N-(2-(4-cyano thiazolidine-3-yl)-2-oxyethyl) quinoline-4-formamide compound and application thereof

Abstract

The invention relates to a novel N-(2-(4-cyano thiazolidine-3-yl)-2-oxyethyl) quinoline-4-formamide derivative and a preparation method of the N-(2-(4-cyano thiazolidine-3-yl)-2-oxyethyl) quinoline-4-formamide derivative. The structure of the compound or the pharmaceutically acceptable salt is C-A-B, A is a quinoline ring, B is an (R)-3-glycyl thiazolidine-4-nitrile side chain, and C is a side chain containing a sulfoximine structure. The compound or the pharmaceutically acceptable salt of the compound, and the pharmaceutical composition containing the compound or the pharmaceutically acceptable salt of the compound have obvious FAP enzyme inhibition activity, and can be used for preparing an FAP small-molecule inhibitor.

Description

Technical Field

[0001] This invention relates to a novel class of N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide derivatives and their preparation methods. These compounds can be used as small molecule inhibitors of FAP. Background Technology

[0002] At the end of the 20th century, the activity of fibroblast activation protein (FAP) was discovered and confirmed. Researchers found that FAP is highly expressed in tumor stroma-activated fibroblasts, sarcoma tumor cells, and granulation tissue, and FAP has also been identified as a membrane protease that can affect the degradation function of the extracellular matrix (ECM) of tumor cells (Cancer Res, 1986, 46(12Pt 1): 6406-6412; Proc NatlAcad Sci USA, 1990, 87(18): 7235-7239; Proc NatlAcad Sci USA, 1990, 87(21): 8296-8300).

[0003] Fibroblast activation protein (FAP) is a 97-kDa type II transmembrane serine protease. Studies have shown that FAP contains both dipeptidyl peptidase and endopeptidase activities (Int J BiochemCell Biol, 2004, 36, 2320-2333). The dipeptidyl peptidase activity allows FAP to catalyze the hydrolysis of peptide bonds in dipeptides, releasing an amino acid residue and a peptide fragment. This process plays a crucial role in protein degradation and metabolism. FAP's dipeptidyl peptidase activity enables it to participate in extracellular matrix remodeling and the regulation of the tumor microenvironment. Furthermore, FAP's dipeptidyl peptidase activity also influences tumor cell growth and migration. Endopeptidase activity refers to the ability of an enzyme to cleave proteins at a specific location within the protein. It plays a vital role in protein processing, modification, and degradation, particularly in the maturation of precursor proteins. The presence of endopeptidase activity allows FAP to specifically recognize and cleave peptide bonds within proteins. Meanwhile, studies have found that under physiological conditions, FAP expression is low in most normal adult tissues, while in cancer patients, FAP is elevated to varying degrees in a variety of tumor cells (Cancer Metastasis Rev, 2020, 39(3):783-803). Based on these two activities of FAP and its expression characteristics, it has become a potential target for the diagnosis and treatment of tumors.

[0004] Current research on FAP inhibitors mainly focuses on diagnostic and therapeutic radiopharmaceuticals, with relatively few studies on small molecule drugs. Most of these studies are still in the drug discovery or preclinical research stage (Pharmaceutical Progress, 2023, 47(5):337-356). The therapeutic areas are mostly tumors, digestive system diseases, and endocrine and metabolic diseases.

[0005] The development of small molecule inhibitors targeting FAP is mainly divided into borate pyrroles, chloromethyl ketones, and cyanopyrroles. Due to the poor stability of first-generation borate pyrrole FAP inhibitors and the poor performance of its representative drug Talabostat in Phase II clinical trials (Cancer Biol Ther, 2007, 6(11):1691-1699), since 2013, the development of small molecule inhibitors targeting FAP has mainly focused on cyanopyrroles. These inhibitors are structurally modified with N-(4-quinoline yl)-glycine-(2-cyanopyrrole) (a) as the core, in order to obtain better stability and selectivity. For example, the Heidelberg research group in Germany first attempted radioactive iodination of FAPI-01 (b) and the modified FAPI-04 (c). Among them, FAPI-04 currently shows excellent stability and affinity, and is expected to be applied in clinical practice (J Nucl Med, 2018, 59(9):1423-1429; J Nucl Med, 2018, 59(9):1415-1422). AZD2389 (d) is a small molecule FAP inhibitor under development by AstraZeneca PLC. It has shown great potential in improving the treatment of metabolic-related fatty liver and other liver fibrosis diseases, and is currently in Phase II clinical trials (WO, 2023 / 247487A1[P]. 2023-12-28).

[0006]

[0007] Although the clinical outcomes of FAP-targeted therapies are often less than ideal, especially given the relatively lagging development of FAP small molecule inhibitors, the significant role of FAP in many pathological conditions still suggests that it can offer some clinical targeting value, making it worthy of further exploration. Therefore, the development of novel FAP small molecule inhibitors remains a promising area for research. Summary of the Invention

[0008] This invention relates to an N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide derivative or a pharmaceutically acceptable salt thereof.

[0009] The compound or its pharmaceutically acceptable salt has the structure CAB;

[0010]

[0011] Wherein, A is a quinoline ring, B is (R)-3-glycylthiazolidin-4-nitrile side chain, and C is a side chain containing a sulfoxide imine structure.

[0012] Furthermore, the present invention provides compounds represented by general formula (I) or pharmaceutically acceptable salts thereof:

[0013]

[0014] Wherein, C is selected from the following structure:

[0015]

[0016] Wherein, R1 and R2 are selected from substituted or unsubstituted C1-C6 alkyl groups, and the substituents are C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, and hydroxyl groups;

[0017] Alternatively, R1 and R2 may combine with sulfur atoms to form a tetrahydrothiophene ring or a thiomorpholine ring;

[0018] R3 is selected from C3-C6 cycloalkyl, C1-C6 alkyl, and C1-C6 alkoxy groups;

[0019] R4 is selected from C1-C6 alkyl and C1-C6 alkoxy groups;

[0020] R5 and R6 are each selected from C1-C6 alkyl and C1-C6 alkoxy groups, respectively;

[0021] Alternatively, R5 and R6 may combine with nitrogen atoms to form an N-methylpiperazine or morpholine ring.

[0022] Furthermore, the present invention preferably uses the following compounds or pharmaceutically acceptable salts thereof:

[0023] Wherein, R1 and R2 are each selected from substituted or unsubstituted C1-C4 alkyl groups, wherein the substituents are C3-C6 cycloalkyl, C1-C4 alkyl, C1-C4 alkoxy, or hydroxyl;

[0024] Alternatively, R1 and R2 may combine with sulfur atoms to form a tetrahydrothiophene ring or a thiomorpholine ring;

[0025] R3 is selected from C3-C6 cycloalkyl, C1-C4 alkyl, and C1-C4 alkoxy groups;

[0026] R4 is selected from C1-C4 alkyl and C1-C4 alkoxy groups;

[0027] R5 and R6 are each selected from C1-C4 alkyl and C1-C4 alkoxy groups, respectively;

[0028] Alternatively, R5 and R6 may combine with nitrogen atoms to form an N-methylpiperazine or morpholine ring.

[0029] Preferably, the compound can be any one of the following compound formulas, but is not limited to the following molecular structures:

[0030]

[0031]

[0032]

[0033] Compounds of formula (I) may exist as tautomers and geometric isomers depending on the type of substituents. In this specification, compounds of formula (I) or their salts are sometimes described as only one type of isomer, but the present invention also includes isomers other than those described herein, as well as isomer isolates or mixtures thereof.

[0034] Furthermore, compounds of formula (I) or their salts sometimes have asymmetric centers or axial asymmetry, and may have enantiomers (optical isomers) based on them. Compounds of formula (I) or their salts comprise any of isolated enantiomers such as (R) bodies, (S) bodies, or mixtures thereof (racemic or non-racemic mixtures). In one manner, the enantiomer is "stereochemically pure." "Stereochemically pure" means a purity that can be recognized by a person skilled in the art as substantially stereochemically pure. Alternatively, the enantiomer is a compound having a stereochemical purity of, for example, 90% ee (enantiomeric excess) or higher, 95% ee or higher, 98% ee or higher, or 99% ee or higher.

[0035] Furthermore, salts of compounds of formula (I) are pharmaceutically acceptable salts of compounds of formula (I), and depending on the type of substituent, sometimes form acid addition salts. Specifically, examples include: acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, di-toluyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid.

[0036] Furthermore, the present invention also includes various hydrates, solvates, and polymorphs of compounds of formula (I) and their salts.

[0037] Furthermore, the present invention also includes pharmaceutically acceptable prodrugs of compounds represented by formula (I). A pharmaceutically acceptable prodrug is a compound having groups that can be decomposed by solvents or converted into amino, hydroxyl, carboxyl, or other groups under physiological conditions.

[0038] Furthermore, this invention comprises all pharmaceutically acceptable compounds of formula (I) labeled with one or more radioactive or non-radioactive isotopes, or salts thereof. Examples of suitable isotopes for isotopic labeling of compounds of this invention include hydrogen (…). 2 H and 3 H, etc.), carbon ( 11 C 13 C and 14 C, etc.), nitrogen ( 13 N and 15 N, etc.), oxygen ( 15 O、 17 O and 18 O, etc.), fluorine ( 18 F, etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I and 125 I, etc.), phosphorus ( 32 P, etc.), sulfur ( 35 These isotopes include S, etc.

[0039] The isotopically labeled compounds of this invention can be used in studies such as the tissue distribution of drugs and / or substrates. For example, radioactive isotopes such as tritium (3H) and carbon-14 (14C) can be used for this purpose because they are easy to label and detect.

[0040] The isotopically labeled compounds of the present invention can generally be manufactured by existing methods known to those skilled in the art, or by using suitable isotopically labeled reagents instead of unlabeled reagents and by the same manufacturing method as in the examples or manufacturing examples.

[0041] Compounds of formula (I) and their salts can be manufactured using various known synthetic methods based on the characteristics of their basic structure or the types of substituents. In this case, depending on the type of functional group, it is sometimes technically effective to pre-replace the functional group with a suitable protecting group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate.

[0042] Furthermore, the prodrug of the compound of formula (I) can be manufactured in the same manner as the protecting group described above, either by introducing a specific group during the process from the starting material to the intermediate, or by further reacting the obtained compound of formula (I). The reaction can be carried out using methods known to those skilled in the art, such as conventional esterification, amidation, and dehydration.

[0043] The following describes a representative method for manufacturing the compound of formula (I).

[0044] The following abbreviations are used in this instruction manual:

[0045] DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; EtOAc = ethyl acetate; EtOH = ethanol; MeCN = acetonitrile; MeOH = methanol; THF = tetrahydrofuran; DCM = dichloromethane; TFAA = trifluoroacetic anhydride; EDCI = 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBT = 1-hydroxybenzotriazole; NaBH(OAc)3 = sodium triacetoxyborohydride.

[0046] Pd(OAc)2 = Palladium acetate; Pd2(dba)3 = Tris(dibenzylideneacetone)palladium; Pd(dba)2 = Di(dibenzylideneacetone)palladium; PPh3 = Triphenylphosphine; Xantphos = 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene; BINAP = 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); DIPEA = N,N-diisopropylethylenediamine.

[0047] K2CO3 = potassium carbonate, Cs2CO3 = cesium carbonate, t-BuONa = sodium tert-butoxide, t-BuOK = potassium tert-butoxide, K3PO4 = potassium phosphate; NaHCO3 = sodium bicarbonate; NaOH = sodium hydroxide; TEA = triethylamine.

[0048] Boc = tert-butoxycarbonyl; tBu = tert-butyl; Et = ethyl; Me = methyl; Ac = acetyl.

[0049] MgSO4 = anhydrous magnesium sulfate; Na2SO4 = anhydrous sodium sulfate; NaHCO3 = sodium bicarbonate; NH4Cl = ammonium chloride; HCl = hydrochloric acid; H2SO4 = sulfuric acid.

