70 (d, J=7.3Hz, 1H), 7.62-7.52 (m, 2H), 7.28 (dd, J=22.7, 8.7Hz, 3H), 7.15 (d, J=8.4Hz, 1H), 7.01 (dd , J=11.2, 3.8Hz, 2H), 5.90-5.82 (m, 2H), 5.39 (dd, J=13.0, 5.4Hz, 1H), 4.35 (s, 1H), 3.81 (d, J=1.3 Hz, 3H), 3.71 (s, 2H), 3.20-3.04 (m, 3H), 2.93-2.85 (m, lH), 2.69-2.58 (m, 1H), 2.22-2.14 (m, 1H).

[0351] Example 46: Preparation of Compound 56

[0352]

[0353] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 48.61%.

[0354] 1 H NMR (400MHz, DMSO-d6) δ9.09 (d, J=2.9Hz, 1H), 8.76 (s, 3H), 8.36 (d, J=8.5Hz, 1H), 7.94-7.8 0 (m, 1H), 7.65 (d, J=7.3Hz, 1H), 7.62-7.54 (m, 2H), 7.16 (dd, J=7.9, 4.9Hz, 1H), 7.08-6.99 (m , 1H), 5.92-5.80 (m, 2H), 5.38 (dd, J=13.0, 5.1Hz, 1H), 4.66-4.49 (m, 3H), 3.81 (s, 3H), 3.79 ( d, J=1.6Hz, 2H), 3.16-3.03(m, 1H), 2.94-2.84(m, 1H), 2.66-2.57(m, 1H), 2.20-2.11(m, 1H).

[0355] Example 47: Preparation of Compound 57

[0356]

[0357] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 66.26%.

[0358] 1 H NMR (400MHz, DMSO-d6) δ10.40 (s, 1H), 8.64 (s, 3H), 8.10 (d, J=8.3Hz, 1H), 7.92-7.85 (m, 1H), 7. 73 (d, J=7.3Hz, 1H), 7.63-7.54 (m, 2H), 7.16 (d, J=8.3Hz, 1H), 7.03 (dd, J=9.5, 5.6Hz, 1H), 5.84 ( q, J=9.6Hz, 2H), 5.37 (dd, J=13.0, 5.4Hz, 1H), 4.38 (s, 1H), 3.82 (s, 3H), 3.75 (s, 2H), 3.53-3.46 (m, 2H), 3.18-3.04 (m, 1H), 2.92-2.83 (m, 1H), 2.62 (dt, J=13.8, 11.9Hz, 1H), 2.22-2.10 (m, 1H).

[0359] Example 48: Preparation of Compound 58

[0360]

[0361] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 61.36%.

[0362] 1 H NMR (400MHz, DMSO-d6) δ10.37 (s, 1H), 8.51 (s, 3H), 8.12 (d, J=8.3Hz, 1H), 7.92-7.85 ( m, 1H), 7.71 (d, J=7.3Hz, 1H), 7.49 (dt, J=15.6, 7.7Hz, 2H), 7.41 (s, 1H), 7.27 (d, J=7.9 Hz, 1H), 5.99-5.86 (m, 2H), 5.39 (dd, J=12.8, 5.1Hz, 1H), 4.25 (s, 1H), 3.83 (s, 3H), 3.5 8-3.38 (m, 3H), 3.18-3.05 (m, 1H), 2.62 (dd, J=13.2, 4.3Hz, 1H), 2.16 (d, J=6.0Hz, 1H).

[0363] Example 49: Preparation of compound 59

[0364]

[0365] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 57.14%.

[0366] 1 H NMR (600MHz, DMSO-d6) δ13.90 (s, 0H), 9.65 (s, 1H), 8.37 (s, 3H), 8.19 (d, J=8.3Hz, 1H), 7.95 (s, 0H ), 7.93-7.87 (m, 1H), 7.69 (d, J=7.3Hz, 1H), 7.52 (d, J=7.8Hz, 1H), 7.49-7.40 (m, 2H), 7.34 (d, J=8. 5Hz, 2H), 7.25 (d, J=8.5Hz, 3H), 5.93 (dd, J=43.6, 9.6Hz, 1H), 5.41 (dd, J=13.0, 5.4Hz, 1H), 4.22 (d , J=5.1Hz, 1H), 3.82 (s, 3H), 3.20-3.07 (m, 3H), 2.91-2.88 (m, 1H), 2.63 (m, 1H), 2.26-2.09 (m, 1H).

[0367] Example 50: Preparation of Compound 60

[0368]

[0369] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 48.25%.

[0370] 1 H NMR (600MHz, DMSO-d6) δ14.22 (s, 1H), 9.07 (s, 1H), 8.62 (s, 3H), 8.38 (dd, J=8.4, 3.4Hz, 1H), 7.92-7.86 (m, 1H), 7.63 (d, J=7.3Hz, 1H), 7.48 (m, 2H), 7.41 (s, 1H), 7.30-7.25 (m, 1H), 5.92 ( m, 2H), 5.39 (m, 1H), 4.61 (dt, J=11.7, 3.6Hz, 1H), 4.57-4.48 (m, 1H), 4.37 (d, J=3.6Hz, 1H), 3 .82(s, 3H), 3.16-3.06(m, 1H), 2.89(dd, J=13.7, 3.0Hz, 1H), 2.69-2.55(m, 1H), 2.17(m, 1H).

[0371] Example 51: Preparation of Compound 61

[0372]

[0373] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 53.25%.

[0374] 1 H NMR (400MHz, DMSO-d6) δ10.41 (s, 1H), 8.64 (s, 4H), 8.10 (d, J=8.3Hz, 1H), 7.94-7.83 (m, 1H), 7.72 (d, J=7.3Hz, 1H), 7.65-7.37 (m, 3H), 7.27 (d, J=8.1Hz, 1H), 5.92 (dd, J=2 1.8, 9.7Hz, 2H), 5.39 (dd, J=13.0, 5.3Hz, 1H), 4.37 (s, 1H), 3.47 (dd, J=16.3, 9.0Hz, 6 H), 3.18-3.08 (m, 1H), 2.89 (d, J=16.7Hz, 1H), 2.67-2.56 (m, 12H), 2.20-2.11 (m, 1H).

[0375] Example 52: Preparation of Compound 62

[0376]

[0377] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 62.25%.

[0378] 1 H NMR (600MHz, DMSO-d6) δ9.65 (s, 1H), 8.54 (s, 3H), 8.19 (d, J=8.4Hz, 1H), 7.93-7.87 (m, 1H), 7.69 ( d, J=7.3Hz, 1H), 7.52 (d, J=7.7Hz, 1H), 7.49-7.40 (m, 2H), 7.31 (d, J=8.5Hz, 2H), 7.25 (d, J=8.5Hz , 3H), 5.93 (dd, J=43.8, 9.6Hz, 1H), 5.41 (dd, J=13.0, 5.4Hz, 1H), 4.33 (t, J=6.6Hz, 1H), 3.82 (s, 3 H), 3.70 (s, 3H), 3.19-3.07 (m, 3H), 2.89 (dd, J=13.6, 3.1Hz, 1H), 2.63 (m, 1H), 2.24-2.07 (m, 1H).

[0379] Example 53: Preparation of compound 63

[0380]

[0381] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 41.36%.

[0382] 1 H NMR (400MHz, DMSO-d6) δ9.09 (s, 1H), 8.75 (s, 3H), 8.36 (d, J=8.4Hz, 1H), 7.92-7.86 (m, 1H), 7 .64 (d, J=7.3Hz, 1H), 7.49 (dt, J=15.5, 7.6Hz, 2H), 7.41 (s, 1H), 7.27 (d, J=7.9Hz, 1H), 5.92 (d t, J=17.7, 7.2Hz, 2H), 5.40 (dd, J=12.8, 5.1Hz, 1H), 4.63-4.51 (m, 3H), 3.82 (s, 3H), 3.80 (d, J =1.7Hz, 3H), 3.16-3.06 (m, 1H), 2.89 (d, J = 16.5Hz, 1H), 2.68-2.56 (m, 1H), 2.22-2.11 (m, 1H).

[0383] Example 54: Preparation of Compound 64

[0384]

[0385] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 38.15%.

[0386] 1 H NMR (400MHz, DMSO-d6) δ8.56 (s, 3H), 8.17-8.08 (m, 1H), 7.88 (ddd, J=7.5, 5.5, 3. 4Hz, 3H), 7.72 (d, J=7.4Hz, 1H), 7.10-7.04 (m, 2H), 5.88 (m, 2H), 5.38 (dd, J=12.6 , 4.9Hz, 1H), 4.21 (t, J=5.5Hz, 1H), 3.84 (s, 3H), 3.55-3.40 (m, 3H), 3.16-3.04 (m , 1H), 2.94-2.85 (m, 1H), 2.62 (ddd, J=17.7, 13.0, 4.2Hz, 1H), 2.19-2.10 (m, 1H).

[0387] Example 55: Preparation of Compound 65

[0388]

[0389] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 49.26%.

[0390] 1 H NMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 8.19 (d, J=8.3Hz, 1H), 7.94-7.82 (m, 3H), 7.68 (d, J=7.3Hz, 1H), 7.34 (d, J=8.6Hz, 2H), 7.22 (d, J=8.5Hz, 2H), 7.15-7.02 (m, 2H), 5. 89 (dd, J=20.6, 9.6Hz, 2H), 5.40 (dd, J=13.0, 5.4Hz, 1H), 3.90 (t, J=6.0Hz, 1H), 3.81 (s, 3H), 3.20-3.00 (m, 3H), 2.95-2.85 (m, 1H), 2.71-2.57 (m, 1H), 2.24-2.06 (m, 1H).

[0391] Example 56: Preparation of Compound 66

[0392]

[0393] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 51.36%.

[0394] 1H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 8.44 (s, 3H), 8.39 (dd, J=8.5, 2.7Hz, 1H), 7. 88 (t, J=7.6Hz, 3H), 7.63 (d, J=7.3Hz, 1H), 7.07 (d, J=8.8Hz, 2H), 5.88 (s, 2H), 5.3 9(dd, J=13.0, 3.5Hz, 1H), 4.65-4.43(m, 2H), 4.18(s, 1H), 3.84(s, 3H), 3.18-3.04 (m, 1H), 2.88 (d, J=17.2Hz, 1H), 2.62 (dt, J=13.3, 11.7Hz, 1H), 2.24-2.11 (m, 1H).

[0395] Example 57: Preparation of Compound 67

[0396]

[0397] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 61.25%.

