Compound containing oxo-pyridino-oxo-alicyclic ring structure and medical application thereof

Abstract

The invention belongs to the technical field of medicines, and provides a compound containing an oxo-pyridino-oxo-alicyclic ring structure as shown in a formula I in the specification. The compound with the novel structure provided by the invention has excellent CGRP antagonistic activity, and has potential treatment on various diseases mediated and regulated by CGRP, especially migraine or neuropathic pain.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a compound containing an oxopyridine and oxo-aliphatic ring structure and its use as a CGRP antagonist to treat related diseases. Background Art

[0002] Migraine is a common neurovascular disease characterized by recurrent, mostly unilateral, moderate to severe throbbing headaches that usually last 4 to 72 hours and are accompanied by symptoms such as nausea, vomiting, and sensitivity to sound and light (phonophobia and photophobia) [1]. Migraine attacks are often preceded by a period of sensory disturbances, which are called migraine with aura. One in seven migraine patients in my country experience aura symptoms [2]. The main types of aura include visual disturbances such as dark spots, bright spots, and flashes, as well as symptoms such as parosmia, dizziness, tinnitus, and difficulty speaking. Currently, more than 1 billion people worldwide are affected by migraine [3]. The rate of medical consultation for migraine patients in my country is only 52.9%, and the correct diagnosis rate by physicians is only 13.8%. In addition, there is a widespread lack of preventive treatment and excessive use of analgesics [2]. Migraine attacks can last for hours or even days and may seriously affect normal daily activities. This creates a significant demand for acute therapies that can quickly relieve headaches. In recent years, with the progress of migraine research at home and abroad, new therapeutic targets such as calcitonin gene-related peptide (CGRP) have emerged, enriching the treatment options for migraine.

[0003] Calcitonin gene-related peptide (CGRP) is a 37-amino acid polypeptide, whose N-terminal disulfide bond and amino-terminal C-terminus play an important role in receptor activation [4]. CGRP is mainly located in the trigeminal ganglion, c-fibers and Aδ fibers in the dorsal root ganglion and the central nervous system [5]. There are two forms of CGRP in the human body, namely α-CGRP and β-CGRP, which differ by only 1-3 amino acids in different species. α-CGRP is highly expressed in sensory neurons, while β-CGRP mainly plays a role in the enteric nervous system [6]. CGRP exerts its biological function by binding to membrane receptors. CGRP receptors are mainly composed of calcitonin receptor-like receptors (CLR) and receptor activity modifying protein 1 (RAMP1), and receptor component protein (RCP) is also required to exert signal transduction function [7]. CGRP primarily plays a role in vasodilation in the body, and studies suggest that it plays an important role in the development and progression of migraine. Clinical evidence shows that CGRP levels in the jugular vein of migraine patients increase during an attack, and intravenous injection of CGRP can cause moderate to severe headaches. The use of CGRP antagonists can relieve migraine pain and related symptoms [4].

[0004] Currently, the specific treatment modalities for acute migraine in the guidelines for diagnosis and treatment of migraine include triptans, ergotamines, ditans, and gempams [2]. Triptans are 5-HT1B / 1D receptor agonists and have been widely used in the acute treatment of migraine over the past two decades. Triptans have a high level of evidence and recommendation in the guidelines, but they also have significant cardiovascular risks, and many patients have low response rates. Ditans are 5-HT1F receptor agonists and do not have the adverse effects of vasoconstriction of triptans, but they have central nervous system depressant effects [8]. Gepandora's antagonists developed for CGRP receptors are a new treatment for migraine without cardiovascular risks or central nervous system depressant effects [7]. This provides a new option for patients who do not respond to triptans and ditans. Currently, marketed gepant-type drugs developed for CGRP receptors include AbbVie's ubrogepant and atogepant, and Pfizer's rimegepant. All three drugs are oral tablets. Migraine patients often experience symptoms such as nausea and vomiting, making oral medications less feasible. Migraine attacks also last for a long time, severely impacting daily life. Pfizer's new drug Zavegepant (vazegepant) was launched in the United States in March 2023 in the form of a nasal spray. The approved indication is the acute treatment of migraine with or without aura in adults, but it cannot be used for migraine prevention. It has the most common adverse reactions (at least 2% of ZAVZPRET-treated patients are more likely to experience them than placebo) - taste disturbance, nausea, nasal discomfort, and vomiting.

[0005] BMS disclosed and protected the compound structure of Zavegepant in patent application CN102834388B filed in 2011. Prior to CN102834388B, BMS also filed related patents from 2003 to 2005, including CN100558728C, CN100558428C, CN1914193A, and CN1972929A, which also disclosed a series of heterocyclic CGRP antagonists related to Zavegepant for the treatment of migraine.

[0006] Boehringer Ingelheim also applied for CN101146799A and WO2005084672A in 2005-2006, which also disclosed a CGRP antagonist, hoping to be used in the treatment of pain and other related diseases.

[0007] The above-mentioned previously marketed drugs or compounds disclosed in the literature related to CGRP action are different from those in the present invention. Considering the current status of the treatment of migraine and neuropathic pain, in order to meet and enrich clinical needs, there is still a demand for compounds with new structures that specifically treat migraine and neuropathic headaches.

[0008] Cited Literature:

[0009] [1]Ashina M, Terwindt GM, Al-Karagholi MA, et al. Migraine: disease characterisation, biomarkers, and precision medicine. Lancet.2021;397(10283):1496-1504.doi:10.1016 / S0140-6736(20)32162-0

[0010] [2] Chinese Medical Doctor Association Neurology Branch, Chinese Society of Research Hospitals Headache and Sensory Disorders Professional Committee. Chinese Guidelines for the Diagnosis and Treatment of Migraine (2022 Edition)[J]. Chinese Journal of Pain Medicine, 2022, 28(12):881-898.

[0011] [3]Ashina M,Katsarava Z,Do TP,et al.Migraine:epidemiology and systems of care.Lancet.2021;397(10283):1485-1495.doi:10.1016 / S0140-6736(20)32160-7

[0012] [4]Russo AF.Calcitonin gene-related peptide(CGRP):a new target formigraine.Annu Rev Pharmacol Toxicol.2015;55:533-552.doi:10.1146 / annurev-pharmtox-010814-124701

[0013] [5]Iyengar S,Ossipov MH,Johnson KW.The role of calcitonin gene-related peptide in peripheral and central pain mechanisms includingmigraine.Pain.2017;158(4):543-559.doi:10.1097 / j.pain.0000000000000831

[0014] [6]Hargreaves R,Olesen J.Calcitonin Gene-Related Peptide Modulators-The History and Renaissance of a New Migraine Drug Class.Headache.2019;59(6):951-970.doi:10.1111 / head.13510

[0015] [7]Russell FA,King R,Smillie SJ,Kodji X,Brain SD.Calcitonin gene-related peptide:physiology and pathophysiology.Physiol Rev.2014;94(4):1099-1142.doi:10.1152 / physrev.00034.2013

[0016] [8]Clemow DB,Johnson KW,Hochstetler HM,Ossipov MH,Hake AM,BlumenfeldAM.Lasmiditan mechanism of action-review of a selective 5-HT1F agonist.JHeadache Pain.2020;21(1):71.Published 2020Jun 10.doi:10.1186 / s10194-020-01132-3. 发明内容

[0017] In order to solve the above-mentioned problems existing in the prior art and meet and enrich clinical needs, the present invention aims to provide a novel compound containing an oxopyrido-oxoaliphatic ring structure that is different in structure from previously marketed drugs or compounds disclosed in the literature, as a CGRP antagonist for the prevention and treatment of CGRP-mediated related diseases, especially migraine and neuralgia.

[0018] Detailed description of the invention:

[0019] First, the present invention provides a compound of formula I or an isomer, pharmaceutically acceptable salt or solvate thereof:

[0020]

[0021] in,

[0022] X 1 is CH, CH2, NH or N, X 2 、X 3 are independently C, CH or N; optionally, X 2 、X 3 Not C or CH, or X 2 、X 3 Not all N at the same time;

[0023] Y 1 is CH2 or NH, Y 2 O or S;

[0024] R 1 and R 2 Each is independently -H or -(C1-C3)alkyl;

[0025] A is the structure shown in the following formula II:

[0026]

[0027] The G chain group and the two carbon atoms to which it is attached together form a 5- to 7-membered aliphatic ring;

[0028] The hydrogen on any C atom of the G chain group is replaced by an oxygen subunit;

[0029] R 3 is independently at each occurrence -H or -(C1-C3)alkyl, and m is 0, 1 or 2.

[0030] In some embodiments, the compound of formula I containing an oxopyridooxyaliphatic ring structure of the present invention is more preferably a structure represented by formula I-1, formula I-2 or I-3:

[0031]

[0032] In some embodiments, R 1 , R 2 , and R 3 are each independently -H or -CH3.

[0033] In some other embodiments, the A group of the present application can be further selected as follows:

[0034] Selection of the G chain group in A: can be further selected as a saturated straight chain C3-C5 alkylidene group, such as prop-1,3-alkylidene, but-1,4-alkylidene or pent-1,5-alkylidene.

[0035] The A group can also be selected as the following structures shown in Formula II-1, II-2 or II-3:

[0036]

[0037] The oxo group is substituted at any one of the 1, 2, 3, 4, 5 labels in Formula II-1, II-2 or II-3. Preferably, the oxo group is substituted at the 1 label in Formula II-1, II-2 or II-3, in which case the A group is correspondingly Surprisingly, the oxo group substituted at the 1 label has particularly superior activity compared to other substitution sites. Furthermore, it is also unexpected that, as shown in the compound of Example 1 of the present application, when the substitution site of the oxo group is changed from 1 to 2 (the substitution site label position is described with reference to Formula II-2), the corresponding compound obtained also has the defect of chemical instability.

[0038] In some embodiments, the A group of the present application is more specifically selected as follows:

[0039]

[0040] Especially preferably, the A group is further specifically selected from:

[0041]

[0042] In some other embodiments, the compound of the present application containing the oxopyridino oxo aliphatic ring structure can be specifically selected from:

[0043]

[0044]

[0045] On the basis of the compounds provided in the foregoing, the present application also provides a series of important intermediate compounds, through which the compounds of the present application having CGRP antagonistic action can be conveniently and smoothly obtained.

[0046] The typical important intermediate compounds provided are intermediate compounds having the structure shown in formula III-1 or III-2 or their isomers, pharmaceutically acceptable salts or solvates:

[0047]

[0048] In formula III-1 or III-2, R 3 is independently -H or -(C1-C3)alkyl at each occurrence, m is 0, 1 or 2; n is 0, 1 or 2; R a is -OH, -OAc or =O; R b is -(C1-C3)alkoxy; R c is -H or an amino protecting group, which may optionally include -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos or -Alloc; "---" represents a single bond or a double bond.

[0049] In some specific embodiments, the intermediate compound of the present invention can be specifically selected from:

[0050]

[0051]

[0052] In the present invention, when a later technical solution further defines a previous technical solution, it may only further define some of the technical features. In this case, the undefined technical features may be optionally defined in the previous technical solution or anywhere in the present invention.

