Indazole benzoic acid derivative containing urea structure as well as preparation method and application of indazole benzoic acid derivative

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an indazole benzoic acid derivative containing a urea structure as well as a preparation method and application of the indazole benzoic acid derivative. The indazole benzoic acid derivative containing the urea structure provided by the invention has a typical benzoic acid structure as a primary pharmacophore of EP4, and molecular docking shows that a benzoic acid part and a key amino acid residue Arg316 form a metal ionic bond. Therefore, the indazole benzoic acid derivative containing the urea structure provided by the invention has high inhibitory activity on human-derived EP4, and can be used as an EP4 inhibitor for preparing drugs for treating PGE2 / EP4 signal transduction mediated diseases.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to an indazole benzoic acid derivative containing a urea structure, and a preparation method and application thereof. Background Art

[0002] Prostaglandin E2 (PGE2) is one of the main products of cyclooxygenase (COX) to arachidonic acid, and it participates in many physiological reactions and pathological reactions. The intracellular signal transduction of PGE2 mediation depends on its combination with one or more specific prostaglandin E receptors (EP1-4) on target cells, and these receptors are coupled with different G proteins. Prostaglandin E receptor 4 (EP4) is expressed in various tissues and cells, including immunity, bone joints, cardiovascular, gastrointestinal and respiratory systems and cancer cells. EP4 and Ga are coupled to activate adenylate cyclase (AC) and catalyze the formation of second messenger cAMP. The main effect of cAMP is to combine and activate protein kinase A (PKA), which in turn phosphorylates the target protein in cells. In addition, EP4 also stimulates non-classical pathway phosphatidylinositol 3 kinase (PI3K) / protein kinase B (PKB, also referred to as Akt), thereby promoting cell survival, and activating extracellular regulated kinase (ERK), thereby promoting migration and proliferation.

[0003] A growing body of preclinical data supports the potential therapeutic value of prostaglandin E receptor 4 (EP4) antagonists in several indications. Most scientific evidence suggests that selective EP4 antagonists may be an effective inflammatory pain relief agent with better intestinal tolerance than NSAIDs and COX-2 inhibitors, which are current standard drugs. Importantly, EP4 antagonists may achieve a safer cardiovascular safety profile because they do not directly interfere with the biosynthesis of prostaglandin E (PGE2) and other prostaglandins (e.g., prostacyclin and thromboxane). EP4 receptor antagonists may also have therapeutic applications in the treatment of migraine, as the involvement of EP4 receptors in PGE2-mediated cerebral vasodilation is an important factor in migraine. Overexpression of COX2 in various tumor types leads to increased PGE2 levels, suggesting that blocking PGE2 signaling with selective EP4 antagonists during cancer treatment may be beneficial for patients in the oncology setting. EP4 receptors have been reported to play an important role in many neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, in which PGE2 is involved. Studies have shown that the PGE2 / EP4 signaling pathway is associated with the occurrence of colorectal cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, bladder cancer, and liver cancer. Activation of this cascade signal, elevated tumor PGE2 levels or EP4 overexpression can promote tumor progression by inactivating host anti-tumor immune cells, enhancing cancer cell proliferation, migration and metastasis, and promoting tumor-related angiogenesis. In contrast, EP4 knockout mice delayed tumorigenesis compared with wild-type mice in the context of APCmin mutation, indicating its tumor-promoting activity. Selective EP4 receptor antagonists can inhibit PGE2-induced cancer cell proliferation in vitro and slow tumor progression and metastasis in various preclinical tumor models. Selective EP4 receptor antagonists also block the induction of myeloid-derived suppressor cells, restore natural killer cell activity, and enhance the production of pro-inflammatory cytokines (TNF-α) and IL-12 by myeloid cells and Th1 cells. These data suggest that inhibition of PGE2 / EP4 signaling may have therapeutic value in cancer and other chronic inflammatory diseases.

[0004] However, there are currently no compounds that can block the PGE2 / EP4 signaling pathway to fill the unmet medical needs. Summary of the invention

[0005] The purpose of the present invention is to provide an indazole benzoic acid derivative containing a urea structure, and a preparation method and application thereof. The indazole benzoic acid derivative containing a urea structure provided by the present invention has high inhibitory activity against EP4 and small side effects, and can be used as an EP4 inhibitor for preparing drugs for diseases mediated by PGE2 / EP4 signaling.

[0006] In order to achieve the above object, the present invention provides the following technical solutions:

[0007] The present invention provides an indazole benzoic acid derivative containing a urea structure, the structure of which is shown in Formula A, Formula B or Formula C:

[0008]

[0009]

[0010] In Formula A, Formula B or Formula C, R1 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, heterocyclic group, substituted heterocyclic group, alkyl group or substituted alkyl group;

[0011] R2 and R3 are independently -H, alkyl, substituted alkyl, R2 and R3 are connected to each other to form cycloalkyl, or R2 and R3 are connected to each other to form substituted cycloalkyl; n is 0, 1, 2 or 3; Z is -O-, -NH- or -S-.

[0012] Preferably, the substituents of the substituted phenyl, substituted naphthyl, substituted heterocyclic and substituted alkyl in R1 are independently halogen groups, -OH, -NH2, -CF3, -OCF3, -NHCH3, -N(CH3)2, -NO2, -CN, -OR, -SR, -NRR', -C(O)R, -C02R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -SO2R, -CONRR', -SO2NRR', -OCOR, -NRCOR', -NRNR', alkyl, cycloalkyl, aromatic, heterocyclic or heteroaryl; in -OR, -SR, -NRR', -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -SO2R, -CONRR', -SO2NR', -OCOR, -NRCOR' or -NRNR', R and R' are independently alkyl.

[0013] Preferably, in R2 and R3, the alkyl group is independently a C1~C6 alkyl group; the substituted alkyl group is independently a substituted C1~C6 alkyl group; the substituent of the substituted alkyl group is independently a halogen group, -OH, -NH2, -NHCH3, -N(CH3)2 or a C1~C6 alkyl group; the R2 and R3 are connected to each other to form a cycloalkyl group, and the R2 and R3 are connected to each other to form a C3~C6 cycloalkyl group; the R2 and R3 are connected to each other to form a substituted cycloalkyl group, and the R2 and R3 are connected to each other to form a substituted C3~C6 cycloalkyl group; the R2 and R3 are connected to each other to form a substituted cycloalkyl group, and the substituent of the substituted cycloalkyl group is a halogen group, -OH, -NH2, -NHCH3, -N(CH3)2 or a C1~C6 alkyl group.

[0014] Preferably, the indazole benzoic acid derivatives containing a urea structure include 4-((2-(2-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 2-(2-(3-(3-chloro-4-fluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-chloro-3-fluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(p-tolyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(2-chloro-4-cyanophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid formic acid, 4-((2-(2-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-fluoro-4-methylphenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3,5-difluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, -2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-cyano-2-methylphenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-cyano-2-fluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(2-bromo-4-cyanophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-cyanophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-cyanophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid,7-hexahydro-s-indol-4-yl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(2-chloro-4-cyanophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid -3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-fluoro-3-methylphenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3-fluoro-4-methylphenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3,4-((2-(3-(3-(4-chloro-3-fluorophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3-chloro-4-fluorophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-(trifluoromethoxy)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, -(4-methoxyphenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-fluorophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-nitrophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(2-bromo-4-cyanophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((1-(2-(3-(3-chloro-4-cyanophenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid, 4-( (1-(2-(3-(3-fluoro-4-methylphenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid, 4-((1-(2-(3-(3,5-difluorophenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid, 4-((1-(2-(3-(3-chloro-4-methylphenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4-((2-(2-((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, -3-fluorophenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexane- 1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(p-tolyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid -formamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexane-1-formamido)ethyl)-2H-indazole-3-formamido)methyl)benzoic acid or 4-((2-(2-((1r,4r)-4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexane-1-formamido)ethyl)-2H-indazole-3-formamido)methyl)benzoic acid.

[0015] The present invention also provides a method for preparing the indazole benzoic acid derivative containing a urea structure as described in the above scheme. The method for preparing the indazole benzoic acid derivative containing a urea structure as shown in formula A comprises the following steps:

[0016] (1) subjecting compound I and compound a to a first nucleophilic substitution reaction to obtain compound b;

[0017] (2) subjecting the compound b to a first hydrolysis reaction to obtain a compound c;

[0018] (3) subjecting the compound c and compound II to a first acylation reaction to obtain compound d;

[0019] (4) subjecting the compound d to a first deprotection reaction to obtain a compound e;

[0020] (5) subjecting the compound e to a second acylation reaction with (trichloromethyl) carbonate to obtain a first intermediate compound; subjecting the first intermediate compound to a second nucleophilic substitution reaction with compound III to obtain compound f; subjecting the compound f to a second hydrolysis reaction to obtain an indazole benzoic acid derivative containing a urea structure as shown in formula A;

[0021] The structural formula of the compound I is The structural formula of the compound II is The structural formula of the compound III is

[0022] The structural formulas of the first intermediate, compound a, compound b, compound c, compound d, compound e and compound f are:

[0023]

[0024]

[0025] The preparation method of the indazole benzoic acid derivative containing a urea structure shown in formula B comprises the following steps:

[0026] (A) subjecting compound I and compound a to a third nucleophilic substitution reaction to obtain compound h;

[0027] (B) subjecting the compound h to a third hydrolysis reaction to obtain a compound i;

[0028] (C) subjecting the compound i and compound II to a third acylation reaction to obtain compound j;

[0029] (D) subjecting the compound j to a second deprotection reaction to obtain a compound k;

[0030] (E) subjecting the compound k to a fourth acylation reaction with (trichloromethyl) carbonate to obtain a second intermediate compound; subjecting the second intermediate compound to a fourth nucleophilic substitution reaction with compound III to obtain compound 1; and subjecting compound 1 to a fourth hydrolysis reaction to obtain an indazole benzoic acid derivative containing a urea structure as shown in formula B;

[0031] The structural formula of the compound I is The structural formula of the compound II is The structural formula of the compound III is

[0032] The structural formulas of the second intermediate, compound a, compound h, compound i, compound j, compound k and compound 1 are:

[0033]

[0034] The preparation method of the indazole benzoic acid derivative containing a urea structure shown in formula C comprises the following steps:

[0035] (I) subjecting compound IV and compound e to a fifth acylation reaction to obtain compound n;

[0036] (II) subjecting the compound n to a third deprotection reaction to obtain a compound o;

[0037] (III) subjecting the compound o to a sixth acylation reaction with (trichloromethyl) carbonate to obtain a third intermediate compound; subjecting the third intermediate compound to a fifth nucleophilic substitution reaction with compound II to obtain compound p; subjecting the compound p to a fifth hydrolysis reaction to obtain an indazole benzoic acid derivative containing a urea structure as shown in formula C;

[0038] The structural formula of the compound II is The structural formula of the compound IV is

[0039] The structural formulas of the third intermediate, compound e, compound n, compound o and compound p are:

[0040]

[0041] The meanings of n, R1, R2 or R3 in compound I, compound II, compound III, the first intermediate, the second intermediate, the third intermediate, compound a, compound b, compound c, compound d, compound e, compound f, compound h, compound i, compound j, compound k, compound l, compound n, compound o and compound p are the same as those in formula A.

[0042] Preferably, the first deprotection reaction is carried out under acidic conditions; the acidic conditions are provided by an acidic reagent; the acidic reagent is trifluoroacetic acid; the molar ratio of the compound d to the acidic reagent is 1:(3-10); the first deprotection reaction is carried out in an organic solvent; the mass ratio of the compound d to the organic solvent is 1-1.2:1-100; the temperature of the first deprotection reaction is -20-50°C, and the insulation time is 2-8h.

[0043] Preferably, the second deprotection reaction is carried out under acidic conditions; the acidic conditions are provided by an acidic reagent; the acidic reagent is trifluoroacetic acid; the molar ratio of compound j to the acidic reagent is 1:(3-10); the second deprotection reaction is carried out in an organic solvent; the mass ratio of compound j to the organic solvent is 1-1.2:1-100; the temperature of the second deprotection reaction is -20-50°C, and the insulation time is 2-8h.

[0044] Preferably, the third deprotection reaction is carried out under acidic conditions; the acidic conditions are provided by an acidic reagent; the acidic reagent is trifluoroacetic acid; the molar ratio of the compound n to the acidic reagent is 1:(3-10); the third deprotection reaction is carried out in an organic solvent; the mass ratio of the compound n to the organic solvent is 1-1.2:1-100; the temperature of the third deprotection reaction is -20-50°C, and the insulation time is 2-8h.

[0045] The present invention also provides the use of the urea-containing indazole benzoic acid derivatives described in the above scheme or the urea-containing indazole benzoic acid derivatives obtained by the preparation method described in the above scheme in the preparation of drugs for treating diseases mediated by PGE2 / EP4 signal transduction.

[0046] Preferably, the PGE2 / EP4 signaling-mediated disease includes cancer, acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea or atherosclerosis.

[0047] The present invention provides an indazole benzoic acid derivative containing a urea structure. The indazole benzoic acid derivative containing a urea structure provided by the present invention has a typical benzoic acid structure as the primary pharmacophore of EP4, and molecular docking shows that the benzoic acid part forms a metal ion bond with the key amino acid residue Arg316. Therefore, the indazole benzoic acid derivative containing a urea structure provided by the present invention has high inhibitory activity against human EP4, and can be used as an EP4 inhibitor for preparing a drug for treating diseases mediated by PGE2 / EP4 signal transduction.

[0048] The present invention also provides a method for preparing the indazole benzoic acid derivatives containing a urea structure described in the above scheme. The preparation method provided by the present invention has simple steps, convenient operation, high feasibility, low cost, and has the prospect of large-scale industrial application.

[0049] The present invention also provides the use of the indazole benzoic acid derivatives containing a urea structure described in the above scheme or the indazole benzoic acid derivatives containing a urea structure obtained by the preparation method described in the above scheme in the preparation of drugs for treating diseases mediated by PGE2 / EP4 signaling. The indazole benzoic acid derivatives containing a urea structure provided by the present invention have high inhibitory activity on human EP4, and can be used as EP4 inhibitors for the preparation of drugs for treating diseases mediated by PGE2 / EP4 signaling, especially cancer, acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea or arteriosclerosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0051] Figure 1 The synthetic route of the indazole benzoic acid derivatives containing a urea structure as shown in formula A of the present invention;

[0052] Figure 2 The synthetic route of the indazole benzoic acid derivatives containing a urea structure as shown in formula B of the present invention;

[0053] Figure 3 The synthetic route of the indazole benzoic acid derivatives containing urea structure shown in formula C of the present invention is shown in the following figure. DETAILED DESCRIPTION

[0054] The present invention provides an indazole benzoic acid derivative containing a urea structure, the structure of which is shown in Formula A, Formula B or Formula C:

[0055]

[0056] In Formula A, Formula B or Formula C, R1 is alkyl, substituted alkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heterocyclic group or substituted heterocyclic group;

[0057] R2 and R3 are independently -H, alkyl, substituted alkyl, R2 and R3 are connected to each other to form a cycloalkyl, or R2 and R3 are connected to each other to form a substituted cycloalkyl;

[0058] n is 0, 1, 2 or 3;

[0059] Z is -O-, -NH- or -S-.

[0060] In the present invention, n is preferably 1, 2 or 3, more preferably 1 or 2.

[0061] In the present invention, the alkyl group in R1 preferably includes one of a straight-chain alkyl group and an adamantyl group; the straight-chain alkyl group is preferably a C1-C3 alkyl group; the C1-C3 alkyl group preferably includes one of a methyl group, an ethyl group, a propyl group and an isopropyl group; the adamantyl group preferably includes one of a memantyl group, a 1,3-dihydroxyadamantyl group, a 5-hydroxy-2-adamantanyl group and a 4-hydroxy-2-adamantanyl group.

[0062] In the present invention, the heterocyclic group in R1 preferably includes one of pyridine, pyrimidine, pyran, pyrazole, piperidine, thiazole and thiophene.

[0063] In the present invention, the substituents of the substituted alkyl, substituted phenyl, substituted naphthyl and substituted heterocyclic groups in R1 independently preferably include halogen groups, -OH, -NH2, -CF3, -OCF3, -NHCH3, -N(CH3)2, -NO2, -CN, -OR, -SR, -NRR', -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -SO2R, -CONRR', -SO2NRR', -OCOR, -NRC OR', -NRNR', alkyl, cycloalkyl, aromatic, heterocyclic or heteroaryl; in -OR, -SR, -NRR', -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -SO2R, -CONRR', -SO2NR', -OCOR, -NRCOR' or -NRNR', R and R' are independently alkyl; in R and R', the alkyl is preferably C1~C3 alkyl; the C1~C3 alkyl preferably includes methyl, ethyl or propyl.

[0064] In the present invention, the halogen group in the R1 substituent preferably includes -F, -Cl or -Br; the alkyl group preferably includes methyl, ethyl or propyl; the cycloalkyl group preferably includes cyclopropane, cyclopentane or cyclohexane; the aromatic group preferably includes phenyl or naphthyl; the heterocyclic group preferably includes tetrahydrofuran, hexahydropyridine or hexahydropyran; the heteroaryl group preferably includes pyridine, pyrimidine, furan or pyran.

[0065] In the present invention, the R1 is preferably a group represented by the following structural formula:

[0066]

[0067] The solid five-pointed stars represent the connection sites.

