Substituted triazine-2, 4-diketone derivative intermediate and preparation method thereof

Abstract

The invention discloses an intermediate of a substituted triazine-2, 4-diketone derivative # imgabs0 and a preparation method of the intermediate, the intermediate is a compound as shown in a formula (II), a salt or an isomer of the compound, and the intermediate and the preparation method of the intermediate can be used for preparing a P2X3 or P2X2 / 3 inhibitor. According to the intermediate and the preparation method thereof, the side reaction is effectively reduced, the impurity content in the product is reduced, the solvent residue of the product is reduced, the product quality is improved, the subsequent reaction is facilitated, and the reaction operation is simple, convenient and feasible, and is more suitable for process production.

Description

Substituted triazine-2,4-dione derivative intermediate and preparation method thereof

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on November 30, 2022, with application number 202211518269.X and invention name “Substituted triazine-2,4-dione derivative intermediates and preparation methods thereof”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention belongs to the field of organic chemical synthesis, and particularly relates to a substituted triazine-2,4-dione derivative intermediate and a preparation method of the intermediate. Background Art

[0003] The P2X3 receptor (P2X purinoceptor 3) is a member of the P2X purinergic receptor family. It has been reported that the P2X3 receptor is associated with a variety of diseases, such as overactive bladder (Cockayne et al., Nature, Vol. 407, pp. 1011-1015 (2000)) and pain (Jarvis et al., PNAS, 99, 17179-17184 (2002)).

[0004] Currently, there are many documents that disclose the regulation of pain sensation in pain subjects by reducing P2X3 or P2X2 / 3 levels, and a series of small molecule compounds have been developed based on this. Chinese patent CN105452234A discloses the following preparation method, wherein compound (A) reacts with compound (vi) under heating reflux in the presence of an acid such as formic acid or acetic acid to obtain compound (B). However, when the inventors repeated this operation method, they found that when R 3 When XH(vi) is an amine, the amine reacts with formic acid and acetic acid, resulting in many side reactions.

[0005] Chinese patent CN112638430A discloses the following preparation method for compounds of formula (XI-1) and formula (XII-1). This method uses harsh reaction conditions of -78°C. LiTMP and BH3 are both dangerous and have high requirements for storage conditions. In addition, column chromatography purification is required in multiple steps. All these factors make the reaction unsuitable for large-scale industrial production, environmentally unfriendly, and have high production costs.

[0006] Therefore, there is a need in the art to develop safer and more effective methods for preparing new molecular compounds of P2X3 inhibitors so as to adapt to the needs of industrial production and meet the demands of clinical medication.

[0007] Summary of the Invention

[0008] The present invention aims to provide a class of substituted triazine-2,4-dione derivative intermediates and their preparation methods, based on the newly developed P2X3 inhibitor molecular compounds. These intermediates can be used to prepare P2X3 or P2X2 / 3 inhibitors. The intermediates and their preparation methods of the present invention effectively reduce side reactions, lower the impurity content in the product, reduce residual solvent in the product, improve product quality, facilitate subsequent reactions, and are simple and easy to operate, making them more suitable for industrial production.

[0009] The first aspect of the present invention provides a compound of formula (II-A), or a salt thereof, or a tautomer thereof:

[0010] in,

[0011] r is 1, 2, or 3;

[0012] (R d ) k Indicates that the hydrogen on the pyridine ring is replaced by k R d substituted, k is selected from 0, 1, 2, 3 or 4; each R d are the same or different and are each independently selected from the following group: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), C1-8 alkoxy (preferably C1-6 alkoxy, more preferably C1-3 alkoxy), C2-4 alkenyl, C2-4 alkynyl, halogenated C1-8 alkyl (preferably halogenated C1-6 alkyl, more preferably halogenated C1-3 alkyl), cyano-substituted C1-8 alkyl (preferably cyano-substituted C1-6 alkyl, more preferably cyano-substituted C1-3 alkyl), halogenated C1-8 alkoxy (preferably halogenated C1-6 alkoxy, more preferably halogenated C1-3 alkoxy), NR a0 R b0 , -SO2C1-3 alkyl, -S(O)C1-3 alkyl, -SC1-3 alkyl, -C(O)NR a1 R b1, -C(O)C1-8 alkyl (preferably -C(O)C1-6 alkyl, more preferably -C(O)C1-3 alkyl), -C(O)OC1-8 alkyl (preferably -C(O)OC1-6 alkyl, more preferably -C(O)OC1-3 alkyl), -OC(O)C1-8 alkyl (preferably -OC(O)C1-6 alkyl, more preferably -OC(O)C1-3 alkyl), C3-6 cycloalkyl, C3-6 cycloalkyloxy, 3 to 6-membered heterocycloalkyl, phenyl and 5 to 6-membered heteroaryl; wherein the 3 to 6-membered heterocycloalkyl, phenyl and 5 to 6-membered heteroaryl are unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of halogen, cyano, hydroxy, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, halo-substituted C1-3 alkyl, halo-substituted C1-3 alkoxy, NR a0 R b0 , -SO2C1-3 alkyl, -S(O)C1-3 alkyl, -SC1-3 alkyl, -C(O)NR a1 R b1 , -C(O)OC1-3 alkyl, -OC(O)C1-3 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl;

[0013] (R a ) n Indicates that the hydrogen on the benzene ring is replaced by n R a substituted, n is 0, 1 or 2; each R a are the same or different and are each independently deuterium, cyano, hydroxy, carboxyl, halogen (preferably fluorine or chlorine), C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), halo-substituted C1-8 alkyl (preferably halo-substituted C1-6 alkyl, more preferably halo-substituted C1-3 alkyl), cyano-substituted C1-8 alkyl (preferably cyano-substituted C1-6 alkyl, more preferably cyano-substituted C1-3 alkyl), C1-8 alkoxy (preferably C1-6 alkoxy, more preferably C1-3 alkoxy), -C(O)C1-8 alkyl (preferably -C(O)C1-6 alkyl, more preferably -C(O)C1-3 alkyl), -C(O)OC1-8 alkyl (preferably -C(O)OC1-6 alkyl, more preferably -C(O)OC1-3 alkyl), -OC(O)C1-8 alkyl (preferably -OC(O)C1-6 alkyl, more preferably -OC(O)C1-3 alkyl) or -C(O)NR a1 R b1 ;

[0014] R cis hydrogen, deuterium, C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), C3-8 cycloalkyl (preferably C3-6 cycloalkyl), C1-8 alkoxy (preferably C1-6 alkoxy, more preferably C1-3 alkoxy), cyano, hydroxy, carboxyl or halogen (preferably fluorine or chlorine);

[0015] (R b ) m Indicates that the hydrogen on the benzene ring is replaced by m R b substituted, m is 0, 1 or 2; each R b are the same or different and are each independently deuterium, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), halogenated C1-8 alkyl (preferably halogenated C1-6 alkyl, more preferably halogenated C1-3 alkyl), cyano-substituted C1-8 alkyl (preferably cyano-substituted C1-6 alkyl, more preferably cyano-substituted C1-3 alkyl), C1-8 alkoxy (preferably C1-6 alkoxy, more preferably C1-3 alkoxy), -SC1 -8 alkyl (preferably -SC1-6 alkyl, more preferably -SC1-3 alkyl), -C(O)C1-8 alkyl (preferably -C(O)C1-6 alkyl, more preferably -C(O)C1-3 alkyl), -C(O)OC1-8 alkyl (preferably -C(O)OC1-6 alkyl, more preferably -C(O)OC1-3 alkyl), -OC(O)C1-8 alkyl (preferably -OC(O)C1-6 alkyl, more preferably -OC(O)C1-3 alkyl), -C(O)NR a1 R b1 , C3-6 cycloalkyl or phenyl; wherein the phenyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of halogen, cyano, hydroxy, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, halogenated C1-3 alkyl, halogenated C1-3 alkoxy, NR a0 R b0 、-SO2C1-3 alkyl、-S(O)C1-3 alkyl、-C(O)NR a1 R b1 , -C(O)OC1-3 alkyl, -OC(O)C1-3 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl;

[0016] R0 is a chiral auxiliary group, preferably R0 is

[0017] R a1 、R b1 are each independently hydrogen or C1-3 alkyl; or R a1、R b1 Together with the nitrogen atom to which it is attached, it forms a 4- to 6-membered saturated monocyclic heterocyclic ring; the 4- to 6-membered saturated monocyclic heterocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, halo-substituted C1-3 alkyl, halo-substituted C1-3 alkoxy, -SO2C1-3 alkyl, -S(O)C1-3 alkyl, -C(O)NH2, -C(O)NH(C1-3 alkyl), -C(O)N(C1-3 alkyl)2, -C(O)OC1-3 alkyl, -OC(O)C1-3 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl;

[0018] R a0 、R b0 are each independently hydrogen, C1-3 alkyl or acetyl; or R a0 、R b0 Together with the nitrogen atom to which it is attached, it forms a 4- to 6-membered saturated monocyclic heterocyclic ring; the 4- to 6-membered saturated monocyclic heterocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, halo-substituted C1-3 alkyl, halo-substituted C1-3 alkoxy, -SO2C1-3 alkyl, -S(O)C1-3 alkyl, -C(O)NH2, -C(O)NH(C1-3 alkyl), -C(O)N(C1-3 alkyl)2, -C(O)OC1-3 alkyl, -OC(O)C1-3 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl.

[0019] In some embodiments, the compound of formula (II-A) is a structure represented by formula (II-B):

[0020] In some embodiments, r is 1.

[0021] In some embodiments, k is 0.

[0022] In some embodiments, k is 1, 2, 3, or 4, and each R d are the same or different and are each independently deuterium, fluorine, chlorine, cyano, hydroxyl, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, fluorinated C1-3 alkyl, chlorinated C1-3 alkyl, cyano-substituted C1-3 alkyl, fluorinated C1-3 alkoxy, chlorinated C1-3 alkoxy, -NR a0 R b0 , -SO2C1-3 alkyl, -S(O)C1-3 alkyl, -SC1-3 alkyl, -C(O)NR a1R b1 , -C(O)C1-3 alkyl, -C(O)OC1-3 alkyl,

[0023] -OC(O)C1-3alkyl.

[0024] In some embodiments, k is 1, 2, 3, or 4, and each R d are the same or different and are each independently deuterium, fluorine, chlorine, cyano, hydroxyl, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, monofluoro C1-3 alkyl, difluoro C1-3 alkyl, trifluoro C1-3 alkyl, monochloro C1-3 alkyl, dichloro C1-3 alkyl, cyano-substituted C1-3 alkyl, monofluoro C1-3 alkoxy, difluoro C1-3 alkoxy, trifluoro C1-3 alkoxy, monochloro C1-3 alkoxy, dichloro C1-3 alkoxy, -NR a0 R b0 , -SO2C1-3 alkyl, -S(O)C1-3 alkyl, -SC1-3 alkyl, -C(O)NR a1 R b1 , -C(O)C1-3 alkyl, -C(O)OC1-3 alkyl, -OC(O)C1-3 alkyl.

[0025] In some embodiments, k is 1, 2, 3, or 4, and each R d are the same or different and are each independently deuterium, fluorine, chlorine, bromine, -CH3, -C2H5, -CH(CH3)2, -OCH3, -OC2H5, -SCH3, -SC2H5, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CH2F, -CH2CF3, -CH2Cl, -CHCl2, -CH2CHCl2, -CH2CH2Cl, -OCH2F, -OCHF2, -OCF3, -OCH2CHF2, -OCH2CH2F, -OCH2CF3, -OCH2Cl, -OCHCl2, -OCH2CHCl2, -OCH2CH2Cl;

[0026] In some embodiments, k is 1. Further, R d is fluorine, -CH2F, -CHF2, -CH2CHF2 or -CH2CH2F.

[0027] In some embodiments, the structure Selected from the following structures:

[0028] In some embodiments, the structure Selected from the following structures:

[0029] In some embodiments, n is 0.

