4-carbonylaminoisoindolin-1-one derivatives, compositions including the same, and methods of use

Abstract

A 4-carbonylamino isoindolin-1-one 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 and reproduction of multiple myeloma.

Description

Technical Field

[0001] This invention relates to a class of 4-carbonylaminoisoindoline-1-one compounds, their preparation methods, pharmaceutical compositions comprising them, and their uses. Background Technology

[0002] Due to continuous changes in population structure, ecological environment, and lifestyle, cancer has gradually become one of the leading diseases threatening human health. Surgery, radiotherapy, and chemotherapy are currently the most common methods used to treat cancer. For solid tumors in a specific part of the body, surgery is the first-line treatment for cancer. After surgery, radiotherapy, which uses high-energy particle beams to destroy remaining cancer cells and prevent cancer recurrence, is also a common treatment method. For smaller tumors or cancers that cannot be treated surgically, such as hematologic malignancies, radiotherapy or chemotherapy can be administered directly. Chemotherapy drugs typically work by binding to cellular DNA to inhibit cell division and kill dividing cells; there are currently over 100 different types of chemotherapy drugs available. However, because radiotherapy and chemotherapy lack selectivity, they often cause severe side effects. In addition, drug resistance to chemotherapy drugs is one of the major obstacles to cancer treatment. Targeted therapy and immunotherapy are new methods for treating cancer proposed in recent years, bringing hope to patients with drug-resistant tumors and advanced-stage cancer. Molecularly targeted drugs and immunotherapies have become the main treatment methods for patients with hematologic malignancies, completely changing the treatment paradigm for hematologic diseases. Therefore, developing more and more precise targeted and immunotherapies is a necessary approach to the prevention, treatment, and management of cancer and other diseases.

[0003] Hematologic disorders, especially malignant hematologic malignancies (MH), have seriously threatened human life and health. Common clinical manifestations include acute leukemia, lymphoma, multiple myeloma, and myelodysplastic syndromes. Multiple myeloma (MM) is a malignant disease characterized by the abnormal proliferation of clonal plasma cells. Due to the malignant proliferation and widespread infiltration of monoclonal plasma cells, which secrete large amounts of monoclonal immunoglobulins, it leads to a series of clinical symptoms such as extensive bone destruction, recurrent infections, anemia, hypercalcemia, and renal insufficiency. Currently, this disease is more prevalent in middle-aged and elderly individuals and is the second most common hematologic malignancy. However, MM remains incurable, and almost all patients experience relapse and drug resistance throughout the course of the disease. Therefore, how to diagnose and treat relapsed MM patients and improve the efficacy and prognosis of treatment is a matter of great concern.

[0004] Newly diagnosed multiple myeloma (MM) patients are usually sensitive to many cytotoxic drugs, and treatment primarily involves induction chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT). While the efficacy is generally sustainable, the vast majority of cases relapse or progression. However, the advent of new drugs such as thalidomide, bortezomib, and lenalidomide has changed the treatment regimen for multiple myeloma. Among these, the main treatment regimens include bortezomib / lenalidomide / dexamethasone (VRD), bortezomib / cyclophosphamide / dexamethasone (VCD), and bortezomib / thalidomide / dexamethasone (VTD).

[0005] Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal diseases originating from hematopoietic stem cells. They are characterized by abnormal myeloid cell development, resulting in ineffective hematopoiesis, refractory cytopenia, and a high risk of transformation into acute myeloid leukemia (AML), thus being called a pre-leukemic malignancy. The risk of MDS increases with age. Recent statistics show an annual incidence of 4 per 100,000, reaching 50 per 100,000 in people over 80 years of age. Most MDS patients require long-term, repeated blood transfusions; statistics show that over 90% of MDS patients require transfusions during their illness, with 30%-45% becoming transfusion-dependent. Long-term transfusions can lead to iron overload, which, without appropriate treatment, can cause severe organ dysfunction or death. Although treatments such as decitabine, azacitidine (AZA), thalidomide, lenalidomide, and hematopoietic stem cell transplantation (HSCT) have improved patients' quality of life, they cannot eliminate the malignant clonal effects of MDS.

[0006] Among them, the immunomodulators thalidomide and lenalidomide are both glutamate derivatives, which mainly achieve targeted therapy of tumors through direct anti-tumor effects, immunomodulatory effects, and anti-angiogenesis mechanisms. (Reference: N. Ferrara, RSKerbel, Angiogenesis as a therapeutic target, Nature, 438(2005)967-974.). Thalidomide was recalled by the FDA in the 1960s due to its ability to cause severe birth defects in infants, but it is still used to treat multiple myeloma and other hematological cancers. Of course, drug safety and serious side effects remain unavoidable facts. Lenalidomide, as a thalidomide derivative, has been approved for the treatment of myelodysplastic syndromes, multiple myeloma, mantle cell lymphoma, follicular lymphoma, or marginal zone lymphoma since it was developed and marketed by Celgene in the United States in 2005. However, the FDA added a black box warning to lenalidomide, which included warnings about embryo-fetal toxicity, hematologic toxicity (including significant neutropenia and thrombocytopenia), and venous and arterial thromboembolism.

[0007] Furthermore, in multiple myeloma, the expression of L-type amino acid transporter 1 (LAT1 / SLC7A5) is abnormally elevated due to the particularly high demand for nutrients such as amino acids from cancer cells. LAT1 is a transmembrane transporter essential for the uptake of L-type amino acids into cells and is abnormally highly expressed in various malignant tumors (Reference: The L-Type Amino Acid Transporter LAT1-An Emerging Target in Cancer, International Journal of Molecular Science (2019).). Therefore, LAT1 is considered an important drug target for cancer treatment.

[0008] In addition to its poor solubility and low bioavailability in water, lenalidomide's high toxicity and side effects have also been major problems plaguing the drug. Therefore, the research goals for next-generation immunomodulatory inhibitors are to reduce toxicity, improve solubility, enhance bioavailability, improve drug targeting, and increase drug concentration in tumor cells. Summary of the Invention

[0009] This invention provides a 4-carbonylaminoisoindoline-1-one compound, such as a compound of 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-labeled mixture thereof, or a nitrogen oxide thereof. It exhibits good anti-multiple myeloma activity and can effectively treat and / or prevent the growth and proliferation of multiple myeloma. Methods for preparing said compound, pharmaceutical compositions, and uses are also provided.

[0010] A compound of formula (I), 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 isotopic label thereof, or a nitrogen oxide thereof,

[0011]

[0012] in:

[0013] A is selected from -O-, -S-, -NH-, or A does not exist;

[0014] Q is selected from substituted alkylene groups or alkylene arylene groups;

[0015] R1 is selected from -H, alkyl, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NHR4, -C(O)NR4R4';

[0016] R2 is selected from -H, optionally substituted alkyl, alkenyl, alkenylalkylene, ynyl, ynylalkylene, aryl, arylalkylene, heteroaryl, heteroarylalkylene;

[0017] R3 is selected from -H, hydroxyl, alkyl, alkenyl, alkenylalkylene, alkynyl, alkynylalkylene, aryl, arylalkylene, heteroaryl, heteroarylalkylene, alkylene-OC(O)R4, alkylene-OC(O)OR4, alkylene-OC(O)NHR4, alkylene-OC(O)NR4R4', or -OR4;

[0018] Each R4 and R4' may be the same or different, and each is independently selected from hydrogen, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alicyclic, optionally substituted alicyclic-heterocyclic, optionally substituted arylalkylene or optionally substituted heteroarylalkylene; or R4 and R4' form an optionally substituted 3-7 membered ring;

[0019] The term "optionally substituted" means unsubstituted or substituted by one or more substituents, wherein the substituents of the "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, arylalkylene, heteroarylalkylene, aryloxy, heteroaryloxy, cycloalkyl, aliheterocyclic, cycloalkyloxy, heterocycloalkyloxy, arylalkoxy, heteroarylalkoxy, alkanoyloxymethyl, alkanoyloxy, alkanoyloxy, or alkanoyloxy.

[0020] Optionally, the alkyl portion of "alkyl", "alkoxy", "arylalkoxy", "heteroarylalkoxy", "alkanoyloxymethyl", "alkoxyacyloxy", "alkanoyloxy", and "alkoxyacyl" 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. 1-7 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, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, or hexadecyl;

[0021] Optionally, the alkylene moiety in "alkylene", "alkenylalkylene", "alkynylalkylene", "arylalkylene", "heteroarylalkylene", "alkylene-OC(O)R4", "alkylene-OC(O)OR4", "alkylene-OC(O)NHR4", or "alkylene-OC(O)NR4R4'" or "alkylene arylene" 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 1-3 The 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;

[0022] Optionally, the cycloalkyl portion in "cycloalkyloxy" and "cycloalkyl" is C 3-8 The cycloalkyl group may optionally be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0023] The alkenyl moiety in "alkenyl" and "alkenyl alkylene" is independently C2-C. 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;

[0024] The alkynyl group in "alkynyl" and "alkynyl alkylene" is independently C2-C. 20 Straight-chain or branched alkenyl 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] Optionally, R1 is selected from -H, or -(C=O)CH3, -(C=O)OC(CH3)3;

[0030] Optionally, R2 is selected from -H, methyl, ethyl, tert-butyl, allyl, propargyl, or benzyl;

[0031] Optionally, R3 is selected from -H, -OH,

[0032] Optionally, the amino acid moiety of the compound of formula (I) is in the D configuration or the L configuration.

[0033] Optionally, the compound of formula (I), or its optical isomer, its pharmaceutically acceptable salt, its solvate, its inclusion complex, its racemate, its isotope label, or its nitride, is selected from the following compounds:

[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 disorders are selected from hematologic malignancies and bone marrow cancers, lymphomas, Kaposi's sarcoma, 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 an oxide thereof;

[0059] This includes obtaining compound (C) from compounds (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) can be prepared by substitution reaction in a suitable solvent (e.g., N,N-dimethylformamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc.) at a temperature of 0°C to 25°C, under the catalysis of a base (e.g., potassium carbonate, cesium carbonate, sodium hydride, bis(trimethylsilylamine) or a suitable solvent) at a temperature of 0°C to 25°C to obtain formula (C).

[0062]

[0063] in,

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

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

[0066] Optionally, equation (B) can be derived from one of the following methods 1-8, but is not limited to these methods:

[0067] Method 1:

[0068]

[0069] 1) The carboxyl group was reacted with thionyl chloride under reflux to obtain acyl chloride; 2) The acyl chloride and paraformaldehyde were reacted under zinc chloride catalyst to obtain compound (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 solution of acid, 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 compound (B).

[0073] Or 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 compound (B).

[0076] Or method 4:

[0077]

[0078] At 0°C, pyridine was added to a dichloromethane solution of methyl 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 compound (B).

[0079] Or method 5:

[0080]

[0081] 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 (B) compound.

[0082] Or method 6:

[0083]

[0084] 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) compound.

[0085] Or method 7:

[0086]

[0087] 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 compound of formula (B).

[0088] Or method 8:

[0089]

[0090] 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, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the corresponding p-benzenesulfonyloxy-substituted compound (B).

[0091] Each Y is selected from -R4, -OR4, -NHR4, NR4R4', where R4 and R4' are as described in equation (I).

[0092] Alternatively, equation (C) can be obtained through the reaction of step A':

[0093] Step A': S1 and S2 are condensed to obtain S3, then S3 is deprotected to obtain S4, and then S4 and S5 are substituted and amino-cleaved under alkaline catalysis to obtain LN-S5, which is then reduced with iron powder to obtain formula (C).

[0094]

[0095] This also includes passing equations (C) and (D) through step B.

[0096] Step B: Formula (C) and formula (D) are subjected to an acylation reaction to obtain formula (E).

[0097] Preferably, formula (C) and p-nitrophenyl chloroformate are dissolved in (such as tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, etc.) and reacted under reflux conditions to obtain formula (E);

[0098] Optionally, after the reflux reaction is completed, the mixture is concentrated under reduced pressure, and ethyl acetate, dichloromethane, or petroleum ether is added and stirred until homogeneous to obtain a suspension. The suspension is then filtered under reduced pressure and washed or directly evaporated to dryness to obtain formula (E).

[0099]

[0100] In equations (C) and (E), R3 is defined as described in equation (I) above;

[0101] Alternatively, it may also include obtaining equation (G) from equations (C) and (F) through step C:

[0102] Step C: Formula (C) and formula (F) are prepared by acylation reaction to obtain formula (G);

[0103] Optionally, the synthesis method of formula (G) is as follows: at low temperature (preferably 0°C), formula (C) is slowly added dropwise to a triphosgene solution in dichloromethane or acetonitrile, and the temperature is slowly raised to 30°C-60°C (preferably 45°C). After the reaction is completed, the solution is concentrated under reduced pressure to obtain formula (G).

[0104]

[0105] In equations (C) and (G), R3 is defined as described in equation (I);

[0106] Alternatively, it may also include obtaining equation (J) from equations (C) and (H) through step D:

[0107] Step D: Combine formula (C) and formula (H) through a condensation reaction to obtain formula (J);

[0108] Optionally, formula (C) and N,N′-carbonyldiimidazole are dispersed in tetrahydrofuran and reacted under reflux. After the reaction is complete, the mixture is concentrated under reduced pressure, and ethyl acetate is added and stirred until homogeneous to obtain a suspension. The suspension is then filtered under reduced pressure and washed or directly evaporated to dryness to obtain formula (J).

[0109]

[0110] In equations (C) and (J), R3 is defined as described in equation (I);

[0111] When A in formula (I) is selected from -O-, -S-, -NH-, formula (E), (G), or (J) is reacted with formula (L) under base catalysis via nucleophilic substitution and optional deprotection reaction to obtain formula (I), as shown in the following synthetic steps E:

[0112] Step E:

[0113]

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

[0115] R5 is Cl, or

[0116] In equation (E, or G or J), R3 is as shown in equation (I);

[0117] 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:

[0118]

[0119] Disperse formula (M) in a suitable solvent (e.g., ethyl acetate or dioxane), then pass hydrogen chloride gas (or add other acids) to deprotect the mixture. React at room temperature or 40°C to precipitate a solid. If no solid is found, add diethyl ether to precipitate another solid. Filter the mixture to obtain formula (N) in the form of a salt.

[0120] 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.

[0121]

[0122] Formula (O) is dispersed in a suitable solvent (e.g., methanol or ethanol) and reduced by palladium carbon hydrogen to obtain formula (N) in its free state. The free state compound can also be obtained by dispersing the salt form of formula (N) in a suitable solvent (e.g., methanol or ethanol) and then adding an equimolar amount of base.

[0123] The preparation of the above-mentioned compound (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 nitrogen oxide, also includes a method for obtaining compound (R) by synthesizing compound (C) and compound (Q) through synthetic method two:

[0124] When A is absent in formula (I), the formula is prepared by synthetic step F: formula (A) or formula (C) is condensed with formula (P) using a suitable condensing agent (e.g., HATU or TBTU) and optionally deprotected to obtain formula (R).

[0125] Step F:

[0126]

[0127] In equation (P), Q is defined as described in equation (I) above.

[0128] In another aspect, the present invention provides the use of the compound of formula (I) or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its inclusion complex, or its racemic mixture, or its isotopic label, or its nitride, or pharmaceutical compositions thereof, in combination with one or more other active pharmaceutical ingredients (“second active compound”), in the preparation of a medicament for the prevention and / or treatment of hematologic disorders; preferably, the disorders are selected from hematologic malignancies and bone marrow cancers, lymphomas, Kaposi's sarcoma, or myelodysplastic syndromes; preferably, the other active pharmaceutical ingredient is dexamethasone and / or pentezomib.

[0129] Preferably, the diseases are selected from blood cancers and bone marrow cancers, such as acute and chronic leukemia and multiple myeloma, including lymphoblastic leukemia, chronic myeloid leukemia, myeloid leukemia, lymphocytic leukemia, idiopathic 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.

[0130] 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)).

[0131] 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.

[0132] Examples of the second active ingredient of the present invention may include one or more of the following substances: melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, octopuzumab, proteasome inhibitors (e.g., bortezomib, carfilzomib, esazozomib, opozomib, or marizomib), histone deacetylase inhibitors (e.g., pabistat, ACY241), and BET inhibitors (e.g., GSK778).

[0133] 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 Cl and 125 I. Compounds containing other isotopes of these and / or other atoms are within the scope of this invention.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] Abbreviations

[0138] DCM: Dichloromethane

[0139] DCE: Dichloroethane

[0140] THF: Tetrahydrofuran

[0141] TFA: Trifluoroacetic acid

[0142] 2-MeTHF: 2-Methyltetrahydrofuran

[0143] DMSO: Dimethyl sulfoxide

[0144] DMF: N,N-dimethylformamide

[0145] DIPEA: N,N-Diisopropylethylamine

[0146] HATU: 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate

[0147] TBTU: O-benzotriazole-N,N,N′,N′-tetramethylureatetrafluoroboric acid

[0148] NMP: N-methylpyrrolidone

[0149] DMAC: N,N-Dimethylacetamide

[0150] LiHMDS: Lithium bis(trimethylsilyl)aminobis(TBS): Tert-butyldimethylsilyl

[0151] LAT1: L-amino acid transfection 1

[0152] RPMI-8226: Human multiple myeloma cells

[0153] NCI-H929: Human myeloma cells Attached Figure Description

[0154] Figure 1 The expression of LAT1 in different cells.