[0398] 1 H NMR (600MHz, DMSO-d6) δ9.04 (s, 1H), 8.99-8.70 (s, 3H), 8.10 (m, 1H), 7.90-7 .87(m, 3H), 7.72(m, 1H), 7.07(d, J=8.9Hz, 2H), 5.88(d, J=10.5Hz, 2H), 5.43- 5.37(m, 1H), 4.30(t, J=5.7Hz, 1H), 3.84(s, 3H), 3.52-3.44(m, 2H), 3.14-3.0 8 (m, lH), 2.89 (dd, J=13.8, 3.2Hz, 1H), 2.66-2.59 (m, lH), 2.18-2.12 (m, 1H).

[0399] Example 58: Preparation of Compound 68

[0400]

[0401] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 62.25%.

[0402] 1H NMR (400MHz, DMSO-d6) δ9.67 (s, 1H), 8.19 (d, J = 8.3Hz, 1H), 7.89 (d, J = 8.9Hz, 3H), 7 .69 (d, J=7.2Hz, 1H), 7.26 (dd, J=28.6, 8.6Hz, 4H), 7.08-7.03 (m, 2H), 5.89 (dd, J=2 1.2, 9.6Hz, 2H), 5.40 (dd, J=13.0, 5.4Hz, 1H), 4.17 (t, J=6.6Hz, 1H), 3.81 (s, 3H), 3 .16-3.04(m, 3H), 2.93-2.85(m, 1H), 2.71-2.57(m, 1H), 2.16(dd, J=8.9, 3.8Hz, 1H).

[0403] Example 59: Preparation of Compound 69

[0404]

[0405] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 59.25%.

[0406] 1 H NMR (400MHz, DMSO-d6) δ8.34 (d, J=8.5Hz, 1H), 8.22 (s, 3H), 7.88 (d, J=8.7Hz, 3H ), 7.64 (d, J=7.3Hz, 1H), 7.07 (d, J=8.9Hz, 2H), 5.89 (d, J=11.5Hz, 2H), 5.39 (dd, J=12.8, 5.0Hz, 1H), 4.58-4.48 (m, 2H), 4.44 (t, J=3.8Hz, 1H), 3.84 (s, 3H), 3.18- 3.05 (m, 1H), 2.89 (dd, J=13.7, 2.9Hz, 1H), 2.66-2.57 (m, 1H), 2.21-2.11 (m, 1H).

[0407] General Synthesis Method 4:

[0408] The synthesis is carried out using steps A', B, and E.

[0409] S1 (1.0 equivalent), EDCI (0.5 equivalent), HOBT (2.5 equivalent), and TEA (5.0 equivalent) were dispersed in dry DCM. A DCM solution of benzyloxyamine (1.0 equivalent) was added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 3 days. DCM, 1N HCl, saturated sodium bicarbonate, and saturated brine were added for extraction. The organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure, and crystallized at room temperature. The crystals were then filtered to obtain S3.

[0410] S3 was dissolved in DCM, and trifluoroacetic acid was added at low temperature. The mixture was stirred at room temperature for 4 hours and then distilled under reduced pressure to obtain a light pink S4. S4 (1.0 equivalent), S5 (1.0 equivalent), and sodium acetate (2.0 equivalent) were dispersed in acetic acid, and molecular sieves were added and stirred overnight at 90°C. The molecular sieves were removed by hot filtration, and after cooling, a white solid precipitated. The solid was washed with water and dried to obtain S6.

[0411] S6 (1.0 equivalent) was placed in a mixed solution of toluene and water, iron powder (2.0 equivalent) and a catalytic amount of ammonium acetate were added, and the mixture was reacted at 100°C for 5 h. Ethyl acetate, water and saturated brine were added for extraction, and the mixture was dried over anhydrous sodium sulfate. After vacuum distillation, the mixture was dispersed in methanol and filtered to obtain formula (C).

[0412] The reaction of formula (C) was continued using general synthesis method 2 to obtain the final product.

[0413] Example 60: Preparation of Compound 70

[0414]

[0415] The hydrochloride was prepared using general method 4, and the final product was a yellow solid with a yield of 61.25%.

[0416] 1 H NMR (600MHz, DMSO-d6) δ9.09 (s, 1H), 8.66 (s, 3H), 8.39 (dd, J=8.5, 3.0Hz, 1H), 7 .90 (dd, J=8.4, 7.5Hz, 1H), 7.65 (d, J=7.3Hz, 1H), 7.51 (dd, J=7.5, 1.8Hz, 2H), 7. 44-7.36 (m, 3H), 5.38 (m, 1H), 4.93 (s, 2H), 4.65-4.52 (m, 2H), 4.39 (t, J=3.7Hz, 1H), 3.13-2.98(m, 1H), 2.87-2.78(m, 1H), 2.59-2.52(m, 1H), 2.19-2.08(m, 1H).

[0417] Example 61: Preparation of Compound 71

[0418]

[0419] The specific synthesis process is as follows: The product of Example 60 was dissolved in methanol, palladium on carbon was added, and the reaction was carried out at room temperature under hydrogen atmosphere. After the reaction was completed, the palladium on carbon was filtered off, the product was evaporated to dryness under reduced pressure, dispersed in ethyl acetate, filtered, and washed with ethyl acetate and n-heptane to obtain the hydrochloride product as a yellow solid with a yield of 83.41%.

[0420] 1H NMR (400MHz, DMSO-d6) δ10.34 (s, 1H), 9.08 (s, 1H), 8.60 (s, 3H), 8.38 (dd, J =8.4, 1.6Hz, 1H), 7.89 (dd, J = 8.4, 7.4Hz, 1H), 7.63 (d, J = 7.3Hz, 1H), 5.34 (d d, J=12.9, 5.3Hz, 1H), 4.66-4.47(m, 2H), 4.32(s, 1H), 3.09-2.97(m, 1H), 2. 79 (dd, J=13.1, 2.7Hz, 1H), 2.56 (dd, J=13.2, 4.5Hz, 1H), 2.13-2.03 (m, 1H).

[0421] Example 62: Preparation of compound 72

[0422]

[0423] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 37.51%.

[0424] 1 H NMR (400MHz, DMSO-d6) δ10.37 (s, 1H), 8.47 (s, 3H), 8.15-8.10 (m, 1H), 7.93-7.8 5(m, 2H), 7.72(m, 2H), 7.44(t, J=7.6Hz, 1H), 7.26(d, J=7.7Hz, 1H), 5.92-5.81(m , 2H), 5.38 (dd, J=12.6, 4.9Hz, 1H), 4.25 (s, 1H), 3.54-3.43 (m, 2H), 3.16-3.06 (m , 1H), 2.90 (d, J=17.6Hz, 1H), 2.62 (m, 1H), 2.29-2.22 (m, 3H), 2.20-2.12 (m, 1H).

[0425] Example 63: Preparation of compound 73

[0426]

[0427] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 42.47%.

[0428] 1H NMR (400MHz, DMSO-d6) δ13.94 (s, 1H), 9.68 (s, 1H), 8.38 (s, 3H), 8.19 (d, J=8.3Hz, 1H), 7.90 (t, J=7.7Hz, 2H), 7.69 (t, J=6.5Hz, 2H), 7.43 (t, J=7.6Hz, 1H), 7.34 (d, J=8.5Hz, 2H), 7.25 (d , J=8.3Hz, 2H), 5.87 (q, J=9.7Hz, 2H), 5.40 (dd, J=13.0, 5.3Hz, 1H), 4.21 (t, J=6.1Hz, 1H), 3 .20-3.06 (m, 3H), 2.90 (d, J=16.8Hz, 1H), 2.72-2.56 (m, 2H), 2.26 (s, 3H), 2.22-2.11 (m, 1H).

[0429] Example 64: Preparation of Compound 74

[0430]

[0431] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 51.46%.

[0432] 1 H NMR (400MHz, DMSO-d6) δ14.24 (s, 1H), 9.08 (d, J=4.7Hz, 1H), 8.58 (s, 3H), 8.38 (dd, J=8.5, 2.4 Hz, 1H), 7.93-7.86 (m, 2H), 7.72 (td, J=7.6, 1.4Hz, 1H), 7.64 (d, J=7.3Hz, 1H), 7.47-7.41 (m, 1 H), 7.26 (d, J=8.1Hz, 1H), 5.86 (s, 2H), 5.38 (m, 1H), 4.64-4.50 (m, 2H), 4.44 (s, 1H), 3.16-3.0 4 (m, 1H), 2.91-2.87 (m, 1H), 2.62 (d, J=10.2Hz, 1H), 2.26 (d, J=0.8Hz, 3H), 2.20-2.13 (m, 1H).

[0433] Example 65: Preparation of Compound 75

[0434]

[0435] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 61.25%.

[0436] 1H NMR (400MHz, DMSO-d6) δ8.68 (s, 3H), 8.09 (dd, J=8.0, 4.0Hz, 1H), 7.93-7.87 (m, 2H), 7.76-7 .70 (m, 2H), 7.43 (dd, J=11.0, 4.3Hz, 1H), 7.26 (dd, J=8.1, 1.0Hz, 1H), 5.91-5.83 (m, 2H), 5.3 8 (dd, J=13.0, 5.3Hz, 1H), 4.37 (t, J=5.5Hz, 1H), 3.75 (d, J=0.8Hz, 3H), 3.55-3.42 (m, 2H), 3 .17-3.05 (m, 1H), 2.90 (dd, J=12.3, 4.3Hz, 1H), 2.62 (m, 1H), 2.26 (s, 3H), 2.19-2.11 (m, 1H).

[0437] Example 66: Preparation of Compound 76

[0438]

[0439] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 52.47%.

[0440] 1 H NMR (600MHz, DMSO-d6) δ9.66 (s, 1H), 8.58 (s, 3H), 8.19 (d, J=8.4Hz, 1H), 7.94-7.86 (m, 2H), 7.69 ( dd, J=11.6, 4.4Hz, 2H), 7.42 (dd, J=11.0, 4.3Hz, 1H), 7.31 (d, J=8.5Hz, 2H), 7.25 (d, J=8.4Hz, 3H), 5.87 (dd, J=22.0, 9.7Hz, 2H), 5.39 (dd, J=13.0, 5.4Hz, 1H), 4.33 (s, 1H), 3.70 (s, 3H), 3.22-3.07 ( m, 3H), 2.90 (dd, J=13.6, 2.8Hz, 1H), 2.64 (dd, J=13.4, 4.5Hz, 1H), 2.26 (s, 3H), 2.20-2.13 (m, 1H).

[0441] Example 67: Preparation of Compound 77

[0442]

[0443] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 59.36%.

