A 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof and its applications.

Abstract

This invention discloses a 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof and its application. The 3-trifluoromethyl-substituted pyrazole compound or its pharmaceutically acceptable salt has the structure shown in formula (I). The 3-trifluoromethyl-substituted pyrazole compound or its pharmaceutically acceptable salt of this invention exhibits excellent inhibitory activity against PDE10A (phosphodiesterase type 10A), and compared to other phosphodiesterase subtypes, it shows high selectivity for phosphodiesterase type 10A, making it a specific drug for inhibiting phosphodiesterase type 10A activity. It also exhibits good metabolic stability, with a half-life of up to 239 min after metabolism by rat liver microsomes, solving the problem of excessively rapid metabolism of pyrazole PDE10A inhibitors such as MP-10.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof and its use. Background Technology

[0002] In the fields of cardiovascular biology and disease, cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) are ubiquitous second messengers in intracellular signal transduction. Cyclic nucleotide phosphodiesterases (PDEs) regulate the duration, amplitude, and compartmentalization of intracellular cyclic nucleotide signaling by catalyzing the hydrolysis of cyclic nucleotides, thereby maintaining the balance of cAMP and cGMP under intracellular physiological conditions. Therefore, PDEs play an important role in the treatment of cardiovascular diseases.

[0003] In mammals, the PDEs superfamily comprises over 100 different isoforms. Due to alternative splicing and the presence of different translation initiation sites, these isoforms are classified into 11 closely related isoenzymes (PDE1-11). Current research indicates that PDE10A (phosphodiesterase type 10A), as a member of the PDEs superfamily, regulates transcriptomes involved in myocardial hypertrophy, fibrosis, and cardiomyopathy. Furthermore, PDE10A is also involved in vascular smooth muscle cell proliferation and pathological vascular remodeling. Therefore, PDE10A inhibitors can exert corresponding therapeutic effects on cardiovascular diseases by inhibiting PDE10A activity. Among the various PDE10A inhibitors reported so far, [the following is a list of specific inhibitors]. For example, pyrazole PDE10A inhibitors are metabolized too quickly, which reduces the time it takes for them to exert their effects and seriously affects the treatment of cardiovascular diseases.

[0004] Therefore, it is of great importance to develop a slow-metabolizing pyrazole PDE10A inhibitor, a 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof. Summary of the Invention

[0005] The purpose of this invention is to solve the problem of excessively rapid metabolism of pyrazole PDE10A inhibitors such as MP-10 in the prior art, and to provide a 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof and its application.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] In a first aspect, the present invention provides a 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof having the structure shown in formula (I):

[0008]

[0009] Formula (I);

[0010] in:

[0011] R1 is H, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , One of them;

[0012] R2 is one of H, F, Cl, Br, nitro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, or cyano.

[0013] X is one of C and N;

[0014] R3 is one of H and F or does not exist;

[0015] It is a six-membered aromatic heterocycle containing an R4 substituent. Y1, Y2, and Y3 are each independently selected from C or N, and R4 is one of H, F, methyl, methoxy, nitrogen oxide, or lactam.

[0016] Preferably, R1 is H, , , , , , , , , , , , , , , , , , , , One of them.

[0017] More preferably, R1 is H, , , , , , , , , , , One of them.

[0018] Preferably, R2 is one of H and F.

[0019] Preferably, R3 is H or does not exist; specifically, in the structure of formula (I), when X is C, R3 is H; when X is N, R3 does not exist.

[0020] Preferably, the for , , , , , , , , , One of them.

[0021] More preferably, the for , , , , One of them.

[0022] Preferably, the 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof is one of the compounds shown in the following structural formulas:

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031] .

[0032] More preferably, the 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof is one of the compounds shown in the following structural formulas:

[0033]

[0034]

[0035]

[0036]

[0037] .

[0038] Preferably, the pharmaceutically acceptable salt is a product obtained by reacting a 3-trifluoromethyl-substituted pyrazole compound having the structure shown in formula (I) with an acid; the acid includes, but is not limited to, one or more of hydrochloric acid, hydrobromic acid, hydrofluoric acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, salicylic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, fumaric acid, citric acid, acetic acid, tartaric acid, succinic acid, malic acid, and glutamic acid.

[0039] Secondly, the present invention provides a method for preparing a 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0040] (1) In the presence of sodium ethoxide, aryl ketones react with ethyl trifluoroacetate to form aryl diketone intermediates;

[0041] (2) The aryl dione intermediate undergoes a condensation and ring-closing reaction with an aromatic hydrazine compound to form a pyrazole intermediate with a 3-trifluoromethyl substituted phenolic hydroxyl group protected;

[0042] (3) The pyrazole intermediate containing phenolic hydroxyl groups protected by 3-trifluoromethyl substituted pyrazole intermediate is obtained by deprotection of the protecting group;

[0043] (4) Reaction of pyrazole intermediates containing phenolic hydroxyl 3-trifluoromethyl substituted with 2-bromomethylquinoline compounds yields 3-trifluoromethyl substituted pyrazole compounds;

[0044] Among them, the aryl ketone compounds are The aryl diketone intermediate is The aromatic hydrazine compound is The 3-trifluoromethyl-substituted pyrazole intermediate containing a phenolic hydroxyl group protection is... The pyrazole intermediate containing a phenolic hydroxyl group substituted with a 3-trifluoromethyl group is... The 2-bromomethylquinoline compound is .

[0045] Preferably, in step (4), after the pyrazole intermediate containing phenolic hydroxyl 3-trifluoromethyl substituted reacts with the 2-bromomethylquinoline compound, a saponification hydrolysis reaction and an amide condensation reaction are further performed; the base used in the saponification hydrolysis reaction is LiOH; the reagents used in the amide condensation reaction include 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), and N,N-dimethylformamide (DMF).

[0046] More preferably, after the saponification hydrolysis reaction and the amide condensation reaction, the treatment further includes a Boc deprotection treatment; the reagents used in the Boc deprotection treatment include trifluoroacetic acid (TFA) and dichloromethane (DCM).

[0047] The synthetic flow chart of the above 3-trifluoromethyl-substituted pyrazole compounds is shown below. Figure 1 As shown, ah represents the reaction reagents and reaction conditions, specifically: a-sodium ethoxide, THF, reflux, overnight; b-ethanol, reflux; c-Pd / C, H2, methanol; d-BBr3, dichloromethane (DCM), -10 o C to room temperature, overnight; e-Cs2CO3, DMF, 80 o C; f-LiOH, THF / H2O, room temperature, overnight; g-various amines, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), N,N-dimethylformamide (DMF), overnight; hi) various amines, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), N,N-dimethylformamide (DMF), overnight; ii) trifluoroacetic acid (TFA), dichloromethane (DCM), overnight.

[0048] Thirdly, the present invention provides the use of a 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the treatment and / or prevention of diseases caused by PDE10A.

[0049] Preferably, the relevant disease is a cardiovascular disease; specifically, it is at least one of myocardial hypertrophy, myocardial remodeling, myocardial fibrosis, and myocardial injury.

[0050] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0051] The 3-trifluoromethyl-substituted pyrazole compounds of this invention, or their pharmaceutically acceptable salts, exhibit excellent inhibitory activity against PDE10A (phosphodiesterase type 10A). Furthermore, compared to other phosphodiesterase subtypes, they demonstrate high selectivity for PDE10A, making them suitable as specific inhibitors of PDE10A activity. They also exhibit good metabolic stability, with a half-life of up to 239 minutes after metabolism via rat liver microsomes, overcoming the problem of rapid metabolism of pyrazole PDE10A inhibitors such as MP-10. In addition, the 3-trifluoromethyl-substituted pyrazole compounds, or their pharmaceutically acceptable salts, have low blood-brain barrier permeability, making them less likely to inhibit PDE10A in the central nervous system. Therefore, when used to treat and / or prevent PDE10A-related diseases, including myocardial hypertrophy, myocardial remodeling, myocardial fibrosis, and myocardial injury, they will not have adverse effects on the central nervous system. Attached Figure Description

[0052] Figure 1 The flowchart shows the synthesis of 3-trifluoromethyl-substituted pyrazole compounds, where ah represents the reagents and reaction conditions, specifically: a-sodium ethoxide, THF, reflux, overnight; b-ethanol, reflux; c-Pd / C, H2, methanol; d-BBr3, dichloromethane (DCM), -10°C. o C to room temperature, overnight; e-Cs2CO3, DMF, 80 o C; f-LiOH, THF / H2O, room temperature, overnight; g-various amines, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), N,N-dimethylformamide (DMF), overnight; hi) various amines, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), N,N-dimethylformamide (DMF), overnight; ii) trifluoroacetic acid (TFA), dichloromethane (DCM), overnight.

[0053] Figure 2 Synthetic flowcharts of pyrazole compounds A1-A3 substituted with 3-trifluoromethyl.

[0054] Figure 3 Synthetic flowcharts of pyrazole compounds A4-A5 substituted with 3-trifluoromethyl.

[0055] Figure 4 Flowchart of the synthesis of pyrazole compound A6, which is substituted with 3-trifluoromethyl.

[0056] Figure 5 Synthetic flowchart of pyrazole compounds A7-A12 substituted with 3-trifluoromethyl.

[0057] Figure 6 A flowchart of the synthesis of A13, a pyrazole compound substituted with 3-trifluoromethyl.

[0058] Figure 7 Synthetic flowchart of pyrazole compounds A14-A15 substituted with 3-trifluoromethyl.

[0059] Figure 8 A flowchart of the synthesis of A16, a pyrazole compound substituted with 3-trifluoromethyl.

[0060] Figure 9 A flowchart of the synthesis of A17, a pyrazole compound substituted with 3-trifluoromethyl.

[0061] Figure 10 Synthetic flowchart of pyrazole compounds B1-B8 substituted with 3-trifluoromethyl.

[0062] Figure 11 Flowchart of the synthesis of pyrazole compound B5, which is substituted with 3-trifluoromethyl.

[0063] Figure 12 Flowchart of the synthesis of pyrazole compound B6, which is substituted with 3-trifluoromethyl.

[0064] Figure 13 Flowchart of the synthesis of pyrazole compound B7, which is substituted with 3-trifluoromethyl.

[0065] Figure 14 Flowchart of the synthesis of pyrazole compound B8, which is substituted with 3-trifluoromethyl.

[0066] Figure 15 Flowchart of the synthesis of pyrazole compound B9, which is substituted with 3-trifluoromethyl.

[0067] Figure 16 Synthetic flowchart of pyrazole compounds with 3-trifluoromethyl substituted C1-C8.

[0068] Figure 17Statistical graphs of heart specific gravity and heart-to-tibia ratio in C57 mice from different experimental groups. Figure 17 A shows the statistical graph of the heart weight of C57 mice in different experimental groups. Figure 17 B is a statistical graph showing the heart-to-tibia ratio of C57 mice in different experimental groups.

[0069] Figure 18 This is a statistical graph showing the changes in atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC) mRNA expression in the myocardial tissue of C57 mice from different experimental groups. Figure 18 Figure A shows the changes in atrial natriuretic peptide (ANP) mRNA expression in the myocardial tissue of C57 mice in different experimental groups. Figure 18 B shows the changes in β-myosin heavy chain (β-MHC) mRNA expression in the myocardial tissue of C57 mice in different experimental groups.

[0070] Figure 19 Graphs showing left ventricular ejection fraction and left ventricular shortening fraction in C57 mice from different experimental groups. Figure 19 A shows the statistical graph of left ventricular ejection fraction in C57 mice from different experimental groups. Figure 19 B is a statistical graph showing the left ventricular shortening fraction of C57 mice in different experimental groups.

[0071] Figure 20 Graphs showing the left ventricular end-systolic diameter and left ventricular end-diastolic diameter in C57 mice from different experimental groups. Figure 20 A shows the statistical graph of the left ventricular end-systolic diameter of C57 mice in different experimental groups. Figure 20 B is a statistical graph showing the end-diastolic diameter of the left ventricle in C57 mice from different experimental groups.