[0068] In the present invention, R2 and R3 are independently preferably -H, alkyl or R2 and R3 are connected to each other to form a cycloalkyl; the alkyl in R2 and R3 is preferably a C1-C6 alkyl; the C1-C6 alkyl is preferably a methyl; the substituted alkyl is preferably a substituted C1-C6 alkyl; the substituted C1-C6 alkyl is preferably a substituted methyl; the substituent of the substituted alkyl is independently preferably a halogen group, -OH, -NH2, -NHCH3, -N(CH3)2 or a C1-C6 alkyl; the R2 and R3 are preferably C1-C6 alkyl; the C1-C6 alkyl is preferably a methyl; the substituted alkyl is preferably a substituted C1-C6 alkyl; the substituted C1-C6 alkyl is preferably a substituted methyl; the substituent of the substituted alkyl is independently preferably a halogen group, -OH, -NH2, -NHCH3, -N(CH3)2 or a C1-C6 alkyl; 3 are connected to each other as cycloalkyl, preferably R2 and R3 are connected to each other as C3~C6 cycloalkyl; the C3~C6 cycloalkyl is preferably cyclopropyl; the R2 and R3 are connected to each other as substituted cycloalkyl, preferably R2 and R3 are connected to each other as substituted C3~C6 cycloalkyl; the substituted C3~C6 cycloalkyl is preferably substituted cyclopropyl; the substituent of the substituted cycloalkyl of R2 and R3 is preferably a halogen group, -OH, -NH2, -NHCH3, -N(CH3)2 or C1~C6 alkyl.

[0069] In the present invention, the indazole benzoic acid derivatives containing urea structure preferably include 4-((2-(2-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-102-A), 4-((2-(2-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-103-A), 4-((2-(2-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-104-A), -2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-104-A), 4-((2-(2-(3-(4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-105-A), 4-((2-(2-(3-(3-chloro-4-fluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-106-A), 4-((2-(2-(3-(4-chloro-3-fluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-107-A), 4-((2-(2-(3-(p-tolyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-107-A), 4-((2-(2-(3-(p-tolyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-108-A), 4-((2-(2-(3-(2-chloro-4-cyanophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-109-A), 4-((2-(2-(3-(4-fluoro-3-(trifluoromethyl) 4-((2-(2-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-110-A), 4-((2-(2-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-111-A), 4-((2-(2-(3-(3-fluoro-4-methylphenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-112-A), 4-((2-(2-(3-(3,5-((2-(2-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-113-A), 4-((2-(2-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-114-A), 4-((2-(2-(3-(4-chloro-3-methylphenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-116-A), 4-((2-(2-(3-(4-cyano- -2-methylphenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-120-A), 4-((2-(2-(3-(4-cyano-2-fluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-121-A), 4-((2-(2-(3-(2-bromo-4-cyanophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-124-A), 4-((2-(2-(3-(4-cyanophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-125-A), 4-((2-(2-(3-(1,2,3,5,6,7-hexahydro-s-indol-4-yl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-126-A), 4-((2-(3-(3-(2-chloro-4-cyanophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U101-A), 4-((2-(3-(3-(4-chloro- -3-(trifluoromethyl)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U102-A), 4-((2-(3-(3-(4-fluoro-3-methylphenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U103-A), 4-((2-(3-(3-(3-fluoro-4-methylphenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U104-A), 4-((2-(3-(3-(3,4-((2-(3-(3-(4-chloro-3-fluorophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U106-A), 4-((2-(3-(3-(3-chloro-4-fluorophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U107-A), 4-((2-(3-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U108-A) , 4-((2-(3-(3-(4-chloro-3-methylphenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U109-A), 4-((2-(3-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U110-A), 4-((2-(3-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U111-A), 4-((2-(3-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl 4-((2-(3-(3-(4-(trifluoromethoxy)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U112-A), 4-((2-(3-(3-(4-(trifluoromethoxy)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U113-A), 4-((2-(3-(3-(4-methoxyphenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U114-A), 4-((2-(3-(3-(4-fluorophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U115-A), 4-((2-(3-(3-(4-nitrophenyl)ureido)propyl) -2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U117-A), 4-((2-(3-(3-bromo-4-cyanophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U118-A), 4-((1-(2-(3-(3-chloro-4-cyanophenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-A109-A), 4-((1-(2-(3-(3-fluoro-4-methylphenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-A112-A), 4-((1-(2-(3-(3,5-difluorophenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-A113-A), 4-((1-(2-(3-(3-chloro-4-methylphenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-A115-A), 4-((2-(2-((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C101-A), 4-((2-(2-((1r,4r)-4-(3-(4-chloro-3 -(trifluoromethyl)phenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C102-A), 4-((2-(2-((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C104-A), 4-((2-(2-((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C10 6-A), 4-((2-(2-((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C107-A), 4-((2-(2-((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C110-A), 4-((2-(2-((1r,4r)-4-(3-(p-tolyl)ureido)cyclohexane-1-carboxamido)ethyl)-2 H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C114-A), 4-((2-(2-((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C115-A), 4-((2-(2-((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C116-A), or 4-((2-(2-((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C117-A).4r)-4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C117-A), the structural formula is as follows:

[0070]

[0071]

[0072]

[0073] The present invention also provides a method for preparing the indazole benzoic acid derivative containing a urea structure as described in the above scheme. The method for preparing the indazole benzoic acid derivative containing a urea structure as shown in formula A comprises the following steps:

[0074] (1) subjecting compound I and compound a to a first nucleophilic substitution reaction to obtain compound b;

[0075] (2) subjecting the compound b to a first hydrolysis reaction to obtain a compound c;

[0076] (3) subjecting the compound c and compound II to a first acylation reaction to obtain compound d;

[0077] (4) subjecting the compound d to a first deprotection reaction to obtain a compound e;

[0078] (5) subjecting the compound e to a second acylation reaction with (trichloromethyl) carbonate to obtain a first intermediate compound; subjecting the first intermediate compound to a second nucleophilic substitution reaction with compound III to obtain compound f; subjecting the compound f to a second hydrolysis reaction to obtain an indazole benzoic acid derivative containing a urea structure as shown in formula A;

[0079] The structural formula of the compound I is The structural formula of the compound II is The structural formula of the compound III is

[0080] The structural formulas of the first intermediate, compound a, compound b, compound c, compound d, compound e and compound f are:

[0081]

[0082] The preparation method of the indazole benzoic acid derivative containing a urea structure shown in formula B comprises the following steps:

[0083] (A) subjecting compound I and compound a to a third nucleophilic substitution reaction to obtain compound h;

[0084] (B) subjecting the compound h to a third hydrolysis reaction to obtain a compound i;

[0085] (C) subjecting the compound i and compound II to a third acylation reaction to obtain compound j;

[0086] (D) subjecting the compound j to a second deprotection reaction to obtain a compound k;

[0087] (E) subjecting the compound k to a fourth acylation reaction with (trichloromethyl) carbonate to obtain a second intermediate compound; subjecting the second intermediate compound to a fourth nucleophilic substitution reaction with compound III to obtain compound 1; and subjecting compound 1 to a fourth hydrolysis reaction to obtain an indazole benzoic acid derivative containing a urea structure as shown in formula B;

[0088] The structural formula of the compound I is The structural formula of the compound II is The structural formula of the compound III is

[0089] The structural formulas of the second intermediate, compound a, compound h, compound i, compound j, compound k and compound 1 are:

[0090]

[0091] The preparation method of the indazole benzoic acid derivative containing a urea structure shown in formula C comprises the following steps:

[0092] (I) subjecting compound IV and compound e to a fifth acylation reaction to obtain compound n;

[0093] (II) subjecting the compound n to a third deprotection reaction to obtain a compound o;

[0094] (III) subjecting the compound o to a sixth acylation reaction with (trichloromethyl) carbonate to obtain a third intermediate compound; subjecting the third intermediate compound to a fifth nucleophilic substitution reaction with compound II to obtain compound p; subjecting the compound p to a fifth hydrolysis reaction to obtain an indazole benzoic acid derivative containing a urea structure as shown in formula C;

[0095] The structural formula of the compound II is The structural formula of the compound IV is

[0096] The structural formulas of the third intermediate, compound e, compound n, compound o and compound p are:

[0097]

[0098]

[0099] The meanings of n, R1, R2 or R3 in compound I, compound II, compound III, the first intermediate, the second intermediate, the third intermediate, compound a, compound b, compound c, compound d, compound e, compound f, compound h, compound i, compound j, compound k, compound l, compound n, compound o and compound p are the same as those in formula A.

[0100] The present invention prepares an indazole benzoic acid derivative containing a urea structure as shown in formula A: the present invention conducts a first nucleophilic substitution reaction between compound I and compound a to obtain compound b. In the present invention, the molar ratio of compound a to compound I is preferably 1:(1-2), more preferably 1:(1-1.5), and further preferably 1:(1-1.2).

[0101] In the present invention, the first nucleophilic substitution reaction is preferably carried out in the presence of an acid binding agent; the acid binding agent preferably includes one or more of potassium carbonate, cesium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene, more preferably cesium carbonate; the molar ratio of the compound a to the acid binding agent is preferably 1:(1-4), more preferably 1:(1.1-3), and further preferably 1:(1.2-2).

[0102] In the present invention, the first nucleophilic substitution reaction is preferably carried out in the presence of a phase transfer catalyst and a non-phase transfer catalyst; the phase transfer catalyst is preferably an ammonium salt; the ammonium salt preferably includes one or more of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate and benzyltriethylammonium chloride, more preferably tetrabutylammonium bromide (TBAB); the non-phase transfer catalyst is preferably an iodine salt; the iodine salt preferably includes one or both of potassium iodide and sodium iodide, more preferably potassium iodide (KI); the molar ratio of the compound a and the phase transfer catalyst is preferably 1:(0.1-1), more preferably 1:(0.1-0.7), and further preferably 1:(0.1-0.4); the molar ratio of the compound a and the non-phase transfer catalyst is preferably 1:(0.1-1), more preferably 1:(0.1-0.5), and further preferably 1:(0.1-0.3).

[0103] In the present invention, the first nucleophilic substitution reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, ethanol and tetrahydrofuran, more preferably acetonitrile; the mass ratio of the compound a to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:10-50, further preferably 1-1.1:30-40.

[0104] In the present invention, the temperature of the first nucleophilic substitution reaction is preferably 40-80° C., more preferably 80° C., and the insulation time is preferably 3-8 h, more preferably 3 h.

[0105] In the present invention, after the first nucleophilic substitution reaction, the method preferably further comprises adding water to the obtained reaction system, extracting with ethyl acetate, drying, filtering and concentrating.

[0106] After obtaining compound b, the present invention performs a first hydrolysis reaction on compound b to obtain compound c. In the present invention, the first hydrolysis reaction is preferably performed in the presence of an alkaline agent; the alkaline agent includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate, more preferably lithium hydroxide; the molar ratio of compound b to the alkaline agent is preferably 1:(1-20), more preferably 1:(1-10), and further preferably 1:(2-5).

[0107] In the present invention, the first hydrolysis reaction is preferably carried out in a mixed solvent of water and an organic solvent; the organic solvent preferably includes one or more of acetonitrile, methanol and tetrahydrofuran, more preferably tetrahydrofuran; the volume ratio of water to the organic solvent is preferably 1:1 to 5, more preferably 1:1 to 2, and further preferably 1:1.

[0108] In the present invention, the temperature of the first hydrolysis reaction is preferably 30-70°C, more preferably 50°C, and the insulation time is preferably 2-10h, more preferably 3h.

[0109] In the present invention, after the first hydrolysis reaction, the obtained hydrolysis reaction liquid is preferably concentrated, water is added, the pH value of the system is adjusted to 1-7 with hydrochloric acid under ice bath conditions, solids are precipitated, suction filtered and dried; the concentration is preferably reduced pressure concentration; the pressure of the reduced pressure concentration is preferably 0.05-0.30MPa, more preferably 0.10-0.15MPa; the temperature of the ice bath condition is preferably -10-10°C, more preferably 0-5°C. The present invention removes the organic solvent in the hydrolysis reaction liquid by concentration.

[0110] After obtaining compound c, the present invention conducts a first acylation reaction between compound c and compound II to obtain compound d. In the present invention, the molar ratio of compound c to compound II is preferably 1:(1-10), more preferably 1:(1-3), and further preferably 1:(1-1.2).

[0111] In the present invention, the first acylation reaction is preferably carried out in the presence of an organic base and a condensing agent; the molar ratio of the compound c and the organic base is preferably 1:(2-4), more preferably 1:(2.5-3.5), and further preferably 1:3; the molar ratio of the compound c and the condensing agent is preferably 1:(1.2-2), more preferably 1:(1.4-1.8), and further preferably 1:1.5.

[0112] In the present invention, the organic base preferably includes one or more of triethylamine, pyridine and N,N-diisopropylethylamine, and more preferably N,N-diisopropylethylamine.

[0113] In the present invention, the condensing agent preferably includes one or more of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N,N'-dicyclohexylcarbodiimide, and more preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0114] In the present invention, the first acylation reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of dichloromethane, chloroform and tetrahydrofuran, more preferably tetrahydrofuran; the mass ratio of the compound c to the organic solvent is preferably 1:1-100, more preferably 1:5-10.

[0115] In the present invention, the temperature of the first acylation reaction is preferably 10-30° C., more preferably 25° C., and the insulation time is preferably 30-60 min, more preferably 30 min.

[0116] In the present invention, after the first acylation reaction, the obtained reaction solution is preferably concentrated (referred to as concentrated A), water is added, ethyl acetate is added for extraction, drying, suction filtration and concentration (referred to as concentrated B) in sequence; the concentrated A and concentrated B are independently preferably concentrated under reduced pressure; the pressure of the reduced pressure concentration is preferably 0.05 to 0.30 MPa, more preferably 0.10 to 0.15 MPa. The present invention removes the organic solvent in the reaction solution by concentrated A and concentrated B.

[0117] After obtaining compound d, the present invention performs a first deprotection reaction on compound d to obtain compound e. In the present invention, the first deprotection reaction is preferably performed under acidic conditions; the acidic conditions are preferably provided by an acidic reagent; the acidic reagent is preferably trifluoroacetic acid; the molar ratio of compound d to the acidic reagent is preferably 1:(3-10), more preferably 1:5.

[0118] In the present invention, the first deprotection reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, dichloromethane and tetrahydrofuran, more preferably dichloromethane; the mass ratio of the compound d to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:5-10.

[0119] In the present invention, the temperature of the first deprotection reaction is preferably -20 to 50°C, more preferably 30°C, and the insulation time is preferably 2 to 8h, more preferably 3h.

[0120] In the present invention, after the first deprotection reaction, the method preferably further comprises concentrating the obtained reaction solution; the concentration is preferably carried out under reduced pressure; the pressure of the reduced pressure concentration is preferably 0.05 to 0.30 MPa, more preferably 0.10 to 0.15 MPa.

[0121] After obtaining compound e, the present invention conducts a second acylation reaction between the compound e and (trichloromethyl) carbonate (BTC) to obtain a first intermediate compound. In the present invention, the molar ratio of the compound e to BTC is preferably 1:(0.3-0.5), more preferably 1:0.5.

[0122] In the present invention, the second acylation reaction is preferably carried out in the presence of an acid binding agent; the acid binding agent is preferably an organic base; the organic base preferably includes one or more of triethylamine, pyridine and N,N-diisopropylethylamine, more preferably triethylamine; the molar ratio of the compound e to the acid binding agent is preferably 1:(4-6), more preferably 1:6.

[0123] In the present invention, the second acylation reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, dichloromethane and tetrahydrofuran, more preferably dichloromethane; the mass ratio of the compound e to the organic solvent is preferably 1:1-100, more preferably 1:5-10.

[0124] In the present invention, the temperature of the second acylation reaction is preferably -78 to -30°C, more preferably -78°C, and the insulation time is preferably 30 to 60 min, more preferably 30 min.

[0125] In the present invention, the second acylation reaction preferably further comprises concentrating the obtained reaction solution; the concentration is preferably concentrated under reduced pressure; the concentration temperature is preferably 20-50°C, more preferably 30°C.

[0126] After obtaining the first intermediate compound, the present invention conducts a second nucleophilic substitution reaction between the first intermediate compound and compound III to obtain compound f. In the present invention, the molar ratio of compound III to compound c is preferably (1.0-1.5):1, more preferably (1.1-1.3):1, and further preferably 1.2:1.

[0127] In the present invention, the second nucleophilic substitution reaction is preferably carried out in the presence of an acid binding agent; the acid binding agent is preferably an organic base; the organic base preferably includes one or more of triethylamine, pyridine and N,N-diisopropylethylamine, more preferably triethylamine; the molar ratio of the compound III to the acid binding agent is preferably 1:(4-6), more preferably 1:6.

[0128] In the present invention, the second nucleophilic substitution reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, dichloromethane and tetrahydrofuran, more preferably dichloromethane; the mass ratio of the compound III to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:5-10.

[0129] In the present invention, the temperature of the second nucleophilic substitution reaction is preferably -10 to -30°C, more preferably 25°C, and the insulation time is preferably 30 to 60 min, more preferably 30 min.

[0130] In the present invention, after the second nucleophilic substitution reaction, the method preferably further comprises adding water to the obtained reaction system, extracting with ethyl acetate, drying, filtering and concentrating.

[0131] In the present invention, the concentration temperature is preferably 20-50°C, more preferably 30°C; the concentration is preferably reduced-pressure concentration; the reduced-pressure concentration pressure is preferably 0.05-0.30 MPa, more preferably 0.10-0.15 MPa.