[0050] The method for preparing the compound of general formula (I) or a pharmaceutically acceptable salt thereof according to the present invention comprises the following steps:

[0051]

[0052] Step 1: Preparation of compound A-4:

[0053] (1) 5-bromoindigo (A-1) reacts with pyruvic acid under alkaline conditions via a Pfitzinger reaction to give intermediate A-2;

[0054] The amount of pyruvic acid added is 1-1.2 times that of A-1; as a base, it can be K2CO3, KOH, or NaOH, preferably NaOH; as a solvent, it can be N,N-dimethylformamide, methanol, ethanol, or water, preferably water.

[0055] The reaction temperature is 110-120℃, and the reaction time is 10-20 minutes. After the reaction is completed, adjust the pH to 2-3 with hydrochloric acid solution.

[0056] Heating can be achieved using microwave reaction or oil bath heating, with the reaction under reflux for 4-5 hours, preferably using oil bath reaction.

[0057] (2) Intermediate A-2 was decarboxylated to obtain intermediate A-3;

[0058] Using diphenyl ether as a solvent, the reaction was carried out at 180-200℃ for 4-5 hours.

[0059] (3) Intermediate A-3 was esterified to obtain the parent core A-4;

[0060] Using sulfuric acid as a catalyst and ethanol as a solvent, the reaction was carried out under reflux for 4-5 hours. After the reaction, the pH was adjusted to 7 with saturated sodium bicarbonate solution. Step 2: Preparation of compound B:

[0061] (1) Intermediate B-2 was prepared by amide condensation of (R)-3-(tert-butoxycarbonyl)thiazolidin-4-carboxylic acid (B-1);

[0062] Using ethyl acetate as the reaction solvent, B-1, Boc anhydride, and pyridine were first added to the reaction system, and the mixture was stirred at room temperature for 3-4 hours. Then, ammonia water was added as the ammonia source, and the reaction was carried out overnight at room temperature.

[0063] (2) Intermediate B-2 was de-Boced in an acidic solvent to obtain intermediate B-3;

[0064] The acid is hydrochloric acid; the solvent can be methanol or ethyl acetate, preferably ethyl acetate. The reaction is carried out in an ice-water bath for 2-3 hours.

[0065] (3) Intermediate B-3 and Boc-glycine were condensed under alkaline conditions to prepare intermediate B-4;

[0066] The amount of Boc-glycine added is 1-1.1 times that of B-3. EDCI is used as an amide condensing agent, and HOBT is used as an activating agent. The base can be TEA or DIPEA, preferably TEA. The solvent can be ethyl acetate, acetonitrile, or N,N-dimethylformamide, preferably N,N-dimethylformamide. The reaction is carried out overnight at room temperature.

[0067] (4) Intermediate B-4 was cyano-treated under alkaline conditions to prepare intermediate B-5.

[0068] Trifluoroacetic anhydride is used as the dehydrating agent. The solvent can be one of THF, MeOH, or DMF, preferably THF. The reaction is carried out overnight at room temperature. The base is pyridine.

[0069] (5) The intermediate B-5 was de-Boced under acidic conditions to obtain the side chain B.

[0070] The acid is hydrochloric acid, and the solvent can be methanol or ethyl acetate, preferably ethyl acetate. The reaction is carried out in an ice-water bath for 2-3 hours.

[0071] Step 3: Preparation of compounds of general formula (I):

[0072] (1) In a solvent, the parent nucleus A-4 and the side chain C react with phosphorus ligands via a Buchwald-Hartwig coupling reaction under alkaline conditions and with the action of a catalyst to obtain intermediate A-5-C.

[0073] The amount of side chain C fed is 1.0 to 2.0 times that of the parent core A-4, preferably 1.5 times.

[0074] The catalyst is Pd(OAc)2, Pd2(dba)3, Pd(dba)2, etc., with Pd2(dba)3 being preferred.

[0075] The phosphorus ligand is PPh3, Xantphos, or BINAP, with Xantphos being preferred.

[0076] The alkali is K2CO3, Cs2CO3, t-BuONa, t-BuOK, or K3PO4, with t-BuONa being preferred.

[0077] The solvent is toluene, EtOAc, DMF, or 1,4-dioxane, preferably 1,4-dioxane.

[0078] The reaction is heated in an oil bath at reflux temperature for 24-36 hours.

[0079] The reaction can also be carried out using microwave, with a reaction temperature of 140-160℃ and a reaction time of 35-45 minutes. Microwave reaction is preferred.

[0080] (2) Intermediate A-5-C was hydrolyzed under alkaline conditions to prepare intermediate AC.

[0081] The preferred base is NaOH, and the preferred reaction solvent is methanol.

[0082] The amount of NaOH added is 1 to 4 times that of intermediate A-5-C, preferably 2 times.

[0083] The reaction temperature is from 50°C to reflux temperature, preferably reflux temperature. The reaction time is 1 to 2 hours, preferably 1.5 hours.

[0084] (3) Intermediate AC and side chain B are condensed by amide to obtain compound I.

[0085] The amount of B added is 1 to 1.5 times that of intermediate AC. EDCI is used as an amide condensing agent, and HOBT is used as an activator. The base can be TEA or DIPEA, preferably DIPEA. The solvent can be at least one of ethyl acetate, acetonitrile, or N,N-dimethylformamide, preferably a mixture of ethyl acetate and N,N-dimethylformamide, with no particular requirement on the ratio, but preferably 1:1 to 1.5.

[0086] The compounds of formula (I) are separated and purified as free compounds, their salts, hydrates, solvates or polymorphs.

[0087] Salts of compounds of formula (I) can also be produced by conventional salt-forming reactions. Separation and purification can be performed using common chemical operations such as extraction, fractional crystallization, and various chromatographic methods.

[0088] Various isomers can be manufactured by selecting appropriate starting material compounds, or they can be separated by utilizing the differences in physicochemical properties between the isomers. For example, optical isomers can be obtained by conventional optical resolution methods for racemates (e.g., stepwise crystallization by introducing diastereomeric salts of optically active bases or acids, chromatography using chiral columns, etc.), or they can be prepared from appropriate optically active starting material compounds.

[0089] The compounds of general formula (I) of the present invention or their pharmaceutically acceptable salts have good FAP enzyme inhibitory activity and can be used to prepare small molecule FAP inhibitors. Detailed Implementation

[0090] The present invention will be described in detail below.

[0091] In this specification, unless otherwise specified, the following terms shall have the meanings described below. The definitions below are for clarity and not for limitation. When a term is not specifically defined herein, it shall be used in the sense that is generally accepted by those skilled in the art.

[0092] For convenience, concentration in mol / L is expressed as M. For example, a compound concentration of 1000nM means the compound concentration is 1000 nmol / L. 1N hydrochloric acid solution means the solution contains H+. + The concentration is 1 mol / L.

[0093] Example 1: 6-Bromoquinoline-2,4-dicarboxylic acid (A-2)

[0094]

[0095] 5-Bromoindigo (A-1) (6 g, 26.54 mmol) and pyruvic acid (2.8 g, 31.85 mmol) were added to a reaction flask, followed by 40 mL of 10% sodium hydroxide aqueous solution. The reaction system was heated to 100 °C and reacted for 5 h. The reaction was monitored by thin-layer chromatography until completion. The pH was adjusted to 2 with 1 N hydrochloric acid solution to obtain a suspension. The suspension was filtered under reduced pressure, the filter cake was washed with water, and dried to obtain 7.46 g of the intermediate 6-bromoquinoline-2,4-dicarboxylic acid (A-2) brown solid, with a yield of 95%. MS m / z (ESI), [M+H + 295.99, 297.96.

[0096] Example 2: 6-Bromoquinoline-4-carboxylic acid (A-3)

[0097]

[0098] A-2 (1 g, 3.38 mmol) was thoroughly ground and added to a reaction flask, followed by 10 mL of diphenyl ether. The reaction system was heated to 200 °C and reacted for 4 h. Thin-layer chromatography indicated the reaction was complete. After cooling to room temperature, 3 mL of acetone was added for dilution, and the mixture was filtered under reduced pressure. The filter cake was washed with 2 mL each of acetone and anhydrous diethyl ether. 0.78 g of the intermediate 6-bromoquinoline-4-carboxylic acid (A-3) as a black solid was obtained, with a yield of 92%. MS m / z (ESI), [M+H] + 250.02, 252.02.

[0099] Example 3: Ethyl 6-bromoquinoline-4-carboxylate (A-4)

[0100]

[0101] Add A-3 (1.27 g, 5.04 mmol) and 30 mL of ethanol to a reaction flask, then slowly add 5.08 mL of sulfuric acid dropwise under an ice-water bath, controlling the temperature below 10 °C. After the addition is complete, heat the reaction system to 80 °C and react at this temperature for 4 h. The reaction is then monitored by thin-layer chromatography to indicate completion. Cool to room temperature, adjust the pH to 7 with saturated sodium bicarbonate solution, extract the reaction solution with ethyl acetate (30 mL x 3), combine the organic phases, wash with saturated brine (10 mL), and dry with 3 g of anhydrous magnesium sulfate. Filter under reduced pressure, concentrate under reduced pressure, and obtain a crude black oily substance. Purify the crude product by column chromatography (stationary phase: silica gel, eluent: petroleum ether: ethyl acetate = 15:1) to obtain 1.21 g of pale yellow solid ethyl 6-bromoquinoline-4-carboxylic acid (A-4), yield 85.11%. MS m / z (ESI), [M+H] + 279.93, 281.80. 1H NMR (400MHz, CDCl3) δ9.03(d,J=1.9Hz,1H),9.01(dd,J=4.4,1.4Hz,1H),8.02(dd,J=9.0,1.4Hz,1H),7.94( dd,J=4.4,1.4Hz,1H),7.84(dt,J=9.0,1.8Hz,1H),4.51(qd,J=7.2,1.4Hz,2H),1.48(td,J=7.2,1.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ165.76,150.30,150.26,147.88,134.10,133.46,131.81,131.75,128.22,126.33,123.11,122.98,62.22,14.39.

[0102] Example 4: (R)-4-formylthiazolidin-3-carboxylic acid tert-butyl ester (B-2)

[0103]

[0104] Under nitrogen protection, (R)-3-(tert-butoxycarbonyl)thiazolyl-4-carboxylic acid (B-1) (10 g, 42.87 mmol), pyridine (4 g, 50.57 mmol), and Boc anhydride (10 g, 45.82 mmol) were added to a reaction flask, followed by dissolution in 80 mL of EA. The reaction system was stirred at room temperature for 3 h. Then, 3.5 mL of 25% ammonia solution was added dropwise, and the reaction system was stirred overnight at room temperature. The reaction was monitored for completion by thin-layer chromatography. The reaction mixture was diluted with 0.5 volume of water, and the phases were separated. The organic phase was washed successively with 15 mL of saturated sodium bicarbonate solution and 15 mL of saturated sodium chloride solution, and then dried over 3 g of anhydrous magnesium sulfate. The mixture was filtered under reduced pressure and concentrated under reduced pressure to obtain a crude, pale yellow oil. Purification by flash column chromatography (stationary phase: silica gel, developing solvent: petroleum ether: ethyl acetate = 10:1) yielded 7.5 g of 75% clear oil of the intermediate tert-butyl(R)-4-carbamoylthiazoline-3-carboxylic acid tert-butyl ester (B-2). MS m / z (ESI), [M+H] + 233.14.

[0105] Example 5 (R)-Thiazolidin-4-carboxamide hydrochloride (B-3)

[0106]

[0107] Under ice-water bath conditions, B-2 (3.1 g, 13.34 mmol) was dissolved in 10 mL of ethyl acetate, and then 60 mL of ethyl hydrochloride was slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred under ice-water bath conditions for 2 h. The reaction was monitored for completion by thin-layer chromatography. The solution was filtered under reduced pressure to give 2.1 g of intermediate (R)-thiazolidin-4-carboxamide (B-3) hydrochloride, with a yield of 92.51%. MS m / z (ESI), [M+H] + 133.06.