[0072] exist Figure 17-20 In the text, "*" and "#" indicate significant differences, with "*" indicating p < 0.05, "**" indicating p < 0.01, "***" indicating p < 0.001, "****" indicating p < 0.0001, "#" indicating p < 0.05, "##" indicating p < 0.01, "###" indicating p < 0.001, and "ns" indicating p > 0.05. Detailed Implementation

[0073] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0074] Example 1 Synthesis and structural characterization of 3-trifluoromethyl-substituted pyrazole compounds A1-A3

[0075] The synthetic flow chart of 3-trifluoromethyl-substituted pyrazole compounds A1-A3 is shown below. Figure 2 As shown, specifically:

[0076] (1) Synthesis of intermediate M1: In a 125 mL round-bottom flask, 4-acetylpyridine (1.21 g, 10.0 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and sodium ethoxide (1.36 g, 20.0 mmol) was carefully added. The mixture was heated and stirred at 65 °C for 0.5 h. Ethyl trifluoroacetate (2.84 g, 20.0 mmol) was slowly added dropwise to the reaction mixture using a constant pressure dropping funnel. After the addition was complete, the mixture was refluxed overnight, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure by distillation, and the pH was adjusted to 4-5 by adding saturated citric acid aqueous solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure by distillation to obtain a yellow oily intermediate M1, which could be used directly in the next step without purification.

[0077] (2) Synthesis of intermediate M2: In a 125 mL round-bottom flask, intermediate M1 was dissolved in anhydrous ethanol (40 mL), and 4-methoxyphenylhydrazine hydrochloride (3.49 g, 20.0 mmol) was added. The mixture was heated and stirred at 80 °C for 3 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated by vacuum distillation, and the crude product was purified by silica gel column chromatography to obtain a yellow oily intermediate M2 (1.88 g, yield 59%). The synthesis of intermediate M2... 1 H NMR (400 MHz, DMSO-d6)δ= 8.58 (dd, J = 4.4, 1.6Hz, 2H), 7.41 (s, 1H), 7.34 (dd, J = 6.8, 2.0 Hz, 2H), 7.26 (dd, J = 4.4, 1.6Hz, 2H), 7.04 (dd, J = 6.8, 2.0 Hz, 2H), 3.82 (s, 3H).

[0078] (3) Synthesis of intermediate M3: In a 125 mL round-bottom flask, intermediate M2 (1.88 g, 5.89 mmol) was dissolved in anhydrous dichloromethane (30 mL). Boron tribromide (7.38 g, 29.5 mmol) was slowly added dropwise at 0 °C (ice-water bath). After the addition was complete, the reaction was stirred at 0 °C for 0.5 h, then slowly raised to room temperature for 24 h. The reaction progress was monitored by TLC. After the reaction was completed, methanol was slowly added dropwise at 0 °C to quench the reaction. Then, the mixture was concentrated by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain a yellow solid compound intermediate M3 (1.26 g, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ=10.08 (brs, 1H), 8.92-8.80 (m, 2H), 7.80-7.58 (m, 3H), 7.27 (d, J = 8.4 Hz, 2H), 6.87 (d, J =8.4 Hz, 2H).

[0079] (4) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A1: In a 50 mL round-bottom flask, intermediate M3 (100 mg, 0.33 mmol) and (2-bromomethyl)quinoline (73 mg, 0.33 mmol) were dissolved in anhydrous DMF (10 mL), and cesium carbonate (213 mg, 0.66 mmol) was added. The reaction mixture was heated to 80 °C for 4 hours, and the reaction progress was monitored by TLC. After the reaction was completed, cesium carbonate was removed by filtration, and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a pale yellow solid compound A1 (114 mg, yield 78%). 1 H NMR (400 MHz, CDCl3)δ= 8.57 (d, J = 4.0 Hz, 2H), 8.21 (d, J = 6.8 Hz, 1H), 8.08 (d, J = 6.4 Hz, 1H), 7.84 (d, J = 6.4 Hz, 1H), 7.75 (t, J = 6.0 Hz, 1H), 7.64 (d, J = 6.8 Hz, 1H), 7.57 (d, J = 6.0 Hz, 1H), 7.23 (d, J = 6.8 Hz, 2H), 7.10 (d, J = 4.0 Hz, 2H), 7.05 (d, J = 7.2 Hz, 2H),6.86 (s, 1H), 5.41 (s, 3H).

[0080] (5) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A2: Using intermediate M3 (100 mg, 0.33 mmol) and methyl (2-bromomethyl)quinoline-4-carboxylate (280 mg, 1.0 mmol) as starting materials, the experiment was carried out according to the synthesis method of step (4) A1, yielding a pale yellow solid compound A2 (322 mg, yield 64%). 1H NMR (400 MHz, DMSO-d6)δ=8.62 (d, J = 6.8 Hz, 1H), 8.57 (d, J = 4.0 Hz, 2H), 8.13 (d, J = 6.8 Hz, 1H), 8.10 (s, 1H),7.89 (t, J = 6.0 Hz, 1H), 7.77 (t, J = 6.0 Hz, 1H), 7.42 (s,1H), 7.38 (d, J = 7.2 Hz, 2H), 7.26 (d, J = 4.0 Hz, 2H), 7.21 (d, J = 7.2 Hz,2H), 5.50 (s, 2H), 4.01 (s, 3H).

[0081] (6) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A3: Using intermediate M4 (100 mg, 0.33 mmol) and (2-bromomethyl)-N-methylquinoline-4-carboxamide (91 mg, 0.33 mmol) as starting materials, the synthesis was carried out according to the method of step (4) A1, yielding a pale yellow solid compound A3 (155 mg, yield 86%). 1 H NMR (400 MHz, DMSO-d6)δ= 8.77 (d, J = 4.8 Hz, 1H), 8.57 (dd, J = 4.8, 1.6 Hz, 2H), 8.14 (d, J = 8.0Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.41 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.26 (dd, J= 4.8, 1.6 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 5.45 (s, 2H), 2.88 (d, J = 4.8Hz, 3H).

[0082] Example 2 Synthesis and structural characterization of 3-trifluoromethyl-substituted pyrazole compounds A4-A5

[0083] The synthetic flow charts for 3-trifluoromethyl-substituted pyrazole compounds A4-A5 are shown below. Figure 3 As shown, specifically:

[0084] (1) Synthesis of intermediate M4: In a 125 mL round-bottom flask, 3-trifluoromethyl-substituted pyrazole compound A2 (300 mg, 0.59 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (45 mg, 1.18 mmol) was carefully added at 0 °C, and the mixture was stirred at 0 °C to room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was completed, water (2 mL) was added at 0 °C to quench the reaction for 10 minutes. The mixture was then filtered under reduced pressure on a diatomaceous earth pad. The filtrate was concentrated by distillation under reduced pressure to obtain the yellow oily intermediate M4.

[0085] (2) Synthesis of intermediate M5: Intermediate M4 prepared in step (1) was dissolved in anhydrous dichloromethane (20 mL), and thionyl chloride (1 mL) was carefully added at 0 °C. The mixture was then stirred at room temperature for 2 hours, and the reaction was monitored by TLC. After the reaction was completed, the product was concentrated under reduced pressure to obtain a yellow oily crude product. The pH was adjusted to 9-10 with saturated sodium bicarbonate solution, and the product was extracted with ethyl acetate. After concentration of the organic phase by reduced pressure distillation, the product was purified by silica gel column chromatography to obtain a white solid intermediate M5 (195 mg, 66% yield in 2 steps). 1 H NMR (400 MHz, CDCl3) δ = 8.57 (d, J = 4.4 Hz, 2H), 8.12 (t, J =8.0 Hz, 2H), 7.79 (t, J = 6.0 Hz, 1H), 7.71 (s, 1H), 7.66(T, J = 6.0 Hz, 1H), 7.24 (d, J = 6.8 Hz, 2H), 7.10 (d, J = 4.8 Hz, 2H), 7.06 (d, J = 7.2 Hz, 2H), 6.86 (s, 1H), 5.40 (s, 2H), 5.01 (s, 2H).

[0086] (3) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A4: In a 15 mL sealed tube, intermediate M5 (80 mg, 0.16 mmol) and dimethylamine hydrochloride (26.4 mg, 0.32 mmol) were dissolved in acetonitrile (8 mL), and potassium carbonate (67 mg, 0.48 mmol) was added. The tube was sealed, stirred, and heated to 80 °C overnight. The reaction progress was monitored by TLC. After the reaction was completed, potassium carbonate was removed by filtration, and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a pale yellow solid compound A4 (52 mg, yield 64%).1 H NMR (400 MHz, CDCl3)δ= 8.56 (d, J = 4.0 Hz, 2H), 8.22 (d, J = 6.8Hz, 1H), 8.08 (d, J = 6.8 Hz, 1H), 7.73 (t, J = 6.0 Hz, 1H), 7.63 (s, 1H),7.58 (t, J = 6.0 Hz, 1H), 7.22 (d, J = 7.2 Hz, 2H), 7.10 (d, J = 4.0 Hz, 2H),7.06 (d, J = 7.2 Hz, 2H), 6.86 (s, 1H), 5.39 (s, 2H), 3.86 (s, 2H), 2.32 (s, 6H).

[0087] (4) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A5: Using intermediate M5 (100 mg, 0.33 mmol) and 3-hydroxyazacyclobutane hydrochloride (35.4 mg, 0.32 mmol) as starting materials, the synthesis method of A5 in step (3) was followed to obtain a pale yellow solid compound A5 (59 mg, yield 69%). 1 H NMR (400 MHz, DMSO-d6)δ=8.57 (dd, J = 4.8, 1.6 Hz, 2H), 8.15 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.0Hz, 1H), 7.77 (t, J = 7.2 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.61 (s, 1H),7.41 (s, 1H), 7.36 (d, J = 8.8 Hz, 2H), 7.25 (dd, J = 4.8, 1.2 Hz, 2H), 7.17(d, J = 8.8 Hz, 2H), 5.42 (s, 2H), 5.38 (d, J = 6.4 Hz, 1H), 3.28-4.23 (m,1H), 4.09 (s, 2H), 3.58 (t, J = 7.2 Hz, 2H), 2.89 (t, J = 7.2 Hz, 2H).

[0088] Example 3 Synthesis and structural characterization of 3-trifluoromethyl-substituted pyrazole compound A6

[0089] The synthetic flowchart of 3-trifluoromethyl-substituted pyrazole compound A6 is shown below. Figure 4As shown, specifically:

[0090] (1) Synthesis of intermediate M6: In a 125 mL round-bottom flask, 1-(2-methylquinoline-4-yl)acetone (1.87 g, 10.0 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 mL). Then, 3-hydroxyazacyclobutane hydrochloride (1.95 g, 20.0 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.56 g, 12.0 mmol), and diisopropylethylamine (4.95 g, 30.0 mmol) were added sequentially. The reaction mixture was stirred overnight at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the crude product was obtained by vacuum distillation and purified by silica gel column chromatography to give intermediate M6 (1.95 g, 85% yield), a pale yellow oily compound. 1 H NMR (400 MHz, CDCl3)δ= 8.05 (d, J = 8.4Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.2Hz, 1H), 7.28 (s, 1H), 3.48 (s, 3H), 3.38 (s, 3H), 2.77 (s, 3H).

[0091] (2) Synthesis of intermediate M7: In a 125 mL round-bottom flask, intermediate M6 (230 mg, 1.0 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Methylmagnesium bromide (1 mL, 2 M in THF) was slowly added dropwise at 0 °C. The reaction mixture was allowed to rise naturally to room temperature overnight, and the reaction progress was monitored by TLC. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction. Ethyl acetate was added for extraction, and the organic phase was distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to give intermediate M7 (155 mg, 84% yield), a pale yellow solid compound. 1 H NMR (400 MHz, CDCl3)δ= 8.37 (d, J = 6.8 Hz, 1H),8.06 (d, J = 6.8 Hz, 1H), 7.73 (t, J = 6.0 Hz, 1H), 7.57 (t, J = 6.0 Hz, 1H),7.49 (s, 1H), 2.81 (s, 3H), 2.74 (s, 3H).

[0092] (3) Synthesis of intermediate M8: In a 125 mL round-bottom flask, intermediate M7 (185 mg, 1.0 mmol) was dissolved in carbon tetrachloride (10 mL), followed by the sequential addition of N-bromosuccinimide (214 mg, 1.2 mmol) and azobisisobutyronitrile (16.4 mg, 0.1 mmol). The reaction mixture was refluxed overnight under an argon atmosphere, and the reaction progress was monitored by TLC. After the reaction was completed, the crude product was obtained by vacuum distillation, and purified by silica gel column chromatography to give intermediate M8 (134 mg, yield 51%) as a white solid compound. 1 H NMR (400 MHz, CDCl3)δ= 8.42 (dd, J = 8.8, 0.8 Hz, 1H), 8.12 (dd, J = 8.8,0.8 Hz, 1H), 7.79 (s, 1H), 7.78 (dt, J = 6.8, 1.2 Hz, 1H), 7.64 (dt, J = 6.8,1.2 Hz, 1H), 4.75 (s, 2H), 2.77 (s, 3H).