[0155] Figure 2 The trend of tumor volume change in mice in the RPMI-8226 model (n=7).

[0156] Figure 3 The trend of tumor volume change in mice in the NCI-H929 model (n=7). Detailed Implementation

[0157] 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.

[0158] The embodiments of the present invention are described in detail below, but the provided embodiments do not limit the present invention in any way.

[0159] Example

[0160] General Synthesis Method 1:

[0161] The synthesis is carried out using step F.

[0162] Formula (A) (1.0 equivalent), Formula (P) (1.0 equivalent), triethylamine (1.0 equivalent) and TBTU (1.0 equivalent) were dissolved in DMF and stirred at room temperature for 12 h.

[0163] 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 with anhydrous sodium sulfate, evaporated under reduced pressure, purified by silica gel column chromatography, and then TFA and DCM were added. The mixture was stirred at room temperature for 1 hour, and the reaction solution was evaporated under reduced pressure to obtain a white solid.

[0164] The above product was dissolved in methanol, Pd / C was added, and the mixture was stirred at room temperature for 1 hour under hydrogen atmosphere. The solution was filtered and collected, then evaporated to dryness under reduced pressure to obtain the final product.

[0165] Example 1: Preparation of compound 43

[0166]

[0167] The product was prepared using general synthesis method 1, yielding a white solid product with a yield of 83%.

[0168] 1 H NMR (400MHz, DMSO-d6) δ11.16 (s, 1H), 11.03 (s, 1H), 8.10-7.52 (m, 4H), 7.50 (d, J=4.3Hz, 2H), 5.15 (dd, J=13.4, 5 .1Hz, 1H), 4.39(m, 2H), 3.69(s, 1H), 3.08-2.89(m, 2H), 2.73-2.60(m, 2H), 2.36-2.28(m, 1H), 2.06-2.03(m, 1H).

[0169] General Synthesis Method 2:

[0170] The synthesis is carried out using steps B and E.

[0171] Formula (C) (1.0 equivalent) and Formula (D) (1.5 equivalent) were dissolved in THF and stirred under reflux for 2 hours. The mixture was concentrated under reduced pressure, and ethyl acetate was added and stirred until homogeneous to obtain a suspension. The suspension was filtered under reduced pressure and washed with ethyl acetate or directly evaporated to dryness to obtain Formula (E).

[0172] Dissolve formulas (E) and (L) (1.1 equivalents) in DMF, add DIPEA (1.5 equivalents) dropwise while stirring at room temperature, continue stirring at room temperature until the raw materials disappear, add acid water to adjust the pH to 3-4, add ethyl acetate, and then wash the organic phase successively with saturated ammonium chloride aqueous solution, water, and saturated sodium chloride aqueous solution. Collect the organic phase and dry it with anhydrous sodium sulfate. Filter the filtrate and evaporate it to dryness under reduced pressure. After purification by silica gel column chromatography, deprotection or no deprotection is used to obtain formula (I).

[0173] The synthesis method of formula (L) is as follows: Boc-protected amino acid (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).

[0174] Example 2: Preparation of compound 44

[0175]

[0176] The hydrochloride was prepared using general synthesis method 2, and was obtained as a white solid with a yield of 86.36%.

[0177] 1 H NMR (600MHz, DMSO-d6) δ11.02 (s, 1H), 9.70 (s, 1H), 8.59 (s, 2H), 7.82-7.70 (m, 1H), 7.50 (dd, J=6.3, 2.5Hz, 2H), 5.14 (dt, J=13.3, 4.7Hz, 1H), 4 .63 (ddd, J=12.1, 8.7, 3.5Hz, 1H), 4.51-4.33 (m, 3H), 4.30 (s, 1H), 2.99 -2.88(m, 1H), 2.67-2.59(m, 1H), 2.37-2.27(m, 1H), 2.08-2.01(m, 1H).

[0178] Example 3: Preparation of compound 45

[0179]

[0180] The product was prepared using general synthesis method 1, yielding a white solid product with a yield of 86%.

[0181] 1 H NMR (400MHz, DMSO-d6) δ10.68 (d, J=14.6Hz, 1H), 7.95-7.93 (m, 1H), 7.49-7.45 (m, 2H), 5.13 (dd, J=13.1, 4.9Hz, 1H), 4.49 -4.33(m, 2H), 3.46-3.42(m, 1H), 3.17(s, 1H), 2.94-2.88(m, 1H), 2.61-2.55(m, 3H), 2.37-2.31(m, 1H), 2.03-1.96(m, 3H).

[0182] Example 4: Preparation of compound 46

[0183]

[0184] The hydrochloride was prepared using general synthesis method 2, yielding a white solid with a yield of 33.72%.

[0185] 1 H NMR (400MHz, DMSO-d6) δ11.04 (s, 1H), 10.21 (s, 1H), 8.76 (s, 3H), 7.79 (dt, J=8.0, 4.0Hz, 1H), 7.59- 7.50 (m, 2H), 7.31 (d, J=8.6Hz, 2H), 7.22 (d, J=8.6Hz, 2H), 5.15 (dd, J=13.3, 5.1Hz, 1H), 4.53 (d, J=1 7.6Hz, 1H), 4.43 (d, J=17.6Hz, 1H), 4.29 (t, J=6.4Hz, 1H), 3.70 (s, 3H), 3.18 (ddd, J=21.2, 14.2, 6.5 Hz, 2H), 2.98-2.86 (m, 1H), 2.62 (d, J=16.8Hz, 1H), 2.38 (dd, J=13.1, 4.5Hz, 1H), 2.11-2.00 (m, 1H).

[0186] Example 5: Preparation of Compound 47

[0187]

[0188] The hydrochloride was prepared using general synthesis method 2, yielding a white solid with a yield of 55.55%.

[0189] 1H NMR (600MHz, DMSO-d6) δ11.02 (s, 1H), 9.54 (d, J=15.4Hz, 1H), 8.49 (s, 2H), 7.8 4-7.69 (m, 1H), 7.60-7.32 (m, 2H), 5.23-5.10 (m, 2H), 4.45 (dd, J=17.4, 13.1Hz , 1H), 4.34 (dd, J=17.4, 8.6Hz, 1H), 4.09 (s, 1H), 3.00-2.86 (m, 1H), 2.65-2.59 (m, 1H), 2.31 (qd, J=13.0, 5.4Hz, 1H), 2.08-2.00 (m, 1H), 1.41 (d, J=6.6Hz, 3H).

[0190] Example 6: Preparation of compound 49

[0191]

[0192] The sample was prepared using general synthesis method 2, yielding a white solid with a yield of 82.91%.

[0193] 1 H NMR (600MHz, DMSO-d6) δ12.88 (s, 1H), 10.99 (s, 1H), 10.32 (s, 1H), 8.27 (d, J=8.1Hz, 1H) , 7.75-7.70 (m, 1H), 7.56-7.49 (m, 2H), 5.13 (dd, J=12.9, 4.6Hz, 1H), 4.46-4.30 (m, 3H), 3 .40 (ddd, J=13.6, 7.1, 5.1Hz, 1H), 3.09 (dt, J=13.7, 8.2Hz, 1H), 2.96-2.87 (m, 1H), 2.60 ( d, J=16.8Hz, 1H), 2.37 (td, J=13.3, 8.9Hz, 1H), 2.06-1.99 (m, 1H), 1.85 (d, J=1.9Hz, 3H).

[0194] Example 7: Preparation of Compound 50

[0195]

[0196] The sample was prepared using general synthesis method 2, yielding a white solid. The yield was 86.36%.

[0197] 1H NMR (DMSO-d6, 600MHz): δ8.12(s, 1H), 7.62(s, 1H), 7.37(s, 1H), 7.21-7.26(m, 2H), 4.75-4.76(m, 1H), 4.39-4.57(m, 3H), 3.50(s, 2H), 3.01(s, 2H), 2.67-2.77(m, 1H), 2.04-2.33(m, 4H), 1.41-1.72(m, 3H).

[0198] Example 8: Preparation of Compound 72

[0199]

[0200] The methanesulfonate was prepared using general synthesis method 2, and deprotected with methanesulfonic acid to obtain a white solid with a yield of 27.31%.

[0201] 1 H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 10.17 (s, 1H), 8.44 (s, 3H), 7.82-7.76 (m, 1H) , 7.57-7.51 (m, 2H), 7.26 (dd, J=23.2, 8.6Hz, 4H), 5.16 (dd, J=13.3, 5.1Hz, 1H), 4.5 1 (d, J=17.6Hz, 1H), 4.39 (dd, J=20.0, 11.5Hz, 2H), 3.72 (s, 3H), 3.12 (d, J=5.1Hz, 2 H), 2.99-2.87 (m, 1H), 2.62 (d, J=16.5Hz, 1H), 2.40-2.30 (m, 4H), 2.09-1.99 (m, 1H).

[0202] Example 9: Preparation of Compound 73

[0203]

[0204] The hydrochloride was prepared using general synthesis method 2, yielding a white solid with a yield of 58.84%.

[0205] 1H NMR (400MHz, DMSO-d6) δ11.04 (s, 1H), 10.20 (s, 1H), 8.47 (s, 3H), 7.78 (dd, J=8.9, 4.0Hz, 1H) , 7.57-7.49 (m, 2H), 7.34 (d, J=8.5Hz, 2H), 7.22 (d, J=8.5Hz, 2H), 5.15 (dd, J=13.3, 5.1Hz, 1H ), 4.52 (d, J = 17.7Hz, 1H), 4.42 (d, J = 17.7Hz, 1H), 4.18 (t, J = 6.2Hz, 1H), 3.16 (d, J = 6.1Hz, 2H ), 3.02-2.86 (m, 1H), 2.62 (d, J=16.8Hz, 1H), 2.37 (dd, J=13.1, 4.4Hz, 1H), 2.10-2.00 (m, 1H).

[0206] Example 10: Preparation of Compound 74

[0207]

[0208] The sulfate was prepared using general synthesis method 2, and deprotection was performed with concentrated sulfuric acid to obtain a white solid sulfate with a yield of 54.82%.

[0209] 1 H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 10.16 (s, 1H), 8.42 (s, 3H), 7.82-7.76 (m, 1H), 7.54 (d, J=3.6Hz, 2H), 7.26 (dd, J=21.2, 8.4Hz, 4H), 5.16 (dd, J= 13.2, 4.9Hz, 1H), 4.53-4.35 (m, 3H), 3.72 (s, 3H), 3.11 (d, J=6.6Hz, 2H), 2 .98-2.89(m, 1H), 2.64-2.59(m, 1H), 2.38-2.34(m, 1H), 2.08-2.01(m, 1H).

[0210] General Synthesis Method 3:

[0211] The synthesis is carried out using steps A, C (or D), and E.

[0212] Step 1: Preparation of chloromethyl reagent

[0213] (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).

[0214] (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).

[0215] Step Two:

[0216] 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).

[0217] Disperse formula (C) (1.0 equivalent), formula (F) (0.43 equivalent), or formula (H) (1.0 equivalent) in acetonitrile, stir at 40°C for 1 h, and evaporate under reduced pressure to obtain formula (G) or formula (J).

[0218] Step 3:

[0219] Dissolve formula (L) in DCM, cool to 0°C, and add DIPEA and a DCM solution of formula (G) or formula (J). After reacting at low temperature for 30 minutes, quench with dilute acid water, dry the organic phase with anhydrous sodium sulfate, and purify by vacuum distillation and column chromatography to obtain formula (M) or formula (O). Then, deprotect to obtain formula (I).

[0220] Example 11: Preparation of Compound 75

[0221]

[0222] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 92.31%.

[0223] 1H NMR (600MHz, DMSO-d6) δ10.18 (s, 1H), 8.55 (s, 3H), 7.94 (d, J = 7.3Hz, 2H), 7.81 (d, J = 6.6Hz, 1H ), 7.68 (t, J = 7.4Hz, 1H), 7.57-7.43 (m, 4H), 7.25 (dd, J = 44.2, 8.4Hz, 4H), 5.94 (d, J = 9.6Hz, 1H) , 5.87 (d, J=9.6Hz, 1H), 5.38 (dd, J=13.4, 5.0Hz, 1H), 4.56 (d, J=17.6Hz, 1H), 4.45 (d, J=17.5H z, 1H), 4.33 (s, 1H), 3.71 (s, 3H), 3.20-3.07 (m, 3H), 2.89 (d, J=16.3Hz, 1H), 2.19-2.07 (m, 1H).

[0224] Example 12: Preparation of Compound 77

[0225]

[0226] The hydrochloride was prepared using general synthesis method 2, yielding a white solid with a yield of 78.42%.

[0227] 1 H NMR (400MHz, DMSO-d6) δ11.06 (s, 1H), 9.49 (s, 1H), 9.09 (s, 1H), 8.63-7.92 (m, 4H), 7. 44 (td, J=16.7, 7.3Hz, 4H), 7.18 (d, J=8.5Hz, 2H), 5.16 (dd, J=13.3, 5.1Hz, 1H), 4.46 (d , J=17.2Hz, 1H), 4.33 (d, J=17.2Hz, 1H), 4.13 (t, J=6.1Hz, 1H), 3.12-2.99 (m, 2H), 3.00 -2.86 (m, 1H), 2.63 (d, J=16.9Hz, 1H), 2.32 (qd, J=13.1, 4.3Hz, 1H), 2.11-2.01 (m, 1H).

[0228] Example 13: Preparation of Compound 78

[0229]

[0230] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 85.62%.

[0231] 1H NMR (400MHz, DMSO-d6) δ13.92 (s, 1H), 10.20 (s, 1H), 8.38 (s, 3H), 8.02-7.90 (m, 2H), 7.81 (dd, J=6.1, 2.8Hz , 1H), 7.68 (dt, J=8.7, 1.3Hz, 1H), 7.62-7.41 (m, 4H), 7.32 (d, J=8.6Hz, 2H), 7.22 (d, J=8.6Hz, 2H), 5.94 (d, J=9.7Hz, 1H), 5.87 (d, J=9.6Hz, 1H), 5.39 (dd, J=13.4, 5.0Hz, 1H), 4.56 (d, J=17.7Hz, 1H), 4.44 (d, J=17.6H z, 1H), 4.21 (s, 1H), 3.23-3.08 (m, 3H), 2.95-2.82 (m, 1H), 2.44 (dd, J=13.3, 8.9Hz, 1H), 2.18-2.08 (m, 1H).

[0232] Example 14: Preparation of Compound 82

[0233]

[0234] The hydrochloride was prepared using general synthesis method 2, yielding a white solid with a yield of 78.31%.

[0235] 1 H NMR (600MHz, DMSO-d6) δ11.02 (s, 1H), 9.68 (s, 1H), 8.70 (s, 3H), 7.71 (dd, J=10. 9, 4.7Hz, 1H), 7.58-7.40 (m, 2H), 5.15 (dd, J=13.3, 5.0Hz, 1H), 4.66-4.56 (m, 1H ), 4.50-4.40 (m, 3H), 4.35 (dd, J=17.5, 4.7Hz, 1H), 3.79 (d, J=3.6Hz, 3H), 2.99- 2.85 (m, 1H), 2.66-2.60 (m, 1H), 2.31 (qd, J=13.2, 4.4Hz, 1H), 2.09-2.01 (m, 1H).

[0236] Example 15: Preparation of Compound 83

[0237]

[0238] The hydrochloride was prepared using general synthesis method 2, yielding a white solid with a yield of 90.57%.

[0239] 1H NMR (600MHz, DMSO-d6) δ11.03 (d, J=4.3Hz, 1H), 9.64 (d, J=3.5Hz, 1H), 8.72 (s, 3H), 7 .72 (dd, J=8.9, 4.4Hz, 1H), 7.52 (t, J=6.3Hz, 2H), 5.27-5.06 (m, 2H), 4.44 (dd, J=17. 5, 3.6Hz, 1H), 4.33 (dd, J=17.5, 4.4Hz, 2H), 3.77 (d, J=5.0Hz, 3H), 2.99-2.87 (m, 1H) , 2.63 (d, J = 18.1Hz, 1H), 2.36-2.26 (m, 1H), 2.11-2.02 (m, 1H), 1.41 (d, J = 6.6Hz, 3H).

[0240] Example 16: Preparation of Compound 84

[0241]

[0242] The hydrochloride was prepared using general synthesis method 2, yielding a white solid with a yield of 56.93%.

[0243] 1 H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 11.58 (s, 1H), 8.62 (s, 3H), 7.74-7.70 (m, 1H), 7.58-7.52 (m, 2H), 5.15 (dd, J=13.3, 5.1Hz, 1H), 4.45-4.3 2(m, 3H), 3.75(d, J=1.76Hz, 3H), 3.47-3.40(m, 2H), 2.98-2.86(m, 1H), 2.62 (d, J=16.8Hz, 1H), 2.38 (dd, J=13.1, 4.5Hz, 1H), 2.11-2.00 (m, 1H).

[0244] Example 17: Preparation of Compound 85

[0245]

[0246] The hydrochloride was prepared using general synthesis method 2, yielding a white solid with a yield of 54.28%.

