Research and development and preparation method of novel IDO1 enzyme inhibitor based on diazaspirodecane structure and application of novel IDO1 enzyme inhibitor in fields of tumor immunoregulation and neuropsychiatric diseases

Abstract

The invention discloses a compound which can effectively inhibit the activity of indoleamine 2, 3-dioxygenase 1 (IDO1) and has a diazaspirodecane structure, and the compound comprises a racemate, R and S-optical pure isomers and pharmaceutically acceptable salts, hydrates or solvates of the compound, wherein the racemate, the R and S-optical pure isomers and the pharmaceutically acceptable salts, hydrates or solvates of the compound can be used for effectively inhibiting the activity of indoleamine 2, 3-dioxygenase 1 (IDO1). The invention further relates to a preparation method of the compound and application of the compound in the fields of treating and / or preventing IDO-mediated tumor immunoregulation and neuropsychiatric diseases independently or jointly.

Description

Technical Field

[0001] The present invention relates to a compound having a diazaspirodecane structure which can effectively inhibit the activity of indoleamine 2,3-dioxygenase (IDO), comprising a racemic form thereof, R and S - optically pure isomers and pharmaceutically acceptable salts, hydrates or solvates thereof. The present invention also relates to a method for preparing the compound and its use alone or in combination in the treatment and / or prevention of IDO-mediated tumor immunomodulation and neuropsychiatric diseases. Background Art

[0002] Indoleamine 2,3-dioxygenase (IDO) is a monomeric protein containing heme, which is widely distributed in various tissues and cells. As the first key enzyme and rate-limiting enzyme in the kynurenine metabolic pathway, it catalyzes the decomposition of l-tryptophan (Trp) into kynurenine (Kyn). IDO is relatively conserved among species, with mice and humans having 63% sequence identity at the amino acid level. Overactivation of IDO can lead to abnormal metabolism of l-tryptophan, which in turn participates in the occurrence and development of tumors, chronic infections, autoimmune diseases and neuropsychiatric diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), depression and other diseases. Therefore, the development of small molecule inhibitors of IDO can be used as a potential strategy for the treatment of the above diseases.

[0003] IDO and tumor immunity: IDO is overexpressed in a variety of tumor cells, leading to the depletion of l-tryptophan and accumulation of kynurenine in the tumor microenvironment, which in turn upregulates regulatory T cells (T reg ) ratio, reduce the infiltration of tumor lymphocytes (TILs), promote effector T cells (T eff), promote the inactivation and apoptosis of NK cells, and mediate tumor immune escape, which is closely related to the occurrence, development, metastasis and poor prognosis of malignant tumors. Tumors adapt to and utilize the regulatory mechanisms of the immune system to escape the surveillance of the immune system, and the activation of IDO may be a potential means for tumors to escape immunotherapy (including PD-1 and PD-L1). Therefore, by developing IDO inhibitors, used alone or in combination, it is expected to achieve good tumor treatment effects by enhancing the immune response of the tumor microenvironment. At present, small molecule inhibitors of IDO have been reported, such as epacadostat developed by Incyte in combination with PD-1 inhibitor pembrolizumab for the treatment of advanced melanoma, which showed good application prospects in Phase I / II clinical trials, but failed to achieve the expected efficacy in Phase III clinical trials and was terminated. Although IDO inhibitors face major challenges and setbacks in the combined application of tumor immunotherapy, there are still many clinical trials actively exploring the possibility of combining them with a variety of other tumor treatments. Dr. Park and his team from the Dana-Farber Cancer Institute affiliated with Harvard Medical School presented the results of a Phase I clinical trial of epacadostat combined with preoperative chemoradiotherapy at the 2024 AACR (American Association for Cancer Research) Annual Meeting. They found that epacadostat combined with preoperative chemoradiotherapy showed good safety and tolerability in the treatment of patients with locally advanced rectal cancer, and its efficacy was not inferior to standard therapy. Currently, Incyte is working with several companies to conduct clinical trials of epacadostat combined with other drugs for the treatment of cervical cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, non-small cell lung cancer, triple-negative breast cancer, urothelial cancer and other solid tumors. These studies are expected to provide new treatment options for more cancer patients and improve treatment effects and quality of life. This series of studies have shown that IDO inhibitors still have important application value in the treatment of cancer.

[0004] IDO and AD: In 2024, a research team led by Katrin I. Andreasson of Stanford University School of Medicine published a blockbuster research result in the top journal Science. They found that two important pathological toxins of AD, Aβ oligomers and tau oligomers, activate indoleamine 2,3-dioxygenase 1 (IDO1) of astrocytes, thereby inhibiting glycolysis of astrocytes, resulting in the obstruction of lactate production, an important "fuel" for neurons. IDO1 inhibitors can restore the sugar metabolism of astrocytes, promote lactate production, and rescue the plasticity of hippocampal neuronal synapses. Whether it is an AD mouse model driven by Aβ pathology or an AD mouse model driven by tau pathology, IDO1 inhibitors can improve the cognition of all model mice without changing the levels of Aβ or tau in the brain. The specific mechanism is as follows: Aβ pathology and tau pathology activate the astrocyte IDO1 enzyme, causing tryptophan (TRP) to be metabolized into kynurenine (KYN). KYN then binds to the aryl hydrocarbon receptor (AhR) and triggers AhR translocation to the nucleus, prompting AhR to dimerize with the AhR nuclear transporter (ARNT). In this way, hypoxia-inducible factor 1 (HIF1), which regulates the transcription of glycolysis-related genes, cannot bind to ARNT, thereby inhibiting the glycolysis process and lactate production, leading to insufficient neuronal energy supply, impaired synaptic plasticity, and cognitive impairment; inhibiting IDO1 can reverse the above series of changes and improve cognition in the case of Aβ pathology and tau pathology. Given that abnormal brain energy metabolism exists in many neurodegenerative diseases, drugs targeting IDO1 are expected to become a universal therapy for the treatment of neurodegenerative diseases.

[0005] In view of the broad prospects shown by IDO inhibitors in tumor immunotherapy and diseases such as AD, their development has attracted the attention of many biopharmaceutical companies. A series of patent applications for IDO inhibitors have been published, but new compounds with better drugability and higher response rates are still needed to be developed. After continuous efforts, the present invention has designed a compound having a structure shown in general formula (I), and found that compounds having such a structure show excellent effects and functions of inhibiting IDO activity. Summary of the invention

[0006] The purpose of the present invention is to provide a class of compounds (including synthesis methods) that can inhibit or regulate IDO1, and compositions (such as drug combinations) containing the compounds; the present invention also relates to the use of such compounds and compositions for treating or preventing a series of diseases, disorders and conditions mediated in whole or in part by IDO.

[0007] In a first aspect, the present invention provides a diazaspirodecane compound represented by general formula (I), comprising a racemic body, R and SOptically pure isomers, and pharmaceutically acceptable salts, hydrates or solvates thereof, wherein: (I) Subscript n is: 0, 1 or 2; The configuration of C* can be independently S type, R Type or racemic; A and E rings are each independently selected from the following group: substituted or unsubstituted C6~C 10 Aryl or substituted or unsubstituted 5-12 membered heteroaryl; B and D are each independently selected from the group consisting of N or CH; R 1 and R 5 Selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, nitro, hydroxyl, thiol, carboxyl, -S(O)2OH, substituted or unsubstituted C1~C 10 Straight chain or branched chain alkyl, substituted or unsubstituted C1~C 10 Alkoxy, substituted or unsubstituted C2~C6 branched or branched alkenyl, substituted or unsubstituted C2~C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3~C 10 1-membered carbocyclic group, substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted saturated or partially unsaturated 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C2~C6 acyl group, substituted or unsubstituted C2~C6 ester group, substituted or unsubstituted C0~C6 amino group, substituted or unsubstituted C1~C6 amide group, optional C1~C6 alkyl-sulfonyl group or substituted or unsubstituted C1~C6 alkyl-sulfinyl group; R 2 , R 3 and R 4 Each is independently selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, nitro, amino, C1~C6 amino, hydroxyl, hydroxymethyl, carboxyl, C1~C6 amide, thiol, -S(O)2OH, C1~C6 alkyl-sulfonyl, C1~C6 alkyl-sulfinyl, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy, substituted or unsubstituted C3~C8 cycloalkyl, substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted C3~C 12 a saturated or unsaturated heterocyclic group; wherein the heteroaryl or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; The substitution in the substituted or unsubstituted means that the group is substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1~C6 alkyl, C1~C6 haloalkyl, C1~C6 alkoxy, C1~C6 alkoxycarbonyl, C1~C6 haloalkoxy, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkylsulfonyl, C3~C8 saturated or partially unsaturated carbocyclic group, C6~C 10 Aryl, 3-12 membered saturated or partially unsaturated heterocyclic group and 5-12 membered heteroaryl; The halogen is F, Cl, Br or I.

[0008] Preferably, ring A is selected from the group consisting of a benzene ring, a pyridine ring, and a naphthalene ring.

[0009] Preferably, the E ring is selected from the following group: quinoline ring, indole ring.

[0010] Preferably, R 1 Selected from the following group: substituted or unsubstituted C1~C 10 Straight chain or branched alkyl, substituted or unsubstituted saturated or partially unsaturated C3~C 10 Membered carbocyclic group.