[0093] (4) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A6: In a 50 mL round-bottom flask, intermediates M8 (134 mg, 0.51 mmol) and M3 (154 mg, 0.51 mmol) were dissolved in anhydrous DMF (8 mL), and cesium carbonate (326 mg, 1.02 mmol) was added. The reaction mixture was stirred and heated to 80 °C overnight, and the reaction progress was monitored by TLC. After the reaction was completed, cesium carbonate was removed by filtration, and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a pale yellow solid compound A7 (162 mg, yield 65%). 1 H NMR (400 MHz, CDCl3)δ= 8.58 (dd, J = 4.8, 1.6 Hz, 2H), 8.43(d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H), 7.80 (dt, J =7.2, 1.6 Hz, 1H), 7.66 (dt, J = 7.2, 1.6 Hz, 1H), 7.26 (dd, J = 6.8, 2.0 Hz, 2H), 7.12 (dd, J = 4.8, 1.6 Hz, 2H), 7.08 (dd, J = 6.8, 2.0 Hz, 2H), 6.87 (s,1H), 5.43 (s, 2H), 2.76 (s, 3H).

[0094] Example 4 Synthesis and structural characterization of 3-trifluoromethyl-substituted pyrazole compounds A7-A12

[0095] The synthetic flow chart of 3-trifluoromethyl-substituted pyrazole compounds A7-A12 is shown below. Figure 5 As shown, specifically:

[0096] (1) Synthesis of intermediate M9: In a 125 mL round-bottom flask, 3-trifluoromethyl-substituted pyrazole compound A3 (322 mg, 0.64 mmol) was dissolved in tetrahydrofuran / water (20 mL / 5 mL), and lithium hydroxide (46 mg, 1.92 mmol) was added. The reaction mixture was stirred overnight at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, methanol was removed by vacuum distillation to obtain an aqueous solution of the crude product. The pH of the system was adjusted to 4-5 with 3M hydrochloric acid, and a solid precipitated. The solid was filtered under reduced pressure, the filter cake was washed with water, and dried in air to obtain a yellow solid intermediate M9 (246 mg, yield 79%).

[0097] (2) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A7: In a 125 mL round-bottom flask, intermediate M9 (490 mg, 1.0 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL), followed by the sequential addition of ammonium chloride (267 mg, 5.0 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (456 mg, 1.2 mmol), and diisopropylethylamine (258 mg, 2.0 mmol). The reaction mixture was stirred overnight at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and saturated brine (30 mL) was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give a pale yellow solid compound A7 (408 mg, yield 83%). 1 H NMR (400MHz, CDCl3)δ= 8.57 (dd, J = 4.8, 1.6 Hz, 2H), 8.31 (d, J = 8.4 Hz, 1H), 8.12(d, J = 8.4 Hz, 1H), 7.80 (dt, J = 8.4, 1.2 Hz, 1H), 7.77 (s, 1H), 7.65 (t,J = 7.2 Hz, 1H), 7.24 (dd, J = 6.8, 2.0 Hz, 2H), 7.11 (dd, J = 4.8, 1.6 Hz,2H), 7.05 (dd, J = 6.8, 2.0 Hz, 2H), 6.87 (s, 1H), 6.20 (brs, 2H), 5.40 (s, 2H).

[0098] (3) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A8: Using intermediate M9 (100 mg, 0.20 mmol) and N,N-dimethylethylenediamine (22 mg, 0.24 mmol) as raw materials, the synthesis method of A7 in step (2) was followed to obtain a pale yellow solid compound A8 (78 mg, yield 68%). 1 H NMR (400 MHz, DMSO-d6)δ= 8.76 (d, J= 5.6 Hz, 1H), 8.57 (d, J = 6.0 Hz, 2H), 8.18 (d, J = 8.0 Hz, 1H), 8.07 (d, J= 8.4 Hz, 1H ), 7.84 (t, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.67 (s,1H), 7.41 (s, 1H), 7.38 (d, J = 9.2 Hz, 2H), 7.26 (d, J = 6.0 Hz, 2H), 7.21(d, J = 8.8 Hz, 2H), 5.45 (s, 2H), 3.51-3.41 (m, 2H), 2.48 (d, J = 6.4 Hz, 2H), 2.22 (s, 6H).

[0099] (4) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A9: Using intermediate M9 (100 mg, 0.20 mmol) and N,N-diethylethylenediamine (28.4 mg, 0.24 mmol) as starting materials, the synthesis was carried out according to the method of step (2) A7, yielding a pale yellow solid compound A9 (52.4 mg, yield 44%). 1H NMR (400 MHz, DMSO-d6)δ= 8.72(t, J = 4.0 Hz, 1H), 8.57 (d, J = 4.8 Hz, 2H), 8.22 (d, J = 6.8 Hz, 1H), 8.07(d, J = 6.4 Hz, 1H), 7.83 (t, J = 5.6 Hz, 1H), 7.68 (s, 1H), 7.67 (t, J =5.6 Hz, 1H), 7.41 (s, 1H), 7.38 (d, J = 7.2 Hz, 2H), 7.26 (d, J = 4.8 Hz,2H), 7.20 (d, J = 6.8 Hz, 2H), 5.45 (s, 2H), 3.48-3.39 (m, 2H), 2.71-2.62 (m,2H), 2.52-2.60 (m, 4H), 0.99 (t, J = 5.6 Hz, 6H).

[0100] (5) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A10: Using intermediate M9 (100 mg, 0.20 mmol) and ethanolamine (15 mg, 0.24 mmol) as raw materials, the synthesis was carried out according to the method of step (2) A7, yielding a pale yellow solid compound A10 (44 mg, yield 40%). 1 H NMR (400 MHz, DMSO-d6)δ= 8.81 (t, J = 5.2Hz, 1H), 8.57 (d, J = 5.2 Hz, 2H), 8.16 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4Hz, 1H ), 7.83 (t, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.42 (s, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 5.2 Hz, 2H), 7.21 (d, J= 8.4 Hz, 2H), 5.44 (s, 2H), 4.81 (t, J = 5.6 Hz, 1H), 3.65-3.55 (m, 2H), 3.48-3.38 (m, 2H).

[0101] (6) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A11: Using intermediate M9 (100 mg, 0.20 mmol) and (R)-(-)-1-amino-2-propanol (18.4 mg, 0.24 mmol) as starting materials, the experiment was carried out according to the synthesis method of step (2) A7, yielding a pale yellow solid compound A11 (52 mg, yield 47%). 1 H NMR (400 MHz, CDCl3)δ= 8.57(dd, J = 4.4, 1.6 Hz, 2H), 8.22 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz,1H), 7.78 (dt, J = 6.8, 1.2 Hz, 1H), 7.66 (s, 1H), 7.62 (dt, J = 6.8, 1.2 Hz,1H), 7.65 (s, 1H), 7.23 (dd, J = 6.8, 2.0 Hz, 2H), 7.10 (dd, J = 4.4, 1.2 Hz,2H), 7.05 (d, J = 6.8, 2.0 Hz, 2H), 6.87 (s, 1H), 6.34 (d, J = 7.6 Hz, 1H), 5.40 (s, 2H), 3.88-3.83 (m, 1H), 3.72-3.65 (m, 1H), 1.35 (d, J = 6.8 Hz, 3H).

[0102] (7) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A12: Using intermediate M9 (100 mg, 0.20 mmol) and N,N-diethyl-3-azacyclobutane (26 mg, 0.24 mmol) as starting materials, the synthesis was carried out according to the method of step (2) A7, yielding a pale yellow solid compound A12 (104 mg, yield 85%). 1H NMR (400 MHz, DMSO-d6)δ=8.57 (dd, J = 4.4, 1.6 Hz, 2H), 8.09 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.0Hz, 1H), 7.86 (dt, J = 7.2, 1.2 Hz, 1H), 7.71 (dt, J = 7.2, 1.2 Hz, 1H), 7.68 (s, 1H), 7.41 (s, 1H), 7.36 (dd, J = 6.8, 2.0 Hz, 2H), 7.25 (dd, J =4.4, 1.6 Hz, 2H), 7.20 (dd, J = 7.2, 2.0 Hz, 2H), 5.48 (s, 2H), 4.28-4.17 (m,1H), 4.03-3.91 (m, 1H), 3.85-3.75 (m, 1H), 3.71-3.61 (m, 1H), 3.61-3.51 (m,1H), 2.49-2.38 (m, 4H), 0.87 (t, J = 6.8 Hz, 6H).

[0103] Example 5 Synthesis and structural characterization of 3-trifluoromethyl-substituted pyrazole compound A13

[0104] The synthetic flowchart of the 3-trifluoromethyl-substituted pyrazole compound A13 is shown below. Figure 6 As shown, specifically:

[0105] Synthesis of 3-trifluoromethyl-substituted pyrazole compound A13: In a 50 mL round-bottom flask, 3-trifluoromethyl-substituted pyrazole compound A7 (102 mg, 0.21 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and Lawson's reagent (84.2 mg, 0.21 mmol) was added. The reaction mixture was stirred overnight at 90 °C, and the reaction progress was monitored by TLC. After the reaction was completed, saturated sodium bicarbonate aqueous solution (10 mL) was added to adjust the pH to 9-10, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give a yellow solid compound A13 (72.8 mg, yield 69%). 1H NMR(400 MHz, CDCl3)δ= 10.53 (brs, 1H), 10.06 (brs, 1H), 8.58 (dd, J = 4.8, 1.6Hz, 2H), 8.06 (t, J = 8.4 Hz, 2H), 7.82 (t, J = 7.2 Hz, 1H), 7.68 (t, J = 7.2Hz, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.27 (dd, J =4.4, 1.6 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 5.43 (s, 2H).

[0106] Example 6 Synthesis and structural characterization of 3-trifluoromethyl-substituted pyrazole compounds A14-A15

[0107] The synthetic flow chart of 3-trifluoromethyl-substituted pyrazole compounds A14-A15 is shown below. Figure 7 As shown, specifically:

[0108] (1) Synthesis of intermediate M10: In a 125 mL round-bottom flask at 0 °C, 1.65 g (10 mmol) of 6-fluoroindoline-2,3-dione was dissolved in 20 mL of an aqueous solution of potassium hydroxide (2.80 g, 50.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The temperature of the reaction system was lowered to 0 °C, and 6 mL of acetone was added dropwise. After the addition was complete, the temperature was raised to 70 °C and the reaction was allowed to proceed overnight. After the reaction was completed, the acetone was removed by vacuum distillation. The pH was adjusted to 3-4 with dilute hydrochloric acid, and a large amount of solid precipitated. The solid was filtered under reduced pressure, and the filter cake was washed with water and dried to obtain a grayish-white solid intermediate M10 (1.45 g, yield 71%). 1 H NMR(400 MHz, DMSO-d6)δ= 13.97 (brs, 1H), 8.73 (dd, J = 9.2, 6.4 Hz, 1H), 7.84(s, 1H), 7.76 (d, J = 10.4, 2.8 Hz, 1H), 7.58 (dt, J = 8.8, 22.8 Hz, 1H), 2.72 (s, 3H).

[0109] (2) Synthesis of intermediate M11: In a 50 mL round-bottom flask, intermediate M10 (379 mg, 1.85 mmol) was dissolved in anhydrous methanol (10 mL), and thionyl chloride (1 mL) was slowly added dropwise. The reaction mixture was refluxed overnight, and the reaction progress was monitored by TLC. After the reaction was completed, the crude product was obtained by vacuum distillation. The pH was adjusted to 9-10 with saturated sodium bicarbonate solution, and the product was extracted with ethyl acetate. The organic phase was concentrated by vacuum distillation and purified by silica gel column chromatography to obtain a white solid intermediate M11 (326 mg, 80% yield). 1 H NMR (400 MHz, CDCl3)δ= 8.75 (dd, J = 9.2, 6.0 Hz, 1H), 7.79 (s,1H), 7.73(dd, J = 10.0, 2.8 Hz, 1H), 7.58 (dt, J = 8.8, 2.8 Hz, 1H), 4.04 (s, 3H), 2.80 (s, 3H).

[0110] (3) Synthesis of intermediate M12: In a 50 mL round-bottom flask, intermediate M11 (326 mg, 1.50 mmol) was dissolved in carbon tetrachloride (10 mL), followed by the addition of N-bromosuccinimide (318 mg, 1.80 mmol) and azobisisobutyronitrile (24.6 mg, 0.15 mmol). The reaction mixture was refluxed overnight under an argon atmosphere, and the reaction progress was monitored by TLC. After the reaction was completed, the crude product was obtained by vacuum distillation, and purified by silica gel column chromatography to give a white solid intermediate M12 (200 mg, yield 45%). 1 H NMR (400 MHz, CDCl3)δ= 8.82 (dd, J = 9.6, 6.0 Hz, 1H), 8.06 (s,1H), 7.73 (dd, J = 9.6, 2.8 Hz, 1H), 7.58 (dt, J = 8.0, 2.8 Hz, 1H), 4.72 (s,2H), 4.06 (s,3H).