[0132] After obtaining compound f, the compound f is subjected to a second hydrolysis reaction to obtain an indazole benzoic acid derivative containing a urea structure as shown in formula A. In the present invention, the second hydrolysis reaction is preferably carried out in the presence of an alkaline agent; the alkaline agent preferably includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate, more preferably lithium hydroxide; the molar ratio of the compound f to the alkaline agent is preferably 1:(1-20), more preferably 1:(1-10), and further preferably 1:(2-5).

[0133] In the present invention, the second hydrolysis reaction is preferably carried out in a mixed solvent of water and an organic solvent; the organic solvent preferably includes one or more of acetonitrile, methanol and tetrahydrofuran, more preferably tetrahydrofuran; the volume ratio of water to the organic solvent is preferably 1:1 to 5, more preferably 1:1 to 2, and further preferably 1:1.

[0134] In the present invention, the temperature of the second hydrolysis reaction is preferably 30-70°C, more preferably 50°C, and the insulation time is preferably 2-10h, more preferably 3h.

[0135] In the present invention, after the second hydrolysis reaction, it is preferred that the obtained hydrolysis reaction liquid is sequentially concentrated, water is added, the pH value of the system is adjusted to 1 to 7 with hydrochloric acid under ice bath conditions, solids are precipitated, suction filtered and dried; the concentration is preferably reduced pressure concentration; the pressure of the reduced pressure concentration is preferably 0.05 to 0.30 MPa, more preferably 0.10 to 0.15 MPa; the temperature of the ice bath conditions is preferably -10 to 10°C, more preferably 0 to 5°C. The present invention removes the organic solvent in the hydrolysis reaction liquid by concentration. The main synthetic routes of the indazole benzoic acid derivatives containing urea structure shown in the above-mentioned preparation formula A of the present invention are as follows Figure 1 shown.

[0136] The present invention prepares an indazole benzoic acid derivative containing a urea structure as shown in formula B: the present invention conducts a third nucleophilic substitution reaction between compound I and compound a to obtain compound h. In the present invention, the molar ratio of compound a to compound I is preferably 1:(1-2), more preferably 1:(1.0-1.6), and further preferably 1:(1.0-1.2).

[0137] In the present invention, the third nucleophilic substitution reaction is preferably carried out in the presence of an acid binding agent; the acid binding agent preferably includes one or more of potassium carbonate, cesium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene, more preferably cesium carbonate; the molar ratio of the compound a to the acid binding agent is preferably 1:(1.0-4.0), more preferably 1:(1.1-3.0), and further preferably 1:(1.2-2.0).

[0138] In the present invention, the third nucleophilic substitution reaction is preferably carried out in the presence of a phase transfer catalyst and a non-phase transfer catalyst; the phase transfer catalyst is preferably an ammonium salt; the ammonium salt preferably includes one or more of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate and benzyltriethylammonium chloride, more preferably tetrabutylammonium bromide (TBAB); the non-phase transfer catalyst is preferably an iodine salt; the iodine salt preferably includes one or both of potassium iodide and sodium iodide, more preferably potassium iodide (KI); the molar ratio of the compound a and the phase transfer catalyst is preferably 1:(0.1-1), more preferably 1:(0.1-0.6), and further preferably 1:(0.1-0.3); the molar ratio of the compound a and the non-phase transfer catalyst is preferably 1:(0.1-1), more preferably 1:(0.1-0.6), and further preferably 1:0.1.

[0139] In the present invention, the third nucleophilic substitution reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, ethanol and tetrahydrofuran, more preferably acetonitrile; the mass ratio of the compound a to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:10-50, and further preferably 1-1.1:30-40.

[0140] In the present invention, the temperature of the third nucleophilic substitution reaction is preferably 40-80° C., more preferably 80° C., and the insulation time is preferably 3-8 h, more preferably 3 h.

[0141] In the present invention, after the third nucleophilic substitution reaction, the steps of adding water to the obtained reaction system, extracting with ethyl acetate, drying, filtering and concentrating are preferably included.

[0142] In the present invention, the concentration temperature is preferably 20-50°C, more preferably 30°C; the concentration is preferably reduced-pressure concentration; the reduced-pressure concentration pressure is preferably 0.05-0.30 MPa, more preferably 0.10-0.15 MPa.

[0143] After obtaining compound h, the present invention performs a third hydrolysis reaction on compound h to obtain compound i. In the present invention, the third hydrolysis reaction is preferably carried out in the presence of an alkaline agent; the alkaline agent preferably includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate, more preferably lithium hydroxide; the molar ratio of compound h to the alkaline agent is preferably 1:(1-20), more preferably 1:(1-10), and further preferably 1:(2-5).

[0144] In the present invention, the third hydrolysis reaction is preferably carried out in a mixed solvent of water and an organic solvent; the organic solvent preferably includes one or more of acetonitrile, methanol and tetrahydrofuran, more preferably tetrahydrofuran; the volume ratio of water to the organic solvent is preferably 1:1 to 5, more preferably 1:1 to 2, and further preferably 1:1.

[0145] In the present invention, the temperature of the third hydrolysis reaction is preferably 30-70° C., more preferably 50° C., and the insulation time is preferably 2-10 h, more preferably 3 h.

[0146] In the present invention, after the third hydrolysis reaction, the method preferably further comprises concentrating the obtained hydrolysis reaction liquid, adding water, adjusting the system pH value to 1-7 with hydrochloric acid under ice bath conditions, precipitating solids, suction filtering and drying; the concentration is preferably reduced pressure concentration; the pressure of the reduced pressure concentration is preferably 0.05-0.30 MPa, more preferably 0.10-0.15 MPa; the temperature of the ice bath conditions is preferably -10-10°C, more preferably 0-5°C. The present invention removes the organic solvent in the hydrolysis reaction liquid by concentration.

[0147] After obtaining compound i, the present invention conducts a third acylation reaction between compound i and compound II to obtain compound j. In the present invention, the molar ratio of compound i to compound II is preferably 1:(1-10), more preferably 1:(1-3), and further preferably 1:(1-1.2).

[0148] In the present invention, the third acylation reaction is preferably carried out in the presence of an organic base and a condensing agent; the molar ratio of the compound i to the organic base is preferably 1:(2-4), more preferably 1:3; the molar ratio of the compound i to the condensing agent is preferably 1:(1.2-2), more preferably 1:1.5.

[0149] In the present invention, the organic base preferably includes one or more of triethylamine, pyridine and N,N-diisopropylethylamine, and more preferably N,N-diisopropylethylamine; the condensing agent preferably includes one or more of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N,N'-dicyclohexylcarbodiimide, and more preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0150] In the present invention, the third acylation reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of dichloromethane, chloroform and tetrahydrofuran, more preferably tetrahydrofuran.

[0151] In the present invention, the temperature of the third acylation reaction is preferably 10-30° C., more preferably 25° C., and the insulation time is preferably 30-60 min, more preferably 30 min.

[0152] In the present invention, after the third acylation reaction, the obtained reaction solution is preferably concentrated (referred to as concentrated C), water is added, ethyl acetate is added for extraction, drying, suction filtration and concentration (referred to as concentrated D) in sequence; the concentrated C and concentrated D are independently preferably concentrated under reduced pressure; the pressure of the reduced pressure concentration is preferably 0.05 to 0.30 MPa, more preferably 0.10 to 0.15 MPa. The present invention removes the solvent in the reaction solution by concentrated C and concentrated D.

[0153] After obtaining compound j, the present invention performs a second deprotection reaction on compound j to obtain compound k. In the present invention, the second deprotection reaction is preferably performed under acidic conditions; the acidic conditions are preferably provided by an acidic reagent; the acidic reagent is preferably trifluoroacetic acid.

[0154] In the present invention, the molar ratio of the compound j to the acidic reagent is preferably 1:(3-10), more preferably 1:5.

[0155] In the present invention, the second deprotection reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, dichloromethane and tetrahydrofuran, more preferably dichloromethane; the mass ratio of the compound j to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.1:5-10.

[0156] In the present invention, the temperature of the second deprotection reaction is preferably -20 to 50°C, more preferably 30°C, and the insulation time is preferably 2 to 8h, more preferably 3h.

[0157] In the present invention, after the second deprotection reaction, the obtained reaction solution is preferably concentrated; the concentration is preferably reduced pressure concentration; the pressure of the reduced pressure concentration is preferably 0.05 to 0.30 MPa, more preferably 0.10 to 0.15 MPa; the temperature of the ice bath condition is preferably -10 to 10°C, more preferably 0 to 5°C.

[0158] After obtaining compound k, the present invention conducts a fourth acylation reaction between the compound k and (trichloromethyl) carbonate to obtain a second intermediate compound. In the present invention, the molar ratio of the compound k to BTC is preferably 1:(0.3-0.5), more preferably 1:0.5.

[0159] In the present invention, the fourth acylation reaction is preferably carried out in the presence of an acid binding agent; the acid binding agent is preferably an organic base; the organic base preferably includes one or more of triethylamine, pyridine and N,N-diisopropylethylamine, more preferably triethylamine; the molar ratio of the compound k to the acid binding agent is preferably 1:(4-6), more preferably 1:6.

[0160] In the present invention, the fourth acylation reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, dichloromethane and tetrahydrofuran, more preferably dichloromethane; the mass ratio of the compound II to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:5-10.

[0161] In the present invention, the temperature of the fourth acylation reaction is preferably -78 to -30°C, more preferably -78°C, and the insulation time is preferably 30 to 60 min, more preferably 30 min.

[0162] In the present invention, the fourth acylation reaction preferably further comprises concentrating the obtained reaction solution; the concentration is preferably concentrated under reduced pressure; the concentration temperature is preferably 10 to 30°C, more preferably 25°C.

[0163] After obtaining the second intermediate compound, the present invention conducts a fourth nucleophilic substitution reaction between the second intermediate compound and compound III to obtain compound 1. In the present invention, the molar ratio of compound III to compound i is preferably (1.0-1.5):1, more preferably 1.2:1.

[0164] In the present invention, the fourth nucleophilic substitution reaction is preferably carried out in the presence of an acid binding agent; the acid binding agent is preferably an organic base; the organic base preferably includes one or more of triethylamine, pyridine and N,N-diisopropylethylamine, more preferably triethylamine; the molar ratio of the compound III to the acid binding agent is preferably 1:(4-6), more preferably 1:6.

[0165] In the present invention, the fourth nucleophilic substitution reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, dichloromethane and tetrahydrofuran, more preferably dichloromethane; the mass ratio of the compound III to the organic solvent is preferably 1:1-100, more preferably 1:5-10.

[0166] In the present invention, the temperature of the fourth nucleophilic substitution reaction is preferably -10 to -30°C, more preferably 25°C, and the insulation time is preferably 30 to 60 min, more preferably 30 min.

[0167] In the present invention, after the fourth nucleophilic substitution reaction, the steps of sequentially adding water to the obtained reaction system, extracting with ethyl acetate, drying, filtering and concentrating are preferably included.

[0168] In the present invention, the concentration temperature is preferably 20-50°C, more preferably 30°C; the concentration is preferably reduced-pressure concentration; the reduced-pressure concentration pressure is preferably 0.05-0.30 MPa, more preferably 0.10-0.15 MPa.

[0169] After obtaining compound 1, the present invention performs a fourth hydrolysis reaction on the compound 1 to obtain an indazole benzoic acid derivative containing a urea structure as shown in formula B. In the present invention, the fourth hydrolysis reaction is preferably carried out in the presence of an alkaline agent; the alkaline agent preferably includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate, more preferably lithium hydroxide; the molar ratio of the compound 1 to the alkaline agent is preferably 1: (1 to 20), more preferably 1: (1 to 10), and further preferably 1: (2 to 5).

[0170] In the present invention, the fourth hydrolysis reaction is preferably carried out in a mixed solvent of water and an organic solvent; the organic solvent preferably includes one or more of acetonitrile, methanol and tetrahydrofuran, more preferably tetrahydrofuran; the volume ratio of water to the organic solvent is preferably 1:1 to 5, more preferably 1:1 to 2, and further preferably 1:1.

[0171] In the present invention, the temperature of the fourth hydrolysis reaction is preferably 30-70° C., more preferably 50° C., and the insulation time is preferably 2-10 h, more preferably 3 h.

[0172] In the present invention, after the fourth hydrolysis reaction, the obtained hydrolysis reaction liquid is preferably concentrated, water is added, the pH value of the system is adjusted to 1-7 with hydrochloric acid under ice bath conditions, solids are precipitated, suction filtered and dried; the concentration is preferably concentrated under reduced pressure. The present invention removes the solvent of the hydrolysis reaction liquid by concentration. The present invention prepares the indazole benzoic acid derivatives containing urea structure shown in formula B, and the main synthetic route is as follows Figure 2 shown.

[0173] The present invention prepares an indazole benzoic acid derivative containing a urea structure as shown in formula C: the present invention performs a fifth acylation reaction on compound IV and compound e to obtain compound n. In the present invention, the molar ratio of compound IV to compound e is preferably (1.0-1.5):1, more preferably (1.1-1.4):1, and further preferably 1.2:1.

[0174] In the present invention, the fifth acylation reaction is preferably carried out in the presence of an organic base and a condensing agent; the molar ratio of the compound e to the organic base is preferably 1:(2-4), more preferably 1:(2.4-3.5), and further preferably 1:3; the molar ratio of the compound e to the condensing agent is preferably 1:(1.2-2), more preferably 1:(1.2-1.5), and further preferably 1:1.5.

[0175] In the present invention, the organic base preferably includes one or more of triethylamine, pyridine and N,N-diisopropylethylamine, and more preferably N,N-diisopropylethylamine; the condensing agent preferably includes one or more of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N,N'-dicyclohexylcarbodiimide, and more preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0176] In the present invention, the fifth acylation reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of dichloromethane, chloroform and tetrahydrofuran, more preferably tetrahydrofuran; the mass ratio of the compound e to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:5-10.

[0177] In the present invention, the temperature of the fifth acylation reaction is preferably 10-30° C., more preferably 25° C., and the insulation time is preferably 30-60 min, more preferably 30 min.

[0178] In the present invention, after the first acylation reaction, the obtained reaction solution is preferably concentrated (referred to as concentrated E), water is added, ethyl acetate is added for extraction, drying, suction filtration and concentration (referred to as concentrated F) in sequence; the concentrated E and concentrated F are independently preferably concentrated under reduced pressure; the pressure of the reduced pressure concentration is preferably 0.05 to 0.30 MPa, more preferably 0.10 to 0.15 MPa. The present invention removes the solvent in the reaction solution by concentrating E and concentrating F.

[0179] After obtaining compound n, the present invention performs a third deprotection reaction on compound n to obtain compound o. In the present invention, the third deprotection reaction is preferably performed under acidic conditions; the acidic conditions are preferably provided by an acidic reagent; the acidic reagent is preferably trifluoroacetic acid; the molar ratio of compound n to the acidic reagent is preferably 1:(3-10), more preferably 1:5.

[0180] In the present invention, the third deprotection reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, dichloromethane and tetrahydrofuran, more preferably dichloromethane; the mass ratio of the compound n to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:5-10.

[0181] In the present invention, the temperature of the third deprotection reaction is preferably -20 to 50°C, more preferably 30°C, and the insulation time is preferably 2 to 8 hours, more preferably 3 hours.

[0182] In the present invention, after the third deprotection reaction, the reaction solution is preferably concentrated; the concentration is preferably reduced pressure concentration; the pressure of the reduced pressure concentration is preferably 0.05 to 0.30 MPa, more preferably 0.10 to 0.15 MPa.

[0183] After obtaining compound o, when Z is -O- or -S-, the present invention conducts a sixth acylation reaction between the compound o and (trichloromethyl) carbonate to obtain a third intermediate compound. In the present invention, the molar ratio of the compound o to BTC is preferably 1:(0.3-0.5), more preferably 1:0.5.

[0184] In the present invention, the sixth acylation reaction is preferably carried out in the presence of an acid binding agent; the acid binding agent is preferably an organic base; the organic base preferably includes one or more of triethylamine, pyridine and N,N-diisopropylethylamine, more preferably triethylamine; the molar ratio of the compound o to the acid binding agent is preferably 1:(4-6), more preferably 1:6.

[0185] In the present invention, the sixth acylation reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of dichloromethane, chloroform and tetrahydrofuran, more preferably tetrahydrofuran; the mass ratio of the compound o to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:5-10.

[0186] In the present invention, the temperature of the sixth acylation reaction is preferably -78 to -30°C, more preferably -78°C, and the insulation time is preferably 30 to 60 min, more preferably 30 min.

[0187] In the present invention, the sixth acylation reaction preferably further comprises concentrating the obtained reaction solution; the concentration is preferably concentrated under reduced pressure; the concentration temperature is preferably 20 to 50°C, more preferably 40°C.

[0188] After obtaining the third intermediate compound, the present invention conducts a fifth nucleophilic substitution reaction between the third intermediate compound and compound II to obtain compound p.

[0189] In the present invention, the fifth nucleophilic substitution reaction is preferably carried out in the presence of an acid binding agent; the acid binding agent is preferably an organic base; the organic base preferably includes one or more of triethylamine, pyridine and N,N-diisopropylethylamine, more preferably triethylamine; the molar ratio of the compound II to the acid binding agent is preferably 1:(4-6), more preferably 1:6.

