An indazole benzoic acid derivative containing a urea structure and a preparation method and application thereof

Abstract

The application belongs to the technical field of medicines, and particularly relates to 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 application has a typical benzoic acid structure as a primary pharmacophore of EP4, and molecular docking shows that the benzoic acid part forms a metal ion bond with a key amino acid residue Arg316. Therefore, the indazole benzoic acid derivative containing a urea structure provided by the application has high inhibitory activity on human EP4, and can be used as an EP4 inhibitor to prepare a medicine for treating a disease mediated by PGE2 / EP4 signal transmission.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an indazole benzoic acid derivative containing a urea structure, its preparation method, and its application. Background Technology

[0002] Prostaglandin E2 (PGE2) is one of the major products of arachidonic acid action by cyclooxygenase (COX) and participates in many physiological and pathological responses. PGE2-mediated intracellular signaling depends on its binding to one or more specific prostaglandin E receptors (EP1-4) on target cells, which are coupled to various G proteins. Prostaglandin E receptor 4 (EP4) is expressed in a variety of tissues and cells, including the immune, bone and joint, cardiovascular, gastrointestinal, and respiratory systems, as well as cancer cells. EP4 coupling with Ga activates adenylate cyclase (AC) and catalyzes the formation of the second messenger cAMP. The main function of cAMP is to bind to and activate protein kinase A (PKA), which in turn phosphorylates target proteins in the cell. In addition, EP4 also stimulates the non-canonical pathway of phosphatidylinositol 3-kinase (PI3K) / protein kinase B (PKB, also known as Akt), thereby promoting cell survival, and activates extracellular regulated kinases (ERKs), 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 remedy for inflammatory pain, with superior intestinal tolerability compared to NSAIDs and COX-2 inhibitors, which are currently the standard of care. Importantly, EP4 antagonists can achieve greater cardiovascular safety because they do not directly interfere with the biosynthesis of prostaglandin E (PGE2) and other prostaglandins such as prostacyclin and thromboxane. EP4 receptor antagonists may also have therapeutic applications in the treatment of migraines, as the EP4 receptor is involved in PGE2-mediated cerebral vasodilation, a crucial factor in migraines. 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 important roles in many neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, where PGE2 is involved. Studies have shown that the PGE2 / EP4 signaling pathway is involved in the development of colorectal cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, bladder cancer, and liver cancer. Activation of this cascade signaling, leading to 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-associated angiogenesis. In contrast, EP4 knockout mice with APCmin mutations showed delayed tumorigenesis compared to wild-type mice, indicating their 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 bone marrow-derived suppressor cells, restore natural killer cell activity, and enhance the production of pro-inflammatory cytokines (TNF-α) and IL-12 by bone marrow cells and Th1 cells. These data suggest that inhibiting 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, thus filling an unmet medical need. Summary of the Invention

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

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] This invention provides an indazole benzoic acid derivative containing a urea structure, with the structure shown in formula A, B, or C:

[0008]

[0009]

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

[0011] R2 and R3 are independently -H, alkyl, substituted alkyl, R2 and R3 are interconnected to form a cycloalkyl or R2 and R3 are interconnected to form a 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 groups in R1 are independently 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, -NRCOR', -NRNR', alkyl, cycloalkyl, aromatic, heterocyclic or heteroaryl; wherein 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 C1 to C6 alkyl; the substituted alkyl group is independently substituted C1 to C6 alkyl; the substituent of the substituted alkyl group is independently a halogen group, -OH, -NH2, -NHCH3, -N(CH3)2 or C1 to C6 alkyl; the cycloalkyl groups connected to each other in R2 and R3 are C3 to C6 cycloalkyl groups; the substituted cycloalkyl groups connected to each other in R2 and R3 are C3 to C6 cycloalkyl groups; the substituent of the substituted cycloalkyl groups connected to each other in R2 and R3 are halogen groups, -OH, -NH2, -NHCH3, -N(CH3)2 or C1 to C6 alkyl groups.

[0014] Preferably, the urea-containing indazole benzoic acid derivatives include 4-((2-(2-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-(( 2-(2-(3-(3-chloro-4-fluorophenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-chloro-3-fluorophenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(p-tolyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(2-chloro-4-cyanophenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid Formic acid, 4-((2-(2-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-fluoro-4-methylphenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3,5-difluorophenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-chloro-3-methylphenyl)ureo)ethyl) -2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-cyano-2-methylphenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-cyano-2-fluorophenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(2-bromo-4-cyanophenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-cyanophenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(4-cyanophenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(1,2,3,5,6,7-Hexahydro-S-indol-4-yl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(2-chloro-4-cyanophenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureo)propyl)-2H-indazole) -3-carbamoyl)methyl)benzoic acid, 4-((2-(3-(3-(4-fluoro-3-methylphenyl)ureo)propyl)-2H-indazole-3-carbamoyl)methyl)benzoic acid, 4-((2-(3-(3-(3-fluoro-4-methylphenyl)ureo)propyl)-2H-indazole-3-carbamoyl)methyl)benzoic acid, 4-((2-(3-(3-(3,5-Difluorophenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-chloro-3-fluorophenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3-chloro-4-fluorophenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-chloro-3-methylphenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl) 4-((2-(3-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3 ...3-(4 -(4-methoxyphenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-fluorophenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(4-nitrophenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(3-(3-(2-bromo-4-cyanophenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((1-(2-(3-(3-chloro-4-cyanophenyl)ureoethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid, 4-( (1-(2-(3-(3-fluoro-4-methylphenyl)uryl)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid, 4-((1-(2-(3-(3,5-difluorophenyl)uryl)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid, 4-((1-(2-(3-(3,5-difluorophenyl)uryl)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)uryl)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)uryl)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureo)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureo)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(4-chloro) -3-fluorophenyl)ureo)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureo)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureo)cyclohexane- 1-Formamido)ethyl)-2H-indazole-3-formamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(p-tolyl)ureo)cyclohexane-1-formamido)ethyl)-2H-indazole-3-formamido)methyl)benzoic acid, 4-((2-(2-((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureo)cyclohexane-1-formamido)ethyl)-2H-indazole-3 4-((2-(2-((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureo)cyclohexane-1-carbamate)ethyl)-2H-indazole-3-carbamate)methyl)benzoic acid, or 4-((2-(2-((1r,4r)-4-(3-(4-(trifluoromethyl)phenyl)ureo)cyclohexane-1-carbamate)ethyl)-2H-indazole-3-carbamate)methyl)benzoic acid.

[0015] The present invention also provides a method for preparing the urea-containing indazole benzoic acid derivatives described in the above-described scheme. The method for preparing the urea-containing indazole benzoic acid derivatives shown in Formula A includes the following steps:

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

[0017] (2) Compound b is subjected to a first hydrolysis reaction to obtain compound c;

[0018] (3) Compound c and compound II are subjected to a first acylation reaction to obtain compound d;

[0019] (4) Compound d is subjected to a first deprotection reaction to obtain compound e;

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

[0021] The structural formula of compound I is as follows: The structural formula of compound II is as follows: The structural formula of compound III is as follows:

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

[0023]

[0024]

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

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

[0027] (B) The compound h is subjected to a third hydrolysis reaction to obtain compound i;

[0028] (C) Compound i and compound II are subjected to a third acylation reaction to obtain compound j;

[0029] (D) Compound j is subjected to a second deprotection reaction to obtain compound k;

[0030] (E) Compound k and (trichloromethyl) carbonate are subjected to a fourth acylation reaction to obtain a second intermediate compound; the second intermediate compound and compound III are subjected to a fourth nucleophilic substitution reaction to obtain compound l; compound l is subjected to a fourth hydrolysis reaction to obtain an indazole benzoic acid derivative with a urea structure as shown in Formula B;

[0031] The structural formula of compound I is as follows: The structural formula of compound II is as follows: The structural formula of compound III is as follows:

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

[0033]

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

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

[0036] (II) Compound n is subjected to a third deprotection reaction to obtain compound o;

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

[0038] The structural formula of compound II is as follows: The structural formula of compound IV is as follows:

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

[0040]

[0041] The meanings of n, R1, R2 or R3 in compounds I, II, III, first intermediate, second intermediate, third intermediate, a, b, c, d, e, f, h, i, j, k, l, n, o and p are the same as 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 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 compound d to the organic solvent is 1-1.2:1-100; the temperature of the first deprotection reaction is -20 to 50°C, and the holding time is 2-8 hours.