[0444] 1H NMR (400MHz, DMSO-d6) δ9.09 (d, J=2.3Hz, 1H), 8.75 (s, 3H), 8.36 (d, J=8.5Hz, 1H), 7.96-7. 87 (m, 2H), 7.72 (t, J=6.9Hz, 1H), 7.65 (d, J=7.2Hz, 1H), 7.48-7.42 (m, 1H), 7.26 (d, J=8.0H z, 1H), 5.86 (s, 2H), 5.39 (dd, J=13.2, 5.1Hz, 1H), 4.67-4.51 (m, 3H), 3.79 (d, J=2.1Hz, 3H) , 3.18-3.05(m, 1H), 2.94-2.88(m, 1H), 2.69-2.57(m, 1H), 2.26(s, 3H), 2.20-2.13(m, 1H).

[0445] Example 68: Preparation of Compound 78

[0446]

[0447] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 57.25%.

[0448] 1 H NMR (400MHz, DMSO-d6) δ9.67 (s, 1H), 8.18 (d, J = 8.4Hz, 1H), 8.06 (s, 2H), 7.93-7.8 6 (m, 1H), 7.69 (d, J=7.3Hz, 1H), 7.27 (dd, J=26.7, 8.5Hz, 4H), 5.61 (dd, J=24.0, 9.4 Hz, 2H), 5.35 (dd, J=13.0, 5.4Hz, 1H), 4.25 (t, J=6.5Hz, 1H), 3.69 (s, 3H), 3.16-3.0 3 (m, 3H), 2.86 (d, J=3.2Hz, 1H), 2.80 (s, 6H), 2.65-2.55 (m, 1H), 2.19-2.10 (m, 1H).

[0449] Example 69: Preparation of Compound 79

[0450]

[0451] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 48.25%.

[0452] 1H NMR (400MHz, DMSO-d6) δ7.48 (dd, J=8.4, 7.1Hz, 1H), 7.19 (s, 2H), 7.02 (t, J=7.3Hz, 2H), 6.55 (s, 2H), 5.63-5.57 (m, 2H), 5.22 (dd, J=1 3.0, 5.4Hz, 1H), 4.38 (d, J=4.0Hz, 1H), 3.77-3.63 (m, 3H), 3.04 (ddd, J=25.7, 15.7, 8.7Hz, 2H), 2.86-2.72 (m, 9H), 2.15-2.05 (m, 2H).

[0453] Example 70: Preparation of Compound 80

[0454]

[0455] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 53.46%.

[0456] 1 H NMR (400MHz, DMSO-d6) δ10.39 (s, 1H), 8.66 (s, 3H), 8.10 (d, J=8.3Hz, 1H), 7.97-7 .82 (m, 1H), 7.72 (d, J=7.3Hz, 1H), 5.61 (dd, J=20.7, 9.6Hz, 2H), 5.32 (dd, J=13.0 , 5.4Hz, 1H), 4.37 (t, J=5.4Hz, 1H), 3.84-3.68 (m, 3H), 3.47 (ddd, J=22.2, 16.2, 5 .7Hz, 2H), 3.12-2.99(m, 1H), 2.80(s, 6H), 2.68-2.54(m, 2H), 2.20-2.06(m, 1H).

[0457] Example 71: Preparation of Compound 81

[0458]

[0459] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 57.15%.

[0460] 1H NMR (400MHz, DMSO-d6) δ8.57 (d, J=8.9Hz, 2H), 8.13 (d, J=8.2Hz, 1H), 7.88 (t, J=7.8Hz, 1H), 7.72 (d, J=7.3Hz, 1H), 5.61 (dd, J=20.8, 9.5Hz, 2H), 5 .33(dd, J=12.9, 5.3Hz, 1H), 4.19(s, 1H), 3.58-3.36(m, 3H), 3.16-2.97( m, 2H), 2.83 (d, J=23.5Hz, 6H), 2.66-2.53 (m, 2H), 2.12 (d, J=5.6Hz, 1H).

[0461] Example 72: Preparation of Compound 82

[0462]

[0463] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 62.36%.

[0464] 1 H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 8.58 (s, 2H), 8.38 (dd, J=8.5, 1.8Hz, 1H), 7.89 (t, J=7 .9Hz, 1H), 7.63 (d, J=7.3Hz, 1H), 5.61 (ddd, J=11.4, 9.5, 3.1Hz, 2H), 5.33 (ddd, J=13.0, 5. 1, 2.6Hz, 1H), 4.57 (dtd, J=18.1, 11.6, 4.8Hz, 2H), 4.34 (s, 1H), 3.17 (s, 1H), 3.06 (dd, J=2 2.1, 8.8Hz, 1H), 2.86 (s, 1H), 2.77 (d, J=27.5Hz, 6H), 2.66-2.52 (m, 2H), 2.19-2.06 (m, 1H).

[0465] Example 73: Preparation of Compound 83

[0466]

[0467] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 42.47%.

[0468] 1H NMR (400MHz, DMSO-d6) δ9.67 (s, 1H), 8.18 (d, J = 8.3Hz, 1H), 7.90 (t, J = 7.8Hz, 1H), 7.69 (d, J=7.3Hz, 1H), 7.29 (dd, J=46.5, 8.4Hz, 4H), 5.61 (dd, J=24.2, 9. 4Hz, 2H), 5.34 (dd, J=13.0, 5.3Hz, 1H), 3.99 (d, J=6.1Hz, 1H), 3.23-2.99 (m, 4 H), 2.85 (d, J=14.7Hz, 1H), 2.80 (s, 6H), 2.69-2.53 (m, 2H), 2.21-2.08 (m, 1H).

[0469] Example 74: Preparation of Compound 84

[0470]

[0471] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 58.47%.

[0472] 1 H NMR (400MHz, DMSO-d6) δ9.66 (s, 1H), 8.29 (s, 3H), 8.18 (s, 1H), 7.95-7.83 (m, 1H), 7. 69 (d, J=7.2Hz, 1H), 7.28 (dd, J=30.8, 8.6Hz, 4H), 5.62 (dd, J=20.0, 9.3Hz, 2H), 5.35 (dd, J=12.9, 5.4Hz, 1H), 4.26 (t, J=6.5Hz, 1H), 3.69 (s, 3H), 3.24-3.01 (m, 7H), 2.85 (dd, J=13.8, 3.1Hz, 1H), 2.64-2.55 (m, 1H), 2.21-2.07 (m, 1H), 1.02 (t, J=6.5Hz, 6H).

[0473] Example 75: Preparation of Compound 85

[0474]

[0475]

[0476] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 46.25%.

[0477] 1H NMR (600MHz, DMSO-d6) δ9.08 (s, 1H), 8.82 (s, 3H), 8.36 (d, J=8.5Hz, 1H), 7.92-7.8 6 (m, 1H), 7.64 (d, J=7.3Hz, 1H), 5.66-5.55 (m, 2H), 5.33 (ddd, J=13.0, 5.3, 3.1Hz, 1H), 4.66-4.53 (m, 3H), 3.80 (s, 3H), 3.17 (d, J=26.0Hz, 4H), 3.07 (dd, J=22.0, 9.7 Hz, 1H), 2.85 (dd, J=13.8, 3.0Hz, 1H), 2.56 (m, 1H), 2.21-2.05 (m, 1H), 1.02 (s, 6H).

[0478] Example 76: Preparation of Compound 86

[0479]

[0480] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 56.14%.

[0481] 1 H NMR (600MHz, DMSO-d6) δ8.92 (s, 3H), 8.11 (dd, J=8.3, 1.4Hz, 1H), 7.91-7.86 (m, 1H ), 7.71 (d, J=7.3Hz, 1H), 5.66-5.57 (m, 2H), 5.33 (dd, J=13.0, 5.4Hz, 1H), 4.31 (t, J=4.7Hz, 1H), 3.74(s, 3H), 3.53-3.43(m, 2H), 3.17(d, J=23.0Hz, 4H), 3.09-3.03( m, 1H), 2.85 (dd, J=13.8, 3.1Hz, 1H), 2.56 (m, 1H), 2.15-2.08 (m, 1H), 1.02 (s, 6H).

[0482] Example 77: Preparation of Compound 87

[0483]

[0484] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 66.14%.

[0485] 1H NMR (600MHz, DMSO-d6) δ8.13 (d, J=8.4Hz, 1H), 7.88 (t, J=7.8Hz, 1H), 7.71 ( d, J=7.2Hz, 1H), 5.61 (m, 2H), 5.35-5.30 (m, 1H), 4.17 (m, 1H), 3.46 (dd, J=6 0.7, 12.3Hz, 2H), 3.17 (d, J=23.6Hz, 4H), 3.11-3.03 (m, 1H), 2.84 (d, J=17. 6Hz, 1H), 2.56 (dd, J=13.5, 4.4Hz, 1H), 2.12 (d, J=7.0Hz, 1H), 1.02 (s, 6H).

[0486] Example 78: Preparation of Compound 88

[0487]

[0488] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 47.36%.

[0489] 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 8.53 (s, 2H), 8.38 (d, J = 8.2Hz, 1H), 7.91-7.84 (m, 1H), 7.63 (d, J = 7.2Hz, 1H), 5.66-5.56 (m, 2H), 5.38-5.28 (m , 1H), 4.55 (dd, J=41.2, 11.9Hz, 2H), 4.34 (s, 1H), 3.23-3.03 (m, 5H), 2.84 (d, J=17.4Hz, lH), 2.61-2.53 (m, lH), 2.14 (d, J=4.5Hz, 1H), 1.01 (s, 5H).

[0490] Example 79: Preparation of Compound 89

[0491]

[0492] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 57.25%.

[0493] 1H NMR (600MHz, DMSO-d6) δ9.64 (s, 1H), 8.34 (s, 2H), 8.19 (d, J=8.4Hz, 1H), 7.90 (t, J=7.8 Hz, 1H), 7.69 (d, J=7.2Hz, 1H), 7.35 (d, J=7.6Hz, 2H), 7.24 (d, J=7.2Hz, 2H), 5.62 (dd, J =28.7, 9.3Hz, 2H), 5.34 (dd, J = 12.9, 5.4Hz, 1H), 4.15 (s, 1H), 3.23-3.04 (m, 7H), 2.85 ( d, J=16.8Hz, 1H), 2.57 (ddd, J=26.3, 13.1, 4.4Hz, 1H), 2.17-2.08 (m, 1H), 1.02 (s, 6H).

[0494] Example 80: Preparation of Compound 90

[0495]

[0496] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 67.52%.