[0011] Preferably, R 2 , R 3 and R 4 Each is independently selected from the following group: hydrogen, halogen, cyano, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy.

[0012] Preferably, the compound is selected from the following group: Compound 1- , compound 2- , compound 3- , compound 4- , compound 5- , compound 6- , compound 7- , compound 8- , compound 9- , compound 10- , compound 11- , compound 12- , compound 13- , compound 14- , compound 15- , compound 16- , compound 17- , compound 18- , compound 19- , compound 20- , compound 21- , compound 22- , compound 23- , compound 24- , compound 25- , compound 26- , compound 27- , compound 28- , compound 29- , compound 30- , compound 31- , compound 32- , compound 33- .

[0013] In a second aspect, the present invention provides a method for preparing a compound having the general formula (I), comprising the steps of: (1) , wherein Ha is a halogen; in an inert solvent, under the catalysis of a base, the compound of formula Ia reacts with the halogen substituent of formula Ib to obtain a compound of formula Ic; the base includes triethylamine and potassium carbonate; (2) ; The compound of formula Id is dissolved in an organic solvent, and subjected to an ammonolysis reaction with the compound of formula Ic under the catalysis of an alkaline solution to obtain a compound of formula Ie; the solvent comprises tetrahydrofuran, toluene or a combination thereof; the base comprises a lithium bistrimethylsilylamide solution or a trimethylaluminum solution; (3) ; The compound of formula Ie is dissolved in an organic solvent, and the compound of formula Ie is deprotected under the catalysis of an acid solution to obtain a compound If; the organic solvent comprises methanol, ethanol, tetrahydrofuran, dioxane, or a combination thereof; the acid solution comprises an aqueous hydrochloric acid solution; (4) ; The compound of formula If is dissolved in an organic solvent, and in the presence of a Lewis acid and a reducing agent, subjected to a reductive amination reaction with a compound of formula Ig to obtain a compound of formula Ih; the organic solvent comprises dichloromethane and methanol; the Lewis acid comprises tetraisopropyl titanate; the reducing agent comprises sodium cyanoborohydride; wherein R 1 , R 2 , R 3 , R 4 , n, A ring, and E ring are defined as described in the first aspect.

[0014] In a third aspect, the present invention provides a pharmaceutical composition comprising the compound described in the first aspect and a pharmaceutically acceptable carrier and excipient; the compound characteristics include their racemates, R-isomers and S-isomers, and pharmaceutically acceptable salts, hydrates or solvates.

[0015] In a fourth aspect, the present invention provides a method for treating or preventing a disease, disorder or symptom mediated at least in part by IDO, the method comprising administering an effective dose of a compound as described in the first aspect; wherein the disease, disorder or symptom is cancer and a neuropsychiatric-related disease; wherein the cancer is prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, gastric cancer, endometrial cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer, mesothelial cancer, lymphoma, leukemia, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer, adrenal cancer, thyroid cancer, kidney cancer, bone cancer, toe blastoma, mesothelioma, sarcoma, choriocarcinoma, basal cell carcinoma of the skin or testicular seminoma; wherein the neuropsychiatric-related diseases include Alzheimer's disease, Parkinson's disease, depression, Huntington's disease, amyotrophic lateral sclerosis and schizophrenia.

[0016] It should be understood that within the scope of the present invention, the above-mentioned technical features and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0017] The technical solution of the present invention is further explained and illustrated by means of specific embodiments below.

[0018] After extensive and in-depth research, the inventors synthesized a series of compounds of general formula (I) through rational design, and found through biological activity tests that they have good IDO inhibitory activity. On this basis, the present invention was completed.

[0019] In this document, unless otherwise specified, the term "substituted" refers to one or more hydrogen atoms on a group being replaced by a substituent selected from the following groups: C1~C 10 Alkyl, C3~C 10 Cycloalkyl, C1~C 10 Alkoxy, halogen, hydroxyl, carboxyl, cyano, C1~C 10 Aldehyde, C2~C 10 Acyl, C2~C 10 Ester group, amino group, phenyl group; the phenyl group includes unsubstituted phenyl group or substituted phenyl group having 1-3 substituents, the substituents are selected from: halogen, C1~C 10 Alkyl, C3~C 10 Cycloalkyl, C1~C10 Alkoxy, cyano, hydroxy, nitro, amino.

[0020] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom may be optionally R Configuration or S configuration, or R Configuration and S A mixture of configurations.

[0021] The notation “C x ~C y " represents a range of carbon atoms, wherein x and y are both integers, for example, C3-C8 cycloalkyl represents a cycloalkyl group having 3-8 carbon atoms, i.e., a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms. It should also be understood that "C3-C8" also includes any sub-range therein, such as C3-7, C3-6, C 4-7 , C 4-6 , C 5-6 wait.

[0022] "Alkyl" refers to a saturated straight or branched hydrocarbon group containing a specific number of carbon atoms, for example 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. The limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl, the tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1.1.2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl and 2-ethylbutyl. The alkyl can be optionally substituted.

[0023] "Alkenyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond and a specific number of carbon atoms, such as 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1,4-pentadienyl and 1,4-butadienyl. The alkenyl can be optionally substituted.

[0024] "Alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond and a specific number of carbon atoms, such as 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl. The alkynyl may be optionally substituted.

[0025] "Cycloalkyl" refers to a saturated cyclic hydrocarbon substituent containing a specific number of carbon atoms. The cycloalkyl can be a monocyclic carbocyclic ring, typically containing 3 to 8, 3 to 7, or 3 to 6 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The cycloalkyl can alternatively be a double or tricyclic ring fused together, such as decahydronaphthyl. The cycloalkyl can be optionally substituted.

[0026] "Alkoxy" refers to a group of an alkyl-oxy structure containing a specific number of carbon atoms, for example, a straight or branched alkoxy group of 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy. The alkoxy group may be optionally substituted.

[0027] "Heterocyclyl or heterocycloalkyl" refers to a saturated or partially saturated cyclic group having a specific number of ring atoms (e.g., 3-10 ring atoms) and one or more ring atoms being a heteroatom selected from N, S and O. It may be a monocyclic, bicyclic or polycyclic form, such as a bridged ring or a spirocyclic form. Non-limiting examples of heterocyclyl or heterocycloalkyl may be oxetanyl, azetidinyl, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl, etc. The heterocyclyl or heterocycloalkyl may be optionally substituted.

[0028] "Aryl or aromatic ring" refers to an aromatic monocyclic or fused polycyclic group having a specific number of carbon atoms, for example, phenyl and naphthyl. The aryl group may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring. The aryl or aromatic ring may be optionally substituted.

[0029] "Heteroaryl or heteroaromatic ring" refers to a cyclic aromatic group with a specific number of ring atoms and one or more atoms of which are heteroatoms selected from N, S and O. For example, furanylthienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolylisoxazolyl, thiazolyl, isothiazolyl, quinolyl, etc. The heteroaryl group may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl or heteroaromatic ring may be optionally substituted. "Acyl" refers to a -C(=O)R group containing a specific number of carbon atoms, non-limiting examples of which include -C(=O)CH3, -C(=O)C2H5, -C(=O)C3H7, -C(=O)C4H9. The acyl group may be optionally substituted.

[0030] "Ester group" refers to a -C(=O)OR group containing a specific number of carbon atoms, non-limiting examples of which include -C(=O)OCH3, -C(=O)OC2H5, -C(=O)OC3H7, -C(=O)OC4H9. The ester group may be optionally substituted.

[0031] "Amine" refers to a -NR group containing a specific number of carbon atoms. 1 R 2 Groups, non-limiting examples include -NH2, -NHCH3, -NHC(=O)CH3, -NHCH2CH3, -N(CH3)2. The amine group may be optionally substituted. Herein, the amine group is intended to include amino, i.e. -NH2.

[0032] "Amide" refers to a -C(=O)NR group containing a specific number of carbon atoms. 1 R 2 Groups, non-limiting examples include -C(=O)NH2, -C(=O)NHCH3, -C(=O)NH(CH3)2. The amide group may be optionally substituted.

[0033] "Sulfonamide" refers to a -S(=O)NR group containing the specified number of carbon atoms. 1 R 2 Groups, non-limiting examples include -S(=O)NH2, -S(=O)NHCH3, -S(=O)NH(CH3)2. The sulfonamide group may be optionally substituted.

[0034] "Sulfonyl" refers to a -S(=O)2- group containing the specified number of carbon atoms.

[0035] "Sulfinyl" refers to a -S(=O)- group containing the specified number of carbon atoms.

[0036] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0037] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0038] "Optionally substituted" means that one or more hydrogen atoms in the group are independently replaced by a corresponding number of substituents. The substituents are only in their possible chemical positions, and the substituents include but are not limited to C1~C 10 Alkyl, C3~C 10 Cycloalkyl, C1~C 10 Alkoxy, halogen, hydroxyl, carboxyl, cyano, C1~C 10Aldehyde, C2~C 10 Acyl, C2~C 10 Ester group, amino group, phenyl group; the phenyl group includes unsubstituted phenyl group or substituted phenyl group having 1-3 substituents, the substituents are selected from: halogen, C1~C 10 Alkyl, C3~C 10 Cycloalkyl, C1~C 10 Alkoxy, cyano, hydroxy, nitro, amino.