[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 to 50°C, and the holding time is 2-8 hours.

[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 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 compound n to the organic solvent is 1-1.2:1-100; the temperature of the third deprotection reaction is -20 to 50°C, and the holding time is 2-8 hours.

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

[0046] Preferably, the diseases mediated by the PGE2 / EP4 signaling include cancer, acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea, or arteriosclerosis.

[0047] This invention provides a urea-containing indazole benzoic acid derivative. The urea-containing indazole benzoic acid derivative provided by this invention has a typical benzoic acid structure as the primary pharmacophore of EP4, and molecular docking shows that the benzoic acid moiety forms a metal ionic bond with the key amino acid residue Arg316. Therefore, the urea-containing indazole benzoic acid derivative provided by this invention exhibits high inhibitory activity against human EP4 and can be used as an EP4 inhibitor in the preparation of drugs for treating diseases mediated by PGE2 / EP4 signaling.

[0048] This invention also provides a method for preparing the urea-containing indazole benzoic acid derivatives described in the above-described scheme. The preparation method provided by this invention is simple in steps, convenient in operation, highly feasible, and low in cost, and has the potential for large-scale industrial application.

[0049] This invention also provides the application of the urea-containing indazole benzoic acid derivatives described in the above-described schemes, or the urea-containing indazole benzoic acid derivatives obtained by the preparation method described in the above-described schemes, in the preparation of drugs for treating PGE2 / EP4 signaling-mediated diseases. The urea-containing indazole benzoic acid derivatives provided by this invention exhibit high inhibitory activity against human EP4 and can be used as EP4 inhibitors in the preparation of drugs for treating PGE2 / EP4 signaling-mediated diseases, particularly cancer, acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea, or arteriosclerosis. Attached Figure Description

[0050] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

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

[0052] Figure 2 This is a synthetic route diagram of the indazole benzoic acid derivative containing a urea structure as shown in Formula B of the present invention.

[0053] Figure 3 This is a synthetic route diagram for the indazole benzoic acid derivatives containing a urea structure as shown in Formula C of the present invention. Detailed Implementation

[0054] This invention provides an indazole benzoic acid derivative containing a urea structure, with the structure shown in formula A, B, or C:

[0055]

[0056] In formula A, formula B or formula C, R1 is an alkyl group, a substituted alkyl group, a phenyl group, a substituted phenyl group, a naphthyl group, a substituted naphthyl group, a heterocyclic group or a 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 can be -O-, -NH-, or -S-.

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

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

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

[0063] In this invention, the substituents of the substituted alkyl, substituted phenyl, substituted naphthyl, and substituted heterocyclic groups described in R1 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, and -NRC. OR', -NRNR', alkyl, cycloalkyl, aromatic, heterocyclic or heteroaryl; wherein -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; wherein the alkyl in R and R' is preferably C1 to C3 alkyl; wherein the C1 to C3 alkyl preferably includes methyl, ethyl or propyl.

[0064] In this 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 hexahydropyrran; and the heteroaryl group preferably includes pyridine, pyrimidine, furan, or pyran.

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

[0066]

[0067] Among them, solid pentagrams represent connection points.

[0068] In this invention, R2 and R3 are independently preferably -H, alkyl, or R2 and R3 are interconnected as cycloalkyl groups; the alkyl group in R2 and R3 is preferably a C1-C6 alkyl group; the C1-C6 alkyl group is preferably methyl; the substituted alkyl group is preferably a substituted C1-C6 alkyl group; the substituted C1-C6 alkyl group is preferably a substituted methyl group; the substituent of the substituted alkyl group is independently preferably a halogen group, -OH, -NH2, -NHCH3, -N(CH3)2, or a C1-C6 alkyl group; the R2 and R3 are independently preferably -H, alkyl ... 3. The cycloalkyl groups connected together are preferably C3-C6 cycloalkyl groups, where R2 and R3 are connected together; the C3-C6 cycloalkyl groups are preferably cyclopropyl groups; the substituted cycloalkyl groups connected together are preferably C3-C6 cycloalkyl groups, where R2 and R3 are connected together; the substituted C3-C6 cycloalkyl groups are preferably substituted cyclopropyl groups; the substituents of the substituted cycloalkyl groups connected together are preferably halogen groups, -OH, -NH2, -NHCH3, -N(CH3)2 or C1-C6 alkyl groups.

[0069] In this invention, the urea-containing indazole benzoic acid derivatives preferably include 4-((2-(2-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-102-A), 4-((2-(2-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-103-A), 4-((2-(2-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-103-A), 4-((2-(2-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureoyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid, 4-((2-(2-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureoyl ... 4-((2-(2-(3-(4-(trifluoromethoxy)phenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-104-A), 4-((2-(2-(3-(3-chloro-4-fluorophenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-105-A), 4-((2-(2-(3-(3-chloro-4-fluorophenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-106-A), 4-((2-(2-(3-(4-chloro-3-fluoro) ...5-A), 4-((2-(2-(3-( (Phenyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-107-A), 4-((2-(2-(3-(p-tolyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-108-A), 4-((2-(2-(3-(2-chloro-4-cyanophenyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-109-A), 4-((2-(2-(3-(4-fluoro-3-(trifluoromethyl)) 4-((2-(2-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-110-A), 4-((2-(2-(3-(3-fluoro-4-methylphenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-111-A), 4-((2-(2-(3-(3-fluoro-4-methylphenyl)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-112-A), 4-((2-(2-(3-(3,5-Difluorophenyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-113-A), 4-((2-(2-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-114-A), 4-((2-(2-(3-(4-chloro-3-methylphenyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-116-A), 4-((2-(2-(3-(4-chloro-3-methylphenyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-116-A), 4-((2-(2-(3-(4-cyano) 2-Methylphenyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-120-A), 4-((2-(2-(3-(4-cyano-2-fluorophenyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-121-A), 4-((2-(2-(3-(2-bromo-4-cyanophenyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-124-A), 4-((2-(2-(3-(4-cyanophenyl)ureoyl ...ureoyl)ureoyl)ureoyl)ureoyl)ureoyl)ureoyl)ureoyl)ureoyl)ureoyl 4-((2-(2-(3-(1,2,3,5,6,7-hexahydro-s-indole-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)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U102-A), 4-((2-(3-(3-(4-fluoro-3-methylphenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U103-A), 4-((2-(3-(3-(3-fluoro-4-methylphenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U104-A), 4-((2-(3-(3-(3-(3,5-Difluorophenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U105-A), 4-((2-(3-(3-(4-chloro-3-fluorophenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U106-A), 4-((2-(3-(3-(3-chloro-4-fluorophenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U107-A), 4-((2-(3-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureopropyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U108-A) 4-((2-(3-(3-(4-chloro-3-methylphenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U109-A), 4-((2-(3-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U110-A), 4-((2-(3-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U111-A), 4-((2-(3-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U111-A), 4-((2-(3-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (Sypto-3-carboxamido)methyl)benzoic acid (denoted as SYP-U112-A), 4-((2-(3-(3-(4-(trifluoromethoxy)phenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U113-A), 4-((2-(3-(3-(4-methoxyphenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U114-A), 4-((2-(3-(3-(4-fluorophenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U115-A), 4-((2-(3-(3-(4-nitrophenyl)ureo)propyl) -2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U117-A), 4-((2-(3-(3-(2-bromo-4-cyanophenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-U118-A), 4-((1-(2-(3-(3-chloro-4-cyanophenyl)ureo)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-A109-A), 4-((1-(2-(3-(3-fluoro-4-methylphenyl)ureo)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-A112-A), 4-((1-(2-(3-(3,5-Difluorophenyl)ureoyl)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-A113-A), 4-((1-(2-(3-(3-chloro-4-methylphenyl)ureoyl)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-A115-A), 4-((2-(2-((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureoyl)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))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))cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C101-A), -(trifluoromethyl)phenyl)ureo)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)ureo)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)ureo)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)ureo)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)ureo)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 ...2-(2-((1r,4r)-4-(3-(p-tolyl)ureo)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)ureo)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C110-A), H-Indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C114-A), 4-((2-(2-((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureo)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)ureo)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)ureo)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (denoted as SYP-C116-A)4r)-4-(3-(4-(trifluoromethyl)phenyl)ureo)cyclohexane-1-carbamate)ethyl)-2H-indazole-3-carbamate)methyl)benzoic acid (denoted as SYP-C117-A), the specific structural formula is shown below:

[0070]

[0071]

[0072]

[0073] The present invention also provides a method for preparing the urea-containing indazole benzoic acid derivatives described in the above-described scheme. The method for preparing the urea-containing indazole benzoic acid derivatives shown in Formula A includes the following steps:

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

[0075] (2) Compound b is subjected to a first hydrolysis reaction to obtain compound c;

[0076] (3) Compound c and compound II are subjected to a first acylation reaction to obtain compound d;

[0077] (4) Compound d is subjected to a first deprotection reaction to obtain compound e;

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

[0079] The structural formula of compound I is as follows: The structural formula of compound II is as follows: The structural formula of compound III is as follows:

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

[0081]

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

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

[0084] (B) The compound h is subjected to a third hydrolysis reaction to obtain compound i;

[0085] (C) Compound i and compound II are subjected to a third acylation reaction to obtain compound j;

[0086] (D) Compound j is subjected to a second deprotection reaction to obtain compound k;

[0087] (E) Compound k and (trichloromethyl) carbonate are subjected to a fourth acylation reaction to obtain a second intermediate compound; the second intermediate compound and compound III are subjected to a fourth nucleophilic substitution reaction to obtain compound l; compound l is subjected to a fourth hydrolysis reaction to obtain an indazole benzoic acid derivative with a urea structure as shown in Formula B;

[0088] The structural formula of compound I is as follows: The structural formula of compound II is as follows: The structural formula of compound III is as follows:

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

[0090]

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

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

[0093] (II) Compound n is subjected to a third deprotection reaction to obtain compound o;

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

[0095] The structural formula of compound II is as follows: The structural formula of compound IV is as follows:

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

[0097]

[0098]

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

[0100] This invention prepares indazole benzoic acid derivatives containing a urea structure as shown in Formula A: Compound I and compound a undergo a first nucleophilic substitution reaction to obtain compound b. In this invention, the molar ratio of compound a to compound I is preferably 1:(1-2), more preferably 1:(1-1.5), and even more preferably 1:(1-1.2).

[0101] In this 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 compound a to the acid-binding agent is preferably 1:(1-4), more preferably 1:(1.1-3), and even more preferably 1:(1.2-2).

[0102] In this 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 iodide salt; the iodide salt preferably includes one or two of potassium iodide and sodium iodide, more preferably potassium iodide (KI); the molar ratio of compound a to the phase transfer catalyst is preferably 1:(0.1-1), more preferably 1:(0.1-0.7), and even more preferably 1:(0.1-0.4); the molar ratio of compound a to the non-phase transfer catalyst is preferably 1:(0.1-1), more preferably 1:(0.1-0.5), and even more preferably 1:(0.1-0.3).

[0103] In this 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 compound a to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:10-50, and even more preferably 1-1.1:30-40.

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

[0105] In this invention, the first nucleophilic substitution reaction preferably further includes adding water to the resulting 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 carried out in the presence of an alkaline reagent; the alkaline reagent 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 reagent is preferably 1:(1-20), more preferably 1:(1-10), and even more preferably 1:(2-5).

[0107] In this 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 organic solvent is preferably 1:1 to 5, more preferably 1:1 to 2, and even more preferably 1:1.

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

[0109] In this invention, the process after the first hydrolysis reaction preferably includes sequentially concentrating the resulting hydrolysis reaction solution, adding water, adjusting the pH of the system to 1-7 with hydrochloric acid under ice bath conditions, precipitating solids, filtration, and drying; the concentration is preferably vacuum concentration; the pressure of the vacuum 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. This invention removes organic solvents from the hydrolysis reaction solution through concentration.

[0110] After obtaining compound c, the present invention performs a first acylation reaction on 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 to 10), more preferably 1:(1 to 3), and even more preferably 1:(1 to 1.2).

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

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

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

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

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

[0116] In this invention, the first acylation reaction preferably further includes concentrating the resulting reaction solution sequentially (denoted as Concentration A), adding water, extracting with ethyl acetate, drying, filtering, and concentrating again (denoted as Concentration B); Concentration A and Concentration B are independently preferably concentrated under reduced pressure; the pressure for the reduced pressure concentration is preferably 0.05–0.30 MPa, more preferably 0.10–0.15 MPa. This invention removes organic solvents from the reaction solution through Concentration A and Concentration 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 carried out 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 this 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 compound d to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:5-10.

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

[0120] In this invention, the reaction solution is preferably concentrated after the first deprotection reaction; the concentration is preferably vacuum concentration; the pressure of the vacuum concentration is preferably 0.05-0.30 MPa, more preferably 0.10-0.15 MPa.

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

[0122] In this 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 compound e to the acid-binding agent is preferably 1:(4-6), more preferably 1:6.

[0123] In this 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 compound e to the organic solvent is preferably 1:1 to 100, more preferably 1:5 to 10.

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

[0125] In this invention, the second acylation reaction preferably further includes concentrating the resulting reaction solution; the concentration is preferably vacuum concentration; the concentration temperature is preferably 20-50°C, more preferably 30°C.

[0126] After obtaining the first intermediate compound, the present invention performs a second nucleophilic substitution reaction on 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 even more preferably 1.2:1.

[0127] In this 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 compound III to the acid-binding agent is preferably 1:(4-6), more preferably 1:6.

[0128] In this 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 compound III to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:5-10.

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

[0130] In this invention, the second nucleophilic substitution reaction preferably further includes adding water to the resulting reaction system, extracting with ethyl acetate, drying, filtering, and concentrating.

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

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

[0133] In this 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 organic solvent is preferably 1:1 to 5, more preferably 1:1 to 2, and even more preferably 1:1.

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

[0135] In this invention, the second hydrolysis reaction preferably further includes, sequentially, concentrating the resulting hydrolysis reaction solution, adding water, adjusting the pH of the system to 1-7 with hydrochloric acid under ice bath conditions, precipitating solids, filtration, and drying; the concentration is preferably vacuum concentration; the pressure of the vacuum 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. This invention removes the organic solvent from the hydrolysis reaction solution through concentration. The main synthetic route for the urea-containing indazole benzoic acid derivatives with the structure shown in Formula A of this invention is as follows: Figure 1 As shown.

[0136] This invention prepares indazole benzoic acid derivatives containing a urea structure as shown in Formula B: Compound I and compound a undergo a third nucleophilic substitution reaction to obtain compound h. In this invention, the molar ratio of compound a to compound I is preferably 1:(1-2), more preferably 1:(1.0-1.6), and even more preferably 1:(1.0-1.2).