[0111] (4) Synthesis of intermediate M13: In a 50 mL round-bottom flask, intermediates M12 (192 mg, 0.64 mmol) and M3 (197 mg, 0.64 mmol) were dissolved in anhydrous DMF (10 mL), and cesium carbonate (417 mg, 1.28 mmol) was added. The reaction mixture was stirred and heated to 80 °C for 4 hours, and the reaction progress was monitored by TLC. After the reaction was completed, cesium carbonate was removed by filtration, and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a pale yellow solid intermediate M13 (146 mg, yield 43%). 1 H NMR (400 MHz, CDCl3)δ= 8.83 (dd, J = 7.6, 4.8 Hz, 1H), 8.58 (d, J =4.8 Hz, 2H), 8.12 (s, 1H), 7.76 (dd, J = 7.6, 2.0 Hz, 1H), 7.46 (dt, J =7.6, 2.0 Hz, 1H), 7.26 (d, J = 7.2 Hz, 2H), 7.12 (dd, J = 4.0, 1.2 Hz, 2H), 7.07 (d, J = 7.2 Hz, 2H), 6.87 (s, 1H), 5.40 (s, 2H), 4.06 (s, 3H).

[0112] (5) Synthesis of intermediate M14: In a 50 mL round-bottom flask, intermediate M13 (146 mg, 0.28 mmol) was dissolved in tetrahydrofuran / water (8 mL / 2 mL), and lithium hydroxide (20 mg, 0.84 mmol) was added. The reaction mixture was stirred overnight at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, methanol was removed by vacuum distillation to obtain an aqueous solution of the crude product. The pH of the system was adjusted to 4-5 with 3M hydrochloric acid, and a solid precipitated. The solid was filtered under reduced pressure, the filter cake was washed with water, and dried in air to obtain crude intermediate M14 (136 mg, yield 96%), which was directly used in the next step of the reaction.

[0113] (6) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A14: Using intermediate M14 (80 mg, 0.16 mmol) and methylamine hydrochloride (13 mg, 0.19 mmol) as starting materials, the synthesis method of step (2) A7 in Example 4 was followed to obtain a pale yellow solid compound A14 (68 mg, yield 83%). 1H NMR (400 MHz, DMSO-d6)δ= 8.82 (d,J = 4.4 Hz, 1H), 8.56 (d, J = 5.6 Hz, 2H), 8.25 (dd, J = 8.4, 6.4 Hz, 1H), 7.83 (dd, J = 10.0, 2.4 Hz, 1H), 7.71 (s, 1H), 7.62 (dt, J = 8.8, 2.8 Hz,1H), 7.42 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 6.0 Hz, 2H), 7.21(d, J = 8.8 Hz, 2H), 5.45 (s, 2H), 2.87 (d, J = 4.8 Hz, 3H).

[0114] (7) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A15: Using intermediate M14 (80 mg, 0.16 mmol) and N,N-diethylethylenediamine (22 mg, 0.19 mmol) as starting materials, the synthesis method of A7 in step (2) of Example 4 was followed to obtain a pale yellow solid compound A15 (75 mg, yield 79%). 1 H NMR (400 MHz, DMSO-d6)δ=8.57 (dd, J = 4.4, 1.6 Hz, 2H), 8.09 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0Hz, 1H ), 7.85 (dt, J = 7.2, 1.6 Hz, 1H), 7.70 (dt, J = 8.4, 1.2 Hz, 1H), 7.68 (s, 1H), 7.41 (s, 1H), 7.36 (dd, J = 6.8, 2.0 Hz, 2H), 7.25 (d, J = 6.8, 2.0 Hz, 2H), 7.20 (dd, J = 7.2, 2.0 Hz, 2H), 5.48 (s, 2H), 4.23 (dd, J = 9.6,8.0 Hz, 1H), 3.96 (dd, J = 8.8, 6.0 Hz, 1H), 3.80 (t, J = 8.0 Hz, 1H), 3.67(t, J = 8.0 Hz, 1H), 3.62-3.52 (m, 1H), 2.43 (q, J = 6.4 Hz, 4H), 0.87 (d, J = 6.8 Hz, 6H).

[0115] Example 7 Synthesis and structural characterization of 3-trifluoromethyl-substituted pyrazole compound A16

[0116] The synthetic flowchart of the 3-trifluoromethyl-substituted pyrazole compound A16 is shown below. Figure 8 As shown, specifically:

[0117] (1) Synthesis of intermediate M15: Intermediate M1 (10.0 mmol) was dissolved in anhydrous ethanol (40 mL), and 5-hydrazino-2-methoxypyridine hydrochloride (3.51 g, 20.0 mmol) was added. The mixture was heated and stirred overnight at 80 °C, and the reaction progress was monitored by TLC. After the reaction was completed, the solvent ethanol was removed by vacuum distillation, and the crude product was purified by silica gel column chromatography to obtain a yellow oily intermediate M15 (1.09 g, yield 34%). 1 H NMR (400 MHz, CDCl3)δ= 8.63 (d, J = 4.4 Hz,2H), 7.74 (dd, J = 3.6, 1.2 Hz, 1H) 7.58 (dd, J = 7.2, 2.4 Hz, 1H), 7.14 (dd,J = 6.0, 1.2 Hz, 2H), 6.89 (s, 1H), 6.81 (d, J = 7.2 Hz, 1H), 3.97 (s, 3H).

[0118] (2) Synthesis of intermediate M16: In a 125 mL round-bottom flask, intermediate M15 (1.09 g, 3.40 mmol) was dissolved in ethanol (20 mL), and concentrated hydrochloric acid (2 mL) was added. The reaction mixture was stirred and refluxed overnight, and the reaction progress was monitored by TLC. After the reaction was completed, the crude product was obtained by vacuum distillation, and purified by silica gel column chromatography to give a yellow solid intermediate M16 (865 mg, yield 83%). 1 H NMR (400 MHz, DMSO-d6)δ= 11.96 (brs, 1H), 8.65 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 2.8 Hz, 1H) 7.52 (dd, J = 9.6, 2.8 Hz, 1H), 7.41 (s, 1H), 7.40 (d, J = 6.0 Hz, 2H), 6.41 (d, J = 9.6 Hz, 1H), 2.47 (s, 3H).

[0119] (3) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A16: In a 125 mL round-bottom flask, intermediate M16 (80 mg, 0.26 mmol) and (2-bromomethyl)-N-methylquinoline-4-carboxamide (73 mg, 0.26 mmol) were dissolved in anhydrous DMF (8 mL), and cesium carbonate (254 mg, 0.78 mmol) was added. The reaction mixture was stirred and heated to 80 °C overnight, and the reaction progress was monitored by TLC. After the reaction was completed, cesium carbonate was removed by filtration, and the filtrate was distilled under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to give a pale yellow solid compound A16 (86 mg, yield 65%). 1 H NMR (400 MHz, DMSO-d6)δ= 8.76 (q, J =4.4, Hz, 1H), 8.64 (dd, J = 4.8, 1.6 Hz, 2H), 8.39 (d, J = 2.8Hz, 1H ), 8.10(d, J = 8.0 Hz, 1H), 7.87-7.76 (m, 2H), 7.67-7.57 (m, 2H), 7.51 (dd, J = 4.8,1.6 Hz, 2H), 7.48 (d, J = 3.2 Hz, 2H), 6.52 (d, J = 10.0 Hz, 1H), 5.42 (s,2H), 2.88 (d, J = 4.4 Hz, 3H).

[0120] Example 8 Synthesis and structural characterization of 3-trifluoromethyl-substituted pyrazole compound A17

[0121] The synthetic flowchart of the 3-trifluoromethyl-substituted pyrazole compound A17 is shown below. Figure 9 As shown, specifically:

[0122] (1) Synthesis of intermediate M17: Intermediate M1 (10 mmol) was dissolved in anhydrous ethanol (40 mL), and 3-fluoro-4-methoxyphenylhydrazine hydrochloride (3.13 g, 20.0 mmol) was added. The mixture was heated and stirred overnight at 80 °C, and the reaction progress was monitored by TLC. After the reaction was completed, the solvent ethanol was removed by vacuum distillation, and the crude product was purified by silica gel column chromatography to obtain a yellow oily compound M17 (1.08 g, yield 32%). 1 H NMR (400 MHz, DMSO-d6)δ= 8.61 (d, J = 4.4 Hz, 2H), 7.19-7.09 (m, 3H), 7.03-6.90 (m, 2H), 6.86 (s, 1H), 3.93 (s, 3H).

[0123] (2) Synthesis of intermediate M18: In a 125 mL round-bottom flask, intermediate M17 (184 mg, 0.55 mmol) was dissolved in anhydrous dichloromethane (6 mL). Boron tribromide (273 mg, 1.10 mmol) was slowly added dropwise at 0 °C (ice-water bath). After the addition was complete, the mixture was stirred at 0 °C for 0.5 h, then slowly raised to room temperature for 24 h. The reaction progress was monitored by TLC. After the reaction was completed, methanol was slowly added dropwise at 0 °C to quench the reaction. The mixture was then concentrated by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain a yellow solid intermediate M18 (152 mg, yield 86%). 1 H NMR (400 MHz, DMSO-d6)δ=10.51 (brs, 1H), 8.60 (d, J = 4.8 Hz, 2H), 7.41 (s, 1H), 7.37 (d, J = 11.2Hz, 1H), 7.28 (d, J = 4.8 Hz, 2H), 7.07-6.98 (m, 2H), 6.86 (s, 1H).

[0124] (3) Synthesis of 3-trifluoromethyl-substituted pyrazole compound A17: Using intermediate M18 (88 mg, 0.27 mmol) and (2-bromomethyl)-N-methylquinoline-4-carboxamide (91 mg, 0.33 mmol) as starting materials, the synthesis method of A16 in step (3) of Example 7 was followed to obtain a pale yellow solid compound A17 (96 mg, yield 68%). 1 H NMR (400 MHz, DMSO-d6)δ= 8.78 (q, J = 3.6, Hz, 1H), 8.59 (d, J = 4.8 Hz, 2H), 8.14 (d, J =6.8 Hz, 1H), 8.07 (d, J = 6.4 Hz, 1H), 7.84 (t, J = 6.0 Hz, 1H), 7.669 (s,1H), 7.68 (t, J = 6.0 Hz, 2H), 7.55 (dd, J = 9.2, 2.0 Hz, 1H), 7.44 (s, 1H),7.41 (t, J = 7.2 Hz, 1H), 7.29 (d, J = 4.8 Hz, 2H), 7.21 (d, J = 6.8 Hz, 1H), 5.53 (s, 2H), 2.88 (d, J = 3.6 Hz, 3H).

[0125] Example 9 Synthesis and structural characterization of 3-trifluoromethyl-substituted pyrazole compounds B1-B9

[0126] The synthetic flow chart of 3-trifluoromethyl-substituted pyrazole compounds B1-B8 is shown below. Figure 10 As shown, the synthetic flowchart of the 3-trifluoromethyl-substituted pyrazole compound B5 is as follows: Figure 11 As shown, the synthetic flowchart of the 3-trifluoromethyl-substituted pyrazole compound B6 is as follows: Figure 12 As shown, the synthetic flowchart of the 3-trifluoromethyl-substituted pyrazole compound B7 is as follows: Figure 13 As shown, the synthetic flowchart of the 3-trifluoromethyl-substituted pyrazole compound B8 is as follows: Figure 14 As shown, the synthetic flowchart of the 3-trifluoromethyl-substituted pyrazole compound B9 is also shown below. Figure 15 As shown; specifically:

[0127] (1) Synthesis of intermediate M19: In a 125 mL round-bottom flask, 4-methoxyacetophenone (600 mg, 4.0 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium ethoxide (544 mg, 8.0 mmol) was carefully added. The mixture was heated and stirred at 65 °C for 0.5 h. Ethyl trifluoroacetate (1.14 g, 20.0 mmol) was slowly added dropwise to the reaction mixture using a constant pressure dropping funnel. After the addition was complete, the mixture was refluxed overnight, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated by vacuum distillation, and the pH was adjusted to 4-5 by adding saturated citric acid aqueous solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain a yellow oily crude product. The crude product was dissolved in anhydrous ethanol (20 mL), and 4-benzyloxyphenylhydrazine hydrochloride (2.0 g, 8.0 mmol) was added. The mixture was heated and stirred overnight at 80 °C, and the reaction progress was monitored by TLC. After the reaction was complete, the solvent ethanol was removed by vacuum distillation, and the crude product was purified by silica gel column chromatography to give a yellow solid intermediate M19 (794 mg, yield 47%). M19... 1 H NMR (400 MHz, CDCl3)δ= 7.46-7.31 (m, 5H), 7.22 (d, J = 9.2 Hz,2H), 7.14 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.4 Hz,2H), 6.66 (s, 1H), 5.06 (s, 2H), 3.80 (s, 3H).