[0053] As mentioned above, the present invention provides a class of compounds having the structural characteristics of general formula I. Studies have found that these compounds can effectively inhibit the production of cAMP stimulated by CGRP, thereby acting as CGRP antagonists to prevent, alleviate or treat CGRP-related diseases, especially migraine or neuropathic pain. Specifically, the novel compounds provided by the present invention have low IC 50 The IC values ​​of some specific structural compounds with common characteristics, such as novel compounds with specific substitution sites of oxygen subunits, are particularly surprising and significantly lower. 50 value.

[0054] Based on the above, the present invention also provides a pharmaceutical composition comprising any of the aforementioned compounds of the present invention or its isomers, pharmaceutically acceptable salts or solvates, the pharmaceutical composition also comprising a pharmaceutically acceptable excipient, and the pharmaceutical composition can be presented in any pharmaceutically acceptable dosage form and administration route.

[0055] Secondly, the present invention also provides the use of the aforementioned compounds or pharmaceutical compositions of the present invention as CGRP antagonists, and further provides the use of the compounds or pharmaceutical compositions of the present invention as CGRP antagonists in the preparation of medicaments for preventing, treating, or alleviating CGRP-mediated diseases, including migraine and neuropathic pain. Accordingly, the present invention also provides a new method for preventing, treating, or alleviating migraine, neuropathic pain, or CGRP-mediated diseases, comprising administering any of the aforementioned compounds of the present invention, or an isomer, pharmaceutically acceptable salt, or solvate thereof. DETAILED DESCRIPTION

[0056] Unless stated to the contrary or otherwise defined, the following terms used in the specification and claims have the following meanings.

[0057] "Alkyl" refers to an aliphatic hydrocarbon group, including a saturated hydrocarbon group. An alkyl group may be a straight-chain or branched chain alkyl group. For example, -(C1-C6)alkyl or -(C1-C3)alkyl. -(C1-C6)alkyl refers to an alkyl group having 1 to 6 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, and n-hexyl.

[0058] "Ring" refers to any covalently closed structure, including, for example, a carbocyclic ring (e.g., an aryl group, a cycloalkyl group), a heterocyclic group (e.g., a heteroaryl group, a heterocycloalkyl group), an aromatic group (e.g., an aryl group, a heteroaryl group), a non-aromatic group (e.g., a cycloalkyl group, a heterocycloalkyl group, etc.). The ring can be a monocyclic ring or a polycyclic ring. Typical polycyclic rings generally include bicyclic and tricyclic rings. The rings of the present invention generally have 3-20 ring atoms, for example, 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, 11 ring atoms, 12 ring atoms, 13 ring atoms, 14 ring atoms, 15 ring atoms, 16 ring atoms, 17 ring atoms, 18 ring atoms, 19 ring atoms or 20 ring atoms.

[0059] An "aliphatic ring" is a non-aromatic, saturated or unsaturated cyclic hydrocarbon whose skeletal atoms are all carbon atoms. In the present invention, an aliphatic ring typically has 3 to 8, 3 to 6, or 5 to 7 ring carbon atoms and may also be referred to as a 3- to 8-membered aliphatic ring, a 3- to 6-membered aliphatic ring, or a 5- to 7-membered aliphatic ring. Typical examples of aliphatic rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, and cycloheptene.

[0060] "Cycloalkyl" refers to a saturated cyclic hydrocarbon substituent, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The cycloalkyl group may be substituted or unsubstituted.

[0061] "Membered" refers to the number of atoms that make up the ring. Typical five-membered rings include cyclopentyl, pyrrole, imidazole, thiazole, furan, and thiophene. Typical six-membered rings include cyclohexane, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, and benzene. A ring containing heteroatoms among its backbone atoms is considered a heterocycle.

[0062] "Parallel ring" or "parallel ring structure" refers to a structure formed by two rings sharing two adjacent backbone ring atoms, for example wait.

[0063] "Oxylidene" and "oxo" have the same meaning, both are "=O", which means that the hydrogen on the carbon is replaced by "=O".

[0064] "Substituted" means that one or more hydrogen atoms, preferably up to 5 (e.g., 1, 2, 3, 4, 5), more preferably 1 to 3 hydrogen atoms, in a group can be replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) without undue effort which substitutions are possible or impossible. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond.

[0065] "Antagonist" refers to a drug that has no intrinsic activity but can block the effects mediated by receptor agonists after binding to the receptor.

[0066] The term "substituted or unsubstituted" herein refers to any group that is monosubstituted or polysubstituted by a specified substituent to the extent that such monosubstituted or polysubstituted (including multiple substitutions on the same moiety) is chemically permitted, and each substituent can be located at any available position on the group and can be attached through any available atom on the substituent. "Any available position" refers to any position on the group that is chemically accessible by methods known in the art or methods taught herein and does not produce an overly unstable molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and can therefore be the same or different.

[0067] The term "compounds of the present invention" as used herein is intended to encompass compounds of the general formula (I) as defined herein or any preferred or specific embodiment thereof (including compounds such as formula (I-1) and example compounds), their stereoisomers, pharmaceutically acceptable salts, tautomers or solvates.

[0068] The term "pharmaceutically acceptable" as used herein refers to molecular entities and compositions that are or are approvable by relevant agencies in various countries, or listed in generally recognized pharmacopeias for use in animals, and more particularly in humans, or that do not produce adverse, allergic or other untoward reactions when administered in appropriate amounts to animals, such as humans.

[0069] The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and can be inorganic acid addition salts or organic acid addition salts and base addition salts.

[0070] In the chemical structure of this article Indicates that the structure here has a chirality, but chirality separation has not been performed in the current compound, which means that the current compound contains different chirality structures.

[0071] In the chemical structure of this article It means that the double bond structure here contains cis and trans configurations, but cis and trans separation is not performed in the current compound, which means that the current compound contains different cis and trans configurations.

[0072] It should be understood that when selecting the various groups in the compound structure of the present invention, the groups that are connected, coordinated or influenced by each other should be selected accordingly under the premise of complying with the chemical valence rules.

[0073] According to the contents of the present invention, in accordance with common technical knowledge and means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0074] To further illustrate the present invention, the active compound provided by the present invention, its preparation method and application are described in detail below with reference to the examples.

[0075] The following abbreviations or terms have the following meanings:

[0076] K2CO3 represents potassium carbonate; H2O represents water;

[0077] DMF stands for N,N-dimethylformamide; KF stands for potassium fluoride;

[0078] DIPEA or DIEA represents N,N-diisopropylethylamine; n-BuLi represents n-butyllithium;

[0079] THF stands for tetrahydrofuran; TFA stands for trifluoroacetic acid;

[0080] HCl / Dioxane means hydrogen chloride dioxane solution; HCl means hydrogen chloride solution;

[0081] DMSO represents dimethyl sulfoxide; CH3I or MeI represents methyl iodide;

[0082] H2 represents hydrogen gas; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium;

[0083] t-BuOK represents potassium tert-butoxide; MeOH represents methanol;

[0084] EtOH represents ethanol; TEA represents triethylamine;

[0085] DCM represents dichloromethane; DCE represents 1,2-dichloroethane;

[0086] dioxane represents 1,4-dioxane; NBS represents N-bromosuccinimide;

[0087] NaH represents sodium hydride; NaBH4 represents sodium borohydride;

[0088] Zn represents zinc; I2 represents iodine;

[0089] Pd / C represents palladium on carbon; CH3CN or MeCN represents acetonitrile;

[0090] NH4OAc: ammonium acetate; KHMDS represents potassium bis(trimethylsilyl)amide;

[0091] NaOH represents sodium hydroxide; LiOH represents lithium hydroxide;

[0092] TCDI represents N,N'-thiocarbonyldiimidazole; TosCl represents p-toluenesulfonyl chloride;

[0093] s-BuLi: sec-butyllithium; DMSu: dimethyl succinate;

[0094] t-BuONa: sodium tert-butoxide; t-BuOH: tert-butanol;

[0095] TMSCN: trimethylsilyl cyanide; MgBrMe: methyl magnesium bromide;

[0096] CH3COOH: acetic acid; H2SO4: sulfuric acid;

[0097] Ag2CO3: silver carbonate; H2O2: hydrogen peroxide;

[0098] Ac2O: acetic anhydride; DMP or Dess-Martin: Dess-Martin periodinane;

[0099] KOH: potassium hydroxide; N2H4: hydrazine hydrate;

[0100] Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

[0101] Ruphos represents 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl;

[0102] TBTU stands for O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate;

[0103] The following first provides exemplary methods for synthesizing intermediate compounds of the compounds of the present invention. The starting materials and other additives used in the synthesis of the provided intermediate compounds can be obtained through common commercial channels or by combining conventional chemical reaction synthesis methods with methods reported in prior art literature. Some intermediate compounds can also be obtained directly through common commercial channels or by combining conventional chemical reaction synthesis methods with methods reported in prior art literature.

[0104] Intermediate Preparation Example 1: Preparation of (R)-2-amino-3-(7-methyl-1H-indazol-5-yl)propionic acid methyl ester trifluoroacetate

[0105] Step 1: Preparation of (S)-(2-((tert-Butoxycarbonyl)amino)-3-methoxy-3-oxypropyl)zinc iodide

[0106]

[0107] Under a nitrogen atmosphere, activated zinc powder (2.37 g) was added to a 100 mL three-necked flask. Iodine (926.37 mg) was dissolved in anhydrous N,N-dimethylformamide and added dropwise to the flask. The system was then reacted at 60°C for 15 minutes. Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionate (6.00 g) was dissolved in anhydrous N,N-dimethylformamide (35 mL) and slowly added dropwise to the reaction system. The reaction was continued at 70°C for 2.5 hours. After the reaction was completed, the reaction system was brought to room temperature and the resulting solution was directly used in the next reaction.

[0108] Step 2: Preparation of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(7-methyl-1H-indazol-5-yl)propionate

[0109]

[0110] Under a nitrogen atmosphere, 5-bromo-7-methyl-1H-indazole (2.26 g), tris(dibenzylideneacetone)dipalladium (489.52 mg), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (499.29 mg) were dissolved in anhydrous N,N-dimethylformamide (5 mL). The solution from the first step was added to the reaction system, and the mixture was heated at 70°C for 3 hours. After completion of the reaction, the reaction system was filtered through celite, and the filtrate was collected. 30 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain 2.1 g of the title compound.

[0111] MS (ESI) m / z (M+H) + =334.1.

[0112] Step 3: Preparation of (R)-2-amino-3-(7-methyl-1H-indazol-5-yl)propionic acid methyl ester trifluoroacetate

[0113]

[0114] Methyl (R)-2-((tert-Butoxycarbonyl)amino)-3-(7-methyl-1H-indazol-5-yl)propanoate (1 g) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (10 mL) and allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction system was concentrated to obtain the crude product, which was used directly in the next reaction without purification.

[0115] MS (ESI) m / z (M+H) + =234.1.