[0030] In some embodiments, n is 1 or 2, and each R a the same or different, each independently being cyano, hydroxyl, carboxyl, fluorine, chlorine, C1-3 alkyl, fluorinated C1-3 alkyl, chlorinated C1-3 alkyl, cyano-substituted C1-3 alkyl, C1-3 alkoxy, -C(O)C1-3 alkyl, -C(O)OC1-3 alkyl, -OC(O)C1-3 alkyl or -C(O)NR a1 R b1 .

[0031] In some embodiments, n is 1; R a is cyano, hydroxy, carboxyl, fluorine, chlorine, C1-3 alkyl, C1-3 alkoxy, -C(O)C1-3 alkyl, -C(O)OC1-3 alkyl, -OC(O)C1-3 alkyl or -C(O)NR a1 R b1 .

[0032] In some embodiments, n is 1 or 2, and each R a are the same or different, and are each independently deuterium, fluorine, chlorine, -CH3, -OCH3, -CF3, -CH2Cl or -CHCl2.

[0033] In some embodiments, n is 1, and R a For fluorine.

[0034] In some embodiments, the structure Selected from the following structures:

[0035] In some embodiments, R c It is hydrogen, C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, cyano, hydroxy, carboxyl, fluorine or chlorine.

[0036] In some embodiments, R c is F, Cl, Br, I, H, deuterium, -CH3 or OCH3.

[0037] In some embodiments, R c is F, Cl, Br, H or deuterium.

[0038] In some embodiments, R c is deuterium, H or F.

[0039] In some embodiments, R c For H.

[0040] In some embodiments, m is 0,

[0041] In some embodiments, m is 1 or 2, and each R b The same or different, each independently represents cyano, hydroxyl, carboxyl, fluorine, chlorine, bromine, C1-3 alkyl, halogenated C1-3 alkyl, cyano-substituted C1-3 alkyl, C1-3 alkoxy, -SC1-3 alkyl, -C(O)C1-3 alkyl, C(O)OC1-3 alkyl, -OC(O)C1-3 alkyl or -C(O)NH2.

[0042] In some embodiments, m is 1; R b is cyano, hydroxy, carboxyl, fluorine, chlorine, C1-3 alkyl, C1-3 alkoxy, -C(O)C1-3 alkyl, -C(O)OC1-3 alkyl, -OC(O)C1-3 alkyl or -C(O)NR a1 R b1 .

[0043] In some embodiments, m is 1 or 2, and each R b are the same or different and are each independently deuterium, F, Cl, Br, -CH3, -C2H5, -CH(CH3)2, -OCH3, -OC2H5, -CH2F, -CHF2, -CH2CHF2, -CH2CH2F, -CH2Cl, cyclopropyl, cyclobutyl, cyclopentyl or phenyl. Further, R b It is F, Cl, Br, -CH3, -C2H5 or deuterium.

[0044] In some embodiments, m is 1. Further, R b For chlorine.

[0045] In some embodiments, the structure for The structure shown.

[0046] In some embodiments, R0 is

[0047] In some embodiments, R0 is

[0048] In some embodiments, R0 is

[0049] In some embodiments, the compound of formula (II-A), or a salt thereof, or a tautomer thereof is selected from the following structures:

[0050] The second aspect of the present invention provides a method for preparing the compound of the first aspect, or a salt thereof, or a tautomer thereof, comprising the following steps:

[0051] S1: subjecting the compound of formula (III) to a nucleophilic substitution reaction with the compound of formula (AI) to obtain the compound of formula (II-A):

[0052] Among them, R A is a leaving group, such as R A Can be -SR e , where R e is a C1-20 alkyl group or a benzyl group, preferably a methyl group, an ethyl group, a dodecyl group or a benzyl group, more preferably a dodecyl group or a benzyl group.

[0053] Step S1 is to carry out a nucleophilic substitution reaction between the compound of formula (III-A) and the compound of formula (AI) to obtain the compound of formula (II-A):

[0054] In some embodiments, the compound of formula (III) is a structure represented by formula (III-A),

[0055] where R e It is a C1-20 alkyl group or a benzyl group, preferably a methyl group, an ethyl group, a dodecyl group or a benzyl group, more preferably a dodecyl group or a benzyl group.

[0056] In some embodiments, the nucleophilic substitution reaction described in step S1 is performed in the presence of an acid.

[0057] Furthermore, the acid is a saturated or partially unsaturated carbocyclic substituted carboxylic acid or a branched carboxylic acid.

[0058] Furthermore, the acid is selected from one or more of pivalic acid, cyclohexanecarboxylic acid, cyclopropylcarboxylic acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, isobutyric acid and 2-ethylbutyric acid, preferably one or more of cyclohexanecarboxylic acid, cyclopentanecarboxylic acid and cycloheptanecarboxylic acid, more preferably one or more of cyclohexanecarboxylic acid and cyclopentanecarboxylic acid.

[0059] In some embodiments, the molar ratio of the compound of formula (III-A) to the acid in step S1 is 1:1-10; preferably 1:3-8; more preferably 1:4-7.

[0060] In some embodiments, the nucleophilic substitution reaction in step S1 is carried out at 50°C-200°C, preferably 80°C-140°C, more preferably 90°C-130°C, and even more preferably 90°C-110°C.

[0061] In some embodiments, the molar ratio of the compound of formula (III-A) to the compound of formula (AI) in step S1 is 1:0.8-1.5; preferably 1:0.9-1.2; more preferably 1:1.

[0062] In some embodiments, after the reaction in step S1 is completed, a post-treatment step is further included, and the post-treatment step includes adding an alkaline aqueous solution for washing.

[0063] In some embodiments, the base is selected from one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, ammonium chloride, potassium hydroxide, potassium carbonate, potassium bicarbonate, and calcium bicarbonate.

[0064] In some embodiments, the step S1 further includes a purification step after the reaction is completed.

[0065] In some embodiments, the purification step is recrystallization.

[0066] In some embodiments, the recrystallization is to disperse the crude compound of formula (II-A) in a good solvent, and add an anti-solvent to obtain a fine product of the compound of formula (II-A).

[0067] In some embodiments, the recrystallization is performed by dispersing the crude compound of formula (II-A) in a good solvent to obtain a solution, and then adding the obtained solution to an anti-solvent to obtain a fine product of the compound of formula (II-A).

[0068] In some embodiments, the good solvent is selected from one or more of ethyl acetate, toluene, dichloromethane, carbon trichloride, carbon tetrachloride and xylene; preferably ethyl acetate.

[0069] In some embodiments, the anti-solvent is selected from one or more of n-hexane, n-heptane, isopropyl ether, cyclohexane, methyl tert-butyl ether and petroleum ether; preferably n-heptane.

[0070] In some embodiments, the adding of the anti-solvent or the adding of the anti-solvent further comprises the step of stirring,

[0071] In some embodiments, the stirring temperature is -10°C-60°C, preferably 0-50°C, more preferably 10°C-40°C, and most preferably 20°C-30°C.

[0072] In some embodiments, the stirring time is 0.5-12 hours, preferably 0.5-6 hours, more preferably 0.5-3 hours, and most preferably 0.5-2 hours. In some embodiments, the stirring is followed by a separation and / or drying step. The separation step can be performed according to conventional operations in the art (e.g., filtration, suction filtration, centrifugation, etc.), and the drying step can be performed according to conventional operations in the art (e.g., vacuum drying, etc.). These conventional operations are not particularly limited.

[0073] The third aspect of the present invention provides a compound of formula (III-A) or a salt thereof:

[0074] Among them, R e is a C1-20 alkyl group or a benzyl group, preferably a methyl group, an ethyl group, a dodecyl group or a benzyl group, more preferably a dodecyl group or a benzyl group;

[0075] r、R c 、R b , m, and R0 are as defined in the specification.

[0076] The compound of formula (III-A) or its salt described in the present invention can be used to prepare the compound of formula (I) described in the present invention.

[0077] A fourth aspect of the present invention provides a method for preparing a compound of formula (III-A) or a salt thereof, the method comprising the following steps:

[0078] S2: reacting the compound of formula (IV) with the compound of formula (V) or the compound of formula (XI) to obtain a compound of formula (III-A),

[0079] Among them, R f is p-toluenesulfonyl (-OTs), methylsulfonyl (-OMs) or halogen.

[0080] The method optionally further comprises S3: reacting the compound of formula (VI) to obtain the compound of formula (IV),

[0081] Among them, R g is a C1-10 alkyl group (preferably a C1-8 alkyl group, more preferably a C1-6 alkyl group, further preferably a C1-3 alkyl group), a C3-8 cycloalkyl group, a C6-10 aryl group or a C5-10 heteroaryl group, wherein the C1-10 alkyl group, the C3-8 cycloalkyl group, the C6-10 aryl group or the C5-10 heteroaryl group is unsubstituted or substituted by one or more (such as 1, 2, 3, 4, etc.) R g1 Substituted, the R g1 R is selected from halogen, -NO2, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, C5-10 heteroaryl and C1-6 alkoxy. g Preferred is tert-butyl.

[0082] Optionally, the process further comprises S4: reacting the compound of formula (VII) with the compound of formula (VIII) to obtain the compound of formula (VI);

[0083] Among them, R h is halogen, -OMs or -OTs;

[0084] Optionally, the method further comprises S5: reacting the compound of formula (IX) with Rg-N=C=O to obtain the compound of formula (VII),

[0085] Optionally, the method further comprises S6: reacting the compound of formula (X) with thiourea to obtain a compound of formula (IX),

[0086] Wherein, X is fluorine, chlorine, bromine or iodine, preferably bromine.

[0087] In some embodiments, the method for preparing the compound of formula (III-A) or a salt thereof comprises the following steps:

[0088] S6: reacting the compound of formula (X) with thiourea to obtain a compound of formula (IX);

[0089] S5: reacting the compound of formula (IX) with Rg-N=C=O to obtain the compound of formula (VII);

[0090] S4: reacting the compound of formula (VII) with the compound of formula (VIII) to obtain the compound of formula (VI);

[0091] S3: reacting the compound of formula (VI) to obtain the compound of formula (IV); and

[0092] S2: reacting the compound of formula (IV) with the compound of formula (V) to obtain a compound of formula (III-A);

[0093] Among them, R e 、R c 、R b ,m,R f , R0, r, R g 、R h , X is as defined in the specification.

[0094] In some embodiments, the reaction of the compound of formula (IV) with the compound of formula (V) in step S2 is carried out in the presence of a base, wherein the base includes but is not limited to one or more of sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, lithium hydroxide, DMAP and DBU.

[0095] In some embodiments, the reaction of the compound of formula (IV) with the compound of formula (V) in step S2 is carried out in a solvent selected from one or more of dichloromethane, THF, acetonitrile, DMF, toluene, xylene and N-methylpyrrolidone.

[0096] In some embodiments, the reaction temperature of the reaction of the compound of formula (IV) with the compound of formula (V) in step S2 is 15°C-60°C, preferably 20°C-55°C, and more preferably 30°C-55°C.

[0097] In some embodiments, the molar ratio of the compound of formula (IV) to the compound of formula (V) in step S2 is 1:0.7-1.5; preferably 1:0.9-1.3; more preferably 1:1.2.

[0098] In some embodiments, step S2 further comprises a purification step of the compound of formula (III-A).

[0099] Furthermore, in some embodiments, the purification step is to disperse the crude product of formula (III-A) in a solvent, stir, and separate to obtain a pure product of the compound of formula (III-A).

[0100] Furthermore, in some embodiments, the solvent is one or more of n-heptane, n-hexane, cyclohexane, isopropyl ether, and methyl tert-butyl ether, preferably n-heptane.

[0101] Furthermore, in some embodiments, the separation is selected from one or more of filtration, suction filtration, and centrifugal separation; preferably filtration.

[0102] Furthermore, in some embodiments, the filtrate collected after separation also includes a step of removing impurities.

[0103] Furthermore, in some embodiments, the impurity removal includes adding activated carbon (such as medicinal carbon, etc.) to remove impurities.