[0108] Example 6 (R)-(2-(4-carbamoylthiazolidin-3-yl)-2-oxoethyl)tert-butyl carbamate (B-4)

[0109]

[0110] Under nitrogen protection, Boc-glycine (2.57 g, 13.35 mmol) and β-3 hydrochloride (2.25 g, 14.69 mmol) were dissolved in 40 mL of LDM and transferred to a reaction flask. Then, EDCI (5.10 g, 26.7 mmol), HOBT (5.47 g, 20.5 mmol), and triethylamine (6.76 g, 66.75 mmol) were added. The reaction mixture was allowed to react overnight at room temperature. The reaction endpoint was monitored by thin-layer chromatography. The reaction was quenched with 1 volume of saturated ammonium chloride solution, and the reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined phases were washed with saturated brine (10 mL) and dried over anhydrous magnesium sulfate (3 g). The mixture was filtered under reduced pressure and concentrated to obtain a crude, colorless oily product. The crude product was purified by column chromatography (stationary phase: silica gel, developing solvent: petroleum ether: ethyl acetate = 8:1). 2.09 g of intermediate (R)-(2-(4-carbamoylthiazolidin-3-yl)-2-oxoethyl)tert-butyl carbamate (B-4) was obtained as a white solid, with a yield of 54.17%. MS m / z (ESI), [M+H] + 290.10.

[0111] Example 7 (R)-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)tert-butyl carbamate (B-5)

[0112]

[0113] Under nitrogen protection, B-4 (0.94 g, 2.21 mmol) and pyridine (0.64 g, 8.09 mmol) were added, followed by dissolution in 40 mL of anhydrous tetrahydrofuran. Trifluoroacetic anhydride (0.82 g, 3.94 mmol) was then added to the reaction mixture. The reaction mixture was stirred at room temperature and reacted overnight. The endpoint was monitored by thin-layer chromatography. The reaction was quenched with 1 volume of ice water, and the reaction mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (10 mL), then dried over anhydrous magnesium sulfate (3 g). The mixture was filtered under reduced pressure and concentrated to give a crude, colorless oily product. Purification was achieved by flash column chromatography (stationary phase: silica gel, eluent: petroleum ether: ethyl acetate = 10:1). This yielded 0.67 g of intermediate (R)-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)carbamate tert-butyl ester (B-5) as a white solid, in 68% yield. MS m / z (ESI), [M+H] + 271.98, [M+Na] + 29403. 1 H NMR (400MHz, CDCl3) δ5.35(s,1H),5.29(d,J=4.5Hz,1H),4.56(s,2H),4.17-3.90(m,2H),3.28(d,J=4.4Hz,2H),1.45(s,9H).

[0114] Example 8 (R)-3-glycylthiazolidin-4-nitrile hydrochloride (B)

[0115]

[0116] B-5 (1 g, 3.69 mmol) was dissolved in 5 mL of ethyl acetate under an ice-water bath, and then 20 mL of ethyl acetate hydrochloride was slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred under an ice-water bath for 2 h. The reaction endpoint was monitored by thin-layer chromatography. 0.69 g of (R)-3-glycylthiazolidin-4-onitrile (B) hydrochloride was obtained, with a yield of 90%. MS m / z (ESI), [M+H] + 171.93.

[0117] Example 9: Iminodimethyl-6-thione (Ca1)

[0118]

[0119] Dimethyl sulfide (Ca1-1) (1 g, 16.1 mmol) and ammonium carbamate (2.51 g, 32.19 mmol) were added to a reaction flask, followed by 15 mL of methanol. The mixture was stirred at room temperature for 0.5 h. Iodophenyl diacetate (10.82 g, 33.8 mmol) was then added to the reaction system, and the mixture was stirred at room temperature for 2 h. The reaction endpoint was monitored by thin-layer chromatography. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of dichloromethane, and 4 eq of sodium bicarbonate were added with stirring for 15 min. Then, 2 eq of anhydrous sodium sulfate were added with stirring for 15 min. The mixture was filtered under reduced pressure and concentrated to obtain a crude colorless oil. Purification was performed by flash column chromatography (stationary phase: silica gel, developing solvent: petroleum ether: ethyl acetate = 15:1). 1.18 g of the intermediate iminodimethyl-6-thione (Ca1) clear oil was obtained, with a yield of 78.67%. MS m / z (ESI), [M+H] + 93.96.

[0120] Example 10 6-((dimethyl(oxo)-λ) 6 ethyl quinoline-4-carboxylate (A-5-Ca1) (-sulfonamide)amino)quinoline-4-carboxylate

[0121]

[0122] Under nitrogen protection, A-4 (0.25 g, 0.89 mmol) and Ca1 (0.13 g, 1.34 mmol) were dissolved in 10 mL of 1,4-dioxane and transferred to a reaction tube. Sodium tert-butoxide (0.1 g, 1.07 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.03 g, 0.05 mmol), and tris(dibenzylideneacetone)dipalladium (0.02 g, 0.02 mmol) were added. The reaction tube was placed in a microwave synthesizer and reacted at 150 °C for 45 min. After the reaction, the mixture was cooled to room temperature. Diatomaceous earth was filtered, and the filter cake was washed with an appropriate amount of ethyl acetate. The filtrate was concentrated under reduced pressure to obtain a crude yellow-green oily substance. The crude product was purified by preparative chromatography to obtain the intermediate 6-((dimethyl(oxo)-λ) 6 Ethyl quinoline-4-carboxylate (A-5-Ca1), a yellow-green oil, 0.09 g, yield 35.33%. MS m / z (ESI), [M+H] + 293.25.

[0123] Example 11 6-((dimethyl(oxo)-λ) 6 -sulfonamide)amino)quinoline-4-carboxylic acid (A-Ca1)

[0124]

[0125] Transfer A-5-Ca1 (0.09 g, 0.3 mmol) to a reaction flask, add 4 mL of methanol and 4 eq of sodium hydroxide, and heat the reaction system to reflux for 1.5 h. The reaction was monitored by thin-layer chromatography until completion. Add hydrochloric acid to adjust the pH to 5, concentrate under reduced pressure to obtain the intermediate 6-((dimethyl(oxo)-λ). 6 A yellow solid of (-sulfonamide)amino)quinoline-4-carboxylic acid (A-Ca1), which requires no further purification and can be used directly in the next reaction. MS m / z (ESI), [M+H + 265.15.

[0126] Example 12(R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((dimethyl(oxo)-λ) 6 (-sulfoxide)amino)quinoline-4-carboxamide (DXY-a1)

[0127]

[0128] Under nitrogen protection, a solution of N,N-dimethylformamide (3 mL) containing A-Ca1 (0.08 g, 0.3 mmol) was added to a reaction flask containing ethyl acetate (2 mL) containing B hydrochloride (0.08 g, 0.47 mmol). EDCI (0.11 g, 0.6 mmol), HOBT (0.1 g, 0.75 mmol), and DIPEA (0.2 g, 1.5 mmol) were then added. The reaction mixture was allowed to react overnight at room temperature. The endpoint was monitored by thin-layer chromatography. The reaction was quenched with 1 volume of cooled saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate (10 mL x 4), and the organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate (2 g). The mixture was filtered under reduced pressure and concentrated under reduced pressure to obtain a crude yellow oily product. The crude product was purified by preparative chromatography and then freeze-dried to obtain compound (R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((dimethyl(oxo)-λ) 6 (-sulfoxide)amino)quinoline-4-carboxamide (DXY-a1), yellow solid, 0.04 g, yield 32%. MS m / z (ESI), [M+H + 418.27. 1H NMR (400MHz, CDCl3) δ8.77(d,J=4.3Hz,1H),7.99(d,J=9.0Hz,1H),7.82(d,J=2.4Hz,1H),7.48(dd,J=9.1,2.4Hz,1H),7.44(d,J=4.4 Hz,1H),7.15(t,J=4.7Hz,1H),5.24(dd,J=5.7,3.4Hz,1H),4.64(s,2H),4.49-4.26(m,2H),3.36-3.29(m,2H),3.24(d,J=3.1Hz,6H).

[0129] Example 13 1-Iminotetrahydro-1H-λ 6 -Thiophene-1-oxide (Ca2)

[0130]

[0131] Using tetrahydrothiophene (Ca2-1) (1 g, 11.34 mmol) as a starting material, it was prepared according to the method of Example 9 and purified by flash column chromatography (stationary phase: silica gel, developing solvent: petroleum ether: ethyl acetate = 15:1). The intermediate 1-iminotetrahydro-1H-λ was obtained. 6 Thiophene-1-oxide (Ca2) transparent oil 1.16 g, yield 85.61%. MS m / z (ESI), [M+H] + 120.15.

[0132] Example 14 6-((1-Tetrahydro-1λ) 6 ethyl quinoline-4-carboxylate (A-5-Ca2-)-thiophene-1-yl)amino)quinoline-4-carboxylate

[0133]

[0134] Using Ca2+ (0.16 g, 1.34 mmol) and ethyl 6-bromoquinoline-4-carboxylate (A-4) (0.25 g, 0.89 mmol) as starting materials, the intermediate A-5-Ca2 was prepared according to the method of Example 10. After purification by preparative chromatography, 0.1 g of a yellow-green oily intermediate A-5-Ca2 was obtained, with a yield of 35.71%. MS m / z (ESI), [M+H] + 319.23.

[0135] Example 15 6-((1-Tetrahydro-1λ) 6 (-Thiophene-1-yl)amino)quinoline-4-carboxylic acid (A-Ca2)

[0136]

[0137] Using A-5-Ca2 (0.1 g, 0.31 mmol) as a starting material, a yellow solid containing the intermediate A-Ca2 was prepared according to the method of Example 11. This solid required no further purification and was used directly in the next reaction. MS m / z (ESI), [M+H] + 290.34.

[0138] Example 16(R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((1-tetrahydro-1λ) 6 -Thiophene-1-yl)amino)quinoline-4-carboxamide (DXY-a2)

[0139]

[0140] Using A-Ca2 (0.09 g, 0.31 mmol) and B (0.08 g, 0.47 mmol) as raw materials, the compound was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.04 g of a pale yellow solid (DXY-a2, yield 30%) was obtained. MS m / z (ESI), [M+H) + 444.30. 1 H NMR (400MHz, CDCl3) δ8.76(d,J=4.4Hz,1H),8.00(d,J=9.0Hz,1H),7.79(d,J= 2.5Hz,1H),7.48(dd,J=9.0,2.4Hz,1H),7.45(d,J=4.4Hz,1H),7.11(t,J=4.8 Hz,1H),5.24(dd,J=5.7,3.5Hz,1H),4.64(s,2H),4.50-4.26(m,2H),3.47(q, J=5.4Hz,2H),3.38-3.23(m,J=7.6,6.7Hz,4H),2.31(dq,J=35.0,6.4Hz,4H).

[0141] Example 17 4-Imine-1,4λ 6 -oxathion 4-oxide (Ca3)

[0142]

[0143] The intermediate 4-imino-1,4λ was prepared from thiomorpholine (Ca3-1) (1 g, 9.6 mmol) according to the method of Example 9 and purified by flash column chromatography (stationary phase: silica gel, developing solvent: petroleum ether: ethyl acetate = 15:1). 6 1.15 g of oxathione 4-oxide (Ca3) clear oil, yield 88.35%. MS m / z (ESI), [M+H]+ 135.98.