[0128] (2) Synthesis of intermediate M20: In a 50 mL round-bottom flask, intermediate M19 (794 mg, 1.87 mmol) was dissolved in anhydrous methanol (10 mL), and Pd / C (159 mg, 20% wt) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere, and the reaction progress was monitored by TLC. After the reaction was completed, Pd / C was removed by filtration, and the filtrate was distilled under reduced pressure to give a white solid intermediate M20 (512 mg, yield 82%). The synthesis of M20... 1 H NMR (400 MHz, DMSO-d6)δ= 7.20 (d, J = 8.8 Hz, 2H), 7.13 (dd, J =8.8 Hz, 2H), 7.04 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 3.75 (s, 3H).

[0129] (3) Synthesis of 3-trifluoromethyl-substituted pyrazole compound B1: Using intermediate M20 (100 mg, 0.30 mmol) and (2-bromomethyl)-N-methylquinoline-4-carboxamide (83 mg, 0.30 mmol) as starting materials, the synthesis was carried out according to the method described in step (3) A16 of Example 7, yielding a pale yellow solid compound B1 (132 mg, yield 83%). 1 H NMR (400 MHz, DMSO-d6)δ= 8.79 (brs, 1H), 8.14 (d, J = 6.8 Hz, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.84 (t, J = 6.0 Hz, 1H), 7.70 (s, 1H), 7.68 (t, J = 6.0 Hz, 1H), 7.32(d, J = 6.8 Hz, 2H), 7.21 (d, J = 6.8 Hz, 2H), 7.18 (d, J = 7.2 Hz, 2H), 7.08(s, 1H), 6.93(d, J = 6.4 Hz, 2H), 5.43 (s, 2H), 3.75 (s, 3H), 2.88 (d, J = 3.6 Hz, 3H).

[0130] (4) Synthesis of intermediate M21: In a 125 mL round-bottom flask, 4-methoxyacetophenone (1.38 g, 10.0 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium ethoxide (1.36 g, 20.0 mmol) was carefully added. The mixture was heated and stirred at 65 °C for 0.5 h. Ethyl trifluoroacetate (2.84 g, 20.0 mmol) was slowly added dropwise to the reaction mixture using a constant pressure dropping funnel. After the addition was complete, the mixture was refluxed overnight, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated by vacuum distillation, and the pH was adjusted to 4-5 by adding saturated citric acid aqueous solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain a yellow oily crude product. The crude product was dissolved in anhydrous ethanol (20 mL), and 4-methoxyphenylhydrazine hydrochloride (3.48 g, 20.0 mmol) was added. The mixture was heated and stirred overnight at 80 °C, and the reaction progress was monitored by TLC. After the reaction was complete, the solvent ethanol was removed by vacuum distillation, and the crude product was purified by silica gel column chromatography to give a pale yellow solid intermediate M21 (842 mg, yield 25%). M21... 1 H NMR (400 MHz, CDCl3)δ= 7.25-7.16 (m, 4H), 7.02 (t, J = 6.8 Hz, 2H), 6.87 (d, J = 6.8 Hz, 2H), 6.71 (s, 1H), 3.82 (s, 3H).

[0131] (5) Synthesis of intermediate M22: In a 125 mL round-bottom flask, intermediate M21 (842 mg, 2.50 mmol) was dissolved in anhydrous dichloromethane (10 mL). Boron tribromide (1.25 g, 5.0 mmol) was slowly added dropwise at 0 °C (ice-water bath). After the addition was complete, the mixture was stirred at 0 °C for 0.5 h, then slowly raised to room temperature for 24 h. The reaction progress was monitored by TLC. After the reaction was completed, methanol was slowly added dropwise at 0 °C to quench the reaction. The mixture was then concentrated by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain a yellow solid intermediate M22 (676 mg, yield 84%). 1 H NMR (400 MHz, CDCl3)δ= 7.22-7.17 (m, 2H), 7.13 (dd, J = 6.8, 2.0 Hz, 2H), 7.06-6.98 (m, 2H), 6.78 (d, J =6.8, 2.0 Hz, 2H), 6.72 (s, 1H), 5.73 (brs, 1H).

[0132] (6) Synthesis of 3-trifluoromethyl-substituted pyrazole compound B2: Using intermediate M22 (100 mg, 0.31 mmol) and (2-bromomethyl)-N-methylquinoline-4-carboxamide (86.6 mg, 0.31 mmol) as starting materials, the synthesis method of step (3) A16 in Example 7 was followed to obtain a pale yellow solid intermediate B2 (78 mg, yield 48%). 1 H NMR(400 MHz, DMSO-d6)δ= 8.76 (brs, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.07 (d, J =8.4 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.69 (s, 1H), 7.67 (t, J = 7.2 Hz,1H), 7.40-7.28 (m, 4H), 7.23 (t, J = 8.8 Hz, 2H), 7.20-7.10 (m, 3H), 5.43 (s,2H), 2.88 (d, J = 4.4 Hz, 3H).

[0133] (7) Synthesis of intermediate M23: 3-Acetylpyridine (1.21 g, 10.0 mmol) was used instead of 4-methoxyacetophenone (1.38 g, 10.0 mmol) in step (4) to obtain a yellow oily intermediate M23 (1.21 g, 38% yield). M23... 1 H NMR (400 MHz, DMSO-d6)δ= 8.56 (d, J = 14.4 Hz, 2H), 7.48 (s,1H), 7.30-7.17 (m, 3H), 6.95-6.85 (m, 2H), 6.82 (s, 1H), 3.82 (s, 3H).

[0134] (8) Synthesis of intermediate M24: Intermediate M23 (1.21 g, 3.78 mmol) and boron tribromide (1.90 g, 7.56 mmol) were used to replace intermediate M21 (842 mg, 2.50 mmol) and boron tribromide (1.25 g, 5.0 mmol) in step (5), respectively, to obtain yellow solid compound intermediate M24 (1.02 g, yield 88%). 1H NMR (400 MHz, DMSO-d6)δ= 8.78-8.83 (m, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.82 (dd, J = 8.0,5.6 Hz, 1H), 7.45 (s, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H).

[0135] (9) Synthesis of 3-trifluoromethyl-substituted pyrazole compound B3: Using intermediate M24 (65 mg, 0.21 mmol) and (2-bromomethyl)-N-methylquinoline-4-carboxamide (65 mg, 0.23 mmol) as starting materials, the synthesis was carried out according to the method of step (3) A16 in Example 7, yielding a pale yellow solid compound B3 (75 mg, yield 70%). 1 H NMR (400 MHz, DMSO-d6)δ= 8.79 (brs, 1H), 8.56 (d, J = 7.2 Hz, 2H), 8.14 (d, J = 6.8 Hz, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.84 (t, J = 6.0 Hz, 1H), 7.71 (s, 1H), 7.70-7.62 (m, 2H), 7.40 (t, J = 6.0 Hz, 1H), 7.37 (d, J = 6.8 Hz, 2H), 7.34 (s,1H), 7.19 (d, J = 6.8 Hz, 2H), 5.43 (s, 2H), 2.88 (d, J = 3.2 Hz, 3H).

[0136] (10) Synthesis of intermediate M25: 2-acetylpyridine (605 mg, 5.0 mmol), sodium ethoxide (510 mg, 10.0 mmol), and 4-methoxyphenylhydrazine hydrochloride (1.74 g, 10.0 mmol) were used in place of 4-methoxyacetophenone (1.38 g, 10.0 mmol), sodium ethoxide (1.36 g, 20.0 mmol), and 4-methoxyphenylhydrazine hydrochloride (3.48 g, 20.0 mmol) in step (4), respectively, to obtain a yellow oily intermediate M25 (1.42 g, 2-step yield 89%). M25... 1H NMR (400MHz, DMSO-d6)δ= 8.65 (d, J = 4.8 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.75 (dt,J = 8.0, 1.6 Hz, 1H), 7.46 (d, J = 6.8 Hz, 2H), 7.45 (s, 1H), 7.27 (t, J =7.2 Hz, 1H), 7.00 (dd, J = 6.8, 2.0 Hz, 2H), 3.88 (s, 3H).

[0137] (11) Synthesis of intermediate M26: Intermediate M25 (1.42 g, 4.45 mmol) and boron tribromide (2.23 g, 8.89 mmol) were used to replace intermediate M21 (842 mg, 2.50 mmol) and boron tribromide (1.25 g, 5.0 mmol) in step (5), respectively, to obtain yellow solid compound intermediate M26 (978 mg, yield 72%). 1 H NMR (400MHz, DMSO- d 6 ) δ = 10.08 (brs, 1H), 8.66 (d, J = 4.4 Hz, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.94 (dt, J = 8.0, 1.6 Hz, 1H), 7.57 (s, 1H), 7.94 (dt, J = 6.0, 0.8 Hz, 1H), 7.39 (d, J = 8.8, Hz, 2H), 6.93 (d, J = 6.8, Hz, 2H), 6.72 (s, 1H), 5.73(brs, 1H).

[0138] (12) Synthesis of 3-trifluoromethyl-substituted pyrazole compound B4: Using intermediate M26 (100 mg, 0.33 mmol) and (2-bromomethyl)-N-methylquinoline-4-carboxamide (91 mg, 0.33 mmol) as starting materials, the synthesis method of A16 in step (3) of Example 7 was performed, yielding a pale yellow solid compound B4 (57 mg, yield 47%). 1H NMR (400MHz, DMSO-d6)δ= 8.77 (q, J = 4.4 Hz, 1H), 8.66 (d, J = 4.8 Hz, 1H), 8.15 (d,J = 8.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.89 (t,J = 8.0 Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.68 (t, J = 8.0 Hz,1H), 7.57 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 6.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 5.49 (s, 2H), 2.88 (d, J = 4.4 Hz, 3H).

[0139] (13) Synthesis of intermediate M27: In a 125 mL round-bottom flask, 4-pyridazinic acid (1.0 g, 8.06 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL). N-methoxy-N-methylamine hydrochloride (1.57 g, 16.12 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.68 g, 9.67 mmol), and diisopropylethylamine (4.17 g, 32.24 mmol) were added sequentially. The reaction mixture was stirred overnight at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the crude product was obtained by vacuum distillation and purified by silica gel column chromatography to give intermediate M27 (890 mg, 66% yield) as a white solid and a pale yellow solid. 1 H NMR (400 MHz, CDCl3)δ= 9.45 (s, 1H), 9.34 (dd, J =5.2, 1.2 Hz, 1H), 7.75 (dd, J = 5.2, 1.2 Hz, 1H), 3.58 (s, 3H), 3.42 (s, 3H).

[0140] (14) Synthesis of intermediate M28: In a 125 mL round-bottom flask, intermediate M27 (890 mg, 5.32 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and the solution was heated to 0°C. oMethylmagnesium bromide (2.66 mL, 2 M in THF) was slowly added dropwise under C conditions. The reaction mixture was allowed to naturally warm to room temperature and reacted overnight, with TLC monitoring the reaction progress. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was then distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to give a yellow oily intermediate, M28 (190 mg, 29% yield). M28... 1 H NMR (400 MHz, CDCl3)δ= 9.61 (dd, J = 2.4, 1.2 Hz, 1H), 9.48 (dd, J = 5.2, 1.2 Hz, 1H), 7.87 (dd, J = 5.2, 2.4 Hz, 1H), 2.70(s, 3H).

[0141] (15) Synthesis of intermediate M29: Intermediate M28 (250 mg, 2.05 mmol), sodium ethoxide (279 mg, 4.10 mmol), ethyl trifluoroacetate (582 mg, 4.10 mmol), and 4-methoxyphenylhydrazine hydrochloride (716 mg, 4.10 mmol) were used to replace 4-methoxyacetophenone (1.38 g, 10.0 mmol), sodium ethoxide (1.36 g, 20.0 mmol), ethyl trifluoroacetate (2.84 g, 20.0 mmol), and 4-methoxyphenylhydrazine hydrochloride (3.48 g, 20.0 mmol) in step (4), respectively, to obtain yellow solid intermediate M29 (292 mg, 2-step yield 44%). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.16(dd, J = 5.6, 1.2 Hz, 1H), 9.08 (dd, J = 2.4, 1.2 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.23 (s, 1H), 7.01 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H).