[0104] In some embodiments, the reaction of the compound of formula (IV) with the compound of formula (XI) in step S2 is a Mitsunobu reaction, which can be carried out according to conventional Mitsunobu reaction conditions, such as in the presence of diethyl azodicarboxylate and triphenylphosphine or diisopropyl azodicarboxylate and triphenylphosphine, and the reaction temperature is -30°C to 120°C (preferably 0-100°C, more preferably 25°C to 80°C), etc.

[0105] In some embodiments, the molar ratio of the compound of formula (IV) to the compound of formula (XI) in step S2 is 1:0.7-1.5; preferably 1:0.9-1.3; more preferably 1:1.

[0106] In some embodiments, the reaction in step S3 is carried out in the presence of an acid selected from one or more of hydrochloric acid, dilute sulfuric acid, trifluoroacetic acid, and acetic acid. Further, the acid is selected from one or more of hydrochloric acid and trifluoroacetic acid.

[0107] In some embodiments, the reaction in step S3 is carried out in a solvent selected from the group consisting of: DMF, N-methylmorpholine, DMSO, dichloromethane, methanol, ethanol, chloroform, carbon tetrachloride, acetone, THF, and isopropanol. Further, the solvent is selected from the group consisting of: THF, ethanol, methanol, and dichloromethane.

[0108] In some embodiments, the reaction in step S3 is carried out at -20°C to 50°C, preferably 10°C to 40°C, and more preferably 15°C to 35°C. In some embodiments, step S3 also includes a purification step. Furthermore, the purification step is recrystallization. Furthermore, the recrystallization is carried out in a solvent selected from one or more of ethyl acetate, THF, and acetone.

[0109] In some embodiments, the reaction in step S4 is carried out in the presence of a base, wherein the base is selected from one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, DMAP, and DBU. Further, the base is selected from one or more of potassium carbonate, DBU, and DMAP.

[0110] In some embodiments, the reaction in step S4 is carried out in the presence of a base, and the molar ratio of the compound of formula (VII) to the base is 1:1-2; preferably 1:1-1.5; more preferably 1:1.2.

[0111] In some embodiments, the reaction in step S4 is carried out in a solvent selected from one or more of DMF, N-methylmorpholine, DMSO, dichloromethane, methanol, ethanol, isopropanol, acetonitrile, and THF. Further, the solvent is selected from one or more of DMF, DMSO, and N-methylmorpholine.

[0112] In some embodiments, the reaction in step S4 is carried out at 0° C.-50° C., preferably 10° C.-40° C., and more preferably 15° C.-35° C. In some embodiments, the molar ratio of the compound of formula (VII) to the compound of formula (VIII) in step S4 is 1:0.7-1.5; preferably 1:0.9-1.2; and more preferably 1:1.

[0113] In some embodiments, the reaction in step S5 is performed in the presence of CDI and DBU.

[0114] In some embodiments, the molar ratio of the compound of formula (IX) to DBU in step S5 is 1:2-5, preferably 1:2-3.

[0115] In some embodiments, the molar ratio of the compound of formula (IX) to CDI in step S5 is 1:1-3; preferably 1:1-2; more preferably 1:1-1.5.

[0116] In some embodiments, the reaction in step S5 is carried out in a solvent selected from one or more of DMF, N-methylmorpholine, DMSO, dichloromethane, chloroform, and THF. Further, the solvent is selected from one or more of DMF and N-methylmorpholine.

[0117] In some embodiments, the DBU in step S5 is added at a reaction temperature of -10°C to 5°C; preferably 0°C to 5°C.

[0118] In some embodiments, the reaction in step S5 is carried out at 20°C-60°C; preferably 30°C-50°C; more preferably 40°C-45°C.

[0119] In some embodiments, the molar ratio of the compound of formula (IX) to Rg-N=C=O in step S5 is 1:0.7-1.5; preferably 1:0.9-1.2; more preferably 1:1-1.1.

[0120] In some embodiments, step S6 is to mix the compound of formula (X), thiourea, and a reaction solvent, react at an appropriate temperature, and perform post-treatment to obtain the compound of formula (IX).

[0121] In some embodiments, the reaction solvent in step S6 is selected from one or more of methanol, ethanol, isopropanol, dichloromethane, toluene, acetone and THF, preferably one or more of ethanol, methanol, isopropanol, acetone and THF, and more preferably one or more of ethanol, methanol and isopropanol.

[0122] In some embodiments, the reaction temperature in step S6 is 40°C-120°C, preferably 60°C-100°C, more preferably 70°C-90°C.

[0123] In some embodiments, the molar ratio of the compound of formula (X) to thiourea in step S6 is 1:0.7-1.5; preferably 1:0.9-1.2; more preferably 1:1-1.1.

[0124] The fifth aspect of the present invention provides a compound of formula (V) or a salt thereof:

[0125] Among them, R f is -OTs, -OMs or halogen;

[0126] r and R0 are as defined in the specification.

[0127] In some embodiments, the compound of formula (V) is selected from the following structures:

[0128] The compound of formula (V) or its salt described in the present invention can be used to prepare the compound of formula (I) described in the present invention.

[0129] A sixth aspect of the present invention provides a method for preparing a compound of formula (V) or a salt thereof, comprising the following steps:

[0130] S7: reacting the compound of formula (XI) to obtain the compound of formula (V),

[0131] The method optionally further comprises S8: reacting the compound of formula (XII) to obtain the compound of formula (XI),

[0132] Among them, R i is a hydroxyl protecting group, further, the hydroxyl protecting group includes but is not limited to benzyl (-Bn), trimethylsilyl (TMS) or triisopropylsilyl (TIPS);

[0133] Optionally, the method further comprises S9: reacting the compound of formula (XIII) to obtain the compound of formula (XII),

[0134] Optionally, the method further comprises S10: reacting the compound of formula (XIV) to obtain the compound of formula (XIII),

[0135] Among them, R j is a C1-6 alkyl group, preferably -CH3 or -CH2CH3;

[0136] Optionally, the process further comprises S11: reacting the compound of formula (XIV) to obtain the compound of formula (XIII), and then chirally resolving the compound of formula (XIII) to obtain a chirally pure compound of formula (XIII);

[0137] When r is 1, the method optionally further comprises S12: reacting the compound of formula (XV) with a phosphonoester to obtain a compound of formula (XIV),

[0138] In some embodiments, the method for preparing the compound of formula (V) or a salt thereof comprises the following steps:

[0139] S10: reacting the compound of formula (XIV) to obtain the compound of formula (XIII);

[0140] S9: reacting the compound of formula (XIII) to obtain the compound of formula (XII);

[0141] S8: reacting the compound of formula (XII) to obtain the compound of formula (XI); and

[0142] S7: reacting the compound of formula (XI) to obtain the compound of formula (V);

[0143] And optionally, further comprising S11: reacting the compound of formula (XIV) to obtain the compound of formula (XIII), and then chirally resolving the compound of formula (XIII) to obtain a chirally pure compound of formula (XIII);

[0144] When r is 1, optionally, further comprising S12: reacting a compound of formula (XV) with a phosphonoester to obtain a compound of formula (XIV);

[0145] Among them, r, R0, R f 、R i 、R j As defined in the specification.

[0146] In some embodiments, in step S7, the compound of formula (XI) reacts with a reaction reagent to obtain a compound of formula (V), wherein the reaction reagent is selected from one or more of a chlorination reagent, a bromination reagent, an iodination reagent, p-toluenesulfonyl chloride, and methanesulfonyl chloride.

[0147] Furthermore, in some embodiments, the chlorination agent includes but is not limited to one or more of phosphorus trichloride, phosphorus pentachloride, thionyl chloride and N-chlorosuccinimide.

[0148] Furthermore, in some embodiments, the bromination reagent includes but is not limited to one or more of N-bromosuccinimide, phenyltrimethylammonium tribromide, liquid bromine and dibromohydantoin.

[0149] Furthermore, in some embodiments, the iodine reagent includes but is not limited to one or more of sodium iodide and potassium iodide.

[0150] In some embodiments, the reaction in step S7 is carried out in a solvent, including but not limited to one or more of diethyl ether, THF, dichloromethane, DMF, N-methylmorpholine, DMSO and cyclohexane.

[0151] In some embodiments, the reaction temperature in step S7 is -20°C to 120°C, preferably 0-50°C.

[0152] In some embodiments, step S7 further comprises a purification step for the compound of formula (V).

[0153] Furthermore, in some embodiments, the purification step is recrystallization.

[0154] Furthermore, in some embodiments, the recrystallization method includes but is not limited to cooling crystallization and adding an anti-solvent. For example, it can be refluxed in ethanol followed by cooling crystallization.

[0155] In some embodiments, the reaction in step S8 is a deprotection reaction of the hydroxyl protecting group, which can be carried out according to conventional hydroxyl protecting group removal conditions in the art, for example, commonly used hydroxyl protecting group removal reagents such as H2 / Pd-C, Raney Ni and EtSH / BF3 can be used.

[0156] In some embodiments, in step S9, the compound of formula (XIII) reacts with a chiral auxiliary reagent to obtain a compound of formula (XII).

[0157] Furthermore, in some embodiments, chiral auxiliary reagents include but are not limited to

[0158] In some embodiments, the reaction in step S9 is carried out in the presence of a condensing agent, and the condensing agent is selected from one or more of DMAP, CDI, EDCI, HATU and HBTU.

[0159] In some embodiments, the reaction in step S9 is carried out in the presence of a base, and the base is selected from one or more of DMAP, triethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate.

[0160] In some embodiments, the solvent for the reaction in step S9 includes, but is not limited to, one or more of dichloromethane, acetonitrile, acetone, THF, cyclohexane, n-hexane, toluene, ethyl acetate, DMF, N-methylmorpholine, and DMSO.

[0161] In some embodiments, the reaction temperature in step S9 is -10°C to 50°C, preferably 10°C to 30°C.

[0162] In some embodiments, the reaction in step S10 is an ester hydrolysis reaction, which can be carried out using conventional ester hydrolysis reaction conditions in the art, such as carrying out an ester hydrolysis reaction in a solvent under alkaline conditions (such as in the presence of sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium tert-butoxide, etc.), followed by acidification to obtain a compound of formula (XIII). These reaction conditions are not particularly limited.

[0163] In some embodiments, the chiral resolution in step S11 is selected from one or more of physical resolution, chemical resolution, and biological resolution.

[0164] In some embodiments, the chiral resolution is a chemical resolution method.

[0165] In some embodiments, the chiral resolving agent used in the chemical resolution method includes but is not limited to (S)-(-)-α-phenylethylamine (S-1-phenylethylamine), quinidine, quinine, quinine, cinchonine, dehydroabietylamine, strychnine, strychnine, cinchonine, cinchonidine, (+)-3-aminomethylpinane, abietyleneamine, (1R)-3-endo-aminoborneol, endo-borneolamine, N-methylglucosamine, N-octylglucosamine, (1R, 2S)-(-)-ephedrine, (1S, 2R)-2-amino-1,2-diphenylethanol, (1S, 2S)-(+) -2-amino-1-phenyl-1,3-propanediol, (1S,2S)-2-amino-1-(4-nitro)phenyl-1,3-propanediol, (S)-N-benzyl-α-phenylethylamine, (S)-(4-isopropyl)-α-phenylethylamine, (S)-(4-nitro)-α-phenylethylamine, (S)-(-)-α-naphthylethylamine, cis-N-benzyl-2-(hydroxymethyl)-cyclohexylamine, arginine, phenylalanine, (S)-p-hydroxyphenylglycine, proline, L-phenylalaninamide, (R)-(-)-2-phenylglycinol and (S)-(-)-3-phenylalaninol.

[0166] Furthermore, in some embodiments, the chiral resolving agent is selected from one or more of (S)-(-)-α-phenylethylamine, (S)-N-benzyl-α-phenylethylamine, (S)-(4-isopropyl)-α-phenylethylamine, (S)-(4-nitro)-α-phenylethylamine and (S)-(-)-α-naphthylethylamine.

[0167] Furthermore, in some embodiments, the chiral resolving agent is (S)-(-)-α-phenylethylamine.