[0039] Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, those containing an asymmetric center R and S Configuration and double bond Z and E Isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof are within the scope of the present invention.

[0040] "Tautomers" means that structural isomers of different energies can interconvert over a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions via migration of a proton, such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole, and valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0041] "Pharmaceutically acceptable salt" refers to a salt form of the compound of formula (I) that is therapeutically effective and non-toxic. It can form anionic salts from any acidic group (such as a carboxyl group), or form cationic salts from any basic group (such as an amino group). Many such salts are known in the art. Cationic salts formed on any acidic group (such as a carboxyl group), or anionic salts formed on any basic group (such as an amino group). Many of these salts are known in the art, such as cationic salts including salts of alkali metals (such as sodium and potassium) and alkaline earth metals (such as magnesium and calcium) and organic salts (such as ammonium salts). Anionic salts can also be conveniently obtained by treating the basic form of I with the corresponding acid, such acid includes inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1,2,3-propanetriol, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexylsulfinic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, etc. These salts are well known to the skilled person, and the skilled person can prepare any salt provided by the knowledge in the art. In addition, the skilled person can take a certain salt and give up another salt based on factors such as solubility, stability, and easy preparation. The determination and optimization of these salts are within the experience of the skilled person.

[0042] "Pharmaceutical composition" refers to a composition containing one or more compounds described herein or their pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0043] The present invention also provides a method for preparing the compound. The preparation of the compound described in the general formula (I) of the present invention can be completed by the following exemplary methods and examples, but these methods and examples should not be considered in any way to limit the scope of the present invention. The compound described in the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of methods known in the art and the method described in the present invention. The product obtained from each step of the reaction is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for the synthesis can be synthesized or purchased according to the literature.

[0044] Example 1: Synthesis of Compound 1 Synthesis route: Synthesis of compound 1-3: Compound 1-1 (4.8 g, 20 mmol) was dissolved in 30 ml of acetonitrile, potassium carbonate (2.8 g, 20 mmol) and ethyl 2-bromobutyrate (4.3 g, 22 mmol) were added in sequence, the system was placed in an oil bath and heated to reflux, after TLC monitoring of the reaction was complete, it was cooled to room temperature and filtered, the filtrate was evaporated to dryness under reduced pressure, and then separated and purified by column chromatography to obtain 5.1 g of compound 1-3 in total, with a yield of 72%.

[0045] Synthesis of compound 1-4: Compound 1-3 (3.5 g, 10 mmol) and p-chloroaniline (1.4 g, 11 mmol) were dissolved in 10 ml toluene, followed by addition of 1M lithium bis(trimethylsilyl)amide solution (12 ml, 12 mmol), stirred at room temperature, and after TLC monitoring of the reaction was complete, ammonium chloride solution was added to quench the reaction. The organic phase was separated, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and purified by column chromatography to obtain 2.3 g of compound 1-4 in total, with a yield of 53%.

[0046] Synthesis of compound 1-5: Compound 1-4 (2.2 g, 5 mmol) was dissolved in 10 ml methanol, 5 ml concentrated hydrochloric acid was added, and the mixture was stirred at room temperature. After the reaction was completed as monitored by TLC, sodium hydroxide solution was added to adjust the mixture to neutral. The solution was evaporated to dryness under reduced pressure, and then separated and purified by column chromatography to obtain 1.4 g of compound 1-5 with a yield of 84%.