[0116] Intermediate Preparation Example 2: Preparation of (R)-3-(7-methyl-1H-indazol-5-yl)-2-((phenoxycarbonyl)amino)propionic acid methyl ester

[0117]

[0118] In an ice-water bath, dissolve (R)-2-amino-3-(7-methyl-1H-indazol-5-yl)propionic acid methyl ester trifluoroacetate (990 mg) in dichloromethane (20 mL), and add N,N-diisopropylethylamine (1.16 g) dropwise. Phenyl chloroformate (469.71 mg) is then dissolved in dichloromethane (10 mL) and added dropwise to the reaction system. The reaction mixture is allowed to react for 1 hour. After completion of the reaction, the reaction solution is poured into water and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by silica gel column chromatography to obtain 1 g of the title compound.

[0119] MS (ESI) m / z (M+H) + =354.1.

[0120] Intermediate Preparation 3: Preparation of (R)-2-amino-3-(7-methyl-lH-indazol-5-yl)- 1 -(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)propan- 1 -one trifluoroacetate salt

[0121]

[0122] First Step: Preparation of (R)-2-((tert-butoxycarbonyl)amino)-3-(7-methyl-lH- indazol-5-yl)propanoic acid

[0123]

[0124] Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(7-methyl-lH-indazol-5-yl)propanoate (100 mg) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), sodium hydroxide (120 mg) was added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, the pH of the system was adjusted to 5-6 with an appropriate amount of hydrochloric acid (0.5 N), and the product was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 90.0 mg of the crude product.

[0125] MS (ESI) m / z (M+H) + = 320.1.

[0126] Second Step: Preparation of tert-butyl (R)-(3-(7-methyl-lH-indazol-5-yl)-l-(4-(l- methylpiperidin-4-yl)piperazin-l-yl)-l-oxoprop-2-yl)carbamate

[0127]

[0128] (R)-2-((tert-butoxycarbonyl)amino)-3-(7-methyl-lH-indazol-5-yl)propanoic acid (50 mg), l-(l-methylpiperidin-4-yl)piperazine (57.18 mg), O-benzotriazol-N,N,N',N'- tetramethyluronium tetrafluoroborate (60.02 mg), and N,N-diisopropylethylamine (40.32 mg) were dissolved in acetonitrile (10 mL), and the reaction was allowed to proceed at room temperature for 4 h. After the reaction was completed, the crude product was concentrated and purified by column chromatography to give 30 mg of the title compound.

[0129] MS (ESI) m / z (M+H) + = 485.2.

[0130] Third Step: Preparation of (R)-2-amino-3-(7-methyl-lH-indazol-5-yl)-l-(4-(l- methylpiperidin-4-yl)piperazin-l-yl)propan-l-one trifluoroacetate salt

[0131]

[0132] Dissolve tert-butyl (R)-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate (30 mg) in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) and react at room temperature for 1 hour. After the reaction, concentrate to obtain the crude product, which is used in the next reaction without purification.

[0133] MS (ESI) m / z (M+H) + =385.2.

[0134] Intermediate Preparation Example 4: Preparation of 4-methoxy-3-((7-methyl-1H-indazol-5-yl)methyl)-4-oxobutanoic acid

[0135] Step 1: Preparation of 7-methyl-1H-indazole-5-carbaldehyde

[0136]

[0137] Under a nitrogen atmosphere at -78°C, 5-bromo-7-methyl-1H-indazole (500 mg) was dissolved in tetrahydrofuran (5 mL). n-Butyl lithium (1.5 M, 2.4 mL) and sec-butyl lithium (1 M, 3.6 mL) were added and stirred for 1 hour. N,N-dimethylformamide (533 mg) was added dropwise and the reaction continued for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was brought to room temperature, and an appropriate amount of water was added. The mixture was extracted three times with ethyl acetate. The organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to yield 350 mg of the title compound.

[0138] MS (ESI) m / z (M+H) + =161.1.

[0139] Step 2: Preparation of 3-(methoxycarbonyl)-4-(7-methyl-1H-indazol-5-yl)but-3-enoic acid

[0140]

[0141] Dissolve 7-methyl-1H-indazole-5-carbaldehyde (350 mg) in tert-butanol (5 mL), add sodium tert-butoxide (422.4 mg) and dimethyl succinate (481.8 mg), and react at 50°C for 5 hours. LCMS analysis indicates the reaction is complete. Bring the reaction mixture to room temperature, add an appropriate amount of water, and extract three times with ethyl acetate. Combine the organic phases, backwash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate to yield 800 mg of a crude product.

[0142] MS (ESI) m / z (M+H) + = 275.1

[0143] Step 3: Preparation of 4-methoxy-3-((7-methyl-lH-indazol-5-yl)methyl)-4- oxobutanoic acid

[0144]

[0145] 3-(Methoxycarbonyl)-4-(7-methyl-lH-indazol-5-yl)but-3-enoic acid (800 mg) was dissolved in methanol (10 mL) and ethyl acetate (10 mL), and palladium carbon (100 mg) was added. Hydrogen was bubbled into the reaction system, and the reaction was allowed to proceed at room temperature overnight. LCMS detection showed that the reaction was complete. The reaction solution was filtered, the filtrate was collected, and excess solvent was removed by rotary evaporation to obtain 800 mg of a crude product.

[0146] MS (ESI) m / z (M+H) + = 277.1.

[0147] Intermediate Preparation Example 5: Preparation of 4'-methyl-l,4'- bipiperidinium dihydrochloride

[0148]

[0149] Step 1: Preparation of tert-butyl 4'-cyano-[l,4'-bipiperidin]-l'-carboxylate

[0150]

[0151] Tert-butyl 4-oxopiperidine-l-carboxylate (2 g), piperidine (1.7 g), and trimethylsilyl cyanide (1.29 g) were dissolved in 1,2-dichloroethane (20 mL), and the reaction was allowed to proceed at 70 °C overnight. After the reaction was complete, a small amount of water was added to the reaction solution, which was extracted with ethyl acetate. The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain 1.1 g of the title compound.

[0152] MS (ESI) m / z (M+H) + = 294.2.

[0153] Step 2: Preparation of tert-butyl 4'-methyl-[l,4'-bipiperidin]-l'-carboxylate

[0154]

[0155] Under a nitrogen atmosphere and in an ice-water bath, tert-butyl 4'-cyano-[1,4'-dipiperidinyl]-1'-carboxylate (700 mg) was dissolved in anhydrous tetrahydrofuran (5 mL). Methylmagnesium bromide solution (3N, 2.4 mL) was slowly added dropwise. The mixture was allowed to react for 1 hour, then returned to room temperature and continued to react for 1 hour. After completion of the reaction, a small amount of water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain 480 mg of the title compound.

[0156] MS (ESI) m / z (M+H) + =283.2.

[0157] Step 3: Preparation of 4'-methyl-1,4'-dipiperidine hydrochloride

[0158]

[0159] Dissolve tert-butyl 4'-methyl-[1,4'-dipiperidinyl]-1'-carboxylate (100 mg) in a hydrochloric acid / 1,4-dioxane solution (4 N, 4 mL) and react at room temperature for 2 hours. After the reaction, concentrate to obtain 70 mg of a crude product.

[0160] MS (ESI) m / z (M+H) + =183.2.

[0161] Intermediate Preparation Example 6: Preparation of tert-butyl (E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate

[0162]

[0163] Dissolve 1-Boc-4-ethynylpiperidine (5.0 g) and bis(cyclopentadienyl)zirconium chloride hydride (307.32 mg) in toluene (50 mL), add 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.67 g) dropwise, and heat at 60°C to react overnight. After the reaction, concentrate the reaction solution, and purify the crude product by column chromatography to remove the other configuration, yielding 5.3 g of the title compound.

[0164] Intermediate Preparation Example 7: Preparation of 3-(piperidin-4-yl)-1,5,6,7-tetrahydroquinoline-2,8-dione hydrochloride

[0165]

[0166] Step 1: Preparation of 3-(2-oxocyclohexyl)propionitrile

[0167]

[0168] Dissolve cyclohexanone (5 g), cyclohexylamine (504.82 mg) and acrylonitrile (4.05 g) in acetic acid (30.63 mg) and react at 120° C. for 3 hours. After the reaction, the reaction solution is concentrated and the crude product is purified by silica gel column chromatography to obtain 7.1 g of the title compound.

[0169] Step 2: Preparation of 5,6,7,8-tetrahydroquinolin-2(1H)-one

[0170]

[0171] Under ice-water bath conditions, 3-(2-oxocyclohexyl)propionitrile (5.9 g) was dissolved in concentrated sulfuric acid (50 mL), brought to room temperature, and reacted at 50°C for 5 hours. After the reaction, the reaction solution was poured into an appropriate amount of ice water, and an appropriate amount of ammonia was added to adjust the system pH to about 8. The solution was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4.3 g of a crude product.

[0172] Step 3: Preparation of 3-bromo-5,6,7,8-tetrahydroquinolin-2(1H)-one

[0173]

[0174] Dissolve 5,6,7,8-tetrahydroquinolin-2(1H)-one (4g) in N,N-dimethylformamide (40mL), add N-bromosuccinimide (5.25g), and react at room temperature for 3 hours. After the reaction, pour the reaction system into an appropriate amount of water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate until a small amount of solvent remains. Add an appropriate amount of petroleum ether to precipitate a large amount of solid, which is then filtered and collected. The filtrate is concentrated, and the crude product is separated and purified by silica gel column chromatography to obtain the title compound. The combined yield is 4.10g.

[0175] Step 4: Preparation of 3-bromo-2-methoxy-5,6,7,8-tetrahydroquinoline

[0176]

[0177] Under a nitrogen atmosphere, 3-bromo-5,6,7,8-tetrahydroquinolin-2(1H)-one (3.66 g) and silver carbonate (5.3 g) were dissolved in toluene (40 mL). Methyl iodide (2.96 g) was added and the mixture was allowed to react overnight at 50°C. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was collected and concentrated. The crude product was separated and purified by silica gel column chromatography to obtain 3.4 g of the title compound.

[0178] Step 5: Preparation of 3-bromo-2-methoxy-5,6,7,8-tetrahydroquinoline 1-oxide

[0179]

[0180] Dissolve 3-bromo-2-methoxy-5,6,7,8-tetrahydroquinoline (2.50 g) in acetic acid (40 mL), add hydrogen peroxide (30%, 3.50 mL), and react at 80°C for 4 hours. Additional hydrogen peroxide (30%, 1.50 mL) is added and allowed to react for another 2 hours. Additional hydrogen peroxide (30%, 1 mL) is then added and allowed to react overnight. After completion of the reaction, the reaction mixture is poured into an appropriate amount of water, and the pH is adjusted to approximately 8 with saturated sodium bicarbonate aqueous solution. Extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by silica gel column chromatography to afford 630 mg of the title compound.

[0181] Step 6: Preparation of 3-bromo-2-methoxy-5,6,7,8-tetrahydroquinoline-8-acetate

[0182]

[0183] 3-Bromo-2-methoxy-5,6,7,8-tetrahydroquinoline 1-oxide (354 mg) was dissolved in acetic anhydride (2.5 mL) and reacted at 80°C for 4 hours. After the reaction, the reaction solution was poured into an appropriate amount of water, and the pH of the system was adjusted to approximately 8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography to obtain 210 mg of the title compound.