[0168] In some embodiments, in step S11, the obtained compound of formula (XIII) and a chiral resolving agent are added to a solvent and reacted at an appropriate temperature. After the reaction is completed, the solid is collected and acidified by adding acid to obtain an isomer of the compound of formula (XIII).

[0169] Further, in some embodiments, the solvent includes but is not limited to one or more of water, methanol, ethanol, isopropanol, acetonitrile, THF, acetone, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, cyclohexane, DMF, N-methylmorpholine, DMSO and toluene.

[0170] Furthermore, in some embodiments, the temperature is -20°C-60°C, preferably 0°C-30°C.

[0171] Furthermore, in some embodiments, the acid is selected from one or more of formic acid, acetic acid, hydrochloric acid, dilute sulfuric acid, citric acid, potassium hydrogen sulfate and dipotassium hydrogen phosphate.

[0172] Further, in some embodiments, the acidification is carried out in a solvent, including but not limited to one or more of water, methanol, ethanol, isopropanol, acetonitrile, THF, acetone, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, cyclohexane, DMF, DMSO, N-methylpyrrolidone, N-methylmorpholine and toluene.

[0173] In some embodiments, the phosphonoester described in step S12 is triethyl phosphonoacetate.

[0174] In some embodiments, the reaction in step S12 is carried out in the presence of a base, and the base is selected from one or more of sodium hydride, potassium hydride, potassium tert-butoxide and potassium hydroxide.

[0175] In some embodiments, the reaction in step S12 is carried out in a solvent, and the solvent is selected from one or more of toluene, dichloromethane, DMSO, DMF and N-methylmorpholine.

[0176] In some embodiments, the reaction temperature of the reaction in step S12 is -10°C-120°C, preferably 50°C-120°C.

[0177] A seventh aspect of the present invention provides a method for preparing a compound of formula (I), or a salt thereof, or a tautomer thereof, comprising the following steps:

[0178] S13: reacting the compound of formula (II-A) to obtain the compound of formula (I),

[0179] Among them, R d ,k,R a 、n、R c 、R b , m, r, and R0 are as defined in the specification.

[0180] In some embodiments, the reaction of step S13 is carried out in the presence of a base, and the base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium tert-butoxide, potassium bicarbonate and potassium carbonate, preferably lithium hydroxide.

[0181] In some embodiments, the solvent in step S13 is selected from one or more of methanol, ethanol, isopropanol, acetone, DMF, DMSO, acetonitrile, water, and THF.

[0182] In some embodiments, the temperature in step S13 is -15°C to 100°C, preferably 0°C to 80°C, and more preferably 25°C to 60°C.

[0183] In some embodiments, the reaction of step S13 further includes an acidification step, and the acid is selected from one or more of hydrochloric acid, dilute sulfuric acid, phosphoric acid, formic acid, citric acid, potassium hydrogen sulfate, dipotassium hydrogen phosphate and acetic acid, preferably hydrochloric acid.

[0184] In some embodiments, the molar ratio of the compound (II-A) to the base in step S13 is 1:2-10; preferably 1:3-9.

[0185] In some embodiments, the method for preparing the compound of formula (I) further comprises one or more or all of the following optional steps:

[0186] S12: reacting the compound of formula (XV) with a phosphonoester to obtain a compound of formula (XIV);

[0187] S11: reacting the compound of formula (XIV) to obtain the compound of formula (XIII), and then performing chiral resolution on the compound of formula (XIII) to obtain a chirally pure compound of formula (XIII);

[0188] S10: reacting the compound of formula (XIV) to obtain the compound of formula (XIII);

[0189] S9: reacting the compound of formula (XIII) to obtain the compound of formula (XII);

[0190] S8: reacting the compound of formula (XII) to obtain the compound of formula (XI);

[0191] S7: reacting the compound of formula (XI) to obtain the compound of formula (V);

[0192] S6: reacting the compound of formula (X) with thiourea to obtain a compound of formula (IX);

[0193] S5: reacting the compound of formula (IX) with Rg-N=C=O to obtain the compound of formula (VII);

[0194] S4: reacting the compound of formula (VII) with the compound of formula (VIII) to obtain the compound of formula (VI);

[0195] S3: reacting the compound of formula (VI) to obtain the compound of formula (IV);

[0196] S2: reacting the compound of formula (IV) with the compound of formula (V) or the compound of formula (XI) to obtain a compound of formula (III-A);

[0197] S1: subjecting the compound of formula (III-A) to a nucleophilic substitution reaction with the compound of formula (AI) in the presence of an acid to obtain a compound of formula (II-A);

[0198] Among them, R A 、R e 、R f 、R g 、R h , X, R i 、R j As defined in the specification.

[0199] Through the inventor's careful and in-depth research, it is found that the preparation method of the compound of formula (II-A) provided by the present invention, if using Lewis acid, mineral acid, aromatic substituted organic acid and straight-chain carboxylic acid as reaction reagent, then cause reaction or no product generation or serious side reaction, and using branched carboxylic acid or saturated or partially unsaturated carbocyclic substituted carboxylic acid as reaction reagent, reaction can be carried out smoothly. In addition, post-reaction treatment is carried out and it is found that the carboxylic acid using saturated or partially unsaturated carbocyclic substituted carbocyclic is more conducive to post-processing operation, such as using cyclohexanecarboxylic acid, can be removed by only washing with alkaline aqueous solution during post-processing, and operation is simpler, and residual amount is low in the product. After adopting branched carboxylic acid reaction, it is difficult to remove by alkali cleaning during post-processing, and a large amount of residues are arranged in the product.

[0200] The compounds of formula (II-A) and formula (III) provided by the present invention can be used to prepare the compound of formula (I); the chiral auxiliary groups in the compounds of formula (II-A) and formula (III) not only have the function of protecting the carboxyl group on the cyclopropyl group, but also can maintain the chiral center of the cyclopropyl group, thereby reducing the occurrence of side reactions and by-products in the reaction; and the compound of formula (I) can be prepared in a simple, effective, environmentally friendly and low-cost manner.

[0201] The preparation method of the compound of formula (IV) provided by the present invention uses higher alkyl sulfides and aromatic sulfides, thereby avoiding the environmental pollution problem caused by the use of lower alkyl sulfides. The method is environmentally friendly, has high product quality, is simple and easy to operate, and is more suitable for large-scale industrial production.

[0202] The preparation method of the compound of formula (V) provided by the present invention avoids the use of expensive, dangerous, and harsh reaction conditions such as tert-butyl lithium reaction reagents, avoids the use of special reaction equipment, is simple and easy to operate, and is environmentally friendly; on the other hand, the method further purifies the chiral compound by introducing a chiral auxiliary group during the reaction process, and can also make the product into a solid, which is more conducive to the post-processing of the reaction and further purification of the product; on the other hand, by introducing a chiral resolution method during the reaction process, the chiral purity of the product is improved, the side reactions of subsequent reactions are reduced, the impurities of the product are reduced, and complex post-processing operations are avoided. In short, the method is simple and easy to operate, low in cost, environmentally friendly, and more suitable for the needs of large-scale industrial production.

[0203] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0204] The accompanying drawings are used to provide further understanding of the present invention and constitute a part of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0205] Figure 1 is an ellipsoid diagram of the molecular structure of the compound of formula (V-21);

[0206] FIG2 is an X-ray powder diffraction (XRPD) pattern of the compound of formula (I-4);

[0207] Figure 3 shows the effects of different treatment groups on paw withdrawal thresholds 2 hours after administration, where * and *** indicate P < 0.05 and P < 0.001, respectively, compared between the test compound group and the solvent group;

[0208] FIG4 shows the effects of different treatment groups on paw withdrawal threshold 4 hours after administration, where ** indicates P<0.01 compared with the test compound group and the solvent group. DETAILED DESCRIPTION

[0209] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention is further described below with reference to the accompanying drawings and examples. It should be understood that the described examples are only some examples of the present invention, not all examples. All other examples derived by persons of ordinary skill in the art based on the examples of the present invention fall within the scope of protection of the present invention.

[0210] Definition of terms

[0211] As used herein, "alkyl" refers to straight-chain and branched saturated aliphatic hydrocarbon groups, C1-10 alkyl is an alkyl group containing 1 to 10 carbon atoms, preferably C1-6 alkyl, more preferably C1-4 alkyl, more preferably C1-3 alkyl, and the definition is similar; non-limiting examples of alkyl include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2 ,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3 , 3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof are more preferred.

[0212] As used herein, "cycloalkyl" and "cycloalkyl ring" are used interchangeably and refer to saturated monocyclic, bicyclic or polycyclic hydrocarbon groups, which may be fused to aryl or heteroaryl groups. The cycloalkyl ring may be optionally substituted. In certain embodiments, the cycloalkyl ring contains one or more carbonyl groups, such as oxo groups. "C3-8 cycloalkyl" refers to a monocyclic cycloalkyl group having 3 to 8 carbon atoms, and non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc. Preferably, it is C3-6 cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0213] As used herein, "alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined above. 1-6 Alkoxy, more preferably C 1-3 Alkoxy. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like.

[0214] As used herein, "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0215] "Halo" refers to a group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by a halogen.

[0216] For example, "haloalkyl" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, wherein alkyl is as defined above. Preferably, it is a haloC1-8 alkyl group, more preferably a haloC1-6 alkyl group, and more preferably a haloC1-3 alkyl group. Examples of haloalkyl groups include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.

[0217] For another example, "haloalkoxy" refers to an alkoxy group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogen groups, wherein alkoxy is as defined above. Preferably, it is a haloalkoxy group, more preferably a haloalkoxy group, and even more preferably a haloalkoxy group. Haloalkoxy groups include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, and difluoroethoxy.

[0218] "Heteroaryl" and "heteroaryl ring" are used interchangeably and refer to a group of a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In the present invention, heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused to one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings. The heteroaryl ring may be optionally substituted. "5 to 10 membered heteroaryl" refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms. "5- to 6-membered heteroaryl" refers to a monocyclic heteroaryl group having 5 to 6 ring atoms, of which 1, 2, 3, or 4 are heteroatoms. Non-limiting examples include thienyl, furanyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl. "Heteroatom" refers to nitrogen, oxygen, or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings.

[0219] "Saturated monocyclic heterocycle" means a saturated monocyclic ring in which one, two or three ring carbon atoms are selected from nitrogen, oxygen or S(O) t (wherein t is an integer from 0 to 2) is substituted with a heteroatom, excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. A "3- to 6-membered saturated monocyclic heterocycle" has 3 to 6 ring atoms, of which 1, 2, or 3 are heteroatoms as defined above. Preferably, the 5- to 6-membered saturated monocyclic heterocycle has 5 to 6 ring atoms, of which 1 or 2 are heteroatoms as defined above. Non-limiting examples of saturated monocyclic heterocycles include an oxetane ring, an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a pyrroline ring, an oxazolidine ring, a piperazine ring, a dioxolane ring, a dioxane ring, a morpholine ring, a thiomorpholine ring, a thiomorpholine-1,1-dioxide, a tetrahydropyran ring, an azetidine-2-one ring, an oxetane-2-one ring, a pyrrolidine-2-one ring, a pyrrolidine-2,5-dione ring, a piperidin-2-one ring, a dihydrofuran-2(3H)-one ring, a dihydrofuran-2,5-dione ring, a tetrahydro-2H-pyran-2-one ring, a piperazin-2-one ring, a morpholine-3-one ring, and the like.

[0220] "Amino" refers to NH2, "cyano" refers to CN, "nitro" refers to NO2, "benzyl" refers to -CH2-phenyl, "benzyl" refers to -CH2-phenyl, "oxo" refers to =O, "carboxy" refers to -C(O)OH, "acetyl" refers to -C(O)CH3, "hydroxymethyl" refers to -CH2OH, "hydroxyethyl" refers to -CH2CH2OH or -CHOHCH3, "hydroxy" refers to -OH, "cyanomethyl" refers to -CH2CN, and "cyanoethyl" refers to -CH2CH2CN.