[0047] Synthesis of compound 1: Compound 1-5 (336 mg, 1 mmol) was dissolved in 5 ml of toluene, potassium carbonate (138 mg, 1 mmol) and 4-bromoquinoline (207 mg, 1 mmol) were added in sequence, and the mixture was placed in an oil bath and heated to reflux. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness under reduced pressure. Finally, the mixture was separated and purified by column chromatography to obtain a total of 198 mg of compound 1 with a yield of 43%. 1 H NMR (600 MHz, CDCl3) d H 9.15 (s, 1H), 8.38 (d, J = 6.0 Hz, 1H), 8.22(dd, J = 8.5, 1.3 Hz, 1H), 8.12 (dd, J = 8.4, 1.4 Hz, 1H), 7.64 (ddd, J = 8.4, 6.8,1.2 Hz, 1H), 7.52 (brd, J = 8.8 Hz, 2H), 7.41 (ddd,J = 8.5, 6.8, 1.4 Hz, 1H),7.26 (brd, J = 8.8 Hz, 2H), 6.47 (d, J = 6.0 Hz, 1H), 3.85 (t, J = 6.9 Hz, 2H), 3.62 (s, 2H), 2.99 (dd, J = 7.2, 5.3 Hz, 1H), 2.73 (m, 1H), 2.63 (m, 2H), 2.56(m, 1H), 1.99 (t, J = 6.9 Hz, 2H), 1.78 (m, 6H), 1.02 (t, J = 7.4 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 171.5, 153.9, 146.4, 136.6, 130.3, 129.1, 129.0, 126.9,125.3, 124.3, 120.8, 120.2, 116.7, 102.4, 71.0, 62.6, 50.8, 40.6, 35.7, 35.3,35.2, 21.2, 11.6. (+)-HRESIMS calcd ( m / z ) for C 27 H 32 ClN4O: [M + H] + 463.2259, found 463.2255. Example 2: Synthesis of Compound 2 Synthesis route: Synthesis of compound 2: Compound 1-5 (336 mg, 1 mmol) was dissolved in 3 ml of dichloromethane, and then 4-quinolinecarboxaldehyde (157 mg, 1 mmol) and tetraisopropyl titanate (340 mg, 1.2 mmol) were added in sequence. oC oil bath and stirred for 1h. After the reaction was completed by TLC monitoring, 3 ml of methanol and sodium cyanoborohydride (94 mg, 1.5 mmol) were added to the system in sequence and stirred for 1h. After the reaction was completed by TLC monitoring, the system was filtered and washed with ethyl acetate. The filtrate was collected and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was suspended in water, then extracted with ethyl acetate for 3 times, the ethyl acetate phases were combined, evaporated to dryness under reduced pressure, and separated and purified by column chromatography to obtain a total of 278 mg of compound 3 with a yield of 58%. 1 H NMR (600 MHz, CDCl3) d H 9.22 (s, 1H), 8.86 (d, J = 4.3 Hz, 1H), 8.23 ​​(dd, J = 8.4, 1.4 Hz, 1H), 8.12(dd, J = 8.4, 1.2 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.54 (ddd, J =8.4, 6.8, 1.3 Hz, 1H), 7.49 (brd, J = 8.8, 2H), 7.42 (d, J = 4.3 Hz, 1H), 7.27(brd, J = 8.8, 2H), 4.02 (s, 2H), 2.88 (dd, J = 7.0, 5.3 Hz, 1H), 2.68 (t, J = 7.0Hz, 2H), 2.56 (m, 2H), 2.46 (m, 4H), 1.78 (m, 2H), 1.66 (m, 6H), 1.01 (t, J =7.4 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 172.0, 150.4, 148.4, 145.1, 136.6,130.1, 129.2, 129.1, 128.9, 127.6, 126.4, 124.2, 120.8, 120.6, 71.1, 66.2,57.3, 53.9, 48.4, 40.3, 38.5, 36.8, 21.0, 11.7. (+)-HRESIMS calcd ( m / z ) forC 28 H 34 ClN4O: [M + H] + 477.2416, found 477.2407. Example 3: Synthesis of Compound 3 Referring to the synthetic route of compound 2, compound 3 was obtained. 1 H NMR (600 MHz, CDCl3) d H 8.84 (d, J =4.3 Hz, 1H), 8.21 (dd, J = 8.4, 1.4 Hz, 1H), 8.11 (dd, J = 8.4, 1.3 Hz, 1H), 7.69(ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.53 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.41 (d, J =4.3 Hz, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 4.00 (m, 2H), 3.22 (s, 3H), 2.96 (dd, J = 9.2, 5.1 Hz, 1H), 2.61 (m, 2H), 2.46 (m, 2H), 2.41(s, 2H), 2.30 (m, 1H), 2.23 (m, 1H), 1.75 (ddd, J = 13.4, 9.2, 7.1 Hz, 1H),1.59 (t, J = 7.0 Hz, 2H), 1.49 (m, 5H), 0.76 (t, J = 7.4 Hz, 3H). 13 C NMR (150 MHz,CDCl3) d C171.9, 150.4, 148.4, 145.3, 142.7, 133.5, 130.0, 129.6, 129.2, 129.1,127.6, 126.3, 124.2, 120.7, 66.4, 65.3, 57.3, 53.9, 47.0, 46.8, 40.5, 38.5,37.4, 37.0, 19.7, 11.2. (+)-HRESIMS calcd ( m / z ) for C 29 H 36 ClN4O: [M + H] + 491.2572, found 491.2573. Example 4: Synthesis of Compound 4 Referring to the synthetic route of compound 2, compound 4 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.57 (s,1H), 8.85 (d, J = 4.3 Hz, 1H), 8.28 (d, J = 4.9 Hz, 1H), 8.23 ​​(d, J = 8.3 Hz, 1H),8.21 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 8.6, 6.7 Hz, 1H),7.68 (dd, J = 8.4, 7.3, 1H), 7.54 (dd, J = 8.3, 6.7 Hz, 1H), 7.43 (d, J = 4.3 Hz,1H), 7.01 (dd, J = 7.3, 4.9 Hz, 1H), 4.02 (s, 2H), 2.90 (t, J = 6.1 Hz, 1H), 2.66(t, J = 7.0 Hz, 2H), 2.57 (m, 2H), 2.48 (s, 2H), 2.46 (m, 2H), 1.78 (m, 2H),1.68 (m, 6H), 1.00 (t, J = 7.5 Hz, 3H).13 C NMR (150 MHz, CDCl3) d C 172.7, 151.4,150.4, 148.4, 148.1, 145.0, 138.4, 130.0, 129.2, 127.6, 126.3, 124.1, 120.8,119.7, 113.8, 71.4, 66.3, 57.2, 53.8, 48.4, 40.3, 38.2, 36.8, 21.1, 11.6.(+)-HRESIMS calcd ( m / z ) for C 27 H 34 N5O: [M + H] + 444.2758, found 444.2760. Example 5: Synthesis of Compound 5 Referring to the synthetic route of compound 2, compound 5 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.34 (s,1H), 8.86 (d, J = 4.3 Hz, 1H), 8.55 (s, 1H), 8.33 (d, J = 4.8 Hz, 1H), 8.23 ​​(d, J =8.5 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.5, 1H), 7.70 (dd, J = 8.3,6.7 Hz, 1H), 7.54 (dd, J = 8.2, 6.8, Hz, 1H), 7.42 (d, J = 4.3 Hz, 1H), 7.25 (dd, J = 8.5, 4.8 Hz, 1H), 4.03 (s, 2H), 2.94 (m, 1H), 2.68 (t, J = 7.0 Hz, 2H), 2.60(m, 2H), 2.49 (m, 2H), 2.48 (s, 2H), 1.79 (m, 2H), 1.68 (m, 6H), 1.02 (t, J =7.4 Hz, 3H).13 C NMR (150 MHz, CDCl3) d C 172.5, 150.4, 148.4, 145.2, 145.0,141.0, 134.8, 130.1, 129.2, 127.6, 126.6, 126.4, 124.2, 123.8, 120.8, 71.1,66.2, 57.2, 53.8, 48.4, 40.2, 38.4, 36.7, 20.9, 11.7. (+)-HRESIMS calcd ( m / z )for C 27 H 34 N5O: [M + H] + 444.2758, found 444.2762. Example 6: Synthesis of Compound 6 Referring to the synthetic route of compound 2, compound 6 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.46 (s,1H), 8.85 (d, J = 4.3 Hz, 1H), 8.48 (d, J = 5.1 Hz, 2H), 8.22 (dd, J = 8.4, 1.4 Hz,1H), 8.11 (dd, J = 8.5, 1.3 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.54(ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.48 (m, 2H), 7.42 (d, J = 4.3 Hz, 1H), 4.02 (s,2H), 2.95 (m, 1H), 2.68 (t, J = 7.0 Hz, 2H), 2.59 (m, 2H), 2.47 (m, 2H), 2.46(s, 2H), 1.78 (m, 2H), 1.67 (m, 6H), 1.01 (t, J = 7.5 Hz, 3H). 13 C NMR (150 MHz,CDCl3) dC 172.7, 150.9, 150.4, 148.4, 145.0, 144.8, 130.1, 129.2, 127.6, 126.4,124.2, 120.8, 113.4, 71.2, 66.1, 57.2, 53.8, 48.4, 40.2, 38.4, 36.7, 20.7,11.8. (+)-HRESIMS calcd ( m / z ) for C 27 H 34 N5O: [M + H] + 444.2758, found 444.2762. Example 7: Synthesis of Compound 7 Referring to the synthetic route of compound 2, compound 7 was obtained. 1 H NMR (600 MHz, CDCl3) d H 10.00 (s,1H), 8.86 (d, J = 4.3 Hz, 1H), 8.46 (dd, J = 8.3, 1.5 Hz, 1H), 8.23 ​​(dd, J = 8.3,1.4 Hz, 1H), 8.12 (dd, J = 8.4, 1.2 Hz, 1H), 7.71 (ddd, J = 8.4, 6.8, 1.4 Hz,1H), 7.55 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 7.44 (d, J = 4.3 Hz, 1H), 7.35 (dd, J =8.1, 1.5 Hz, 1H), 7.26 (m, 1H), 7.01 (td, J = 7.7, 1.6 Hz, 1H), 4.03 (s, 2H), 2.96 (dd, J = 6.9, 5.2 Hz, 1H), 2.68 (t, J = 7.0 Hz, 2H), 2.61 (m, 2H), 2.50 (m,2H), 2.49 (s, 2H), 1.80 (m, 2H), 1.69 (m, 6H), 1.04 (t, J= 7.5 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 172.3, 150.4, 148.4, 145.1, 135.0, 130.1, 129.2, 129.2,127.8, 127.6, 126.4, 124.3, 124.2, 122.8, 120.9, 120.8, 71.3, 66.3, 57.3,53.9, 48.4, 40.3, 38.4, 36.8, 21.0, 11.9. (+)-HRESIMS calcd ( m / z ) forC 28 H 34 ClN4O: [M + H] + 477.2416, found 477.2408. Example 8: Synthesis of Compound 8 Referring to the synthetic route of compound 2, compound 8 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.25 (s,1H), 8.85 (d, J = 4.3 Hz, 1H), 8.23 ​​(dd, J = 8.4, 1.3 Hz, 1H), 8.11 (dd, J = 8.4,1.2 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.65 (t, J = 2.1 Hz, 1H), 7.54(ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.42 (d, J = 4.3 Hz, 1H), 7.39 (ddd, J = 8.2, 2.1,1.0 Hz, 1H), 7.22 (t, J = 8.1 Hz, 1H), 7.05 (ddd, J = 8.0, 2.1, 1.0 Hz, 1H), 4.02(s, 2H), 2.89 (m, 1H), 2.67 (t, J= 7.0 Hz, 2H), 2.57 (m, 2H), 2.46 (m, 4H), 1.77 (m, 2H), 1.66 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 172.0, 150.4, 148.4, 145.1, 139.2, 134.8, 130.1, 130.0, 129.2, 127.6, 126.3,124.2, 124.0, 120.8, 119.4, 117.4, 71.1, 66.3, 57.2, 53.8, 48.4, 40.2, 38.5,36.7, 21.0, 11.7. (+)-HRESIMS calcd ( m / z ) for C 28 H 34 ClN4O: [M + H] + 477.2416, found 477.2416. Example 9: Synthesis of Compound 9 Referring to the synthetic route of compound 2, compound 9 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.18 (s,1H), 8.84 (d, J = 4.3 Hz, 1H), 8.22 (dd, J = 8.4, 1.3 Hz, 1H), 8.11 (dd, J = 8.4,1.2 Hz, 1H), 7.69 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.53 (ddd, J = 8.4, 6.8, 1.2Hz, 1H), 7.49 (m, 2H), 7.41 (d, J = 4.3 Hz, 1H), 6.99 (m, 2H), 4.01 (s, 2H), 2.88 (dd, J = 6.9, 5.2 Hz, 1H), 2.66 (t, J= 7.0 Hz, 2H), 2.56 (m, 2H), 2.45 (m,4H), 1.77 (m, 2H), 1.64 (m, J = 11.9, 7.9, 7.4 Hz, 6H), 1.00 (t, J = 7.5 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 171.8, 159.2 (d, J = 243.0 Hz), 150.3, 148.4, 145.1,134.1 (d, J = 2.7 Hz), 130.0, 129.2, 127.5, 126.3, 124.1, 121.1 (d, J = 7.7 Hz),120.7, 115.7 (d, J = 22.4 Hz), 71.0, 66.3, 57.2, 53.8, 48.4, 40.2, 38.5, 36.7,21.1, 11.6. (+)-HRESIMS calcd ( m / z ) for C 28 H 34 FN4O: [M + H] + 461.2711, found461.2712. Example 10: Synthesis of Compound 10 Referring to the synthetic route of compound 2, compound 10 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.23 (s,1H), 8.85 (d, J = 4.3 Hz, 1H), 8.23 ​​(dd, J = 8.6, 1.3 Hz, 1H), 8.11 (dd, J = 8.4,1.2 Hz, 1H), 7.70 (ddd, J = 8.3, 6.7, 1.3 Hz, 1H), 7.54 (ddd, J = 8.2, 6.7, 1.2Hz, 1H), 7.45 (brd, J = 8.8 Hz , 2H), 7.42 (d, J= 4.3 Hz, 1H), 7.41 (brd, J = 8.8Hz, 2H), 4.02 (s, 2H), 2.88 (t, J = 6.1 Hz, 1H), 2.67 (t, J = 7.0 Hz, 2H), 2.57(m, 2H), 2.46 (m, 4H), 1.77 (m, 2H), 1.66 (m, 6H), 1.00 (t, J = 7.5 Hz, 3H). 