[0137] In this 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 compound a to the acid-binding agent is preferably 1:(1.0-4.0), more preferably 1:(1.1-3.0), and even more preferably 1:(1.2-2.0).

[0138] In this 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 iodide salt; the iodide salt preferably includes one or two of potassium iodide and sodium iodide, more preferably potassium iodide (KI); the molar ratio of compound a to the phase-transfer catalyst is preferably 1:(0.1-1), more preferably 1:(0.1-0.6), and even more preferably 1:(0.1-0.3); the molar ratio of compound a to the non-phase-transfer catalyst is preferably 1:(0.1-1), more preferably 1:(0.1-0.6), and even more preferably 1:0.1.

[0139] In this 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 compound a to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:10-50, and even more preferably 1-1.1:30-40.

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

[0141] In this invention, the third nucleophilic substitution reaction preferably further includes adding water to the resulting reaction system, extracting with ethyl acetate, drying, filtering, and concentrating.

[0142] In this invention, the concentration temperature is preferably 20-50°C, more preferably 30°C; the concentration is preferably vacuum concentration; the vacuum 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 reagent; the alkaline reagent 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 alkaline reagent is preferably 1:(1-20), more preferably 1:(1-10), and even more preferably 1:(2-5).

[0144] In this 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 organic solvent is preferably 1:1 to 5, more preferably 1:1 to 2, and even more preferably 1:1.

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

[0146] In this invention, the third hydrolysis reaction preferably further includes, sequentially, concentrating the resulting hydrolysis reaction solution, adding water, adjusting the pH of the system to 1-7 with hydrochloric acid under ice bath conditions, precipitating solids, filtering, and drying; the concentration is preferably vacuum concentration; the pressure of the vacuum 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. This invention removes organic solvents from the hydrolysis reaction solution through concentration.

[0147] After obtaining compound i, the present invention performs a third acylation reaction on 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 to 10), more preferably 1:(1 to 3), and even more preferably 1:(1 to 1.2).

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

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

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

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

[0152] In this invention, the third acylation reaction preferably further includes sequentially concentrating the resulting reaction solution (denoted as Concentration C), adding water, extracting with ethyl acetate, drying, filtering, and concentrating again (denoted as Concentration D); Concentration C and Concentration D are independently preferably concentrated under reduced pressure; the pressure for the reduced pressure concentration is preferably 0.05–0.30 MPa, more preferably 0.10–0.15 MPa. This invention removes the solvent from the reaction solution through Concentration C and Concentration D.

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

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

[0155] In this 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 compound j to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.1:5-10.

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

[0157] In this invention, the second deprotection reaction preferably further includes concentrating the resulting reaction solution; the concentration is preferably vacuum concentration; the pressure of the vacuum concentration is preferably 0.05-0.30 MPa, more preferably 0.10-0.15 MPa; the temperature of the ice bath condition is preferably -10-10°C, more preferably 0-5°C.

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

[0159] In this 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 compound k to the acid-binding agent is preferably 1:(4-6), more preferably 1:6.

[0160] In this 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 compound II to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:5-10.

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

[0162] In this invention, the fourth acylation reaction preferably further includes concentrating the resulting reaction solution; the concentration is preferably vacuum concentration; the concentration temperature is preferably 10-30°C, more preferably 25°C.

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

[0164] In this 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 compound III to the acid-binding agent is preferably 1:(4-6), more preferably 1:6.

[0165] In this 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 compound III to the organic solvent is preferably 1:1 to 100, more preferably 1:5 to 10.

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

[0167] In this invention, the fourth nucleophilic substitution reaction preferably further includes adding water, extracting with ethyl acetate, drying, filtering, and concentrating the resulting reaction system in sequence.

[0168] In this invention, the concentration temperature is preferably 20-50°C, more preferably 30°C; the concentration is preferably vacuum concentration; the vacuum 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 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 reagent; the alkaline reagent preferably includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate, more preferably lithium hydroxide; the molar ratio of compound 1 to the alkaline reagent is preferably 1:(1-20), more preferably 1:(1-10), and even more preferably 1:(2-5).

[0170] In this 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 organic solvent is preferably 1:1 to 5, more preferably 1:1 to 2, and even more preferably 1:1.

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

[0172] In this invention, the fourth hydrolysis reaction preferably further includes, sequentially, concentrating the resulting hydrolysis reaction solution, adding water, adjusting the pH of the system to 1-7 with hydrochloric acid under ice bath conditions, precipitating solids, filtering, and drying; the concentration is preferably vacuum concentration. This invention removes the solvent from the hydrolysis reaction solution through concentration. This invention prepares indazole benzoic acid derivatives containing a urea structure as shown in Formula B, and the main synthetic route is as follows: Figure 2 As shown.

[0173] This invention prepares indazole benzoic acid derivatives containing a urea structure as shown in formula C: Compound IV and compound e undergo a fifth acylation reaction to obtain compound n. In this 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 even more preferably 1.2:1.

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

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

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

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

[0178] In this invention, the first acylation reaction preferably further includes concentrating the resulting reaction solution sequentially (denoted as Concentration E), adding water, extracting with ethyl acetate, drying, filtering, and concentrating again (denoted as Concentration F); Concentration E and Concentration F are independently preferably concentrated under reduced pressure; the pressure of the reduced pressure concentration is preferably 0.05–0.30 MPa, more preferably 0.10–0.15 MPa. This invention removes the solvent from the reaction solution through Concentration E and Concentration 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 carried out 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 this 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 compound n to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:5-10.

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

[0182] In this invention, the third deprotection reaction preferably further includes concentrating the resulting reaction solution; the concentration is preferably vacuum concentration; the pressure of the vacuum concentration is preferably 0.05-0.30 MPa, more preferably 0.10-0.15 MPa.

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

[0184] In this 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 compound o to the acid-binding agent is preferably 1:(4-6), more preferably 1:6.

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

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

[0187] In this invention, the sixth acylation reaction preferably further includes concentrating the resulting reaction solution; the concentration is preferably vacuum concentration; the concentration temperature is preferably 20-50°C, more preferably 40°C.

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

[0189] In this 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 compound II to the acid-binding agent is preferably 1:(4-6), more preferably 1:6.

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

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

[0192] In this invention, the fifth nucleophilic substitution reaction preferably further includes sequentially adding water, extracting with ethyl acetate, drying, filtering, and concentrating the resulting reaction product.

[0193] In this invention, the concentration temperature is preferably 20-50°C, more preferably 30°C; the concentration is preferably vacuum concentration; the vacuum 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 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 carried out in the presence of an alkaline reagent; the alkaline reagent preferably includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate, more preferably lithium hydroxide; the molar ratio of compound p to the alkaline reagent is preferably 1:(1-20), more preferably 1:(1-10), and even more preferably 1:(2-5).

[0195] In this 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 organic solvent is preferably 1:1 to 5, more preferably 1:1 to 2, and even more preferably 1:1.

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

[0197] In this invention, the hydrolysis reaction preferably further includes, sequentially, concentrating the resulting hydrolysis reaction solution, adding water, adjusting the pH of the system to 1-7 with hydrochloric acid under ice bath conditions, precipitating solids, filtration, and drying; the concentration is preferably vacuum concentration; the pressure of the vacuum 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. This invention removes the solvent from the hydrolysis reaction solution through concentration. The main synthetic route for the urea-containing indazole benzoic acid derivatives with the structure shown in Formula C of this invention is as follows: Figure 3 As shown.

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

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

[0200] To further illustrate the present invention, the following detailed description of the invention's solutions, in conjunction with the accompanying drawings and embodiments, is provided, but should not be construed as limiting the scope of protection of the present invention.