[0221] "Saturated or partially unsaturated carbocycle" refers to a saturated or partially unsaturated full carbon ring system, wherein "partially unsaturated" refers to a ring portion including at least one double bond or triple bond, and "partially unsaturated" is intended to cover rings with multiple unsaturated sites, but is not intended to include aryl or heteroaryl moieties. In certain embodiments, the saturated or partially unsaturated carbocycle contains one or more carbonyl groups, such as an oxo group. The saturated or partially unsaturated carbocycle preferably has 3 to 7 ring carbon atoms, more preferably a saturated or partially unsaturated carbocycle with 3 to 6 ring carbon atoms, more preferably a saturated carbocycle with 3 to 6 ring carbon atoms. Non-limiting examples of saturated or partially unsaturated carbocycles include cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, cycloheptyl rings, cycloheptatrienyl rings, cyclopentanone rings, cyclopentane-1,3-dione rings, etc.

[0222] In the present invention, the compound of formula (II-A) and the compound of formula (I) exist in tautomers.

[0223] Understandably, and is a tautomer, and The tautomer structures of the intermediate general formula are all within the protection scope of the present invention. The same applies to the general formula or compound, which will not be described here one by one.

[0224] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight. Unless otherwise defined, the terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the described contents may be applied to the present invention.

[0225] Reagents and instruments

[0226] H NMR spectroscopy ( 1 H NMR) was performed on a Bruker AVANCE-400 nuclear magnetic spectrometer, with tetramethylsilane (TMS) as the internal standard.

[0227] Liquid chromatography-mass spectrometry (LC-MS): Agilent 1290 HPLC System / 6130 / 6150MS liquid chromatography-mass spectrometer (manufacturer: Agilent), column: Waters BEH / CHS, 50×2.1 mm, 1.7 μm.

[0228] High performance liquid chromatography (HPLC) analysis was performed using an Agilent 1260 Infinity HPLC, OpenLAB CDS Chemstation workstation, a chromatographic column XBridge C18 4.6×250 mm, ID 5 μm column, and a DAD detector.

[0229] Known starting materials can be synthesized by methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0230] As used herein, room temperature / normal temperature refers to approximately 20-30°C. Overnight refers to approximately 10-16 hours. Ethanol refers to anhydrous ethanol (AR). About means within ±10% of the value. Yield = actual product mass / theoretical product mass x 100%.

[0231] The present invention uses DMF: N,N-dimethylformamide, DCM: dichloromethane, DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene, CDI: N,N'-carbonyldiimidazole, CDCl3: deuterated chloroform, DMAP: 4-dimethylaminopyridine, EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, PE: petroleum ether, EA: ethyl acetate, DEAD: diethyl azodicarboxylate, THF: tetrahydrofuran, MeOH: methanol, LiOH: lithium hydroxide, MTBE: methyl tert-butyl ether, KHSO4: potassium hydrogen sulfate, DMSO: dimethyl sulfoxide, H2: hydrogen, Pd-C: palladium on carbon, Raney Ni: Raney nickel, EtSH: ethanethiol, and BF3: boron trifluoride.

[0232] Preparation of intermediate A-5

[0233] Step 1: Add 2-fluoronicotinaldehyde (449.65 mg, 3.59 mmol), 4-nitrophenol (500 mg, 3.59 mmol), and cesium carbonate (1.76 g, 5.39 mmol) to DMF (10 mL). Stir the reaction mixture at 60°C for 2 hours. Filter the reaction mixture and concentrate under reduced pressure. Purify the mixture by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to obtain 2-(4-nitrophenoxy)nicotinaldehyde (450 mg). MS m / z (ESI): 244.9 [M+1] + .

[0234] Step 2: Dissolve 2-(4-nitrophenoxy)nicotinaldehyde (420 mg, 1.72 mmol) in DCM (20 mL), cool to 0°C under argon, and add diethylaminosulfur trifluoride (1.39 g, 8.60 mmol) dropwise. The reaction mixture is allowed to warm to room temperature and stirred for 16 hours. Saturated sodium bicarbonate solution (30 mL) is added, and the mixture is extracted with DCM (30 mL x 3). The organic phase is dried, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to yield Intermediate A-5 (405 mg). MS m / z (ESI): 267.0 [M+1] + .

[0235] Preparation of intermediate A-7

[0236] Step 1: Add methyl 2-fluoropyridine-3-carboxylate (557.57 mg, 3.59 mmol), 4-nitrophenol (500 mg, 3.59 mmol), and cesium carbonate (1.76 g, 5.39 mmol) to DMF (10 mL). Stir the reaction mixture at 80°C for 16 hours. Filter the reaction mixture and concentrate under reduced pressure. Purify the mixture by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to obtain methyl 2-(4-nitrophenoxy)nicotinate (650 mg). LC-MS m / z (ESI): 275.0 [M+1]. + .

[0237] Step 2: Dissolve methyl 2-(4-nitrophenoxy)nicotinate (470 mg, 1.71 mmol) in THF (20 mL). Cool to -78°C under argon, then add dropwise a 1 M (mol / L) solution of lithium aluminum hydride in THF (2.57 mL). Continue stirring at -78°C for 1 hour. Quench the reaction by adding sodium sulfate decahydrate. Filter and concentrate under reduced pressure. Purify by silica gel column chromatography (PE / EA = 1 / 0 to 0 / 1) to yield (2-(4-nitrophenoxy)pyridin-3-yl)methanol (405 mg). MS m / z (ESI): 247.0 [M+1]. + .

[0238] Step 3: Dissolve (2-(4-nitrophenoxy)pyridin-3-yl)methanol (200 mg, 812.29 μmol) in DCM (10 mL), cool to 0°C under argon, and add bis(2-methoxyethyl)aminosulfur trifluoride (539.13 mg, 2.44 mmol) dropwise. The reaction mixture is allowed to warm to room temperature and stirred for 5 hours. Saturated sodium bicarbonate solution (30 mL) is added, and the mixture is extracted with DCM (30 mL x 3). The organic phase is dried, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE / EA = 1 / 0 to 3 / 1) yields 3-(fluoromethyl)-2-(4-nitrophenoxy)pyridine (177 mg). MS m / z (ESI): 249.0 [M+1] + .

[0239] Step 4: 3-(Fluoromethyl)-2-(4-nitrophenoxy)pyridine (100 mg, 402.89 μmol), iron powder (112.50 mg, 2.01 mmol), and ammonium chloride (107.75 mg, 2.01 mmol) were added to methanol (2 mL), THF (2 mL), and water (2 mL). The reaction mixture was stirred at 75°C for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) afforded A-7 (82 mg). MS m / z (ESI): 219.1 [M+1] + .

[0240] Preparation of intermediate A-6

[0241] Using methyl 6-fluoropyridine-2-carboxylate as starting material, intermediate A-6 was obtained by referring to the preparation method of intermediate A-7. MS m / z (ESI): 219.1 [M+1] + .

[0242] Example 1: Preparation of Compound IV-1

[0243] To a 10L reactor, bromododecane X-1 (1.18 kg), anhydrous ethanol (5.9 L) and thiourea (360 g) were added in sequence, stirring was started, the oil bath was heated to an internal temperature of 75-80°C, and the temperature was controlled and stirred overnight; after reacting overnight, the temperature was lowered to 20°C to 30°C, the solvent was concentrated and removed, MTBE (3 L) was added and the mixture was beaten and stirred for 1 h, filtered, and the filter cake was dried under reduced pressure at 45°C to give IX-1 (1.09 kg, yield 71%, white powdery solid).

[0244] Add IX-1 (200 g), tert-butyl isocyanate (64.0 g), and DMF (800 mL) to a three-necked flask. Slowly add DBU (98.4 g) dropwise with stirring, maintaining the internal temperature at no more than 5°C. After the addition is complete, maintain the internal temperature at 0°C to 5°C and stir for 1 hour. Then, add CDI (119.7 g) to the reaction flask, followed by the slow addition of DBU (103.07 g). After the addition is complete, raise the internal temperature of the reaction system to 45°C and stir overnight. The reaction solution was added to water (4 L), stirred, extracted with ethyl acetate (1 L × 3), and the organic phases were combined. The organic phases were washed with aqueous hydrochloric acid solution (1 mol / L, 600 mL × 2), washed with water (600 mL × 2), and washed with saturated aqueous sodium chloride solution (600 mL × 1). Dry with an appropriate amount of anhydrous sodium sulfate, filter, and concentrate to constant weight to obtain VII-1 (230 g, purity 95.9%, yield 101.3%, colorless oil). 1 H NMR (400MHz, CDCl3) δ (ppm): 10.37 (br s,1H),3.15(t,J=7.2Hz,2H),1.72-1.65(m,2H),1.25(s,9H),1.44-1.35(m,2H),1.31-1.19(m,16H),0.87(t,J=6.8Hz,3H). MS m / z(ESI):314.1[M-56+H] + .

[0245] VII-1 (190 g), 1-(bromomethyl)-4-chlorobenzene (105.6 g), potassium carbonate (85.3 g), and DMF (950 mL) were added to a 2 L three-necked flask and stirred at room temperature overnight. The reaction solution was added to water (4.75 L), stirred, and extracted with ethyl acetate (950 mL × 3). The combined organic phases were washed with water (950 mL × 3) and saturated sodium chloride solution (950 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to constant weight to obtain VI-1 (235 g, purity 95.0%, yield 92.5%, orange-yellow oil). 1 H NMR (400MHz, CDCl3) δ (ppm): 7.32-7.29 (m, 2H), 7.27-7.24 (m, 2H), 5.01 (s, 2H), 3.16 (t, J = 7.6Hz, 2H),1.71-1.63(m,2H),1.65(s,9H),1.43-1.33(m,2H),1.30-1.20(m,16H),0.88(t,J=6.4Hz,3H).

[0246] VI-1 (235 g) and trifluoroacetic acid (705 mL) were added to a three-necked flask and stirred at room temperature for 2 hours. The reaction solution was concentrated, and the concentrate was added to water (1.18 L). The pH of the aqueous phase was adjusted to 7-8 with an appropriate amount of solid sodium carbonate. The mixture was beaten for 2 hours and filtered. The filter cake was rinsed with an appropriate amount of water and concentrated under reduced pressure to a constant weight to obtain IV-1 (190 g, crude product, yield 91.3%, purity 95.2%).

[0247] The crude product of IV-1 (100 g) and ethyl acetate (1 L) were added to a three-necked flask and heated to reflux. After the system was basically dissolved, the heating was turned off and the temperature was naturally stirred to cool and precipitate. After cooling to room temperature, it was stirred for 1 hour and filtered. The filter cake was rinsed with ethyl acetate (100 mL × 1), and the filter cake was dried under reduced pressure to constant weight to obtain IV-1 (89 g, yield 89%, purity 99.6%, white solid). 1 H NMR (400MHz, CDCl3) δ (ppm): 10.37 (br s,1H),7.34-7.26(m,4H),5.10(s,2H),3.20(t,J=7.2Hz,2H),1.71-1.6 4(m,2H),1.42-1.33(m,2H),1.31-1.19(m,16H),0.87(t,J=6.4Hz,3H). MS m / z(ESI):438.2[M+1] + .

[0248] Example 2: Preparation of Compound V-21

[0249] Under nitrogen, sodium hydride (14.6 g) was placed in a 1 L reaction flask, followed by toluene (500 mL). Triethyl phosphoacetate (75.1 g) was then added dropwise. After the addition was complete, the temperature was raised to 45°C and stirring was continued for 1 h. XV-1 (50 g) was then added dropwise. After the addition was complete, the temperature was raised to 100°C and the reaction was allowed to react overnight. The internal temperature was lowered to 0-10°C. Saturated ammonium chloride solution (2 × 100 mL) was added to the reaction solution for washing. The mixture was separated and the toluene phase was collected and used directly in the next reaction.