[0190] In the present invention, the fifth nucleophilic substitution reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of dichloromethane, chloroform and tetrahydrofuran, more preferably tetrahydrofuran; the mass ratio of the compound II to the organic solvent is preferably 1:1-100, more preferably 1:5-10.

[0191] In the present invention, the temperature of the fifth nucleophilic substitution reaction is preferably -10 to -30°C, more preferably 25°C, and the insulation time is preferably 30 to 60 min, more preferably 30 min.

[0192] In the present invention, after the fifth nucleophilic substitution reaction, the steps of sequentially adding water to the obtained reaction product, extracting with ethyl acetate, drying, filtering and concentrating are preferably included.

[0193] In the present invention, the concentration temperature is preferably 20-50°C, more preferably 30°C; the concentration is preferably reduced-pressure concentration; the reduced-pressure concentration pressure is preferably 0.05-0.30 MPa, more preferably 0.10-0.15 MPa.

[0194] After obtaining compound p, the present invention performs a fifth hydrolysis reaction on the compound p to obtain an indazole benzoic acid derivative containing a urea structure as shown in formula C. In the present invention, the fifth hydrolysis reaction is preferably performed in the presence of an alkaline agent; the alkaline agent preferably includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate, more preferably lithium hydroxide; the molar ratio of the compound p to the alkaline agent is preferably 1:(1-20), more preferably 1:(1-10), and further preferably 1:(2-5).

[0195] In the present invention, the fifth hydrolysis reaction is preferably carried out in a mixed solvent of water and an organic solvent; the organic solvent preferably includes one or more of acetonitrile, methanol and tetrahydrofuran, more preferably tetrahydrofuran; the volume ratio of water to the organic solvent is preferably 1:1 to 5, more preferably 1:1 to 2, and further preferably 1:1.

[0196] In the present invention, the temperature of the hydrolysis reaction is preferably 30-70° C., more preferably 50° C., and the insulation time is preferably 2-10 h, more preferably 3 h.

[0197] In the present invention, after the hydrolysis reaction, the hydrolysis reaction preferably further comprises sequentially concentrating the obtained hydrolysis reaction liquid, adding water, adjusting the system pH value to 1-7 with hydrochloric acid under ice bath conditions, precipitating solids, suction filtering and drying; the concentration is preferably reduced pressure concentration; the pressure of the reduced pressure concentration is preferably 0.05-0.30MPa, more preferably 0.10-0.15MPa; the temperature of the ice bath conditions is preferably -10-10°C, more preferably 0-5°C. The present invention removes the solvent in the hydrolysis reaction liquid by concentration. The main synthetic routes of the indazole benzoic acid derivatives containing urea structure shown in the above-mentioned preparation formula C of the present invention are as follows Figure 3 shown.

[0198] The present invention also provides the use of the urea-containing indazole benzoic acid derivatives described in the above scheme or the urea-containing indazole benzoic acid derivatives obtained by the preparation method described in the above scheme in the preparation of drugs for treating diseases mediated by PGE2 / EP4 signal transduction.

[0199] In the present invention, the diseases mediated by PGE2 / EP4 signaling preferably include cancer, acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea, cancer or arteriosclerosis.

[0200] In order to further illustrate the present invention, the scheme of the present invention is described in detail below in conjunction with the accompanying drawings and embodiments, but they should not be understood as limiting the protection scope of the present invention.

[0201] Example 1 Synthesis of methyl 2-(2-((tert-butyloxycarbonyl)amino)ethyl)-2H-indazole-3-carboxylate

[0202] To a 100 mL single-necked bottle, 1H-indazole-3-carboxylic acid methyl ester (compound a, 9.97 g, 56.59 mmol) was added, followed by 30 mL of acetonitrile, Cs2CO3 (22.13 g, 67.91 mmol), KI (0.94 g, 5.66 mmol), and finally N-Boc-bromoethane (compound I, 13.95 g, 62.25 mmol). The mixture was heated to reflux for 2 h and the reaction was complete after monitoring by TLC. The reaction solution was concentrated under reduced pressure to remove acetonitrile, dissolved in DCM (50 mL), washed with H2O (25 mL × 1), and washed with saturated brine (30 mL × 1). Dry over anhydrous magnesium sulfate, filter after 4 hours, and concentrate under reduced pressure to obtain 20.43 g of yellow oil, which was loaded on a column with 8x silica gel, mixed with 1.2x silica gel, and eluent (EA:PE=1:25), with a separation degree of 0.6Rs, and column chromatography was performed to obtain methyl 2-(2-((tert-butyloxycarbonyl)amino)ethyl)-2H-indazole-3-carboxylate (compound b, 5.51 g of white solid, yield 30.48%). mp 76-78°C.

[0203] Example 2 Synthesis of 2-(2-((tert-Butyloxycarbonyl)amino)ethyl)-2H-indazole-3-carboxylic acid

[0204] To a 100 mL single-necked bottle, methyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)-2H-indazole-3-carboxylate (compound b, 5.48 g, 17.17 mmol) was added, and NaOH (1.37 g, 34.34 mmol) was added, and then 30 mL of H2O was added. After 12 h, the reaction was completed as monitored by TLC. The reaction solution was moved to an ice bath, and 1N hydrochloric acid was slowly added dropwise to pH = 3. A white solid gradually precipitated, and the mixture was filtered to obtain 2-(2-((tert-butoxycarbonyl)amino)ethyl)-2H-indazole-3-carboxylic acid (compound c, 4.52 g of white solid, yield 86.20%).

[0205] Example 3 Synthesis of methyl 4-((2-(2-((tert-butyloxycarbonyl)amino)ethyl)-2H-indazole-3-carboxamido)methyl)benzoate

[0206] To a 100 mL single-necked bottle, 2-(2-((tert-butoxycarbonyl)amino)ethyl)-2H-indazole-3-carboxylic acid (compound c, 4.52 g, 14.81 mmol) was added, dissolved in 20 mL of dry THF, HATU (6.76 g, 17.78 mmol) was added, DIEA (5.74 g, 44.44 mmol) was added, and after stirring for 0.5 h, 4-aminomethylbenzoic acid methyl ester hydrochloride (compound II, 3.88 g, 19.26 mmol) was added. After 1.5 h, the reaction was complete as monitored by TLC. The reaction solution was concentrated under reduced pressure to remove THF, dissolved in DCM (50 mL), washed with H2O (25 mL×1), and washed with saturated brine (30 mL×1). The mixture was dried over anhydrous magnesium sulfate, filtered after 4 h, and concentrated under reduced pressure to give 9.81 g of a yellow oil, which was loaded onto a column using 4x silica gel and mixed with 1.2x silica gel, using an eluent (EA:PE=1:10) to give methyl 4-((2-(2-((tert-butyloxycarbonyl)amino)ethyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound d, 5.65 g of a white solid, with a yield of 84.36%).

[0207] Example 4 Synthesis of methyl 4-((2-(2-aminoethyl)-2H-indazole-3-carboxamido)methyl)benzoate

[0208] To a 100 mL single-necked bottle, add methyl 4-((2-(2-((tert-butoxycarbonyl)amino)ethyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound d, 5.65 g, 12.49 mmol), add DCM 10 mL, TFA 4 mL, and stir at room temperature for 2 h. The reaction is monitored by TLC to be complete. The reaction solution is evaporated to dryness under reduced pressure to obtain methyl 4-((2-(2-aminoethyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound e, 7.34 g light yellow viscous oily liquid, yield 126.12%).

[0209] Example 5 Synthesis of methyl 4-((2-(2-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoate

[0210] Solid phosgene ((trichloromethyl) carbonate, 0.16 g, 0.53 mmol) and dry DCM (50 mL) were added to a three-necked flask, and the temperature was cooled to below -78°C by cold hydrazine. A solution of 3-fluoro-4-trifluoromethoxyaniline (Compound III, 0.21 g, 1.07 mmol) and triethylamine (0.33 g, 3.22 mmol) in dry dichloromethane (5 mL) was added dropwise. After the addition was completed, the mixture was returned to room temperature to stop the reaction. The obtained reaction solution was concentrated to dryness under reduced pressure, and dry DCM (10 mL) was added to the residue to dissolve it to obtain an isocyanate solution for later use. To a three-necked flask, methyl 4-((2-(2-aminoethyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound e, 0.40 g, 0.85 mmol), triethylamine (0.65 g, 6.39 mmol), and dry dichloromethane (10 mL) were added, and the above isocyanate solution was added dropwise. After the addition was completed, TLC showed that the reaction was complete; a white solid gradually precipitated, which was filtered off with suction, and the filter cake was rinsed with H2O (2 mL×2) to give methyl 4-((2-(2-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound f, 0.38 g white solid, yield 80.85%).

[0211] Example 6 Synthesis of 4-((2-(2-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-102-A)

[0212] Add methyl 4-((2-(2-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound f, 0.16 g, 0.29 mmol) to a 25 mL single-necked bottle, add NaOH (0.11 g, 2.87 mmol), and then add 10 mL of H2O. After 12 hours, the reaction is complete as monitored by TLC. Move the reaction solution to an ice bath, slowly add 1N hydrochloric acid dropwise to pH = 3, and gradually precipitate a white solid. The white solid obtained by suction filtration is SYP-102-A, with a yield of 0.14 g and a yield of 89.74%. mp 238~241℃. 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),9.13(t,J=6.0Hz,1H),8.14(s,1H),7.78(dd,J=19.2,7.6Hz,4H),7.70(d,J=8.6Hz,1H),7.38 (t,J=8.9Hz,1H),7.29(q,J=8.7Hz,4H),7.18(t,J=7.6Hz,1H),4.79(t,J=6.3Hz,2H),4.49(d,J=5.8Hz,2H),3.65(d,J=6.0Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ170.4,160.5,156.0,155.3,152.9,147.3,142.9,142.8,140.9,130.0,129.7, 126.9,126.3,124.5,123.1,122.0,120.8,119.5,117.9,114.0,114.0,106.0,105.8,67.5,52.3,43.2.

[0213] Example 7 Synthesis of 4-((2-(2-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-103-A)

[0214] According to the method of Examples 5 and 6, 3-fluoro-4-trifluoromethoxyaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-fluoro-4-trifluoromethoxyaniline), and a white solid, namely SYP-103-A, was obtained with a yield of 0.14 g and a yield of 87.52%. mp>300°C. 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),9.12(s,1H),8.24(s,1H),7.91-7.73(m,4H),7.71(d,J=8.7Hz,1H),7.57(t,J=8.7Hz,1H),7.3 6(d,J=8.5Hz,1H),7.32(d,J=7.6Hz,3H),7.19(t,J=7.6Hz,1H),4.81(t,J=6.2Hz,2H),4.52(d,J=5.8Hz,2H),3.67(d,J=6.1Hz,2H). 13 C NMR (100MHz, DMSO-d6) δ170.2,160.4,155.8,147.9,141.4,129.9,127.8,126.4,123.2,120.7,117.9,113.3,105.8,52.2,43.2.

[0215] Example 8 Synthesis of 4-((2-(2-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-104-A)

[0216] According to the method of Examples 5 and 6, 3-chloro-4-trifluoromethylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-chloro-4-trifluoromethylaniline), and a white solid, namely SYP-104-A, was obtained with a yield of 0.13 g and a yield of 79.22%. mp 223~227℃. 1 H NMR (600MHz, DMSO-d6) δ12.89(s,1H),9.21(s,1H),9.13(t,J=5.9Hz,1H),7.94(d,J= 8.1Hz,2H),7.88(d,J=8.5Hz,1H),7.83(d,J=2.1Hz,1H),7.73(d,J=8.7Hz,1H),7.66( d,J=8.7Hz,1H),7.51(d,J=8.0Hz,2H),7.40-7.31(m,2H),7.25(d,J=8.5Hz,1H),6.55 (t,J=5.8Hz,1H),4.83(t,J=6.0Hz,2H),4.62(d,J=5.9Hz,2H),3.69(q,J=6.0Hz,2H). 13C NMR (150MHz, DMSO-d6) δ167.6,160.3,155.0,147.2,145.7,144.7,131.6,130.0,129.9,129.2,128. 8,128.7,127.7,126.5,125.1,123.5,120.9,120.6,119.4,119.0,118.7,118.0,116.0,52.2,43.1.

[0217] Example 9 Synthesis of 4-((2-(2-(3-(4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-105-A)

[0218] According to the method of Examples 5 and 6, 4-trifluoromethoxyaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-trifluoromethoxyaniline), and a white solid, namely SYP-105-A, was obtained with a yield of 0.15 g and a yield of 89.55%. mp 256~258℃. 1 H NMR (600MHz, DMSO-d6) δ10.25 (s, 1H), 9.19 (t, J = 5.9Hz, 1H), 7.86 (s, 1H), 7. 80(d,J=8.5Hz,1H),7.77(d,J=7.8Hz,2H),7.70(d,J=8.6Hz,1H),7.61(d,J=6 .0Hz,1H),7.30(t,J=5.4Hz,2H),7.26(d,J=7.8Hz,2H),7.19(dd,J=19.1,7. 6Hz, 3H), 4.79 (t, J = 6.2Hz, 2H), 4.49 (d, J = 5.8Hz, 2H), 3.64 (q, J = 6.1Hz, 2H). 13 C NMR(100MHz,DMSO-d6)δ170.4,160.5,156.1,147.3,142.2,141.1,140.7,137.6,130.0,129 .7,126.8,126.3,123.1,122.0,121.9,120.8,120.7,119.0,117.9,52.4,43.2,40.7,40.5.

[0219] Example 10 Synthesis of 4-((2-(2-(3-(3-chloro-4-fluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-106-A)

[0220] According to the method of Examples 5 and 6, 3-chloro-4-fluoroaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-chloro-4-fluoroaniline), and a white solid, namely SYP-106-A, was obtained with a yield of 0.13 g and a yield of 80.07%. mp 237~242℃. 1 H NMR (600MHz, DMSO-d6) δ12.87(s,1H),9.13(t,J=6.0Hz,1H),8.95(s,1H),7.93(d,J=8.2Hz,2H),7.89(d,J=8.5Hz,1H),7.73(d,J=8.7Hz,2 H),7.59(dd,J=12.4,2.5Hz,1H),7.51(d,J=8.2Hz,2H),7.40-7.32(m,2H),7.25(t,J=7.1Hz,1H),7.10-7.03(m,1H),6.43(t,J=5.8Hz,1H). 13 C NMR(150MHz,DMSO-d6)δ167.6,160.3,158.8,156.4,155.3,147.2,144.8,141.6,141.6,130.7,130.0,1 29.9,129.2,127.7,126.4,123.5,120.9,120.6,118.0,115.0,110.9,110.8,106.3,106.0,52.4,43.1.

[0221] Example 11 Synthesis of 4-((2-(2-(3-(4-chloro-3-fluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-107-A)

[0222] According to the method of Examples 5 and 6, 4-chloro-3-fluoroaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-chloro-3-fluoroaniline), and a white solid, namely SYP-107-A, was obtained with a yield of 0.14 g and a yield of 85.17%. mp 227~232℃. 1H NMR(600MHz,DMSO-d6)δ9.19(s,1H),9.16(t,J=6.1Hz,1H),7.93(d,J=8.2Hz,2H),7 .88(d,J=8.4Hz,1H),7.73(d,J=8.5Hz,1H),7.60(dd,J=12.4,2.4Hz,1H),7.50(d,J= 8.1Hz,2H),7.40-7.31(m,2H),7.27-7.20(m,1H),7.08(dd,J=8.8,2.4Hz,1H),6.62( t,J=5.7Hz,1H),4.81(t,J=6.1Hz,2H),4.62(d,J=5.9Hz,2H),3.67(q,J=6.0Hz,2H). 13 C NMR (150MHz, DMSO-d6) δ167.9,160.3,158.8,156.4,155.4,147.2,144.5,141.8,141.7,130.6,130.5,129. 9,129.2,127.7,126.4,123.5,120.9,120.6,118.0,115.0,114.9,110.8,110.7,106.2,105.9,52.4,43.1.

[0223] Example 12 Synthesis of 4-((2-(2-(3-(p-tolyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-108-A)

[0224] According to the method of Examples 5 and 6, 4-methylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-methylaniline), and a white solid, namely SYP-108-A, was obtained with a yield of 0.12 g and a yield of 76.33%. mp 235~241℃. 1 H NMR(600MHz,DMSO-d6)δ9.16(t,J=6.0Hz,1H),8.60(s,1H),7.93(d,J=8.0Hz,2H),7 .87(d,J=8.5Hz,1H),7.74(d,J=8.6Hz,1H),7.48(d,J=7.9Hz,2H),7.37-7.32(m,1H) ,7.26(d,J=8.3Hz,2H),7.25-7.20(m,1H),7.01(d,J=8.2Hz,2H),6.42(t,J=5.9Hz,1 H), 4.80 (t, J = 6.2Hz, 2H), 4.61 (d, J = 5.9Hz, 2H), 3.65 (q, J = 6.1Hz, 2H), 2.20 (s, 3H).13 CNMR(150MHz,DMSO-d6)δ168.2,160.3,155.7,147.2,144.1,138.4,130.2,129.9, 129.5,129.3,127.6,126.4,123.5,120.9,120.6,118.3,118.0,52.5,43.1,20.8.