[0201] Example 1: Synthesis of methyl 2-(2-((tert-Butoxycarbonyl)amino)ethyl)-2H-indazole-3-carboxylic acid

[0202] Add methyl 1H-indazole-3-carboxylate (compound a, 9.97 g, 56.59 mmol) to a 100 mL single-necked flask, add 30 mL of acetonitrile, add Cs₂CO₃ (22.13 g, 67.91 mmol), add KI (0.94 g, 5.66 mmol), and finally add N-Boc-bromoethane (compound I, 13.95 g, 62.25 mmol). Heat under reflux for 2 h, and monitor the reaction for completeness by TLC. Concentrate the resulting reaction solution under reduced pressure to remove acetonitrile, dissolve in DCM (50 mL), wash with H₂O (25 mL × 1), and wash with saturated saline (30 mL × 1). The sample was dried over anhydrous magnesium sulfate for 4 hours, then filtered and concentrated under reduced pressure to obtain 20.43 g of a yellow oily substance. The sample was packed into an 8x silica gel column, mixed with 1.2x silica gel, and eluent (EA:PE = 1:25). The resolution was 0.6 Rs. Column chromatography yielded methyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)-2H-indazole-3-carboxylic acid (compound b, 5.51 g white solid, yield 30.48%). The mp values ​​were 76–78 °C.

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

[0204] Methyl 2-(2-((tert-Butoxycarbonyl)amino)ethyl)-2H-indazole-3-carboxylic acid (compound b, 5.48 g, 17.17 mmol) was added to a 100 mL single-necked flask, followed by NaOH (1.37 g, 34.34 mmol) and 30 mL of H2O. After 12 h, the reaction was monitored by TLC until it was complete. The reaction solution was then transferred to an ice bath, and 1 N hydrochloric acid was slowly added dropwise until the pH value reached 3. A white solid gradually precipitated out. The solid was filtered to obtain 2-(2-((tert-Butoxycarbonyl)amino)ethyl)-2H-indazole-3-carboxylic acid (compound c, 4.52 g white solid, yield 86.20%).

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

[0206] 2-(2-((tert-Butoxycarbonyl)amino)ethyl)-2H-indazole-3-carboxylic acid (compound c, 4.52 g, 14.81 mmol) was added to a 100 mL single-necked flask and dissolved in 20 mL of dry THF. HATU (6.76 g, 17.78 mmol) and DIEA (5.74 g, 44.44 mmol) were added. After stirring for 0.5 h, methyl 4-aminomethylbenzoate hydrochloride (compound II, 3.88 g, 19.26 mmol) was added. After 1.5 h, the reaction was monitored by TLC until it was complete. The resulting 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 saline (30 mL × 1). The sample was dried over anhydrous magnesium sulfate for 4 hours, then filtered and concentrated under reduced pressure to obtain 9.81 g of a yellow oily substance. The sample was packed into a 4x silica gel column, mixed with 1.2x silica gel, and eluent (EA:PE = 1:10). Column chromatography yielded methyl 4-((2-(2-((tert-butoxycarbonyl)amino)ethyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound d, 5.65 g white solid, yield 84.36%).

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

[0208] Methyl 4-((2-(2-((tert-Butoxycarbonyl)amino)ethyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound d, 5.65 g, 12.49 mmol) was added to a 100 mL single-necked flask, along with 10 mL of DCM and 4 mL of TFA. The mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was evaporated to dryness under reduced pressure to obtain methyl 4-((2-(2-aminoethyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound e, 7.34 g, pale yellow viscous oily liquid, yield 126.12%).

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

[0210] Add solid phosgene (trichloromethyl) carbonate, 0.16 g, 0.53 mmol) and dry DCM (50 mL) to a three-necked flask. Cool the flask to below -78 °C and add dropwise 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). After the addition is complete, restore the temperature to room temperature to stop the reaction. Concentrate the resulting reaction solution to dryness under reduced pressure. Add dry DCM (10 mL) to the residue to dissolve it, and obtain an isocyanate solution for later use. 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 to a three-necked flask. The above isocyanate solution was added dropwise. After the addition was complete, TLC showed that the reaction was complete. A white solid gradually precipitated out. The mixture was filtered, and the filter cake was washed with H2O (2 mL × 2) to give methyl 4-((2-(2-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-102-A)

[0212] Methyl 4-((2-(2-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureoyl)ethyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound f, 0.16 g, 0.29 mmol) was added to a 25 mL single-necked flask, followed by 0.11 g of NaOH (2.87 mmol) and 10 mL of H₂O. After 12 h, the reaction was monitored by TLC until it was complete. The reaction solution was then transferred to an ice bath, and 1 N hydrochloric acid was slowly added dropwise until the pH reached 3. A white solid gradually precipitated out. The white solid obtained by filtration was SYP-102-A, with a yield of 0.14 g and a yield of 89.74%. The reaction temperature was mp 238–241 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-103-A)

[0214] Following the methods described in Examples 5 and 6, using 3-fluoro-4-trifluoromethoxyaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 3-fluoro-4-trifluoromethoxyaniline in Example 5), a white solid, namely SYP-103-A, was obtained with a yield of 0.14 g and a recovery rate of 87.52%. The temperature was above 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-104-A)

[0216] Following the methods described in Examples 5 and 6, using 3-chloro-4-trifluoromethylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 3-chloro-4-trifluoromethylaniline in Example 5), a white solid, namely SYP-104-A, was obtained with a yield of 0.13 g and a recovery rate of 79.22%. The temperature was mp 223–227 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-105-A)

[0218] Following the methods described in Examples 5 and 6, using 4-trifluoromethoxyaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 4-trifluoromethoxyaniline in Example 5), a white solid, namely SYP-105-A, was obtained with a yield of 0.15 g and a recovery rate of 89.55%. The temperature was mp 256–258 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-106-A)

[0220] Following the methods described in Examples 5 and 6, using 3-chloro-4-fluoroaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 3-chloro-4-fluoroaniline in Example 5), a white solid, namely SYP-106-A, was obtained with a yield of 0.13 g and a recovery rate of 80.07%. The temperature range was 237–242 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-107-A)

[0222] Following the methods described in Examples 5 and 6, using 4-chloro-3-fluoroaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 4-chloro-3-fluoroaniline), a white solid, namely SYP-107-A, was obtained with a yield of 0.14 g and a recovery rate of 85.17%. The temperature range was 227–232 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-108-A)

[0224] Following the methods described in Examples 5 and 6, using 4-methylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 4-methylaniline), a white solid, namely SYP-108-A, was obtained with a yield of 0.12 g and a recovery rate of 76.33%. The temperature range was 235–241 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-109-A)

[0226] Following the methods described in Examples 5 and 6, using 2-chloro-4-cyanoaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 2-chloro-4-cyanoaniline), a white solid, namely SYP-109-A, was obtained, with a yield of 0.13 g and a recovery rate of 83.13%. The temperature was mp 221–224 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-110-A)

[0228] Following the methods described in Examples 5 and 6, using 4-fluoro-3-trifluoromethylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 4-fluoro-3-trifluoromethylaniline in Example 5), a white solid, namely SYP-110-A, was obtained with a yield of 0.14 g and a recovery rate of 83.24%. The temperature range was mp 216–220 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-111-A)

[0230] Following the methods described in Examples 5 and 6, using 4-chloro-3-trifluoromethylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 4-chloro-3-trifluoromethylaniline in Example 5), a white solid, namely SYP-111-A, was obtained with a yield of 0.14 g and a recovery rate of 81.83%. The temperature range was 218–220 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-112-A)

[0232] Following the methods described in Examples 5 and 6, using 3-fluoro-4-methylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 3-fluoro-4-methylaniline in Example 5), a white solid, namely SYP-112-A, was obtained with a yield of 0.15 g and a recovery rate of 85.16%. The temperature was mp 244–248 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-113-A)