[0250] Sodium hydroxide (24.4 g) was dissolved in water (122 g), and the toluene solution was added. The mixture was heated to 90°C and refluxed for 3 hours. The temperature was then lowered and the organic phase was separated. Toluene (200 mL) was added to the aqueous phase, and the pH of the aqueous phase was adjusted to about 2.0 with concentrated hydrochloric acid. The mixture was allowed to stand for stratification, and the toluene phase was separated. The phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain 31.5 g of crude product. The crude product was dissolved in MTBE (about 160 mL), and S-1-phenylethylamine (18.5 g) was added dropwise. A large amount of solid precipitated. The mixture was stirred for 1 hour and filtered. The filter cake was rinsed with an appropriate amount of MTBE to obtain 46 g of wet filter cake. The filter cake was dissolved in water (460 mL), and MTBE (about 460 mL) was added. The pH was adjusted to about 2.5 with concentrated hydrochloric acid. After stirring, the mixture was allowed to stand and the liquid was separated. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and dried to obtain XIII-1 (24 g, yield 40%, purity 96.1%). 1 H NMR (400MHz, CDCl3) δ (ppm): 10.00 (br s,1H),7.37-7.26(m,5H),4.53(s,2H),3.48(dd,J=10.40Hz,J=5.84Hz,1H),3.39-3.34(dd,J=10. 40Hz, J=6.56Hz,1H),1.85-1.77(m,1H),1.60-1.56(m,1H),1.30-1.25(m,1H),0.97-0.92(m,1H). MS m / z(ESI):229.1[M+Na] + .

[0251] XIII-1 (202 g), L-menthol (153.1 g), DMAP (23.9 g), EDCI (244.1 g), and dichloromethane (1 L) were added to a 2 L three-necked flask and stirred at room temperature overnight. The organic phase was washed with hydrochloric acid solution (1 mol / L, 1 L x 2) and then with water (1 L x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain XII-1 (320 g, crude product, approximately 95% yield), which was used directly in the next reaction.

[0252] The crude product XII-1 (14.5 g) was dissolved in 100 mL of ethanol, 10% palladium carbon (1.45 g) was added, and the reaction solution was heated to reflux in a hydrogen atmosphere. The reaction was allowed to react overnight, the palladium carbon was filtered off, and the solvent was dried to obtain 10.5 g of a white solid. Petroleum ether (52.5 mL) was added to dissolve the solid, heated to 70-75 ° C to dissolve it, cooled to 0 ° C ~ 10 ° C to precipitate the solid, and filtered to obtain a filter cake. Petroleum ether (52.5 mL) was added to the filter cake, heated to 70-75 ° C to dissolve it, cooled to 0 ° C ~ 10 ° C to precipitate the solid, and filtered to obtain a filter cake. The filter cake was dried to obtain XI-1 (6.8 g, white solid, two-step yield 60.2%). 1 H NMR (400MHz, CDCl3) δ (ppm): 4.65 (td, J = 10.88Hz, J = 4.36Hz, 1H), 3.57 (dd, J = 11.44Hz, J=6.28Hz,1H),3.51(dd,J=11.40Hz,J=6.68Hz,1H),1.99-1.96(m,1H),1.90-1.82(m,2 H),1.74-1.63(m,3H),1.56-1.50(m,1H),1.48-1.41(m,1H),1.39-1.32(m,1H),1.23-1 .18(m,1H),1.01-0.94(m,2H),0.90-0.87(m,6H),0.85-0.83(m,1H),0.75-0.74(m,3H). MS m / z(ESI):277.2[M+Na] + .

[0253] Dissolve XI-1 (144 g) in dichloromethane (1.4 L), add triethylamine (68.7 g), and add p-toluenesulfonyl chloride (129.5 g) in batches. React at room temperature overnight. The reaction solution is washed with hydrochloric acid aqueous solution (1 mol / L, 720 mL × 2), and the organic phase is dried over anhydrous sodium sulfate. Filter and spin-dry to obtain V-21 (247 g, crude product, light yellow solid). The crude product is refluxed with ethanol (650 mL) at 75°C to 80°C, crystallized at 10°C to 20°C, and the above recrystallization process is repeated twice. Filter and dry to obtain V-21 (165 g, yield 71.3%, purity 99.8%). 1H NMR (400MHz, CDCl3) δ (ppm): 7.79 (d, J = 8.20Hz, 2H), 7.35 (d, J = 8.08Hz, 2H), 4.6 4(td,J=10.88Hz,J=4.36Hz,1H),3.98-3.90(m,2H),2.45(s,3H),1.97-1.94(m,1 H),1.85-1.79(m,1H),1.75-1.64(m,3H),1.55-1.50(m,1H),1.48-1.45(m,1H),1 .39-1.33(m,1H),1.22-1.18(m,1H),1.13-0.80(m,10H),0.73(d,J=6.96Hz,3H).

[0254] The obtained compound of formula (V-21) (500 mg) was added to a mixed solvent of toluene (2 mL) and n-heptane (2 mL), heated to 70°C to dissolve, and then allowed to stand at room temperature overnight to obtain colorless crystals, which were single crystals of the compound of formula (V-21). Single crystal X-ray diffraction (SXRD, instrument model: D8venture, manufacturer: Bruker) analysis was performed to obtain the molecular three-dimensional structure ellipsoid diagram of the compound of formula (V-21) as shown in Figure 1. The analysis results showed that the Flack constant was 0.01 (6), the chiral C7 and C10 were in R configuration, and the chiral C4, C12 and C14 were in S configuration, that is, the compound of formula (V-21) was (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl (1S, 2S)-2-((tosyloxy)methyl)cyclopropanecarboxylate.

[0255] Example 3: Preparation of Compound XI-2

[0256] Compound XIII-1 (5.0 g) was dissolved in dichloromethane (50 mL), and (R)-4-benzyl-2-oxazolidinone (4.3 g), EDCI (6.0 g), and DMAP (0.6 g) were added. The mixture was reacted at 20-25°C overnight. The reaction solution was washed with hydrochloric acid solution (1 mol / L, 25 mL × 2) and water (25 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (mobile phase: PE:EA = 1:1) to obtain XII-2 (7.8 g, colorless oil, crude product), which was used directly in the next reaction.

[0257] The crude product XII-2 (3.0 g) from the previous step was diluted with ethanol (30 mL), and 10 wt% palladium carbon was added. After the reaction was refluxed overnight under a hydrogen atmosphere, the palladium carbon was filtered off and the solvent was removed by vortexing to obtain XI-2 (1.8 g, crude product). After purification by silica gel column chromatography (PE:EA=1:1), the product was concentrated to obtain XI-2 (1.5 g, colorless oil, total yield of two steps 60%). 1 H NMR (400MHz, CDCl3) δ (ppm): 7.33-7.17 (m, 5H), 4.64-4.59 (m, 1H), 4.23-4.15 (m, 2H), 3.84 (dd, J = 11.68, J = 5.12, 1H), 3.30 (dd, J = 11 .68,J=8.28,1H),3.23(dd,J=13.40,J=2.80,1H),2.82(m,2H),2.70(s,1H),1.84-1.76(m,1H),1.51-1.46(m,1H),1.00-0.95(m,1H).

[0258] Example 4: Preparation of Compound III-1

[0259] Compound IV-1 (50.0 g) and compound V-21 (56.3 g) were weighed and placed in a three-necked flask. DMF (500 mL) was added and stirred. Potassium carbonate (25.4 g) was added, and the temperature was raised to 35°C and allowed to react overnight. Ethyl acetate (750 mL) and water (2.5 L) were added to the reaction solution and stirred. The mixture was allowed to stand and the organic phase was separated. The aqueous phase was further extracted with ethyl acetate (750 mL x 2). The organic phases were combined. The organic phases were washed with saturated brine (1 L x 3) and dried over anhydrous sodium sulfate. The mixture was filtered, the ethyl acetate was removed by vacuum vortexing, and n-heptane (250 mL) was added and stirred for 3 hours. The white solid was removed by filtration. Medicinal charcoal (5.0 g) was added to the filtrate and stirring continued for 3 hours. The mixture was filtered using diatomaceous earth. The n-heptane was removed by vacuum vortexing to obtain III-1 (74 g, 90% yield, 96% purity, as a colorless oil). 1H NMR (400MHz, CDCl3) δ (ppm): 7.30 (dd, J = 18.4Hz, J = 8.6Hz, 4H), 5.13 (d, J = 16.0Hz, 1H), 5.06 ( d,J=16.0Hz,1H),4.63(td,J=10.8Hz,J=4.3Hz,1H),3.96(dd,J=13.6Hz,J=6.8Hz,1H),3.80( dd,J=13.6Hz,J=7.7Hz,1H),3.21(t,J=14.8Hz,2H),2.35(s,2H),1.97-1.94(m,1H),1.88-1. 81(m,2H),1.50-1.19(m,22H),1.19-1.13(m,1H),1.11-0.81(m,14H),0.73(d,J=6.9Hz,3H).

[0260] Example 5: Preparation of Compound III-1

[0261] Compound XI-1 (5.0 g), compound IV-1 (8.6 g), triphenylphosphine (6.19 g), and THF (40 ml) were added to a 100 mL three-necked flask and stirred. The temperature was lowered to -5°C and DEAD (4.1 g) was slowly added dropwise. After the temperature was restored to room temperature, the mixture was stirred overnight until the reaction was complete. The reaction solution was dried, water (50 mL) was added, and MTBE was extracted (20 mL x 3). After drying, the product was purified by silica gel column chromatography (ethyl acetate: n-heptane = 1:3 (volume ratio)) to obtain III-1 (9.22 g, 69.6% yield, oil).

[0262] Example 6: Preparation of Compound II-4

[0263] To a 250 mL three-necked flask, add III-1 (33 g) and toluene (33 mL), start stirring, then add A-4 (10 g) and cyclohexanecarboxylic acid (31.4 g), heat to an internal temperature of 100 ° C, and heat to react for 6 hours. The system is cooled to room temperature, ethyl acetate (330 mL) is added to dilute the system, and then washed with 0.5 mol / L sodium hydroxide solution (330 mL × 3), washed with saturated brine (330 ml × 1), dried over anhydrous sodium sulfate, filtered, and the organic phase is concentrated to constant weight. Ethyl acetate (33 ml) is added to dissolve the concentrate, and the concentrate is added dropwise to n-heptane (990 ml). After the addition is complete, stir at room temperature for 1 hour, filter, and the filter cake is pulled dry to constant weight to obtain II-4 (28.1 g, yield 85.0%, purity 94.2%, light yellow solid). 1H NMR (400MHz, DMSO-d6): δ (ppm): 10.67 (br, 0.3H), 9.36 (s, 1H), 8.15-8.14 (d, J=3.08Hz, 1H), 7.83-7.79 (td, J=8.64Hz, J=3.12 Hz,1H),7.43-7.41(d,J=8.32Hz,2H),7.35-7.33(d,J=8.56Hz,2H),7.12-7.10 (d,J=8.80Hz,2H),5.32-5.23(m,2H),4.56-4.49(td,J=10.92Hz,J=4.36Hz,1H) ,3.71-3.69(m,2H),1.18-1.73(m,,2H),1.66-1.57(m,4H),1.49-1.47(m,1H), 1.34-1.28(m,1H),1.22(s,1H),1.04-0.81(m,12H),0.67-0.65(d,J=6.92,3H). MS m / z(ESI):676.2[M+1] + .

[0264] Referring to the preparation method of Example 1-6, the intermediate A-4 was replaced with the corresponding intermediate shown in the following table to prepare the compound of formula (II) shown in Table 1:

[0265] Table 1

[0266] Example 30: Preparation of Compound I-4

[0267] In a 500 mL three-necked flask, II-4 (22.5 g), THF (225 mL), MeOH (112.5 mL), and water (90 mL) were added and stirred. LiOH (6.5 g) was then added and the temperature was raised to 55-60°C. The mixture was stirred overnight. The solvent was removed by vortexing under reduced pressure. Water (225 mL) was added to the residue and stirred. MTBE (112.5 mL x 3) was added and the aqueous phase was collected. The pH was adjusted to 3.97 with saturated KHSO4 solution. Stirring was continued for 1 hour. The mixture was filtered and the filter cake was rinsed with water. The filter cake was dried in a vacuum oven at 60°C overnight to obtain an off-white solid I-4 (13.1 g, yield 73.2%, purity 96.0%). MS m / z (ESI): 538.1 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.26 (br, 0.2H), 8.14 (d, J = 3.1 Hz, 1H), 7.84-7.76 (m, 1H), 7.38 (dd, J = 19.6, 8.5 Hz, 4H), 7.29-7.00 (m, 5H), 5.23 (s, 2H), 3.67 (ddd, J = 20.7, 13.7, 6.5 Hz, 2H), 1.57 (d, J = 3.8 Hz, 2H), 0.97-0.88 (m, 2H). The obtained solid was subjected to XRPD detection, and its XRPD pattern is shown in Figure 2.