[0184] Step 7: Preparation of tert-butyl 4-(8-acetoxy-2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0185]

[0186] Under a nitrogen atmosphere, 3-bromo-2-methoxy-5,6,7,8-tetrahydroquinoline-8-acetate (210 mg), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (324.67 mg), potassium carbonate (241.87 mg), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (50.79 mg) were dissolved in 1,4-dioxane (10 mL) and water (2 mL) and reacted at 90°C for 4 hours. After the reaction, the reaction solution was filtered through celite, the filtrate was collected, an appropriate amount of water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified on a preparative silica gel plate to obtain 225 mg of the title compound.

[0187] Step 8: Preparation of tert-butyl 4-(8-hydroxy-2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0188]

[0189] Dissolve tert-butyl 4-(8-acetoxy-2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (225 mg) in methanol (10 mL), add potassium carbonate (386.98 mg), and react at room temperature for 2 hours. After completion of the reaction, filter the reaction mixture through celite, collect the filtrate, and concentrate it. The crude product is separated and purified on a preparative silica gel plate to obtain 200 mg of the title compound.

[0190] Step 9: Preparation of tert-butyl 4-(8-hydroxy-2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl)piperidine-1-carboxylate

[0191]

[0192] Dissolve tert-butyl 4-(8-hydroxy-2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg) in methanol (15 mL), add palladium carbon (20 mg), replace the hydrogen atmosphere three times, and react at room temperature for 3 hours. After the reaction is completed, the reaction system is filtered through celite, the filtrate is collected and concentrated, and the crude product is separated and purified on a preparative silica gel plate to obtain 200 mg of the title compound. Step 10: Preparation of tert-butyl 4-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinolin-3-yl)piperidine-1-carboxylate

[0193]

[0194] Dissolve tert-butyl 4-(8-hydroxy-2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl)piperidine-1-carboxylate (200 mg) in dichloromethane (10 mL), add Dess-Martin oxidant (699.83 mg), and react at room temperature for 2 hours. After the reaction, pour the reaction solution into an appropriate amount of water, adjust the pH to approximately 8 with saturated sodium bicarbonate aqueous solution, and extract with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is separated and purified on a preparative silica gel plate to obtain 170 mg of the title compound.

[0195] Step 11: Preparation of 3-(piperidin-4-yl)-1,5,6,7-tetrahydroquinoline-2,8-dione hydrochloride

[0196]

[0197] Dissolve tert-butyl 4-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinolin-3-yl)piperidine-1-carboxylate (40 mg) in concentrated hydrochloric acid (0.6 mL) and anhydrous ethanol (0.80 mL) and react at 90°C for 2 hours. After the reaction, concentrate to obtain 31 mg of the crude product, which can be used directly in the next step without purification.

[0198] MS (ESI) m / z (M+H) + =247.1.

[0199] Intermediate Preparation Example 8: Preparation of 5,5-dimethyl-3-(piperidin-4-yl)-5,6-dihydro-1H-cyclopenta[b]pyridine-2,7-dione hydrochloride

[0200] Step 1: Preparation of 4-(6-methoxy-2-methylpyridin-3-yl)isoxazole

[0201]

[0202] Under a nitrogen atmosphere, 3-bromo-6-methoxy-2-methylpyridine (10.0 g), potassium carbonate (10.25 g), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (2.54 g) were dissolved in 1,4-dioxane (70 mL) and water (20 mL). The system was heated to 90°C, and a solution of 4-isoxazoleboronic acid pinacol ester (9.65 g dissolved in 80 mL of 1,4-dioxane) was added dropwise over 3 hours. The reaction was continued for 1.5 hours. The system was brought to room temperature, quenched by the addition of water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain 7.0 g of the title compound.

[0203] MS (ESI) m / z (M+H) + =191.1.

[0204] Step 2: Preparation of 2-(6-methoxy-2-methylpyridin-3-yl)acetonitrile

[0205]

[0206] Dissolve 4-(6-methoxy-2-methylpyridin-3-yl)isoxazole (7.0 g) in methanol (80 mL), add potassium fluoride (10.7 g), and heat in a sealed autoclave at 120°C for 4 hours. Cool the reaction to room temperature and concentrate to remove the solvent. Quench the reaction with water and extract three times with ethyl acetate. Combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by column chromatography to obtain 5.1 g of the title compound.

[0207] MS (ESI) m / z (M+H) + =163.1.

[0208] Step 3: Preparation of 2-(6-methoxy-2-methylpyridin-3-yl)-2-methylpropionitrile

[0209]

[0210] Under a nitrogen atmosphere, 2-(6-methoxy-2-methylpyridin-3-yl)acetonitrile (5.1 g) was dissolved in N,N-dimethylformamide (50 mL). Sodium hydride (3.78 g) was added at -20°C and the reaction was allowed to proceed for 10 minutes. Iodomethane (11.18 g) was added and the reaction was continued for 1.5 hours. Saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain 5.8 g of the title compound. MS (ESI) m / z (M+H) + =191.1.

[0211] Step 4: Preparation of 2-methoxy-5,5-dimethyl-5,7-dihydro-6H-cyclopenta[b]pyridin-6-one

[0212]

[0213] Under a nitrogen atmosphere, 2-(6-methoxy-2-methylpyridin-3-yl)-2-methylpropionitrile (5.8 g) was dissolved in anhydrous tetrahydrofuran (60 mL). Potassium bis(trimethylsilyl)amide (1 M, 45 mL) was added dropwise at -40°C. The mixture was allowed to react at room temperature for 0.5 hours. The reaction was quenched by the addition of saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to yield 5.02 g of the title compound.

[0214] MS (ESI) m / z (M+H) + =192.1.

[0215] Step 5: Preparation of 2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadien[b]pyridin-6-ol

[0216]

[0217] Dissolve 2-methoxy-5,5-dimethyl-5,7-dihydro-6H-cyclopenta[b]pyridin-6-one (4.3 g) in methanol (40 mL) and add sodium borohydride (1.08 g) in portions. Let the mixture react at room temperature for 1 hour. After completion of the reaction, monitor the reaction by LCMS and remove the solvent by concentration. Quench the reaction by adding saturated ammonium chloride solution and extract three times with ethyl acetate. The combined organic phases are washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by column chromatography to yield 4.1 g of the title compound.

[0218] MS (ESI) m / z (M+H) + =194.1.

[0219] Step 6: Preparation of 2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-6-yl 4-methylbenzenesulfonate

[0220]

[0221] Dissolve 2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadien[b]pyridin-6-ol (4.1 g) in 1,2-dichloroethane (30 mL). Add N-methylimidazole (3.48 g) and p-toluenesulfonyl chloride (5.26 g) sequentially. Heat at 70°C for 3 hours. Add water (80 mL) to stop the reaction. Extract three times with dichloromethane. Combine the organic phases, wash sequentially with water and saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by column chromatography to yield 6.3 g of the title compound.

[0222] MS (ESI) m / z (M+H) + =348.1.

[0223] Step 7: Preparation of 2-methoxy-5,5-dimethyl-5H-cyclopentadienyl[b]pyridine

[0224]

[0225] Dissolve 2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-6-yl 4-methylbenzenesulfonate (6.3 g) in dimethyl sulfoxide (50 mL), add potassium tert-butoxide (4.07 g), and heat at 50°C for 2 hours. After the reaction, concentrate the system, quench with saturated ammonium chloride solution, and extract three times with ethyl acetate. The organic phases are combined, washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by column chromatography to yield 2.85 g of the title compound.

[0226] MS (ESI) m / z (M+H) + =176.1.

[0227] Step 8: Preparation of 2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadienyl[b]pyridine

[0228]

[0229] Dissolve 2-methoxy-5,5-dimethyl-5H-cyclopentadien[b]pyridine (0.4 g) in methanol (10 mL), add palladium on carbon (10%, 100 mg), replace the air in the system, and heat at 50°C under a hydrogen atmosphere for 2 hours. After the reaction is complete, filter, collect the filtrate, and concentrate to obtain 400 mg of the crude product.

[0230] MS (ESI) m / z (M+H) + =178.1.

[0231] Step 9: Preparation of 2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadienyl[b]pyridine 1-oxide

[0232]

[0233] Dissolve 2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadien[b]pyridine (1.3 g) in acetic acid (10 mL). Heat the mixture to 80°C and add 30% aqueous hydrogen peroxide (20 mL) dropwise over 6 hours. Continue the reaction for another 6 hours. After the reaction is complete, concentrate the mixture under reduced pressure to yield 1.7 g of crude product, which is used directly in the next step.

[0234] MS (ESI) m / z (M+H) + =194.1.

[0235] Step 10: Preparation of 2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadienyl[b]pyridine-7-acetate

[0236]

[0237] Dissolve the crude product of 2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadien[b]pyridine 1-oxide (1.7 g) in acetic anhydride (20 mL) and react at 110°C for 3 hours. Cool the reaction mixture to room temperature, concentrate under reduced pressure to remove the solvent, add an appropriate amount of water, and adjust the pH to neutral with saturated sodium bicarbonate solution. Extract three times with ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by silica gel flash column chromatography to obtain 420 mg of the title compound.

[0238] MS (ESI) m / z (M+H) + =236.1.

[0239] Step 11: Preparation of 3-bromo-2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadienyl[b]pyridine-7-acetate

[0240]

[0241] Dissolve 2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadien[b]pyridine-7-acetate (420 mg) in N,N-dimethylformamide (8 mL), add N-bromosuccinimide (380 mg), and react at 70°C for 3 hours. After the reaction, add an appropriate amount of water and extract with ethyl acetate (100 mL). The organic phases are combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by silica gel flash column chromatography to obtain 530 mg of the title compound.

[0242] MS (ESI) m / z (M+H) + =314.1.

[0243] Step 12: Preparation of tert-butyl 4-(7-acetoxy-2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0244]

[0245] Under a nitrogen atmosphere, 3-bromo-2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadienyl[b]pyridine-7-acetate (530 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (521 mg), potassium carbonate (276 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (36 mg) were dissolved in 1,4-dioxane (7 mL) and water (0.8 mL) and reacted at 80°C for 4 hours. After the reaction, an appropriate amount of water was added to the system, and the mixture was extracted with ethyl acetate (20 mL). The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography to obtain 570 mg of the title compound.

[0246] MS (ESI) m / z (M+H) + =417.1.

[0247] Step 13: Preparation of tert-butyl 4-(7-acetoxy-2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-3-yl)piperidine-1-carboxylate

[0248]

[0249] Dissolve tert-butyl 4-(7-acetoxy-2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (570 mg) in methanol (30 mL), add 10% palladium on carbon (80 mg), and react at 50°C under a hydrogen atmosphere for 2 hours. After completion of the reaction, the solid was removed by filtration and washed with methanol (100 mL). The filtrate was collected and concentrated under reduced pressure to obtain 570 mg of a crude product.

[0250] MS (ESI) m / z (M+H) + =419.1.