[0497] 1 H NMR (400MHz, DMSO-d6) δ9.67 (s, 1H) δ8.49 (s, 3H), 8.20 (d, J = 8.4Hz, 1H), 7.90 (t, J = 7.9Hz, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.36 (d, J=8.2Hz, 2H), 7.24 (d, J=8.2Hz, 2H), 5.82-5.54 (m, 2H), 5.36 (dd, J=13.1, 5.4Hz, 1H), 4.18 (t , J=6.3Hz, 1H), 3.23-2.96 (m, 3H), 2.85 (dt, J=17.2, 3.5Hz, 1H), 2.60 (qd, J=13.2, 4.4Hz, 1H), 2.28 (t, J=7.2H z, 2H), 2.14 (tt, J=7.6, 4.3Hz, 1H), 1.49 (t, J=7.1Hz, 2H), 1.22 (dd, J=9.6, 4.7Hz, 12H), 0.83 (t, J=6.5Hz, 3H).

[0498] Example 81: Preparation of Compound 91

[0499]

[0500] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 62.46%.

[0501] 1 H NMR (600MHz, DMSO-d6) δ8.17 (td, J=9.5, 8.9, 3.2Hz, 1H), 7.87 (dd, J=8.4, 7.3Hz, 1H), 7.72-7.62 (m, 1H), 5.74-5.56(m, 2H), 5.40-5.23(m, 1H), 3.60-3.48(m, 2H), 3.25(dt, J=13.6, 6.7Hz, 2H), 3.07(dd t, J=17.5, 12.9, 6.4Hz, 1H), 2.84 (dt, J=17.5, 3.7Hz, 1H), 2.59 (qd, J=13.1, 4.2Hz, 1H), 2.27 (t, J=7 .3Hz, 2H), 2.19-2.04 (m, 1H), 1.49 (p, J=7.3Hz, 2H), 1.22 (q, J=9.2, 7.9Hz, 12H), 0.96-0.70 (m, 3H).

[0502] Example 82: Preparation of compound 92

[0503]

[0504] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 71.62%.

[0505] 1 H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 8.60 (s, 3H), 8.39 (dd, J=8.6, 2.1Hz, 1H), 7.89 (t, J=7.9Hz, 1H), 7.62 (d, J=7.4Hz, 1H), 5.70-5.62 (m, 2H), 5.34 (ddd, J=13.2, 5.3, 2.2Hz, 1H), 4.56 (ddt, J=38.7, 11.7, 3.7Hz, 2H), 4.32 (t, J=4.1Hz, 1H), 3.08 (ddd, J=18.1, 13.9, 5.4Hz, 1H), 2.84 (dt, J=17.1, 3.4Hz, 1H), 2.59 (tt, J=12.8, 6.2Hz, 1 H), 2.27 (t, J=7.3Hz, 2H), 2.17-2.09 (m, 1H), 1.49 (t, J=7.2Hz, 2H), 1.23-1.19 (m, 13H), 0.83 (t, J=6.5Hz, 3H).

[0506] Example 83: Preparation of Compound 93

[0507]

[0508] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 59.25%.

[0509] 1 H NMR (400MHz, DMSO-d6) δ9.68 (S, 1H), 8.29-8.11 (m, 1H), 7.91 (s, 1H), 7.68 (s, lH), 7.32 (d, J = 75.2Hz, 2H), 5.70 (d, J = 28.0Hz, 2H), 5.52-5.20 (m, 1H), 4.20(s, 1H), 3.17(s, 3H), 2.87(s, 1H), 2.28(s, 1H), 2.15(s, 1H), 1 .99 (s, 1H), 1.49 (s, 2H), 1.22 (d, J = 12.4Hz, 14H), 0.84 (d, J = 7.4Hz, 3H).

[0510] Example 84: Preparation of Compound 94

[0511]

[0512]

[0513] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 69.25%.

[0514] 1 H NMR (400MHz, DMSO-d6) δ8.50 (s, 3H), 8.13 (d, J=8.2Hz, 1H), 7.88 (t, J=7.9Hz, 1H), 7 .71 (d, J=7.3Hz, 1H), 5.81-5.56 (m, 2H), 5.34 (dd, J=13.1, 5.3Hz, 1H), 4.34-4.08 (m, 2H), 3.58-3.37(m, 5H), 3.17-2.91(m, 2H), 2.93-2.75(m, 1H), 2.27(t, J=7.3Hz, 2H), 2.19-2.06 (m, 1H), 1.57-1.42 (m, 2H), 1.22 (d, J=5.1Hz, 12H), 0.84 (t, J=6.6Hz, 3H).

[0515] Example 85: Preparation of Compound 95

[0516]

[0517] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 59.25%.

[0518] 1 H NMR (400MHz, DMSO-d6) δ8.21 (d, J=8.3Hz, 1H), 7.90 (dd, J=8.4, 7.3Hz, 1H), 7.67 (d, J=7.2 Hz, 2H), 7.34 (d, J=8.6Hz, 2H), 7.27-7.04 (m, 2H), 5.73-5.55 (m, 2H), 5.35 (dd, J=13.1, 5. 4Hz, 1H), 3.46 (t, J=6.0Hz, 1H), 3.24-2.98 (m, 3H), 2.99-2.77 (m, 2H), 2.60 (qd, J=13.2, 4 .4Hz, 2H), 2.28 (t, J=7.2Hz, 2H), 1.57-1.41 (m, 2H), 1.20 (s, 14H), 0.84 (t, J=6.8Hz, 3H).

[0519] Example 86: Preparation of Compound 96

[0520]

[0521] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 49.25%.

[0522] 1 H NMR (600MHz, DMSO-d6) δ9.62 (s, 1H), 8.21 (d, J = 8.3Hz, 1H), 7.90 (t, J = 7.9Hz, 1H), 7.67 (d, J = 7.2Hz, 1H), 7. 36 (d, J=8.3Hz, 2H), 7.19 (d, J=8.4Hz, 2H), 5.66 (dd, J=18.3, 9.6Hz, 2H), 5.35 (dd, J=13.1, 5.3Hz, 1H), 3.62 ( s, 1H), 3.20-3.05 (m, 2H), 2.99 (dd, J=14.4, 7.4Hz, 1H), 2.85 (d, J=16.9Hz, 1H), 2.60 (dt, J=13.4, 8.8Hz, 1H) , 2.28 (t, J=7.2Hz, 2H), 2.20-2.10 (m, 1H), 1.48 (d, J=6.8Hz, 2H), 1.33-1.10 (m, 22H), 0.84 (t, J=6.9Hz, 3H).

[0523] Example 87: Preparation of Compound 97

[0524]

[0525] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 71.23%.

[0526] 1 H NMR (600MHz, DMSO-d6) δ9.97 (s, 1H), 8.05 (d, J = 8.5Hz, 1H), 7.79 (t, J = 7.9Hz, 1H), 7.40 (d, J = 7.2Hz, 1H), 5.77-5.53 (m, 2H), 5.57 (dd, J=12.8, 4.5Hz, 1H), 4.6l (d, J=9.9Hz, 1H), 4.44-4.34 (m, 1H), 3.68 (s, 1H), 3.15-3.05 (m, 1H), 2.84 (d, J=17.1Hz, 1H), 2.63-2.55 (m, lH), 2.34 (t, J =7.2Hz, 2H), 2.18-2.09(m, 1H), 1.53-1.45(m, 2H), 1.33-1.26(m, 22H), 0.85(t, J=6.9Hz, 3H).

[0527] Example 88: Preparation of Compound 98

[0528]

[0529] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 52.62%.

[0530] 1 H NMR (600MHz, DMSO-d6) δ9.02 (s, 1H), 8.41 (d, J = 8.5Hz, 1H), 7.87 (t, J = 7.9Hz, 1H), 7.59 (d, J = 7.2Hz, 1H), 5.77-5.53 (m, 2H), 5.34 (dd, J=12.8, 4.5Hz, 1H), 4.61 (d, J=9.9Hz, 1H), 4.44-4.34 (m, 1H), 3.80 (s, 1H), 3.15-3.05 (m, 1H), 2.84 (d, J=17.1Hz, 1H), 2.63-2.55 (m, 1H), 2.27 (t, J =7.2Hz, 2H), 2.18-2.09(m, 1H), 1.53-1.45(m, 2H), 1.32-1.14(m, 22H), 0.85(t, J=6.9Hz, 3H).

[0531] Example 89: Preparation of Compound 99

[0532]

[0533] The hydrochloride was prepared using general synthesis method 4, yielding a yellow solid with a yield of 60.17%.

[0534] 1 H NMR (600MHz, DMSO-d6) δ9.09 (s, 1H), 8.66 (s, 3H), 8.39 (dd, J=8.5, 3.0Hz, 1H), 7 .90 (dd, J=8.4, 7.5Hz, 1H), 7.65 (d, J=7.3Hz, 1H), 7.51 (dd, J=7.5, 1.8Hz, 2H), 7. 44-7.36 (m, 3H), 5.38 (m, 1H), 4.93 (s, 2H), 4.65-4.52 (m, 2H), 4.39 (t, J=3.7Hz, 1H), 3.13-2.98(m, 1H), 2.87-2.78(m, 1H), 2.59-2.52(m, 1H), 2.19-2.08(m, 1H).

[0535] Example 90: Preparation of Compound 100

[0536]

[0537] The synthesis method was the same as in Example 61, yielding a yellow solid hydrochloride with a yield of 80.12%.

[0538] 1 H NMR (400MHz, DMSO-d6) δ10.34 (s, 1H), 9.08 (s, 1H), 8.60 (s, 3H), 8.38 (dd, J =8.4, 1.6Hz, 1H), 7.89 (dd, J = 8.4, 7.4Hz, 1H), 7.63 (d, J = 7.3Hz, 1H), 5.34 (d d, J=12.9, 5.3Hz, 1H), 4.66-4.47(m, 2H), 4.32(s, 1H), 3.09-2.97(m, 1H), 2. 79 (dd, J=13.1, 2.7Hz, 1H), 2.56 (dd, J=13.2, 4.5Hz, 1H), 2.13-2.03 (m, 1H).

[0539] Example 91: Preparation of Compound 101

[0540]

[0541] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 58.25%.