[0268] With reference to the preparation method of Example 30, the intermediates in Table 1 were used as raw materials to prepare the compounds shown in Table 2. Wherein, using II-1, II-9 or II-17 as raw materials, the compound of formula (I-1) was prepared; using II-2, II-10 or II-18 as raw materials, the compound of formula (I-2) was prepared; using II-3, II-11 or II-19 as raw materials, the compound of formula (I-3) was prepared; using II-12 or II-20 as raw materials, the compound of formula (I-4) was prepared; using II-5, II-13 or II-21 as raw materials, the compound of formula (I-5) was prepared; using II-6, II-14 or II-22 as raw materials, the compound of formula (I-6) was prepared; using II-7, II-15 or II-23 as raw materials, the compound of formula (I-7) was prepared; using II-8, II-16 or II-24 as raw materials, the compound of formula (I-8) was prepared.

[0269] Table 2

[0270] Example 38

[0271] The conditions for the nucleophilic substitution reaction of the compound of formula (III-A) and the compound of formula (AI) were screened:

[0272] (1) The compound of formula (III-2) (0.19 mmol, 100 mg) and the compound of formula (A-4) (0.19 mmol, 38 mg) were reacted in the presence of an acid (0.95 mmol) by heating to 100°C. During the reaction, an appropriate amount of solvent may or may not be added, depending on the reaction requirements. The reaction conditions and results are shown in Table 3.

[0273] Table 3

[0274] As can be seen from the above results, when using acetic acid, some acylation reactions still occur, and when using acetic acid, post-processing needs to be carried out by column chromatography, which is cumbersome to operate and is unfavorable for industrialized production. When using cyclohexanecarboxylic acid, the reaction can react completely, and post-processing is simple and easy, and only alkaline water washing is required to remove cyclohexanecarboxylic acid, thus avoiding cumbersome column chromatography purification operations.

[0275] (2) The compound of formula (III-1) (0.15 mmol, 100 mg) and the compound of formula (A-4) (0.15 mmol, 30.7 mg) were reacted in the presence of a reaction reagent (0.75 mmol) by heating to 100°C. During the reaction, an appropriate amount of solvent may or may not be added, depending on the reaction requirements. The reaction conditions and results are shown in Tables 4 and 5.

[0276] Table 4 Note: a: The boiling point of dimethyltetrahydrofuran is 80℃ and it cannot be heated to 100℃.

[0277] From the above experimental results, it was found that the use of Lewis acids, inorganic acids, aromatic-substituted organic acids and straight-chain carboxylic acids as reaction reagents resulted in either no product formation or serious side reactions, while the use of branched carboxylic acids or saturated or partially unsaturated carbocyclic-substituted carboxylic acids as reaction reagents allowed the reaction to proceed smoothly.

[0278] Table 5

[0279] In addition, after the reaction, it was found that the use of saturated or partially unsaturated carbon ring-substituted carboxylic acids is more conducive to post-processing operations. For example, when using cyclohexanecarboxylic acid, it can be removed by washing with an alkaline aqueous solution (such as a 0.5 mol / L sodium hydroxide aqueous solution), which is simpler to operate and has low residue in the product. After the reaction using branched carboxylic acids (such as pivalic acid, isobutyric acid, 2-ethylbutyric acid, etc.), it is difficult to remove them by alkaline washing during post-processing, and there are a lot of residues in the product (the weight of the crude product obtained exceeds 100%). Biological test

[0280] Test Example 1: FLIPR assay to screen compounds for hP2X3 / hP2X 2 / 3 Receptor antagonist activity

[0281] The materials are shown in Table 6:

[0282] Table 6

[0283] Cell preparation: Cells 1321N1 / hP2X3 and 1321N1 / hP2X2 / 3 (supplier Chempartner) were stably transfected with Versene digestion solution, centrifuged, resuspended in plating medium (DMEM + 10% DFBS), and counted. The cell count was adjusted to 3 × 105 cells / mL, 50 μL of cells were plated in each well of a 384-well test plate, and the plate was placed in a 5% CO2, 37°C incubator for 16-24 h.

[0284] The cell culture medium formula is shown in Table 7:

[0285] Table 7

[0286] The experimental dye solution (Dye) formula is shown in Table 8:

[0287] Table 8

[0288] Compound preparation: 1. Test sample: Prepare the test compound at 180 times the required concentration in DMSO (54 mM DMSO stock solution) in a 384-well polypropylene microplate that meets the Echo standard. Add 500 nL per well to the 384-well compound plate and supplement with 30 μL of assay buffer (containing 1.26 mM Ca 2+ 1× HBSS+2mM CaCl2+20mM HEPES) and shake for 20-40min to mix.

[0289] 2. Agonist: Prepare agonist (α, β-meATP) at 3 times the required concentration in assay buffer (the final concentration for hP2X3 and hP2X2 / 3 cells is 3000 nM) and add 45 μL of agonist to each well of a 384-well compound plate.

[0290] Dye incubation: Take out the cell plate, remove the cell supernatant, and add 30 μL Dye ( Calcium 4 Assay Kit, diluted in assay buffer) and incubated for 1 h.

[0291] FLIPR assay: Add 15 μL of compound to each well of the cell plate (FLIPR instrument loading). After 15 minutes, add 22.5 μL of agonist to each well and detect the fluorescence signal (excitation wavelength 470 nm-495 nm, emission wavelength 515 nm-575 nm).

[0292] Data processing: The difference between the peak and valley values ​​of the signal was taken as the basic data. The highest concentration data of the positive drug was taken as 100% inhibition rate, and the DMSO data was taken as 0% inhibition rate. The inhibitory effect curve of the compound was fitted by (log (inhibitor) vs. response--Variable slope) on the software Graphpad Prism 6 and the IC was calculated. 50 value.

[0293] Assay uniformity criteria: Perform ≥12 max values ​​(DMSO treatment results) and ≥12 min values ​​(maximum concentration of the positive drug treatment results) on each plate. Calculate the Z score. If Z ≥ 0.5, the replicate wells are considered uniform and the data reliable. The Z score calculation formula is: Z = 1 - 3 * (SDmax + SDmin) / (MEANmax - MEANmin). The test results are shown in Tables 9 and 10.

[0294] Table 9 Inhibitory activity of compounds against P2X3

[0295] Table 10 The ratio of the inhibitory activity of the compounds on P2X2 / 3 to the inhibitory activity on P2X3

[0296] As can be seen from Tables 9 and 10, the compound of formula (I-4) of the present application has a high inhibitory activity against P2X3, a low inhibitory activity against P2X2 / 3, and a high inhibitory selectivity.

[0297] Test Example 2: Evaluation of analgesic effect in rat CFA inflammatory pain model

[0298] Experimental Animals: 50 male Sprague-Dawley rats, weighing 230-260 g, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. After purchase, animals were provided with food and water ad libitum at a temperature of 20-25°C and a humidity of 40-70%. They were housed in individual cages and tail-tagged. The experimental design, group assignments, and drug treatments are shown in Table 11.

[0299] Table 11 Experimental design, grouping and drug treatment

[0300] Complete Freund's adjuvant (CFA) and saline were mixed in equal amounts to create an emulsion, which was then injected subcutaneously into rats. Animals were placed in a custom-designed pain test multi-unit metal mesh cage and allowed to acclimate for 15 minutes. After the animals had completed their grooming and exploratory activities and had adapted to the testing environment, a series of calibrated von Frey filaments (0.4, 0.6, 1.0, 1.4, 2, 4, 6, 8, 10, and 15 g) were applied to the hind paw for 6-8 seconds. A withdrawal reflex was recorded as a pain response, and pain was assessed using the paw withdrawal threshold (PWT). The experiment was conducted blindly, and results are presented as mean ± standard deviation. Data were analyzed using GraphPad Prism 5-point t-tests. P < 0.05 was considered statistically significant. The specific experimental results are shown in Figures 3 and 4. It can be seen from Figures 3 and 4 that 2 hours after administration, the compound of formula (I-4) significantly inhibited mechanical allodynia in the rat CFA inflammatory pain model. The effective dose in the rat CFA inflammatory pain model was 30 mg / kg, and the medium and high doses (60 mg / kg) still had a good analgesic effect 4 hours after administration.

[0301] Test Example 3: Pharmacokinetic study in rats after single administration

[0302] Experimental Animals: 24 male Sprague-Dawley rats, SPF grade, weighing 200-240 g, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. Animals were provided with food and water ad libitum at a temperature of 20-25°C and a humidity of 40-70%. They were housed in individual cages and tail-tagged. The experimental design, group assignments, and drug treatments are shown in Table 12.

[0303] Table 12 Experimental design, grouping and drug treatment

[0304] Animals were randomly divided into groups based on body weight. Each group received a single oral dose according to the dose design shown in Table 12. The drug vehicle consisted of a 1 / 3 0.5% HPC (pH 7.5) and 2 / 3 20% captisol (pH 7.4) aqueous solution (HPC manufacturer: Sigma-Aldrich, batch number: MKBJ6793V; captisol manufacturer: Bidex Pharmaceuticals, batch number: DQP029). Animals were fasted overnight before dosing and resumed feeding 4 hours after dosing, with free access to water. Whole blood was collected from each dose group at 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 7 hr, and 24 hr after dosing. Plasma samples were obtained by centrifugation and quantitatively analyzed by LC-MS / MS. The pharmacokinetic profile of each group in SD rats was investigated. The results are shown in Table 13. The exposure of the compound of formula (I-4) at each dose was comparable to that of D1.

[0305] Table 13 Pharmacokinetic parameters in rats

[0306] Test Example 4: Toxicity Test

[0307] Experimental Animals: 16 male and 16 female Sprague-Dawley rats (SPF grade). Male Sprague-Dawley rats weighed approximately 240 g and were 6-9 weeks old; female Sprague-Dawley rats weighed approximately 200 g and were 6-9 weeks old. All experimental animals were purchased from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd. and provided with food and water ad libitum. The animals were housed at a temperature of 20-26°C, a humidity of 40-70%, and 100% fresh air with 15 or more air changes per hour. The lighting was automated, with a 12-hour light-dark cycle. Males and females were housed in separate cages, with no more than five animals per cage.

[0308] Animals were randomly divided into groups based on sex and body weight. Each group received oral administration of the drug according to the dosage design shown in Table 14, once daily for 14 consecutive days. The drug solvent was a 5 wt% polyethylene glycol stearate (Solutol) + 1 wt% RC591 (Solutol manufacturer: BASF, lot number: BCCD3924; RC591 manufacturer: Du Pont, USA, lot number: DN19833862) aqueous solution. Blood samples were collected before the first and last doses, and 30 minutes, 1 hour, 4 hours, 7 hours, 10 hours, and 24 hours after each dose. The toxicokinetic process of each group in SD rats was investigated. The results are shown in Table 15.

[0309] Table 14 Experimental dosage design

[0310] Safety window calculation basis: According to Test Example 3, the onset dose of the compound of formula (I-4) in the rat pain model is 30 mg / kg, the peak concentration (Cmax) at this dose is about 18.4 μg / mL, and the area under the drug concentration-time curve (AUC) is about 249hr*μg / mL. Synchronous test example 3 experiment, the onset dose of the D1 compound in the rat pain model is 60 mg / kg, the Cmax at this dose is about 141 μg / mL, and the AUC is about 1566hr*μg / mL. Safety window (Cmax) = Cmax at the last dose ÷ Cmax at the onset dose, safety window (AUC 0-t ) = AUC at the last dose ÷ AUC at the effective dose.