[0144] Example 18 6-((4-Oxide-1,4λ) 6 ethyl quinoline-4-carboxylate (A-5-Ca3)-(oxasulfur-4-yl)amino)quinoline-4-carboxylate

[0145]

[0146] Using Ca3 (0.36 g, 2.68 mmol) and A-4 (0.5 g, 1.78 mmol) as raw materials, the intermediate A-5-Ca3 was prepared according to the method of Example 10. After purification by preparative chromatography, 0.32 g of the yellow-green oily intermediate A-5-Ca3 was obtained, with a yield of 53.3%. MS m / z (ESI), [M+H] + 335.24.

[0147] Example 19 6-((4-Oxide-1,4λ) 6 (-oxasulfur-4-yl)amino)quinoline-4-carboxylic acid (A-Ca3)

[0148]

[0149] Using A-5-Ca3 (0.32 g, 0.96 mmol) as a starting material, a yellow solid containing the intermediate A-Ca3 was prepared according to the method of Example 11. No further purification was required, and it was directly used in the next reaction. MS m / z (ESI), [M+H] + 307.21.

[0150] Example 20(R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((4-oxo-1,4λ) 6 (-oxathio-4-yl)amino)quinoline-4-carboxamide (DXY-a3)

[0151]

[0152] Using A-Ca3 (0.28 g, 0.91 mmol) and B (0.28 g, 1.36 mmol) as raw materials, the compound was prepared according to the method of Example 12. After purification by preparative chromatography, the compound was freeze-dried to obtain 0.13 g of a pale yellow solid (DXY-a3, yield 31%). MS m / z (ESI), [M+H] + 460.21. 1H NMR (400MHz, CDCl3) δ8.77(dd,J=8.3,4.3Hz,1H),7.99(dd,J=10.9,8.9Hz,1H),7.84( dd,J=11.9,2.4Hz,1H),7.53(ddd,J=9.4,4.8,2.5Hz,1H),7.44(dd,J=6.8,4.3Hz,1H), 7.09(dd,J=11.2,5.5Hz,1H),5.26(td,J=6.0,3.4Hz,1H),4.65(s,2H),4.39(ddt,J=65 .0,17.6,4.5Hz,2H),3.74(dq,J=85.8,5.3Hz,4H),3.37(s,4H),3.33(d,J=5.5Hz,2H).

[0153] Example 21: Diethyl(imino)-λ 6 -Thione (Ca4)

[0154]

[0155] The intermediate Ca4-1 (0.5 g, 5.54 mmol) was prepared according to the method of Example 9, using diethyl sulfide (Ca4-1) as the starting material, and purified by flash column chromatography (stationary phase: silica gel, developing solvent: petroleum ether: ethyl acetate = 15:1). 0.58 g of clear Ca4-1 intermediate was obtained, with a yield of 86.57%. MS m / z (ESI), [M+H] + 122.16.

[0156] Example 22 6-((diethyl(oxo)-λ) 6 ethyl quinoline-4-carboxylate (A-5-Ca4)

[0157]

[0158] Using Ca4 (0.13 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as raw materials, the intermediate A-5-Ca4 was prepared according to the method of Example 10. After purification by preparative chromatography, 0.08 g of the yellow-green oily intermediate A-5-Ca4 was obtained, with a yield of 35.24%. MS m / z (ESI), [M+H] + 321.25.

[0159] Example 23 6-((diethyl(oxo)-λ) 6 -sulfonamide)amino)quinoline-4-carboxylic acid (A-Ca4)

[0160]

[0161] Using A-5-Ca4 (0.08 g, 0.25 mmol) as the starting material, a yellow solid containing the intermediate A-Ca4 was prepared according to the method of Example 11. This solid required no further purification and was used directly in the next reaction. MS m / z (ESI), [M+H] + 293.22.

[0162] Example 24(R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((diethyl(oxo)-λ) 6 -sulfoxide)amino)quinoline-4-carboxamide (DXY-a4)

[0163]

[0164] Using A-Ca4 (0.07 g, 0.24 mmol) and B (0.07 g, 0.33 mmol) as raw materials, the compound DXY-a4 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.03 g of a pale yellow solid was obtained, with a yield of 30%. MS m / z (ESI), [M+H] + 446.36. 1 H NMR (400MHz, CDCl3) δ8.74(d,J=4.4Hz,1H),7.96(dd,J=9.0,1.8Hz,1H),7.82(s,1H),7.53(dd,J=9.2,2.5Hz,1H),7.42(d,J=4.4Hz,1H), 7.11(d,J=4.9Hz,1H),5.23(d,J=4.9Hz,1H),4.63(s,2H),4.51-4.24(m,2H),3.31(d,J=5.0Hz,2H),3.30-3.20(m,4H),1.47-1.36(m,6H). 13 C NMR (101MHz, CDCl3) δ167.93,166.68,147.27,146.00,145.40,139.14,130.87,129.13, 125.60,119.20,116.66,114.34,50.06,47.72,46.03,45.85,42.68,33.80,7.98,7.86.

[0165] Example 25 (Cyclopropylmethyl)(Methyl)thion (Ca5-2)

[0166]

[0167] (Bromomethyl)cyclopropane (Ca5-1) (1.0 g, 7.41 mmol) was added to acetonitrile (10.0 mL), followed by sodium methanethiol aqueous solution (4.0 mL). The reaction system was sealed at 80 °C for 5 hours, and TLC analysis showed product formation. The mixture was diluted with 1 volume of ice water and extracted with dichloromethane (10 mL x 3 times). The resulting organic phase was washed with 5 mL of saturated sodium chloride aqueous solution, dried over 2 g of anhydrous magnesium sulfate, and filtered under reduced pressure to obtain a dichloromethane solution containing intermediate Ca5-2. This solution was used directly in the next reaction without further purification.

[0168] Example 26 (cyclopropylmethyl)(imino)(methyl)-16-thione (Ca5)

[0169]

[0170] A dichloromethane solution containing Ca5- was used as the starting material, and the preparation was carried out according to the method of Example 9. Purification was performed by flash column chromatography (stationary phase: silica gel, developing solvent: petroleum ether: ethyl acetate = 15:1). 0.92 g of intermediate Ca5 clear oil was obtained, with a yield of 93.88%. MS m / z (ESI), [M+H] + 134.18.

[0171] Example 27 6-(((cyclopropylmethyl)(methyl)(oxo)-λ 6 (-Sulfanamide group)amino)quinoline-4-carboxylic acid ethyl ester (A-5-Ca5)

[0172]

[0173] Using Ca5 (0.14 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as raw materials, the intermediate A-5-Ca5 was prepared according to the method of Example 10. After purification by preparative chromatography, 0.09 g of the yellow-green oily intermediate A-5-Ca5 was obtained, with a yield of 38.13%. MS m / z (ESI), [M+H] + 333.26.

[0174] Example 28 6-(((cyclopropylmethyl)(methyl)(oxo)-λ 6 -sulfinamide group)amino)quinoline-4-carboxylic acid (A-Ca5)

[0175]

[0176] Using A-5-Ca5 (0.09 g, 0.27 mmol) as the starting material, a yellow solid containing the intermediate A-Ca5 was prepared according to the method of Example 11. This solid required no further purification and was used directly in the next reaction. MS m / z (ESI), [M+H] +305.22.

[0177] Example 29 (R)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(((cyclopropylmethyl)(methyl)(oxo)-λ) 6 -Sulfanamide group)amino)quinoline-4-carboxamide (DXY-a5)

[0178]

[0179] Using A-Ca5 (0.08 g, 0.27 mmol) and B (0.07 g, 0.33 mmol) as raw materials, the compound DXY-a5 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.04 g of a pale yellow solid was obtained, with a yield of 32%. MS m / z (ESI), [M+H] + 458.34. 1 H NMR (400MHz, CDCl3) δ8.81-8.75(m,1H),7.99(d,J=8.9Hz,1H),7.83(s,1H),7.57-7.49(m,1H),7.44(d,J=4.3Hz,1H),7.13(d,J=5.0Hz,1H),5.29-5 .24(m,1H),4.65(s,2H),4.51-4.29(m,2H),3.32(p,J=7.0Hz,4H),3.18(d ,J=2.5Hz,3H),2.00(s,1H),0.77(d,J=8.3Hz,2H),0.39(q,J=7.7Hz,2H).

[0180] Example 30 Imino(methyl)(propyl)-λ 6 -Thione (Ca6)

[0181]

[0182] The intermediate Ca6-1 (0.5 g, 5.54 mmol) was prepared according to the method of Example 9, using methyl propyl sulfide (Ca6-1) as the starting material. Purification was performed by flash column chromatography (stationary phase: silica gel, developing solvent: petroleum ether: ethyl acetate = 15:1). 0.53 g of clear Ca6 oil was obtained, with a yield of 79.10%. MS m / z (ESI), [M+H] + 122.23.

[0183] Example 31 6-((methyl(oxo)(propyl)-λ) 6 ethyl quinoline-4-carboxylate (A-5-Ca6)

[0184]

[0185] Using Ca6 (0.13 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as raw materials, the intermediate A-5-Ca6 was prepared according to the method of Example 10. After purification by preparative chromatography, 0.12 g of the yellow-green oily intermediate A-5-Ca6 was obtained, with a yield of 52.75%. MS m / z (ESI), [M+H] + 321.25.

[0186] Example 32 6-((methyl(oxo)(propyl)-λ) 6 -sulfonamide)amino)quinoline-4-carboxylic acid (A-Ca6)

[0187]

[0188] Using A-5-Ca6 (0.08 g, 0.25 mmol) as a starting material, a yellow solid containing the intermediate A-Ca6 was prepared according to the method of Example 11. This solid required no further purification and was used directly in the next reaction. MS m / z (ESI), [M+H] + 293.24.

[0189] Example 33(R)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((methyl(oxo)(propyl)-λ) 6 -Sulfanyl)amino)quinoline-4-carboxamide (DXY-a6)

[0190]

[0191] Using A-Ca6 (0.07 g, 0.24 mmol) and B (0.07 g, 0.33 mmol) as raw materials, the compound DXY-a6 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.03 g of a pale yellow solid was obtained, with a yield of 30%. MS m / z (ESI), [M+H] +446.36.1H NMR (400MHz, CDCl3) δ8.75(d,J=4.4Hz,1H),7.97(d,J=8.9Hz,1H),7.81(dd,J=5.3 ,2.7Hz,1H),7.50(dd,J=9.0,2.4Hz,1H),7.43(d,J=4.4Hz,1H),7.15(d,J=5.0Hz, 1H),5.23(dt,J=8.7,4.4Hz,1H),4.63(s,2H),4.49-4.25(m,2H),3.31(t,J=3.7Hz ,2H),3.12(d,J=3.7Hz,3H),2.06-1.87(m,2H),1.78(s,2H),1.08(t,J=7.4Hz,3H).

[0192] Example 34 Ethyl(imino)(methyl)-λ 6 -Thione (Ca7)

[0193]

[0194] The intermediate Ca7-1 (0.42 g, 5.51 mmol) was prepared according to the method of Example 9, using methyl ethyl sulfide (Ca7-1) as the starting material. Purification was performed by flash column chromatography (stationary phase: silica gel, developing solvent: petroleum ether: ethyl acetate = 15:1). 0.49 g of clear Ca7-1 intermediate was obtained, with a yield of 83.10%. MS m / z (ESI), [M+H] + 108.19.

[0195] Example 35 6-((ethyl(methyl)(oxo)-λ) 6 -Thioimino)amino)quinoline-4-carboxylic acid ethyl ester (A-5-Ca7)

[0196]

[0197] Using Ca7 (0.12 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as raw materials, the intermediate A-5-Ca7 was prepared according to the method of Example 10. After purification by preparative chromatography, 0.06 g of the yellow-green oily intermediate A-5-Ca7 was obtained, with a yield of 27.65%. MS m / z (ESI), [M+H] + 307.19.