[0542] 1H NMR (600MHz, DMSO-d6) δ9.65 (s, 1H), 8.74 (s, 3H), 8.21 (d, J = 8.4Hz, 1H), 8.03-7.87 (m, 1H), 7.68 (d, J = 7.3Hz, 1H), 7.3 3 (d, J=8.6Hz, 2H), 7.24 (d, J=8.4Hz, 2H), 5.66 (dd, J=18.4, 9.6Hz, 2H), 5.36 (dd, J=13.1, 5.4Hz, 1H), 4.29 (t, J=6.5Hz, 1H), 3.69 (s, 3H), 3.23 (dd, J=14.1, 5.8Hz, 1H), 3.19-3.03 (m, 2H), 2.85 (dd, J=13.9, 3.0Hz, 1H), 2.60 (qd, J=13.2, 4.4 Hz, 1H), 2.32-2.24 (m, 2H), 2.19-2.08 (m, 1H), 1.49 (dd, J=13.8, 6.9Hz, 2H), 1.27-1.16 (m, 24H), 0.84 (t, J=7.0Hz, 3H).

[0543] Example 92: Preparation of Compound 102

[0544]

[0545] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 65.53%.

[0546] 1 H NMR (600MHz, DMSO-d6) δ9.14-8.69 (m, 2H), 8.05 (S, 1H), 7.79 (S, 1H), 7.4 (S, 1H), 7.73-7.62 (m, 1H), 5. 53-5.49 (m, 2H), 5.37-5.27 (m, 1H), 4.44 (S, 1H), 3.78-3.66 (m, 3H), 3.47 (qd, J=14.6, 6.1Hz, 2H), 3.07 (ddd, J=19.5, 12.4, 5.5Hz, 1H), 2.84 (dd, J=13.7, 3.0Hz, 1H), 2.59 (qd, J=13.1, 4.6Hz, 1H), 2.27-2.21 (m, 2H), 2.12 (dd, J=9.1, 3.7Hz, 1H), 1.66 (d, J=6.7Hz, 2H), 1.26 (s, 22H), 0.88 (dd, J=9.2, 4.1Hz, 3H).

[0547] Example 93: Preparation of Compound 103

[0548]

[0549] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 61.22%.

[0550] 1 H NMR (600MHz, DMSO-d6) δ9.14-8.69 (m, 2H), 8.64-8.39 (m, 1H), 8.19-8.08 (m, 1H), 7.91-7.80 (m, 1H), 7.73-7. 62 (m, 1H), 5.70-5.60 (m, 2H), 5.37-5.27 (m, 1H), 4.36-4.24 (m, 1H), 3.78-3.71 (m, 3H), 3.47 (qd, J=14.6, 6.1 Hz, 2H), 3.07 (ddd, J=19.5, 12.4, 5.5Hz, 1H), 2.84 (dd, J=13.7, 3.0Hz, 1H), 2.59 (qd, J=13.1, 4.6Hz, 1H), 2.2 8-2.24 (m, 2H), 2.12 (dd, J=9.1, 3.7Hz, 1H), 1.48 (d, J=6.7Hz, 2H), 1.21 (s, 22H), 0.85 (dd, J=9.2, 4.1Hz, 3H).

[0551] Example 94: Preparation of Compound 111

[0552]

[0553] The hydrochloride was prepared using general synthesis method 1, yielding a pale yellow solid with a yield of 56.25%.

[0554] 1 H NMR (600MHz, DMSO-d6) δ11.16 (s, 1H), 9.66 (s, 1H), 8.54 (s, 3H), 8.18 (d, J=8. 4Hz, 1H), 7.89 (t, J=7.9Hz, 1H), 7.68 (d, J=7.3Hz, 1H), 7.28 (dd, J=35.7, 8.5H z, 4H), 5.17 (dd, J=12.9, 5.4Hz, 1H), 4.48-4.23 (m, 1H), 3.71 (s, 3H), 3.15 (qd , J=14.2, 6.6Hz, 2H), 3.03-2.81(m, 1H), 2.69-2.53(m, 2H), 2.16-2.02(m, 1H).

[0555] Example 95: Preparation of compound S9

[0556]

[0557] The hydrochloride was prepared using general synthesis method 4, yielding a pale yellow solid with a yield of 60.25%.

[0558] 1 H NMR (600MHz, DMSO-d6) δ9.69 (s, 1H), 8.41 (s, 2H), 8.19 (d, J=8.4Hz, 1H), 7.96-7.87 (m, 1H), 7.71 (d, J=7.3Hz, 1H), 7.51 (dd, J=7.6, 2.0Hz, 2H), 7.40 (q, J=5.3Hz, 3H), 7.35 (d, J=8.6Hz, 2H), 7.25 (d, J=8.5Hz, 2H), 5.40 (dd, J=12.9, 5.3Hz, 1H), 4.93 (s, 2H), 4.18 (t, J=6.4Hz, 1H), 3.19-3.10 (m , 2H), 3.07-2.99 (m, 1H), 2.85-2.78 (m, 1H), 2.61-2.53 (m, 1H), 2.12 (ddd, J=7.8, 4.3, 2.1Hz, 1H).

[0559] Example 96: Preparation of compound S10

[0560]

[0561] The synthesis method was the same as in Example 61, yielding a yellow solid hydrochloride in 52.73% yield.

[0562] 1 H NMR (600MHz, DMSO-d6) δ10.33 (s, 1H), 9.67 (s, 1H), 8.32 (s, 3H), 8.18 (d, J=8.4Hz, 1H), 7.90 (t, J=7.9Hz, 1H), 7.69 (d, J=7.3Hz, 1H), 7.34 (d, J=8.6Hz, 2H), 7.25 (d, J=8.5Hz, 1H), 5.36 ( dd, J=12.9, 5.3Hz, 1H), 4.24-4.16 (m, 2H), 3.16-3.09 (m, 1H), 3.04 (ddd, J=17.2, 13.7, 5.4H z, 3H), 2.80 (ddd, J=17.1, 4.5, 2.6Hz, 6H), 2.56 (dd, J=13.3, 4.7Hz, 20H), 2.13-2.03 (m, 1H).

[0563] Example 97: Preparation of Compound 112

[0564]

[0565]

[0566] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 62.45%.

[0567] 1 H NMR (600MHz, DMSO-d6) δ9.64 (s, 1H), 8.61 (s, 3H), 8.20 (d, J = 8.4Hz, 1H), 7.90 (t, J = 7.9Hz, 1H), 7.68 (d, J = 7.3Hz, 1H), 7.32 (d, J=8.3Hz, 2H), 7.24 (d, J=8.4Hz, 2H), 5.66 (q, J=9.7Hz, 2H), 5.35 (dd, J=13.1, 5.4Hz, 1 H), 4.32 (t, J=6.6Hz, 1H), 3.70 (s, 3H), 3.21-3.03 (m, 3H), 2.85 (dt, J=17.3, 3.6Hz, 1H), 2.60 (qd, J=13.2, 4.4Hz, 1H), 2.28 (t, J=7.3Hz, 2H), 1.53-1.45 (m, 2H), 1.21 (q, J=11.0, 8.8Hz, 12H), 0.83 (t, J=7.0Hz, 3H).

[0568] Example 98: Preparation of Compound 113

[0569]

[0570] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 71.36%.

[0571] 1 H NMR (400MHz, DMSO-d6) δ8.53 (dd, J=22.6, 8.4Hz, 1H), 8.13 (t, J=7.8Hz, 1H), 7.91-7.61 (m, 3H), 7.46 (dd, J=8.4, 5.5Hz, 1H), 5.7l-5.58 (m, J=3.3Hz, 3H), 5.33 (dt, J=13.3, 4.9Hz, 1H), 3.70 (d, J =7.1Hz, 3H), 2.85 (ddd, J=14.5, 6.6, 3.5Hz, 1H), 2.58 (dt, J=13.9, 4.5Hz, 1H), 2.27 (td, J=7.3, 3.5Hz, 3H), 2.15-2.07 (m, 1H), 1.55-1.39 (m, 3H), 1.21 (t, J=6.4Hz, 14H), 0.83 (q, J=2.8Hz, 3H).

[0572] Example 99: Preparation of Compound 114

[0573]

[0574] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 63.45%.

[0575] 1 H NMR (400MHz, DMSO-d6) δ8.27 (d, J=8.4Hz, 1H), 7.86 (dd, J=8.5, 7.3Hz, 1H), 7.61 (d, J=7.3Hz, 1H), 5.71-5.57 (m, 2H), 5.32 (dd, J=13.1, 5.4Hz, 1H), 4.26 (dd, J=5.3, 1.4Hz, 2H), 3.65 (s, 3H) , 3.07 (ddd, J=17.8, 13.7, 5.4Hz, 1H), 2.91-2.78 (m, 1H), 2.67-2.54 (m, 1H), 2.27 (t, J=7.2Hz, 2H), 2.11 (d, J=12.8Hz, 1H), 1.49 (s, 2H), 1.21 (d, J=5.6Hz, 14H), 0.83 (td, J=6.7, 3.9Hz, 3H).

[0576] Example 100: Preparation of Compound 115

[0577]

[0578] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 68.14%.

[0579] 1 H NMR (400MHz, DMSO-d6) δ9.66 (s, 1H), 8.61 (s, 3H), 8.20 (d, J=8.3Hz, 1H), 7.90 (dd, J=8.4, 7.3Hz, 1H), 7 .68 (d, J=7.3Hz, 1H), 7.36-7.20 (m, 4H), 5.73-5.61 (m, 2H), 5.36 (dd, J=13.0, 5.4Hz, 1H), 4.33 (t, J=6. 6Hz, 1H), 3.70 (s, 3H), 3.23-3.02 (m, 3H), 2.85 (dt, J=16.9, 3.6Hz, 1H), 2.60 (qd, J=13.2, 4.4Hz, 1H), 2 .28 (t, J=7.2Hz, 2H), 2.19-2.07 (m, 1H), 1.55-1.43 (m, 2H), 1.21 (d, J=6.6Hz, 16H), 0.87-0.79 (m, 3H).

[0580] Example 101: Preparation of Compound 116

[0581]

[0582] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 59.25%.

[0583] 1 H NMR (400MHz, DMSO-d6) δ8.53 (dd, J=23.8, 8.2Hz, 1H), 8.14 (d, J=8.3Hz, 1H), 7.91-7.78 (m, 1H), 7.76-7.64 (m, 1H), 5.64 (dd, J=9.3, 5.0Hz, 2H), 5.32 (tt, J=8.5, 4.8Hz, 1H), 3.69 (d, J=5.9Hz, 2H), 3.32-3.20 (m, 2H), 3.07 (dq, J=16.1, 6.9, 4.9Hz, 1H), 2.84 (dd, J=18.2, 4.0Hz, 1H), 2.59 (ddt, J=13.4, 8.8, 4.4Hz, 1H), 2.30- 2.24 (m, 2H), 2.16-2.07 (m, 1H), 1.49 (t, J=7.0Hz, 2H), 1.20 (d, J=5.0Hz, 16H), 0.84 (td, J=6.7, 3.3Hz, 3H).