13 CNMR (150 MHz, CDCl3) d C 171.9, 150.4, 148.4, 145.1, 137.1, 132.0, 130.0, 129.2,127.6, 126.3, 124.2, 121.0, 120.8, 116.4, 71.1, 66.2, 57.2, 53.9, 48.4, 40.2,38.5, 36.7, 21.0, 11.7. (+)-HRESIMS calcd ( m / z ) for C 28 H 34 BrN4O: [M + H] + 521.1911, found 521.1891. Example 11: Synthesis of Compound 11 Referring to the synthetic route of compound 2, compound 11 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.22 (s,1H), 8.84 (d, J = 4.3 Hz, 1H), 8.22 (dd, J = 8.4, 1.4 Hz, 1H), 8.11 (dd, J = 8.4,1.3 Hz, 1H), 7.69 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.59 (brd, J = 8.8 Hz, 2H),7.54 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.41 (d, J= 4.3 Hz, 1H), 7.33 (, 2H), 4.01(s, 2H), 2.87 (m, 1H), 2.66 (t, J = 7.0 Hz, 2H), 2.56 (m, 2H), 2.45 (m, 4H), 1.76 (m, 2H), 1.65 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 172.0, 150.3, 148.4, 145.1, 138.0, 137.8, 130.0, 129.2, 127.5, 126.3, 124.1,121.3, 120.7, 86.9, 71.1, 66.3, 57.2, 53.8, 48.4, 40.2, 38.4, 36.7, 20.9,11.7. (+)-HRESIMS calcd ( m / z ) for C 28 H 34 IN4O: [M + H] + 569.1772, found 569.1773. Example 12: Synthesis of Compound 12 Referring to the synthetic route of compound 2, compound 12 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.09 (s,1H), 8.85 (d, J = 4.4 Hz, 1H), 8.22 (dd, J = 8.4, 1.3 Hz, 1H), 8.11 (dd, J = 8.4,1.2 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.54 (ddd, J = 8.4, 6.8, 1.2Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H ), 7.42 (d, J = 4.4 Hz 1H), 7.11 (d, J= 8.1 Hz,2H), 4.01 (s, 2H), 2.87 (dd, J = 6.9, 5.2 Hz, 1H), 2.66 (t, J = 7.0 Hz, 2H), 2.56(m, 2H), 2.46 (m, 4H), 2.30 (s, 3H), 1.77 (m, 2H), 1.65 (m, 6H), 1.00 (t, J =7.5 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 171.5, 150.4, 148.4, 145.1, 135.5,133.6, 130.0, 129.6, 129.2, 127.5, 126.3, 124.1, 120.7, 119.5, 71.1, 66.3,57.2, 53.8, 48.4, 40.2, 38.4, 36.6, 21.2, 20.9, 11.5. (+)-HRESIMS calcd ( m / z )for C 29 H 37 N4O: [M + H] + 457.2962, found 457.2960. Example 13: Synthesis of Compound 13 Referring to the synthetic route of compound 2, compound 13 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.18 (s,1H), 8.86 (d, J = 4.4 Hz, 1H), 8.23 ​​(dd, J = 8.4, 1.3 Hz, 1H), 8.12 (dd, J = 8.4,1.2 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.55 (m, 3H), 7.42 (d, J = 4.4Hz, 1H), 7.31 (m, 2H), 7.08 (m, 1H), 4.03 (s, 2H), 2.89 (s, 1H), 2.67 (t, J=7.0 Hz, 2H), 2.59 (m, 2H), 2.47 (m, 4H), 1.79 (m, 2H), 1.67 (m, 6H), 1.01 (t, J = 7.5 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 171.8, 150.4, 148.4, 145.1, 138.0,130.1, 129.2, 129.1, 127.6, 126.4, 124.2, 124.0, 120.8, 119.5, 71.1, 66.3,57.3, 53.9, 48.4, 40.3, 38.7, 36.8, 21.2, 11.6. (+)-HRESIMS calcd ( m / z ) forC 28 H 35 N4O: [M + H] + 443.2805, found 443.2805. Example 14: Synthesis of Compound 14 Referring to the synthetic route of compound 2, compound 14 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.37 (s,1H), 8.85 (d, J = 4.3 Hz, 1H), 8.22 (dd, J = 8.4, 1.4 Hz, 1H), 8.11 (dd, J = 8.4,1.2 Hz, 1H), 7.85 (t, J = 2.0 Hz, 1H), 7.72 (dd, J = 8.1, 1.5 Hz,1H), 7.69 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.53 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.41 (d, J = 4.5Hz, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.32 (dt, J= 8.1, 1.5 Hz, 1H), 4.01 (s, 2H), 2.90 (dd, J = 7.1, 5.2 Hz, 1H), 2.67 (t, J = 7.0 Hz, 2H), 2.57 (m, 2H), 2.46 (m,4H), 1.78 (m, 2H), 1.66 (m, 6H), 1.01 (t, J = 7.5 Hz, 3H). 13 C NMR (150 MHz,CDCl3) d C 172.2, 150.4, 148.4, 145.1, 138.6, 131.5 (q, J = 32.2 Hz), 130.1, 129.6,129.2, 127.6, 126.4, 124.2, 124.0 (q, J = 272.4 Hz), 122.4, 120.8, 120.5 (q, J =3.9 Hz), 116.0 (q, J = 4.0 Hz), 71.1, 66.3, 57.2, 53.8, 48.4, 40.2, 38.5, 36.7,20.9, 11.7. (+)-HRESIMS calcd ( m / z ) for C 29 H 34 F3N4O: [M + H] + 511.2679, found511.2679. Example 15: Synthesis of Compound 15 Referring to the synthetic route of compound 2, compound 15 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.52 (s,1H), 8.86 (d, J = 4.3 Hz, 1H), 8.22 (dd, J = 8.4, 1.3 Hz, 1H), 8.11 (dd, J = 8.4,1.2 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.66 (d, J= 8.6 Hz, 2H), 7.59(d, J = 8.6 Hz, 2H), 7.54 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.42 (d, J = 4.3 Hz,1H), 4.03 (s, 2H), 2.92 (dd, J = 7.1, 5.2 Hz, 1H), 2.68 (t, J = 7.0 Hz, 2H), 2.57(m, 2H), 2.46 (m, 4H), 1.77 (m, 2H), 1.65 (m, 6H), 1.02 (t, J = 7.5 Hz, 3H). 13 CNMR (150 MHz, CDCl3) d C 172.3, 150.3, 148.3, 144.9, 141.8, 133.3, 130.0, 129.1,127.4, 126.3, 124.0, 120.7, 119.2, 118.9, 106.8, 77.2, 77.0, 76.8, 71.0,66.2, 57.1, 53.7, 48.4, 40.1, 38.3, 36.7, 20.6, 11.7. (+)-HRESIMS calcd ( m / z )for C 29 H 34 N5O: [M + H] + 468.2758, found 468.2758. Example 16: Synthesis of Compound 16 Referring to the synthetic route of compound 2, compound 16 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.03 (s,1H), 8.85 (d, J = 4.3 Hz, 1H), 8.23 ​​(dd, J = 8.4, 1.4 Hz, 1H), 8.11 (dd, J = 8.4,1.3 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.54 (ddd,J = 8.4, 6.8, 1.3Hz, 1H), 7.45 (m, 2H), 7.42 (d, J = 4.4 Hz, 1H), 6.85 (m, 2H), 4.02 (s, 2H), 3.77 (s, 3H), 2.86 (dd, J = 6.8, 5.3 Hz, 1H), 2.66 (t, J = 7.0 Hz, 2H), 2.56 (m,2H), 2.46 (m, 4H), 1.77 (m, 2H), 1.65 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 171.5, 156.2, 150.4, 148.4, 145.1, 131.3, 130.1, 129.2,127.6, 126.4, 124.2, 121.1, 120.8, 114.3, 71.1, 66.6, 57.3, 55.7, 53.9, 48.4,40.3, 38.5, 36.8, 21.2, 11.5. (+)-HRESIMS calcd ( m / z ) for C 29 H 37 N4O2: [M + H] + 473.29118, found 473.2912. Example 17: Synthesis of Compound 17 Referring to the synthetic route of compound 2, compound 17 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.92 (s,1H), 8.87 (d, J = 4.3 Hz, 1H), 8.25 (dd, J = 7.5, 1.1 Hz, 1H), 8.24 (dd, J = 8.4,1.3 Hz, 1H), 8.13 (dd, J = 8.4, 1.2 Hz, 1H), 7.87 (dd, J = 7.8, 1.5 Hz, 1H), 7.84(d,J = 8.2 Hz, 1H), 7.71 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.64 (d, J = 8.2 Hz,1H), 7.55 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.52 (td, J = 7.5, 1.4 Hz, 1H), 7.49(td, J = 7.5, 1.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 4.04 (s, 2H), 3.04 (dd, J =6.9, 5.2 Hz, 1H), 2.69 (t, J = 7.0 Hz, 4H), 2.59 (m, 2H), 2.51 (s, 2H), 1.89(m, 2H), 1.73 (m, 6H), 1.09 (t, J = 7.4 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 172.0,150.4, 148.4, 145.1, 134.2, 132.7, 130.0, 129.2, 129.1, 127.6, 126.4, 126.2,126.2, 126.1, 125.9, 124.6, 124.1, 120.8, 120.0, 118.2, 71.5, 65.2, 57.2,53.8, 48.4, 40.3, 38.6, 36.6, 21.4, 11.6. (+)-HRESIMS calcd ( m / z ) forC 32 H 37 N4O: [M + H] + 493.2962, found 493.2964. Example 18: Synthesis of Compound 18 Referring to the synthetic route of compound 2, compound 18 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.37 (s,1H), 8.86 (d, J= 4.3 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.23 (dd, J = 8.4, 1.4 Hz,1H), 8.13 (dd, J = 8.4, 1.2 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 7.8 Hz,1H), 7.76 (d, J = 8.0 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.54 (ddd, J =8.4, 6.8, 1.2 Hz, 1H), 7.48 (dd, J = 8.8, 2.2 Hz, 1H), 7.44 (td, J = 7.6, 1.0 Hz,1H), 7.42 (d, J = 4.3 Hz, 1H), 7.37 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 4.02 (s,2H), 2.94 (dd, J = 7.2, 5.1 Hz, 1H), 2.67 (t, J = 7.0 Hz, 2H), 2.60 (m, 2H), 2.50(m, 2H), 2.47 (s, 2H), 1.82 (m, 2H), 1.69 (m, 6H), 1.05 (t, J = 7.4 Hz, 3H). 13 CNMR (150 MHz, CDCl3) d C 171.9, 150.4, 148.4, 145.1, 135.4, 134.0, 130.6, 130.0,129.2, 128.8, 127.7, 127.6, 127.5, 126.6, 126.3, 124.9, 124.1, 120.7, 119.7,115.9, 71.1, 66.2, 57.2, 53.8, 48.4, 40.2, 38.4, 36.7, 21.1, 11.7. (+)-HRESIMS calcd ( m / z) for C 32 H 37 N4O: [M + H] + 493.2962, found 493.2966. Example 19: Synthesis of Compound 19 Referring to the synthetic route of compound 2, compound 19 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.25 (s,1H), 8.85 (d, J = 4.3 Hz, 1H), 8.22 (dd, J = 8.4, 1.4 Hz, 1H), 8.11 (dd, J = 8.4,1.3 Hz, 1H), 7.84 (dd, J = 6.1, 2.6 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.4 Hz,1H), 7.54 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.42 (m, 2H), 7.04 (dd, J = 8.6, 8.1Hz, 1H), 4.02 (s, 2H), 2.89 (s, 1H), 2.67 (t, J = 7.0 Hz, 2H), 2.57 (d, J = 11.2Hz, 2H), 2.46 (s, 4H), 1.77 (m, 2H), 1.65 (dt, J = 11.7, 5.6 Hz, 6H), 1.00 (t, J = 7.5 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 172.2, 155.6 (d, J = 244.3 Hz), 150.4,148.4, 145.1, 135.0 (d, J = 3.3 Hz), 130.1, 129.2, 127.6, 126.4, 124.2, 124.2,120.8, 119.9 (d, J = 6.5 Hz), 116.5 (d, J= 23.1 Hz), 109.1 (d, J = 21.9 Hz), 70.9,66.1, 57.2, 53.8, 48.4, 40.2, 38.6, 36.7, 20.9, 11.7. (+)-HRESIMS calcd ( m / z )for C 28 H 33 BrFN4O: [M + H] + 539.1816, found 539.1803. Example 20: Synthesis of Compound 20 Referring to the synthetic route of compound 2, compound 20 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.43 (s,1H), 8.82 (d, J = 4.4 Hz, 1H), 8.20 (dd, J = 8.4, 1.4 Hz, 1H), 8.09 (dd, J = 8.4,1.3 Hz, 1H), 7.66 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.51 (ddd, J = 8.4, 6.7, 1.3Hz, 1H), 7.48 (brd, J = 8.8 Hz, 2H), 7.39 (d, J = 4.4 Hz, 1H), 7.23 (brd, J = 8.8Hz, 2H), 3.98 (s, 2H), 3.14 (q, J = 7.0 Hz, 1H), 2.64 (m, 2H), 2.44 (m, 6H), 1.63 (m, 6H), 1.22 (d, J = 7.1 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C172.2, 150.2,148.2, 145.0, 136.6, 129.9, 129.1, 128.9, 128.6, 127.4, 126.2, 124.1, 120.6,120.4, 66.1, 64.5, 57.1, 53.7, 48.0, 40.0, 38.3, 36.6, 10.7. (+)-HRESIMScalcd ( m / z ) for C 27 H 32 ClN4O: [M + H] + 463.2259, found 463.2257. Example 21: Synthesis of Compound 21 Referring to the synthetic route of compound 2, compound 21 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.27 (s,1H), 8.86 (d, J = 4.3 Hz, 1H), 8.23 ​​(dd, J = 8.4, 1.4 Hz, 1H), 8.12 (dd, J = 8.4,1.2 Hz, 1H), 7.71 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.55 (ddd, J = 8.4, 6.8, 1.2Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 4.3 Hz, 1H), 7.27 (d, J = 8.5 Hz,2H), 4.03 (s, 2H), 2.96 (t, J = 6.0 Hz, 1H), 2.68 (t, J = 7.0 Hz, 2H), 2.57 (m,2H), 2.47 (m, 4H), 1.67 (m, 8H), 1.51 (m, 1H), 1.38 (m, 1H), 0.93 (t, J = 7.3Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C172.2, 150.4, 148.5, 145.1, 136.7, 130.1,129.2, 129.1, 128.9, 127.6, 126.4, 124.2, 120.8, 120.6, 69.6, 66.4, 57.3,53.9, 48.7, 40.3, 38.6, 36.9, 29.8, 20.7, 14.4. (+)-HRESIMS calcd ( m / z ) forC 29 H 36 ClN4O: [M + H] + 491.2572, found 491.2578. Example 22: Synthesis of Compound 22 Referring to the synthetic route of compound 2, compound 22 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.28 (s,1H), 8.84 (d, J = 4.3 Hz, 1H), 8.22 (dd, J = 8.4, 1.4 Hz, 1H), 8.11 (dd, J = 8.4,1.3 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.54 (ddd, J = 8.4, 6.8, 1.3Hz, 1H), 7.49 (brd, J = 8.8 Hz, 2H), 7.41 (d, J = 4.3 Hz, 1H), 7.25 (brd, J = 8.8Hz, 2H), 4.01 (s, 2H), 2.94 (dd, J = 7.4, 4.9 Hz, 1H), 2.66 (t, J = 7.0 Hz, 2H),2.56 (m, 2H), 2.45 (m, 4H), 1.72 (m, 1H), 1.66 (m, 7H), 1.45 (m, 1H), 1.31(m, 3H), 0.88 (t, J = 7.1 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 172.1, 150.3, 148.3,145.1, 136.6, 130.0, 129.2, 129.0, 128.8, 127.5, 126.3, 124.1, 120.7, 120.6,69.7, 66.2, 57.2, 53.8, 48.5, 40.2, 38.5, 36.7, 29.5, 27.3, 23.0, 14.0. (+)-HRESIMS calcd ( m / z ) for C 30 H 38 ClN4O: [M + H] + 505.2729, found 505.2734. Example 23: Synthesis of