[0251] Step 14: Preparation of tert-butyl 4-(7-hydroxy-2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-3-yl)piperidine-1-carboxylate

[0252]

[0253] Dissolve tert-butyl 4-(7-acetoxy-2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-3-yl)piperidine-1-carboxylate (570 mg) in tetrahydrofuran (3 mL), add a solution of sodium hydroxide (146 mg) in water (0.5 mL), and allow to react at room temperature for 1 hour. After the reaction, add an appropriate amount of water, extract with ethyl acetate (20 mL), wash with water and brine, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by silica gel flash column chromatography to obtain 500 mg of the title compound.

[0254] MS (ESI) m / z (M+H) + =377.1.

[0255] Step 15: Preparation of tert-butyl 4-(2-methoxy-5,5-dimethyl-7-oxo-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-3-yl)piperidine-1-carboxylate

[0256]

[0257] Dissolve tert-butyl 4-(7-hydroxy-2-methoxy-5,5-dimethyl-6,7-dihydro-5H-cyclopentadien[b]pyridin-3-yl)piperidine-1-carboxylate (500 mg) in dichloromethane (10 mL), add Dess-Martin periodinane (846 mg), and react at room temperature for 2 hours. After the reaction, add an appropriate amount of water, extract with dichloromethane (20 mL), wash with water and brine, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by silica gel flash column chromatography to obtain 450 mg of the title compound.

[0258] MS (ESI) m / z (M+H) + =375.1.

[0259] Step 16: Preparation of 5,5-dimethyl-3-(piperidin-4-yl)-5,6-dihydro-1H-cyclopenta[b]pyridine-2,7-dione hydrochloride

[0260]

[0261] Dissolve tert-butyl 4-(2-methoxy-5,5-dimethyl-7-oxo-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-3-yl)piperidine-1-carboxylate (100 mg) in a 4M hydrogen chloride / 1,4-dioxane solution (5 mL) and react at 90°C for 6 hours. Cool the reaction mixture to room temperature and concentrate under reduced pressure to remove the solvent to obtain 110 mg of crude product, which was used directly in the next step.

[0262] MS (ESI) m / z (M+H) + =261.1.

[0263] Intermediate Preparation Example 9: Preparation of 3-(piperidin-4-yl)-5,6-dihydro-1H-cyclopenta[b]pyridine-2,7-dione hydrochloride

[0264] Step 1: Preparation of 3-(2-oxocyclopentyl)propionitrile.

[0265]

[0266] Dissolve cyclopentanone (10 g) and acrylonitrile (9.5 g) in acetic acid (100 mL) in an ice-water bath, add cyclohexylamine (5.9 g), and react at 120°C for 3 hours. TLC indicates completion of the reaction. Slowly add an appropriate amount of ice water to quench the reaction solution, extract with ethyl acetate, combine the organic phases, backwash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by column chromatography to obtain 4 g of the title compound.

[0267] Step 2: Preparation of 6,7-dihydro-5H-cyclopenta[b]pyridin-2-ol

[0268]

[0269] Dissolve 3-(2-oxocyclopentyl)propionitrile (3.9 g) in concentrated sulfuric acid (10 mL) in an ice-water bath and allow to react at room temperature for 12 hours. TLC indicates the reaction is complete. Add the reaction solution dropwise to an appropriate amount of water, filter, collect the solid, and dry to obtain 3 g of the title compound.

[0270] Step 3: Preparation of 2-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridine

[0271]

[0272] Dissolve 1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one (3.0 g) in toluene (30 mL), add silver carbonate (18.2 g) and iodomethane (9.4 g), and react at 50°C for 3 hours. TLC shows the reaction is complete. Add an appropriate amount of water to the reaction solution, extract three times with ethyl acetate, combine the organic phases, backwash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by column chromatography to obtain 1.1 g of the title compound.

[0273] The title compound was prepared using the corresponding common commercial reagents as raw materials and a preparation method similar to that of the intermediate preparation example 8.

[0274] MS (ESI) m / z (M+H) + =233.1.

[0275] Intermediate Preparation Example 10: Preparation of 3-(piperidin-4-yl)-5,6,7,8-tetrahydro-1H-cyclohepta[b]pyridine-2,9-dione hydrochloride

[0276]

[0277] The title compound was prepared using the corresponding common commercial reagents as raw materials and a preparation method similar to that of the intermediate preparation example 9.

[0278] MS (ESI) m / z (M+H) + =261.2.

[0279] Intermediate Preparation Example 11: Preparation of 5,5-dimethyl-3-(piperidin-4-yl)-1,5,6,7-tetrahydroquinoline-2,8-dione hydrochloride

[0280] Step 1: Preparation of 7,8-dihydro-5H-spiro[quinolin-6,2'-[1,3]dioxolane]-2-ol

[0281]

[0282] Dissolve 1,4-cyclohexanedione monoethylene glycol ketal (20 g) and ethyl propiolate (25.1 g) in methanolic ammonia (120 mL, 7 M) and react at 120°C under high pressure for 24 hours. LCMS indicated complete reaction. The reaction mixture was brought to room temperature, whereupon a large amount of solid precipitated. This solid was filtered, washed twice with methanol, and dried to yield 9.8 g of the title compound.

[0283] MS (ESI) m / z (M+H) + =208.1.

[0284] Step 2: Preparation of 2-methoxy-7,8-dihydro-5H-spiro[quinoline-6,2'-[1,3]dioxolane]

[0285]

[0286] Dissolve 7,8-dihydro-5H-spiro[quinolin-6,2'-[1,3]dioxolane]-2-ol (9.8 g), iodomethane (26.85 g), and silver carbonate (15.88 g) in chloroform (100 mL) and react at 65°C for 3 hours. LCMS indicated complete reaction. The reaction mixture was filtered, and the filtrate was collected and concentrated. The crude product was purified by column chromatography to yield 7.2 g of the title compound.

[0287] MS (ESI) m / z (M+H) + =222.1.

[0288] Step 3: Preparation of 2-methoxy-7,8-dihydroquinolin-6(5H)-one

[0289]

[0290] Dissolve 2-methoxy-7,8-dihydro-5H-spiro[quinoline-6,2'-[1,3]dioxolane] (7.2 g) in dilute hydrochloric acid (40 mL) and acetone (40 mL) and react at 75°C for 3 hours. LCMS indicated complete reaction. The reaction mixture was brought to room temperature, neutralized with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to yield 5.5 g of the title compound.

[0291] MS (ESI) m / z (M+H) + =178.1.

[0292] Step 4: Preparation of 2-methoxy-5,5-dimethyl-7,8-dihydroquinolin-6(5H)-one

[0293]

[0294] Dissolve potassium tert-butoxide (2.85 g) in anhydrous tetrahydrofuran (10 mL) in an ice-water bath. Slowly add a solution of 2-methoxy-7,8-dihydroquinolin-6(5H)-one (1.5 g) in anhydrous tetrahydrofuran (5 mL) dropwise. Allow to react for 0.5 hours. Add iodomethane (2.76 g) and bring the mixture to room temperature overnight. LCMS indicates completion of the reaction. The reaction mixture is quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by column chromatography to yield 1.2 g of the title compound.

[0295] MS (ESI) m / z (M+H) + =206.1.

[0296] Step 5: Preparation of 2-methoxy-5,5-dimethyl-5,6,7,8-tetrahydroquinoline

[0297]

[0298] Dissolve 2-methoxy-5,5-dimethyl-7,8-dihydroquinolin-6(5H)-one (0.4 g), potassium hydroxide (0.98 g), and hydrazine hydrate (1.17 g) in diethylene glycol (4 mL) and react at 180°C for 1 hour. LCMS indicates complete reaction. Cool the reaction system to room temperature, add an appropriate amount of water, and extract three times with dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by column chromatography to yield 0.17 g of the title compound.

[0299] MS (ESI) m / z (M+H) + =192.1.

[0300] The title compound was prepared using the corresponding common commercial reagents as raw materials and a preparation method similar to that of the intermediate preparation example 8.

[0301] MS (ESI) m / z (M+H) + =275.2.

[0302] Intermediate Preparation Example 12: Preparation of 3-(piperidin-4-yl)-1,5,7,8-tetrahydro-2H-spiro[quinoline-6,2'-[1,3]dioxolane]-2-one hydrochloride

[0303]

[0304] Step 1: Preparation of 1,5,7,8-tetrahydro-2H-spiro[quinoline-6,2'-[1,3]dioxolane]-2-one

[0305]

[0306] Dissolve 1,4-cyclohexanedione monoethylene glycol ketal (20 g) and ethyl propiolate (25.1 g) in methanolic ammonia (120 mL, 7 M) and react at 120°C under high pressure for 24 hours. LCMS indicated complete reaction. The reaction mixture was brought to room temperature, whereupon a large amount of solid precipitated. This solid was filtered, washed twice with methanol, and dried to yield 9.8 g of the title compound.

[0307] MS (ESI) m / z (M+H) + =208.1.

[0308] Step 2: Preparation of 3-bromo-1,5,7,8-tetrahydro-2H-spiro[quinoline-6,2'-[1,3]dioxolane]-2-one

[0309]

[0310] Dissolve 1,5,7,8-tetrahydro-2H-spiro[quinolin-6,2'-[1,3]dioxolane]-2-one (500 mg) in N,N-dimethylformamide (10 mL). Add dropwise a solution of N-bromosuccinimide (429 mg) in N,N-dimethylformamide (2 mL). Allow to react at room temperature for 2 hours. After completion of the reaction, quench the reaction with water, extract with ethyl acetate, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 450 mg of the title compound, which was used directly in the next step.

[0311] MS (ESI) m / z (M+H) + =286.1.

[0312] Step 3: Preparation of tert-butyl 4-(2-oxo-1,5,7,8-tetrahydro-2H-spiro[quinoline-6,2'-[1,3]dioxolane]-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0313]

[0314] Under a nitrogen atmosphere, 3-bromo-1,5,7,8-tetrahydro-2H-spiro[quinolin-6,2'-[1,3]dioxolane]-2-one (450 mg), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (486 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (115 mg), and potassium carbonate (652 mg) were dissolved in 1,4-dioxane (4.5 mL) and water (1.5 mL) and reacted at 80°C for 2 hours. LCMS showed the reaction was complete. The reaction mixture was brought to room temperature, quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain 400 mg of the title compound.

[0315] MS (ESI) m / z (M+H) + =389.2.

[0316] Step 4: Preparation of tert-butyl 4-(2-oxo-1,5,7,8-tetrahydro-2H-spiro[quinoline-6,2'-[1,3]dioxolane]-3-yl)piperidine-1-carboxylate

[0317]

[0318] Under a hydrogen atmosphere, tert-butyl 4-(2-oxo-1,5,7,8-tetrahydro-2H-spiro[quinoline-6,2'-[1,3]dioxolane]-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg) and palladium on carbon (50 mg) were dissolved in tetrahydrofuran (2.5 mL) and methanol (5 mL) and allowed to react at room temperature for 12 hours. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was collected and concentrated to yield 400 mg of the title compound. MS (ESI) m / z (M+H)+ = 391.2.