[0311] Table 15 Toxicokinetic analysis of rat toxicity study

[0312] During the test period, no significant abnormalities were observed in the body weight of the animals in each group, and no animals died or were dying. The data in Table 15 also show that the compound of formula (I-4) has a relatively high safety window.

[0313] The structure of compound D1 (CAS: 1640808-39-4) in Test Example 3 and Test Example 4 is shown below, and it can be obtained from commercial sources or prepared according to existing techniques.

[0314] All documents mentioned in this invention are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above disclosure, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the appended claims.

[0315] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0316] The embodiments described above only express several implementation methods of the present invention, which are convenient for understanding the technical solutions of the present invention in a specific and detailed manner, but they cannot be understood as limiting the scope of protection of the invention patent. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present invention, several variations and improvements can be made, which all fall within the scope of protection of the present invention. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present invention are all within the scope of protection of the claims attached to the present invention. Therefore, the scope of protection of the patent of the present invention shall be based on the content of the attached claims, and the description and drawings can be used to interpret the content of the claims.

[0317] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A compound of formula (II-A), or a salt thereof, or a tautomer thereof: in, r is 1, 2, or 3; (R d ) k Indicates that the hydrogen on the pyridine ring is replaced by k R d substituted, k is selected from 0, 1, 2, 3 or 4; each R d are the same or different and are each independently selected from the following group: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), C1-8 alkoxy (preferably C1-6 alkoxy, more preferably C1-3 alkoxy), C2-4 alkenyl, C2-4 alkynyl, halogenated C1-8 alkyl (preferably halogenated C1-6 alkyl, more preferably halogenated C1-3 alkyl), cyano-substituted C1-8 alkyl (preferably cyano-substituted C1-6 alkyl, more preferably cyano-substituted C1-3 alkyl), halogenated C1-8 alkoxy (preferably halogenated C1-6 alkoxy, more preferably halogenated C1-3 alkoxy), NR a0 R b0 , -SO2C1-3 alkyl, -S(O)C1-3 alkyl, -SC1-3 alkyl, -C(O)NR a1 R b1 , -C(O)C1-8 alkyl (preferably -C(O)C1-6 alkyl, more preferably -C(O)C1-3 alkyl), -C(O)OC1-8 alkyl (preferably -C(O)OC1-6 alkyl, more preferably -C(O)OC1-3 alkyl), -OC(O)C1-8 alkyl (preferably -OC(O)C1-6 alkyl, more preferably -OC(O)C1-3 alkyl), C3-6 cycloalkyl, C3-6 cycloalkyloxy, 3 to 6-membered heterocycloalkyl, phenyl and 5 to 6-membered heteroaryl; wherein the 3 to 6-membered heterocycloalkyl, phenyl and 5 to 6-membered heteroaryl are unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of halogen, cyano, hydroxy, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, halo-substituted C1-3 alkyl, halo-substituted C1-3 alkoxy, NR a0 R b0 , -SO2C1-3 alkyl, -S(O)C1-3 alkyl, -SC1-3 alkyl, -C(O)NR a1 R b1 , -C(O)OC1-3 alkyl, -OC(O)C1-3 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; (R a ) n Indicates that the hydrogen on the benzene ring is replaced by n R a substituted, n is 0, 1 or 2; each R a are the same or different and are each independently deuterium, cyano, hydroxy, carboxyl, halogen (preferably fluorine or chlorine), C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), halo-substituted C1-8 alkyl (preferably halo-substituted C1-6 alkyl, more preferably halo-substituted C1-3 alkyl), cyano-substituted C1-8 alkyl (preferably cyano-substituted C1-6 alkyl, more preferably cyano-substituted C1-3 alkyl), C1-8 alkoxy (preferably C1-6 alkoxy, more preferably C1-3 alkoxy), -C(O)C1-8 alkyl (preferably -C(O)C1-6 alkyl, more preferably -C(O)C1-3 alkyl), -C(O)OC1-8 alkyl (preferably -C(O)OC1-6 alkyl, more preferably -C(O)OC1-3 alkyl), -OC(O)C1-8 alkyl (preferably -OC(O)C1-6 alkyl, more preferably -OC(O)C1-3 alkyl) or -C(O)NR a1 R b1 ; R c is hydrogen, deuterium, C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), C3-8 cycloalkyl (preferably C3-6 cycloalkyl), C1-8 alkoxy (preferably C1-6 alkoxy, more preferably C1-3 alkoxy), cyano, hydroxy, carboxyl or halogen (preferably fluorine or chlorine); (R b ) m Indicates that the hydrogen on the benzene ring is replaced by m R b substituted, m is 0, 1 or 2; each R b are the same or different and are each independently deuterium, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), halogenated C1-8 alkyl (preferably halogenated C1-6 alkyl, more preferably halogenated C1-3 alkyl), cyano-substituted C1-8 alkyl (preferably cyano-substituted C1-6 alkyl, more preferably cyano-substituted C1-3 alkyl), C1-8 alkoxy (preferably C1-6 alkoxy, more preferably C1-3 alkoxy), -SC1 -8 alkyl (preferably -SC1-6 alkyl, more preferably -SC1-3 alkyl), -C(O)C1-8 alkyl (preferably -C(O)C1-6 alkyl, more preferably -C(O)C1-3 alkyl), -C(O)OC1-8 alkyl (preferably -C(O)OC1-6 alkyl, more preferably -C(O)OC1-3 alkyl), -OC(O)C1-8 alkyl (preferably -OC(O)C1-6 alkyl, more preferably -OC(O)C1-3 alkyl), -C(O)NR a1 R b1 , C3-6 cycloalkyl or phenyl; wherein the phenyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of halogen, cyano, hydroxy, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, halogenated C1-3 alkyl, halogenated C1-3 alkoxy, NR a0 R b0 、 -SO2C1-3 alkyl, -S(O)C1-3 alkyl, -C(O)NR a1 R b1 , -C(O)OC1-3 alkyl, -OC(O)C1-3 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; R0 is a chiral auxiliary group, preferably R0 is R a1 、R b1 are each independently hydrogen or C1-3 alkyl; or R a1 、R b1 Together with the nitrogen atom to which it is attached, it forms a 4- to 6-membered saturated monocyclic heterocyclic ring; the 4- to 6-membered saturated monocyclic heterocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, halo-substituted C1-3 alkyl, halo-substituted C1-3 alkoxy, -SO2C1-3 alkyl, -S(O)C1-3 alkyl, -C(O)NH2, -C(O)NH(C1-3 alkyl), -C(O)N(C1-3 alkyl)2, -C(O)OC1-3 alkyl, -OC(O)C1-3 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl; R a0 、R b0 are each independently hydrogen, C1-3 alkyl or acetyl; or R a0 、R b0 Together with the nitrogen atom to which it is attached, it forms a 4- to 6-membered saturated monocyclic heterocyclic ring; the 4- to 6-membered saturated monocyclic heterocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, halo-substituted C1-3 alkyl, halo-substituted C1-3 alkoxy, -SO2C1-3 alkyl, -S(O)C1-3 alkyl, -C(O)NH2, -C(O)NH(C1-3 alkyl), -C(O)N(C1-3 alkyl)2, -C(O)OC1-3 alkyl, -OC(O)C1-3 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl.

2. The compound according to claim 1, or a salt thereof, or a tautomer thereof, characterized in that The structure of formula (II-A) is the structure shown in formula (II-B):

3. The compound according to claim 1, or a salt thereof, or a tautomer thereof, characterized in that The formula (II-A) is selected from the following structures:

4. A method for preparing the compound of formula (II-A) according to claim 1, or a salt thereof, or a tautomer thereof, comprising the following steps: S1: subjecting the compound of formula (III) to a nucleophilic substitution reaction with the compound of formula (AI) to obtain the compound of formula (II-A): Among them, R A For the leaving group.

5. The preparation method according to claim 4, characterized in that The compound of formula (III) has a structure shown in formula (III-A), where R e It is a C1-20 alkyl group or a benzyl group, preferably a methyl group, an ethyl group, a dodecyl group or a benzyl group, more preferably a dodecyl group or a benzyl group.

6. The preparation method according to claim 4, characterized in that The nucleophilic substitution reaction is carried out in the presence of an acid. Preferably, the acid is a saturated or partially unsaturated carbocyclic substituted carboxylic acid, or a branched carboxylic acid. More preferably, the acid is selected from one or more of pivalic acid, cyclohexanecarboxylic acid, cyclopropylcarboxylic acid, cyclobutylcarboxylic acid, cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, isobutyric acid and 2-ethylbutyric acid. Further preferably, the acid is selected from one or more of cyclohexanecarboxylic acid, cyclopentanecarboxylic acid and cycloheptanecarboxylic acid.

7. A compound of formula (III-A) or a salt thereof: in, R e is a C1-20 alkyl group or a benzyl group, preferably a methyl group, an ethyl group, a dodecyl group or a benzyl group, more preferably a dodecyl group or a benzyl group; r、R c 、R b , m, R0 as defined in claim 1.

8. The method for preparing the compound of formula (III-A) or a salt thereof according to claim 7, characterized in that: The preparation method comprises the following steps: S2: reacting the compound of formula (IV) with the compound of formula (V) or the compound of formula (XI) to obtain a compound of formula (III-A), Among them, R f is -OTs, -OMs or halogen.

9. The preparation method according to claim 8, characterized in that The preparation method further comprises S3: reacting the compound of formula (VI) to obtain the compound of formula (IV), Among them, R g is a C1-10 alkyl group (preferably a C1-8 alkyl group, more preferably a C1-6 alkyl group, and further preferably a C1-3 alkyl group), a C3-8 cycloalkyl group, a C6-10 aryl group, or a C5-10 heteroaryl group, wherein the C1-10 alkyl group, the C3-8 cycloalkyl group, the C6-10 aryl group, or the C5-10 heteroaryl group is unsubstituted or replaced by one or more R g1 Substituted, the R g1 is selected from halogen, -NO2, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, C5-10 heteroaryl and C1-6 alkoxy; Optionally, the process further comprises S4: reacting the compound of formula (VII) with the compound of formula (VIII) to obtain the compound of formula (VI); Among them, R h is halogen, -OMs or -OTs; Optionally, the method further comprises S5: reacting the compound of formula (IX) with Rg-N=C=O to obtain the compound of formula (VII), Optionally, the method further comprises S6: reacting the compound of formula (X) with thiourea to obtain a compound of formula (IX), Wherein, X is fluorine, chlorine, bromine or iodine, preferably bromine.

10. A compound of formula (V) or a salt thereof: in, R f is -OTs, -OMs or halogen; r, R0 are as defined in claim 1.

11. The compound of formula (V) or a salt thereof according to claim 10, characterized in that The compound of formula (V) is selected from the following structures:

12. The method for preparing the compound of formula (V) or a salt thereof according to claim 10, characterized in that: The preparation method comprises the following steps: S7: reacting the compound of formula (XI) to obtain the compound of formula (V), 13. The preparation method according to claim 12, characterized in that The preparation method further comprises S8: reacting the compound of formula (XII) to obtain the compound of formula (XI), Among them, R i is a hydroxyl protecting group, further, the hydroxyl protecting group includes -Bn, TMS or TIPS; Optionally, the method further comprises S9: reacting the compound of formula (XIII) to obtain the compound of formula (XII), Optionally, the method further comprises S10: reacting the compound of formula (XIV) to obtain the compound of formula (XIII), Among them, R j is a C1-6 alkyl group, preferably -CH3 or -CH2CH3; Optionally, the process further comprises S11: reacting the compound of formula (XIV) to obtain the compound of formula (XIII), and then chirally resolving the compound of formula (XIII) to obtain a chirally pure compound of formula (XIII); When r is 1, the method further optionally comprises S12: reacting the compound of formula (XV) with a phosphonoester to obtain a compound of formula (XIV), 14. A method for preparing a compound of formula (I), a salt thereof, or a tautomer thereof, characterized in that: The following steps are involved: S13: reacting the compound of formula (II-A) to obtain the compound of formula (I); Among them, R d ,k,R a ,n,R c 、R b , m, r, R0 as defined in claim 1.

Images