[0584] Example 102: Preparation of Compound 117

[0585]

[0586] The hydrochloride was prepared using general synthesis method 3, yielding a pale yellow solid with a yield of 67.15%.

[0587] 1H NMR (400MHz, DMSO-d6) δ8.25 (t, J=11.5Hz, 1H), 7.86 (dd, J=8.5, 7.3Hz, 1H), 7.60 (d, J=7. 3Hz, 1H), 6.54 (s, 1H), 5.68-5.61 (m, 2H), 5.28 (ddd, J=37.7, 13.0, 5.3Hz, 2H), 4.26 (dd, J =5.4, 1.4Hz, 2H), 3.65 (s, 3H), 3.14-2.99 (m, 2H), 2.83 (d, J = 17.9Hz, 1H), 2.59 (dt, J = 13. 2, 6.6Hz, 1H), 1.48 (d, J=6.8Hz, 3H), 1.21 (d, J=6.3Hz, 18H), 0.83 (dt, J=7.1, 2.8Hz, 3H).

[0588] Example 103: Preparation of Compound 118

[0589]

[0590] The sample was prepared using general synthesis method 1, yielding a white solid with a yield of 58.35%.

[0591] 1 H NMR (600MHz, DMSO) δ11.14 (s, 1H), 9.64 (s, 1H), 8.61 (s, 3H), 8.18 (d, J=8.4Hz, 1H), 7. 89 (t, J=7.9Hz, 1H), 7.67 (d, J=7.3Hz, 1H), 7.29 (dd, J=48.1, 8.5Hz, 4H), 5.16 (dd, J=12 .9, 5.4Hz, 1H), 4.27 (t, J=6.8Hz, 1H), 4.17-4.06 (m, 2H), 3.16 (ddd, J=21.7, 14.1, 6.8H z, 2H), 2.96-2.85 (m, 1H), 2.66-2.53 (m, 2H), 2.12-2.01 (m, 1H), 1.13 (t, J=7.1Hz, 3H).

[0592] Example 104: Preparation of Compound 119

[0593]

[0594] The sample was prepared using general synthesis method 1, yielding a white solid with a yield of 56.75%.

[0595] 1H NMR (400MHz, DMSO) δ11.16 (s, 1H), 9.67 (s, 1H), 8.68 (s, 3H), 8.18 (d, J=8.3Hz, 1H), 7.94-7.85 ( m, 1H), 7.68 (d, J=7.0Hz, 1H), 7.29 (dd, J=35.1, 8.6Hz, 4H), 5.17 (dd, J=12.7, 5.4Hz, 1H), 4.27 (t , J=6.8Hz, 1H), 4.20-3.98 (m, 2H), 3.23 (dd, J=14.1, 5.8Hz, 1H), 3.11 (dd, J=14.1, 7.7Hz, 1H), 2 .91 (ddd, J=16.7, 13.7, 5.3Hz, 1H), 2.67-2.52 (m, 2H), 2.20-2.02 (m, 1H), 1.12 (t, J=7.1Hz, 3H).

[0596] Example 105: Preparation of Compound 120

[0597]

[0598] The sample was prepared using general synthesis method 3, yielding a white solid with a yield of 67.4%.

[0599] 1 H NMR (400MHz, DMSO) δ9.10 (s, 1H), 8.91 (s, 3H), 8.36 (d, J=8.4Hz, 1H), 7.91 (dd, J=21.2 , 7.8Hz, 3H), 7.70 (t, J=7.4Hz, 1H), 7.64 (d, J=7.2Hz, 1H), 7.56 (t, J=7.6Hz, 2H), 5.93 (s, 2H), 5.40 (dd, J=13.0, 5.1Hz, 1H), 4.67-4.51 (m, 3H), 3.79 (d, J=3.0Hz, 3H), 3.20- 3.04 (m, 1H), 2.90 (d, J=16.9Hz, 1H), 2.64 (dd, J=20.6, 7.1Hz, 1H), 2.22-2.11 (m, 1H).

[0600] Example 106: Preparation of Compound 121

[0601]

[0602] The sample was prepared using general synthesis method 1, yielding a white solid with a yield of 58.1%.

[0603] 1H NMR (400MHz, DMSO) δ11.16 (s, 1H), 9.66 (s, 1H), 8.60 (s, 3H), 8.18 (d, J=8.4Hz, 1H), 7.95-7.83 (m, 1H ), 7.68 (d, J = 7.2Hz, 1H), 7.33 (d, J = 8.6Hz, 2H), 7.25 (d, J = 8.5Hz, 2H), 5.17 (dd, J = 12.7, 5.4Hz, 1H), 4.96-4.85 (m, 1H), 4.32-4.16 (m, 1H), 3.22 (dd, J=14.0, 5.8Hz, 1H), 3.06 (dd, J=14.0, 8.1Hz, 1H), 2. 97-2.85 (m, 1H), 2.71-2.54 (m, 2H), 2.14-2.02 (m, 1H), 1.19 (t, J=13.7Hz, 3H), 1.07 (d, J=6.2Hz, 3H).

[0604] Example 107: Preparation of Compound 122

[0605]

[0606] The sample was prepared using general synthesis method 1, yielding a white solid with a yield of 49.3%.

[0607] 1 H NMR (400MHz, DMSO) δ11.16 (s, 1H), 9.63 (s, 1H), 8.19 (d, J=8.5Hz, 1H), 7.89 (t, J= 7.9Hz, 1H), 7.67 (d, J=7.2Hz, 1H), 7.34-7.26 (m, 2H), 7.19 (d, J=8.3Hz, 2H), 5.17 ( dd, J=12.9, 5.3Hz, 1H), 4.20 (s, 1H), 4.08 (dd, J=9.6, 4.8Hz, 2H), 3.75 (s, 2H), 3.0 9-2.83 (m, 3H), 2.69-2.55 (m, 3H), 2.07 (d, J = 11.3Hz, 1H), 1.25 (d, J = 11.6Hz, 2H).

[0608] Example 108: Preparation of Compound 123

[0609]

[0610] The sample was prepared using general synthesis method 1, yielding a white solid with a yield of 59.5%.

[0611] 1H NMR (400MHz, DMSO) δ11.16 (s, 1H), 9.66 (s, 1H), 8.66 (s, 3H), 8.18 (d, J = 8.3Hz, 1H), 7.89 (t, J = 7.8Hz, 1H), 7.68 (d, J=7.2Hz, 1H), 7.29 (dd, J=32.4, 8.3Hz, 4H), 5.17 (dd, J=12.6, 5.2Hz, 1H), 4.30 (t, J=6.6Hz, 1H), 4. 07 (t, J=6.4Hz, 2H), 3.23 (dd, J=14.1, 5.6Hz, 1H), 3.10 (dd, J=14.2, 7.8Hz, 1H), 2.90 (d, J=13.4Hz, 1H), 2. 66-2.56 (m, 2H), 2.13-2.01 (m, 1H), 1.56-1.42 (m, 2H), 1.22 (dq, J=14.8, 7.2Hz, 2H), 0.85 (t, J=7.3Hz, 3H).

[0612] Example 109: Preparation of Compound 124

[0613]

[0614] The sample was prepared using general synthesis method 1, yielding a white solid with a yield of 62.5%.

[0615] 1 H NMR (600MHz, DMSO) δ11.15 (s, 1H), 9.63 (s, 1H), 8.66 (s, 3H), 8.19 (d, J = 8.4Hz, 1H), 7.89 (t, J = 7.9Hz, 1H), 7.6 7 (d, J=7.3Hz, 1H), 7.29 (dd, J=49.4, 8.5Hz, 4H), 5.17 (dd, J=12.9, 5.4Hz, 1H), 4.29 (s, 1H), 4.06 (t, J=6.6Hz, 2H), 3.23 (dd, J=14.1, 5.8Hz, 1H), 3.10 (dd, J=14.1, 7.9Hz, 1H), 2.91 (ddd, J=17.2, 14.0, 5.4Hz, 1H), 2.57 (dd d, J=23.2, 17.9, 10.7Hz, 2H), 2.14-2.03 (m, 1H), 1.54-1.39 (m, 2H), 1.32-1.16 (m, 6H), 0.85 (t, J=7.0Hz, 3H).

[0616] Example 110: Preparation of Compound 125

[0617]

[0618] The sample was prepared using general synthesis method 1, yielding a white solid with a yield of 69.3%.

[0619] 1 H NMR (400MHz, DMSO) δ11.17 (s, 1H), 9.66 (d, J = 17.1Hz, 1H), 8.63 (s, 2H), 8.45 (s, 1H), 8.18 (d, J = 8.3Hz, 1H), 7.96-7.82 (m, 1H), 7.68 (d, J=7.3Hz, 1H), 7.37 (ddd, J=8.9, 8.4, 6.2Hz, 2H), 7.25 (dd, J=8.6, 2.7Hz, 2H), 5.17 (dd, J=12.7, 5.4Hz, 1H), 4. 34 (s, 1H), 4.19 (ddd, J = 10.8, 6.8, 3.7Hz, 1H), 4.05 (ddd, J = 11.2, 6.5, 4.9Hz, 1H), 3.71-3.65 (m, 2H), 3.38 (ddd, J = 12.9, 1 1.2, 5.4Hz, 2H), 3.32-3.26 (m, 1H), 3.18 (dd, J=14.2, 6.1Hz, 2H), 2.98-2.83 (m, 1H), 2.71-2.55 (m, 2H), 2.12-2.02 (m, 1H).

[0620] Test case

[0621] Experiment 1: Solubility Test

[0622] Experimental Method: Approximately 0.5 mL of distilled water was taken in a 5 mL centrifuge tube and slowly added to the dried compound until it could not be dissolved (the solution remained cloudy even after shaking at 25°C). The solution was filtered into another clean, pre-weighed 5 mL EP tube, weighed again, and the weight of the solution was calculated. The filtrate was freeze-dried, weighed, and the mass of the remaining solid solute was calculated. The mass of the solvent was then calculated, and finally, the solubility of the compound in water was determined. The results are shown in Table 1.

[0623] Table 1. Solubility of the compounds of the present invention

[0624]

[0625]

[0626] Conclusion: The compounds described in this invention exhibit significantly higher water solubility than the already marketed drug pomalidomide, with a solubility increase of tens to hundreds of times. This high water solubility theoretically increases and enhances drug excretion by the kidneys, reducing the nephrotoxic side effects of pomalidomide. Furthermore, this high water solubility facilitates the formulation and clinical application of these compounds.