Compound 23 Referring to the synthetic route of compound 2, compound 23 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.31 (s,1H), 8.86 (d, J = 4.3 Hz, 1H), 8.23 ​​(dd, J = 8.4, 1.4 Hz, 1H), 8.12 (dd, J = 8.4,1.3 Hz, 1H), 7.71 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.55 (ddd, J = 8.4, 6.8, 1.3Hz, 1H), 7.51 (brd, J = 8.8 Hz, 2H), 7.42 (d, J = 4.3 Hz, 1H), 7.27 (brd, J = 8.8Hz, 2H), 4.03 (s, 2H), 3.00 (m, 1H), 2.68 (t, J = 7.0 Hz, 2H), 2.58 (m, 2H), 2.48 (m, 3H), 1.72 (m, 1H), 1.65 (m, 7H), 1.45 (m, 1H), 1.26 (m, 7H), 0.85(t, J = 6.9 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 172.2, 150.4, 148.4, 144.5, 136.7,130.1, 129.3, 129.1, 127.6, 126.4, 124.2, 120.8, 120.7, 111.2, 69.6, 66.3,57.2, 53.8, 48.4, 40.2, 38.4, 36.6, 31.7, 29.6, 27.6, 27.3, 22.7, 14.2. (+)-HRESIMS calcd ( m / z ) for C 31 H 40 ClN4O: [M + H] + 519.2885, found 519.2890. Example 24: Synthesis of Compound 24 Referring to the synthetic route of compound 2, compound 24 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.28 (s,1H), 8.84 (d, J = 4.3 Hz, 1H), 8.21 (dd, J = 8.4, 1.4 Hz, 1H), 8.11 (dd, J = 8.4,1.3 Hz, 1H), 7.68 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.53 (ddd, J = 8.4, 6.8, 1.3Hz, 1H), 7.49 (brd, J = 8.8 Hz, 2H), 7.41 (d, J = 4.3 Hz, 1H), 7.25 (brd, J = 8.8Hz, 2H), 4.00 (s, 2H), 2.93 (dd, J = 7.4, 5.0 Hz, 1H), 2.65 (t, J = 7.0 Hz, 2H),2.54 (m, 2H), 2.45 (m, 4H), 1.72 (m, 1H), 1.64 (m, 7H), 1.45 (m, 1H), 1.27(m, 7H), 0.85 (t, J= 6.8 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 171.9, 150.4, 148.4,145.0, 136.6, 130.1, 129.3, 129.1 128.9 127.6 126.4 124.2, 120.8, 120.7,69.7, 66.4, 57.2, 53.8, 48.4, 40.2, 38.5, 36.7, 32.1, 27.6, 27.0, 22.6, 14.2.(+)-HRESIMS calcd ( m / z ) for C 32 H 42 ClN4O: [M + H] + 533.3042, found 533.3045. Example 25: Synthesis of Compound 25 Referring to the synthetic route of compound 2, compound 25 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.24 (s,1H), 8.90 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 2.1 Hz, 1H),7.79 (dd, J = 8.4, 1.4 Hz, 1H), 7.68 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.53 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.49 (m, 2H), 7.25 (m, 2H), 3.76 (s, 2H), 2.87 (dd, J = 7.1, 5.1 Hz, 1H), 2.64 (t, J = 7.0 Hz, 2H), 2.55 (m, 2H), 2.43 (m, 4H), 1.76(m, 2H), 1.64 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 171.9,151.9, 147.6, 136.6, 135.1, 132.1, 129.3, 129.1, 129.0, 128.8, 128.1, 127.7,126.7, 120.6, 71.0, 65.8, 58.0, 53.7, 48.3, 40.1, 38.6, 36.8, 20.9, 11.7.(+)-HRESIMS calcd ( m / z ) for C 28 H 34 ClN4O: [M + H] + 477.2416, found 477.2420. Example 26: Synthesis of Compound 26 Referring to the synthetic route of compound 2, compound 26 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.25 (s,1H), 9.16 (s, 1H), 8.42 (s, 1H), 8.28 (dd, J = 8.4, 1.0 Hz, 1H), 7.95 (dd, J =8.1, Hz, 1H), 7.69 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.58 (ddd, J = 8.1, 6.8, 1.2Hz, 1H), 7.48 (m, 2H), 7.24 (m, 2H), 3.93 (s, 2H), 2.86 (m, 1H), 2.61 (t, J =7.0 Hz, 2H), 2.53 (m, 2H), 2.41 (m, 4H), 1.75 (m, 2H), 1.60 (m, 6H), 0.98 (t, J = 7.5 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C171.6, 152.7, 142.9, 136.6, 135.3,130.2, 129.1, 128.9, 128.6, 128.4, 128.0, 127.1, 124.0, 120.7, 71.0, 66.0,56.0, 53.6, 48.6, 40.1, 38.4, 36.6, 21.0, 11.6. (+)-HRESIMS calcd ( m / z ) forC 28 H 34 ClN4O: [M + H] + 477.2416, found 477.2420. Example 27: Synthesis of Compound 27 Referring to the synthetic route of compound 2, compound 27 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.48 (s,1H), 8.97 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.49 (brd, J = 8.8 Hz, 2H), 7.46 (d, J = 8.2 Hz, 1H) 7.25 (brd, J = 8.8 Hz, 2H), 7.21 (ddd, J =8.0, 7.0, 1.2 Hz, 1H), 7.16 (ddd, J = 7.5, 7.0, 1.1 Hz, 1H), 4.29 (s, 2H), 3.75(m, 2H), 3.24 (m, 1H), 3.03 (m, 1H), 2.88 (t, J = 6.3 Hz, 1H), 2.52 (m, 2H), 2.41 (m, 2H), 1.85 (m, 4H), 1.71 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H). 13 C NMR (150MHz, CDCl3) d C171.3, 136.4, 136.1, 129.1, 129.1, 128.1, 127.0, 122.8, 120.9,120.8, 117.7, 112.4, 103.9, 71.0, 62.2, 57.7, 51.8, 49.6, 48.1, 40.6, 36.6,21.3, 11.4. (+)-HRESIMS calcd ( m / z ) for C 27 H 34 ClN4O: [M + H] + 465.2416, found465.2414. Example 28: Synthesis of Compound 28 Referring to the synthetic route of compound 2, compound 28 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.13 (s,1H), 9.02 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.52 (brd, J = 8.8 Hz, 2H), 7.37 (d, J = 8.1 Hz, 1H), 7.25 (brd, J = 8.8 Hz, 2H), 7.13 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H),7.05 (ddd, J = 7.9, 7.0, 1.2 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 3.12 (m, 2H), 3.02 (m, 4H), 2.92 (dd, J = 7.3, 5.2 Hz, 1H), 2.82 (m, 2H), 2.53 (m, 2H), 2.42(m, 2H), 1.72 (m, 8H), 0.98 (t, J = 7.4 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C171.5,136.5, 136.4, 129.1, 129.1, 127.0, 122.6, 122.3, 120.9, 119.6, 118.5, 111.7,111.3, 103.9, 71.0, 64.2, 56.9, 53.3, 48.2, 40.4, 37.3, 37.2, 23.0, 21.2,11.5. (+)-HRESIMS calcd ( m / z ) for C 28 H 36 ClN4O: [M + H] + 479.2572, found479.2572. Example 29: Synthesis of Compound 29 Referring to the synthetic route of compound 2, compound 29 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.22 (s,1H), 8.83 (d, J = 4.3 Hz, 1H), 8.44 (d, J = 2.2 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H),7.75 (dd, J = 9.0, 2.2 Hz, 1H), 7.49 (brd, J = 8.8 Hz, 2H), 7.40 (d, J = 4.3 Hz,1H), 7.25 (brd, J = 8.8 Hz, 2H), 3.95 (s, 2H), 2.88 (dd, J = 7.0, 5.2 Hz, 1H),2.64 (t, J = 7.0 Hz, 2H), 2.56 (m, 2H), 2.44 (m, 4H), 1.77 (m, 2H), 1.65 (m,6H), 1.00 (t, J = 7.5 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C171.8, 150.6, 146.9,144.3, 136.5, 132.5, 131.6, 129.0, 128.7, 128.7, 126.8, 121.3, 120.5, 120.4,77.3, 77.1, 76.9, 70.9, 66.1, 57.3, 53.7, 48.4, 40.2, 38.4, 36.7, 20.9, 11.6.(+)-HRESIMS calcd ( m / z ) for C 28 H 33 BrClN4O: [M + H] + 555.1521, found 555.1514. Example 30: Synthesis of Compound 30 Referring to the synthetic route of compound 2, compound 30 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.56 (s,1H), 8.85 (d, J = 4.3 Hz, 1H), 8.23 ​​(dd, J = 8.4, 1.4 Hz, 1H), 8.12 (dd, J = 8.4,1.3 Hz, 1H), 7.71 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.66 (brd, J = 8.8 Hz, 2H),7.59 (brd, J = 8.8 Hz, 2H), 7.54 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.42 (d, J = 4.3Hz, 1H), 4.03 (s, 2H), 2.98 (dd, J = 7.5, 5.0 Hz, 1H), 2.68 (t, J = 7.0 Hz, 2H),2.57 (m, 2H), 2.46 (m, 4H), 1.67 (m, 8H), 1.46 (m, 1H), 1.33 (m, 3H), 0.89(t, J = 7.1 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 172.6, 150.4, 148.4, 145.1, 142.0,133.4, 130.0, 129.3, 127.6, 126.4, 124.2, 120.8, 119.2, 119.1, 106.8, 69.8,66.2, 57.2, 53.9, 48.6, 40.2, 38.5, 36.6, 29.6, 27.1, 23.0, 14.1. (+)-HRESIMScalcd ( m / z ) for C 31 H 38 N5O: [M + H] + 496.3071, found 496.3081. Example 31: Synthesis of Compound 31 Referring to the synthetic route of compound 2, compound 31 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.56 (s,1H), 8.79 (d, J = 4.4 Hz, 1H), 8.11 (dd, J = 8.4, 1.3 Hz, 1H), 8.06 (dd, J = 8.4,1.4 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.68 (brd, J = 8.8 Hz, 2H),7.60 (brd, J = 8.8 Hz, 2H), 7.56 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.27 (d, J = 4.4Hz, 1H), 3.27 (m, 2H), 3.00 (dd, J = 7.5, 5.0 Hz, 1H), 2.80 (m, 2H), 2.70 (t, J =6.9 Hz, 2H), 2.60 (m, 2H), 2.51 (m, 4H), 2.14 (m, 1H), 1.68 (m, 7H), 1.47 (m,1H), 1.34 (m, 3H), 0.90 (t, J= 7.1 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 172.6,150.2, 148.4, 146.5, 142.0, 133.4, 130.3, 129.2, 127.6, 126.5, 123.5, 121.3,119.2, 119.0, 106.7, 69.8, 66.1, 56.7, 53.7, 48.4, 40.0, 38.7, 36.7, 31.6,29.6, 27.1, 23.0, 14.1. (+)-HRESIMS calcd ( m / z ) for C 32 H 40 N5O: [M + H] + 510.3227, found 510.3234. Example 32: Synthesis of Compound 32 Referring to the synthetic route of compound 2, compound 32 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.66 (s,1H), 8.24 (d, J = 7.9 Hz, 1H), 8.19 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.59 (d, J =8.4 Hz, 2H), 7.44 (t, J = 8.6 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.38 (d, J = 7.5Hz, 1H), 7.36 (t, J = 8.5 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 7.19 (d, J = 6.5 Hz,1H), 4.20 (s, 2H), 3.01 (dd, J = 7.6, 4.9 Hz, 1H), 2.76 (t, J= 6.9 Hz, 2H), 2.61(s, 2H), 2.58 (m, 2H), 2.47 (m, 2H), 1.75 (m, 1H), 1.64 (m, 4H), 1.44 (m,1H), 1.30 (m, 6H), 0.89 (t, J = 7.1 Hz, 3H). 13 C NMR (150 MHz, CDCl3) d C 172.5,142.1, 140.0, 139.7, 133.4, 125.6, 125.5, 124.2, 123.4, 122.1, 120.6, 119.4,119.3, 119.1, 110.5, 109.9, 106.9, 69.8, 65.8, 58.8, 53.2, 48.7, 40.1, 38.3,32.1, 29.5, 27.1, 23.0, 22.8, 14.1. (+)-HRESIMS calcd ( m / z ) for C 34 H 40 N5O: [M +H] + 534.3227, found 534.3236. Example 33: Synthesis of Compound 33 Referring to the synthetic route of compound 2, compound 33 was obtained. 1 H NMR (600 MHz, CDCl3) d H 9.57 (s,1H), 8.31 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.61 (d, J =8.4 Hz, 2H), 7.45 (t, J = 8.5 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.34 (t, J = 7.1Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 7.05 (d, J= 6.8 Hz,1H), 3.49 (m, 2H), 3.02 (dd, J = 7.4, 5.0 Hz, 1H), 2.97 (t, J = 8.3 Hz, 2H), 2.85(m, 2H), 2..65 (s, 2H), 2.60 (m, 2H), 2.51 (m, 2H), 1.74 (m, 7H), 1.48 (m,1H), 1.36 (m, 3H), 1.26 (m, 1H), 0.92 (t, J = 7.0 Hz, 3H). 13 C NMR (150 MHz,CDCl3) d C 172.6, 142.0, 140.0, 139.7, 133.5, 130.1, 126.0, 125.5, 123.1, 122.6,121.5, 120.6, 119.7, 119.3, 119.1, 110.7, 109.0, 106.9, 69.8, 65.8,56.7,53.7, 48.5, 40.0, 38.6, 33.5, 29.6, 27.1, 23.0, 14.1. (+)-HRESIMS calcd ( m / z )for C 35 H 42 N5O: [M + H] + 548.3384, found 548.3383. Activity test example 1: Initial screening of IDO1 intracellular activity inhibition The experimental steps are as follows: 5000 Hela cells were inoculated in a 96-well cell culture plate, and 25ng / ul IFN-γ, 30μg / ml tryptophan and compounds were added to each well. After 48 hours of culture, 140ul of supernatant was taken, 10ul of trichloroacetic acid solution was added, and incubated at 50°C for 30 minutes. Centrifuge at 4000rpm for 20 minutes, take 100ul of supernatant and mix with an equal volume of 2% p-dimethylaminobenzaldehyde acetic acid solution, incubate at room temperature for 5 minutes, and detect the absorbance at 492nm. Each experiment was repeated three times, and three parallel wells were set each time. IC was calculated using Graphpad 50 The experimental results are shown in Table 1.