[0198] Example 36 6-((ethyl(methyl)(oxo)-λ) 6 -Thioimino)amino)quinoline-4-carboxylic acid (A-Ca7)

[0199]

[0200] Using A-5-Ca7 (0.06 g, 0.19 mmol) as a starting material, a yellow solid containing the intermediate A-Ca7 was prepared according to the method of Example 11. This solid required no further purification and was used directly in the next reaction. MS m / z (ESI), [M+H] + 279.26.

[0201] Example 37 (R)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((ethyl(methyl)(oxo)-λ) 6 -Sulfanyl)amino)quinoline-4-carboxamide (DXY-a7)

[0202]

[0203] Using A-Ca7 (0.05 g, 0.18 mmol) and B (0.04 g, 0.22 mmol) as raw materials, the compound DXY-a7 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.02 g of a pale yellow solid was obtained, with a yield of 26%. MS m / z (ESI), [M+H] + 432.32. 1 H NMR (400MHz, CDCl3) δ8.71(d,J=4.3Hz,1H),7.96(d,J=9.0Hz,1H),7.82-7.77(m,1H),7.48(d,J=9.2Hz,1H),7.42(d,J=4.4Hz,1H),7.29(d,J=6.5Hz,1 H),5.21(dt,J=7.8,4.0Hz,1H),4.62(s,2H),4.45-4.26(m,2H),3.33(d,J= 7.5Hz,2H),3.30(d,J=6.0Hz,2H),3.10(s,3H),1.44(td,J=8.4,2.7Hz,3H).

[0204] Example 38: Ethyl(imino)(propyl-λ) 6 -Thione (Ca8)

[0205]

[0206] Using Ca8-1 (0.5 g, 4.80 mmol) as the starting material, the intermediate was prepared according to the method of Example 9 and purified by flash column chromatography (stationary phase: silica gel, developing solvent: petroleum ether: ethyl acetate = 15:1). 0.6 g of clear Ca8-1 intermediate was obtained, with a yield of 92.45%. MS m / z (ESI), [M+H] + 136.18.

[0207] Example 39 6-((ethyl(oxo)(propyl)-λ) 6 -Thioimino)amino)quinoline-4-carboxylic acid ethyl ester (A-5-Ca8)

[0208]

[0209] Using Ca8 (0.14 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as raw materials, the intermediate A-5-Ca8 was prepared according to the method of Example 10. After purification by preparative chromatography, 0.08 g of the yellow-green oily intermediate A-5-Ca8 was obtained, with a yield of 33.76%. MS m / z (ESI), [M+H] + 335.27.

[0210] Example 40 6-((ethyl(oxo)(propyl)-λ) 6 -Thioimino)amino)quinoline-4-carboxylic acid (A-Ca8)

[0211]

[0212] Using A-5-Ca8 (0.08 g, 0.24 mmol) as the starting material, a yellow solid containing the intermediate A-Ca8 was prepared according to the method of Example 11. No further purification was required, and it was directly used in the next reaction. MS m / z (ESI), [M+H] + 307.23.

[0213] Example 41(R)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((ethyl(oxo)(propyl)-λ) 6 -Thioimino)amino)quinoline-4-carboxamide (DXY-a8)

[0214]

[0215] Using A-Ca8 (0.07 g, 0.24 mmol) and B (0.06 g, 0.29 mmol) as raw materials, the compound DXY-a8 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.03 g of a pale yellow solid was obtained, with a yield of 27%. MS m / z (ESI), [M+H] +460.33.1H NMR (400MHz, CDCl3) δ8.75 (t, J=3.6Hz, 1H), 7.96 (dd, J=9.1, 2.5Hz, 1H), 7.82 (s, 1H), 7.5 3(dd,J=8.9,3.1Hz,1H),7.43(t,J=3.6Hz,1H),7.11(d,J=5.9Hz,1H),5.27(d,J=19.1Hz,1 H),4.64(d,J=2.5Hz,2H),4.51-4.25(m,2H),3.28(s,2H),3.25-3.16(m,2H),2.90(dd,J=3 0.4, 2.5Hz, 2H), 1.88 (d, J = 6.6Hz, 2H), 1.40 (td, J = 7.3, 3.4Hz, 3H), 1.05 (t, J = 7.6Hz, 3H).

[0216] Example 42 (2-hydroxyethyl)(imino)(methyl)-λ 6 -Thione (Ca9)

[0217]

[0218] Using 2-(methylthio)ethanol (Ca9-1) (0.5 g, 5.4 mmol) as the starting material, the intermediate was prepared according to the method of Example 9 and purified by flash column chromatography (stationary phase: silica gel, developing solvent: petroleum ether: ethyl acetate = 15:1). 0.6 g of clear Ca9 oil was obtained, with a yield of 90.23%. MS m / z (ESI), [M+H] + 124.14.

[0219] Example 43 6-(((2-hydroxyethyl)(methyl)(oxo)-λ 6 ethyl quinoline-4-carboxylate (A-5-Ca9)

[0220]

[0221] Using Ca9 (0.13 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as raw materials, the intermediate A-5-Ca9 was prepared according to the method of Example 10. After purification by preparative chromatography, 0.03 g of the yellow-green oily intermediate A-5-Ca9 was obtained, with a yield of 33.76%. MS m / z (ESI), [M+H]+323.20.

[0222] Example 44 6-(((2-hydroxyethyl)(methyl)(oxo)-λ 6 -sulfonamide)amino)quinoline-4-carboxylic acid (A-Ca9)

[0223]

[0224] Using A-5-Ca9 (0.03 g, 0.09 mmol) as a starting material, a yellow solid containing the intermediate A-Ca9 was prepared according to the method of Example 11. This solid required no further purification and was used directly in the next reaction. MS m / z (ESI), [M+H] + 295.05.

[0225] Example 45(R)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(((2-hydroxyethyl)(methyl)(oxo)-λ) 6 -sulfoxide)amino)quinoline-4-carboxamide (DXY-a9)

[0226]

[0227] Using A-Ca9 (0.03 g, 0.1 mmol) and B (0.03 g, 0.12 mmol) as raw materials, the compound DXY-a9 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 1 mg of a pale yellow solid was obtained, with a yield of 2.25%. MS m / z (ESI), [M+H] + 448.30.

[0228] Example 46 Cyclopropyl (thiomorpholino) methyl ketone (Cb1-2)

[0229]

[0230] Thiomorpholine (Cb1-1) (0.6 g, 5.82 mmol) and DIPEA (1.5 g, 11.64 mmol) were added to a reaction flask, dissolved in 18 mL of toluene. The reaction system was transferred to a low-temperature (constant temperature) stirred reaction bath, cooled to -20 °C, and stirred at this temperature for 2 h. Then, cyclopropylformyl chloride (0.67 g, 6.4 mmol) was slowly added dropwise to the reaction system over 20 min. After the addition was complete, stirring was continued at this temperature for 1 h, followed by stirring at room temperature for 1 h. The reaction endpoint was monitored by thin-layer chromatography. One volume of water was added for dilution, and the mixed phase (20 mL x 3) was extracted with dichloromethane. The combined phases were washed with saturated brine (5 mL) and dried over anhydrous magnesium sulfate (3 g). The mixture was filtered under reduced pressure and concentrated to obtain a crude colorless oil. The crude product was purified by flash column chromatography (stationary phase: silica gel, developing solvent: petroleum ether: ethyl acetate = 12:1). 0.91 g of the intermediate Cb1-2 transparent oil was obtained, with a yield of 91.37%. MSm / z(ESI),[M+H) + 172.24.

[0231] Example 47 Cyclopropyl (1-imino-1-oxo-1λ) 6-Thiomorpholine)methyl ketone (Cb1)

[0232]

[0233] Using Cb1-2 (0.91 g, 5.31 mmol) as the starting material, the intermediate was prepared according to the method of Example 9 and purified by flash column chromatography (stationary phase: silica gel, developing solvent: dichloromethane: methanol = 50:1). 1.1 g of colorless solid Cb1 was obtained, with a yield of 99%. MS m / z (ESI), [M+H] + 203.20.

[0234] Example 48 6-((4-(cyclopropanecarbonyl)-1-oxidation-1λ) 6 -Thiomorpholine-1-methylene)amino)quinoline-4-carboxylic acid ethyl ester (A-5-Cb1)

[0235]

[0236] Using Cb1 (0.22 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as raw materials, the intermediate A-5-Cb1 was prepared according to the method of Example 10. After purification by preparative chromatography, 0.07 g of yellow-green oil was obtained, with a yield of 24.56%. MS m / z (ESI), [M+H] + 402.29.

[0237] Example 49 6-((4-(cyclopropanecarbonyl)-1-oxidation-1λ) 6 -Thiomorpholine-1-methylenedimethylamino)quinoline-4-carboxylic acid (A-Cb1)

[0238]

[0239] Using A-5-Cb1 (0.07 g, 0.17 mmol) as the starting material, a white solid containing intermediate A-Cb1 was prepared according to the method of Example 11. No further purification was required, and it was directly used in the next reaction. MS m / z (ESI), [M+H]+374.26.

[0240] Example 50(R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((4-(cyclopropanecarbonyl)-1-oxo-1λ) 6 -Thiomorpholine-1-methylenedimethylamino)quinoline-4-carboxamide (DXY-b1)

[0241]

[0242] Using A-Cb1 (0.06 g, 0.16 mmol) and B (0.04 g, 0.19 mmol) as starting materials, the compound DXY-b1 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.03 g of a white solid was obtained, with a yield of 37%. MS m / z (ESI), [M+H] + 527.39. 1 H NMR (400MHz, CDCl3) δ8.75 (d, J=4.4Hz, 1H), 7.97 (dd, J=9.1, 2.0Hz, 1H), 7.85 (s, 1H ),7.55-7.47(m,1H),7.43(d,J=4.6Hz,1H),7.29(d,J=5.3Hz,1H),5.20(s,1H),4.6 3(s,2H),4.36(dd,J=36.4,5.1Hz,4H),4.06-3.69(m,2H),3.59-3.41(m,2H),3.31( dt,J=5.4,2.4Hz,2H),3.29-3.13(m,2H),0.98(p,J=3.1Hz,2H),0.85-0.80(m,2H). 13 C NMR (101MHz, CDCl3) δ172.61,167.87,166.78,147.74,145.50,144.46,139.33,131.18,128.98,125 .51,119.39,116.79,114.85,51.34,51.21,50.15,47.80,44.07,42.64,40.91,33.76,11.08,8.18.

[0243] Example 51 1-Thiomorpholine ethanol-1-one (Cb2-1)

[0244]

[0245] The intermediate Cb2-1 was prepared by replacing cyclopropylformyl chloride with formyl chloride, following the method of Example 46, and purified by flash column chromatography (stationary phase: silica gel, developing solvent: petroleum ether: ethyl acetate = 12:1). 0.76 g of clear oil was obtained, with a yield of 90%. MS m / z (ESI), [M+H] + 146.18.

[0246] Example 52 1-(1-imino-1-oxo-1λ6-thiomorpholino)acetyl-1-one (Cb2)

[0247]

[0248] Using Cb2-1 (0.76 g, 5.24 mmol) as the starting material, the preparation was carried out according to the method of Example 9, and purified by flash column chromatography (stationary phase: silica gel, developing solvent: dichloromethane: methanol = 50:1). 0.83 g of colorless solid Cb2 intermediate was obtained, with a yield of 90%. MS m / z (ESI), [M+H] + 177.20.

[0249] Example 53: 6-((4-acetyl-1-oxo-1λ6-thiomorpholine-1-ylidene)amino)quinoline-4-carboxylic acid ethyl ester (A-5-Cb2)

[0250]

[0251] Using Cb2 (0.19 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as raw materials, the intermediate A-5-Cb2 was prepared according to the method of Example 10. After purification by preparative chromatography, 0.22 g of the yellow-green oil was obtained, with a yield of 81.48%. MS m / z (ESI), [M+H] + 376.29.