[0234] Following the methods described in Examples 5 and 6, using 3,5-difluoroaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 3,5-difluoroaniline), a white solid, namely SYP-113-A, was obtained with a yield of 0.14 g and a recovery rate of 84.81%. The temperature range was mp 257–262 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-114-A)

[0236] Following the methods described in Examples 5 and 6, using 3-chloro-4-trifluoromethoxyaniline as the raw material (i.e., replacing 3-chloro-4-trifluoromethoxyaniline with 3-chloro-4-trifluoromethoxyaniline in Example 5), a white solid, namely SYP-114-A, was obtained with a yield of 0.13 g and a recovery rate of 80.43%. The temperature was mp 240–243 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-116-A)

[0238] Following the methods described in Examples 5 and 6, using 4-chloro-3-methylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 4-chloro-3-methylaniline in Example 5), a white solid, namely SYP-116-A, was obtained with a yield of 0.14 g and a recovery rate of 84.34%. The temperature was mp 235–238 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-120-A)

[0240] Following the methods described in Examples 5 and 6, using 4-cyano-2-methylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 4-cyano-2-methylaniline), a white solid, namely SYP-120-A, was obtained with a yield of 0.15 g and a recovery rate of 85.23%. The temperature was mp 241–245 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-121-A)

[0242] Following the methods described in Examples 5 and 6, using 4-cyano-2-fluoroaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 4-cyano-2-fluoroaniline), a white solid, namely SYP-121-A, was obtained, with a yield of 0.14 g and a recovery rate of 84.12%. The temperature was mp 227–230 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-124-A)

[0244] Following the methods described in Examples 5 and 6, using 2-bromo-4-cyanoaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 2-bromo-4-cyanoaniline), a white solid, namely SYP-124-A, was obtained, with a yield of 0.14 g and a recovery rate of 83.15%. The temperature was mp 207–209 °C. 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)ureo)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-125-A)

[0246] Following the methods described in Examples 5 and 6, using 4-cyanoaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 4-cyanoaniline), a white solid, namely SYP-125-A, was obtained with a yield of 0.13 g and a recovery rate of 81.45%. The temperature range was mp 249–254 °C. 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-Butoxycarbonyl)amino)propyl)-2H-indazole-3-carboxylic acid

[0248] Following the method described in Example 1, using N-Boc-bromopropane (compound I) as the starting material (i.e., replacing N-Boc-bromoethane in Example 1 with N-Boc-bromopropane), 4.38 g of methyl 2-(3-((tert-butoxycarbonyl)amino)propyl)-2H-indazole-3-carboxylic acid (compound b) was obtained as a white solid, with a yield of 34.25%.

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

[0250] Following the method described in Example 2, methyl 2-(3-((tert-butyloxycarbonyl)amino)propyl)-2H-indazole-3-carboxylic acid (compound b) was used as a starting material and hydrolyzed to obtain 2.54 g of 2-(3-((tert-butyloxycarbonyl)amino)propyl)-2H-indazole-3-carboxylic acid (compound c), a white solid, with a yield of 88.25%.

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

[0252] Following the method described in Example 3, 2-(3-((tert-Butoxycarbonyl)amino)propyl)-2H-indazole-3-carboxylic acid (compound c) was used as a starting material and condensed to obtain methyl 4-((2-(3-((tert-Butoxycarbonyl)amino)propyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound d), 2.15 g 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] Following the method described in Example 4, methyl 4-((2-(3-((tert-butoxycarbonyl)amino)propyl)-2H-indazole-3-carboxamido)methyl)benzoate (compound d) was deprotected to obtain methyl 4-((2-(3-aminopropyl)-2H-indazole-3-carboxamido)methyl)benzoate (e), 3.25 g of white solid, with a yield of 115.52%.

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

[0256] Following the methods described in Examples 5 and 6, using 2-chloro-4-cyanoaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 2-chloro-4-cyanoaniline in Example 5), a white solid, namely SYP-U101-A, was obtained with a yield of 0.15 g and a recovery rate of 85.23%. The temperature was mp 265–267 °C. 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)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U102-A)

[0258] Following the methods described in Examples 5 and 6, using 4-chloro-3-trifluoromethylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 4-chloro-3-trifluoromethylaniline in Example 5), a white solid, namely SYP-U102-A, was obtained with a yield of 0.15 g and a recovery rate of 85.62%. The temperature range was mp 229–231 °C. 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)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U103-A)

[0260] Following the methods described in Examples 5 and 6, using 4-fluoro-3-methylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 4-fluoro-3-methylaniline in Example 5), a white solid, namely SYP-U104-A, was obtained with a yield of 0.13 g and a recovery rate of 82.32%. The temperature range was 218–222 °C. 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-(3-fluoro-4-methylphenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U104-A)

[0262] Following the methods described in Examples 5 and 6, using 3-fluoro-4-methylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 3-fluoro-4-methylaniline in Example 5), a white solid, namely SYP-U101-A, was obtained with a yield of 0.16 g and a recovery rate of 88.23%. The temperature range was 236–239 °C. 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)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U105-A)

[0264] Following the methods described in Examples 5 and 6, using 3,5-difluoroaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 3,5-difluoroaniline), a white solid, namely SYP-U105-A, was obtained with a yield of 0.13 g and a recovery rate of 83.32%. The temperature range was 224–229 °C. 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)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U106-A)

[0266] Following the methods described in Examples 5 and 6, using 4-chloro-3-fluoroaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 4-chloro-3-fluoroaniline), a white solid, namely SYP-U106-A, was obtained with a yield of 0.14 g and a recovery rate of 83.34%. The temperature range was mp 238–244 °C. 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-(3-chloro-4-fluorophenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U107-A)

[0268] Following the methods described in Examples 5 and 6, using 3-chloro-4-fluoroaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 3-chloro-4-fluoroaniline in Example 5), a white solid, namely SYP-U107-A, was obtained with a yield of 0.17 g and a recovery rate of 88.12%. The temperature was mp 242–245 °C. 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-(3-chloro-4-(trifluoromethyl)phenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U108-A)

[0270] Following the methods described in Examples 5 and 6, using 3-chloro-4-trifluoromethylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 3-chloro-4-trifluoromethylaniline in Example 5), a white solid, namely SYP-U108-A, was obtained with a yield of 0.11 g and a recovery rate of 79.23%. The temperature range was mp 234–237 °C. 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)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U109-A)

[0272] Following the methods described in Examples 5 and 6, using 4-chloro-3-methylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 4-chloro-3-methylaniline in Example 5), a white solid, namely SYP-U109-A, was obtained with a yield of 0.15 g and a recovery rate of 82.52%. The temperature was mp 235–240 °C. 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-(3-fluoro-4-(trifluoromethyl)phenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U110-A)

[0274] Following the methods described in Examples 5 and 6, using 3-fluoro-4-trifluoromethylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 3-fluoro-4-trifluoromethylaniline in Example 5), a white solid, namely SYP-U110-A, was obtained with a yield of 0.15 g and a recovery rate of 85.61%. The temperature range was 232–237 °C. 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)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U111-A)

[0276] Following the methods described in Examples 5 and 6, using 4-fluoro-3-trifluoromethylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 4-fluoro-3-trifluoromethylaniline in Example 5), a white solid, namely SYP-U111-A, was obtained with a yield of 0.14 g and a recovery rate of 83.26%. The temperature range was mp 239–242 °C. 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-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U112-A)

[0278] Following the methods described in Examples 5 and 6, using 3-fluoro-4-trifluoromethoxyaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 3-fluoro-4-trifluoromethoxyaniline in Example 5), a white solid, namely SYP-U112-A, was obtained with a yield of 0.12 g and a recovery rate of 81.25%. The temperature was maintained at 251–254 °C. 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)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U113-A)