[0247] 1H NMR (600MHz, DMSO-d6) δ11.02 (s, 1H), 8.38 (s, 2H), 7.73 (dd, J=12.9, 7.8Hz, 1H), 7.57-7.51 (m, 2H), 5.15 (dd, J=13.3, 3.4Hz, 1H), 4.47-4.31 (m, 2H), 4.13 (s, 1H), 3.47 (dd, J=14.6, 5.0Hz, 1H), 3.36 (dd, J=14.8, 6.3Hz, 1H), 2.97-2. 86 (m, 1H), 2.64-2.59 (m, 1H), 2.37-2.29 (m, 1H), 2.04 (dd, J=9.0, 3.7Hz, 1H).

[0248] Example 18: Preparation of Compound 86

[0249]

[0250] The hydrochloride was prepared using general synthesis method 3, and the hydrochloride was obtained as a white solid with a yield of 82.87%.

[0251] 1 H NMR (600MHz, DMSO-d6) δ9.70 (s, 1H), 8.75 (s, 3H), 7.99-7.91 (m, 2H), 7.75 (d, J=4.8Hz, 1 H), 7.69 (t, J=7.4Hz, 1H), 7.57-7.49 (m, 4H), 5.93 (d, J=9.7Hz, 1H), 5.88 (d, J=9.6Hz, 1H) , 5.37 (dd, J=13.4, 4.9Hz, 1H), 4.65-4.55 (m, 1H), 4.55-4.30 (m, 4H), 3.78 (d, J=3.5Hz, 3H ), 3.22-3.09 (m, 1H), 2.89 (dd, J=13.6, 2.5Hz, 1H), 2.44-2.38 (m, 1H), 2.19-2.10 (m, 1H).

[0252] Example 19: Preparation of Compound 87

[0253]

[0254] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 84.25%.

[0255] 1H NMR (600MHz, DMSO-d6) δ10.65 (d, J=7.8Hz, 1H), 8.75 (s, 3H), 8.00-7.88 (m, 2H), 7.76 (ddd, J=12.9, 7 .9, 0.8Hz, 1H), 7.69 (t, J=7.4Hz, 1H), 7.64-7.45 (m, 4H), 5.93 (d, J=9.6Hz, 1H), 5.88 (d, J=9.6Hz, 1H ), 5.38 (dd, J=13.5, 5.0Hz, 1H), 4.50 (dd, J=17.5, 14.3Hz, 1H), 4.42-4.26 (m, 2H), 3.74 (d, J=3.0Hz, 3H), 3.51-3.40(m, 2H), 3.21-3.07(m, 1H), 2.91-2.84(m, 1H), 2.48-2.41(m, 1H), 2.17-2.08(m, 1H).

[0256] Example 20: Preparation of Compound 88

[0257]

[0258] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 56.85%.

[0259] 1 H NMR (600MHz, DMSO-d6) δ9.68 (s, 1H), 8.78 (s, 3H), 7.96-7.89 (m, 2H), 7.80-7.74 (m, 1H), 7.69 (td, J=7.4, 1.3Hz, 1H), 7.58-7.49 (m, 4H), 5.94 (dd, J=9.6, 4.2Hz, 1H), 5.88 (dd, J=9.6, 1.9Hz, 1H), 5.37 (ddd, J=13. 5, 10.9, 5.0Hz, 1H), 5.23-5.16 (m, 1H), 4.51 (dd, J=17.4, 7.4Hz, 1H), 4.42-4.30 (m, 2H), 3.75 (d, J=10.2H z, 3H), 3.21-3.11 (m, 1H), 2.93-2.86 (m, 1H), 2.44-2.35 (m, 1H), 2.19-2.09 (m, 1H), 1.41 (d, J=6.6Hz, 3H).

[0260] Example 21: Preparation of Compound 89

[0261]

[0262] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 71.08%.

[0263] 1 H NMR (600MHz, DMSO-d6) δ9.65 (s, 1H), 8.61 (s, 2H), 7.96-7.91 (m, 2H), 7.85-7.77 (m, 1H), 7.68 (td, J=7.5 , 1.3Hz, 1H), 7.60-7.47 (m, 4H), 5.94 (dd, J=9.7, 1.8Hz, 1H), 5.87 (d, J=9.6Hz, 1H), 5.36 (dt, J=11.4, 5.6 Hz, 1H), 5.26-5.13 (m, 1H), 4.53 (d, J=17.5Hz, 1H), 4.39 (dd, J=17.4, 5.6Hz, 1H), 4.13 (d, J=4.0Hz, 1H), 3 .20-3.10 (m, 1H), 2.90 (dd, J=13.7, 2.6Hz, 1H), 2.46-2.36 (m, 1H), 2.18-2.10 (m, 1H), 1.43-1.39 (m, 3H).

[0264] Example 22: Preparation of Compound 90

[0265]

[0266] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 76.65%.

[0267] 1 H NMR (600MHz, DMSO-d6) δ7.96-7.90 (m, 2H), 7.76 (dd, J=12.6, 7.9Hz, 1H), 7.69 (t, J=7.4Hz, 1H), 7.6 1-7.50 (m, 4H), 5.93 (d, J=9.6Hz, 1H), 5.88 (d, J=9.7Hz, 1H), 5.38 (ddd, J=13.5, 4.8, 3.3Hz, 1H), 4. 49 (dd, J=17.5, 12.5Hz, 1H), 4.38 (dd, J=17.5, 11.2Hz, 1H), 4.17-4.07 (m, 1H), 3.50-3.43 (m, 1H), 3 .41-3.36 (m, 1H), 3.20-3.12 (m, 1H), 2.88 (d, J=17.6Hz, 1H), 2.48-2.39 (m, 1H), 2.16-2.06 (m, 1H).

[0268] Example 23: Preparation of Compound 91

[0269]

[0270] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 72.36%.

[0271] 1 H NMR (400MHz, DMSO-d6) δ9.72 (s, 1H), 8.58 (s, 3H), 8.02-7.82 (m, 2H), 7.84-7.7 2 (m, 1H), 7.74-7.64 (m, 1H), 7.62-7.40 (m, 4H), 5.99-5.79 (dd, J=25.1, 9.6Hz, 2 H), 5.44-5.30 (m, 1H), 4.67-4.57 (m, 1H), 4.56-4.35 (m, 3H), 4.28 (t, J=4.2Hz, 1 H), 3.22-3.07(m, 1H), 2.95-2.83(m, 1H), 2.43-2.35(m, 1H), 2.20-2.06(m, 1H).

[0272] Example 24: Preparation of Compound 93

[0273]

[0274]

[0275] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 90.57%.

[0276] 1 H NMR (600MHz, DMSO-d6) δ10.16 (s, 1H), 8.55 (s, 3H), 7.83-7.78 (m, 1H), 7.58-7.52 (m, 2H), 7.29 (d, J=8.5H z, 2H), 7.22 (d, J = 8.5Hz, 2H), 5.69 (d, J = 9.4Hz, 1H), 5.61 (d, J = 9.4Hz, 1H), 5.33 (dd, J = 13.5, 5.0Hz, 1H), 4.77 (m, J=6.3Hz, 1H), 4.48 (dd, J=67.0, 17.6Hz, 2H), 4.32 (t, J=6.6Hz, 1H), 3.71 (s, 3H), 3.19-3.07 (m, 3 H), 2.86 (dd, J=17.1, 14.3Hz, 1H), 2.41 (dd, J=13.2, 4.4Hz, 1H), 2.15-2.04 (m, 1H), 1.22 (d, J=6.2Hz, 6H).

[0277] Example 25: Preparation of Compound 94

[0278]

[0279] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 90.57%.

[0280] 1 H NMR (600MHz, DMSO-d6) δ10.57 (s, 1H), 8.59 (s, 3H), 7.75 (dd, J=15.8, 8.0Hz, 1H), 7.56 (m, J=15. 4, 7.7Hz, 2H), 5.65 (dd, J=54.0, 9.4Hz, 2H), 5.34 (dd, J=13.5, 5.0Hz, 1H), 4.77 (m, J=12.5, 6.2Hz , 1H), 4.38 (m, J=26.0, 22.9, 13.9Hz, 3H), 3.75 (d, J=2.5Hz, 3H), 3.50-3.38 (m, 2H), 3.16-3.06 ( m, 1H), 2.85 (d, J=16.1Hz, 1H), 2.44-2.39 (m, 1H), 2.13-2.07 (m, 1H), 1.22 (d, J=6.2, 1.8Hz, 6H).

[0281] Example 26: Preparation of Compound 95

[0282]

[0283] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 59.68%.

[0284] 1 H NMR (600MHz, DMSO-d6) δ10.57 (s, 1H), 8.45 (s, 3H), 7.80-7.72 (m, 1H), 7.56 (m, J=15.4, 7.6Hz, 2H), 5.70 (d, J=9.4Hz, 1H), 5.61 (d, J=9.4Hz, 1H), 5.33 (m, J=13.5, 5.0, 2.9Hz, 1H), 4.77 (m, J=6.2Hz, 1H), 4.46 (d d, J=17.5, 13.1Hz, 1H), 4.35 (dd, J=17.5, 11.1Hz, 1H), 4.18 (d, J=4.9Hz, 1H), 3.50-3.40 (m, 2H), 3.16-3 .07 (m, 1H), 2.85 (d, J = 17.4Hz, 1H), 2.42 (d, J = 4.4Hz, 1H), 2.13-2.06 (m, 1H), 1.22 (d, J = 6.2, 1.8Hz, 6H).

[0285] Example 27: Preparation of Compound 96

[0286]

[0287] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 65.42%.

[0288] 1 H NMR (600MHz, DMSO-d6) δ13.85 (s, 1H), 10.16 (s, 1H), 8.37 (s, 3H), 7.80 (dd, J=6.3, 2.4Hz, 1H) , 7.58-7.52 (m, 2H), 7.33 (d, J=8.5Hz, 2H), 7.22 (d, J=8.5Hz, 2H), 5.65 (dd, J=47.4, 9.4Hz, 2H ), 5.33 (dd, J=13.4, 5.0Hz, 1H), 4.77 (dt, J=12.5, 6.2Hz, 1H), 4.48 (dd, J=66.4, 17.5Hz, 2H), 4.20 (s, 1H), 3.18-3.06 (m, 3H), 2.91-2.80 (m, 2H), 2.14-2.06 (m, 1H), 1.22 (d, J=6.2Hz, 6H).

[0289] Example 28: Preparation of Compound 97

[0290]

[0291] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 67.24%.

[0292] 1 H NMR (400MHz, DMSO-d6) δ9.72 (d, J=5.3Hz, 1H), 8.77 (s, 3H), 7.79-7.70 (m, 1H), 7.56-7.49 (m, 2H) , 5.65 (dd, J=36.3, 9.4Hz, 2H), 5.33 (dd, J=13.5, 5.0Hz, 1H), 4.84-4.71 (m, 1H), 4.62 (td, J=11.7 , 3.3Hz, 1H), 4.45 (dt, J=15.3, 6.1Hz, 3H), 4.35 (dd, J=17.5, 4.1Hz, 1H), 3.79 (d, J=2.6Hz, 3H), 3 .18-3.04(m, 1H), 2.89-2.8l(m, 1H), 2.43-2.34(m, 1H), 2.15-2.06(m, 1H), 1.22(d, J=6.2Hz, 6H).

[0293] Example 29: Preparation of Compound 98

[0294]

[0295] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 37.95%.

[0296] 1 H NMR (400MHz, DMSO-d6) δ10.59 (s, 1H), 8.62 (s, 3H), 7.75 (t, J=8.1Hz, 1H), 7.63-7 .51 (m, 2H), 5.63 (dd, J=27.7, 9.4Hz, 2H), 5.32 (dd, J=13.4, 4.9Hz, 1H), 4.5l-4.30 (m, 3H), 3.75 (s, 3H), 3.54 (s, 4H), 3.44 (d, J = 5.0Hz, 2H), 3.32 (d, J = 4.6Hz, 4H), 3. 16-3.06 (m, 1H), 2.84 (d, J=17.1Hz, 1H), 2.42-2.32 (m, 1H), 2.10 (d, J=5.5Hz, 1H).

[0297] Example 30: Preparation of Compound 99

[0298]

[0299] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 26.70%.

[0300] 1 H NMR (400MHz, DMSO-d6) δ10.18 (s, 1H), 8.54 (s, 3H), 7.80 (dd, J=5.9, 3.1Hz, 1H), 7.59-7.53 (m, 2H), 7.26 (m, J=30.4, 8.6Hz, 4H), 5.63 (dd, J=34.2, 9.3Hz, 2H), 5.3l (dd, J=13.4, 5.0Hz, 1H), 4 .47(dd, J=52.7, 17.5Hz, 2H), 4.33(s, 1H), 3.71(s, 3H), 3.52(s, 4H), 3.32-3.26(m, 4H), 3.11( m, J=13.3, 6.6Hz, 3H), 2.84 (d, J=16.6Hz, 1H), 2.40 (dd, J=13.0, 4.4Hz, 1H), 2.15-2.06 (m, 1H).

[0301] Example 31: Preparation of Compound 100

[0302]

[0303] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 61.23%.

[0304] 1 H NMR (400MHz, DMSO-d6) δ9.70 (s, 1H), 8.67 (s, 3H), 7.74 (d, J=4.3Hz, 1H), 7.56-7 .51 (m, 2H), 5.62 (dd, J=29.7, 9.3Hz, 2H), 5.31 (dd, J=13.4, 5.0Hz, 1H), 4.66-4.5 8 (m, 1H), 4.53-4.30 (m, 4H), 3.79 (s, 3H), 3.54 (s, 4H), 3.31 (m, J=4.7Hz, 4H), 3.1 4-3.04 (m, 1H), 2.84 (d, J = 16.0Hz, 1H), 2.39-2.31 (m, 1H), 2.11 (d, J = 5.4Hz, 1H).

[0305] Example 32: Preparation of Compound 101

[0306]

[0307] The hydrochloride was prepared using general synthetic method 3, with the chloromethyl reagent being commercially available. The hydrochloride was obtained as a white solid with a yield of 69.55%.

[0308] 1 H NMR (400MHz, DMSO-d6) δ9.72 (s, 1H), 8.43 (s, 3H), 7.84-7.72 (m, 1H), 7.50 (m, J=6.3 Hz, 2H), 5.69 (dd, J=9.4, 1.7Hz, 1H), 5.61 (d, J=9.4Hz, 1H), 5.39-5.25 (m, 1H), 4.83- 4.71 (m, 1H), 4.65-4.55 (m, 1H), 4.53-4.32 (m, 3H), 4.13 (s, 1H), 3.18-3.04 (m, 2H), 2.85 (d, J=16.9Hz, 1H), 2.41-2.30 (m, 1H), 2.14-2.05 (m, 1H), 1.22 (d, J=6.2Hz, 6H).

[0309] Example 33: Preparation of Compound 102

[0310]

[0311]

[0312] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 52.86%.

[0313] 1 H NMR (400MHz, DMSO-d6) δ10.18 (s, 1H), 7.84-7.77 (m, 1H), 7.57-7.51 (m, 2H), 7.33 (d, J=8.2Hz, 2H), 7.19 (d, J=8.3Hz, 2H), 5.63 (dd, J=34.7, 9.3Hz, 2H), 5.31 (dd, J=13.5, 5.0Hz, 1H), 4.48 (d d, J=53.3, 17.6Hz, 2H), 3.90 (s, 1H), 3.81-3.75 (m, 1H), 3.50 (s, 4H), 3.31-3.29 (m, 4H), 3.09 ( dd, J=19.3, 14.5Hz, 3H), 2.84 (d, J=16.6Hz, 1H), 2.40 (d, J=9.1Hz, 1H), 2.11 (d, J=5.9Hz, 1H).

[0314] Example 34: Preparation of Compound 103

[0315]

[0316] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 37.44%.

[0317] 1 H NMR (400MHz, DMSO-d6) δ10.56 (d, J=4.3Hz, 1H), 8.43 (s, 3H), 7.75 (t, J=7.9Hz, 1H), 7.56 (dt, J=15. 1, 7.5Hz, 2H), 5.63 (dd, J=28.7, 9.4Hz, 2H), 5.31 (dd, J=13.4, 3.1Hz, 1H), 4.46 (dd, J=17.6, 8.4Hz, 1H), 4.34 (dd, J=17.5, 6.9Hz, 1H), 4.23 (s, 1H), 3.54 (s, 4H), 3.47 (d, J=9.5Hz, 2H), 3.34-3.29 (m, 4 H), 3.12-3.04 (m, 1H), 2.84 (d, J=16.8Hz, 1H), 2.39 (dd, J=13.2, 4.4Hz, 1H), 2.10 (d, J=5.3Hz, 1H).

[0318] Example 35: Preparation of Compound 104

[0319]

[0320] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 42.45%.

[0321] 1 H NMR (400MHz, DMSO-d6) δ10.19 (s, 1H), 8.62 (s, 3H), 7.80 (dd, J=5.9, 2.9Hz, 1H), 7.57-7 .50 (m, 2H), 7.30 (d, J=8.6Hz, 2H), 7.21 (d, J=8.6Hz, 2H), 5.63 (dd, J=20.3, 9.6Hz, 2H), 5 .34 (dd, J=13.4, 5.0Hz, 1H), 4.47 (dd, J=59.4, 17.6Hz, 2H), 4.31 (t, 1H), 3.70 (s, 3H), 3 .23-3.08(m, 3H), 2.90-2.81(m, 1H), 2.42-2.31(m, 1H), 2.19-2.05(m, 1H), 1.11(s, 9H).

[0322] Example 36: Preparation of Compound 105

[0323]

[0324] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 48.97%.