[0319] Step 5: Preparation of 3-(piperidin-4-yl)-1,5,7,8-tetrahydro-2H-spiro[quinoline-6,2'-[1,3]dioxolane]-2-one hydrochloride

[0320]

[0321] Dissolve tert-butyl 4-(2-oxo-1,5,7,8-tetrahydro-2H-spiro[quinoline-6,2'-[1,3]dioxolane]-3-yl)piperidine-1-carboxylate (400 mg) in dichloromethane (8 mL) and hydrochloric acid-dioxane (4N, 4 mL) at room temperature for 2 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated to yield 279 mg of the title compound.

[0322] MS (ESI) m / z (M+H)+ = 291.2.

[0323] Intermediate Preparation Example 13: Preparation of 3-(piperidin-4-yl)-7,8-dihydroquinoline-2,5(1H,6H)-dione hydrochloride

[0324] Step 1: Preparation of 3-amino-2-cyclohexen-1-one

[0325]

[0326] Dissolve 1,3-cyclohexanedione (4.5 g) and acetamine (3.4 g) in ethanol (45 mL) and reflux at 90°C for 4 hours. After the reaction, concentrate the mixture and purify the crude product by column chromatography to obtain 3.6 g of the title compound.

[0327] MS (ESI) m / z (M+H) + = 112.1.

[0328] Step 2: Preparation of 7,8-dihydro-1H,6H-quinoline-2,5-dione

[0329]

[0330] Dissolve 3-amino-2-cyclohexen-1-one (3.6 g) and ethyl propiolate (3.18 g) in N,N-dimethylformamide (16 mL). React at 120°C overnight and then at 190°C for 4 hours. After the reaction, filter to obtain 1.4 g of a solid, which is used directly in the next step.

[0331] MS (ESI) m / z (M+H)+ = 164.1.

[0332] Step 3: Preparation of 3-bromo-7,8-dihydroquinoline-2,5(1H,6H)-dione

[0333]

[0334] Dissolve 7,8-dihydro-1H,6H-quinoline-2,5-dione (1.4 g) in N,N-dimethylformamide (14 mL). Add N-bromosuccinimide (1.53 g) in portions and allow to react at room temperature for 2 hours. LCMS indicates the reaction is complete. A white solid precipitates upon completion of the reaction. Filter and collect the solid to yield 1.3 g of the title compound.

[0335] MS (ESI) m / z (M+H) + = 242.0.

[0336] Step 4: Preparation of tert-butyl 4-(2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0337]

[0338] Under a nitrogen atmosphere, 3-bromo-7,8-dihydroquinoline-2,5(1H,6H)-dione (650 mg), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (830 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (196 mg), and potassium carbonate (1.11 g) were dissolved in dioxane (13 mL) and water (4 mL) and reacted at 80°C for 2 hours. LCMS showed the reaction was complete. The reaction mixture was brought to room temperature, quenched with water, and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain 730 mg of the title compound.

[0339] MS (ESI) m / z (M+H)+ = 345.2.

[0340] Step 5: Preparation of tert-butyl 4-(2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)piperidine-1-carboxylate

[0341]

[0342] Under a hydrogen atmosphere, tert-butyl 4-(2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (730 mg) and palladium on carbon (73 mg) were dissolved in methanol (14 mL) and reacted at room temperature for 2 hours. LCMS showed the reaction was complete. The filtrate was collected and concentrated to yield 600 mg of the title compound.

[0343] MS (ESI) m / z (M+H)+ = 347.2.

[0344] Step 6: Preparation of 3-(piperidin-4-yl)-7,8-dihydroquinoline-2,5(1H,6H)-dione hydrochloride

[0345]

[0346] Dissolve tert-butyl 4-(2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)piperidine-1-carboxylate (600 mg) in dichloromethane (6 mL) and hydrochloric acid / dioxane (4N, 6 mL) and allow to react at room temperature for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was concentrated to yield 480 mg of the title compound.

[0347] MS (ESI) m / z (M+H) + =247.1.

[0348] The following examples provide methods for synthesizing the compounds of the present invention. The raw materials or reagents required for synthesizing the compounds of the present invention in the following examples can be obtained through common commercial channels, or according to the synthesis methods of the intermediate compounds provided above, or by combining conventional chemical reaction synthesis methods with methods reported in prior art literature.

[0349] Example 1: Preparation of (R)-4-(2,8-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropane-2-yl)piperidine-1-carboxamide

[0350]

[0351] Step 1: Preparation of (R)-methyl 2-(4-(2,8-dioxy-1,2,5,6,7,8-hexahydroquinone-3-yl)piperidine-1-carboxamide)-3-(7-methyl-1H-indazol-5-yl)propanoate

[0352]

[0353] Methyl (R)-3-(7-methyl-1H-indazol-5-yl)-2-((phenoxycarbonyl)amino)propanoate (50 mg), 3-(piperidin-4-yl)-1,5,6,7-tetrahydroquinoline-2,8-dione hydrochloride (40.15 mg), and triethylamine (73.41 mg) were dissolved in acetonitrile (5 mL) and reacted at 70°C for 2 hours. After the reaction, a solid precipitated from the reaction system, which was filtered, washed with a small amount of water, collected, and dried. The filtrate was concentrated to obtain a crude product, which was separated and purified on a preparative silica gel plate to obtain the title compound. The two products were combined to obtain 64 mg of the title compound. MS (ESI) m / z (M+H) + =506.2.

[0354] Step 2: Preparation of (R)-2-(4-(2,8-dioxy-1,2,5,6,7,8-hexahydroquinone-3-yl)piperidine-1-carboxamide)-3-(7-methyl-1H-indazol-5-yl)propanoic acid

[0355]

[0356] Methyl (R)-2-(4-(2,8-dioxy-1,2,5,6,7,8-hexahydroquinone-3-yl)piperidine-1-carboxamide)-3-(7-methyl-1H-indazol-5-yl)propanoate (60 mg) was dissolved in tetrahydrofuran (1 mL), water (0.2 mL), and methanol (0.2 mL). Lithium hydroxide (14.94 mg) was added and allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction system was concentrated to obtain 50 mg of a crude product.

[0357] MS (ESI) m / z (M+H) + =492.2.

[0358] Step 3: Preparation of (R)-4-(2,8-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)piperidine-1-carboxamide

[0359]

[0360] (R)-2-(4-(2,8-dioxy-1,2,5,6,7,8-hexahydroquinone-3-yl)piperidine-1-carboxamide)-3-(7-methyl-1H-indazol-5-yl)propanoic acid (50 mg), 1-(1-methylpiperidin-4-yl)piperazine (55.54 mg), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (38.85 mg), and N,N-diisopropylethylamine (52.21 mg) were dissolved in N,N-dimethylformamide (2 mL) and reacted at room temperature overnight. After completion of the reaction, the reaction system was separated and purified by preparative HPLC to obtain 18 mg of the title compound.

[0361] MS (ESI) m / z (M+H) + =657.3.

[0362] 1 H NMR(400MHz,CD3OD)δ7.99(s,1H),7.43(s,1H),7.32(s,1H),7.10(s,1H),4.97(dd,J=9.4,6.4Hz,1H),4 .55(s,2H),4.21-4.14(m,2H),3.80(d,J=13.1Hz,1H),3.41-3.33(m,1H),3.28-3.20(m,1H),3.15-2.99( m,6H),2.96-2.86(m,2H),2.80(t,J=6.1Hz,2H),2.56(s,3H),2.51-2.45(m,1H),2.41(s,3H),2.30-2.1 9(m,3H),2.15-2.09(m,2H),2.03-1.95(m,1H),1.93-1.80(m,3H),1.55-1.24(m,6H),1.15-1.04(m,1H).

[0363] Example 2: Preparation of 3-(1-(3-((7-methyl-1H-indazol-5-yl)methyl)-4-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-4-oxobutanoyl)piperidin-4-yl)-1,5,6,7-tetrahydroquinoline-2,8-dione

[0364]

[0365] Step 1: Preparation of methyl 4-(4-(2,8-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)piperidin-1-yl)-2-((7-methyl-1H-indazol-5-yl)methyl)-4-oxobutanoate

[0366]

[0367] 4-Methoxy-3-((7-methyl-1H-indazol-5-yl)methyl)-4-oxobutanoic acid (80 mg), 3-(piperidin-4-yl)-1,5,6,7-tetrahydroquinoline-2,8-dione hydrochloride (72 mg), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (111 mg), and N,N-diisopropylethylamine (112 mg) were dissolved in N,N-dimethylformamide (2.0 mL) and reacted at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction solution was quenched with saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative liquid chromatography to obtain 45 mg of the title compound. MS (ESI) m / z (M+H) + =505.2.

[0368] The title compound was prepared using a similar preparation method to that of Example 1 using corresponding common commercially available reagents and the products of the aforementioned intermediate preparation examples and examples as raw materials.

[0369] MS (ESI) m / z (M+H) + =656.4.

[0370] 1H NMR (400MHz, DMSO-d6) δ13.01(s,1H),10.81(s,1H),7.96(s,1H),7.36–7.17(m,2H),6.95(s,1H),4.46( d,J=12.7Hz,1H),3.97(d,J=13.4Hz,1H),3.68(d,J=11.9Hz,1H),3.44(s,1H),3.14–2.80(m,5H),2.80– 2.64(m,6H),2.58–2.53(m,3H),2.48(s,3H),2.43–2.28(m,2H),2.16(d,J=10.8Hz,1H),2.08(s,3H),2. 00(q,J=6.3Hz,2H),1.76–1.73(m,6H),1.41(t,J=12.7Hz,1H),1.26(t,J=6.2Hz,4H),1.24–1.12(m,3H).

[0371] Example 3: Preparation of (R)-4-(5,5-dimethyl-2,7-dioxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropane-2-yl)piperidine-1-thiosulfamide

[0372]

[0373] (R)-2-Amino-3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)propan-1-one trifluoroacetate (15.4 mg) was dissolved in acetonitrile (1 mL), and N,N-diisopropylethylamine (27.0 mg) and N,N'-thiocarbonyldiimidazole (7.2 mg) were added. The mixture was allowed to react at room temperature for 1 hour. 5,5-Dimethyl-3-(piperidin-4-yl)-5,6-dihydro-1H-cyclopenta[b]pyridine-2,7-dione hydrochloride (11.0 mg) was added to the mixture, and the temperature was raised to 50°C for 1 hour. TLC indicated the reaction was complete, and the mixture was concentrated. The residue was redissolved in N,N-dimethylformamide (2 mL), purified by reverse phase preparative chromatography, and freeze-dried to obtain 9.8 mg of the title compound.

[0374] MS (ESI) m / z (M+H) + =687.3.

[0375] 1 H NMR (400MHz, DMSO-d6) δ12.97(s,1H),11.80(s,1H),7.91(s,1H),7.60(d,J=7.5Hz,1H),7.52(s,1H),7.33(s,1H),6.95(s ,1H),5.48(q,J=7.5Hz,1H),4.79(t,J=13.6Hz,2H),3.47–3.41(m,1H),3.20(s,1H),3.10(t,J=9.6Hz,1H),3.03–2.89(m,5 H),2.66–2.60(m,2H),2.40(d,J=6.2Hz,3H),2.27(d,J=8.3Hz,1H),2.22–2.14(m,1H),2.03(s,3H),1.93(dd,J=15.2,7.4 Hz,1H),1.84(dq,J=12.1,6.0,3.3Hz,1H),1.77–1.63(m,4H),1.49–1.31(m,5H),1.23(d,J=2.2Hz,6H),1.19–1.07(m,5H).