[0225] Example 13 Synthesis of 4-((2-(2-(3-(2-chloro-4-cyanophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-109-A)

[0226] According to the method of Examples 5 and 6, 2-chloro-4-cyanoaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 2-chloro-4-cyanoaniline), and a white solid, namely SYP-109-A, was obtained with a yield of 0.13 g and a yield of 83.13%. mp 221~224℃. 1 H NMR(600MHz,DMSO-d6)δ9.14(t,J=6.0Hz,1H),8.48(s,1H),8.38(d,J=8.8H z,1H),7.96(d,J=2.0Hz,1H),7.93-7.86(m,3H),7.74(d,J=8.5Hz,1H),7.68 (dd,J=8.8,2.0Hz,1H),7.48(d,J=7.7Hz,3H),7.39-7.32(m,1H),7.27-7.22 (m,1H),4.84(t,J=6.0Hz,2H),4.61(d,J=6.0Hz,2H),3.71(q,J=5.9Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ167.9,160.2,154.7,147.3,144.4,141.7,133.3,132.3,129.9,129.3, 127.6,126.5,123.5,121.1,121.0,120.6,120.1,118.6,118.0,104.2,52.3,43.1,40.7,40.5.

[0227] Example 14 Synthesis of 4-((2-(2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-110-A)

[0228] According to the method of Examples 5 and 6, 4-fluoro-3-trifluoromethylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-fluoro-3-trifluoromethylaniline), and a white solid, namely SYP-110-A, was obtained with a yield of 0.14 g and a yield of 83.24%. mp 216~220℃. 1 H NMR (600MHz, DMSO-d6) δ9.14 (t, J = 6.0 Hz, 1H), 9.06 (s, 1H), 7.93 (dd, J = 7.0, 4. 7Hz,3H),7.88(d,J=8.5Hz,1H),7.74(d,J=8.7Hz,1H),7.61-7.53(m,1H),7.50( d,J=8.0Hz,2H),7.35(dd,J=9.1,6.7Hz,2H),7.24(t,J=7.4Hz,1H),6.54(t,J= 5.7Hz, 1H), 4.83 (t, J = 6.1Hz, 2H), 4.62 (d, J = 6.0Hz, 2H), 3.68 (q, J = 6.0Hz, 2H). 13 C NMR(150MHz,DMSO-d6)δ167.9,160.3,155.5,147.2,144.5,137.8,137.8,129.9,129.2,1 27.6,126.4,123.9,123.8,123.5,120.9,120.6,118.0,117.9,117.7,115.7,52.3,43.1.

[0229] Example 15 Synthesis of 4-((2-(2-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-111-A)

[0230] According to the method of Examples 5 and 6, 4-chloro-3-trifluoromethylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-chloro-3-trifluoromethylaniline), and a white solid, namely SYP-111-A, was obtained with a yield of 0.14 g and a yield of 81.83%. mp 218~220℃. 1H NMR(600MHz,DMSO-d6)δ12.89(s,1H),9.13(t,J=6.0Hz,1H),8.97(s,1H),7.93(d,J =8.2Hz,2H),7.91(dd,J=6.5,2.7Hz,1H),7.89(d,J=8.5Hz,1H),7.74(d,J=8.7Hz,1H ),7.55(m,,1H),7.51(d,J=8.1Hz,2H),7.38-7.32(m,2H),7.27-7.22(m,1H),6.44( t,J=5.8Hz,1H),4.83(t,J=6.1Hz,2H),4.63(d,J=5.9Hz,2H),3.68(q,J=6.0Hz,2H). 13 C NMR (150MHz, DMSO-d6) δ167.6,160.3,155.5,147.2,144.7,137.7,130.0,129.2,127. 7,126.4,123.9,123.9,123.5,120.9,120.6,118.0,117.9,117.7,115.8,52.3,43.1.

[0231] Example 16 Synthesis of 4-((2-(2-(3-(3-fluoro-4-methylphenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-112-A)

[0232] According to the method of Examples 5 and 6, 3-fluoro-4-methylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-fluoro-4-methylaniline), and a white solid, namely SYP-112-A, was obtained with a yield of 0.15 g and a yield of 85.16%. mp 244~248℃. 1 H NMR (600MHz, DMSO-d6) δ9.57(s,1H),9.20(t,J=5.9Hz,1H),7.85(d,J=7.9Hz,2H),7.83(d ,J=8.4Hz,1H),7.72(d,J=8.6Hz,1H),7.44(d,J=12.9Hz,1H),7.38(d,J=7.9Hz,2H),7.35- 7.29(m,1H),7.24(s,1H),7.20(t,J=7.1Hz,1H),7.08(t,J=8.6Hz,1H),7.02(dd,J=8.3,2. 1Hz, 1H), 4.79 (t, J = 6.2Hz, 2H), 4.56 (d, J = 6.0Hz, 2H), 3.64 (q, J = 6.1Hz, 2H), 2.13 (s, 3H).13 C NMR(150MHz,DMSO-d6)δ169.4,162.2,160.4,159.8,155.8,147.2,142.3,140.9,140.8,131.6,131.5,129.8, 129.6,127.2,126.4,123.3,120.9,120.7,117.9,116.0,115.9,113.7,104.9,104.6,52.4,43.1,40.3,14.0.

[0233] Example 17 Synthesis of 4-((2-(2-(3-(3,5-difluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-113-A)

[0234] According to the method of Examples 5 and 6, 3,5-difluoroaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3,5-difluoroaniline), and a white solid, namely SYP-113-A, was obtained with a yield of 0.14 g and a yield of 84.81%. mp 257~262℃. 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.13(t,J=5.9Hz,1H),7.81(t,J=7.2Hz,3H),7.71(d,J=8.7Hz,2H),7.33(dd,J=14.6 ,7.8Hz,3H),7.27-7.12(m,3H),6.64(t,J=9.3Hz,1H),4.80(t,J=6.1Hz,2H),4.53(d,J=5.8Hz,2H),3.65(d,J=6.0Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ169.7,164.3,164.2,161.9,161.8,160.4,155.8,147.3,144.4, 142.0,129.8,127.2,126.4,123.2,120.8,120.7,117.9,100.8,100.5,95.9,52.3,43.2.

[0235] Example 18 Synthesis of 4-((2-(2-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-114-A)

[0236] According to the method of Examples 5 and 6, 3-chloro-4-trifluoromethoxyaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-chloro-4-trifluoromethoxyaniline), and a white solid, namely SYP-114-A, was obtained with a yield of 0.13 g and a yield of 80.43%. mp 240~243℃. 1 H NMR (400MHz, DMSO-d6) δ9.35 (s, 1H), 9.13 (t, J = 6.0Hz, 1H), 7.92 (d, J = 7.8Hz, 2H),7.89-7.79(m,2H),7.73(d,J=8.6Hz,1H),7.47(d,J=7.9Hz,2H),7.38(t, J=8.4Hz,1H),7.33(dd,J=9.1,2.3Hz,2H),7.23(t,J=7.5Hz,1H),6.84(t,J=5 .7Hz, 1H), 4.82 (t, J = 6.1Hz, 2H), 4.61 (d, J = 5.9Hz, 2H), 3.67 (q, J = 6.0Hz, 2H). 13 C NMR(100MHz,DMSO-d6)δ168.2,160.3,155.4,147.2,144.0,141.5,137.9,129.9,129.3,1 27.6,126.5,126.4,123.9,123.5,120.9,120.6,119.4,119.2,118.0,117.8,52.3,43.1.

[0237] Example 19 Synthesis of 4-((2-(2-(3-(4-chloro-3-methylphenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-116-A)

[0238] According to the method of Examples 5 and 6, 4-chloro-3-methylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-chloro-3-methylaniline), and a white solid, namely SYP-116-A, was obtained with a yield of 0.14 g and a yield of 84.34%. mp 235~238℃. 1H NMR(600MHz, DMSO-d6)δ9.81(s,1H),9.20(t,J=5.9Hz,1H),7.80(t,J=7.4Hz,3H),7.70(d,J=8.6Hz,1H),7.56(s,1H),7.48(d,J=2.6Hz,1H), 7.36-7.32(m,1H),7.30(d,J=7.8Hz,3H),7.23-7.15(m,2H),4.78(t,J=6.2Hz,2H),4.51(d,J=5.9Hz,2H),3.63(q,J=6.1Hz,2H),2.25(s,3H). 13 C NMR(150MHz,DMSO-d6)δ170.1,160.4,156.0,147.3,141.2,140.5,135.6,129.9,129.7, 129.2,127.0,126.3,124.9,123.2,120.8,120.7,120.4,117.9,117.3,52.4,43.2,20.4.

[0239] Example 20 Synthesis of 4-((2-(2-(3-(4-cyano-2-methylphenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-120-A)

[0240] According to the method of Examples 5 and 6, 4-cyano-2-methylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-cyano-2-methylaniline), and a white solid, namely SYP-120-A, was obtained with a yield of 0.15 g and a yield of 85.23%. mp 241~245℃. 1 H NMR(400MHz,DMSO-d6)δ12.89(s,1H),9.13(s,1H),8.17(d,J=8.4Hz,1H),8 .04(s,1H),7.91(t,J=9.7Hz,3H),7.74(d,J=8.6Hz,1H),7.52(dd,J=22.7, 8.7Hz,4H),7.35(t,J=7.5Hz,1H),7.25(t,J=7.4Hz,1H),7.06(d,J=5.4Hz, 1H), 4.83 (s, 2H), 4.60 (d, J = 4.7Hz, 2H), 3.70 (d, J = 5.3Hz, 2H), 2.16 (s, 3H). 13CNMR(100MHz,DMSO-d6)δ167.7,160.3,155.2,147.2,144.7,143.4,134.1,131.1,129.8,129 .2,127.7,126.8,126.5,123.5,121.0,120.6,119.9,119.2,118.0,103.2,52.4,43.1,18.0.

[0241] Example 21 Synthesis of 4-((2-(2-(3-(4-cyano-2-fluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-121-A)

[0242] According to the method of Examples 5 and 6, 4-cyano-2-fluoroaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-cyano-2-fluoroaniline), and a white solid, namely SYP-121-A, was obtained with a yield of 0.14 g and a yield of 84.12%. mp 227~230℃. 1 H NMR (400MHz, DMSO-d6) δ12.89 (s, 1H), 9.12 (t, J = 5.6Hz, 1H), 8.88 (s, 1H), 8. 36(t,J=8.4Hz,1H),7.93-7.88(m,3H),7.76(t,J=10.0Hz,2H),7.56(d,J=8. 7Hz,1H),7.49(d,J=8.0Hz,2H),7.30(dt,J=15.0,7.1Hz,2H),6.98(t,J=5.4 Hz, 1H), 4.83 (t, J = 5.3Hz, 2H), 4.61 (d, J = 5.5Hz, 2H), 3.72 (d, J = 5.5Hz, 2H). 13 C NMR(100MHz,DMSO-d6)δ167.7,160.2,154.7,151.8,149.4,147.3,144.7,134.0,130.0,129.3,12 7.7,126.5,123.5,121.0,120.6,119.8,119.2,119.0,118.8,118.0,102.9,102.8,52.30,43.05.

[0243] Example 22 Synthesis of 4-((2-(2-(3-(2-bromo-4-cyanophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-124-A)

[0244] According to the method of Examples 5 and 6, 2-bromo-4-cyanoaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 2-bromo-4-cyanoaniline), and a white solid, namely SYP-124-A, was obtained with a yield of 0.14 g and a yield of 83.15%. mp 207~209℃. 1 H NMR (400MHz, DMSO-d6) δ12.88(s,1H),9.10(t,J=5.9Hz,1H),8.30(d,J=8.8 Hz,1H),8.22(s,1H),8.09(d,J=1.8Hz,1H),7.91(t,J=8.3Hz,3H),7.76-7.6 0(m,2H),7.56(t,J=5.8Hz,1H),7.50(d,J=8.2Hz,2H),7.30(dt,J=15.1,7.0 Hz,2H),4.84(t,J=5.8Hz,2H),4.62(d,J=5.8Hz,2H),3.71(d,J=5.8Hz,2H). 13 C NMR (100MHz, DMSO-d6) δ167.6,160.2,154.7,147.3,144.8,142.8,136.6,132.7,129. 9,129.2,127.7,126.5,123.6,121.0,120.6,118.4,118.1,111.4,104.9,52.3,43.1.

[0245] Example 23 Synthesis of 4-((2-(2-(3-(4-cyanophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-125-A)

[0246] According to the method of Examples 5 and 6, 4-cyanoaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-cyanoaniline), and a white solid, namely SYP-125-A, was obtained with a yield of 0.13 g and a yield of 81.45%. mp 249~254℃. 1H NMR (400MHz, DMSO-d6) δ12.88(s,1H),9.43(s,1H),9.18(t,J=5.9Hz,1H),7. 93(d,J=8.2Hz,2H),7.88(d,J=8.5Hz,1H),7.73(d,J=8.7Hz,1H),7.64(d,J=8 .8Hz,2H),7.56(d,J=8.8Hz,2H),7.51(d,J=8.2Hz,2H),7.29(dt,J=14.9,6. 9Hz, 2H), 4.82 (t, J = 6.0Hz, 2H), 4.61 (d, J = 5.8Hz, 2H), 3.68 (q, J = 5.9Hz, 2H). 13 C NMR(100MHz,DMSO-d6)δ167.7,160.3,155.2,147.2,145.37,144.7,133.6,130 .0,129.3,127.7,126.5,123.5,121.0,120.6,119.9,118.0,102.8,52.3,43.1.

[0247] Example 24 Synthesis of methyl 2-(3-((tert-butyloxycarbonyl)amino)propyl)-2H-indazole-3-carboxylate

[0248] According to the method of Example 1, using N-Boc-bromopropane (Compound I) as raw material (i.e., N-Boc-bromoethane in Example 1 was replaced by N-Boc-bromopropane), 2-(3-((tert-butoxycarbonyl)amino)propyl)-2H-indazole-3-carboxylic acid methyl ester (Compound b) was obtained as a white solid (4.38 g) with a yield of 34.25%.

[0249] Example 25 Synthesis of 2-(3-((tert-Butyloxycarbonyl)amino)propyl)-2H-indazole-3-carboxylic acid

[0250] According to the method of Example 2, 2-(3-((tert-butoxycarbonyl)amino)propyl)-2H-indazole-3-carboxylic acid methyl ester (Compound b) was used as the raw material and hydrolyzed to obtain 2-(3-((tert-butoxycarbonyl)amino)propyl)-2H-indazole-3-carboxylic acid (Compound c), 2.54 g of white solid, with a yield of 88.25%.

[0251] Example 26 Synthesis of methyl 4-((2-(3-((tert-butyloxycarbonyl)amino)propyl)-2H-indazole-3-carboxamido)methyl)benzoate

[0252] According to the method of Example 3, 2-(3-((tert-butoxycarbonyl)amino)propyl)-2H-indazole-3-carboxylic acid (Compound c) was used as the raw material for condensation to obtain methyl 4-((2-(3-((tert-butoxycarbonyl)amino)propyl)-2H-indazole-3-carboxamido)methyl)benzoate (Compound d), 2.15 g of a white solid, with a yield of 83.21%.

[0253] Example 27 Synthesis of methyl 4-((2-(3-aminopropyl)-2H-indazole-3-carboxamido)methyl)benzoate

[0254] According to the method of Example 4, methyl 4-((2-(3-((tert-butoxycarbonyl)amino)propyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound d) was used as the starting material and deprotection was performed to obtain methyl 4-((2-(3-aminopropyl)-2H-indazole-3-carboxamido)methyl)benzoate (e), 3.25 g of a white solid, with a yield of 115.52%.

[0255] Example 28 Synthesis of 4-((2-(3-(3-(2-chloro-4-cyanophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U101-A)

[0256] According to the method of Examples 5 and 6, 2-chloro-4-cyanoaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 2-chloro-4-cyanoaniline), and a white solid, namely SYP-U101-A, was obtained with a yield of 0.15 g and a yield of 85.23%. mp 265~267℃. 1 H NMR(400MHz, DMSO-d6)δ9.19(t,J=5.9Hz,1H),8.61(s,1H),8.42(d,J=8.8Hz,1H) ,7.97(d,J=1.9Hz,1H),7.93-7.91(m,2H),7.85(d,J=8.5Hz,1H),7.73-7.63(m,3 H),7.45(d,J=8.2Hz,2H),7.36-7.32(m,1H),7.25-7.21(m,1H),4.77(t,J=6.9Hz ,2H),4.61(d,J=5.8Hz,2H),3.13(dd,J=12.3,6.5Hz,2H),2.08(p,J=6.8Hz,2H). 13C NMR (100MHz, DMSO-d6): δ168.3,160.3,154.7,147.1,143.4,141.9,133.3,132.3,129.9,128.9 ,127.4,126.4,123.4,121.1,120.9,120.6,120.0,118.6,117.9,104.1,50.3,43.1,37.1,31.2.

[0257] Example 29 Synthesis of 4-((2-(3-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U102-A)

[0258] According to the method of Examples 5 and 6, 4-chloro-3-trifluoromethylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-chloro-3-trifluoromethylaniline), and a white solid, SYP-U102-A, was obtained with a yield of 0.15 g and a yield of 85.62%. mp 229~231℃. 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),9.19(t,J=5.9Hz,1H),9.10(s,1H),8.05(d,J=2.4Hz,1H) ,7.94(d,J=8.2Hz,2H),7.86(d,J=8.5Hz,1H),7.72(d,J=8.7Hz,1H),7.59(dd,J=8.8,2.4Hz,1H) ,7.52(t,J=8.3Hz,3H),7.35(dd,J=8.0,7.2Hz,1H),7.26-7.22(m,1H),6.47(t,J=5.7Hz,1H),4 .75(t,J=6.9Hz,2H), 4.63(d,J=5.9Hz,2H), 3.10(dd,J=12.7,6.5Hz,2H), 2.07(p,J=6.8Hz,2H). 13 C NMR (100MHz, DMSO-d6): δ167.6,160.3,155.4,147.1,144.8,140.6,132.3,130.0,128.8,12 7.7,126.4,123.5,122.8,121.8,120.9,120.5,117.9,116.7,116.6,50.3,43.0,37.1,31.5.