[0325] 1 H NMR (400MHz, DMSO-d6) δ9.70 (s, 1H), 8.52 (s, 3H), 7.82-7.73 (m, 1H), 7.52 (d , J=4.3Hz, 2H), 5.62 (dd, J=31.8, 9.3Hz, 2H), 5.30 (d, J=8.4Hz, 1H), 4.63 (d, J =8.5Hz, 1H), 4.54-4.24(m, 4H), 3.54(s, 4H), 3.31-3.28(m, 4H), 3.09(d, J=1 2.3Hz, 1H), 2.84 (d, J=17.1Hz, 1H), 2.39 (s, 1H), 2.10 (dd, J=9.8, 4.3Hz, 1H).

[0326] Example 37: Preparation of Compound 106

[0327]

[0328] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 68.45%.

[0329] 1H NMR (400MHz, DMSO-d6) δ10.63 (s, 1H), 8.70 (s, 3H), 7.78-7.71 (m, 1H), 7.56 (m, J=15.2, 7. 5Hz, 2H), 5.63 (dd, J=21.5, 9.6Hz, 2H), 5.34 (dd, J=13.4, 5.0Hz, 1H), 4.47 (dd, J=17.6, 9. 2Hz, 1H), 4.37-4.29 (m, 2H), 3.74 (s, 3H), 3.44 (t, J=5.4Hz, 2H), 3.13 (m, J=18.1, 13.5, 4. 8Hz, 1H), 2.90-2.80 (m, 1H), 2.38 (dd, J=13.2, 4.4Hz, 1H), 2.15-2.06 (m, 1H), 1.11 (s, 9H).

[0330] Example 38: Preparation of Compound 107

[0331]

[0332] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 57.36%.

[0333] 1 H NMR (400MHz, DMSO-d6) δ10.19 (s, 1H), 8.59 (s, 3H), 7.80 (dd, J=5.8, 2.9Hz, 1H), 7.54 (dd, J=8 .2, 5.3Hz, 2H), 7.30 (d, J=8.5Hz, 2H), 7.21 (d, J=8.5Hz, 2H), 5.59 (dd, J=25.2, 9.3Hz, 2H), 5.3 2 (dd, J=13.3, 5.0Hz, 1H), 4.47 (dd, J=59.1, 17.6Hz, 2H), 4.32 (s, 1H), 3.70 (s, 3H), 3.24-3.07 (m, 6H), 2.84 (d, J=16.5Hz, 1H), 2.38 (dd, J=13.2, 4.1Hz, 1H), 2.15-2.06 (m, 1H), 1.01 (s, 6H).

[0334] Example 39: Preparation of Compound 108

[0335]

[0336] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 58.41%.

[0337] 1H NMR (400MHz, DMSO-d6) δ9.71 (s, 1H), 8.70 (s, 3H), 7.74 (s, 1H), 7.53 (s, 2H), 5.63 (dd, J=20.0, 9.3Hz, 2H), 5.33 (d, J=9.4Hz, 1H), 4.68-4.27 (m, 5H), 3.79 (s, 3H), 3.1l (d, J=12.1Hz, 1H), 2.86 (d, J=23.9Hz, 1H), 2.36 (d, J=12.8Hz, 1H), 2.12 (s, 1H), 1.11 (s, 9H).

[0338] Example 40: Preparation of 109

[0339]

[0340] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 51.78%.

[0341] 1 H NMR (400MHz, DMSO-d6) δ10.18 (s, 1H), 8.17 (s, 2H), 7.80 (dd, J=5.9, 3.0Hz, 1H), 7.54 (dd, J= 8.3, 5.2Hz, 2H), 7.31 (d, J=8.5Hz, 2H), 7.21 (d, J=8.5Hz, 2H), 5.63 (dd, J=20.5, 9.6Hz, 2H), 5 .34 (dd, J=13.3, 5.0Hz, 1H), 4.46 (dd, J=58.1, 17.6Hz, 2H), 4.07 (s, 1H), 3.12 (ddd, J=18.1, 13.4, 7.0Hz, 3H), 2.85 (d, J=16.4Hz, 1H), 2.45-2.31 (m, 2H), 2.15-2.05 (m, 1H), 1.11 (s, 9H).

[0342] Example 41: Preparation of Compound 110

[0343]

[0344] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 28.51%.

[0345] 1H NMR (400MHz, DMSO-d6) δ10.58 (s, 1H), 8.45 (s, 2H), 7.75 (m, 1H), 7.56 (m, 2H) , 5.63 (dd, J=21.1, 9.6Hz, 2H), 5.34 (dd, J=12.6, 4.1Hz, 1H), 4.40 (m, 2H), 4. 20 (d, J=2.8Hz, 1H), 3.48 (dd, J=14.7, 5.1Hz, 2H), 3.40 (d, J=6.1Hz, 2H), 3.1 3 (m, 2H), 2.84 (d, J=17.4Hz, 1H), 2.39 (dd, J=13.1, 4.3Hz, 1H), 1.11 (s, 9H).

[0346] Example 42: Preparation of Compound 111

[0347]

[0348] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 23.09%.

[0349] 1 H NMR (400MHz, DMSO-d6) δ9.69 (s, 1H), 8.32 (s, 3H), 7.81-7.71 (m, 1H), 7.55-7.48 (m, 2H ), 5.63 (dd, J=19.7, 9.6Hz, 2H), 5.38-5.28 (m, 1H), 4.60 (d, J=12.0Hz, 1H), 4.48 (dd, J =17.5, 6.0Hz, 1H), 4.34 (dd, J = 17.4, 4.1Hz, 2H), 4.13 (s, 1H), 3.12 (dd, J = 23.4, 10.2H z, 2H), 2.85 (d, J=16.8Hz, 1H), 2.37 (s, 1H), 2.14-2.06 (m, 1H), 1.12 (d, J=9.2Hz, 9H).

[0350] Example 43: Preparation of Compound 112

[0351]

[0352] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 61.94%.

[0353] 1H NMR (400MHz, DMSO-d6) δ10.19 (s, 1H), 8.33 (s, 2H), 7.90 (dd, J=7.8, 1.5Hz, 1H), 7.80 (dd, J=6.3, 2.6Hz, 1H), 7. 73-7.66 (m, 1H), 7.60-7.52 (m, 2H), 7.41 (t, J=7.7Hz, 1H), 7.33 (d, J=8.5Hz, 2H), 7.23 (dd, J=16.2, 8.0Hz, 3H), 5.84 (dd, J=24.0, 9.7Hz, 2H), 5.76 (s, 1H), 5.36 (dd, J=13.3, 5.0Hz, 1H), 4.50 (dd, J=51.1, 17.6Hz, 2H), 4.13 (s , 1H), 3.21-3.04 (m, 4H), 2.89 (d, J=17.0Hz, 1H), 2.44 (dd, J=13.2, 4.4Hz, 1H), 2.25 (s, 3H), 2.18-2.08 (m, 1H).

[0354] Example 44: Preparation of compound 113

[0355]

[0356] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 49.26%.

[0357] 1 H NMR (400MHz, DMSO-d6) δ10.53 (s, 1H), 8.34 (s, 2H), 7.76 (t, J=6.7Hz, 1H), 7.56 (dt, J=15.1 , 7.4Hz, 2H), 5.63 (dd, J=30.2, 9.6Hz, 2H), 5.32 (d, J=8.2Hz, 1H), 4.40 (m, 2H), 4.21 (s, 1H), 3.47 (dd, J=14.7, 4.8Hz, 2H), 3.17-3.04 (m, 1H), 2.84 (d, J=17.1Hz, 1H), 2.40 (d, J=13.0Hz , 1H), 2.28 (t, J=7.3Hz, 2H), 2.10 (s, 1H), 1.49 (s, 2H), 1.23 (s, 10H), 0.84 (t, J=6.7Hz, 3H).

[0358] Example 45: Preparation of Compound 114

[0359]

[0360] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 65.29%.

[0361] 1 H NMR (400MHz, DMSO-d6) δ10.53 (s, 1H), 8.32 (s, 3H), 7.90 (dd, J=7.8, 1.6Hz, 1H), 7.79-7.68 ( m, 2H), 7.56 (dt, J=15.2, 7.5Hz, 2H), 7.42 (td, J=7.6, 1.1Hz, 1H), 7.25 (dd, J=8.1, 1.0Hz, 1H ), 5.84 (dd, J=22.4, 10.0Hz, 2H), 5.37 (d, J=13.5Hz, 1H), 4.42 (m, 3H), 4.20 (s, 1H), 3.47 (m, 2H), 3.21-3.11(m, 2H), 2.89(d, J=17.3Hz, 1H), 2.42(s, 1H), 2.26(s, 3H), 2.16-2.09(m, 1H).

[0362] Example 46: Preparation of Compound 115

[0363]

[0364] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 56.50%.

[0365] 1 H NMR (400MHz, DMSO-d6) δ9.67 (s, 1H), 8.47 (s, 3H), 7.90 (dd, J=7.8, 1.6Hz, 1H), 7.73 (m, 2H), 7.5 2 (dd, J=8.2, 5.3Hz, 2H), 7.42 (t, J=7.6Hz, 1H), 7.25 (d, J=8.1Hz, 1H), 5.84 (dd, J=20.3, 9.7Hz, 2 H), 5.41-5.31 (m, 1H), 4.64 (m, 1H), 4.50 (dd, J=17.5, 6.6Hz, 1H), 4.43-4.33 (m, 2H), 4.29 (s, 1H ), 3.22-3.09 (m, 2H), 2.89 (d, J=16.8Hz, 1H), 2.44-2.37 (m, 1H), 2.26 (s, 3H), 2.18-2.09 (m, 1H).

[0366] Example 47: Preparation of Compound 116

[0367]

[0368] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 37.55%.

[0369] 1 H NMR (400MHz, DMSO-d6) δ10.56 (s, 1H), 8.55 (s, 2H), 7.90 (dd, J=7.8, 1.5Hz, 1H), 7.72 (m, 2H) , 7.56 (dt, J=15.2, 7.6Hz, 2H), 7.45-7.40 (m, 1H), 7.25 (d, J=8.1Hz, 1H), 5.84 (dd, J=20.1, 9 .8Hz, 2H), 5.37 (dd, J=13.2, 5.2Hz, 1H), 4.46 (m, 1H), 4.40-4.32 (m, 2H), 3.75 (s, 3H), 3.48- 3.40 (m, 2H), 3.20-3.12 (m, 1H), 2.89 (d, J = 17.2Hz, 1H), 2.26 (s, 3H), 2.14 (d, J = 5.4Hz, 1H).

[0370] Example 48: Preparation of Compound 117

[0371]

[0372] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 45.95%.

[0373] 1 H NMR (600MHz, DMSO-d6) δ9.75 (s, 1H), 8.84 (s, 3H), 7.91 (d, J=7.7Hz, 1H), 7.82-7.66 (m, 2H), 7.52 (dd, J=8.1, 5.3 Hz, 2H), 7.43 (t, J=7.6Hz, 1H), 7.25 (d, J=8.0Hz, 1H), 5.91-5.76 (m, 2H), 5.36 (dd, J=13.4, 4.9Hz, 1H), 4.62 (td, J =12.0, 3.4Hz, 1H), 4.55-4.30 (m, 4H), 4.03 (q, J = 7.1Hz, 1H), 3.41 (s, 2H), 3.16 (ddd, J = 18.2, 11.9, 5.4Hz, 1H), 2. 90 (dd, J=14.0, 2.6Hz, 1H), 2.48-2.34 (m, 1H), 2.13 (dd, J=18.8, 13.7Hz, 1H), 1.99 (s, 1H), 1.17 (t, J=7.1Hz, 1H).

[0374] Example 49: Preparation of Compound 118

[0375]

[0376] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 50.98%.

[0377] 1 H NMR (400MHz, DMSO-d6) δ10.71 (d, J=4.2Hz, 1H), 8.82 (s, 3H), 7.83-7.68 (m, 1H), 7.55 (dt, J=15.1, 7.4Hz, 2 H), 5.63 (dd, J=30.1, 9.6Hz, 2H), 5.53-5.28 (m, 1H), 4.49 (dd, J=17.6, 9.3Hz, 1H), 4.41-4.26 (m, 2H), 3.75 (d, J=11.8Hz, 3H), 3.54-3.40 (m, 2H), 3.22-3.03 (m, 1H), 2.85 (d, J=16.7Hz, 1H), 2.40 (qd, J=13.2, 4.1Hz, 1H), 2.28 (t, J=7.3Hz, 2H), 2.15-2.05 (m, 1H), 1.60-1.42 (m, 2H), 1.33-1.14 (m, 8H), 0.84 (t, J=6.8Hz, 3H).

[0378] Example 50: Preparation of Compound 119

[0379]

[0380] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 31.28%.

[0381] 1 H NMR (600MHz, DMSO-d6) δ10.59 (s, 1H), 8.49 (s, 3H), 7.75 (dd, J=13.0, 7.9Hz, 1H), 7.56 (dt, J=1 5.3, 7.5Hz, 2H), 5.58 (tt, J=19.2, 5.6Hz, 2H), 5.32 (ddd, J=13.4, 4.8, 2.8Hz, 1H), 4.47 (dd, J=1 7.5, 13.0Hz, 1H), 4.35 (dd, J=17.5, 10.8Hz, 1H), 4.21 (d, J=4.2Hz, 1H), 3.52-3.44 (m, 1H), 3.4 3-3.29 (m, 4H), 3.18-3.07 (m, 1H), 2.80 (d, J=2.7Hz, 6H), 2.45-2.34 (m, 1H), 2.16-2.07 (m, 1H).

[0382] Example 51: Preparation of Compound 120

[0383]

[0384] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 43.77%.

[0385] 1 H NMR (600MHz, DMSO-d6) δ9.71 (s, 1H), 8.60 (s, 3H), 7.90-7.64 (m, 1H), 7.64-7. 40 (m, 2H), 5.68-5.50 (m, 2H), 5.31 (dt, J=13.4, 4.3Hz, 1H), 4.63 (ddd, J=12.0, 8.6, 3.5Hz, 1H), 4.57-4.28(m, 4H), 3.43(dt, J=21.3, 10.7Hz, 1H), 3.18-3.05( m, 1H), 2.80 (d, J=3.7Hz, 6H), 2.36 (qd, J=13.2, 4.3Hz, 1H), 2.16-2.04 (m, 1H).

[0386] Example 52: Preparation of Compound 121

[0387]

[0388] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 60.30%.

[0389] 1 H NMR (400MHz, DMSO-d6) δ9.74 (s, 1H), 8.82 (s, 1H), 7.75 (dd, J=9.8, 5.0Hz, 1H), 7.55-7.49 (m, 1H), 5.63 (dd, J=28.7, 9.6Hz, 1H), 5.32 (dd, J=13.5, 5.0Hz, 1H), 4.62 (ddd, J=10.3, 7.0, 3.3Hz, 1H), 4.53-4.40 ( m, 1H), 3.78 (d, J=1.0Hz, 1H), 3.17-3.06 (m, 1H), 2.89-2.81 (m, 1H), 2.37 (dd, J=13.1, 4.4Hz, 1H), 2.28 (t, J=7.3Hz, 1H), 2.14-2.07 (m, 1H), 1.53-1.44 (m, 1H), 1.21 (d, J=15.0Hz, 4H), 0.84 (t, J=6.7Hz, 2H).

[0390] Example 53: Preparation of Compound 122

[0391]

[0392] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 57.39%.

[0393] 1 H NMR (600MHz, DMSO-d6) δ10.19 (s, 1H), 7.81 (dd, J=5.5, 3.2Hz, 1H), 7.56-7.48 (m, 2H), 7.34 (d, J=8 .4Hz, 2H), 7.20 (d, J=8.5Hz, 2H), 5.72-5.52 (m, 2H), 5.35-5.24 (m, 1H), 4.55 (d, J=17.5Hz, 1H), 4.4 1 (d, J=17.5Hz, 1H), 4.03 (s, 1H), 3.17 (s, 2H), 2.88-2.81 (m, 1H), 2.46-2.35 (m, 1H), 2.27 (t, J=7.3 Hz, 2H), 2.14-2.07 (m, 1H), 1.54-1.45 (m, 2H), 1.24 (d, J=9.0Hz, 8H), 0.84 (dt, J=14.0, 6.9Hz, 3H).

[0394] Example 54: Preparation of 123

[0395]

[0396]

[0397] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 23.59%.

[0398] 1 H NMR (400MHz, DMSO-d6) δ9.73 (s, 1H), 8.62 (s, 3H), 7.77 (dd, J=9.6, 4.9Hz, 1H), 7.57-7 .48 (m, 2H), 5.63 (dd, J=27.9, 9.6Hz, 2H), 5.40-5.24 (m, 1H), 4.64 (dt, J=11.9, 3.3Hz, 1 H), 4.56-4.29(m, 4H), 3.21-3.01(m, 1H), 2.91-2.77(m, 1H), 2.42-2.31(m, 1H), 2.28(t , J=7.3Hz, 2H), 2.16-2.06 (m, 1H), 1.48 (dd, J=13.8, 6.9Hz, 2H), 0.84 (t, J=6.8Hz, 3H).

[0399] Example 55: Preparation of Compound 124

[0400]

[0401] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 62.13%.