[0376] Example 4: Preparation of (R)-4-(2,8-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropane-2-yl)piperidine-1-thiocarboxamide

[0377]

[0378] The title compound was prepared by a similar procedure to that described in Example 1 using the appropriate commercially available reagents and products from the previous intermediate preparations and examples as starting materials.

[0379] MS (ESI) m / z (M+H) + = 673.3.

[0380] 1 H NMR (400 MHz, CD3OD) δ 7.99 (s, 1H), 7.45 (s, 1H), 7.33 (s, 1H), 7.12 (s, 1H), 5.74-5.70 (m, 1H), 4.92-4.85 (m, 3H), 4.59 (br, 1H), 3.77-3.70 (m, 1H), 3.33 (br, 1H), 3.23-3.07 (m, 6H), 2.88-2.82 (m, 2H), 2.79 (t, J = 6.0 Hz, 2H), 2.56 (s, 3H), 2.50-2.44 (m, 1H), 2.32-2.26 (m, 1H), 2.22 (s, 3H), 2.14-2.09 (m, 2H), 1.99-1.86 (m, 6H), 1.67 - 1.04 (m, 8H).

[0381] Example 5: Preparation of (R)-4-(5,5-dimethyl-2,7-dioxo-2,5,6,7-tetrahydro-1H- cyclopenta[b]pyridin-3-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4- yl)piperazin-1-yl)-1-oxopropan-2-yl)piperidine-1-carboxamide

[0382]

[0383] The title compound was prepared by a similar procedure to that described in Example 1 using the appropriate commercially available reagents and products from the previous intermediate preparations and examples as starting materials.

[0384] MS (ESI) m / z (M+H) + = 671.1.

[0385] 1H NMR (400MHz, DMSO-d6) δ12.95(s,1H),11.72(s,1H),7.90(s,1H),7.49(s,1H),7.30(s,1H),6.93(s,1H),6.59( d,J=8.0Hz,1H),4.71(q,J=7.7Hz,1H),4.08(d,J=12.9Hz,2H),3.57–3.48(m,1H),3.14(dd,J=12.4,8.4Hz,1H), 3.00(dd,J=11.4,7.5Hz,1H),2.92–2.79(m,3H),2.69–2.59(m,4H),2.40(d,J=4.2Hz,5H),2.27(d,J=14.9Hz,1H ),2.18–2.13(m,1H),2.02(s,3H),1.89–1.77(m,2H),1.69–1.60(m,4H),1.47–1.16(m,12H),1.16–1.05(m,2H).

[0386] Example 6: Preparation of (R)-4-(2,8-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1-oxopropane-2-yl)piperidine-1-carboxamide

[0387]

[0388] The title compound was prepared using a similar preparation method to that in Example 1 using corresponding common commercially available reagents and the products of the aforementioned intermediate preparation examples and examples as raw materials.

[0389] MS (ESI) m / z (M+H) + =657.3.

[0390] 1H NMR (400MHz, DMSO-d6) δ13.00 (s, 1H), 10.80 (s, 1H), 7.96 (d, J = 2.8Hz, 1H), 7.38 (s, 0.3H), 7.35 (s, 0.7H), 7 .22(s,0.7H),7.09(s,0.3H),7.01(s,0.3H),7.00(s,0.7H),6.72-6.64(m,1H),4.86-4.73(m,1H),4.33(d,J =12.4Hz,1H),4.17-4.06(m,2H),3.97-3.84(m,1H),3.04–2.63(m,9H),2.47-2.44(m,3H),2.42–2.07(m,10 .3H),2.04-1.86(m,5H),1.74-1.60(m,3H),1.47–1.14(m,4.3H),0.69–0.53(m,0.7H),0.07-0.01(m,0.7H).

[0391] Example 7: Preparation of (R)-4-(2,7-dioxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropane-2-yl)piperidine-1-carboxamide

[0392]

[0393] The title compound was prepared using a similar preparation method to that in Example 1 using corresponding common commercially available reagents and the products of the aforementioned intermediate preparation examples and examples as raw materials.

[0394] MS (ESI) m / z (M+H) + =643.1.

[0395] 1H NMR (400MHz, DMSO-d6) δ12.94(s,1H),11.83(s,1H),7.90(s,1H),7.28(d,J=11.2Hz,2H),6.94(s,1H),6.62(d,J=8.1Hz,1H),4.7 1(q,J=7.8Hz,1H),4.05(d,J=13.0Hz,2H),3.49(d,J=13.3Hz,1H),3.10–3.00(m,1H),2.90(dd,J=13.1,7.8Hz,1H),2.81(dd,J=13 .0,7.5Hz,2H),2.73(t,J=4.8Hz,2H),2.69–2.56(m,5H),2.54–2.46(m,2H),2.40(s,3H),2.27(d,J=13.1Hz,1H),2.20–2.12(m,1H ),2.03(s,3H),1.95–1.77(m,2H),1.65(q,J=17.9,11.3Hz,4H),1.48(t,J=9.5Hz,1H),1.32(d,J=12.2Hz,2H),1.27–1.03(m,5H).

[0396] Example 8: Preparation of (R)-4-(2,9-dioxo-2,5,6,7,8,9-hexahydro-1H-cyclohepta[b]pyridin-3-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropane-2-yl)piperidine-1-carboxamide

[0397]

[0398] The title compound was prepared using a similar preparation method to that in Example 1 using corresponding common commercially available reagents and the products of the aforementioned intermediate preparation examples and examples as raw materials.

[0399] MS (ESI) m / z (M+H) + =671.4.

[0400] 1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),10.45(s,1H),7.96(s,1H),7.36(s,1H),7.22(s,1H),7.00(s,1H),6.67(d, J=8.0Hz,1H),4.77(q,J=7.8Hz,1H),4.12(d,J=13.0Hz,2H),3.57(d,J=13.0Hz,1H),3.25–3.22(m,1H),3.12–3.0 7(m,1H),2.99–2.94(m,1H),2.91–2.86(m,2H),2.80–2.77(m,2H),2.75–2.64(m,7H),2.47(s,3H),2.36–2.34(m, 1H),2.24–2.21(m,1H),2.10(s,3H),1.97–1.85(m,2H),1.76–1.69(m,7H),1.54–1.49(m,1H),1.40–1.12(m,7H).

[0401] Example 9: Preparation of (R)-N-(1-([1,4'-bipiperidinyl]-1'-yl)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl)-4-(2,8-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)piperidine-1-carboxamide

[0402]

[0403] The title compound was prepared using a similar preparation method to that in Example 1 using corresponding common commercially available reagents and the products of the aforementioned intermediate preparation examples and examples as raw materials.

[0404] MS (ESI) m / z (M+H) + =642.4.

[0405] 1H NMR(400MHz, DMSO-d6)δ12.93(s,0.3H),δ12.96(s,0.7H),10.71(s,0.3H),10.74(s,0.7H)7.92(s,0.3H),7.95(s,0.7H),7.34(s,0.3H ),7.30(s,0.7H),7.17(s,0.7H),7.05(s,0.3H),6.97(s,0.3H),6.94(s,0.7H),6.68–6.53(m,1H),4.90–4.63(m,1H),4.36–4.23(m,1H ),4.15–4.00(m,2H),4.95–4.78(m,1H),2.98–2.78(m,3H),2.74–2.54(m,5H),2.43–2.39(m,4H),2.36–2.23(m,3H),2.19–2.05(m,1H) ,2.01–1.89(m,3H),1.85–1.75(m,1H),1.75–1.51(m,3H),1.42–1.38(m,2H),1.32–1.01(m,8H),0.07–0.05(m,1H),0.04–0.01(m,1H).

[0406] Example 10: Preparation of (R)-4-(5,5-dimethyl-2,8-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)piperidine-1-carboxamide

[0407]

[0408] The title compound was prepared using a similar preparation method to that in Example 1 using corresponding common commercially available reagents and the products of the aforementioned intermediate preparation examples and examples as raw materials.

[0409] MS (ESI) m / z (M+H) + =684.8.

[0410] 1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),10.59(s,1H),7.96(s,1H),7.36(s,2H),7.00(s,1H),6.65(d,J =8.0Hz,1H),4.82-4.72(m,1H),4.13(d,J=12.0Hz,2H),3.62-3.54(m,1H),3.25-3.16(m,1H),3.15-3 .03(m,1H),3.00-2.85(m,3H),2.72-2.57(m,6H),2.47(s,4H),2.39-2.30(m,1H),2.27-2.16(m,1H), 2.10(s,3H),1.98-1.83(m,4H),1.80-1.64(m,4H),1.52-1.33(m,5H),1.27(s,6H),1.24-1.10(m,2H).

[0411] Example 11: Preparation of (R)-4-(2,8-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4'-methyl-[1,4'-bipiperidinyl]-1'-yl)-1-oxopropane-2-yl)piperidine-1-carboxamide

[0412]

[0413] The title compound was prepared using a similar preparation method to that in Example 1 using corresponding common commercially available reagents and the products of the aforementioned intermediate preparation examples and examples as raw materials.

[0414] MS (ESI) m / z (M+H) + =656.3.

[0415] 1H NMR(400MHz,DMSO-d6)δ13.02(s,0.5H),13.00(s,0.5H),10.78(s,1H),7.96(s,0.5H),7.95(s,0.5H),7.37(s,0.5H),7.35(s,0.5H), 7.18(s,0.5H),7.12(s,0.5H),7.01(s,0.5H),6.97(s,0.5H),6.66-6.62(m,1H),4.82-4.74(m,1H),4.12(d,J=13.0Hz,2H),3.85-3.75 (m,0.5H),3.65-3.57(m,0.5H),3.26–2.81(m,5.5H),2.76–2.63(m,4.5H),2.59-2.51(m,1.5H),2.47(s,1.5H),2.46(s,1.5H),2.30- 2.20(m,4H),2.05-1.96(m,2H),1.74-1.55(m,3H),1.50-1.09(m,10.5H),0.79-0.69(m,2H),0.47(s,1.5H),0.15(t,J=12.0Hz,0.5H).

[0416] Example 12: Preparation of (R)-4-(2,6-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropane-2-yl)piperidine-1-carboxamide

[0417]

[0418] Step 1: Preparation of methyl (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,5,7,8-tetrahydro-2H-spiro[quinoline-6,2]'-[1,3]dioxolane]-3-yl)piperidine-1-carboxamido)propanoate

[0419]

[0420] Dissolve 3-(piperidin-4-yl)-1,5,7,8-tetrahydro-2H-spiro[quinolin-6,2'-[1,3]dioxolane]-2-one hydrochloride (279 mg), methyl (R)-3-(7-methyl-1H-indazol-5-yl)-2-((phenoxycarbonyl)amino)propanoate (345 mg), and triethylamine (517 mg) in acetonitrile (5 mL) and react at 80°C for 2 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated, and the crude product was purified by column chromatography to obtain 480 mg of the title compound.