[0142] (16) Synthesis of intermediate M30: Intermediate M29 (292 mg, 0.91 mmol) and boron tribromide (457 mg, 1.82 mmol) were used to replace intermediate M21 (842 mg, 2.50 mmol) and boron tribromide (1.25 g, 5.0 mmol) in step (5), respectively, to obtain a pale yellow solid compound intermediate M30 (232 mg, yield 83%). 1 H NMR (400MHz, DMSO- d 6 ) δ = 10.10 (brs, 1H), 9.25 (dd, J = 5.6, 1.2 Hz, 1H), 9.17 (dd, J =2.4, 1.2 Hz, 1H), 7.60 (s, 1H), 7.44 (dd, J = 5.2, 2.4 Hz, 1H), 7.26 (dd, J =6.8, 2.0 Hz, 2H), 6.86 (dd, J = 6.8, 2.4 Hz, 2H).

[0143] (17) Synthesis of 3-trifluoromethyl-substituted pyrazole compound B5: Using intermediate M30 (100 mg, 0.33 mmol) and (2-bromomethyl)-N-methylquinoline-4-carboxamide (91 mg, 0.33 mmol) as starting materials, the synthesis was carried out according to the method described in step (3) A16 of Example 7, yielding a pale yellow solid compound B5 (97 mg, yield 59%). 1 H NMR (400MHz, DMSO- d 6 ) δ = 9.25 (d, J = 5.2 Hz, 1H), 9.21 (s, 1H), 8.78 (q, J = 4.4 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.73(s, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.62 (s, 1H), 7.46 (s, 1H), 7.44 (d,J = 8.8Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 5.47 (s, 2H), 2.89 (d, J = 4.8 Hz, 3H).

[0144] (18) Synthesis of intermediate M31: In a 15 mL sealed glass tube, 5-acetyl-2(1H)-pyridone (137 mg, 1.0 mmol) and iodomethane (284 mg, 2.0 mmol) were dissolved in anhydrous DMF (6 mL), and potassium carbonate (414 mg, 3.0 mmol) was added. The reaction mixture was sealed and heated with stirring for 40 °C. o The reaction was incubated overnight at C, and the reaction progress was monitored by TLC. After the reaction was complete, potassium carbonate was removed by filtration, and the filtrate was distilled under reduced pressure to obtain a crude product. This crude product was then purified by silica gel column chromatography to give a pale yellow solid intermediate, M31 (104 mg, 69% yield). M31... 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.15 (d, J = 2.0 Hz, 1H), 7.88 (dd, J =8.0, 2.0 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 3.63 (s, 3H), 2.46 (s, 3H).

[0145] (19) Synthesis of intermediate M32: M31 (151 mg, 1.0 mmol), sodium ethoxide (136 mg, 2.0 mmol), ethyl trifluoroacetate (282 mg, 2.0 mmol), and 4-methoxyphenylhydrazine hydrochloride (349 mg, 2.0 mmol) were used to replace 4-methoxyacetophenone (1.38 g, 10.0 mmol), sodium ethoxide (1.36 g, 20.0 mmol), ethyl trifluoroacetate (2.84 g, 20.0 mmol), and 4-methoxyphenylhydrazine hydrochloride (3.48 g, 20.0 mmol) in step (4), respectively, to obtain a yellow solid intermediate M32 (168 mg, 48% yield in two steps). M32... 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.33 (d, J =2.4 Hz, 1H), 7.28 (dd, J= 6.8, 2.0 Hz, 2H), 7.02 (dd, J = 9.6, 2.8 Hz, 1H), 6.93(dd, J = 6.8, 2.0, 2H), 6.64 (s, 1H), 6.47 (d, J = 9.6 Hz, 1H), 3.85 (s, 3H), 3.52 (s, 3H).

[0146] (20) Synthesis of intermediate M33: Intermediate M32 (168 mg, 0.48 mmol) and boron tribromide (241 g, 0.96 mmol) were used to replace intermediate M21 (842 mg, 2.50 mmol) and boron tribromide (1.25 g, 5.0 mmol) in step (5), respectively, to obtain a yellow solid compound intermediate M33 (102 mg, yield 63%). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.97 (brs, 1H), 7.99 (d, J = 2.8 Hz, 1H), 7.24 (dd, J = 6.8, 2.0 Hz,2H), 7.03 (s, 1H), 7.94 (dd, J = 8.8, 2.4 Hz, 1H), 6.84 (dd, J = 6.8, 2.0 Hz, 2H), 6.30 (d, J = 9.6 Hz, 1H), 3.42 (s, 3H).

[0147] (21) Synthesis of 3-trifluoromethyl-substituted pyrazole compound B6: Using intermediate M33 (102 mg, 0.30 mmol) and (2-bromomethyl)-N-methylquinoline-4-carboxamide (127 mg, 0.45 mmol) as starting materials, the synthesis method of A16 in step (3) of Example 7 was followed to obtain a pale yellow solid compound B6 (112 mg, yield 59%). 1 H NMR (400MHz, DMSO- d 6 ) δ = 8.12 (d, J = 6.4 Hz, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.72 (t,J =6.4 Hz, 1H), 7.61 (s, 1H), 7.54 (t, J = 6.8 Hz, 1H), 7.34 (s,1H), 7.21 (d, J =6.8 Hz, 2H), 7.00 (d, J = 6.8 Hz, 2H), 6.95 (d, J = 7.6 Hz, 1H), 6.87 (q, J = 3.2Hz, 1H), 6.23 (s, 1H), 6.35 (d, J = 7.6 Hz, 1H), 5.28 (s, 2H), 3.43 (s, 3H), 3.02 (d, J = 3.6 Hz, 3H).

[0148] (22) Synthesis of intermediate M34: 1-(3-fluoropyridin-4-yl)acetone (417 mg, 3.0 mmol), sodium ethoxide (408 mg, 6.0 mmol), ethyl trifluoroacetate (852 mg, 6.0 mmol), and 4-benzyloxyphenylhydrazine hydrochloride (1.50 mg, 6.0 mmol) were used in place of 4-methoxyacetophenone (600 mg, 4.0 mmol), sodium ethoxide (544 mg, 8.0 mmol), ethyl trifluoroacetate (1.14 g, 20.0 mmol), and 4-benzyloxyphenylhydrazine hydrochloride (2.0 g, 8.0 mmol) in step (1), respectively, to obtain a yellow solid intermediate M34 (391 mg, 2-step yield 32%). M34... 1 H NMR (400 MHz, CDCl3) δ = 8.52 (s, 1H), 8.37 (d, J = 5.2 Hz, 1H), 7.50-7.30 (m, 6H), 7.21 (d, J = 8.8Hz, 2H), 7.04 (t, J = 8.8, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.93 (s, 1H), 5.08 (s, 2H).

[0149] (23) Synthesis of intermediate M35: In a 125 mL round-bottom flask, intermediate M34 (391 mg, 0.95 mmol) was dissolved in anhydrous methanol (20 mL), and Pd / C (78 mg, 20% wt) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere, and the reaction progress was monitored by TLC. After the reaction was completed, Pd / C was removed by filtration, and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a white solid intermediate M35 (186 mg, yield 61%). M35... 1 H NMR (400 MHz, CD3OD) δ = 9.97 (brs, 1H), 8.66 (d, J = 1.6 Hz, 1H), 8.48 (d, J = 4.8 Hz, 1H), 7.39 (dd, J = 6.0, 1.2 Hz, 1H), 7.33 (s, 1H), 7.18 (dd, J = 6.8, 2.0 Hz, 2H) 6.79 (dd, J = 6.8, 2.0 Hz, 1H).

[0150] (24) Synthesis of 3-trifluoromethyl-substituted pyrazole compound B7: Using intermediate M35 (86 mg, 0.27 mmol) and (2-bromomethyl)-N-methylquinoline-4-carboxamide (74.3 mg, 0.27 mmol) as starting materials, the synthesis was carried out according to the method of step (3) A16 in Example 7, yielding a pale yellow solid compound B7 (87.4 mg, yield 63%). 1 H NMR (400MHz, DMSO- d 6 ) δ = 8.76 (q, J = 3.2 Hz, 1H), 8.66 (s, 1H), 8.49 (d, J = 4.0 Hz, 1H), 8.15 (d, J = 6.8 Hz, 1H), 8.07 (d, J = 6.8 Hz, 1H), 8.33 (t, J = 6.4 Hz, 1H), 7.70(s, 1H), 7.67 (t, J = 6.8 Hz, 1H), 7.44 (t, J = 4.0 Hz, 1H), 7.37 (s, 1H), 7.36(d, J= 7.2 Hz, 2H), 7.18 (d, J = 7.2 Hz, 2H), 5.42 (s, 2H), 2.88 (d, J = 4.0 Hz, 3H).

[0151] (25) Synthesis of intermediate M36: 1-(2-methylpyridin-4-yl)acetone (1.0 g, 7.40 mmol), sodium ethoxide (1.0 g, 14.8 mmol), ethyl trifluoroacetate (2.10 g, 14.8 mmol), and 4-benzyloxyphenylhydrazine hydrochloride (4.45 g, 17.8 mmol) were used in place of 4-methoxyacetophenone (600 mg, 4.0 mmol), sodium ethoxide (544 mg, 8.0 mmol), ethyl trifluoroacetate (1.14 g, 20.0 mmol), and 4-benzyloxyphenylhydrazine hydrochloride (2.0 g, 8.0 mmol) in step (1), respectively, to obtain a yellow oily intermediate M36 (1.52 g, 50% yield). M36... 1 H NMR (400 MHz, CDCl3)δ=8.45 (d, J = 5.2 Hz, 1H), 7.44-7.34 (m, 5H), 7.22 (dd, J = 6.8, 2.4 Hz, 2H),7.06 (s, 1H), 6.98 (dd, J = 6.8, 2.4 Hz, 2H), 6.88 (dd, J = 5.2, 1.2 Hz, 1H), 6.85 (s, 1H), 5.10 (s, 2H), 2.53 (s, 3H).

[0152] (26) Synthesis of intermediate M37: In a 125 mL round-bottom flask, intermediate M36 (1.52 g, 3.71 mmol) was dissolved in anhydrous methanol (20 mL), and Pd / C (304 mg, 20% wt) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere, and the reaction progress was monitored by TLC. After the reaction was completed, Pd / C was removed by filtration, and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the yellow solid intermediate M37 (1.14 g, 96% yield). M37... 1 H NMR (400 MHz, CD3OD) δ = 8.34 (d, J = 5.2Hz, 1H), 7.23 (s, 1H), 7.16 (dd, J = 6.8, 2.4 Hz, 2H) 7.11 (s, 1H), 7.04 (dd, J=5.2, 1.2 Hz, 1H), 6.85 (dd, J = 6.8, 2.4 Hz, 2H), 2.47 (s, 3H).

[0153] (28) Synthesis of 3-trifluoromethyl-substituted pyrazole compound B8: Using intermediate M37 (100 mg, 0.31 mmol) and (2-bromomethyl)-N-methylquinoline-4-carboxamide (87 mg, 0.31 mmol) as starting materials, the synthesis method of step (3) A16 in Example 7 was followed to obtain yellow solid compound B8 (114 mg, yield 70%). 1 H NMR (400 MHz, CDCl3) δ = 8.40 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 6.4 Hz, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.76 (t, J = 6.0 Hz, 1H), 7.66 (s, 1H), 7.59 (t, J = 6.0 Hz, 1H), 7.21 (d, J =7.2 Hz, 2H), 7.04 (s, 1H), 7.01 (d, J = 7.2 Hz, 2H), 6.83 (m, 1H), 6.82 (d, J =4.4 Hz, 1H), 6.38 (q, J = 3.2 Hz, 1H), 5.34 (s, 2H), 3.07 (d, J = 4.0 Hz, 3H), 2.50 (s, 3H).

[0154] (29) Synthesis of intermediate M38: In a 125 mL round-bottom flask, intermediate M3 (305 mg, 1.0 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid (345 mg, 2.0 mmol) was added. The reaction mixture was stirred overnight at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, the crude product was obtained by vacuum distillation, and purified by silica gel column chromatography to obtain a white solid intermediate M38. 232 mg of the crude product was directly used in the next step of the reaction.