[0252] Example 54 6-((4-acetyl-1-oxo-1λ6-thiomorpholine-1-ylidene)amino)quinoline-4-carboxylic acid (A-Cb2)

[0253]

[0254] Using A-5-Cb2 (0.22 g, 0.59 mmol) as a starting material, a white solid containing the intermediate A-Cb2 was prepared according to the method of Example 11. No further purification was required, and it was directly used in the next reaction. MS m / z (ESI), [M+H) + 348.29.

[0255] Example 55(R)-6-((4-acetyl-1-tetrahydro-2H-λ) 6 (-thiam-1-yl)amino)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide (DXY-b2)

[0256]

[0257] Using A-Cb2 (0.09 g, 0.26 mmol) and B (0.05 g, 0.26 mmol) as raw materials, the compound DXY-b1 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.02 g of a white solid was obtained, with a yield of 15.38%. MS m / z (ESI), [M+H] + 501.29.1 H NMR (400MHz, CDCl3) δ8.81-8.75(m,1H),7.99(d,J=9.0Hz,1H),7.86(d,J=15.4H z,1H),7.56-7.47(m,1H),7.44(d,J=5.0Hz,1H),7.22(d,J=5.4Hz,1H),5.21(d,J =11.1Hz,1H),4.64(d,J=3.8Hz,2H),4.55-4.18(m,4H),3.94(dd,J=48.9,12.7H z,2H),3.45(d,J=18.3Hz,2H),3.32(s,1H),3.24(q,J=11.9Hz,2H),2.14(s,3H).

[0258] Example 56 (2-methoxyethyl)(methyl)thion (Cc1-2)

[0259]

[0260] Under an ice-water bath and nitrogen protection, sodium hydride (0.37 g, 15.38 mmol) was added to a reaction flask containing 10 mL of anhydrous tetrahydrofuran. Mercaptoethanol (Ccl-1) (1.0 g, 12.82 mmol) was then added, and the mixture was stirred in an ice-water bath for 0.5 h. Iodomethane (9.10 g, 64.10 mmol) was then slowly added dropwise. After the addition was complete, the reaction system was transferred to room temperature and stirred for 5 h. Thin-layer chromatography showed product formation. The reaction system was then transferred to an ice-water bath, quenched with one volume of water, and the mixed phase was extracted with dichloromethane (10 mL x 3). The extracts were combined, washed with saturated brine (3 mL), and dried over anhydrous magnesium sulfate (2 g). The solution was filtered under reduced pressure to obtain a dichloromethane solution containing intermediate Ccl-2, which was used directly in the next reaction without further purification.

[0261] Example 57 Imino(2-methoxyethyl)(methyl)-λ6-thione (Cc1)

[0262]

[0263] Using Cc1-2 (1.16 g, 10.89 mmol) as the starting material, the preparation was carried out according to the method of Example 9, and purified by flash column chromatography (stationary phase: silica gel, developing solvent: dichloromethane: methanol = 50:1). 1.34 g of intermediate Cc1 transparent oil was obtained, with a yield of 90%. MS m / z (ESI), [M+H] + 138.25.

[0264] Example 58: 6-(((2-methoxyethyl)(methyl)(oxo)-λ6-sulfonamide)amino)quinoline-4-carboxylic acid ethyl ester (A-5-Ccl)

[0265]

[0266] Using Cc1 (0.15 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as starting materials, the intermediate A-5-Cc1 was prepared according to the method of Example 10. After purification by preparative chromatography, 0.03 g of yellow-green oil was obtained, with a yield of 12.61%. MS m / z (ESI), [M+H] + 337.28.

[0267] Example 59 6-(((2-methoxyethyl)(methyl)(oxo)-λ 6 -Sulfanyl)amino)quinoline-4-carboxylic acid (A-Cc1)

[0268]

[0269] Using A-5-Cc1 (0.03 g, 0.09 mmol) as a starting material, a white solid containing intermediate A-Cc1 was prepared according to the method of Example 11. This solid required no further purification and was used directly in the next reaction. MS m / z (ESI), [M+H] + 309.22.

[0270] Example 60(R)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-(((2-methoxyethyl)(methyl)(oxo)-λ) 6 (-sulfoxide)amino)quinoline-4-carboxamide (DXY-c1)

[0271]

[0272] Using A-Cc1 (0.03 g, 0.09 mmol) and B (0.02 g, 0.11 mmol) as starting materials, the compound DXY-c1 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.02 g of a white solid was obtained, with a yield of 48.19%. MS m / z (ESI), [M+H] + 462.29. 1H NMR (400MHz, CDCl3) δ8.75(d,J=4.4Hz,1H),7.97(d,J=9.0Hz,1H),7.80(d,J= 3.0Hz,1H),7.49(d,J=9.1Hz,1H),7.42(d,J=4.4Hz,1H),7.17(d,J=4.9Hz,1H) ,5.23(t,J=4.6Hz,1H),4.63(s,2H),4.48-4.23(m,2H),3.82(dq,J=6.4,3.6H z,2H),3.52(q,J=5.5Hz,2H),3.38(s,3H),3.31(d,J=5.9Hz,2H),3.22(s,3H).

[0273] Example 61: Ethyl (2-methoxyethyl) sulfide (Cc2-2)

[0274]

[0275] The dichloromethane solution containing intermediate Cc2-2 was prepared by replacing mercaptoethanol (Cc1-1) with 2-(ethylthio)ethanol (Cc2-1) using the method of Example 56. No further purification was required, and it was directly used in the next reaction.

[0276] Example 62: Ethyl(imino)(2-methoxyethyl)-λ 6 -Thione (Cc2)

[0277]

[0278] Using ethyl (2-methoxyethyl) thioether (Cc2-2) (0.72 g, 6.0 mmol) as the starting material, it was prepared according to the method of Example 9, and purified by flash column chromatography (stationary phase: silica gel, developing solvent: dichloromethane: methanol = 50:1). 0.79 g of intermediate Cc2 transparent oil was obtained, with a yield of 90%. MS m / z (ESI), [M+H] + 152.14.

[0279] Example 63 6-(((2-methoxyethyl)(oxo)-λ 6 (-Sulfanamide group)amino)quinoline-4-carboxylic acid ethyl ester (A-5-Cc2)

[0280]

[0281] Using Cc2 (0.15 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as starting materials, the intermediate A-5-Cc1 was prepared according to the method of Example 10. After purification by preparative chromatography, 0.11 g of yellow-green oil was obtained, with a yield of 44.35%. MS m / z (ESI), [M+H] + 351.29.

[0282] Example 64 6-(((2-methoxyethyl)(oxo)-λ 6 -sulfinamide group)amino)quinoline-4-carboxylic acid (A-Cc2)

[0283]

[0284] Using A-5-Cc1 (0.11 g, 0.32 mmol) as the starting material, a yellow solid containing intermediate A-Cc2 was prepared according to the method of Example 11. This solid required no further purification and was used directly in the next reaction. MS m / z (ESI), [M+H] + 323.28.

[0285] Example 65(R)-N-(2-((R)-4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((ethyl(2-methoxyethyl)(oxo)-λ) 6 -Sulfanyl)amino)quinoline-4-carboxamide (DXY-c2)

[0286]

[0287] Using A-Cc2 (0.1 g, 0.31 mmol) and B (0.08 g, 0.38 mmol) as starting materials, the compound DXY-c2 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.05 g of a white solid was obtained, with a yield of 34.01%. MS m / z (ESI), [M+H] + 476.32. 1H NMR (400MHz, CDCl3) δ8.70(d,J=4.5Hz,1H),7.98(d,J=9.0Hz,1H),7.82(d,J=7.1Hz,1 H),7.56-7.49(m,1H),7.47-7.42(m,1H),7.22(s,1H),5.31-5.23(m,1H),4.64(s,2H) ,4.38(ddt,J=53.7,13.9,6.2Hz,2H),3.78(dp,J=13.6,7.3Hz,2H),3.47(t,J=5.9Hz, 2H),3.44-3.37(m,2H),3.36(s,3H),3.32(d,J=6.9Hz,2H),1.43(t,J=7.3Hz,3H).13C NMR (101MHz, CDCl3) δ167.91,166.72,147.47,145.45,139.26,130.98,129.12,125.55,119. 24,116.71,114.52,114.45,66.91,59.19,54.13,53.87,50.08,47.74,42.99,42.66,33.79.

[0288] Example 66: 4-(tetrahydro-2H-thiopyran-4-yl)morpholine (Cd1-2)

[0289]

[0290] Tetrahydrothiaran-4-one (Cd1-1) (1.5 g, 12.9 mmol) and morpholine (2.25 g, 25.8 mmol) were added to a reaction flask, dissolved in 20 mL of dichloromethane, and 0.1 times the volume of acetic acid was added. The mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (5.46 g, 25.8 mmol) was added in portions to the reaction system, and the reaction was carried out overnight at room temperature. The reaction endpoint was determined by thin-layer chromatography. The mixture was quenched with 20 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (20 mL x 3), and the combined phases were washed with saturated brine (5 mL) and dried over anhydrous magnesium sulfate (3 g). The mixture was filtered under reduced pressure and concentrated under reduced pressure to obtain a crude, transparent oily product. Purification was achieved by column chromatography (stationary phase: basic alumina, developing solvent: dichloromethane: methanol = 30:1). 2.19 g of the intermediate Cd1-2 transparent oily product was obtained, with a yield of 90.50%. MSm / z(ESI),[M+H]+188.11.

[0291] Example 67 1-Imine-4-morpholinohexahydro-1λ 6 -Thiaran-1-oxide (Cd1)

[0292]

[0293] Using Cd1-2 (2.19 g, 11.21 mmol) as the starting material, the preparation was carried out according to the method of Example 9, and purified by flash column chromatography (stationary phase: silica gel, developing solvent: dichloromethane: methanol = 50:1). 1.16 g of the intermediate Cd1 transparent oil was obtained, with a yield of 47.35%. MS m / z (ESI), [M+H] + 219.22.

[0294] Example 68 6-((4-morpholino-1-tetrahydro-2H-λ) 6 ethyl quinoline-4-carboxylate (A-5-Cd1)-1-thiam-1-yl)amino)quinoline-4-carboxylate

[0295]

[0296] Using Cd1 (0.35 g, 1.61 mmol) and A-4 (0.3 g, 1.07 mmol) as raw materials, the intermediate A-5-Cd1 was prepared according to the method of Example 10. After purification by preparative chromatography, 0.25 g of yellow-green oil was obtained, with a yield of 56.07%. MS m / z (ESI), [M+H] + 418.26.

[0297] Example 69 6-((4-morpholino-1-tetrahydro-2H-λ) 6 (-Thinan-1-yl)amino)quinoline-4-carboxylic acid (A-Cd1)

[0298]

[0299] Using A-5-Cd1 (0.25 g, 0.60 mmol) as the starting material, a yellow solid containing the intermediate A-Cd1 was prepared according to the method of Example 11. No further purification was required, and it was directly used in the next reaction. MS m / z (ESI), [M+H] + 390.29.

[0300] Example 70(R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((4-morpholino-1-tetrahydro-2H-λ) 6 (-thiaran-1-yl)amino)quinoline-4-carboxamide (DXY-d1)

[0301]

[0302] Using A-Cd1 (0.23 g, 0.58 mmol) and B (0.14 g, 0.7 mmol) as raw materials, the compound DXY-d1 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.09 g of a pale yellow solid was obtained, with a yield of 28.19%. MS m / z (ESI), [M+H] + 543.38. 1 H NMR (400MHz, CDCl3) δ8.76(d,J=4.4Hz,1H),8.00(d,J=8.9Hz,1H),7.87(s,1H),7.52(t,J=9.3Hz,1H) ,7.45(d,J=4.3Hz,1H),7.06(dt,J=14.9,8.2Hz,1H),5.31-5.23(m,1H),4.66(s,2H),4.39(ddd,J=85 .7,17.3,5.0Hz,2H),3.51(d,J=13.8Hz,2H),3.37-3.19(m,2H),3.05(q,J=13.7Hz,2H),2.68(s,4H), 2.52(t,J=11.2Hz,4H), 2.40(d,J=18.6Hz,1H), 2.17(q,J=11.9Hz,2H), 1.85(dd,J=87.1,9.3Hz,2H).