[0402] 1 H NMR (600MHz, DMSO-d6) δ9.71 (s, 1H), 8.58 (s, 2H), 7.86-7.71 (m, 1H), 7.64-7.49 (m, 4H), 7.15 (d, J = 8.4Hz, 1H), 7.02 (t, J=7.5Hz, 1H), 5.81 (dt, J=27.2, 13.6Hz, 2H), 5.35 (dt, J=13.4, 4.4Hz, 1H), 4.62 (tt, J=39.6, 19.8Hz, 1H), 4.51 (dd, J=17.4, 7.6Hz, 1H), 4.48-4.32 (m, 2H), 4.32 (d, J=36.4Hz, 1H), 4.11 (s, 1H), 3.80 (d , J=7.8Hz, 3H), 3.41-3.25 (m, 1H), 2.88 (d, J=17.5Hz, 1H), 2.40 (qd, J=13.1, 4.0Hz, 1H), 2.21-2.02 (m, 1H).

[0403] Example 56: Preparation of Compound 125

[0404]

[0405] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 33.38%.

[0406] 1 H NMR (400MHz, DMSO-d6) δ9.74 (s, 1H), 8.80 (s, 3H), 7.88 (d, J=8.9Hz, 2H), 7.75 (dd, J=10.3, 6.1 Hz, 1H), 7.52 (dd, J=7.1, 5.8Hz, 2H), 7.06 (d, J=8.9Hz, 2H), 5.86 (dd, J=23.3, 9.6Hz, 2H), 5.37 (dd, J=13.4, 4.9Hz, 1H), 4.72-4.32 (m, 5H), 3.84 (s, 3H), 3.78 (d, J=2.8Hz, 3H), 3.24-3.07 (m, 1H), 3.01-2.84(m, 1H), 2.47-2.36(m, 1H), 2.22-2.06(m, 1H), 1.99(s, 1H), 1.25-1.12(m, 1H).

[0407] Example 57: Preparation of Compound 126

[0408]

[0409] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 48.86%.

[0410] 1 H NMR (400MHz, DMSO-d6) δ14.09 (s, 1H), 10.58 (d, J=3.9Hz, 1H), 8.46 (s, 3H), 7.76 (t, J=8.2Hz, 1H), 7.59-7.39 (m, 4 H), 7.27 (d, J=7.9Hz, 1H), 5.89 (dd, J=28.4, 9.6Hz, 2H), 5.38 (d, J=10.4Hz, 1H), 4.49 (dd, J=17.5, 8.5Hz, 1H), 4.3 8 (dd, J=17.6, 6.9Hz, 1H), 4.23 (s, 1H), 4.03 (dd, J=14.3, 7.2Hz, 1H), 3.82 (s, 3H), 3.55-3.40 (m, 3H), 3.25-3.08 ( m, 1H), 2.87 (d, J=13.7Hz, 1H), 2.47-2.32 (m, 1H), 2.19-2.06 (m, 1H), 1.99 (s, 1H), 1.19 (dd, J=20.9, 13.8Hz, 1H).

[0411] Example 58: Preparation of Compound 127

[0412]

[0413] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 41.67%.

[0414] 1 H NMR (600MHz, DMSO-d6) δ9.71 (s, 1H), 8.61 (s, 3H), 7.77 (d, J=10.5Hz, 1H), 7.57-7.38 (m, 5H), 7.26 (d, J=8.1Hz, 1H), 5.89 (dd, J=40.7, 9.6Hz, 2H), 5.36 (dd, J=13.3, 4.5Hz, 1H), 4 .63 (dd, J=15.0, 6.0Hz, 1H), 4.51 (dd, J=17.4, 7.5Hz, 1H), 4.46-4.36 (m, 2H), 4.34 (s, 1H ), 3.26-3.09(m, 1H), 2.97-2.81(m, 1H), 2.43(qd, J=13.2, 4.2Hz, 1H), 2.18-2.08(m, 1H).

[0415] Example 59: Preparation of Compound 128

[0416]

[0417] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 35.98%.

[0418] 1 H NMR (400MHz, DMSO-d6) δ13.90 (s, 1H), 10.20 (s, 1H), 8.44 (s, 2H), 7.81 (dd, J=5.5, 3.5Hz, 1H), 7.5 8-7.53 (m, 2H), 7.51 (d, J=7.6Hz, 1H), 7.48-7.40 (m, 2H), 7.33 (d, J=8.5Hz, 2H), 7.28-7.24 (m, 1H) , 7.22 (d, J=8.5Hz, 2H), 5.90 (dd, J=31.9, 9.6Hz, 2H), 5.38 (dd, J=13.4, 5.0Hz, 1H), 4.51 (dd, J=48 .7, 17.6Hz, 2H), 4.20 (s, 1H), 3.81 (s, 3H), 3.38 (s, 3H), 2.89 (d, J=16.7Hz, 1H), 2.21-2.06 (m, 1H).

[0419] Example 60: Preparation of Compound 129

[0420]

[0421] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 55.52%.

[0422] 1H NMR (600MHz, DMSO-d6) δ10.61 (d, J=9.0Hz, 1H), 8.51 (s, 3H), 7.89 (d, J=8.9Hz, 2H), 7.76 (dd, J=12.3, 7.7Hz, 1H), 7.56 (dt, J= 15.3, 7.6Hz, 2H), 7.06 (d, J=8.9Hz, 2H), 5.86 (dd, J=35.7, 9.8Hz, 2H), 5.37 (ddd, J=13.5, 4.8, 2.8Hz, 1H), 4.50 (dd, J=17.5, l 1.3Hz, 1H), 4.43-4.29 (m, 1H), 4.21 (s, 1H), 3.84 (s, 3H), 3.40 (ddd, J=14.6, 5.9, 2.6Hz , 3H), 3.23-3.09 (m, 1H), 2.88 (d, J=10.5Hz, 1H), 2.48-2.39 (m, 1H), 2.17-2.08 (m, 1H).

[0423] Example 61: Preparation of Compound 130

[0424]

[0425] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 48.59%.

[0426] 1 H NMR (600MHz, DMSO-d6) δ9.73 (s, 1H), 8.65 (s, 3H), 7.89 (d, J=8.8Hz, 2H), 7.83-7.7l (m, 1H) , 7.62-7.40 (m, 2H), 7.06 (d, J=8.8Hz, 2H), 5.86 (dd, J=36.6, 9.6Hz, 2H), 5.43-5.32 (m, 1H) , 4.64 (ddd, J=12.2, 9.0, 3.5Hz, 1H), 4.52 (dd, J=17.5, 6.0Hz, 1H), 4.48-4.29 (m, 4H), 3.84 (s, 3H), 3.20-3.11 (m, 1H), 2.93-2.85 (m, 1H), 2.12 (dd, J=17.3, 10.5Hz, 1H), 1.9l (s, 1H).

[0427] Example 62: Preparation of compound 13l

[0428]

[0429] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 47.64%.

[0430] 1 H NMR (400MHz, DMSO-d6) δ13.89 (s, 1H), 10.22 (s, 1H), 8.50 (s, 3H), 7.96-7.84 (m, 2H), 7.81 (dt, J=7.4, 3. 7Hz, 1H), 7.61-7.53 (m, 2H), 7.33 (t, J=11.3Hz, 2H), 7.22 (d, J=8.5Hz, 2H), 7.05 (d, J=8.9Hz, 2H), 5.87 (d d, J=27.6, 9.6Hz, 2H), 5.38 (dd, J=13.4, 5.0Hz, 1H), 4.51 (dd, J=50.1, 17.6Hz, 2H), 4.19 (s, 1H), 3.83 (s, 3H), 3.17 (t, J=8.5Hz, 2H), 2.89 (dd, J=10.2, 6.5Hz, 1H), 2.50-2.36 (m, 2H), 2.14 (dd, J=8.7, 3.4Hz, 1H).

[0431] Example 63: Preparation of Compound 132

[0432]

[0433] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 48.95%.

[0434] 1 H NMR (400MHz, DMSO-d6) δ10.58 (d, J=67.0Hz, 1H), 8.75 (d, J=148.3Hz, 3H), 7.76 (dt, J=7.6, 5.1Hz, 1H), 7.56 (dt, J=15.2, 7.4Hz, 2H), 5.59 (dd, J=24.0, 9.5Hz, 2H), 5.33 (dd, J=13.3, 3.9Hz, 1H), 4.49 (dd, J=17.6, 7.0H z, 1H), 4.34 (dd, J=17.6, 5.4Hz, 1H), 4.17 (dd, J=8.2, 5.5Hz, 1H), 3.45 (ddd, J=20.6, 14.6, 5.6Hz, 3H), 3.24 -3.05 (m, 5H), 2.87 (dd, J=22.4, 11.9Hz, 1H), 2.39 (qd, J=13.2, 4.2Hz, 1H), 2.15-2.04 (m, 1H), 1.0l (s, 6H).

[0435] Example 64: Preparation of Compound 133

[0436]

[0437] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 53.83%.

[0438] 1 H NMR (600MHz, DMSO-d6) δ9.72 (s, 1H), 8.62 (s, 3H), 7.82-7.67 (m, 1H), 7.58-7.44 (m, 2 H), 5.58 (dt, J=21.6, 10.8Hz, 2H), 5.32 (ddd, J=13.4, 11.0, 4.4Hz, 1H), 4.63 (ddd, J=1 1.8, 6.3, 3.6Hz, 1H), 4.50 (dd, J=17.4, 6.7Hz, 1H), 4.46-4.30 (m, 3H), 3.26-3.05 (m, 5H) , 2.90-2.77 (m, 1H), 2.35 (qd, J=13.2, 4.3Hz, 1H), 2.16-2.06 (m, 1H), 1.11-0.83 (m, 6H).

[0439] Example 65: Preparation of Compound 134

[0440]

[0441] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 49.29%.

[0442] 1 H NMR (600MHz, DMSO-d6) δ13.87 (s, 1H), 10.21 (s, 1H), 8.46 (s, 3H), 7.80 (dd, J=6.4, 2.2Hz, 1H), 7.63-7.50 (m , 2H), 7.34 (d, J=8.4Hz, 2H), 7.21 (d, J=8.4Hz, 2H), 5.58 (dt, J=20.8, 10.4Hz, 2H), 5.37-5.25 (m, 1H), 4.55 (d , J=17.5Hz, 1H), 4.42 (t, J=17.9Hz, 1H), 4.16 (d, J=38.4Hz, 1H), 3.42 (d, J=30.7Hz, 4H), 3.16 (dd, J=13.2, 8. 0Hz, 4H), 2.87 (dt, J=17.0, 11.6Hz, 1H), 2.38 (qd, J=13.2, 4.3Hz, 1H), 2.16-2.06 (m, 1H), 1.09-0.93 (m, 6H).

[0443] Example 66: Preparation of Compound 135

[0444]

[0445] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 48.46%.

[0446] 1 H NMR (600MHz, DMSO-d6) δ10.24 (d, J=54.4Hz, 1H), 8.63 (s, 3H), 7.90 (dd, J=7.8, 1.6Hz, 1H), 7.80 (d, J=6.9Hz, 1H), 7.70 (td , J=7.9, 1.7Hz, 1H), 7.59-7.5l (m, 2H), 7.40 (dd, J=11.8, 4.3Hz, 1H), 7.30 (d, J=8.5Hz, 2H), 7.23 (dd, J=21.0, 8.3Hz, 3H), 5.85 (dd, J=34.3, 9.7Hz, 2H), 5.36 (dd, J=13.4, 5.0Hz, 1H), 4.56 (d, J=17.6Hz, 1H), 4.44 (d, J=17.3Hz, 1H), 4.32 (t, J=6.4 Hz, 1H), 3.70 (s, 3H), 3.22-3.09 (m, 3H), 2.95-2.84 (m, 1H), 2.48-2.38 (m, 1H), 2.25 (s, 3H), 2.13 (dd, J=17.9, 12.7Hz, 1H).

[0447] Example 67: Preparation of Compound 136

[0448]

[0449] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 34.39%.

[0450] 1 H NMR (600MHz, DMSO-d6) δ10.21 (s, 1H), 8.50 (s, 3H), 7.88-7.74 (m, 1H), 7.62-7.48 (m, 2H), 7.34 (d, J=8.4Hz, 2H), 7.21 (d, J=8.4Hz, 2H), 5.58 (dt, J=16.2, 8.1Hz, 2H), 5.37- 5.23 (m, 1H), 4.53 (t, J = 17.0Hz, 1H), 4.42 (d, J = 17.5Hz, 1H), 4.18 (t, J = 6.1Hz, 1H), 3 .21-3.05(m, 3H), 2.90-2.74(m, 7H), 2.40(qd, J=13.2, 4.2Hz, 1H), 2.16-2.04(m, 1H).

[0451] Example 68: Preparation of Compound 137

[0452]

[0453] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 17.41%.

[0454] 1 H NMR (600MHz, DMSO-d6) δ10.63 (s, 1H), 8.71 (s, 3H), 7.75 (dd, J=13.1, 7.8Hz, 1H), 7.68- 7.51 (m, 2H), 5.58 (dt, J = 21.3, 10.6Hz, 2H), 5.41 to 5.18 (m, 1H), 4.46 (t, J = 16.3Hz, 1H), 4 .34 (dd, J=17.5, 10.0Hz, 2H), 3.76 (d, J=16.9Hz, 3H), 3.47 (s, 1H), 3.19-3.02 (m, 1H), 2. 88-2.82 (m, 1H), 2.80 (d, J=4.1Hz, 6H), 2.38 (qd, J=13.3, 4.4Hz, 1H), 2.16-2.01 (m, 1H).

[0455] Example 69: Preparation of Compound 138

[0456]

[0457] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 69.45%.

[0458] 1 H NMR (600MHz, DMSO-d6) δ9.74 (s, 11H), 8.82 (s, 3H), 7.76 (d, J=4.9Hz, 1H), 7.60-7. 43 (m, 2H), 5.65-5.52 (m, 2H), 5.33 (ddd, J=18.7, 13.5, 5.0Hz, 1H), 4.62 (td, J=11. 4, 3.4Hz, 1H), 4.54-4.41 (m, 3H), 4.36 (dd, J=17.4, 6.7Hz, 1H), 3.78 (s, 3H), 3.15- 3.06 (m, 1H), 2.82 (dd, J=29.6, 10.5Hz, 6H), 2.41-2.31 (m, 1H), 2.15-2.07 (m, 1H).

[0459] Example 70: Preparation of Compound 139

[0460]

[0461] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 24.88%.

[0462] 1 H NMR (600MHz, DMSO-d6) δ9.77 (s, 11H), 8.91 (s, 3H), 7.76 (d, J=3.4Hz, 1H), 7.58-7.48 (m, 2H), 5.67 (d, J=9.6H z, 1H), 5.60 (d, J=9.6Hz, 1H), 5.31 (dd, J=13.5, 5.0Hz, 1H), 4.67-4.57 (m, 1H), 4.56-4.43 (m, 3H), 4.36 (dd, J =17.4, 1.6Hz, 1H), 3.78 (s, 3H), 3.21-3.04 (m, 1H), 2.85 (d, J = 17.4Hz, 1H), 2.38 (qd, J = 13.0, 3.7Hz, 1H), 2.2 8 (t, J=7.3Hz, 2H), 2.16-2.07 (m, 1H), 1.55-1.44 (m, 2H), 1.26 (dd, J=20.7, 6.6Hz, 9H), 1.18 (t, J=7.1Hz, 3H).

[0463] Example 71: Preparation of Compound 140

[0464]

[0465] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 52.74%.

[0466] 1 H NMR (400MHz, DMSO-d6) δ10.18 (s, 1H), 8.52 (s, 3H), 7.81 (s, 1H), 7.55 (s, 2H), 7.26 (d, J = 21.7Hz, 3H), 5.64 (d, J = 16.9Hz, 2H), 5.33 (s, 2H), 4.65-4.27 (m, 4H), 3.71 (s, 3H), 3.13 (s, 3H), 2.73 (s, 2H), 2.21 (d, J=54.3Hz, 3H), 1.49 (s, 2H), 1.23 (s, 6H), 0.84 (s, 3H).

[0467] Example 72: Preparation of Compound 141

[0468]

[0469] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 74.75%.

[0470] 1 H NMR (400MHz, DMSO-d6) δ10.63 (d, J=6.4Hz, 1H), 8.69 (s, 3H), 7.84-7.70 (m, 1H), 7.56 (dt, J=15.4, 7.8Hz , 4H), 7.15 (d, J=8.4Hz, 1H), 7.02 (t, J=7.5Hz, 1H), 5.81 (dt, J=17.3, 8.6Hz, 2H), 5.37 (dd, J=13.4, 5.0H z, 1H), 4.48 (dd, J=17.6, 10.9Hz, 1H), 4.35 (dd, J=17.3, 6.6Hz, 2H), 3.81 (s, 3H), 3.75 (t, J=8.0Hz, 3H), 3.56 (t, J=27.0Hz, 2H), 3.22-3.09 (m, 1H), 2.88 (t, J=8.2Hz, 1H), 2.49-2.34 (m, 1H), 2.18-2.05 (m, 1H).

[0471] Example 73: Preparation of Compound 142

[0472]

[0473] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 62.59%.