[0627] Experiment 2: In vitro antitumor activity assay

[0628] Test method:

[0629] MM.1S cells in the logarithmic growth phase were collected, and the cell suspension concentration was adjusted to 2 × 10⁻⁶ cells / mL. 4 Cells were seeded at a density of 5 μM / well in 96-well plates and incubated at 37°C in a 5% CO2 incubator for 2 h. Then, compounds with final concentrations of 50, 10, 1, 0.1, 0.01, 0.001, 0.0005, 0.0001, and 0 μM were added, with three replicates for each compound. DMSO was added to a final concentration of 0.5%. The plates were incubated at 37°C in a 5% CO2 incubator for 72 h. After incubation, 20 μL of 5 mg / mL MTT solution was added to each well, and the plates were incubated at 37°C for another 4 h. The supernatant was carefully aspirated, and 150 μL of DMSO was added. The plates were then placed in a Thermo Multiskan GO microplate reader, shaken for 5 min, and the absorbance (A) at 570 nm was measured. 测定 The absorbance value A was measured after adding DMSO to cell-free blank wells. 空白 As a blank, absorbance value A was measured using the same method with untreated cell pores. 对照 As a control, the cell viability of each well was calculated using the following formula:

[0630] Cell viability (%) = (A 测定 -A 空白 ) / (A 对照 -A 空白 )×100%.

[0631] Cell viability at various drug concentrations was calculated, and the cell viability versus drug concentration was plotted using GraphPad Prism 8.0 software to calculate the IC50. 50 value.

[0632] The compounds of the present invention were subjected to the above-mentioned activity assays. The results showed that all compounds of the present invention exhibited strong inhibitory activity against human multiple myeloma MM.1S cells. The results are shown in Table 2 below. Among them, IC50... 50 Values ​​less than 0.01 μM are considered A; IC 50 Values ​​greater than 0.01 μM and less than 0.05 μM are classified as B; IC 50 Values ​​greater than 0.05 μM and less than 0.1 μM are C; IC 50 Values ​​greater than 0.1 μM and less than 0.5 μM are classified as D.

[0633] Table 2. In vitro antitumor effects of the compounds of this invention

[0634]

[0635]

[0636] Experiment 3: Targeted transport study of amino acid transporter LAT1 / SLC7A5

[0637] 1. Construction of homeostatic cell lines:

[0638] In this experiment, we independently constructed a stable 293T cell line that highly expresses LAT1, which was used for targeted transport assays of the compounds of this invention.

[0639] Experimental method: 6 × 10⁶ 293T cells in logarithmic growth phase were used as the experimental method. 5 Cells were seeded in 6-well cell culture plates and cultured overnight. The constructed LAT1-pQCXIP plasmid expressing the protein C tag was transfected into the cells using PEI reagent. After 6 hours of incubation, the supernatant was discarded, and 2 ml of complete culture medium was added for further culture. 48 hours after transfection, green fluorescent protein expression was observed under a fluorescence microscope. Cells were then screened for 13 days using 8 μg / mL and 5 μg / mL puromycin to obtain 293T cells stably expressing high levels of LAT1.

[0640] The results of the established steady-state cell line construction were analyzed using Western blotting with a protein C antibody to detect LAT1 protein expression. The results are as follows: Figure 1 As shown in the image, the cell line has been successfully constructed.

[0641] 2. Targeted cell absorption assay of the compound of the present invention

[0642] Experimental Methods: This study used 293T and LAT1-293T steady-state cell lines. Cells were evenly seeded into 6cm culture dishes. After confluence the following day, 293T and LAT1-293T cells were collected by trypsin digestion, resuspended in PBS, and pre-incubated at 37°C for 2 hours. The cell concentration was adjusted to 1×10⁻⁶ cells / mL with physiological saline. 7 The concentration of each cell was aliquoted into 1.5 mL centrifuge tubes, 200 μL per tube. The compound was dissolved in DMSO and diluted to 20 μM with physiological saline (final DMSO concentration 0.5%), then added to the corresponding centrifuge tubes, 200 μL per tube, with three replicates per compound. The centrifuge tubes were inverted to mix and incubated at 37 °C for 30 min. After incubation, the cells were centrifuged at 8000 rpm for 2 min, and the cell pellet was collected. The cells were washed twice with pre-cooled physiological saline, and the supernatant was carefully discarded. 50 μL of purified water containing 2% formic acid was added to each tube, and the mixture was vortexed for 2 min. After complete cell lysis, 200 μL of an acetonitrile-methanol mixture (acetonitrile:methanol = 7:3) was added to each tube, and the cells were ready for mass spectrometry analysis.

[0643] Experimental results: As shown in Table 3, the compounds provided by this invention were found in significantly higher concentrations in the lysates of 293T cells with high LAT1 expression than in ordinary 293T cells, indicating that these compounds have significant LAT1 targeting activity.

[0644] Table 3. Absorption of the compounds of the present invention in 293T cells and 293T-LAT1 cells.

[0645]

[0646]

[0647] Experiment 4: In vivo antitumor drug efficacy trial I

[0648] Test method:

[0649] Model preparation: 6-8 week old NOD / SCID female mice were used. Experimental animals were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Animals were housed in an SPF-grade IVC system. All animals had free access to food and water, with a room temperature of 20-25℃, humidity of 40-70%, and a 12h / 12h day / night cycle. Human multiple myeloma RPMI-8226 cells were cultured in 1640 medium containing 10% fetal bovine serum. RPMI-8226 cells in the exponential growth phase were collected and resuspended in 1640 medium to a concentration of 1×10⁻⁶. 8 Add an equal volume of Matrigel gel to each mouse, and subcutaneously inject 0.2 mL per mouse into the axilla to establish a tumor-bearing nude mouse model. Wait until the tumor grows to 150–300 mm. 3 Mice were randomly assigned to groups based on tumor size and body weight to receive the drug. Tumor volume was calculated using the formula: major axis × minor axis. 2 / 2.

[0650] Grouping and Dosing: This experiment consisted of 7 groups: saline group, compound 06 group, compound 11 group, compound 24 group, compound 29 group, compound 101 group, and pomalidomide group, with 7 animals in each group. Administered orally once daily, pomalidomide at a dose of 15 mg / kg body weight, and other drugs at equimolar concentrations compared to lenalidomide, with a dosage volume of 10 mL / kg. After 14 days of continuous administration, the drugs were discontinued for 5 days for observation. Tumor diameter was measured twice weekly to observe the antitumor effect of the test drugs and changes in animal body weight.

[0651] Experimental results: The results are shown in Table 4 and Figure 2As shown, the compound of the present invention has a superior tumor-suppressing effect compared with the clinical control drug pomalidomide, which fully demonstrates the selective accumulation and targeting of the compound of the present invention in tumor cells and tumor tissues.

[0652] Table 4. Drug dosage, mouse body weight change rate, and relative tumor inhibition rate in the RPMI-8226 model.

[0653] compound Dosage (mg / kg) Weight change rate (%) Relative tumor inhibition rate (%) pomalidomide 15 3.96 40.75 06 29 8.50 58.12 11 28 6.19 50.87 24 32 8.20 59.54 29 32 7.83 46.93 101 42 6.79 45.35 111 29 8.69 57.01

[0654] ** p < 0.01, *** p < 0.001, vs solvent control group; weight change rate (%) = (weight on the day of measurement - initial weight at the start of the experiment) / initial weight at the start of the experiment × 100%.

[0655] Experiment 5: In vivo antitumor efficacy trial II

[0656] Test method:

[0657] Model preparation: Human multiple myeloma NCI-H929 cells were cultured in 1640 medium containing 10% fetal bovine serum. NCI-H929 cells in the exponential growth phase were collected and resuspended in 1640 medium to a concentration of 5 × 10⁻⁶ cells / mL. 7 Add an equal volume of Matrigel gel to each mouse, and subcutaneously inject 0.2 mL per mouse into the axilla to establish a tumor-bearing nude mouse model. Wait until the tumor grows to 150–300 mm. 3 Mice were randomly assigned to groups based on tumor size and body weight to receive the drug. Tumor volume was calculated using the formula: major axis × minor axis. 2 / 2.

[0658] Grouping and Dosing: This experiment was divided into 7 groups: saline group, compound 06 group, compound 11 group, compound 24 group, compound 29 group, compound 101 group, and pomalidomide group, with 7 animals in each group. Administered orally once daily, with pomalidomide at a dose of 10 mg / kg body weight. Other drugs were administered at equimolar concentrations compared to pomalidomide, with a dosage of 10 mL / kg. After 14 days of continuous administration, the drugs were discontinued for one day of observation. Tumor diameter was measured twice weekly to observe the antitumor effect of the test drugs and changes in animal body weight.

[0659] Experimental results: The results are shown in Table 5 and Figure 3 As shown, the compound provided by this invention has a superior tumor-suppressing effect compared with the clinical control drug pomalidomide, fully demonstrating the selective accumulation and targeting of the compound in tumor cells and tumor tissues.

[0660] Table 5. Drug dosage, mouse body weight change rate, and relative tumor inhibition rate in the NCI-H929 model.

[0661] compound Dosage (mg / kg) Weight change rate (%) Relative tumor inhibition rate (%) pomalidomide 10.0 10.4 59.32 06 19.4 15.3 85.97 11 18.9 16.4 72.66 24 21.5 16.5 80.79 29 21.6 14.2 69.19 101 28.2 15.4 63.98 111 19.4 16.1 86.52

[0662] ** p < 0.01, *** p < 0.001, vs solvent control group; weight change rate (%) = (weight on the day of measurement - initial weight at the start of the experiment) / initial weight at the start of the experiment × 100%.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, in: A is selected from -O-, -S-, or -NH-; Q is selected from alkylene or alkylene phenylene; R1 is selected from -H, alkyl, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NHR4, -C(O)NR4R4'; R2 is selected from -H, or optionally substituted alkyl groups; R3 is selected from H, hydroxyl, alkyl, alkylene-OC(O)R4, alkylene-OC(O)OR4, alkylene-OC(O)NHR4, alkylene-OC(O)NR4R4', -OR4, or ; Each R4 and R4' may be the same or different, and each is independently selected from hydrogen, alkyl, optionally substituted aryl, or optionally substituted arylalkylene; The term "optionally substituted" refers to unsubstituted or substituted by one or more substituents, wherein the substituents of the "optionally substituted alkyl", "optionally substituted aryl", "optionally substituted arylalkylene" and "optionally substituted 3-7 membered ring" are each independently selected from hydroxyl, alkyl, alkoxy, alkanoyloxy, alkanoyloxymethyl. The term "alkyl", as well as the alkyl portion in "alkoxy", "alkanoyloxymethyl", and "alkanoyloxy", are each independently C10. 1-20 Straight-chain or branched alkyl groups; The alkylene moiety in "alkylene", "alkylphenylene", "arylalkylene", "alkylene-OC(O)R4", "alkylene-OC(O)OR4", "alkylene-OC(O)NHR4" or "alkylene-OC(O)NR4R4'" is each independently C 1-6 Straight-chain or branched alkylene groups; The aryl group in "aryl" and "aryl alkylene" is a 6-10 member monocyclic or bicyclic fused aromatic ring group.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The term "alkyl", as well as the alkyl portion in "alkoxy", "alkanoyloxymethyl", and "alkanoyloxy", are each independently C10. 1-17 Straight-chain or branched alkyl groups.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The term "alkyl", as well as the alkyl portion in "alkoxy", "alkanoyloxymethyl", and "alkanoyloxy", are each independently C10. 1-10 Straight-chain or branched alkyl groups.