[0303] Example 71 1-Methyl-4-(tetrahydro-2H-thiaran-4-yl)piperazine (Cd2-1)

[0304]

[0305] The intermediate Cd2-1 was prepared according to the method of Example 66, replacing morpholine with N-methylpiperazine. Purification was performed by column chromatography (stationary phase: basic alumina, developing solvent: dichloromethane:methanol = 30:1). 1.81 g of the intermediate Cd2-1 white solid was given, yield 70.15%. MS m / z (ESI), [M+H] + 201.05.

[0306] Example 72 1-Imin-4-(4-methylpiperazin-1-yl)hexahydro-1λ 6 -Thiaran-1-oxide (Cd2)

[0307]

[0308] Using 1-methyl-4-(tetrahydro-2H-thiaran-4-yl)piperazine (Cd2-2) (1.81 g, 9.03 mmol) as the starting material, it was prepared according to the method of Example 9, and purified by flash column chromatography (stationary phase: silica gel, developing solvent: dichloromethane:methanol = 50:1). 1.16 g of the intermediate Cd2 (brownish-yellow solid) was obtained, with a yield of 55.5%. MS m / z (ESI), [M+H] + 232.22.

[0309] Example 73 6-((4-(4-methylpiperazin-1-yl)-1-tetrahydro-2H-λ) 6 ethyl quinoline-4-carboxylate (A-5-Cd2) (1-thiam-1-yl)amino)quinoline-4-carboxylate

[0310]

[0311] Using Cd2 (0.25 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as raw materials, the intermediate A-5-Cd2 yellow-green oil was prepared according to the method of Example 10. After purification by preparative chromatography, 0.17 g of intermediate A-5-Cd2 yellow-green oil was obtained, with a yield of 56.60%. MS m / z (ESI), [M+H] + 431.37.

[0312] Example 74 6-((4-(4-methylpiperazin-1-yl)-1-tetrahydro-2H-λ) 6 (-Thinan-1-yl)amino)quinoline-4-carboxylic acid (A-Cd2)

[0313]

[0314] Using A-5-Cd2 (0.17 g, 0.39 mmol) as the starting material, a yellow solid containing the intermediate A-Cd2 was prepared according to the method of Example 11. No further purification was required, and it was directly used in the next reaction. MS m / z (ESI), [M+H] + 403.28.

[0315] Example 75(R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((4-(4-methylpiperazin-1-yl)-1-tetrahydro-2H-λ) 6 (-thiaran-1-yl)amino)quinoline-4-carboxamide (DXY-d2)

[0316]

[0317] Using A-Cd2 (0.14 g, 0.35 mmol) and B (0.09 g, 0.42 mmol) as raw materials, the compound DXY-d2 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.05 g of a pale yellow solid was obtained, with a yield of 28%. MS m / z (ESI), [M+H] + 556.40. 1 H NMR (400MHz, CDCl3) δ8.76(d,J=4.4Hz,1H),8.00(d,J=8.9Hz,1H),7.87(s,1H),7.52(t,J=9.3Hz,1H) ,7.45(d,J=4.3Hz,1H),7.06(dt,J=14.9,8.2Hz,1H),5.31-5.23(m,1H),4.66(s,2H),4.39(ddd,J=85. 7,17.3,5.0Hz,2H),3.51(d,J=13.8Hz,2H),3.37-3.19(m,2H),3.05(q,J=13.7Hz,2H),2.68(s,4H),2 .52(t,J=11.2Hz,4H),2.46(s,3H),2.38(s,1H),2.17(q,J=11.9Hz,2H),1.85(dd,J=87.1,9.3Hz,2H).

[0318] Example 76: N,N-dipropyltetrahydro-2H-thiaran-4-amine (Cd3-1)

[0319]

[0320] Morpholine was replaced with dipropylamine and prepared according to the method of Example 66. Purification was performed by column chromatography (stationary phase: basic alumina, developing solvent: dichloromethane:methanol = 30:1). 1.12 g of the pale yellow solid intermediate Cd3-1 was given, in 64.7% yield. MS m / z (ESI), [M+H] + 202.15.

[0321] Example 77 4-(dipropylamino)-1-iminohexahydro-1λ 6 -Thiaran-1-oxide (Cd3)

[0322]

[0323] Using Cd3-1 (1.12 g, 5.46 mmol) as the starting material, the preparation was carried out according to the method of Example 9, and purified by flash column chromatography (stationary phase: silica gel, developing solvent: dichloromethane: methanol = 50:1). 0.76 g of intermediate Cd3 yellow oil was obtained, with a yield of 59.84%. MS m / z (ESI), [M+H]+ 233.25.

[0324] Example 78: 6-((4-(dipropylamino)-1-tetrahydro-2H-λ6-thiaran-1-yl)amino)quinoline-4-carboxylic acid ethyl ester (A-5-Cd3)

[0325]

[0326] Using Cd3 (0.25 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as raw materials, the intermediate A-5-Cd3 yellow-green oil was prepared according to the method of Example 10. After purification by preparative chromatography, 0.13 g of intermediate A-5-Cd3 yellow-green oil was obtained, with a yield of 43.33%. MS m / z (ESI), [M+H] + 432.39.

[0327] Example 79 6-((4-(dipropylamino)-1-tetrahydro-2H-λ oxide) 6 (-Thinan-1-yl)amino)quinoline-4-carboxylic acid (A-Cd3)

[0328]

[0329] Using A-5-Cd3 (0.13 g, 0.30 mmol) as a starting material, a yellow solid containing the intermediate A-Cd3 was prepared according to the method of Example 11. No further purification was required, and it was directly used in the next reaction. MS m / z (ESI), [M+H] + 404.31.

[0330] Example 80(R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((4-(dipropylamino)-1-tetrahydro-2H-λ6-thiaran-1-yl)amino)quinoline-4-carboxamide (DXY-d3)

[0331]

[0332] Using A-Cd3 (0.11 g, 0.27 mmol) and B (0.07 g, 0.32 mmol) as raw materials, the compound DXY-d3 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.04 g of a pale yellow solid was obtained, with a yield of 28%. MS m / z (ESI), [M+H] + 557.46. 1H NMR (400MHz, CDCl3) δ8.77-8.74(m,1H),8.00(dd,J=9.0,1.7Hz,1H),7.83(d,J=2.2Hz,1H),7.52(dt,J=9. 1,2.2Hz,1H),7.44(d,J=4.4Hz,1H),7.20(d,J=9.9Hz,1H),5.26(d,J=4.8Hz,1H),4.64(s,2H),4.38(ddd,J =61.9,17.5,4.7Hz,2H),3.74-3.62(m,2H),3.32(d,J=6.2Hz,2H),3.11(d,J=10.2Hz,2H),2.77(d,J=11.1 Hz,1H),2.37(d,J=14.9Hz,4H),2.04(d,J=13.7Hz,4H),1.40(q,J=7.3Hz,4H),0.86(td,J=7.3,1.7Hz,6H). 13 C NMR (101MHz, CDCl3) δ167.80,166.62,147.24,145.29,139.05,130.99,129.13,125.52,119.15,116.65,113. 81,56.75,55.04,52.94,52.49,49.99,49.88,49.41,47.63,42.56,33.68,26.52,26.22,26.16,21.98,11.76.

[0333] Example 81: N-Isopropyl-N-methyltetrahydro-2H-thiaran-4-amine (Cd4-1)

[0334]

[0335] The intermediate Cd₄⁻ was prepared according to the method of Example 66, replacing morpholine with N-methylisopropylamine. Purification was performed by column chromatography (stationary phase: basic alumina, developing solvent: dichloromethane:methanol = 30:1). 1.49 g of the intermediate Cd₄⁻ was given as a white solid, yield 89.24%. MS m / z (ESI), [M+H] + 174.08.

[0336] Example 82 1-Imine-4-(isopropyl(methyl)amino)hexahydro-1λ 6 -Thiaran-1-oxide (Cd4)

[0337]

[0338] Using Cd4-1 (1.33 g, 7.67 mmol) as the starting material, the preparation was carried out according to the method of Example 9, and purified by flash column chromatography (stationary phase: silica gel, developing solvent: dichloromethane: methanol = 50:1). 0.82 g of the intermediate Cd4- (brownish-yellow solid) was obtained, with a yield of 52.5%. MS m / z (ESI), [M+H]+205.20.

[0339] Example 83 6-((4-(isopropyl(methyl)amino)-1-tetrahydro-2H-λ) 6 ethyl quinoline-4-carboxylate (A-5-Cd4)-1-ylthionylaminoquinoline-4-carboxylate

[0340]

[0341] Using Cd4 (0.22 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as raw materials, the intermediate A-5-Cd4 yellow-green oil was prepared according to the method of Example 10. After purification by preparative chromatography, 0.11 g of intermediate A-5-Cd4 yellow-green oil was obtained, with a yield of 38.46%. MS m / z (ESI), [M+H] + 404.35.

[0342] Example 84 6-((4-(isopropyl(methyl)amino)-1-tetrahydro-2H-λ) 6 (-Thiaran-1-yl)amino)quinoline-4-carboxylic acid (A-Cd4)

[0343]

[0344] Using A-5-Cd4 (0.11 g, 0.27 mmol) as the starting material, a yellow solid containing the intermediate A-Cd4 was prepared according to the method of Example 11. No further purification was required, and it was directly used in the next reaction. MS m / z (ESI), [M+H] + 376.31.

[0345] Example 85(R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((4-(isopropyl(methyl)amino)-1-tetrahydro-2H-λ) 6 (-Thinan-1-yl)amino)quinoline-4-carboxamide (DXY-d4)

[0346]

[0347] Using A-Cd4 (0.1 g, 0.27 mmol) and B (0.07 g, 0.32 mmol) as raw materials, the compound DXY-d4 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.04 g of a pale yellow solid was obtained, with a yield of 28%. MS m / z (ESI), [M+H] + 529.42. 1 H NMR (400MHz, CDCl3) δ8.75(d,J=4.3Hz,1H),7.99(d,J=9.0Hz,1H),7.83(s,1H),7.53(dd,J=8.7,2.3Hz,1H ),7.44(d,J=4.4Hz,1H),7.15(d,J=5.0Hz,1H),5.26(t,J=4.8Hz,1H),4.65(s,2H),4.39(ddd,J=62.6,17.4 ,4.8Hz,2H),3.60(dt,J=15.9,7.9Hz,2H),3.32(d,J=5.9Hz,2H),3.17(dd,J=12.8,8.0Hz,2H),2.96(h,J= 6.8Hz,1H),2.81(t,J=8.2Hz,1H),2.24(t,J=11.5Hz,2H),2.18(s,3H),2.10(s,2H),1.02(d,J=6.4Hz,6H).

[0348] Example 86: N,N-diethyltetrahydro-2H-thiaran-4-amine (Cd5-1)

[0349]

[0350] Morpholine was replaced with diethylamine and prepared according to the method of Example 66. Purification was performed by column chromatography (stationary phase: basic alumina, developing solvent: dichloromethane:methanol = 30:1). 0.6 g of intermediate Cd5-1 clear oil was obtained, yield 40.27%. MS m / z (ESI), [M+H] + 174.16.

[0351] Example 87 4-(diethylamino)-1-iminohexahydro-1λ 6 -Thiaran-1-oxide (Cd5)

[0352]

[0353] Using Cd5-1 (0.6 g, 3.46 mmol) as the starting material, the intermediate was prepared according to the method of Example 9 and purified by flash column chromatography (stationary phase: silica gel, developing solvent: dichloromethane: methanol = 50:1). 0.4 g of a pale yellow solid Cd5 was obtained, with a yield of 56.66%. MS m / z (ESI), [M+H] + 205.17.