[0155] (30) Synthesis of 3-trifluoromethyl-substituted pyrazole compound B9: Using intermediate M38 (100 mg, 0.31 mmol) obtained in the previous step and (2-bromomethyl)-N-methylquinoline-4-carboxamide (87 mg, 0.31 mmol) as raw materials, the synthesis method of step (3) A16 in Example 7 was followed to obtain a pale yellow solid compound B9 (108 mg, yield 67%). 1 HNMR (400 MHz, DMSO-d6)δ= 8.79 (s, 1H), 8.22 (d, J = 4.8 Hz, 2H), 8.14 (d, J =6.0 Hz, 1H ), 8.07 (d, J = 6.4 Hz, 1H), 7.84 (t, J = 6.0 Hz, 1H), 7.71 (s,1H), 7.68 (t, J = 6.0 Hz, 1H), 7.43-7.30 (m, 3H), 7.28-7.22 (m, 4H), 5.45 (s,2H), 2.88 (d, J = 2.4 Hz, 3H).

[0156] Example 10 Synthesis and structural characterization of 3-trifluoromethyl-substituted pyrazole compounds (C1-C8)

[0157] The synthetic flow chart of 3-trifluoromethyl-substituted pyrazole compounds (C1-C8) is shown below. Figure 16 As shown, specifically:

[0158] (1) Synthesis of intermediate M39: In a 125 mL round-bottom flask, intermediate M37 (1.14 g, 3.57 mmol) and methyl (2-bromomethyl)quinoline-4-carboxylate (1.10 g, 3.93 mmol) were dissolved in anhydrous DMF (30 mL), and cesium carbonate (3.49 g, 10.71 mmol) was added. The reaction mixture was heated to 80 °C and stirred overnight. The reaction progress was monitored by TLC. After the reaction was completed, cesium carbonate was removed by filtration, and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the yellow solid intermediate M39 (1.56 g, yield 84%). 1H NMR (400 MHz, CDCl3)δ= 8.75 (d, J = 6.4 Hz, 1H), 8.43 (d, J= 4.4 Hz, 1H), 8.14-8.12 (m, 2H), 7.79 (t, J = 6.8 Hz, 1H), 7.67 (t, J = 6.8Hz, 1H), 7.25 (dd, J = 5.6, 1.2 Hz, 2H), 7.07 (dd, J = 5.6, 1.2 Hz, 2H), 7.04(s, 1H), 6.85-6.84 (m, 2H), 5.42 (s, 2H), 4.05 (s, 3H), 2.50 (s, 3H).

[0159] (2) Synthesis of intermediate M40: In a 125 mL round-bottom flask, intermediate M39 (3.40 g, 6.56 mmol) was dissolved in methanol / water (30 mL / 10 mL), and sodium hydroxide (525 mg, 13.12 mmol) was added. The reaction mixture was heated to 65 °C and stirred for 3 hours, and the reaction progress was monitored by TLC. After the reaction was completed, methanol was removed by vacuum distillation to obtain an aqueous solution of the crude product. The pH of the system was adjusted to 4-5 with 3M hydrochloric acid, and a solid precipitated. The solid was filtered under reduced pressure, the filter cake was washed with water, and dried in air to obtain a grayish-white solid compound intermediate M40 (2.92 g, yield 88%), which was directly used in the next step of the reaction.

[0160] (3) Synthesis of 3-trifluoromethyl-substituted pyrazole compound C1: In a 50 mL round-bottom flask, intermediate M40 (120 mg, 0.24 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). Then, 3-oxacyclobutamine (20 mg, 0.28 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (108 mg, 0.28 mmol), and diisopropylethylamine (93 mg, 0.72 mmol) were added sequentially. The reaction mixture was stirred overnight at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the crude product was obtained by vacuum distillation and purified by silica gel column chromatography to give a white solid compound C1 (101 mg, yield 76%). 1H NMR (500 MHz, CDCl3) δ= 8.43 (d, J = 5.0 Hz, 1H), 8.19 (d,J = 8.0 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.72 (s,1H), 7.64 (td, J = 7.0, 1.0 Hz, 1H), 7.25 (dd, J = 6.5, 2.0 Hz, 2H), 7.06 (dd, J = 6.5, 2.0 Hz, 2H), 7.05 (s, 1H), 6.85 (d, J = 7.5 Hz, 1H), 6.84 (s,1H), 6.71 (d, J = 7.5 Hz, 1H), 5.40 (s, 2H), 5.35-5.29 (m, 1H), 5.07 (t, J =7.0 Hz, 2H), 4.66 (t, J = 6.5 Hz, 2H), 2.52 (s, 3H).

[0161] (4) Synthesis of 3-trifluoromethyl-substituted pyrazole compound C2: In a 50 mL round-bottom flask, intermediate M40 (150 mg, 0.30 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and compounds (S)-1-tert-butoxycarbonyl-3-aminopyrrolidine (66 mg, 0.36 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (136 mg, 0.36 mmol), and diisopropylethylamine (116 mg, 0.90 mmol) were added sequentially. The reaction mixture was stirred overnight at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, the crude product was obtained by vacuum distillation and purified by silica gel column chromatography to obtain a white solid compound. The obtained compound was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred overnight at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the crude product was obtained by vacuum distillation. The pH was adjusted to 9-10 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the crude product was obtained by vacuum distillation. The crude product was purified by silica gel column chromatography to give a pale yellow solid compound C2 (104 mg, yield 76%). 1 HNMR (400 MHz, DMSO- d 6 ) δ = 8.94 (d, J = 5.2 Hz, 1H), 8.40 (d,J = 4.0 Hz, 1H), 8.11(d, J = 6.8 Hz, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.84 (t, J = 6.0 Hz, 1H), 7.72 (s,1H), 7.69 (t, J = 6.0 Hz, 1H), 7.38 (s, 1H), 7.37 (d, J = 6.8 Hz, 2H), 7.26 (s,1H), 7.21 (d, J = 7.6 Hz, 2H), 6..94 (d, J = 3.6 Hz, 1H), 5.44 (s, 2H), 4.49-4.39(m, 1H), 3.15-3.07 (m, 1H), 3.02-2.92 (m, 1H), 2.89-2.78 (m, 2H), 2.41 (s,3H), 2.14-2.02 (m, 1H), 1.83-1.69 (m, 1H).

[0162] (5) Synthesis of 3-trifluoromethyl-substituted pyrazole compound C3: Using (R)-1-tert-butoxycarbonyl-3-aminopiperidine (71 mg, 0.36 mmol) instead of tert-butyl 3-aminoazacyclobutane-1-carboxylate in step (4), the synthesis of C2 in step (4) of Example 10 was performed to obtain a pale yellow solid compound C3 (112 mg, yield 75%). 1 H NMR (400 MHz, CDCl3) δ = 8.41 (d, J = 5.2 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.08 (d, J =8.4 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.67 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 7.04 (s, 1H), 6.95 (d, J= 7.6Hz, 1H), 6.85-6.80 (m, 2H), 5.35 (s, 2H), 4.27-4.25 (m, 1H), 3.11 (dd, J =11.6, 2.8 Hz, 1H), 2.85-2.74 (m, 3H), 2.50 (s, 3H), 2.39 (brs, 1H), 1.94-1.78(m, 2H), 1.75-1.67 (m, 1H), 1.62-1.53 ​​(m, 1H).

[0163] (6) Synthesis of 3-trifluoromethyl-substituted pyrazole compound C4: Using (S)-(1-aminopropyl-2-yl)carbamate tert-butyl ester (62.2 mg, 0.36 mmol) instead of 3-aminoazacyclobutane-1-carbamate tert-butyl ester in step (4), the synthesis of C2 in step (4) of Example 10 was performed to obtain a pale yellow solid compound C4 (88 mg, yield 68%). 1 HNMR (400 MHz, CDCl3) δ = 8.43 (d, J = 4.0 Hz, 1H), 8.24 (d, J = 6.8 Hz, 1H), 8.10(d, J = 6.8 Hz, 1H), 7.78 (t, J = 6.0 Hz, 1H), 7.71 (s, 1H), 7.61 (t, J = 6.0 Hz, 1H), 7.23 (d, J = 7.2 Hz, 2H), 7.05 (s, 1H), 7.04 (d, J = 7.2 Hz, 2H), 6.84 (s,2H), 6.76 (t, J = 4.0 Hz, 1H), 5.38 (s, 2H), 3.67-3.60 (m, 1H), 3.32-3.17 (m,2H), 2.51 (s, 3H), 1.20 (d, J = 4.8 Hz, 3H), 0.85 (brs, 2H).

[0164] (7) Synthesis of 3-trifluoromethyl-substituted pyrazole compound C5: Using (R)-1-N-Boc-2-methylpiperazine (71 mg, 0.36 mmol) instead of tert-butyl 3-aminoazacyclobutane-1-carboxylate in step (4), the synthesis of C2 in step (4) of Example 10 was performed to obtain a pale yellow solid compound C5 (108 mg, yield 70%). 1 H NMR (400MHz, CDCl3) δ = 8.45 (d, J = 4.0 Hz, 1H), 8.13 (t, J = 6.4 Hz, 1H), 7.98-7.72 (m,2H), 7.67-7.55 (m, 2H), 7.28-7.22 (m, 2H), 7.08 (s, 1H), 7.07-7.03 (m, 2H),6.88-6.82 (m, 2H), 5.42 (d, J = 6.4 Hz, 2H), 4.89-4.71 (m, 1H), 3.28-2.58 (m, 6H), 2.54 (s, 3H), 1.23-0.81 (m, 3H).

[0165] (9) Synthesis of 3-trifluoromethyl-substituted pyrazole compound C6: Using (R)-1-amino-2-propanol (36 mg, 0.48 mmol) instead of 3-oxacyclobutane in step (3), the synthesis of C1 in step (3) of Example 10 was performed to obtain a pale yellow solid compound C6 (86 mg, yield 64%). 1 H NMR (400 MHz, CD3OD) δ = 8.35 (d, J =5.2 Hz, 1H), 8.23 ​​(d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.85 (dt, J = 7.2,1.2 Hz, 1H), 7.83 (s, 1H), 7.69 (dt, J = 7.2, 1.2 Hz, 1H), 7.34 (dd, J = 6.8, 2.4Hz, 2H), 7.26 (s, 1H), 7.21 (dd, J= 6.8, 2.0 Hz, 2H), 7.15 (s, 1H), 7.06 (dd,J = 5.2, 1.2 Hz, 1H), 5.46 (s, 2H), 4.11-4.01 (m, 1H), 3.54 (dd,J = 13.6,4.8 Hz, 1H), 3.45 (dd, J = 13.6, 7.2 Hz, 1H), 2.47 (s, 3H), 1.29 (d, J = 6.4Hz, 3H).

[0166] (10) Synthesis of 3-trifluoromethyl-substituted pyrazole compound C7: Tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (61 mg, 0.28 mmol) was used instead of tert-butyl 3-aminoazacyclobutane-1-carboxylate in step (4), and the synthesis method of C2 in step (4) of Example 10 was followed to obtain a pale yellow solid compound C7 (108 mg, yield 81%). 1 H NMR (400 MHz, CDCl3) δ = 8.43 (d, J = 4.0 Hz, 1H), 8.11 (t, J = 8.0 Hz, 1H), 7.88(t, J = 8.0 Hz, 1H), 7.74-7.84 (m, 1H), 7.68-7.60 (m, 1H), 7.57 (d, J = 4.4 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.11-6.99 (m, 3H), 6.88-6.78 (m, 2H), 5.39 (d, J =9.6 Hz, 2H), 4.03-3.57 (m, 2H), 3.11 (s, 2H), 2.97 (d, J = 6.4 Hz, 1H), 2.76(t, J = 4.4 Hz, 1H), 2.52 (s, 3H), 2.02 (brs, 1H), 0.86-0.78 (m, 1H), 0.74 (s,1H), 0.54 (s, 1H), 0.27-0.02 (m, 1H).

[0167] (11) Synthesis of 3-trifluoromethyl-substituted pyrazole compound C8: Tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (817 mg, 4.12 mmol) was used instead of tert-butyl 3-aminoazacyclobutane-1-carboxylate in step (4), and the synthesis method of C2 in step (4) of Example 10 was followed to obtain white solid compound C8 (1.78 g, yield 75%). 1 H NMR (400 MHz, CDCl3) δ = 8.42 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.03(d, J = 8.0 Hz, 1H), 7.77 (t, J = 6.8, 1.2 Hz, 1H), 7.61 (dt, J = 6.8, 1.2 Hz, 1H),7.57 (s, 1H), 7.23 (dd, J = 6.8, 2.0 Hz, 2H), 7.05 (s, 1H), 7.03 (dd, J = 6.8,2.0 Hz, 2H), 6.84 (s, 1H), 6.83 (d, J = 5.2 Hz, 1H), 5.41 (s, 2H), 4.39 (s,2H), 3.88 (d, J = 9.2 Hz, 2H), 3.86 (s, 2H), 3.79 (d, J = 9.2 Hz, 2H), 3.26 (brs,1H), 2.51 (s, 3H).