4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The term "alkyl", as well as the alkyl portion in "alkoxy", "alkanoyloxymethyl", and "alkanoyloxy", are each independently C10. 1-8 Straight-chain or branched alkyl groups.

5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The term "alkyl", as well as the alkyl portion in "alkoxy", "alkanoyloxymethyl", and "alkanoyloxy", are each independently C10. 1-6 Straight-chain or branched alkyl groups.

6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The "alkyl" and the alkyl portion in "alkoxy", "alkanoyloxymethyl", and "alkanoyloxy" are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl, dodecyl, pentadecyl, or hexadecyl.

7. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The alkylene portion in "alkylene", "alkylphenylene", "arylalkylene", "alkylene-OC(O)R4", "alkylene-OC(O)OR4", "alkylene-OC(O)NHR4" or "alkylene-OC(O)NR4R4'" is independently methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, tert-butylene, sec-butylene, n-pentylene, isopentylene, neopentylene, tert-pentylene, n-hexylene, and isohexylene.

8. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The aryl group in "aryl" and "aryl alkylene" is phenyl or naphthyl.

9. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R1 is selected from -H, or -(C=O)CH3, -(C=O)OC(CH3)3, -(C=O)OBn.

10. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R2 is selected from -H, methyl, ethyl, tert-butyl, isopropyl, n-butyl, n-hexyl, hydroxyethyl, .

11. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R3 is selected from -H, -OH, .

12. The compound of formula (I) according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, characterized in that, The amino acid moiety of the compound of formula (I) is either D-configuration or L-configuration.

13. The compound of formula (I) according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salts are selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, nitric acid, hydrogen sulfate, methanesulfonic acid, hydroxyethanesulfonic acid, tartaric acid, formic acid, acetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, trifluoroacetic acid, pyruvic acid, cinnamic acid, lauric acid, salicylic acid, citric acid, succinic acid, fumaric acid, benzoic acid, anthranilic acid, 2-(4-hydroxybenzoyl)benzoic acid, benzenesulfonic acid, ethanesulfonic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, phenylacetic acid, ascorbic acid, alginic acid, furoic acid, stearic acid, mucilage, mandelic acid, malic acid, pyruvic acid, pantothenic acid, camphorsulfonic acid, gluconic acid, glutamic acid, glucuronic acid, galacturonic acid, glycidic acid, lactic acid, malic acid, maleic acid, aspartic acid, glucohepanoic acid, glycerophosphate, sulfosalicylic acid, hemisulfonic acid, oxalic acid, and malonic acid.

14. The compound of formula (I) according to claim 12, or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salts are selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, nitric acid, hydrogen sulfate, methanesulfonic acid, hydroxyethanesulfonic acid, tartaric acid, formic acid, acetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, trifluoroacetic acid, pyruvic acid, cinnamic acid, lauric acid, salicylic acid, citric acid, succinic acid, fumaric acid, benzoic acid, anthranilic acid, 2-(4-hydroxybenzoyl)benzoic acid, benzenesulfonic acid, ethanesulfonic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, phenylacetic acid, ascorbic acid, alginic acid, furoic acid, stearic acid, mucilage, mandelic acid, malic acid, pyruvic acid, pantothenic acid, camphorsulfonic acid, gluconic acid, glutamic acid, glucuronic acid, galacturonic acid, glycidic acid, lactic acid, malic acid, maleic acid, aspartic acid, glucohepanoic acid, glycerophosphate, sulfosalicylic acid, hemisulfonic acid, oxalic acid, and malonic acid.

15. The following compounds: 。 16. A method for preparing a compound of formula (I) according to any one of claims 1-14 or a pharmaceutically acceptable salt thereof: This includes obtaining formula (C) by passing compounds of formula (A) and (B) through step A: Step A: Obtain formula (C) by substitution reaction of formula (A) and formula (B); Formula (C) is prepared by substitution reaction of formulas (A) and (B) under alkaline catalysis, in a suitable solvent, and at an appropriate temperature. in, In equations (B) and (C), R3 is as described in equation (I), but cannot be H, OR4; In formula (B), B is selected from Cl, Br, I, OTs, and OMs; Alternatively, equation (C) can be obtained through the reaction in step A': Step A': S1 and S2 are condensed to obtain S3, then S3 is deprotected to obtain S4, and then S4 and S5 are ammonolycated under Lewis base catalysis to obtain S6, which is then reduced to obtain R3, a compound of formula (C') selected from OR4. It also includes obtaining formula (E) from compounds of formula (C) and formula (D) through step B: Step B: Acylation of formulas (C) and (D) yields formula (E); Formulas (C) and (D) are dissolved in a solvent and reacted under heating conditions to obtain formula (E). In equations (C) and (E), R3 is defined as described in equation (I) above; Alternatively, it may also include obtaining formula (G) from compounds of formulas (C) and (F) via step C: Step C: Formula (C) and formula (F) are prepared by acylation reaction to obtain formula (G); Formula (C) and Formula (F) are reacted in a suitable solvent. After the reaction is completed, the mixture is concentrated under reduced pressure to obtain Formula (G). In equations (C) and (G), R3 is defined as described in equation (I); Alternatively, it may also include obtaining formula (J) from compounds of formula (C) and formula (H) via step D: Step D: Combine formula (C) and formula (H) through a condensation reaction to obtain formula (J); Disperse formula (C) and formula (H) in a suitable solvent and react them under heating conditions. After the reaction is completed, evaporate the solution directly to obtain formula (J). In equations (C) and (J), R3 is defined as described in equation (I); This also includes reacting formula (E), formula (G), or formula (J) with formula (L) under base catalysis via nucleophilic substitution and optional deprotection reaction to obtain formula (I), as shown in the following synthetic step E: Step E: React formula (E) or (G) or (J) with formula (L) in a suitable solvent. After the reaction is complete, concentrate under reduced pressure to obtain formula (I). in: In formula (L), C is selected from any one of the groups -OH, -SH, and -NH2; R5 is Cl. .

17. The preparation method according to claim 16, characterized in that, In step A, the base is potassium carbonate, cesium carbonate, sodium hydride, or lithium bis(trimethylsilylamine); the solvent is N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or N-methylpyrrolidone; and the temperature is 0 °C to 25 °C.

18. The preparation method according to claim 16, characterized in that, In step B, the solvent is tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, or 2-methyltetrahydrofuran; the temperature is 45 ℃-90 ℃.

19. The preparation method according to claim 16, characterized in that, In step C, the solvent is dichloromethane, acetonitrile, or tetrahydrofuran; the temperature is -20 ℃ to 50 ℃.

20. The preparation method according to claim 16, characterized in that, In step D, the solvent is dichloromethane, acetonitrile, tetrahydrofuran, or dichloroethane; the temperature is 45 ℃-90 ℃.

21. The preparation method according to claim 16, characterized in that, In step E, the solvent is selected from dichloromethane, acetonitrile, N,N-dimethylformamide, or tetrahydrofuran; the temperature is -20 ℃ to 50 ℃.

22. A pharmaceutical composition comprising the compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. The pharmaceutical composition according to claim 22, characterized in that, The pharmaceutically acceptable excipients are selected from: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, or coating materials.

24. The pharmaceutical composition according to claim 23, characterized in that, The pharmaceutically acceptable excipients include fillers comprising one or more of lactose, sucrose, dextrin, starch, mannitol, sorbitol, dicalcium phosphate, calcium sulfate, calcium carbonate, and microcrystalline cellulose; and binders comprising one or more of sucrose, starch, povidone, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene glycol, pharmaceutical grade ethanol, and water. The disintegrant includes one or more of starch, crospovidone, crospovidone sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and effervescent disintegrants.

25. The pharmaceutical composition according to any one of claims 22-24, characterized in that, The pharmaceutical composition can be formulated into solid oral dosage forms, liquid oral dosage forms, or injections; The solid and liquid oral preparations include: tablets, dispersible tablets, sugar-coated preparations, granules, dry powders, capsules, syrups, and solutions; the injectable preparations include: small injections, large-volume infusions, and lyophilized powder injections.

26. Use of the compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 22-25 in the preparation of a medicament for the prevention and / or treatment of hematologic disorders.

27. The use according to claim 26, characterized in that, The diseases mentioned are selected from blood cancer and bone marrow cancer, acute leukemia, chronic leukemia, lymphoma, Kaposi's sarcoma, multiple myeloma, or myelodysplastic syndrome.

28. Use of the compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 22-25, in combination with one or more other active pharmaceutical ingredients, in the preparation of a medicament for the prevention and / or treatment of hematologic disorders.

29. The use according to claim 28, characterized in that, The diseases mentioned are selected from blood cancer and bone marrow cancer, acute leukemia, chronic leukemia, lymphoma, Kaposi's sarcoma, multiple myeloma, or myelodysplastic syndrome.

30. The use according to claim 28 or 29, characterized in that, The active drug is a macromolecule, a small molecule, or a cell therapy.

31. The use according to claim 30, characterized in that, The active drug is a protein, a synthetic inorganic or organometallic molecule, an organic molecule, or a CAR cell.

32. The use according to claim 28 or 29, characterized in that, The active pharmaceutical ingredient includes one or more of the following substances: melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, octopuzumab, proteasome inhibitor, histone deacetylase inhibitor, and BET inhibitor.

33. The use according to claim 32, characterized in that, The proteasome inhibitor is bortezomib, carfilzomib, esazomib, opozomib, or marizomib.

34. The use according to claim 32, characterized in that, The histone deacetylase inhibitor is either Pabistat or ACY241.

35. The use according to claim 32, characterized in that, The BET inhibitor is GSK778.

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