[0259] Example 30 Synthesis of 4-((2-(3-(3-(4-fluoro-3-methylphenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U103-A)

[0260] According to the method of Examples 5 and 6, 4-fluoro-3-methylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-fluoro-3-methylaniline), and a white solid, namely SYP-U104-A, was obtained with a yield of 0.13 g and a yield of 82.32%. mp 218~222℃. 1 H NMR (400MHz, DMSO-d6) δ9.26 (s, 1H), 9.18 (t, J = 5.8Hz, 1H), 7.91 (d, J = 8.0Hz ,2H),7.82(d,J=8.4Hz,1H),7.71(d,J=8.6Hz,1H),7.40-7.30(m,4H),7.23(d t,J=15.0,5.7Hz,2H),7.03(s,1H),6.95(t,J=9.2Hz,1H),4.74(t,J=6.9Hz,2 H),4.59(d,J=5.7Hz,2H),3.08-3.05(m,2H),2.16(s,3H),2.05-1.02(m,2H). 13 C NMR (100MHz, DMSO-d6): δ169.4,160.3,156.9,156.1,154.6,147.0,1412.0,137.5,129.8,12 9.0,127.1,126.3,123.3,120.9,120.6,117.9,117.0,115.1,114.9,50.5,43.1,37.1,31.7.

[0261] Example 31 Synthesis of 4-((2-(3-(3-fluoro-4-methylphenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U104-A)

[0262] According to the method of Examples 5 and 6, 3-fluoro-4-methylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-fluoro-4-methylaniline), and a white solid, namely SYP-U101-A, was obtained with a yield of 0.16 g and a yield of 88.23%. mp 236~239℃. 1H NMR (400MHz, DMSO-d6) δ9.19(d,J=6.2Hz,2H),7.93(d,J=8.1Hz,2H),7.84(d,J=8.5Hz,1 H),7.71(d,J=8.7Hz,1H),7.42(dd,J=20.4,4.9Hz,3H),7.35-7.31(m,1H),7.24-7.21(m ,1H),7.07(t,J=8.6Hz,1H),6.99(dd,J=8.3,1.7Hz,1H),6.83(s,1H),4.74(t,J=6.9Hz, 2H),4.61(d,J=5.8Hz,2H),3.08(dd,J=12.5,6.5Hz,2H),2.12(s,3H),2.08-2.01(m,2H). 13 C NMR (100MHz, DMSO-d6): δ162.2,160.3,159.8,155.8,147.0,143.3,140.9,140.8,131.5,129.9,12 7.4,126.4,123.4,120.9,120.6,117.9,116.0,115.9,113.6,104.9,104.6,50.4,43.1,37.0,31.6.

[0263] Example 32 Synthesis of 4-((2-(3-(3-(3,5-difluorophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U105-A)

[0264] According to the method of Examples 5 and 6, 3,5-difluoroaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3,5-difluoroaniline), and a white solid, namely SYP-U105-A, was obtained with a yield of 0.13 g and a yield of 83.32%. mp 224~229℃. 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),9.16(t,J=5.5Hz,1H),7.92(d,J=7.5Hz,3H),7.81(d,J=8.4Hz,1H),7.70(d,J=8.5Hz,1H),7.32(dd,J=16.2,8. 1Hz,3H),7.21(dd,J=17.6,9.2Hz,3H),6.60(t,J=9.1Hz,1H),4.73(t,J=6 .7Hz,2H),4.57(d,J=5.3Hz,2H),3.10(d,J=5.7Hz,2H),2.07-2.03(m,2H). 13C NMR (100MHz, DMSO-d6): δ164.3,164.2,161.9,161.8,160.2,155.9,147.0,144.7,129.7, 129.1,126.9,126.3,123.3,120.9,120.6,,117.9,100.7,100.4,50.5,43.1,37.1,31.5.

[0265] Example 33 Synthesis of 4-((2-(3-(3-(4-chloro-3-fluorophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U106-A)

[0266] According to the method of Examples 5 and 6, 4-chloro-3-fluoroaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-chloro-3-fluoroaniline), and a white solid, namely SYP-U106-A, was obtained with a yield of 0.14 g and a yield of 83.34%. mp 238~244℃. 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),9.18(t,J=5.8Hz,1H),7.92(d,J=8.0Hz,2H),7.82(d,J=8.5Hz,1H),7.74-7.69(m,3H),7.40-7. 30(m,4H),7.23-7.19(m,2H),4.74(t,J=6.9Hz,2H),4.59(d,J=5.7Hz,2H),3.10(dd,J=12.2,6.2Hz,2H),2.07(dd,J=13.5,6.7Hz,2H). 13 C NMR (100MHz, DMSO-d6): δ169.7,160.3,158.8,156.4,155.9,147.0,142.7,142.0,130.5,129.8,12 9.0,127.1,126.3,123.3,120.9,120.6,117.9,114.9,110.9,105.9,105.7,50.5,43.1,37.1,31.6.

[0267] Example 34 Synthesis of 4-((2-(3-(3-chloro-4-fluorophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U107-A)

[0268] According to the method of Examples 5 and 6, 3-chloro-4-fluoroaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-chloro-4-fluoroaniline), and a white solid, namely SYP-U107-A, was obtained with a yield of 0.17 g and a yield of 88.12%. mp 242~245℃. 1 H NMR (400MHz, DMSO-d6) δ12.86 (s, 1H), 9.20 (t, J = 5.8Hz, 1H), 8.93 (s, 1H), 7 .94(d,J=8.1Hz,2H),7.86(d,J=8.4Hz,1H),7.77-7.71(m,2H),7.51(d,J=8. 1Hz,2H),7.36-7.32(m,1H),7.24(dd,J=9.8,4.7Hz,3H),4.75(t,J=6.9Hz, 2H),4.64(d,J=5.8Hz,2H),3.08(dd,J=12.5,6.4Hz,2H),2.07-2.04(m,2H). 13 C NMR (100MHz, DMSO-d6): δ167.7,160.3,155.6,153.4,151.1,147.1,144.7,138.4,129.9,128.8,127.7,12 6.4,123.4,120.9,120.5,119.5,119.3,119.2,118.2,118.1,117.9,117.2,117.0,50.4,43.0,37.1,31.5.

[0269] Example 35 Synthesis of 4-((2-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U108-A)

[0270] According to the method of Examples 5 and 6, 3-chloro-4-trifluoromethylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-chloro-4-trifluoromethylaniline), and a white solid, SYP-U108-A, was obtained with a yield of 0.11 g and a yield of 79.23%. mp 234~237℃. 1H NMR (400MHz, DMSO-d6) δ12.87(s,1H),9.23(s,1H),9.20(t,J=5.8Hz,1H),7.95(d,J=8.0H z,2H),7.87(d,J=11.4Hz,2H),7.72(d,J=8.6Hz,1H),7.67(d,J=8.7Hz,1H),7.51(d,J=8. 0Hz,2H),7.40(d,J=8.6Hz,1H),7.37-7.33(m,1H),7.26-7.22(m,1H),6.56(t,J=5.3Hz,1 H),4.76(t,J=6.7Hz,2H),4.64(d,J=5.6Hz,2H),3.11(d,J=6.0Hz,2H),2.10-2.06(m,2H). 13 C NMR (100MHz, DMSO-d6): δ167.6,160.3,155.1,147.1,145.9,144.8,131.6,130.0,129.9 ,128.8,127.7,126.4,123.5,120.9,120.5,119.3,117.9,115.9,50.3,43.0,37.1,31.4.

[0271] Example 36 Synthesis of 4-((2-(3-(3-(4-chloro-3-methylphenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U109-A)

[0272] According to the method of Examples 5 and 6, 4-chloro-3-methylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-chloro-3-methylaniline), and a white solid, SYP-U109-A, was obtained with a yield of 0.15 g and a yield of 82.52%. mp 235~240℃. 1 H NMR (400MHz, DMSO-d6) δ9.59(s,1H),9.18(t,J=5.7Hz,1H),7.90(d,J=7.9Hz,2H),7.81(d,J=8.5Hz,1H),7.70(d,J=8.6Hz,1H),7.39-7.26(m,6H ),7.22-7.18(m,1H),6.94(t,J=9.2Hz,1H),4.73(t,J=6.9Hz,2H),4.57 (d,J=5.6Hz,2H),3.08(d,J=6.0Hz,2H),2.16(s,3H),2.05-2.02(m,2H). 13C NMR (100MHz, DMSO-d6): δ170.1,160.2,156.9,156.2,154.5,147.0,140.7,137.70,137.68,129.7,129.1,1 26.8,126.3,124.2,124.0,123.3,120.9,120.6,117.9,117.0,115.1,114.9,50.5,43.1,37.1,31.8,14.9.

[0273] Example 37 Synthesis of 4-((2-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U110-A)

[0274] According to the method of Examples 5 and 6, 3-fluoro-4-trifluoromethylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-fluoro-4-trifluoromethylaniline), and a white solid, namely SYP-U110-A, was obtained with a yield of 0.15 g and a yield of 85.61%. mp 232~237℃. 1 H NMR (400MHz, DMSO-d6) δ12.93(s,1H),9.37(s,1H),9.20(t,J=5.9Hz,1H),7.94(d,J=8. 2Hz,2H),7.86(d,J=8.5Hz,1H),7.70(dd,J=19.2,11.6Hz,2H),7.57(t,J=8.7Hz,1H),7. 51(d,J=8.2Hz,2H),7.36-7.33(m,1H),7.23(dd,J=12.8,6.9Hz,2H),6.62(s,1H),4.75( t,J=6.9Hz,2H),4.63(d,J=5.9Hz,2H),3.11(dd,J=12.8,6.5Hz,2H),2.11-2.04(m,2H). 13 C NMR (100MHz, DMSO-d6): δ167.6,160.3,155.1,147.1,144.8,130.0,129.9,128.8,12 7.7,126.4,123.5,121.0,120.5,117.9,113.3,105.2,105.0,50.3,43.0,37.1,31.4.

[0275] Example 48 Synthesis of 4-((2-(3-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U111-A)

[0276] According to the method of Examples 5 and 6, 4-fluoro-3-trifluoromethylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-fluoro-3-trifluoromethylaniline), and a white solid, SYP-U111-A, was obtained with a yield of 0.14 g and a yield of 83.26%. mp 239~242℃. 1 H NMR(400MHz,DMSO-d6)δ12.89(s,1H),9.19(t,J=5.9Hz,1H),8.94(s,1H),7.95- 7.93(m,3H),7.86(d,J=8.5Hz,1H),7.72(d,J=8.7Hz,1H),7.60-7.56(m,1H),7.5 1(d,J=8.2Hz,2H),7.35(dd,J=12.8,7.1Hz,2H),7.26-7.22(m,1H),4.75(t,J=6. 9Hz, 2H), 4.63 (d, J = 5.9Hz, 2H), 3.09 (dd, J = 12.6, 6.5Hz, 2H), 2.10-2.03 (m, 2H). 13 CNMR (100MHz, DMSO-d6): δ167.6,160.3,155.6,147.1,144.8,137.9,130.3,129.9,128.8 ,127.7,126.4,123.9,123.5,120.9,120.6,117.9,117.7,115.7,50.4,43.0,37.1,31.5.

[0277] Example 39 Synthesis of 4-((2-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U112-A)

[0278] According to the method of Examples 5 and 6, 3-fluoro-4-trifluoromethoxyaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-fluoro-4-trifluoromethoxyaniline), and a white solid, namely SYP-U112-A, was obtained with a yield of 0.12 g and a yield of 81.25%. mp 251~254℃. 1H NMR (400MHz, DMSO-d6) δ13.00 (s, 1H), 9.51 (s, 1H), 9.19 (t, J = 5.9Hz, 1H), 7. 94(d,J=8.1Hz,2H),7.85(d,J=8.5Hz,1H),7.73-7.69(m,2H),7.47(d,J=8.1 Hz,2H),7.39-7.32(m,2H),7.25-7.16(m,2H),6.91(s,1H),4.75(t,J=6.9Hz ,2H),4.62(d,J=5.8Hz,2H),3.10(dd,J=12.7,6.6Hz,2H),2.10-2.03(m,2H). 13 C NMR (100MHz, DMSO-d6): δ168.3,160.3,155.5,152.9,147.1,142.3,142.2,129.9,128.9,12 7.6,126.4,124.6,123.4,120.9,120.6,117.9,114.0,106.2,105.9,50.4,43.0,37.1,31.5.

[0279] Example 40 Synthesis of 4-((2-(3-(3-(4-(trifluoromethoxy)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U113-A)

[0280] According to the method of Examples 5 and 6, 4-trifluoromethoxyaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-trifluoromethoxyaniline), and a white solid, namely SYP-U113-A, was obtained with a yield of 0.11 g and a yield of 78.69%. mp 245~249℃. 1 H NMR (400MHz, DMSO-d6) δ12.88(s,1H),9.19(t,J=5.9Hz,1H),8.88(d,J=5.3Hz,1H),7 .95(d,J=8.2Hz,2H),7.86(d,J=8.5Hz,1H),7.72(d,J=8.6Hz,1H),7.52-7.49(m,4H) ,7.36-7.32(m,1H),7.22(dd,J=16.1,8.5Hz,3H),6.42(t,J=5.6Hz,1H),4.75(t,J=6 .9Hz, 2H), 4.63 (d, J = 5.9Hz, 2H), 3.09 (dd, J = 12.6, 6.5Hz, 2H), 2.06 (p, J = 6.8Hz, 2H). 13C NMR (100MHz, DMSO-d6): δ167.7,160.3,155.6,147.1,144.8,142.4,140.4,130.0,129.98,12 9.95,128.8,127.7,126.4,123.4,122.0,120.9,120.6,119.1,117.9,50.4,43.0,37.1,31.6.

[0281] Example 41 Synthesis of 4-((2-(3-(3-(4-methoxyphenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U114-A)

[0282] According to the method of Examples 5 and 6, 4-methoxyaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-methoxyaniline), and a white solid, namely SYP-U114-A, was obtained with a yield of 0.14 g and a yield of 84.34%. mp 239~242℃. 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),9.19(t,J=5.8Hz,1H),8.33(s,1H),7.95(d,J=8 .1Hz,2H),7.85(d,J=8.5Hz,1H),7.72(d,J=8.6Hz,1H),7.51(d,J=8.1Hz,2H),7.36-7. 22(m,4H),6.80(d,J=8.9Hz,2H),6.17(t,J=5.5Hz,1H),4.74(t,J=6.8Hz,2H),4.64(d ,J=5.7Hz,2H),3.70(d,J=9.6Hz,3H),3.07(dd,J=12.4,6.3Hz,2H),2.06-2.03(m,2H). 13 C NMR (100MHz, DMSO-d6): δ167.7,160.3,155.9,154.4,147.0,144.8,134.1,130.0,128.8 ,127.7,126.4,123.4,120.9,120.6,120.0,117.9,114.3,55.6,50.4,43.0,37.1,31.7.

[0283] Example 42 Synthesis of 4-((2-(3-(3-(4-fluorophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U115-A)

[0284] According to the method of Examples 5 and 6, 4-fluoroaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-fluoroaniline), and a white solid, namely SYP-U115-A, was obtained with a yield of 0.12 g and a yield of 82.13%. mp 231~235℃. 1 H NMR (400MHz, DMSO-d6) δ12.91(s,1H),9.20(t,J=5.9Hz,1H),8.70(s,1H),7.95(d,J=8.2Hz,2 H),7.86(d,J=8.5Hz,1H),7.72(d,J=8.7Hz,1H),7.51(d,J=8.2Hz,2H),7.41-7.38(m,2H),7. 36-7.32(m,1H),7.25-7.22(m,1H),7.04(t,J=8.9Hz,2H),6.35(t,J=5.6Hz,1H),4.74(t,J=6 .9Hz,2H),4.64(d,J=5.8Hz,2H),3.08(dd,J=12.5,6.4Hz,2H),2.04(dd,J=13.6,6.8Hz,2H). 13 C NMR (100MHz, DMSO-d6): δ167.6,160.3,155.8,147.0,144.8,137.4,129.98,129.91,128.8,1 27.8,126.4,123.4,120.9,120.6,119.7,119.6,117.9,115.6,115.4,50.4,43.0,37.1,31.7.

[0285] Example 43 Synthesis of 4-((2-(3-(3-(4-nitrophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U117-A)

[0286] According to the method of Examples 5 and 6, 4-nitroaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-nitroaniline), and a white solid, namely SYP-U117-A, was obtained with a yield of 0.14 g and a yield of 83.89%. mp 239~242℃. 1H NMR (400MHz, DMSO-d6) δ12.89(s,1H),9.55(s,1H),9.20(s,1H),8.13(d,J=8.8Hz,2 H),7.95(d,J=7.7Hz,2H),7.86(d,J=8.1Hz,1H),7.73(d,J=8.6Hz,1H),7.64(d,J=8. 8Hz,2H),7.50(d,J=7.7Hz,2H),7.35(t,J=7.4Hz,1H),7.24(t,J=7.3Hz,1H),6.74( s,1H),4.76(s,2H),4.64(d,J=5.0Hz,2H),3.12(d,J=5.6Hz,2H),2.10-2.07(m,2H). 13 C NMR(100MHz,DMSO-d6)δ168.0,160.3,155.0,147.8,147.1,144.5,140.8,130.0,128 .8,127.7,126.4,125.6,123.5,120.9,120.6,117.9,117.3,50.3,43.1,37.2,31.4.