[0280] Following the methods described in Examples 5 and 6, using 4-trifluoromethoxyaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 4-trifluoromethoxyaniline in Example 5), a white solid, namely SYP-U113-A, was obtained with a yield of 0.11 g and a recovery rate of 78.69%. The temperature was mp 245–249 °C. 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)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U114-A)

[0282] Following the methods described in Examples 5 and 6, using 4-methoxyaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 4-methoxyaniline), a white solid, namely SYP-U114-A, was obtained with a yield of 0.14 g and a recovery rate of 84.34%. The temperature range was mp 239–242 °C. 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)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U115-A)

[0284] Following the methods described in Examples 5 and 6, using 4-fluoroaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 4-fluoroaniline), a white solid, namely SYP-U115-A, was obtained with a yield of 0.12 g and a recovery rate of 82.13%. The temperature was 231–235 °C. 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)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U117-A)

[0286] Following the methods described in Examples 5 and 6, using 4-nitroaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 4-nitroaniline), a white solid, namely SYP-U117-A, was obtained with a yield of 0.14 g and a recovery rate of 83.89%. The temperature range was 239–242 °C. 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)ureo)propyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-U118-A)

[0288] Following the methods described in Examples 5 and 6, using 2-bromo-4-cyanoaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 2-bromo-4-cyanoaniline), a white solid, namely SYP-U118-A, was obtained, with a yield of 0.14 g and a recovery rate of 84.56%. The temperature range was 237–241 °C. 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-carboxylic acid

[0290] Following the method of Example 1, using N-Boc-bromoethane (compound I) as the starting material, the only difference from Example 1 was that the resolution was adjusted to 0.5 Rs during column chromatography, yielding 4.36 g of methyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-indazole-3-carboxylic acid (compound h), a white solid, with a yield of 37.21%. mp 117–118 °C.

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

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

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

[0294] Following the method described in Example 3, methyl 4-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-indazole-3-carboxylic acid (compound i) was condensed to obtain 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-carbamate)methyl)benzoate

[0296] Following the method described in Example 4, methyl 4-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-indazole-3-carboxamido)methyl)benzoate (compound j) was deprotected to obtain methyl 4-((1-(2-aminoethyl)-1H-indazole-3-carboxamido)methyl)benzoate (compound k), 4.56 g of white solid, with a yield of 124.31%.

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

[0298] Following the methods described in Examples 5 and 6, using 3-chloro-4-cyanoaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 3-chloro-4-cyanoaniline in Example 5), a white solid, namely SYP-A109-A, was obtained with a yield of 0.10 g and a recovery rate of 78.35%. The temperature was mp 245–249 °C. 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)ureo)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (SYP-A112-A)

[0300] Following the methods described in Examples 5 and 6, using 3-fluoro-4-methylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 3-fluoro-4-methylaniline in Example 5), a white solid, namely SYP-A112-A, was obtained with a yield of 0.14 g and a recovery rate of 84.38%. The temperature range was mp 259–264 °C. 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)ureo)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (SYP-A113-A)

[0302] Following the methods described in Examples 5 and 6, using 3,5-difluoroaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 3,5-difluoroaniline), a white solid, namely SYP-A113-A, was obtained with a yield of 0.16 g and a recovery rate of 87.35%. The temperature range was mp 247–252 °C. 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)ureo)ethyl)-1H-indazole-3-carboxamido)methyl)benzoic acid (SYP-A115-A)

[0304] Following the methods described in Examples 5 and 6, using 3-chloro-4-methylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 3-chloro-4-methylaniline in Example 5), a white solid, namely SYP-A115-A, was obtained with a yield of 0.14 g and a recovery rate of 84.44%. The temperature was mp 242–245 °C. 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-butoxycarbonyl)amino)cyclohexane-1-carbamate)ethyl)-2H-indazole-3-carbamate)methyl)benzoate

[0306] Following the method described in Example 3, methyl 4-((2-(2-aminoethyl)-2H-indazole-3-carbamate)methyl)benzoate (compound e) and trans-(4-aminocyclohexyl)carbamate tert-butyl ester were used as raw materials to condense and obtain methyl 4-((2-(2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carbamate)ethyl)-2H-indazole-3-carbamate)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-carbamoyl)ethyl)-2H-indazole-3-carbamoyl)methyl)benzoate

[0308] Following the method described in Example 4, methyl 4-((2-(2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carbamate)ethyl)-2H-indazole-3-carbamate)methyl)benzoate (compound n) was deprotected to obtain methyl 4-((2-(2-((1r,4r)-4-aminocyclohexane-1-carbamate)ethyl)-2H-indazole-3-carbamate)methyl)benzoate (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)ureo)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C101-A)

[0310] Following the methods described in Examples 5 and 6, using 2-chloro-4-cyanoaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with 2-chloro-4-cyanoaniline), a white solid, namely SYP-C101-A, was obtained, with a yield of 0.11 g and a recovery rate of 78.23%. The temperature range was mp 249–252 °C. 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)ureo)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C102-A)

[0312] Following the methods described in Examples 5 and 6, using 4-chloro-3-trifluorotoluidine as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 4-chloro-3-trifluorotoluidine in Example 5), a white solid, namely SYP-C102-A, was obtained with a yield of 0.12 g and a recovery rate of 81.02%. The temperature range was mp 279–284 °C. 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)ureo)cyclohexane-1-carbamate)ethyl)-2H-indazole-3-carbamate)methyl)benzoic acid (SYP-C104-A)

[0314] Following the methods described in Examples 5 and 6, using 3-fluoro-4-methylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 3-fluoro-4-methylaniline in Example 5), a white solid, namely SYP-C104-A, was obtained with a yield of 0.11 g and a recovery rate of 79.69%. mp>300℃. 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] Following the methods described in Examples 5 and 6, using 4-chloro-3-fluoroaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 4-chloro-3-fluoroaniline in Example 5), a white solid, namely SYP-C106-A, was obtained with a yield of 0.19 g and a recovery rate of 93.54%. The temperature range was mp 289–292 °C. 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] Following the methods described in Examples 5 and 6, using 3-chloro-4-fluoroaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 2-chloro-4-cyanoaniline in Example 5), a white solid, namely SYP-C107-A, was obtained with a yield of 0.16 g and a recovery rate of 88.56%. The temperature was mp 295–299 °C. 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)ureo)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C110-A)

[0320] Following the methods described in Examples 5 and 6, using 3-fluoro-4-trifluoromethylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 3-fluoro-4-trifluoromethylaniline in Example 5), a white solid, namely SYP-C110-A, was obtained with a yield of 0.14 g and a recovery rate of 85.34%. The temperature range was mp 282–286 °C. 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)ureo)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C114-A)

[0322] Following the methods described in Examples 5 and 6, using p-toluidine as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline in Example 5 with p-toluidine), a white solid, namely SYP-C114-A, was obtained with a yield of 0.14 g and a recovery rate of 85.34%. mp>300℃. 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)ureo)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C115-A)

[0324] Following the methods described in Examples 5 and 6, using 3-chloro-4-trifluoromethoxyaniline as the raw material (i.e., replacing 3-chloro-4-trifluoromethoxyaniline with 3-chloro-4-trifluoromethoxyaniline in Example 5), a white solid, namely SYP-C115-A, was obtained with a yield of 0.17 g and a recovery rate of 86.56%. The temperature was mp 272–277 °C. 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)ureo)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C116-A)

[0326] Following the methods described in Examples 5 and 6, using 4-chloro-3-trifluoromethylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 4-chloro-3-trifluoromethylaniline in Example 5), a white solid, namely SYP-C116-A, was obtained with a yield of 0.14 g and a recovery rate of 84.34%. The temperature was above 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)ureo)cyclohexane-1-carboxamido)ethyl)-2H-indazole-3-carboxamido)methyl)benzoic acid (SYP-C117-A)

[0328] Following the methods described in Examples 5 and 6, using 4-trifluoromethylaniline as the raw material (i.e., replacing 3-fluoro-4-trifluoromethoxyaniline with 4-trifluoromethylaniline in Example 5), a white solid, namely SYP-C117-A, was obtained with a yield of 0.14 g and a recovery rate of 84.37%. The temperature was mp 285–290 °C. 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] Inhibition activity test

[0331] (1) When the density of HEK293 cells reaches 80-90%, pGloSensor is co-transfected at a ratio of 1:1 (mass ratio). TM -22Fc AMP plasmid and Human-EP4 plasmid, 4μg of plasmid can be co-transfected in 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) 2-4 hours before the next day, 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 in serum-free CO2 Independent Medium to 2 × 10⁻⁶ cells / mL. 6 Cells / mL. Add 4% Glo Sensor TM After mixing cAMP Reagent, add 20 μL of cell suspension per well to a 384-well plate and incubate at room temperature in the dark for 1.5–2 h.