[0474] 1 H NMR (400MHz, DMSO-d6) δ9.72 (s, 1H), 8.75 (s, 3H), 7.83-7.68 (m, 1H), 7.66-7.42 (m, 4H), 7.15 (d, J=8.3Hz, 1H), 7.02 (td, J=7.6, 0.9Hz, 1H), 5.81 (dt, J=17.7, 8.9Hz, 2H), 5.36 (d d, J=13.4, 4.8Hz, 1H), 4.62 (td, J=11.7, 3.5Hz, 1H), 4.55-4.33 (m, 4H), 3.88-3.64 (m, 6H ), 3.22-3.08(m, 1H), 2.94-2.83(m, 1H), 2.46-2.31(m, 1H), 2.14(dd, J=9.1, 3.7Hz, 1H).

[0475] Example 74: Preparation of Compound 143

[0476]

[0477] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 70.57%.

[0478] 1 H NMR (400MHz, DMSO-d6) δ10.20 (s, 1H), 8.61 (s, 3H), 7.80 (dd, J=6.2, 2.7Hz, 1H), 7.56 (tdd, J=11.1, 5.9, 2.0Hz, 4H), 7.30 (d, J=8.6Hz, 2H), 7.26-7.18 (m, 2H), 7.14 (d, J=8.2Hz, 1H), 7.00 (td, J=7.6, 0.9Hz, 1H) , 5.83 (dd, J=24.4, 9.6Hz, 2H), 5.37 (dd, J=13.4, 5.0Hz, 1H), 4.47 (dt, J=35.9, 17.9Hz, 2H), 4.33 (s, 1H) , 3.80(s, 3H), 3.70(s, 3H), 3.23-3.08(m, 3H), 2.96-2.79(m, 1H), 2.48-2.35(m, 1H), 2.21-2.09(m, 1H).

[0479] Example 75: Preparation of Compound 144

[0480]

[0481] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 70.38%.

[0482] 1 H NMR (400MHz, DMSO-d6) δ10.61 (d, J=5.3Hz, 1H), 8.66 (s, 3H), 7.76 (ddd, J=9.2, 7.7, 1.2Hz , 1H), 7.63-7.40 (m, 5H), 7.27 (ddd, J=8.1, 2.7, 1.2Hz, 1H), 5.89 (dd, J=26.9, 9.7Hz, 2H), 5.38 (dd, J=13.4, 5.0Hz, 1H), 4.56-4.29 (m, 3H), 3.82 (s, 3H), 3.75 (t, J=7.0Hz, 3H), 3.52 -3.42(m, 2H), 3.24-3.09(m, 1H), 2.98-2.82(m, 1H), 2.48-2.38(m, 1H), 2.19-2.08(m, 1H).

[0483] Example 76: Preparation of Compound 145

[0484]

[0485]

[0486] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 35.54%.

[0487] 1 H NMR (400MHz, DMSO-d6) δ9.75 (s, 1H), 8.83 (s, 3H), 7.76 (dd, J=9.8, 5.4Hz, 1H), 7.58- 7.37 (m, 5H), 7.32-7.16 (m, 1H), 5.89 (dd, J=27.0, 9.7Hz, 2H), 5.37 (dd, J=13.4, 5.0H z, 1H), 4.70-4.57 (m, 1H), 4.55-4.33 (m, 4H), 3.88-3.71 (m, 6H), 3.15 (ddd, J=18.1, 1 2.8, 5.4Hz, 1H), 2.97-2.77 (m, 1H), 2.43 (dt, J=13.0, 9.1Hz, 1H), 2.19-2.05 (m, 1H).

[0488] Example 77: Preparation of Compound 146

[0489]

[0490] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 49.34%.

[0491] 1 H NMR (400MHz, DMSO-d6) δ10.20 (s, 1H), 8.63 (s, 3H), 7.81 (dt, J=7.5, 3.7Hz, 1H), 7 .62-7.40(m, 5H), 7.35-7.12(m, 5H), 5.90(dd, J=31.7, 9.6Hz, 2H), 5.38(dd, J=13 .4, 5.0Hz, 1H), 4.51 (dd, J=48.5, 17.6Hz, 2H), 4.32 (s, 1H), 3.81 (s, 3H), 3.70 (s, 3H), 3.22-3.04(m, 3H), 2.95-2.84(m, 1H), 2.48-2.39(m, 1H), 2.20-2.07(m, 1H).

[0492] Example 78: Preparation of Compound 147

[0493]

[0494] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 67.67%.

[0495] 1H NMR (400MHz, DMSO-d6) δ10.61 (s, 1H), 8.65 (s, 3H), 7.92-7.85 (m, 2H), 7.75 (ddd, J=16.5, 8.8, 5.0Hz, 1H), 7.56 (dt, J=15.2, 7.5Hz, 2H), 7.11-7.00 (m, 2H), 5.86 (dd, J=23.1, 9.6Hz, 2H), 5.38 (dd, J=13.4, 5 .0Hz, 1H), 4.56-4.32 (m, 3H), 3.83 (d, J=6.1Hz, 3H), 3.75 (t, J=7.4Hz, 3H), 3.43 (dd, J=8.8, 3.2Hz, 1H) , 3.15 (ddd, J=18.1, 13.1, 5.3Hz, 1H), 2.89 (s, 1H), 2.73 (s, 1H), 2.47-2.34 (m, 1H), 2.18-2.06 (m, 1H).

[0496] Example 79: Preparation of the compound

[0497]

[0498] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 72.46%.

[0499] 1 H NMR (600MHz, DMSO-d6) δ9.73 (s, 1H), 8.80 (s, 3H), 7.88 (d, J = 8.8Hz, 2H), 7.76 (d, J = 5.0Hz, 1H), 7. 52 (dd, J=7.5, 5.6Hz, 2H), 7.06 (d, J=8.9Hz, 2H), 5.86 (dd, J=33.1, 9.6Hz, 2H), 5.37 (dd, J=13.4, 4 .9Hz, 1H), 4.61 (tt, J=37.9, 19.1Hz, 1H), 4.55-4.35 (m, 4H), 3.84 (s, 3H), 3.78 (d, J=4.0Hz, 3H), 3 .21-3.07 (m, 1H), 2.94-2.82 (m, 1H), 2.42 (qd, J=12.7, 3.8Hz, 1H), 2.13 (dd, J=17.2, 12.0Hz, 1H).

[0500] Example 80: Preparation of Compound 149

[0501]

[0502] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 57.13%.

[0503] 1 H NMR (600MHz, DMSO-d6) δ10.20 (s, 1H), 8.67 (s, 3H), 7.88 (d, J=8.8Hz, 3H), 7.56-7.53 (m, 2H), 7.30 (d, J=8.4H z, 2H), 7.22 (d, J=8.4Hz, 2H), 7.05 (dd, J=8.9, 2.2Hz, 3H), 5.89 (t, J=4.8Hz, 1H), 5.83 (dd, J=9.6, 3.2Hz, 1H) , 5.37 (dd, J=13.3, 5.0Hz, 1H), 4.57 (d, J=17.3Hz, 1H), 4.46 (t, J=11.5Hz, 1H), 4.31 (s, 1H), 4.13 (t, J=6.3Hz , 1H), 3.83 (s, 3H), 3.69 (d, J=6.5Hz, 3H), 3.18-3.15 (m, 1H), 2.92-2.88 (m, 1H), 2.13 (dd, J=10.9, 5.8Hz, 1H).

[0504] Example 81: Preparation of Compound 150

[0505]

[0506] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 63.59%.

[0507] 1 H NMR (600MHz, DMSO-d6) δ10.20 (s, 1H), 8.67 (s, 3H), 7.88 (d, J=8.8Hz, 3H), 7.56-7.53 (m, 2H), 7.30 (d, J=8.4H z, 2H), 7.22 (d, J=8.4Hz, 2H), 7.05 (dd, J=8.9, 2.2Hz, 3H), 5.89 (t, J=4.8Hz, 1H), 5.83 (dd, J=9.6, 3.2Hz, 1H) , 5.37 (dd, J=13.3, 5.0Hz, 1H), 4.57 (d, J=17.3Hz, 1H), 4.46 (t, J=11.5Hz, 1H), 4.31 (s, 1H), 4.13 (t, J=6.3Hz , 1H), 3.83 (s, 3H), 3.69 (d, J=6.5Hz, 3H), 3.18-3.15 (m, 1H), 2.92-2.88 (m, 1H), 2.13 (dd, J=10.9, 5.8Hz, 1H).

[0508] Example 82: Preparation of Compound 151

[0509]

[0510] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 54.86%.

[0511] 1 H NMR (600MHz, DMSO-d6) δ9.77 (s, 1H), 8.91 (s, 3H), 7.76 (d, J=3.3Hz, 1H), 7.61-7.39 (m, 2H), 5.71-5.52(m, 2H), 5.32(td, J=13.5, 6.8Hz, 1H), 4.62(dd, J=13.2, 5.5Hz, 1H), 4.50-4.46(m, 2H), 4.35 (dt, J=17.4, 4.7Hz, 1H), 3.78 (s, 3H), 3.49-3.39 (m, 1H), 2.93-2.79 (m, 2H), 2.42-2 .32 (m, 1H), 2.18-2.07 (m, 1H), 1.91 (s, 1H), 1.20 (tt, J=14.3, 4.9Hz, 2H), 1.07-0.96 (m, 6H).

[0512] Example 83: Preparation of Compound 152

[0513]

[0514] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 59.83%.

[0515] 1 H NMR (400MHz, DMSO-d6) δ10.21 (s, 1H), 8.67 (s, 3H), 7.81 (s, 1H), 7.56 (s, 2H), 7.26 (dd, J=38.8, 8.1Hz , 4H), 5.65 (dd, J=32.6, 9.3Hz, 2H), 5.34 (dd, J=13.3, 4.6Hz, 1H), 4.77 (dt, J=12.2, 6.0Hz, 1H), 4.48 (d d, J=50.0, 17.6Hz, 2H), 4.26 (t, J=6.3Hz, 1H), 4.21-4.06 (m, 2H), 3.35 (s, 2H), 3.17 (ddd, J=26.7, 13. 7, 5.9Hz, 3H), 2.85 (d, J=16.7Hz, 1H), 2.47-2.27 (m, 1H), 2.11 (d, J=5.5Hz, 1H), 1.20 (t, J=9.8Hz, 6H).

[0516] Example 84: Preparation of Compound 153

[0517]

[0518] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 23.32%.

[0519] 1 H NMR (400MHz, DMSO-d6) δ10.20 (s, 1H), 8.63 (s, 3H), 7.81 (dd, J=5.5, 3.2Hz, 1H), 7.62-7.4 6 (m, 2H), 7.30 (d, J=8.5Hz, 2H), 7.21 (d, J=8.5Hz, 2H), 5.68-5.46 (m, 2H), 5.32 (dd, J=13. 4, 5.0Hz, 1H), 4.48 (dd, J=51.3, 17.6Hz, 2H), 4.32 (s, 1H), 3.70 (s, 3H), 3.37 (s, 2H), 3.21 -3.11(m, 2H), 2.91-2.71(m, 6H), 2.40(ddd, J=17.9, 13.5, 4.8Hz, 1H), 2.16-2.04(m, 1H).

[0520] Example 85: Preparation of Compound 154

[0521]

[0522] The hydrochloride was prepared using general synthesis method 2, and the hydrochloride was obtained as a white solid with a yield of 70.84%.

[0523] 1 H NMR (400MHz, DMSO-d6) δ11.05 (s, 1H), 10.60 (d, J=7.5Hz, 1H), 8.63 (s, 2H) , 7.95 (s, 1H), 7.72 (ddd, J=11.6, 7.6, 1.2Hz, 1H), 7.63-7.47 (m, 2H), 5.17 ( dd, J=13.3, 5.1Hz, 1H), 4.38 (qd, J=17.7, 8.3Hz, 3H), 4.20 (qd, J=7.0, 2.6H z, 2H), 3.50-3.38 (m, 2H), 2.89 (s, 3H), 2.73 (s, 2H), 1.24 (t, J=7.1Hz, 3H).

[0524] Example 86 Preparation of Compound 155

[0525]

[0526] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 69.41%.

[0527] 1 H NMR (600MHz, DMSO-d6) δ10.65 (s, 1H), 8.74 (s, 3H), 7.94 (d, J=7.8Hz, 2H), 7.76 (dd, J=12.6, 7.8Hz, 1H), 7.6 9 (t, J=7.4Hz, 1H), 7.62-7.50 (m, 4H), 5.91 (dd, J=33.8, 9.6Hz, 2H), 5.39 (dd, J=13.4, 5.0Hz, 1H), 4.50 (dd, J=17.5, 13.2Hz, 1H), 4.38 (dd, J=17.5, 8.0Hz, 1H), 4.31 (t, J=5.0Hz, 1H), 4.19 (q, J=7.0Hz, 2H), 3.52-3.43 (m, 2H), 3.37 (s, 1H), 2.95-2.84 (m, 1H), 2.49-2.38 (m, 1H), 2.19-2.10 (m, 1H), 1.22 (td, J=7.1, 2.5Hz, 3H).

[0528] Example 87: Preparation of Compound 156

[0529]

[0530] The hydrochloride was prepared using general synthesis method 2, and was obtained as a white solid with a yield of 68.37%.

[0531] 1 H NMR (400MHz, DMSO-d6) δ11.05 (s, 1H), 9.72 (s, 1H), 8.79 (s, 3H), 7.81-7.58 (m, 1H), 7.60-7.35 (m, 2H), 5.16 (dd, J=13.3, 5.1Hz, 1H), 4.70-4.55 (m , 1H), 4.55-4.17 (m, 5H), 3.01-2.88 (m, 1H), 2.62 (d, J=16.9Hz, 1H), 2.31 (qd, J=13.2, 4.3Hz, 1H), 2.10-2.01 (m, 1H), 1.21 (dt, J=28.6, 7.1Hz, 3H).

[0532] Example 88: Preparation of Compound 157

[0533]

[0534] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 54.59%.

[0535] 1H NMR (600MHz, DMSO-d6) δ9.74 (s, 1H), 8.83 (s, 3H), 7.94 (d, J=7.5Hz, 2H), 7.76 (s, 1H), 7.6 9(t, J=7.4Hz, 1H), 7.58-7.41 (m, 4H), 5.91 (dd, J=35.1, 9.6Hz, 2H), 5.38 (dd, J=13.4, 5.0H z, 1H), 4.67-4.57 (m, 1H), 4.56-4.34 (m, 4H), 4.22 (q, J=6.9Hz, 2H), 3.21-3.09 (m, 1H), 2. 90 (d, J=17.1Hz, 1H), 2.42 (tt, J=24.3, 12.1Hz, 1H), 2.20-2.09 (m, 1H), 1.29-1.20 (m, 3H).

[0536] Example 89: Preparation of Compound 158

[0537]

[0538] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 43.68%.

[0539] 1 H NMR (600MHz, DMSO-d6) δ10.21 (s, 1H), 8.71 (s, 3H), 7.94 (d, J = 7.4Hz, 2H), 7.81 (d, J = 6.2Hz, 1H), 7.68 (t, J = 7.4Hz, 1H), 7 .54 (dd, J=14.0, 6.4Hz, 4H), 7.32 (d, J=8.4Hz, 2H), 7.21 (d, J=8.4Hz, 2H), 5.9l (dd, J=39.5, 9.6Hz, 2H), 5.38 (dd, J=13.4 , 5.0Hz, 1H), 4.58 (d, J=17.6Hz, 1H), 4.46 (d, J=17.4Hz, 1H), 4.25 (t, J=6.7Hz, 1H), 4.12 (qq, J=10.9, 7.1Hz, 2H), 3.24 (d d, J=14.0, 5.7Hz, 1H), 3.20-3.05 (m, 2H), 2.95-2.86 (m, 1H), 2.49-2.39 (m, 1H), 2.20-2.11 (m, 1H), 1.11 (t, J=7.1Hz, 3H).

[0540] Example 90: Preparation of Compound 159

[0541]

[0542] The hydrochloride was prepared using general synthesis method 2, yielding a white solid with a yield of 57.53%.

[0543] 1 H NMR (600MHz, DMSO-d6) δ11.03 (s, 1H), 10.18 (s, 1H), 8.66 (s, 3H), 7.86-7.75 (m, 1H), 7.53 (dd, J=7.1, 5.8Hz, 2H), 7.31 (d, J=8.4Hz, 2H), 7.22 (d, J=8.4Hz, 2H), 5.15 (dd, J=13.3, 5.1Hz, 1H), 4.47 (dd, J=58.0, 17.6Hz, 2H) , 4.27 (s, 1H), 4.19-4.05 (m, 2H), 3.21 (dd, J=14.1, 5.9Hz, 1H), 3.09 (dd, J=12.6, 6.2Hz, 1H), 2.98-2.89 (m, 1H ), 2.62 (d, J=17.0Hz, 1H), 2.37 (qd, J=13.2, 4.3Hz, 1H), 2.05 (dd, J=21.8, 16.3Hz, 1H), 1.12 (t, J=7.1Hz, 3H).

[0544] Example 91: Preparation of Compound 163

[0545]

[0546] The product was prepared using general synthesis method 3, yielding a white solid product with a yield of 49.26%.