[0287] Example 44 Synthesis of 4-((2-(3-(3-(2-bromo-4-cyanophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U118-A)

[0288] According to the method of Examples 5 and 6, 2-bromo-4-cyanoaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 2-bromo-4-cyanoaniline), and a white solid, SYP-U118-A, was obtained with a yield of 0.14 g and a yield of 84.56%. mp 237~241℃. 1 H NMR (400MHz, DMSO-d6) δ12.86 (s, 1H), 9.24 (t, J = 5.9Hz, 1H), 8.38-8.33 (m, 2H), 8 .11(d,J=1.9Hz,1H),7.95-7.93(m,2H),7.86(dd,J=9.6,4.9Hz,2H),7.74-7.70(m ,2H),7.51(d,J=8.2Hz,2H),7.36-7.33(m,1H),7.26-7.22(m,1H),4.77(t,J=6.9H z, 2H), 4.63 (d, J = 5.8Hz, 2H), 3.12 (dd, J = 12.3, 6.5Hz, 2H), 2.09 (p, J = 6.8Hz, 2H). 13CNMR(100MHz,DMSO-d6)δ167.7,160.3,154.7,147.1,144.7,143.0,136.6,132.7,130.2,130.0 ,128.8,127.7,126.4,123.5,121.0,120.6,118.5,117.9,111.4,104.6,50.4,43.0,37.1,31.2.

[0289] Example 45 Synthesis of methyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-indazole-3-carboxylate

[0290] According to the method of Example 1, N-Boc-bromoethane (Compound I) was used as the raw material. The only difference from Example 1 was that the separation degree during column chromatography was adjusted to 0.5Rs to obtain 1-(2-((tert-butyloxycarbonyl)amino)ethyl)-1H-indazole-3-carboxylic acid methyl ester (Compound h), 4.36 g of white solid, with a yield of 37.21%. mp 117-118°C.

[0291] Example 46 Synthesis of 1-(2-((tert-Butyloxycarbonyl)amino)ethyl)-1H-indazole-3-carboxylic acid

[0292] According to the method of Example 2, 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-indazole-3-carboxylic acid methyl ester (Compound h) was used as the raw material and hydrolyzed to obtain 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-indazole-3-carboxylic acid (Compound i), 4.52 g of white solid, with a yield of 83.56%.

[0293] Example 47 Synthesis of methyl 4-((1-(2-((tert-butyloxycarbonyl)amino)ethyl)-1H-indazole-3-carboxamido)methyl)benzoate

[0294] According to the method of Example 3, 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-indazole-3-carboxylic acid (Compound i) was used as the raw material for condensation to obtain methyl 4-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-indazole-3-carboxamido)methyl)benzoate (Compound j), 3.89 g of white solid, with a yield of 85.36%.

[0295] Example 48 Synthesis of methyl 4-((1-(2-aminoethyl)-1H-indazole-3-carboxamido)methyl)benzoate

[0296] According to the method of Example 4, methyl 4-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-indazole-3-carboxamido)methyl)benzoate (Compound j) was used as the starting material, and deprotection was performed to obtain methyl 4-((1-(2-aminoethyl)-1H-indazole-3-carboxamido)methyl)benzoate (Compound k), 4.56 g of a white solid, with a yield of 124.31%.

[0297] Example 49 Synthesis of 4-((1-(2-(3-(3-chloro-4-cyanophenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (SYP-A109-A)

[0298] According to the method of Examples 5 and 6, 3-chloro-4-cyanoaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-chloro-4-cyanoaniline), and a white solid, namely SYP-A109-A, was obtained with a yield of 0.10 g and a yield of 78.35%. mp 245~249℃. 1 H NMR(400MHz,DMSO-d6)δ12.84(s,1H),9.01(s,1H),8.41(s,2H),8.19(s,1H) ,7.90(s,3H),7.72(s,2H),7.37(d,J=69.1Hz,5H),4.59(s,4H),3.70(s,2H). 13 C NMR (100MHz, DMSO-d6): δ167.8,162.5,154.7,145.4,141.6,141.5,137.8,133.3,132.3, 129.8,127.8,127.1,122.9,122.8,122.3,121.2,120.3,118.5,110.7,104.4,49.1,42.3.

[0299] Example 50 Synthesis of 4-((1-(2-(3-(3-fluoro-4-methylphenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (SYP-A112-A)

[0300] According to the method of Examples 5 and 6, 3-fluoro-4-methylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-fluoro-4-methylaniline), and a white solid, namely SYP-A112-A, was obtained with a yield of 0.14 g and a yield of 84.38%. mp 259~264℃. 1H NMR (400MHz, DMSO-d6) δ12.84 (s, 1H), 9.02 (t, J = 5.7Hz, 1H), 8.69 (s, 1H), 8.19 (d,J=8.0Hz,1H),7.90(d,J=7.8Hz,2H),7.74(d,J=8.4Hz,1H),7.45(t,J=9.9Hz ,3H),7.36(d,J=12.6Hz,1H),7.27(t,J=7.4Hz,1H),7.08(t,J=8.5Hz,1H),6.90 (d,J=7.8Hz,1H),6.31(s,1H),4.58(s,4H),3.64(d,J=5.3Hz,2H),2.13(s,3H). 13 C NMR (100MHz, DMSO-d6): δ167.8,162.5,162.1,159.8,155.6,145.4,141.4,140.3,137.6,131.6,129 .8,127.8,127.1,122.9,122.8,122.3,116.6,116.4,113.8,110.7,105.1,104.8,49.2,42.3,14.0.

[0301] Example 51 Synthesis of 4-((1-(2-(3-(3,5-difluorophenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (SYP-A113-A)

[0302] According to the method of Examples 5 and 6, 3,5-difluoroaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3,5-difluoroaniline), and a white solid, namely SYP-A113-A, was obtained with a yield of 0.16 g and a yield of 87.35%. mp 247~252℃. 1 H NMR (400MHz, DMSO-d6) δ12.84(s,1H),9.01(s,2H),8.19(d,J=7.9Hz,1H),7.91(d,J=7.6Hz,2H),7.74(d,J=8.3Hz,1H),7.46(t,J =9.7Hz,3H),7.27(t,J=7.2Hz,1H),7.09(d,J=8.7Hz,2H),6.69(t,J=8.6Hz,1H),6.46(s,1H),4.59(s,4H),3.65(d,J=4.8Hz,2H). 13C NMR (100MHz, DMSO-d6): δ167.7,164.3,164.2,162.5,161.9,161.8,155.3,145.4,143.5,141 .4,137.7,129.8,127.8,127.1,122.9,122.8,122.3,110.7,101.0,100.7,96.5,49.1,42.3.

[0303] Example 52 Synthesis of 4-((1-(2-(3-(3-chloro-4-methylphenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (SYP-A115-A)

[0304] According to the method of Examples 5 and 6, 3-chloro-4-methylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-chloro-4-methylaniline), and a white solid, namely SYP-A115-A, was obtained with a yield of 0.14 g and a yield of 84.44%. mp 242~245℃. 1 H NMR (600MHz, DMSO-d6) δ12.87(s,1H),9.04(t,J=6.1Hz,1H),8.69(s,1H),8.20(d,J=8. 1Hz,1H),7.91(d,J=8.1Hz,2H),7.74(d,J=8.5Hz,1H),7.63(s,1H),7.46(dd,J=19.7,8 .0Hz,3H),7.28(t,J=7.5Hz,1H),7.16(d,J=8.3Hz,1H),7.07(d,J=8.1Hz,1H),6.32(t, J=5.5Hz,1H),4.59(dd,J=12.1,6.0Hz,4H),3.64(dd,J=11.3,5.5Hz,2H),2.23(s,3H). 13 C NMR (150MHz, DMSO-d6): δ167.7,162.5,155.6,145.5,141.4,140.0,137.6,133.5,131.5,129.8,128 .0,127.8,127.1,122.9,127.8,127.1,122.9,122.8,122.3,118.2,117.0,110.7,49.2,42.3,19.2.

[0305] Example 53 Synthesis of methyl 4-((2-(2-((1r,4r)-4-((tert-butyloxycarbonyl)amino)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoate

[0306] According to the method of Example 3, methyl 4-((2-(2-aminoethyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound e) and tert-butyl trans-(4-aminocyclohexyl)carbamate were used as raw materials to obtain methyl 4-((2-(2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound n), 7.85 g of white solid, with a yield of 88.39%.

[0307] Example 54 Synthesis of methyl 4-((2-(2-((1r,4r)-4-aminocyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoate

[0308] According to the method of Example 4, 4-((2-(2-((1r,4r)-4-((tert-butyloxycarbonyl)amino)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid methyl ester (Compound n) was used as raw material and deprotection was performed to obtain 4-((2-(2-((1r,4r)-4-aminocyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid methyl ester (Compound o), 8.96 g of white solid, with a yield of 125.36%.

[0309] Example 55 Synthesis of 4-((2-(2-((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C101-A)

[0310] According to the method of Examples 5 and 6, 2-chloro-4-cyanoaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 2-chloro-4-cyanoaniline), and a white solid, namely SYP-C101-A, was obtained with a yield of 0.11 g and a yield of 78.23%. mp 249~252℃. 1 H NMR (400MHz, DMSO-d6) δ9.12(s,1H),8.41(s,2H),7.92(d,J=27.0Hz,5H),7.71(s,2H),7.52(s,2H),7.38(d,J=28.0Hz ,2H),7.24(s,1H),4.71(d,J=52.1Hz,4H),3.59(s,3H),1.95(d,J=34.9Hz,3H),1.70(s,2H),1.33(s,2H),1.09(s,2H). 13C NMR(100MHz,DMSO-d6)δ175.4,167.9,160.2,153.8,147.2,144.4,141.9,133.3,132.3,130.8,129.9,12 9.0,127.7,126.4,123.5,120.9,120.5,119.7,118.6,118.0,103.9,51.9,48.5,43.5,43.1,32.4,28.4.

[0311] Example 56 Synthesis of 4-((2-(2-((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C102-A)

[0312] According to the method of Examples 5 and 6, 4-chloro-3-trifluorotoluidine was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-chloro-3-trifluorotoluidine), and a white solid, namely SYP-C102-A, was obtained with a yield of 0.12 g and a yield of 81.02%. mp 279~284℃. 1 H NMR (400MHz, DMSO-d6) δ12.89(s,1H),9.11(s,1H),8.99(s,1H),8.08(s,1H),7.95(d,J=7.8Hz,2H),7.88 (d,J=7.3Hz,2H),7.72(d,J=8.6Hz,1H),7.52(d,J=6.4Hz,4H),7.34(t,J=7.5Hz,1H),7.24(t,J=7.4Hz,1H ),6.37(d,J=7.4Hz,1H),4.76(d,J=5.3Hz,2H),4.64(d,J=4.4Hz,2H),3.58(d,J=5.3Hz,2H),3.50(s,1H) ,1.99-1.94(m,1H),1.87(d,J=10.7Hz,2H),1.69(d,J=11.6Hz,2H),1.38-1.31(m,2H),1.15-1.10(m,2H). 13 C NMR(100MHz,DMSO-d6)δ175.4,168.0,160.2,154.7,147.2,144.6,140.7,132.3,129.9,129.0,12 7.7,126.4,123.5,122.7,121.6,121.1,120.5,118.0,116.5,51.9,48.4,43.5,43.0,32.5,28.5.

[0313] Example 57 Synthesis of 4-((2-(2-((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C104-A)

[0314] According to the method of Examples 5 and 6, 3-fluoro-4-methylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-fluoro-4-methylaniline), and a white solid, namely SYP-C104-A, was obtained with a yield of 0.11 g and a yield of 79.69%. mp>300°C. 1 H NMR (400MHz, DMSO-d6) δ9.10(dd,J=15.7,10.0Hz,2H),7.90(dd,J=23.3,8.1Hz,4H),7.71(d,J=8.6Hz,1H),7.43(dd,J= 16.8,10.6Hz,3H),7.35-7.32(m,1H),7.25-7.21(m,1H),7.06(t,J=8.6Hz,1H),6.97(d,J=8.1Hz,1H),6.72(d,J=7.5Hz ,1H),4.78(t,J=5.5Hz,2H),4.61(d,J=5.5Hz,2H),3.58(d,J=5.5Hz,2H),3.32-3.31(m,1H),2.12(s,3H),1.93(t,J=11 .7Hz,1H),1.83(d,J=10.1Hz,2H),1.65(d,J=11.6Hz,2H),1.30(dd,J=23.9,11.9Hz,2H),1.05(dd,J=23.1,11.2Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ175.5,162.2,160.2,159.8,155.1,147.2,142.7,141.0,140.9,131.5,129.8,129.1,127.3,1 26.4,123.4,121.0,120.5,118.0,115.8,115.7,113.5,104.7,104.4,51.9,48.1,43.6,43.1,32.7,28.5,13.98,14.0.

[0315] Example 58 Synthesis of 4-((2-(2-((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C106-A)

[0316] According to the method of Examples 5 and 6, 4-chloro-3-fluoroaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-chloro-3-fluoroaniline), and a white solid, namely SYP-C106-A, was obtained with a yield of 0.19 g and a yield of 93.54%. mp 289~292℃. 1 H NMR (400MHz, DMSO-d6) δ9.85 (s, 1H), 9.09 (t, J = 5.6Hz, 1H), 7.93 (d, J = 7.9Hz, 2H), 7.87 (d, J = 8.6Hz, 2H),7.70(t,J=9.8Hz,2H),7.45(d,J=8.0Hz,2H),7.34(dd,J=16.0,7.4Hz,2H),7.25-7.15(m,3H),4 .78(t,J=5.6Hz,2H),4.62(d,J=5.5Hz,2H),3.58(d,J=5.5Hz,2H),3.34(s,1H),1.91(d,J=10.8Hz,1 H),1.83(d,J=10.7Hz,2H),1.65(d,J=11.4Hz,2H),1.30(dd,J=24.2,11.9Hz,2H),1.12-1.06(m,2H). 13 CNMR(100MHz,DMSO-d6)δ175.5,169.3,160.2,158.8,156.4,155.0,147.2,142.6,130.5,129.8,129.1,127. 2,126.4,123.4,121.0,120.5,118.0,114.8,110.1,109.9,105.9,105.6,51.9,48.1,43.6,43.1,32.6,28.5.

[0317] Example 59 Synthesis of 4-((2-(2-((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C107-A)

[0318] According to the method of Examples 5 and 6, 3-chloro-4-fluoroaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 2-chloro-4-cyanoaniline), and a white solid, namely SYP-C107-A, was obtained with a yield of 0.16 g and a yield of 88.56%. mp 295~299℃. 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.93 (d, J = 21.4Hz, 1H), 7.95-7.87 (m, 4 H),7.74(dd,J=19.8,6.5Hz,2H),7.53(dd,J=25.4,7.0Hz,2H),7.34(s,1H), 7.23(s,3H),6.46(s,1H),4.77(s,2H),4.63(s,2H),3.85(s,1H),3.58(s,2H ),1.89(d,J=41.6Hz,3H),1.66(s,2H),1.31(d,J=11.8Hz,2H),1.08(s,2H). 13 C NMR (100MHz, DMSO-d6) δ175.4,168.4,166.6,160.2,154.9,153.2,150.9,147.2,145.4,143.8,138.6,129.9,128. 9,127.9,127.5,126,4,123.5,121.0,120.5,119.0,118.0,117.2,117.0,52.5,51.9,48.2,43.6,43.0,32.6,28.5.

[0319] Example 60 Synthesis of 4-((2-(2-((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C110-A)

[0320] According to the method of Examples 5 and 6, 3-fluoro-4-trifluoromethylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-fluoro-4-trifluoromethylaniline), and a white solid, namely SYP-C110-A, was obtained with a yield of 0.14 g and a yield of 85.34%. mp 282~286℃. 1H NMR (400MHz, DMSO-d6) δ12.89(s,1H),9.45(s,1H),9.12(s,1H),7.95(d,J=7.7Hz,2H),7.88(d,J=7. 2Hz,2H),7.69(dd,J=17.1,11.7Hz,2H),7.56(dd,J=18.6,8.2Hz,3H),7.36-7.32(m,1H),7.26-7.17 (m,2H),4.76(s,2H),4.64(d,J=4.7Hz,2H),3.58(d,J=4.9Hz,2H),3.35(s,1H),1.97(d,J=11.4Hz,1 H),1.87(d,J=10.2Hz,2H),1.70(d,J=11.8Hz,2H),1.33(dd,J=24.2,11.7Hz,2H),1.14-1.06(m,2H). 13 C NMR (100MHz, DMSO-d6) δ175.4,167.7,160.2,154.4,147.2,144.8,130.03,129.96,128.9,127. 8,126.4,123.5,121.0,120.5,118.0,113.1,105.0,104.7,51.9,48.3,43.5,43.0,32.5,28.4.