[0421] MS (ESI) m / z (M+H) + =550.3.

[0422] Step 2: Preparation of (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,5,7,8-tetrahydro-2H-spiro[quinoline-6,2'-[1,3]dioxolane]-3-yl)piperidine-1-carboxamido)propanoic acid

[0423]

[0424] Methyl (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,5,7,8-tetrahydro-2H-spiro[quinolin-6,2]'-[1,3]dioxolane]-3-yl)piperidine-1-carboxamido)propanoate (480 mg) and lithium hydroxide monohydrate (175 mg) were dissolved in methanol (9 mL), tetrahydrofuran (3 mL), and water (3 mL) and reacted at room temperature for 2 hours. LCMS indicated the reaction was complete. An appropriate amount of hydrochloric acid (2N) was added to adjust the pH to 5-6. Water was added and the crude product was freeze-dried to obtain a product that was used directly in the next step.

[0425] MS (ESI) m / z (M+H) + =536.2.

[0426] Step 3: Preparation of (R)-2-(4-(2,6-dioxo-1,2,6,7,8-hexahydroquinolin-3-yl)piperidine-1-carboxamido)-3-(7-methyl-1H-indazol-5-yl)propanoic acid

[0427]

[0428] (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,5,7,8-tetrahydro-2H-spiro[quinolin-6,2'-[1,3]dioxolane]-3-yl)piperidine-1-carboxamido)propanoic acid (300 mg) was dissolved in acetonitrile (3 mL) and hydrochloric acid (3 mL, 2N) and reacted at 90°C for 2 hours. LCMS indicated the reaction was complete. The solvent was removed by concentration under reduced pressure, and the crude product was purified by high pressure reverse preparative purification to afford 182 mg of the title compound.

[0429] MS (ESI) m / z (M+H) + =492.2.

[0430] Step 4: Preparation of (R)-4-(2,6-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropane-2-yl)piperidine-1-carboxamide

[0431]

[0432] (R)-2-(4-(2,6-dioxo-1,2,6,7,8-hexahydroquinolin-3-yl)piperidine-1-carboxamido)-3-(7-methyl-1H-indazol-5-yl)propanoic acid (20 mg), 1-(1-methylpiperidin-4-yl)piperazine (14 mg), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (9 mg), and N,N-diisopropylethylamine (26 mg) were dissolved in N,N-dimethylformamide (1.0 mL) and reacted at room temperature for 2 hours. LCMS showed the reaction was complete. The system was purified by high pressure reverse preparative chromatography to obtain 5 mg of the title compound. MS (ESI) m / z (M+H) + =656.8.

[0433] 1 H NMR (400MHz, DMSO-d6) δ13.01(s,1H),11.59(s,1H),10.20(s,1H),7.96(s,1H),7.36(s,1H),6.96(d,J=29.6Hz ,2H),4.77(q,J=7.6Hz,1H),4.10(d,J=13.2Hz,2H),3.56(d,J=12.8Hz,1H),3.32(s,3H),3.10(t,J=9.6Hz,1H), 2.99–2.88(m,2H),2.84(t,J=7.2Hz,2H),2.78–2.62(m,5H),2.47(s,3H),2.33(s,1H),2.22(s,1H),2.10(s,3H ),2.01–1.85(m,3H),1.78–1.63(m,4H),1.54(d,J=9.6Hz,1H),1.42–1.34(m,2H),1.21(dt,J=21.3,8.4Hz,6H).

[0434] Example 13: Preparation of (R)-4-(2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropane-2-yl)piperidine-1-carboxamide

[0435]

[0436] The title compound was prepared using a similar preparation method to that in Example 1 using corresponding common commercially available reagents and the products of the aforementioned intermediate preparation examples and examples as raw materials.

[0437] MS (ESI) m / z (M+H) + =656.8.

[0438] 1 H NMR (400MHz, DMSO-d6) δ13.00(s,1H),12.05(s,1H),7.96(s,1H),7.49(s,1H),7.35(s,1H),7.00(s,1H),6.67(d,J=8.0Hz,1H),4.77(q, J=7.6Hz,1H),4.10(s,2H),3.55(d,J=13.6Hz,1H),3.26–3.19(m,1H),3.11(t,J=9.8Hz,1H),2.99–2.93(m,1H),2.88(dd,J=13.0,6.9Hz ,1H),2.76(t,J=6.0Hz,3H),2.72–2.63(m,4H),2.47(s,3H),2.42(d,J=6.6Hz,2H),2.31(d,J=8.8Hz,1H),2.20(d,J=11.2Hz,1H),2.09(s,3H),2.03–1.93(m,3H),1.72–1.67(m,3H),1.35(s,2H),1.31–1.21(m,3H),1.16(td,J=12.2,3.6Hz,2H),0.94(d,J=6.4Hz,3H).Biological test data

[0439] Unless otherwise specified, the experimental materials, reagents, operations, and methods used in the following activity test examples can be obtained from commercial channels or can be easily known or prepared based on existing technologies.

[0440] Test Example 1: Cell Functional Antagonism Assay - cAMP Assay

[0441] 1. Experimental Principle

[0442] The CGRP receptor complex is coupled to Gs in the G protein. The binding of CGRP to the CGRP receptor complex leads to the activation of Gs and the production of cAMP (3',5'-cyclic adenosine monophosphate).

[0443] 2. Experimental Purpose

[0444] The compounds of the invention were determined for their ability to inhibit CGRP-stimulated cAMP formation in SK-N-MC cells.

[0445] 3. Experimental Materials

[0446] 3.1 Experimental cell lines:

[0447] SK-N-MC (neuroepithelioma cells), source: National Biomedical Experimental Cell Resource Bank.

[0448] 3.2 Reagents and consumables

[0449] name brand Item No. LANCE Ultra cAMP Kit PerkinElmer TRF0262 α-CGRP (human) MCE HY-P1071 IBMX sigma I7018-100MG HBSS (1×) Gibco 14025076 HEPES1M Gibco 15630080

[0450] 4. Experimental Procedure

[0451] 4.1 Cell preparation:

[0452] Resuscitate and culture SK-N-MC cells in advance. Before use, the cell confluence should be 70%-80%.

[0453] 4.2 Prepare sample diluent, test compound and α-CGRP (human).

[0454] 4.3 Cell plating and drug effects:

[0455] SK-N-MC cells were digested, centrifuged, resuspended in sample diluent, and plated in a 384-well plate. α-CGRP (human) and the test compound were added to each well and mixed thoroughly by pipetting. The plate was sealed with film and incubated in an ELISA incubator at 25°C.

[0456] 4.4 cAMP Assay: Follow the instructions for the LANCE Ultra cAMP Kit. Prepare the Eu-cAMP tracer and ULight anti-cAMP working solutions in a dark environment. Add each solution to the plate and pipette to mix thoroughly. Seal the plate with film and incubate in a microplate incubator at 25°C.

[0457] 4.5 Use the chemiluminescence module of the fully automatic microplate reader to read the luminescence value.

[0458] 4.6 Data Analysis

[0459] The IC50 value was calculated using the nonlinear formula with the LOG value of the compound concentration as the horizontal axis and the Inhibition as the vertical axis. The results are shown in the table below.

[0460] IC of compounds for inhibiting CGRP-stimulated cAMP production in SK-N-MC cells 50 value

[0461]

[0462]

[0463] 5. Conclusion

[0464] The novel compounds provided by the present invention can significantly inhibit the production of cAMP stimulated by CGRP and have a low IC 50 In particular, compounds represented by Examples 1, 4, 7, 8, and 9 exhibited exceptionally significant inhibitory activity. Comparison of Examples 1, 12, and 13 revealed that the substitution site of the oxygen subunit had a surprisingly significant effect on the activity of the compound.

[0465] The present invention is not limited to the above optional implementation modes, and anyone can derive products in various other forms under the guidance of the present invention.

Claims

1. A compound of the following formula I or an isomer, pharmaceutically acceptable salt or solvate thereof: in, X 1 is CH, CH2, NH or N, X 2 、X 3 are independently C, CH or N; optionally, X 2 、X 3 Not C or CH, or X 2 、X 3 Not all N at the same time; Y 1 is CH2 or NH, Y 2 O or S; R 1 and R 2 Each is independently -H or -(C1-C3)alkyl; A is the structure shown in the following formula II: The G chain group and the two carbon atoms to which it is attached together form a 5- to 7-membered aliphatic ring; The hydrogen on any C atom of the G chain group is replaced by an oxygen subunit; R 3 is independently at each occurrence -H or -(C1-C3)alkyl, and m is 0, 1 or 2.

2. The compound according to claim 1 or its isomer, pharmaceutically acceptable salt or solvate: The compound is shown in the following formula I-1, I-2 or I-3:

3. The compound according to claim 1 or its isomer, pharmaceutically acceptable salt or solvate: R 1 、R 2 and R 3 Each is independently -H or -CH3.

4. The compound according to claim 1 or its isomer, pharmaceutically acceptable salt or solvate: The G chain group is a saturated straight-chain C3-C5 fork-type structure.

5. The compound according to claim 1 or its isomer, pharmaceutically acceptable salt or solvate: The G chain group is a propan-1,3-ylidene group, a butan-1,4-ylidene group or a pentan-1,5-ylidene group.

6. The compound according to claim 1 or its isomer, pharmaceutically acceptable salt or solvate: A is a structure represented by the following formula II-1, II-2 or II-3: The oxygen subunit is substituted at any one of the 1, 2, 3, 4, and 5 marks in formula II-1, II-2, or II-3. Preferably, the oxygen subunit is substituted at the 1 mark in formula II-1, II-2, or II-3.

7. The compound according to claim 1 or its isomer, pharmaceutically acceptable salt or solvate: A is selected from: A is further preferably selected from:

8. The compound according to claim 1 or its isomer, pharmaceutically acceptable salt or solvate: The compound is selected from: 。 9. Use of the compound according to any one of claims 1 to 8 or its isomer, pharmaceutically acceptable salt or solvate as a CGRP antagonist.

10. The use according to claim 9, wherein the compound or its isomer, pharmaceutically acceptable salt or solvate is used to prepare a drug for preventing, treating or alleviating CGRP-mediated diseases.

11. The use according to claim 10, wherein the disease comprises migraine and neuropathic pain.

12. An intermediate compound of the following formula III-1 or III-2, or an isomer, pharmaceutically acceptable salt or solvate thereof: In formula III-1 or III-2: R 3 is independently at each occurrence -H or -(C1-C3)alkyl, and m is 0, 1 or 2; n is 0, 1, or 2; R a is -OH, -OAc or =O; R b is -(C1-C3)alkoxy; R c is -H or an amino protecting group, wherein the amino protecting group may optionally include -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos or -Alloc; "---" represents a single bond or a double bond.

13. The intermediate compound according to claim 12 or its isomer, pharmaceutically acceptable salt or solvate: The intermediate compound is selected from: 。

Images