[0547] 1 H NMR (400MHz, DMSO-d6) δ10.19 (s, 1H), 7.80 (dt, J=7.7, 3.8Hz, 1H), 7.55 (dd, J=6.4, 2.9Hz , 1H), 7.31 (d, J=8.5Hz, 1H), 7.15 (d, J=8.5Hz, 1H), 5.63 (dd, J=20.8, 9.6Hz, 1H), 5.33 (dd, J=13.4, 5.0Hz, 1H), 4.47 (dd, J=59.3, 17.6Hz, 1H), 3.42 (dd, J=7.7, 4.7Hz, 1H), 3.16-3.0 7(m, 1H), 2.93-2.81(m, 1H), 2.42-2.33(m, 1H), 2.12(dd, J=14.2, 8.9Hz, 1H), 1.10(s, 4H).

[0548] Example 92: Preparation of Compound 164

[0549]

[0550] The product was prepared using general synthesis method 3, and the free product was a white solid with a yield of 42.11%.

[0551] 1 H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 8.88 (s, 1H), 8.16-8.01 (m, 1H), 8.02-7.8 4(m, 2H), 7.81-7.63(m, 2H), 7.63-7.44(m, 3H), 7.46-7.30(m, 1H), 6.02-5.81(m, 2H), 5.36 (dt, J=16.8, 8.3Hz, 1H), 4.59-4.27 (m, 2H), 3.57-3.23 (m, 4H), 3.25-3 .04(m, 2H), 2.98-2.82(m, 1H), 2.4l(dd, J=29.9, 20.1Hz, 1H), 2.22-2.05(m, 1H).

[0552] Example 93: Preparation of Compound 165

[0553]

[0554] The product was prepared using general synthesis method 2, and the free product was obtained as a white solid with a yield of 67.68%.

[0555] 1 H NMR (400MHz, DMSO-d6) δ11.05 (s, 1H), 10.21 (s, 1H), 7.79 (dd, J=8.5, 4.1Hz, 2H), 7. 67-7.42(m, 3H), 7.40-7.23(m, 2H), 7.23-6.99(m, 2H), 5.15(dd, J=13.3, 5.1Hz, 1H) , 4.47 (dd, J=41.5, 17.7Hz, 2H), 3.46 (dd, J=7.5, 4.8Hz, 2H), 3.13 (dt, J=34.8, 17.5 Hz, 1H), 3.05-2.85 (m, 2H), 2.74-2.60 (m, 1H), 2.49-2.30 (m, 1H), 2.15-2.00 (m, 1H).

[0556] Example 94: Preparation of Compound 166

[0557]

[0558] The product was prepared using general synthesis method 2, and the free product was a white solid with a yield of 49.71%.

[0559] 1 H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 9.61 (s, 1H), 7.73 (s, 1H), 7.55-7.44 (m, 2H), 5.13 (dd, J=13.2, 5.1Hz, 1H), 4.52-4.29 (m, 2H), 4. 27-4.14 (m, 2H), 3.70-3.62 (m, 3H), 3.00-2.85 (m, 1H), 2.60 (dd, J=35.8, 18.4Hz, 2H), 2.35 (qd, J=13.4, 4.5Hz, 1H), 2.10-1.90 (m, 3H).

[0560] Example 95: Preparation of Compound 167

[0561]

[0562] The specific synthesis process is as follows:

[0563] Boc-L-glutamic acid (5 g), EDCI (15.51 g), HOBt (10.93 g), and TEA (14.05 mL) were dispersed in 100 mL of dry dichloromethane. A dichloromethane solution of benzyloxyamine (2.59 mL, 22.24 mmol) was added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 3 days. Dichloromethane was then added, and the mixture was washed successively with 1 M HCl, saturated sodium bicarbonate, and saturated brine. The organic phases were combined, dried over anhydrous Na₂SO₄, and evaporated under reduced pressure until a small amount of solvent remained. Crystallization was carried out at room temperature, and the mixture was filtered to obtain 3.27 g of a white solid product.

[0564] The above product (4.76 g) was dissolved in dichloromethane (145 mL), and trifluoroacetic acid (29 mL) was added at low temperature. The mixture was stirred at room temperature for 4 h, and the solvent was removed by rotary evaporation under reduced pressure to obtain a light pink solid product, which was directly used in the first step.

[0565] The above product (3.98 g) and methyl 2-bromomethyl-3-nitrobenzoate (5 g) were dispersed in acetonitrile (75 ml), and triethylamine (6 ml) was added at low temperature. The mixture was stirred overnight at room temperature, and a solid precipitated. The solid was filtered and dried to obtain 4.9 g of product.

[0566] The above product (500 mg) was placed in a mixed solution of 10 mL toluene and 10 mL water, and iron powder (284 mg) and ammonium acetate (390 mg) were added. The mixture was reacted at 100 °C for 3 h. Ethyl acetate was added, and the mixture was washed successively with water, saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 128 mg of the product.

[0567] The above product (120 mg) and p-nitrophenyl chloroformate (100 mg) were dissolved in tetrahydrofuran and stirred under reflux for 2 h. The mixture was concentrated under reduced pressure, and ethyl acetate was added and stirred until homogeneous to obtain a suspension. The suspension was filtered under reduced pressure and washed with ethyl acetate or directly evaporated to dryness. The residue was used directly in the next step.

[0568] The above residue and compound Boc-L-cysteine ​​(73 mg) were dissolved in DMF, and DIPEA (85 mg) was added dropwise under stirring at room temperature. The stirring was continued at room temperature until the raw material disappeared. Acid water was added to adjust the pH to 3-4, 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 with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain 130 mg of foamy solid.

[0569] The above product was dispersed in ethyl acetate, and then hydrogen chloride gas was introduced. The reaction was carried out at room temperature, and a solid was precipitated. After the reaction was completed, the product was filtered, washed with ethyl acetate and n-heptane, and dried at 50°C to obtain a white solid hydrochloride with a yield of 75.32%.

[0570] 1 H NMR (600MHz, DMSO-d6) δ7.96-7.90 (m, 2H), 7.76 (dd, J=12.6, 7.9Hz, 1H), 7.69 (t, J=7.4Hz, 1H), 7.6 1-7.50 (m, 4H), 5.53 (d, J=9.6Hz, 1H), 5.48 (d, J=9.7Hz, 1H), 5.38 (ddd, J=13.5, 4.8, 3.3Hz, 1H), 4. 49 (dd, J=17.5, 12.5Hz, 1H), 4.38 (dd, J=17.5, 11.2Hz, 1H), 4.17-4.07 (m, 1H), 3.50-3.43 (m, 1H), 3 .41-3.36 (m, 1H), 3.20-3.12 (m, 1H), 2.88 (d, J=17.6Hz, 1H), 2.48-2.39 (m, 1H), 2.16-2.06 (m, 1H).

[0571] Example 96: Preparation of Compound 168

[0572]

[0573] The product of Example 95 was dispersed in methanol, and then palladium on carbon was added. The reaction was carried out at room temperature under hydrogen atmosphere. After the reaction was completed, the palladium on carbon was filtered off, and the reaction solution was added dropwise to tert-butyl methyl ether. A solid precipitated out, and the hydrochloride product was obtained as a white solid with a yield of 55.31%.

[0574] 1 H NMR (600MHz, DMSO-d6) δ10.12 (s, 1H), 8.38 (s, 2H), 7.73 (dd, J=12.9, 7.8Hz, 1H), 7.57-7.51 (m, 2H), 5.15 (dd, J=13.3, 3.4Hz, 1H), 4.47-4.31 (m, 2H), 4.13 (s, 1H), 3.47 (dd, J=14.6, 5.0Hz, 1H), 3.36 (dd, J=14.8, 6.3Hz, 1H), 2.97-2. 86 (m, 1H), 2.64-2.59 (m, 1H), 2.37-2.29 (m, 1H), 2.04 (dd, J=9.0, 3.7Hz, 1H).

[0575] Example 97: Preparation of Compound 169

[0576]

[0577] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 45.71%.

[0578] 1 H NMR (400MHz, DMSO-d6) δ10.20 (s, 1H), 8.40 (s, 2H), 7.86-7.74 (m, 1H), 7.54 (dd, J=7.4, 5.6Hz, 2H), 7.33 (d, J =8.5Hz, 2H), 7.21 (d, J = 8.5Hz, 2H), 5.63 (dd, J = 26.0, 9.6Hz, 2H), 5.32 (dd, J = 13.4, 4.9Hz, 1H), 4.48 (dd, J = 5 3.5, 17.6Hz, 2H), 4.14 (dd, J=28.3, 22.2Hz, 1H), 3.21-3.05 (m, 3H), 2.84 (d, J=17.2Hz, 1H), 2.46-2.33 (m, 1H ), 2.27 (t, J=7.3Hz, 2H), 2.17-2.05 (m, 1H), 1.47 (d, J=6.6Hz, 2H), 1.32-1.12 (m, 20H), 0.85 (t, J=6.8Hz, 3H).

[0579] Example 98: Preparation of Compound 170

[0580]

[0581] The sulfate was prepared using general synthesis method 3, and deprotection was performed under concentrated sulfuric acid conditions to obtain a white solid sulfate with a yield of 40.38%.

[0582] 1H NMR (400MHz, DMSO-d6) δ10.18 (s, 1H), 8.17 (s, 1H), 7.80 (dd, J=5.9, 3.0Hz, 1H), 7.54 (d d, J=8.3, 5.2Hz, 1H), 7.31 (d, J=8.5Hz, 1H), 7.2l (d, J=8.5Hz, 1H), 5.63 (dd, J=20.5, 9.6 Hz, 1H), 5.34 (dd, J=13.3, 5.0Hz, 1H), 4.46 (dd, J=58.1, 17.6Hz, 1H), 4.07 (s, 1H), 3.16- 3.02(m, 2H), 2.85(d, J=16.4Hz, 1H), 2.45-2.31(m, 1H), 2.18-2.05(m, 1H), 1.11(s, 9H).

[0583] Example 99: Preparation of Compound 171

[0584]

[0585] The nitrate was prepared using general synthesis method 3, and deprotected under concentrated nitric acid conditions to obtain a white solid nitrate with a yield of 57.74%.

[0586] 1 H NMR (400MHz, DMSO-d6) δ10.18 (s, 1H), 8.17 (s, 1H), 7.80 (dd, J=5.9, 3.0Hz, 1H), 7.54 (d d, J=8.3, 5.2Hz, 1H), 7.31 (d, J=8.5Hz, 1H), 7.21 (d, J=8.5Hz, 1H), 5.63 (dd, J=20.5, 9.6 Hz, 1H), 5.34 (dd, J=13.3, 5.0Hz, 1H), 4.46 (dd, J=58.1, 17.6Hz, 1H), 4.07 (s, 1H), 3.16- 3.02(m, 2H), 2.85(d, J=16.4Hz, 1H), 2.45-2.31(m, 1H), 2.18-2.05(m, 1H), 1.11(s, 9H).

[0587] Example 100: Preparation of compound 172

[0588]

[0589] The sulfate was prepared using general synthesis method 3, and deprotection was performed under concentrated sulfuric acid conditions to obtain a white solid sulfate with a yield of 53.69%.

[0590] 1H NMR (400MHz, DMSO-d6) δ10.51 (s, 1H), 8.34 (s, 1H), 7.98-7.90 (m, 1H), 7.80- 7.66 (m, 1H), 7.64-7.49 (m, 2H), 5.91 (dd, J=24.2, 9.8Hz, 1H), 5.44-5.36 (m, 1 H), 4.42 (ddd, J=25.9, 17.6, 9.2Hz, 1H), 4.26 (s, 1H), 3.51-3.33 (m, 2H), 3.1 6-3.11 (m, 1H), 2.88 (d, J=17.1Hz, 1H), 2.48-2.40 (m, 1H), 2.17-2.09 (m, 1H).

[0591] Example 101: Preparation of Compound 173

[0592]

[0593] The nitrate was prepared using general synthesis method 3, and deprotected under concentrated nitric acid conditions to obtain a white solid nitrate with a yield of 47.46%.

[0594] 1 H NMR (400MHz, DMSO-d6) δ10.51 (s, 1H), 8.33 (s, 1H), 7.97-7.91 (m, 1H), 7.82-7.73 (m, 1H), 7.69 (t, J=7.4Hz, 1H), 7.56 (dt, J=13.9, 7.5Hz, 2H), 5.91 (dd, J=24.3, 9.7Hz, 1H) , 5.45-5.35(m, 1H), 4.42(ddd, J=25.8, 17.6, 9.0Hz, 1H), 4.22(s, 1H), 3.50-3.37(m, 1H), 3.21-3.11(m, 1H), 2.88(d, J=17.5Hz, 1H), 2.47-2.39(m, 1H), 2.18-2.09(m, 1H).

[0595] Example 102: Preparation of Compound 174

[0596]

[0597] The hydrochloride was prepared using general synthesis method 3, and was obtained as a white solid with a yield of 60.36%.

[0598] 1H NMR (400MHz, DMSO-d6) δ10.58 (s, 1H), 8.44 (s, 3H), 7.87-7.70 (m, 1H), 7.65-7.43 (m, 2H), 5.63 (dd, J=2 9.7, 9.6Hz, 2H), 5.32 (dd, J=13.2, 3.8Hz, 1H), 4.40 (ddd, J=22.9, 17.6, 6.4Hz, 2H), 4.19 (s, 1H), 3.47 ( dd, J=14.6, 5.1Hz, 1H), 3.42-3.37 (m, 2H), 3.20-3.06 (m, 1H), 2.84 (d, J=17.0Hz, 1H), 2.46-2.35 (m, 1H) ), 2.27 (t, J=7.3Hz, 2H), 2.14-2.03 (m, 1H), 1.47 (d, J=6.9Hz, 2H), 1.22 (s, 20H), 0.85 (t, J=6.8Hz, 3H).

[0599] Example 103: Preparation of Compound 175

[0600]

[0601] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 62.47%.

[0602] 1 H NMR (400MHz, DMSO-d6) δ9.70 (s, 1H), 8.54 (s, 3H), 7.76 (dd, J=9.9, 5.1Hz, 1H), 7.58-7.47 (m, 2H), 5.63 (dd, J=27.4, 9.6Hz, 2H), 5.31 (dd, J=13.4, 2.9Hz, 1H), 4.63 (dt, J=11.9, 3.4Hz, 1H), 4.55-4.26 (m, 4H), 3.20-3.05 (m, 1H), 2.84 (d, J=16.8Hz, 1H), 2.43-2.30 (m, 1H), 2.27 (t, J=7. 3Hz, 2H), 2.16-2.05 (m, 1H), 1.47 (d, J=6.6Hz, 2H), 1.33-1.11 (m, 20H), 0.85 (t, J=6.8Hz, 3H).

[0603] Example 104: Preparation of Compound 176

[0604]

[0605]

[0606] The hydrochloride was prepared using general synthesis method 3, yielding a white solid with a yield of 64.32%.

[0607] 1 H NMR (400MHz, DMSO-d6) δ13.88 (s, 1H), 10.21 (s, 1H), 8.47 (s, 3H), 7.80 (dt, J=7.4, 3.7 Hz, 1H), 7.63-7.51 (m, 2H), 7.34 (d, J=8.5Hz, 2H), 7.21 (d, J=8.5Hz, 2H), 5.63 (dd, J=20 .5, 9.6Hz, 2H), 5.34 (dd, J=13.4, 5.0Hz, 1H), 4.47 (dd, J=60.4, 17.6Hz, 2H), 4.20 (s, 1 H), 3.20-3.07(m, 3H), 2.93-2.79(m, 1H), 2.39(m, 1H), 2.19-2.06(m, 1H), 1.11(s, 9H).

[0608] Example 105: Preparation of Compound 177

[0609]

[0610] The sample was prepared using general synthesis method 3, yielding a white solid with a yield of 67.21%.

[0611] 1 H NMR (400MHz, DMSO-d6) δ12.72 (s, 1H), 10.16 (s, 1H), 8.24 (d, J = 8.1Hz, 1H), 7.78 (dt, J = 7.5, 3.8Hz, 1H), 7.58-7.52 (m, 2H), 7.28 (d, J=8.5Hz, 2H), 7.15 (d, J=8.5Hz, 2H), 5.63 (dd, J=20.3 , 9.6Hz, 2H), 5.33 (dd, J=13.4, 5.0Hz, 1H), 4.58-4.34 (m, 3H), 3.17-3.02 (m, 2H), 2.90-2.81 (m, 2H), 2.45-2.33 (m, 1H), 2.11 (dd, J=14.6, 9.4Hz, 1H), 1.79 (d, J=7.2Hz, 3H), 1.10 (s, 9H).

[0612] Example 106: Preparation of Compound 184

[0613]

[0614] The sample was prepared using general synthesis method 3, yielding a white solid with a yield of 67.3%.

[0615] 1 H NMR (400MHz, DMSO) δ10.20 (s, 1H), 8.48 (s, 3H), 7.81 (dd, J=5.8, 3.0Hz, 1H), 7.61-7.50 (m, 2H), 7.33 (d, J=8.5Hz, 2 H), 7.21 (d, J=8.5Hz, 2H), 5.63 (dd, J=20.3, 9.6Hz, 2H), 5.34 (dd, J=13.4, 5.0Hz, 1H), 4.93 (t, J=5.6Hz, 1H), 4.54 ( d, J=17.6Hz, 1H), 4.37 (dd, J=21.4, 12.0Hz, 2H), 4.14 (t, J=4.9Hz, 2H), 3.61-3.52 (m, 2H), 3.19-3.12 (m, 2H), 2.85 (d, J=16.5Hz, 1H), 2.39 (dd, J=13.2, 4.4Hz, 1H), 2.16-2.07 (m, 1H), 1.20-1.02 (m, 9H), 0.85 (dt, J=9.3, 5.8Hz, 1H).