[0048] Table 1: Activity data of some compounds The results show that the diazaspirodecane compounds of the present invention can effectively inhibit IDO activity.

[0049] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A compound having the general formula (I), characterized in that Contains racemate, R- Optical isomers and S- Optical isomers, and pharmaceutically acceptable salts, hydrates or solvates thereof; （I） Wherein, subscript n is: 0, 1 or 2; The configuration of C* can be independently S type, R Type or racemic; Ring A and Ring E are each independently selected from the following group: substituted or unsubstituted C6~C 10 Aryl or substituted or unsubstituted 5-12 membered heteroaryl; B and D are each independently selected from the group consisting of N or CH; R 1 and R 5 Selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, nitro, hydroxyl, thiol, carboxyl, -S(O)2OH, substituted or unsubstituted C1~C 10 Straight chain or branched chain alkyl, substituted or unsubstituted C1~C 10 Alkoxy, substituted or unsubstituted C2~C6 branched or branched alkenyl, substituted or unsubstituted C2~C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3~C 10 1-membered carbocyclic group, substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted saturated or partially unsaturated 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C2~C6 acyl group, substituted or unsubstituted C2~C6 ester group, substituted or unsubstituted C0~C6 amino group, substituted or unsubstituted C1~C6 amide group, optional C1~C6 alkyl-sulfonyl group or substituted or unsubstituted C1~C6 alkyl-sulfinyl group; R 2 , R 3 and R 4 Each is independently selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, nitro, amino, C1~C6 amino, hydroxyl, hydroxymethyl, carboxyl, C1~C6 amide, thiol, -S(O)2OH, C1~C6 alkyl-sulfonyl, C1~C6 alkyl-sulfinyl, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy, substituted or unsubstituted C3~C8 cycloalkyl, substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted C3~C 12 a saturated or unsaturated heterocyclic group; wherein the heteroaryl or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; The substitution in the substituted or unsubstituted means that the group is substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1~C6 alkyl, C1~C6 haloalkyl, C1~C6 alkoxy, C1~C6 alkoxycarbonyl, C1~C6 haloalkoxy, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkylsulfonyl, C3~C8 saturated or partially unsaturated carbocyclic group, C6~C 10 Aryl, 3-12 membered saturated or partially unsaturated heterocyclic group and 5-12 membered heteroaryl; The halogen is F, Cl, Br or I.