[0335] (5) Dilute the compound to be tested to the required concentration with serum-free CO2 Independent Medium.

[0336] (6) If the activity of the agonist PGE2 is to be detected, the 384-well plate after 2 hours of incubation is taken out and placed in the Flex Station3 instrument. The fluorescence signal after adding 5 μL of different concentrations of PGE2 is detected and the readings are continuously read for 30 minutes.

[0337] (7) If the antagonistic activity of the compound against the receptor is to be detected, after incubating the 384-well plate for 1.5 h, add 5 μL of different concentrations of the compound, continue incubating at room temperature in the dark for 30 min, and then use a Flex Station3 instrument to detect and read the EC. 80 The fluorescence signal after PGE2 concentration was continuously read for 30 minutes.

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

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

[0340]

[0341] Table 2. Inhibitory activity of compounds against 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] As can be seen from Table 1, the urea-containing indazole benzoic acid derivatives provided by this invention have a good inhibitory effect on EP4. Experimental results showed that 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 all exhibited an inhibition rate of over 90% against EP4.

[0344] As shown in Table 2, 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 control drug Grapiprant. In particular, the inhibitory activity of SYP-106-A and SYP-109-A against hEP4 is higher than that of Grapiprant, showing very good development prospects.

[0345] As can be seen from the above embodiments, 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 to prepare drugs for treating diseases mediated by PGE2 / EP4 signaling.

[0346] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. Other embodiments can be obtained based on these embodiments without creative effort, 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, With SYP-102-A, SYP-103-A, SYP-104-A, SYP-105-A, SYP-106-A, SYP-107-A, SYP-108-A, SYP-109-A, SYP-110-A, SYP-111-A, SYP-112-A, S YP-113-A, SYP-114-A, SYP-116-A, SYP-U101-A, SYP-U102-A, SYP-U103-A, SYP-U104-A, SYP-U105-A, SYP-U106-A, SYP-U107-A, SYP-U108 Structures shown in SYP-C109-A, SYP-U110-A, SYP-U111-A, SYP-U112-A, SYP-U113-A, SYP-U114-A, SYP-U115-A, SYP-U117-A, SYP-U118-A, SYP-A109-A, SYP-A112-A, SYP-A113-A, SYP-A115-A, SYP-C110-A, SYP-C114-A, SYP-C115-A, SYP-C116-A, SYP-C117-A, SYP-C104-A, or SYP-C107-A: 。 2. A method for preparing an indazole benzoic acid derivative containing a urea structure, characterized in that, The preparation method of the indazole benzoic acid derivative containing a urea structure as shown in Formula A includes the following steps: (1) Compound I and compound a undergo a first nucleophilic substitution reaction to obtain compound b; (2) Compound b is subjected to a first hydrolysis reaction to obtain compound c; (3) Compound c and compound II are subjected to a first acylation reaction to obtain compound d; (4) Compound d is subjected to a first deprotection reaction to obtain compound e; (5) The compound e and (trichloromethyl) carbonate are subjected to a second acylation reaction to obtain a first intermediate compound; the first intermediate compound and compound III are subjected to a second nucleophilic substitution reaction to obtain compound f; the compound f is subjected to a second hydrolysis reaction to obtain an indazole benzoic acid derivative with a urea structure as shown in Formula A; The structural formula of compound I is as follows: The structural formula of compound II is as follows: The structural formula of compound III is as follows: ; The structure of formula A is: The structural formulas of the first intermediate, compound a, compound b, compound c, compound d, compound e, and compound f are as follows: ； The preparation method of the indazole benzoic acid derivative containing a urea structure as shown in Formula B includes the following steps: (A) Compound I and compound a undergo a third nucleophilic substitution reaction to obtain compound h; (B) Compound h is subjected to a third hydrolysis reaction to obtain compound i; (C) Compound i and compound II are subjected to a third acylation reaction to obtain compound j; (D) Compound j is subjected to a second deprotection reaction to obtain compound k; (E) The compound k and (trichloromethyl) carbonate are subjected to a fourth acylation reaction to obtain a second intermediate compound; the second intermediate compound and compound III are subjected to a fourth nucleophilic substitution reaction to obtain compound l; the compound l is subjected to a fourth hydrolysis reaction to obtain an indazole benzoic acid derivative with a urea structure as shown in formula B; The structural formula of compound I is as follows: The structural formula of compound II is as follows: The structural formula of compound III is as follows: ; The structure of formula B is: The structural formulas of the second intermediate, compound a, compound h, compound i, compound j, compound k, and compound l are as follows: ； The preparation method of the indazole benzoic acid derivative containing a urea structure as shown in Formula C includes the following steps: (I) Compound IV and compound e undergo a fifth acylation reaction to yield compound n; (II) Compound n is subjected to a third deprotection reaction to obtain compound o; (III) The compound o and (trichloromethyl) carbonate are subjected to a sixth acylation reaction to obtain a third intermediate compound; the third intermediate compound and compound II are subjected to a fifth nucleophilic substitution reaction to obtain compound p; the compound p is subjected to a fifth hydrolysis reaction to obtain an indazole benzoic acid derivative with a urea structure as shown in formula C; The structural formula of compound II is as follows: The structural formula of compound IV is as follows: ; The structural formulas of the third intermediate, compound e, compound n, compound o, and compound p are as follows: ； The structure of formula C is as follows: ; In formula A, B, or C, R1 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, heterocyclic, substituted heterocyclic, alkyl, or substituted alkyl; R2 and R3 are independently -H, alkyl, substituted alkyl, or R2 and R3 are interconnected to form a cycloalkyl group or R2 and R3 are interconnected to form a substituted cycloalkyl group; n is 0, 1, 2, or 3; Z is -O-. The meanings of n, R1, R2 or R3 in compounds I, II, III, first intermediate, second intermediate, third intermediate, a, b, c, d, e, f, h, i, j, k, l, n, o and p correspond to the corresponding structures of formula A, B or C.

3. The preparation method according to claim 2, 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 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 compound d to the organic solvent is 1~1.2:1~100; the temperature of the first deprotection reaction is -20~50 ℃, and the holding time is 2~8 h.

4. The preparation method according to claim 2, 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 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 ℃, and the holding time is 2~8 h.

5. The preparation method according to claim 2, 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 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 compound n to the organic solvent is 1~1.2:1~100; the temperature of the third deprotection reaction is -20~50 ℃, and the holding time is 2~8 h.

6. The use of the urea-containing indazole benzoic acid derivative of claim 1 in the preparation of a medicament for treating diseases mediated by PGE2 / EP4 signaling.

7. The application according to claim 6, characterized in that, The diseases mediated by the PGE2 / EP4 signaling include cancer, acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea, or arteriosclerosis.

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