[0616] Example 107: Preparation of Compound 185

[0617]

[0618] The sample was prepared using general synthesis method 3, yielding a white solid with a yield of 62.4%.

[0619] 1 H NMR (400MHz, DMSO) δ10.20 (s, 1H), 8.49 (s, 3H), 7.81 (s, 1H), 7.55 (dd, J=8.3, 5.2Hz, 2H), 7.33 (d, J=7.0Hz, 2H), 7. 21 (d, J=8.4Hz, 2H), 5.63 (dd, J=20.4, 9.5Hz, 2H), 5.34 (dd, J=13.3, 5.2Hz, 1H), 5.05 (s, 1H), 4.73 (s, 1H), 4.54 (d, J =17.5Hz, 1H), 4.39 (d, J = 17.6Hz, 2H), 4.24-4.13 (m, 1H), 4.04 (dt, J = 14.0, 6.6Hz, 1H), 3.67 (s, 1H), 3.16 (d, J = 6.5H z, 2H), 2.85 (d, J=17.4Hz, 1H), 2.39 (d, J=12.7Hz, 1H), 2.12 (s, 1H), 1.32-0.97 (m, 9H), 0.84 (dd, J=9.3, 7.0Hz, 1H).

[0620] Example 108: Preparation of Compound 186

[0621]

[0622] The sample was prepared using general synthesis method 3, yielding a white solid with a yield of 64.5%.

[0623] 1 H NMR (400MHz, DMSO) δ10.21 (s, 1H), 8.66 (d, J=3.6Hz, 3H), 7.81 (dd, J=5.4, 3.4Hz, 1H), 7.60-7.50 (m, 2H), 7.31 (d, J=8.5Hz, 2H), 7.21 (d, J=8.5Hz, 2H), 5.63 (dd, J=20.2, 9.6Hz, 2H), 5.34 (dd, J=13.4, 5.0Hz, 1H), 4.97-4.8 3 (m, 1H), 4.55 (d, J = 17.6Hz, 1H), 4.39 (d, J = 17.6Hz, 1H), 4.22 (s, 1H), 3.27-2.99 (m, 3H), 2.85 (d, J = 16.9Hz, 1 H), 2.44-2.30 (m, 1H), 2.11 (dd, J=10.0, 5.1Hz, 1H), 1.16 (d, J=6.2Hz, 3H), 1.11 (s, 9H), 1.05 (t, J=7.5Hz, 3H).

[0624] Example 109: Preparation of Compound 187

[0625]

[0626] The sample was prepared using general synthesis method 3, yielding a white solid with a yield of 60.3%.

[0627] 1H NMR (400MHz, DMSO) δ10.22 (s, 1H), 8.73 (d, J = 3.6Hz, 3H), 7.81 (dd, J = 5.7, 3.1Hz, 1H), 7.65-7.44 (m, 2H), 7.31 (d, J = 8.5Hz, 2H), 7.21 (d, J=8.5Hz, 2H), 5.63 (dd, J=20.2, 9.6Hz, 2H), 5.34 (dd, J=13.4, 5.0Hz, 1H), 4.56 (d, J=17.6Hz, 1H), 4.40 (d, J=17.6Hz, 1H) , 4.28 (d, J=5.4Hz, 1H), 4.10-3.98 (m, 2H), 3.16 (dtd, J=22.1, 14.2, 6.9Hz, 3H), 2.91-2.78 (m, 1H), 2.39 (ddd, J=26.5, 13.4, 4.0 Hz, 1H), 2.11 (dd, J=9.9, 4.8Hz, 1H), 1.52-1.42 (m, 2H), 1.21 (tt, J=14.2, 6.2Hz, 3H), 1.09 (d, J=13.1Hz, 9H), 0.86-0.81 (m, 3H).

[0628] Example 110: Preparation of compound 188

[0629]

[0630] The sample was prepared using general synthesis method 3, yielding a white solid with a yield of 69.5%.

[0631] 1H NMR (400MHz, DMSO) δ10.22 (s, 1H), 8.74 (d, J = 3.5Hz, 3H), 7.81 (dd, J = 6.1, 2.7Hz, 1H), 7.62-7.49 (m, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.20 (d, J=8.5Hz, 2H), 5.63 (dd, J=20.2, 9.6Hz, 2H), 5.34 (dd, J=13.4, 5.0Hz, 1H), 4.56 (d, J=17.6Hz, 1H), 4.40 (d, J=17.6Hz, 1H), 4.27 (d, J=5.7Hz, 1H), 3.16 (dtd, J=21.8, 13.9, 6.7Hz, 3H), 2.90-2.78 (m, 1H), 2.39 (ddd, J=27.0, 13 .6, 4.6Hz, 1H), 2.11 (dd, J=10.1, 5.0Hz, 1H), 1.56-1.43 (m, 2H), 1.22 (t, J=10.3Hz, 6H), 1.11 (s, 9H), 0.87-0.84 (m, 3H).

[0632] Test case

[0633] Experiment 1: Solubility Test

[0634] Experimental method: Take approximately 0.5 mL of distilled water in a 5 mL centrifuge tube and slowly add the dried compound until it cannot be dissolved (it remains cloudy even after shaking at 25°C). Filter the solution into another clean, pre-weighed 5 mL EP tube, weigh it again, and calculate the weight of the solution. Freeze-dry the filtrate, weigh it, and calculate the mass of the remaining solid solute. Calculate the mass of the solvent, and then calculate the solubility of the compound in water. The results are shown in Table 1.

[0635] Table 1. Solubility of the compounds of the present invention

[0636]

[0637]

[0638] Conclusion: The compounds of this invention exhibit significantly higher water solubility than the already marketed drug lenalidomide, 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 lenalidomide. Furthermore, this high water solubility facilitates the formulation and clinical application of these compounds.

[0639] Experiment 2: In vitro anti-multiple myeloma activity assay

[0640] Experimental method: MM.1S cells in the logarithmic growth phase were collected and cultured at a concentration of 2 × 10⁻⁶ cells / mL.4 Cells were seeded at a density of cells / well in 96-well plates and incubated at 37°C in a 5% CO2 incubator for 2 hours. Then, compounds with final concentrations ranging from 0.0001 to 50 μM were added, with four replicates per compound, and the plates were incubated at 37°C in a 5% CO2 incubator for 72 hours. After incubation, 20 μL of 5 mg / mL MTT solution was added to each well. After 4 hours, the supernatant was discarded, and 150 μL of DMSO was added. The absorbance value (A) at 570 nm was measured. 测定 The absorbance value A measured in the cell-free blank well. 空白 The absorbance value measured from the untreated cell wells is A. 对照 The cell viability of each well was calculated using the following formula:

[0641] Cell viability (%) = (A 测定 -A 空白 ) / (A 对照 -A 空白 )×100%.

[0642] The cell viability and drug concentration were plotted using GraphPad Prism software, and the IC50 was calculated. 50 value.

[0643] 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. Among them, IC50... 50 Values ​​less than 0.05 μM are considered A; IC 50 Values ​​greater than 0.05 μM and less than 0.1 μM are classified as B; IC 50 Values ​​greater than 0.1 μM and less than 0.5 μM are C; IC 50 Values ​​greater than 0.5 μM and less than 1 μM are classified as D.

[0644] Table 2. In vitro anti-multiple myeloma efficacy of the compounds of this invention

[0645]

[0646]

[0647] Experiment 3: Activity assay of anti-drug-resistant multiple myeloma cells in combination with dexamethasone alone

[0648] Methods: This study evaluated the effect of dexamethasone as a single agent combined with the compounds of this invention or lenalidomide on the inhibition of proliferation of lenalidomide-resistant multiple myeloma NCI-H929 cells. Cell viability was detected using the MTT assay, as described in Experiment 2.

[0649] The results showed that the compound of this invention had strong inhibitory activity against lenalidomide-resistant NCI-H929 cells, and when used in combination with the second active component dexamethasone, it could synergistically inhibit the proliferation of NCI-H929 cells. The results are shown in Table 3. 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.

[0650] Table 3. Comparison of the antiproliferative activities of the compounds of the present invention, as single agents or in combination with dexamethasone, in lenalidomide-resistant NCI-H929 cells.

[0651]

[0652] Experiment 4: Targeted transport study of amino acid transporter LAT1 / SLC7A5

[0653] 1. Construction of homeostatic cell lines:

[0654] In this experiment, we independently constructed a stable cell line of 293T cells that highly expresses LAT1, which was used for targeted transport assays of the compounds of this invention.

[0655] 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.

[0656] 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, the cell line was successfully constructed. 2. Targeted cell absorption assay of the compounds of this invention.

[0657] Experimental Methods: This study used 293T and LAT1-293T steady-state cell lines. Cells were evenly seeded into 6 cm 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 with physiological saline to 20 μM (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.

[0658] Experimental results: As shown in Table 3, the content of the compound of the present invention in the lysate of 293T cells with high expression of LAT1 was significantly higher than that in ordinary 293T cells, indicating that the compound of the present invention has significant LAT1 targeting.

[0659] Table 3. Absorption of the compounds of the present invention in 293T cells and 293T-LAT1 cells.

[0660]

[0661]

[0662]

[0663] Experiment 5: In vivo antitumor drug efficacy trial I

[0664] Test methods

[0665] (1) Model preparation

[0666] Six- to eight-week-old NOD / SCID female mice were used in the laboratory. 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, and the room temperature was 20–25°C, humidity 40–70%, with a 12h / 12h light / dark 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 final volume of 1×10⁻⁶. 8Add 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.

[0667] (2) Group administration

[0668] This experiment consisted of 9 groups: a saline group, a compound 73 group, a compound 82 group, a compound 90 group, a compound 109 group, a compound 169 group, a compound 174 group, a compound 176 group, and a lenalidomide group, with 7 animals in each group. The drugs were administered orally once daily, with lenalidomide at a dose of 100 mg / kg body weight. The other drugs were administered at equimolar concentrations compared to lenalidomide, with a 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 effects of the test drugs and changes in animal body weight.

[0669] (3) Test Results

[0670] The results are shown in Table 4 and Figure 2 As shown, the compounds of this invention have a superior tumor-suppressing effect compared with the clinical control drug lenalidomide, fully demonstrating the selective accumulation and targeting of the compounds of this invention in tumor cells and tumor tissues.

[0671] Table 4. Drug dosage, mouse body weight change rate, and relative tumor inhibition rate in the RPMI-8226 model.

[0672]

[0673]

[0674] ** 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%

[0675] Experiment 6: In vivo antitumor efficacy trial II

[0676] Test methods

[0677] (1) Model preparation

[0678] 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.

[0679] (4) Group administration

[0680] This experiment consisted of 9 groups: saline group, compound 73 group, compound 82 group, compound 90 group, compound 109 group, compound 169 group, compound 174 group, compound 176 group, and lenalidomide group, with 7 animals in each group. The drugs were administered orally once daily, with lenalidomide at a dose of 100 mg / kg body weight. Other drugs were administered at equimolar concentrations compared to lenalidomide, with a volume 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 effects of the test drugs and changes in animal body weight.

[0681] (5) Test Results

[0682] The results are shown in Table 5 and Figure 3 As shown, the compounds provided by this invention have a superior tumor-suppressing effect compared with the clinical control drug lenalidomide, fully demonstrating the selective accumulation and targeting of the compounds in tumor cells and tumor tissues.

[0683] Table 5. Drug dosage, mouse body weight change rate, and relative tumor inhibition rate in the NCI-H929 model.

[0684]

[0685]

[0686] ** 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)OR 4、 Alkylene-OC(O)NHR4, Alkylene-OC(O)NR4R4', Or -OR4; 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 something that is unsubstituted or substituted with one or more substituents, wherein the substituents of the "optionally substituted alkyl", "optionally substituted aryl", and "optionally substituted arylalkylene" are each independently selected from hydroxyl, alkyl, alkoxy, alkanoyloxymethyl, and alkanoyloxy. The alkyl portion of "alkyl", "alkoxy", "alkoxymethyl", "alkoxyloxy", and "alkoxyloxy" is each independently C10. 1-20 Straight-chain or branched alkyl groups; The alkylene moiety in "alkylene", "arylphenylene", "alkylene-OC(O)R4", "alkylene-OC(O)OR4", "alkylene-OC(O)NHR4", or "alkylene-OC(O)NR4R4'" or "alkylene arylene" 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 alkyl portion of "alkyl", "alkoxy", "alkoxymethyl", "alkoxyloxy", and "alkoxyloxy" is 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 alkyl portion of "alkyl", "alkoxy", "alkoxymethyl", "alkoxyloxy", and "alkoxyloxy" is 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 alkyl portion of "alkyl", "alkoxy", "alkoxymethyl", "alkoxyloxy", and "alkoxyloxy" is each independently C10. 1-7 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 alkyl portion of "alkyl", "alkoxy", "alkoxymethyl", "alkoxyloxy", and "alkoxyloxy" is 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, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, or hexadecyl.

6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The alkylene moiety in "alkylene", "arylphenylene", "alkylene-OC(O)R4", "alkylene-OC(O)OR4", "alkylene-OC(O)NHR4", or "alkylene-OC(O)NR4R4'" or "alkylene arylene" is each independently C 1-3 Straight-chain or branched alkylene groups.

7. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The alkylene portion in "alkylene", "arylphenylene", "alkylene-OC(O)R4", "alkylene-OC(O)OR4", "alkylene-OC(O)NHR4", or "alkylene-OC(O)NR4R4'" or "alkylene arylene" 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, -(C=O)CH3 or -(C=O)OC(CH3)3.

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 compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Selected from the following compounds: 。 16. The compound of formula (I) according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein the method for preparing the compound of formula (I) is as follows: 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 (A) and Formula (B) were prepared by substitution reaction in a suitable solvent under alkaline catalysis at temperatures ranging from 0 °C to 25 °C to obtain Formula (C). in, In equations (B) and (C), R3 is defined as described in equation (I), but not as H, OR4; In formula (B), B is selected from Cl, Br, I, OTs, and OMs; Alternatively, equation (C) can be obtained through the reaction of 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 substituted and amino-cleaved under alkaline catalysis to obtain LN-S5, which is then reduced to obtain formula (C). It also includes obtaining equation (E) by passing equations (C) and (D) through step B. Step B: Acylation of formulas (C) and (D) yields formula (E). Formula (C) and p-nitrophenyl chloroformate were dissolved in a solvent and reacted under reflux to obtain formula (E). In equation (E), R3 is defined as described in equation (I); Alternatively, it may also include obtaining equation (G) from equations (C) and (F) through step C: Step C: Formulas (C) and (F) are refluxed in dichloromethane or acetonitrile to undergo an acylation reaction to obtain formula (G); In equation (G), R3 is defined as described in equation (I); Alternatively, it may also include obtaining equation (J) from equations (C) and (H) through step D: Step D: Combine formula (C) and formula (D) through a condensation reaction to obtain formula (J); Disperse formula (C) and formula (H) in tetrahydrofuran and reflux them under heating conditions. After the reaction is completed, concentrate under reduced pressure, filter and wash with ethyl acetate or directly evaporate to dryness to obtain formula (J). In equation (J), R3 is defined as described in equation (I); Then, formula (E), formula (G), or formula (J) is reacted with formula (L) in N,N-dimethylformamide under base catalysis via nucleophilic substitution and optional deprotection to obtain formula (I), as shown in the following synthetic step E: Step E: 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 alkali is potassium carbonate, cesium carbonate, sodium hydride, or lithium bis(trimethylsilylamine); the solvent is N,N-dimethylformamide, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone.

18. The preparation method according to claim 16, characterized in that, In step B, the solvent is tetrahydrofuran, N,N-dimethylformamide, or N-methylpyrrolidone.

19. The preparation method according to claim 16, characterized in that, In step B, after the reflux reaction is completed, the mixture is concentrated under reduced pressure, and ethyl acetate, dichloromethane or petroleum ether is added and stirred until homogeneous to obtain a suspension. The suspension is then filtered under reduced pressure and washed with ethyl acetate or directly evaporated to dryness to obtain formula (E).

20. The preparation method according to claim 16, characterized in that, In step C, formula (C) is slowly added dropwise to a triphosgene solution in dichloromethane or acetonitrile at low temperature, and the temperature is slowly raised to 30℃-60℃ and refluxed to carry out the acylation reaction. After the reaction is completed, the solution is concentrated under reduced pressure to obtain formula (G).

21. The preparation method according to claim 20, characterized in that, Formula (C) is slowly added dropwise to a triphosgene solution in dichloromethane or acetonitrile at 0°C, and the mixture is slowly heated to 45°C and refluxed to carry out the acylation reaction. After the reaction is completed, the mixture is concentrated under reduced pressure to obtain formula (G).

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

23. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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

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

26. The pharmaceutical composition according to any one of claims 23-25, 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.

27. Use of a compound of formula (I) according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 23-26 in the preparation of a medicament for the prevention and / or treatment of hematologic disorders.

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

29. The use of a compound of formula (I) according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 23-26, 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.

30. The use according to claim 29, characterized in that, The diseases mentioned are selected from leukemia and bone marrow cancer, lymphoma, Kaposi's sarcoma, and myelodysplastic syndrome.

31. The use according to claim 29, characterized in that, The other active pharmaceutical ingredients are dexamethasone and / or pentezomib.

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