[0321] Example 61 Synthesis of 4-((2-(2-((1r,4r)-4-(3-(p-tolyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C114-A)

[0322] According to the method of Examples 5 and 6, p-toluidine was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by p-toluidine), and a white solid, namely SYP-C114-A, was obtained with a yield of 0.14 g and a yield of 85.34%. mp>300°C. 1H NMR(400MHz, DMSO-d6)δ9.10(t,J=5.8Hz,1H),8.71(s,1H),7.94-7.87(m,4H),7.71(d,J=8.6Hz,1H),7.4 7(d,J=8.0Hz,2H),7.35-7.21(m,4H),6.99(d,J=8.2Hz,2H),6.44(d,J=7.6Hz,1H),4.77(t,J=5.7Hz,2H) ,4.62(d,J=5.6Hz,2H),3.58(d,J=5.6Hz,2H),3.32-3.30(m,1H),2.20(s,3H),1.93(t,J=11.8Hz,1H),1. 84(d,J=9.9Hz,2H), 1.65(d,J=11.7Hz,2H), 1.30(dd,J=24.2,11.6Hz,2H), 1.04(dd,J=22.9,11.3Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ175.5,168.8,160.2,155.2,147.2,143.0,138.8,129.9,129.7,1 29.0,127.4,126.4,123.4,121.0,120.5,118.0,51.9,48.0,43.6,43.0,32.8,28.5,20.8.

[0323] Example 62 Synthesis of 4-((2-(2-((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C115-A)

[0324] According to the method of Examples 5 and 6, 3-chloro-4-trifluoromethoxyaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 3-chloro-4-trifluoromethoxyaniline), and a white solid, namely SYP-C115-A, was obtained with a yield of 0.17 g and a yield of 86.56%. mp 272~277℃. 1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),9.12(s,1H),8.96(s,1H),7.96-7.84(m,5H) ,7.72(d,J=8.4Hz,1H),7.54(d,J=6.9Hz,2H),7.41-7.24(m,4H),6.34(d,J=6.6Hz ,1H),4.76(s,2H),4.64(s,2H),3.59(s,2H),3.37(s,1H),1.98(s,1H),1.87(d,J= 9.2Hz, 2H), 1.70 (d, J = 11.0Hz, 2H), 1.33 (d, J = 11.8Hz, 2H), 1.10 (d, J = 11.7Hz, 2H). 13 CNMR(100MHz,DMSO-d6)δ175.4,167.6,160.2,154.6,147.2,144.9,141.5,137.8,130.0,129.9,128.9,1 27.8,126.5,126.4,124.0,123.5,121.0,120.5,118.9,118.0,117.6,51.9,48.4,43.5,43.0,32.6,28.5.

[0325] Example 63 Synthesis of 4-((2-(2-((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C116-A)

[0326] According to the method of Examples 5 and 6, 4-chloro-3-trifluoromethylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-chloro-3-trifluoromethylaniline), and a white solid, namely SYP-C116-A, was obtained with a yield of 0.14 g and a yield of 84.34%. mp>300°C. 1H NMR (400MHz, DMSO-d6) δ12.89(s,1H),9.11(s,1H),8.89(s,1H),8.07(s,1H),7.95(d,J=7.3Hz,2H) ,7.88(d,J=6.6Hz,2H),7.72(d,J=8.1Hz,1H),7.53(s,4H),7.33(d,J=7.5Hz,1H),7.25(d,J=6.9Hz, 1H),6.29(d,J=6.7Hz,1H),4.77(s,2H),4.64(s,2H),3.59(s,2H),3.34(s,1H),1.96(d,J=10.7Hz, 1H), 1.87 (d, J = 10.0Hz, 2H), 1.70 (d, J = 10.9Hz, 2H), 1.33 (d, J = 11.9Hz, 2H), 1.11 (d, J = 11.5Hz, 2H). 13 C NMR(100MHz,DMSO-d6)δ175.42,167.8,160.3,154.6,147.2,144.8,140.6,132.3,130.3,130.0,12 8.9,127.7,126.4,123.5,122.7,121.0,120.5,118.0,116.5,51.9,48.4,43.51,43.0,32.5,28.5.

[0327] Example 64 Synthesis of 4-((2-(2-((1r,4r)-4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C117-A)

[0328] According to the method of Examples 5 and 6, 4-trifluoromethylaniline was used as the raw material (i.e., 3-fluoro-4-trifluoromethoxyaniline in Example 5 was replaced by 4-trifluoromethylaniline), and a white solid, namely SYP-C117-A, was obtained with a yield of 0.14 g and a yield of 84.37%. mp 285~290℃. 1H NMR (400MHz, DMSO-d6) δ12.87(s,1H),9.08(t,J=5.7Hz,1H),8.93(s,1H),7.92(t,J=9.1H z,3H),7.87(d,J=8.5Hz,1H),7.70(d,J=8.6Hz,1H),7.60-7.51(m,6H),7.30-7.27(m,1H), 7.25-7.18(m,1H),6.33(d,J=7.8Hz,1H),4.77(t,J=5.5Hz,2H),4.64(d,J=5.4Hz,2H),3.6 2-3.44(m,2H),3.36(s,1H),2.12(t,J=11.6Hz,1H),1.90-1.58(m,4H),1.27-1.03(m,4H). 13 C NMR (100MHz, DMSO-d6) δ167.8,157.7,154.6,146.9,144.6,129.7,129.5,127.4,126.44,126.40,117.7,46.9,43.9,42.9,32.4.

[0329] Test Example 1

[0330] Inhibitory activity test

[0331] (1) When the density of HEK293 cells reaches 80-90%, co-transfect with pGloSensor at a ratio of 1:1 (mass ratio) TM -22Fc AMP plasmid and Human-EP4 plasmid, 4μg plasmid can be co-transfected into a 6cm dish.

[0332] (2) After 8 hours, the transfection mixture was replaced with DMEM complete medium containing 10% FBS and cultured overnight.

[0333] (3) The next day, 2 to 4 hours in advance, remove the DMEM complete medium and replace it with serum-free medium to starve the cells.

[0334] (4) After starvation, the cells were digested and counted, and the cell density was resuspended to 2×10 in serum-free CO2 Independent Medium. 6 cells / mL. Add 4% Glo Sensor TM After mixing c AMP Reagent, add 20 μL of cell suspension / well into a 384-well plate and incubate at room temperature in the dark for 1.5 to 2 hours.

[0335] (5) Dilute the test compound to the desired concentration using serum-free CO2 Independent Medium.

[0336] (6) If the activity of the agonist PGE2 is to be detected, the 384-well plate is taken out after incubation for 2 hours and placed in the Flex Station 3 instrument to detect the fluorescence signal after adding 5 μL of different concentrations of PGE2, and the reading is performed continuously for 30 minutes.

[0337] (7) If the antagonist activity of the compound on the receptor is to be detected, the 384-well plate is taken out after incubation for 1.5 h, and 5 μL of the compound of different concentrations is added. After incubation at room temperature and away from light for 30 min, the Flex Station 3 instrument is used to detect and read the EC 80 The fluorescence signal after the concentration of PGE2 was measured was read continuously for 30 min.

[0338] The inhibitory activities of the compounds against human EP4 (hEP4) are shown in Table 1.

[0339] Table 1 Inhibitory activity of compounds against human EP4 (hEP4) at 10 μM

[0340]

[0341] Table 2 Inhibitory activity of compounds on human EP4 (hEP4) (IC50, nM)

[0342] serial number <![CDATA[hEP4(IC 50 ,nM)]]> serial number <![CDATA[hEP4(IC 50 ,nM)]]> SYP-106-A 9.87 SYP-112-A >100 SYP-107-A 18.96 SYP-116-A 37.59 SYP-109-A 6.40 SYP-C110-A 30.58 SYP-111-A 56.70 SYP-C116-A 19.56 Grapiprant 13.02

[0343] It can be seen from Table 1 that the indazole benzoic acid derivatives containing a urea structure provided by the present invention have a good inhibitory effect on EP4. The experimental results showed that the inhibition rates of SYP-103-A, SYP-106-A, SYP-107-A, SYP-109-A, SYP-110-A, SYP-111-A, SYP-112-A, SYP-113-A, SYP-116-A, SYP-U104-A, SYP-U105-A, SYP-U106-A, SYP-U107-A, SYP-U108-A, SYP-U109-A, SYP-U110-A, SYP-U111-A, SYP-U112-A, SYP-U113-A, SYP-U114-A, SYP-U115-A, SYP-U117-A, SYP-C110-A, and SYP-C116-A on EP4 were above 90%.

[0344] According to Table 2, it can be seen that the inhibitory activity of SYP-106-A, SYP-107-A, SYP-107-A, SYP-111-A, SYP-116-A, SYP-C110-A, and SYP-C116-A against EP4 is comparable to that of the positive drug Grapiprant, especially the inhibitory activity of SYP-106-A and SYP-109-A against hEP4 is higher than that of the positive drug Grapiprant, showing very good development prospects.

[0345] It can be seen from the above examples that the urea-containing indazole benzoic acid derivatives provided by the present invention have high inhibitory activity against human EP4 and can be used as EP4 inhibitors for preparing drugs for treating diseases mediated by PGE2 / EP4 signaling.

[0346] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. An indazole benzoic acid derivative containing a urea structure, characterized in that: The structure is shown in Formula A, Formula B or Formula C: In Formula A, Formula B or Formula C, R1 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, heterocyclic group, substituted heterocyclic group, alkyl group or substituted alkyl group; R2 and R3 are independently -H, alkyl, substituted alkyl, R2 and R3 are connected to each other to form cycloalkyl, or R2 and R3 are connected to each other to form substituted cycloalkyl; n is 0, 1, 2 or 3; Z is -O-, -NH- or -S-.

2. The indazole benzoic acid derivative containing a urea structure according to claim 1, characterized in that: The substituents of the substituted phenyl, substituted naphthyl, substituted heterocyclic and substituted alkyl in R1 are independently halogen groups, -OH, -NH2, -CF3, -OCF3, -NHCH3, -N(CH3)2, -NO2, -CN, -OR, -SR, -NRR', -C(O)R, -C02R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S02R, -CONRR', -SO2NRR', -OCOR, -NRCOR', -NRNR', alkyl, cycloalkyl, aromatic, heterocyclic or heteroaryl; In the -OR, -SR, -NRR', -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -SO2R, -CONRR', -SO2NR', -OCOR, -NRCOR' or -NRNR', R and R' are independently alkyl.

3. The indazole benzoic acid derivative containing a urea structure according to claim 1, characterized in that: In R2 and R3, the alkyl group is independently a C1~C6 alkyl group; the substituted alkyl group is independently a substituted C1~C6 alkyl group; the substituent of the substituted alkyl group is independently a halogen group, -OH, -NH2, -NHCH3, -N(CH3)2 or a C1~C6 alkyl group; the R2 and R3 are connected to each other to form a cycloalkyl group, and the R2 and R3 are connected to each other to form a C3~C6 cycloalkyl group; the R2 and R3 are connected to each other to form a substituted cycloalkyl group, and the R2 and R3 are connected to each other to form a substituted C3~C6 cycloalkyl group; the R2 and R3 are connected to each other to form a substituted cycloalkyl group, and the substituent of the substituted cycloalkyl group is a halogen group, -OH, -NH2, -NHCH3, -N(CH3)2 or a C1~C6 alkyl group.

4. The indazole benzoic acid derivative containing a urea structure according to any one of claims 1 to 3, characterized in that: The indazole benzoic acid derivatives containing urea structure include 4-((2-(2-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 2-(3-(3-chloro-4-fluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-chloro-3-fluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(p-tolyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(2-chloro-4-cyanophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid , 4-((2-(2-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-fluoro-4-methylphenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3,5-difluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-chloro-3-methylphenyl)ureido)ethyl)- 2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-cyano-2-methylphenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-cyano-2-fluorophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(2-bromo-4-cyanophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-cyanophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-cyanophenyl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid,7-hexahydro-s-indol-4-yl)ureido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(2-chloro-4-cyanophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid -3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-fluoro-3-methylphenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3-fluoro-4-methylphenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3,4-((2-(3-(3-(4-chloro-3-fluorophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3-chloro-4-fluorophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-(trifluoromethoxy)phenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, -(4-methoxyphenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-fluorophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-nitrophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(2-bromo-4-cyanophenyl)ureido)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((1-(2-(3-(3-chloro-4-cyanophenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid, 4-( (1-(2-(3-(3-fluoro-4-methylphenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid, 4-((1-(2-(3-(3,5-difluorophenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid, 4-((1-(2-(3-(3-chloro-4-methylphenyl)ureido)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4-((2-(2-((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, -3-fluorophenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexane- 1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(p-tolyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid -formamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexane-1-formamido)ethyl)-2H-indazole-3-formamido)methyl)benzoic acid or 4-((2-(2-((1r,4r)-4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexane-1-formamido)ethyl)-2H-indazole-3-formamido)methyl)benzoic acid.

5. The method for preparing the indazole benzoic acid derivative containing a urea structure according to any one of claims 1 to 4, characterized in that: The preparation method of the indazole benzoic acid derivative containing a urea structure shown in formula A comprises the following steps: (1) subjecting compound I and compound a to a first nucleophilic substitution reaction to obtain compound b; (2) subjecting the compound b to a first hydrolysis reaction to obtain a compound c; (3) subjecting the compound c and compound II to a first acylation reaction to obtain compound d; (4) subjecting the compound d to a first deprotection reaction to obtain a compound e; (5) subjecting the compound e to a second acylation reaction with (trichloromethyl) carbonate to obtain a first intermediate compound; subjecting the first intermediate compound to a second nucleophilic substitution reaction with compound III to obtain compound f; subjecting the compound f to a second hydrolysis reaction to obtain an indazole benzoic acid derivative containing a urea structure as shown in formula A; The structural formula of the compound I is The structural formula of the compound II is The structural formula of the compound III is The structural formulas of the first intermediate, compound a, compound b, compound c, compound d, compound e and compound f are: The preparation method of the indazole benzoic acid derivative containing a urea structure shown in formula B comprises the following steps: (A) subjecting compound I and compound a to a third nucleophilic substitution reaction to obtain compound h; (B) subjecting the compound h to a third hydrolysis reaction to obtain a compound i; (C) subjecting the compound i and compound II to a third acylation reaction to obtain compound j; (D) subjecting the compound j to a second deprotection reaction to obtain a compound k; (E) subjecting the compound k to a fourth acylation reaction with (trichloromethyl) carbonate to obtain a second intermediate compound; subjecting the second intermediate compound to a fourth nucleophilic substitution reaction with compound III to obtain compound 1; and subjecting compound 1 to a fourth hydrolysis reaction to obtain an indazole benzoic acid derivative containing a urea structure as shown in formula B; The structural formula of the compound I is The structural formula of the compound II is The structural formula of the compound III is The structural formulas of the second intermediate, compound a, compound h, compound i, compound j, compound k and compound 1 are: The preparation method of the indazole benzoic acid derivative containing a urea structure shown in formula C comprises the following steps: (I) subjecting compound IV and compound e to a fifth acylation reaction to obtain compound n; (II) subjecting the compound n to a third deprotection reaction to obtain a compound o; (III) subjecting the compound o to a sixth acylation reaction with (trichloromethyl) carbonate to obtain a third intermediate compound; subjecting the third intermediate compound to a fifth nucleophilic substitution reaction with compound II to obtain compound p; subjecting the compound p to a fifth hydrolysis reaction to obtain an indazole benzoic acid derivative containing a urea structure as shown in formula C; The structural formula of the compound II is The structural formula of the compound IV is The structural formulas of the third intermediate, compound e, compound n, compound o and compound p are: The meanings of n, R1, R2 or R3 in compound I, compound II, compound III, the first intermediate, the second intermediate, the third intermediate, compound a, compound b, compound c, compound d, compound e, compound f, compound h, compound i, compound j, compound k, compound l, compound n, compound o and compound p are the same as those in formula A.

6. The preparation method according to claim 5, characterized in that: The first deprotection reaction is carried out under acidic conditions; the acidic conditions are provided by an acidic reagent; the molar ratio of the compound d to the acidic reagent is 1:(3-10); the first deprotection reaction is carried out in an organic solvent; the mass ratio of the compound d to the organic solvent is 1-1.2:1-100; the temperature of the first deprotection reaction is -20-50°C, and the insulation time is 2-8h.

7. The preparation method according to claim 5, characterized in that: The second deprotection reaction is carried out under acidic conditions; the acidic conditions are provided by an acidic reagent; the molar ratio of the compound j to the acidic reagent is 1:(3-10); the second deprotection reaction is carried out in an organic solvent; the mass ratio of the compound j to the organic solvent is 1-1.2:1-100; the temperature of the second deprotection reaction is -20-50°C, and the insulation time is 2-8h.

8. The preparation method according to claim 5, characterized in that: The third deprotection reaction is carried out under acidic conditions; the acidic conditions are provided by an acidic reagent; the molar ratio of the compound n to the acidic reagent is 1:(3-10); the third deprotection reaction is carried out in an organic solvent; the mass ratio of the compound n to the organic solvent is 1-1.2:1-100; the temperature of the third deprotection reaction is -20-50°C, and the insulation time is 2-8h.

9. Use of the indazole benzoic acid derivative containing a urea structure according to any one of claims 1 to 4 or the indazole benzoic acid derivative containing a urea structure obtained by the preparation method according to claims 5 to 8 in the preparation of drugs for treating diseases mediated by PGE2 / EP4 signal transduction.

10. The use according to claim 9, characterized in that: The diseases mediated by PGE2 / EP4 signaling include cancer, acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea or atherosclerosis.

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