2. The compound according to claim 1, characterized in that Ring A is selected from the group consisting of a benzene ring, a pyridine ring, and a naphthalene ring.

3. The compound according to claim 1, characterized in that The E ring is selected from the following group: quinoline ring, indole ring.

4. The compound according to claim 1, characterized in that R 1 Selected from the following group: substituted or unsubstituted C1~C 10 Straight chain or branched alkyl, substituted or unsubstituted saturated or partially unsaturated C3~C 10 Membered carbocyclic group.

5. The compound according to claim 1, characterized in that R 2 , R 3 and R 4 Each is independently selected from the following group: hydrogen, halogen, cyano, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy.

6. The compound according to claim 1, characterized in that The compound is selected from the following group: Compound 1- , compound 2- , compound 3- , compound 4- , compound 5- , compound 6- , compound 7- , compound 8- , compound 9- , compound 10- , compound 11- , compound 12- , compound 13- , compound 14- , compound 15- , compound 16- , compound 17- , compound 18- , compound 19- , compound 20- , compound 21- , compound 22- , compound 23- , compound 24- , compound 25- , compound 26- , compound 27- , compound 28- , compound 29- , compound 30- , compound 31- , compound 32- , compound 33- .

7. A method for preparing a compound of general formula (I), characterized in that: include: (1) , wherein Ha is a halogen; in an inert solvent, under the catalysis of a base, the compound of formula Ia reacts with the halogen substituent of formula Ib to obtain a compound of formula Ic; the base includes triethylamine and potassium carbonate; （2） ； The compound of formula Id is dissolved in an organic solvent, and subjected to an ammonolysis reaction with the compound of formula Ic under the catalysis of an alkaline solution to obtain a compound of formula Ie; the solvent comprises tetrahydrofuran, toluene or a combination thereof; the base comprises a lithium bistrimethylsilylamide solution or a trimethylaluminum solution; （3） ； The compound of formula Ie is dissolved in an organic solvent, and the compound of formula Ie is deprotected under the catalysis of an acid solution to obtain a compound If; the organic solvent comprises methanol, ethanol, tetrahydrofuran, dioxane, or a combination thereof; the acid solution comprises an aqueous hydrochloric acid solution; （4） ； The compound of formula If is dissolved in an organic solvent, and in the presence of a Lewis acid and a reducing agent, subjected to a reductive amination reaction with a compound of formula Ig to obtain a compound of formula Ih; the organic solvent comprises dichloromethane and methanol; the Lewis acid comprises tetraisopropyl titanate; the reducing agent comprises sodium cyanoborohydride; wherein R 1 , R 2 , R 3 , R 4 , n, A ring, and E ring are as defined in claim 1.

8. A pharmaceutical composition, characterized in that The invention comprises a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier and excipient.

9. The pharmaceutical composition according to claim 8, characterized in that The compounds include their racemates, R-isomers and S-isomers, and pharmaceutically acceptable salts, hydrates or solvates.

10. A method for treating or preventing a disease, disorder or symptom mediated at least in part by IDO, characterized in that: The method comprises administering an effective amount of a compound according to any one of claims 1-6.

11. The method according to claim 10, characterized in that: The diseases, disorders or symptoms are cancer and nerve-related diseases; wherein the cancer is prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, stomach cancer, endometrial cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer, mesothelial cancer, lymphoma, leukemia, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer, adrenal cancer, thyroid cancer, kidney cancer, bone cancer, toe blastoma, mesothelioma, sarcoma, choriocarcinoma, basal cell carcinoma of the skin or testicular seminoma; wherein the nerve-related diseases include Alzheimer's disease, Parkinson's disease, depression, Huntington's disease, amyotrophic lateral sclerosis and schizophrenia.

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