[0354] Example 88 6-((4-(diethylamino)-1-tetrahydro-2H-λ oxide) 6 ethyl quinoline-4-carboxylate (A-5-Cd5) (1-thiam-1-yl)amino)quinoline-4-carboxylate

[0355]

[0356] Using Cd5 (0.22 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as raw materials, the intermediate A-5-Cd5 yellow-green oil was prepared according to the method of Example 10. After purification by preparative chromatography, 0.13 g of intermediate A-5-Cd5 yellow-green oil was obtained, with a yield of 45.45%. MS m / z (ESI), [M+H] + 404.32.

[0357] Example 89 6-((4-(diethylamino)-1-tetrahydro-2H-λ oxide) 6 (-Thiaran-1-yl)amino)quinoline-4-carboxylic acid (A-Cd5)

[0358]

[0359] Using A-5-Cd5 (0.13 g, 0.32 mmol) as the starting material, a yellow solid containing the intermediate A-Cd5 was prepared according to the method of Example 11. No further purification was required, and it was directly used in the next reaction. MS m / z (ESI), [M+H] + 376.28.

[0360] Example 90(R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((4-(diethylamino)-1-tetrahydro-2H-λ) 6 (-Thinan-1-yl)amino)quinoline-4-carboxamide (DXY-d5)

[0361]

[0362] Using A-Cd5 (0.11 g, 0.30 mmol) and B (0.08 g, 0.36 mmol) as raw materials, the compound DXY-d5 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.04 g of a pale yellow solid was obtained, with a yield of 28%. MS m / z (ESI), [M+H] + 529.41. 1 H NMR (400MHz, CDCl3) δ8.77-8.74(m,1H),8.00(dd,J=9.0,1.7Hz,1H),7.83(d,J=2.2Hz,1H),7.52(dt ,J=9.1,2.2Hz,1H),7.44(d,J=4.4Hz,1H),7.20(d,J=9.9Hz,1H),5.26(d,J=4.8Hz,1H),4.64(s,2H), 4.38(ddd,J=61.9,17.5,4.7Hz,2H),3.74-3.62(m,2H),3.32(d,J=6.2Hz,2H),3.11(d,J=10.2Hz,2H ),2.77(d,J=11.1Hz,1H),2.37(d,J=14.9Hz,4H),1.40(q,J=7.3Hz,4H),0.86(td,J=7.3,1.7Hz,6H).

[0363] Example 91: N,N-dimethyltetrahydro-2H-thiaran-4-amine (Cd6-1)

[0364]

[0365] Tetrahydrothiaran-4-one (Cd1-1) (1.5 g, 12.9 mmol) was added to a reaction flask containing 20 mL of dichloromethane, followed by 4 mL of dimethylamine aqueous solution. The mixture was stirred at room temperature for 2 h. The reaction endpoint was determined by thin-layer chromatography. LC-MS detected the target intermediate dimethyl(tetrahydro-4H-thiaran-4-yl)-λ. 4The molecular weight of the azane was determined, and the reaction was successful. The organic phase was separated, dried with 1 g of anhydrous magnesium sulfate, and filtered under reduced pressure. 0.1 eq of acetic acid was added to the filtrate, and the mixture was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (3.64 g, 17.2 mmol) was added in portions to the reaction system, and the reaction was carried out overnight at room temperature. The endpoint was determined by thin-layer chromatography. The reaction was quenched with 20 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (20 mL x 3), and the combined organic phases were washed with saturated brine (5 mL) and dried with anhydrous magnesium sulfate (3 g). The mixture was filtered under reduced pressure and concentrated to obtain a crude transparent oil. The crude product was purified by column chromatography (stationary phase: basic alumina, developing solvent: dichloromethane: methanol = 30:1). 0.8 g of the intermediate N,N-dimethyltetrahydro-2H-thiaran-4-amine (Cd6-1) transparent oil was obtained, with a yield of 64.01%. MS m / z (ESI), [M+H] + 145.22.MSm / z(ESI),[M+H] + 146.18.

[0366] Example 92 4-(dimethylamino)-1-iminohexahydro-1λ 6 -Thiaran-1-oxide (Cd6)

[0367]

[0368] Using Cd6-1 (0.8 g, 5.52 mmol) as the starting material, the intermediate was prepared according to the method of Example 9 and purified by flash column chromatography (stationary phase: silica gel, developing solvent: dichloromethane: methanol = 50:1). 0.25 g of colorless Cd6 solid was obtained, with a yield of 25.77%. MS m / z (ESI), [M+H] + 177.20.

[0369] Example 93 6-((4-(dimethylamino)-1-tetrahydro-2H-λ oxide) 6 ethyl quinoline-4-carboxylate (A-5-Cd6) (1-thiam-1-yl)amino)quinoline-4-carboxylate

[0370]

[0371] Using Cd5 (0.19 g, 1.07 mmol) and A-4 (0.2 g, 0.71 mmol) as raw materials, the intermediate A-5-Cd6 yellow-green oil was prepared according to the method of Example 10. After purification by preparative chromatography, 0.14 g of intermediate A-5-Cd6 yellow-green oil was obtained, with a yield of 52.63%. MS m / z (ESI), [M+H]+376.29.

[0372] Example 94 6-((4-(dimethylamino)-1-tetrahydro-2H-λ oxide) 6(-thiam-1-yl)amino)quinoline-4-carboxylic acid (A-Cd6)

[0373]

[0374] Using A-5-Cd6 (0.14 g, 0.37 mmol) as the starting material, a yellow solid containing the intermediate A-Cd6 was prepared according to the method of Example 11. No further purification was required, and it was directly used in the next reaction. MS m / z (ESI), [M+H] + 348.32.

[0375] Example 95(R)-N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)-6-((4-(dimethylamino)-1-tetrahydro-2H-λ) 6 (-thiaran-1-yl)amino)quinoline-4-carboxamide (DXY-d6)

[0376]

[0377] Using A-Cd6 (0.13 g, 0.37 mmol) and B (0.09 g, 0.45 mmol) as raw materials, the compound DXY-d6 was prepared according to the method of Example 12. After purification by preparative chromatography and freeze-drying, 0.04 g of a pale yellow solid was obtained, with a yield of 28%. MS m / z (ESI), [M+H] + 501.41. 1 H NMR(400MHz, CDCl3) δ8.74(d,J=3.7Hz,1H),7.98(dd,J=9.0,2.8Hz,1H),7.84(s, 1H),7.58(d,J=7.9Hz,1H),7.43(s,1H),7.25(s,1H),5.31-5.23(m,1H),4.64(d, J=2.7Hz,2H),4.50-4.39(m,1H),4.31-4.28(m,1H),3.62(d,J=13.6Hz,2H),3.36 -3.24(m,4H),3.24-3.10(m,4H),3.01(d,J=7.9Hz,1H),2.68(s,3H),2.15(s,3H).

[0378] Example 96: Enzyme inhibitory activity test of FAP small molecule inhibitor

[0379] This embodiment uses FAP fluorescence intensity analysis to detect the enzyme inhibitory activity of a subset of compounds (18 in total, including: DXY-a1~DXY-a9, DXY-b1, DXY-c1~DXY-c2, DXY-d1~DXY-d6). A 20 mM stock solution of the positive control drug (Talabostat) was prepared using DMSO, and a 10 mM stock solution of the selected compounds was prepared for later use. The IC50 of the positive control drug (Talabostat) was used as the indicator. 50 The compound was serially diluted based on a reference concentration of 767.2 nM, with a blank dilution used as the starting point (0 concentration). A 3-fold serial dilution method was used to set up 10 concentration gradient points plus 1 blank control point. The stock solution of the compound was diluted to two concentrations, 100 nM and 10 nM, for detection. 100 nL of each concentration solution was transferred to a 384-well plate, with two replicates per column. After transfer, the 384-well plate was centrifuged at 1000 RPM for 1 minute to ensure sedimentation. 5 μL of recombinant human fibroblast activating protein (rhFAP) was added to each well, and the plate was incubated at 25°C for 10 minutes. 5 μL of the fluorescent substrate Z-Gly-Pro-AMC was added to each well, and the plate was incubated at 25°C in the dark for 60 minutes. Fluorescence intensity was detected using a BMG multi-mode microplate reader with the following parameters set: excitation wavelength (Ex): 380 nm, emission wavelength (Em): 460 nm. The inhibition rate of the compound at the corresponding concentration was calculated by further analyzing the obtained fluorescence signal values. The calculation results are shown in Tables 1 and 2.

[0380] Table 1. Inhibition rate of compounds at 1000 nM

[0381]

[0382] Table 5-4 Inhibition rate of compounds at 10 nM

[0383]

[0384]

[0385] The results showed that when the compound concentration was 1000 nM, the inhibition rate of FAP by the compounds could generally reach over 95%, with DXY-d5 exhibiting the highest inhibition rate at 98.29%. When the compound concentration was 10 nM, most compounds still maintained an inhibition rate of over 95% against FAP, with DXY-b1 showing the highest inhibition rate at 97.48%. These data indicate that the designed compounds all possess good FAP inhibitory activity and can be used as potential small molecule inhibitors for further in-depth research, contributing to the design of more small molecule FAP inhibitors.

[0386] The above are merely embodiments of the present invention and do not limit the scope of the patent. Any equivalent modifications made based on the content of this specification, or direct or indirect applications in other related technical fields, are similarly included within the scope of patent protection of the present invention.

Claims

1. N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide compounds or pharmaceutically acceptable salts thereof, as shown in the following structure: in, A is a quinoline ring, B is a (R)-3-glycylthiazolidin-4-nitrile side chain, and C is a side chain containing a sulfoxide imine structure.

2. The N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, As shown in equation (I): Wherein, C is selected from the following structure: R1 and R2 are selected from substituted or unsubstituted C1-C6 alkyl groups, respectively, wherein the substituents are C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or hydroxyl groups; Alternatively, R1 and R2 may combine with sulfur atoms to form a tetrahydrothiophene ring or a thiomorpholine ring; R3 is selected from C3-C6 cycloalkyl, C1-C6 alkyl, and C1-C6 alkoxy groups; R4 is selected from C1-C6 alkyl and C1-C6 alkoxy groups; R5 and R6 are each selected from C1-C6 alkyl and C1-C6 alkoxy groups, respectively; Alternatively, R5 and R6 may combine with nitrogen atoms to form an N-methylpiperazine or morpholine ring.

3. The N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide compound of claim 2, or a pharmaceutically acceptable salt thereof. in, R1 and R2 are each selected from substituted or unsubstituted C1-C4 alkyl groups, wherein the substituents are C3-C6 cycloalkyl, C1-C4 alkyl, C1-C4 alkoxy, or hydroxyl. Alternatively, R1 and R2 may combine with sulfur atoms to form a tetrahydrothiophene ring or a thiomorpholine ring; R3 is selected from C3-C6 cycloalkyl, C1-C4 alkyl, and C1-C4 alkoxy groups; R4 is selected from C1-C4 alkyl and C1-C4 alkoxy groups; R5 and R6 are each selected from C1-C4 alkyl and C1-C4 alkoxy groups, respectively; Alternatively, R5 and R6 may combine with nitrogen atoms to form an N-methylpiperazine or morpholine ring.

4. The N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, selected from:

5. The N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, The pharmaceutically acceptable salt is a salt formed by the addition of N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide compound to inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, di-toluyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid.

6. A method for preparing the compound of general formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the reaction process is as follows: in, C is as described in claim 2.

7. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

8. The use of the N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 7 in the preparation of FAP inhibitors.

9. The use of the N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 7 in the preparation of an antitumor drug.

10. The application according to claim 9, characterized in that, The N-(2-(4-cyanothiazolidine-3-yl)-2-oxoethyl)quinoline-4-carboxamide compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof exerts its antitumor effect by inhibiting fibroblast activating protein.

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