[0168] Performance testing

[0169] The 3-trifluoromethyl-substituted pyrazole compounds of each embodiment were tested as follows:

[0170] (1) Inhibition test of 3-trifluoromethyl-substituted pyrazole compounds on PDE10A (phosphodiesterase type 10A) activity

[0171] At room temperature, the 3-trifluoromethyl-substituted pyrazole compound to be tested was reacted with 20,000-30,000 cpm of a solution containing 1 μg / mL recombinant clone PDE10A protein, 20 mM Tris-HCl (pH=7.5), 4 mM dithiothreitol, and 10 mM MgCl2.3 The H-cAMP mixture was incubated for 15 minutes, and then the reaction was stopped with 0.2 mol / L ZnSO4 and 0.2 mol / L Ba(OH)2, respectively. The unreacted ions in the supernatant were then measured using a PerkinElmer 2910 counter. 3 H-cAMP was used, and the experiment was repeated at least three times. The IC50 value of 3-trifluoromethyl-substituted pyrazole compounds against the recombinant clone PDE10A (phosphodiesterase type 10A) protein activity was obtained through concentration testing and nonlinear regression calculations. 50 value.

[0172] The results of the activity inhibition tests of the 3-trifluoromethyl-substituted pyrazole compounds against the recombinant clone PDE10A protein in each example are shown in Table 1. Under the same conditions, the activity inhibition test results of the positive control (papaverine) against the recombinant clone PDE10A protein should be controlled within IC50. 50 = in the range of 50~100 nM, to ensure the IC50 of the measured compound. 50 The value data has a unified reference standard:

[0173] Table 1. Results of activity inhibition tests of 3-trifluoromethyl-substituted pyrazole compounds against recombinant clone PDE10A protein in each example.

[0174]

[0175] As shown in Table 1, the 3-trifluoromethyl-substituted pyrazole compounds of the present invention or their pharmaceutically acceptable salts have excellent inhibitory effects on the activity of PDE10A (phosphodiesterase type 10A).

[0176] (2) Metabolic stability test of 3-trifluoromethyl substituted pyrazole compounds

[0177] 1 μM of the target 3-trifluoromethyl-substituted pyrazole compound was incubated with 0.5 mg / mL rat liver microsomes (RLM) and 1.0 mM NADPH in a 0.1 mol / L PBS buffer (pH=7.4) at 37°C. The reaction was timed, and 30 μL of the incubation system was taken at 0, 5, 15, 30, and 60 min, respectively, and 200 μL of pre-cooled methanol (containing 20 μL of 1 μg / mL tolbutamide) was added to terminate the reaction. The remaining content of the target 3-trifluoromethyl-substituted pyrazole compound in the system was then measured using a Thermo ultra-high performance liquid chromatography-tandem mass spectrometry system, and the measurement was repeated three times. The half-life of the 3-trifluoromethyl-substituted pyrazole compound metabolized by rat liver microsomes (RLM) was calculated by logarithmic concentration testing and linear regression. The larger the half-life of 3-trifluoromethyl-substituted pyrazole compounds metabolized by rat liver microsomes (RLM), the slower and more stable the metabolism of 3-trifluoromethyl-substituted pyrazole compounds.

[0178] The metabolic stability test results of the 3-trifluoromethyl-substituted pyrazole compounds in each example are shown in Table 2. Among them, under the same conditions, the metabolic stability half-life of the positive control (phenacetin) is shown in Table 2. T 1 / 2 The test should be conducted within the 30–50 min range to ensure the half-life of the compound being measured. T 1 / 2 The data adheres to a unified reference standard:

[0179] Table 2. Results of metabolic stability tests on 3-trifluoromethyl-substituted pyrazole compounds in each example.

[0180]

[0181] Note: "MP-10" refers to a pyrazole PDE10A inhibitor that is metabolized too quickly, as mentioned in the background section.

[0182] As shown in Table 2, the 3-trifluoromethyl-substituted pyrazole compounds of the present invention or their pharmaceutically acceptable salts have good metabolic stability, and their half-life after metabolism by rat liver microsomes can reach 239 min, which solves the problem of excessively rapid metabolism of pyrazole PDE10A inhibitors such as MP-10.

[0183] (3) Selectivity test of 3-trifluoromethyl-substituted pyrazole compounds for the PDEs superfamily

[0184] Taking 3-trifluoromethyl-substituted pyrazole compound C8 as an example, the selectivity index of 3-trifluoromethyl-substituted pyrazole compound to PDEs superfamily was tested; for specific experimental procedures, refer to (1) the activity inhibition test method of 3-trifluoromethyl-substituted pyrazole compound to PDE10A (phosphodiesterase 10A type).

[0185] The selectivity test results of 3-trifluoromethyl-substituted pyrazole compounds C8 for the PDEs superfamily are shown in Table 3:

[0186] Table 3. Selectivity test results of 3-trifluoromethyl-substituted pyrazole compounds C8 for the PDEs superfamily.

[0187]

[0188] Table 3 shows that the IC50 values ​​of 3-trifluoromethyl-substituted pyrazole compound C8 for PDE10A2 (449-770) are... 50 The lowest value indicates that, compared to other phosphodiesterase subtypes, the 3-trifluoromethyl-substituted pyrazole compounds of this invention have high selectivity for PDE10A (phosphodiesterase type 10A) and can be used as specific drugs to inhibit the activity of phosphodiesterase type 10A.

[0189] (4) Blood-brain barrier permeability test of 3-trifluoromethyl-substituted pyrazole compounds

[0190] Prepare a stock solution of the 3-trifluoromethyl-substituted pyrazole compound to be tested with DMSO at a concentration of 5 mg / mL; take 20 μL of the 5 mg / mL stock solution of the 3-trifluoromethyl-substituted pyrazole compound to be tested and dilute it to 100 µg / mL with 50 mmol / L KH2PO4-K2HPO4 buffer at pH 7.4 as a secondary stock solution.

[0191] Porcine brain tissue extract (PBL, Avanti) was dissolved in dodecane and coated onto a hydrophobic membrane (0.45 mHydrophobic High Protein Binding Immobilon-P Membrane). Then, 200 μL of a secondary stock solution of 100 µg / mL of the target 3-trifluoromethyl-substituted pyrazole compound was added above the hydrophobic membrane as the drug delivery pool. On the other side of the hydrophobic membrane, 300 µL of a pH 7.4 50 mmol / L KH₂PO₄-K₂HPO₄ buffer was added as the receiving pool, ensuring sufficient contact between the receiving solution and the hydrophobic membrane. After standing at room temperature for 12 hours, 200 μL of the secondary stock solution of the target 3-trifluoromethyl-substituted pyrazole compound was added to 300 μL of phosphate-buffered saline-ethanol solution and mixed thoroughly to obtain the theoretical equilibrium concentration solution. The drug concentrations in the acceptor cell solution, theoretical equilibrium concentration solution, and blank well KH₂PO₄-K₂HPO₄ buffer were determined using a UV plate reader, and the effective permeability (Pe) of the compounds was calculated using Microsoft Office Excel software. Taking 3-trifluoromethyl-substituted pyrazole compounds C6-C8 as an example, their effective permeability Pe was tested. A higher Pe value indicates higher blood-brain barrier permeability of the compound. The test results are shown in Table 4.

[0192] Table 4. Blood-brain barrier permeability tests of 3-trifluoromethyl-substituted pyrazole compounds.

[0193]

[0194] As shown in Table 4, the pyrazole PDE10A inhibitor MP-10 has the highest effective permeability Pe value, indicating that compared with MP-10, the 3-trifluoromethyl-substituted pyrazole compounds of this invention have lower blood-brain barrier permeability and are less likely to inhibit PDE10A (phosphodiesterase 10A type) in the central nervous system. Therefore, when the 3-trifluoromethyl-substituted pyrazole compounds of this invention are used to treat and / or prevent PDE10A-related diseases, including myocardial hypertrophy, myocardial remodeling, myocardial fibrosis, and myocardial injury, they will not significantly inhibit PDE10A in the central nervous system.

[0195] (5) Confirmatory experiment on the treatment of myocardial hypertrophy with 3-trifluoromethyl-substituted pyrazole compounds

[0196] Thirty-six C57 mice were randomly divided into six groups: Group 1 was the normal control group (control group); Group 2 was the model group; Group 3 was the C8 group (low-dose group) with 2.5 mg / kg 3-trifluoromethyl-substituted pyrazole compound; Group 4 was the C8 group (medium-dose group) with 5.0 mg / kg 3-trifluoromethyl-substituted pyrazole compound; Group 5 was the C8 group (high-dose group) with 10.0 mg / kg 3-trifluoromethyl-substituted pyrazole compound; and Group 6 was the positive control group (propranolol group) with 10 mg / kg propranolol.

[0197] Except for the normal control group (control group), which received physiological saline, the model group and all other groups were subcutaneously injected with isoproterenol (ISO 5.0 mg / kg / day) for 14 consecutive days to induce myocardial hypertrophy and myocardial injury in C57 mice. Simultaneously, from the first day of modeling, the high-dose group was administered 10.0 mg / kg of 3-trifluoromethyl-substituted pyrazole compound C8 once daily by gavage; the medium-dose group was administered 5.0 mg / kg of 3-trifluoromethyl-substituted pyrazole compound C8 once daily by gavage; the low-dose group was administered 2.5 mg / kg of 3-trifluoromethyl-substituted pyrazole compound C8 once daily by gavage; the positive control group (propranolol group) was administered 10 mg / kg propranolol once daily by gavage; and the normal control group and model group were administered an equal volume of physiological saline once daily by gavage, for 14 consecutive days.

[0198] Twenty-four hours after the last administration, echocardiography was performed using a Technos MPX ultrasound system (ESAOTE, Italy) coupled with an 8.5-MHz image converter. Specifically, C57 mice were anesthetized with isoflurane, their chest area was shaved, and then echocardiography was performed at the level of the papillary muscle using a two-dimensional ultrasound-guided M-mode curve (probe frequency 8.5 MHz). Cardiac function parameters measured included left ventricular ejection fraction (EF%), left ventricular fraction shortening (FS%), left ventricular end-diastolic volume, and left ventricular end-systolic volume. Simultaneously, biological samples were collected, and cardiac indices and the levels of biomarkers in myocardial tissue (natriuretic peptide (ANP) mRNA and β-myosin heavy chain (β-MHC) mRNA expression levels) were measured. The results are shown below. Figure 16-19 As shown.

[0199] Figure 17Statistical graphs of heart specific gravity and heart-to-tibia ratio in C57 mice from different experimental groups. Figure 17 A shows the statistical graph of the heart weight of C57 mice in different experimental groups. Figure 17 B is a statistical graph showing the heart-to-tibia ratio of C57 mice in different experimental groups.

[0200] Figure 18 This is a statistical graph showing the changes in atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC) mRNA expression in the myocardial tissue of C57 mice from different experimental groups. Figure 18 Figure A shows the changes in atrial natriuretic peptide (ANP) mRNA expression in the myocardial tissue of C57 mice in different experimental groups. Figure 18 B shows the changes in β-myosin heavy chain (β-MHC) mRNA expression in the myocardial tissue of C57 mice in different experimental groups.

[0201] Figure 19 Graphs showing left ventricular ejection fraction and left ventricular shortening fraction in C57 mice from different experimental groups. Figure 19 A shows the statistical graph of left ventricular ejection fraction in C57 mice from different experimental groups. Figure 19 B is a statistical graph showing the left ventricular shortening fraction of C57 mice in different experimental groups.

[0202] Figure 20 Graphs showing the left ventricular end-systolic diameter and left ventricular end-diastolic diameter in C57 mice from different experimental groups. Figure 20 A shows the statistical graph of the left ventricular end-systolic diameter of C57 mice in different experimental groups. Figure 20 B is a statistical graph showing the end-diastolic diameter of the left ventricle in C57 mice from different experimental groups.

[0203] exist Figure 17-20 In the text, "*" and "#" indicate significant differences, with "*" indicating p < 0.05, "**" indicating p < 0.01, "***" indicating p < 0.001, "****" indicating p < 0.0001, "#" indicating p < 0.05, "##" indicating p < 0.01, "###" indicating p < 0.001, and "ns" indicating p > 0.05.

[0204] from Figure 17-20 It can be seen that, compared with the model group, the 3-trifluoromethyl-substituted pyrazole compound C8 of the present invention can reduce the heart-to-body weight ratio, heart-to-tibia ratio and myocardial tissue biomarker content, increase the left ventricular ejection fraction and left ventricular shortening fraction, and shorten the left ventricular end-systolic diameter and left ventricular end-diastolic diameter. As a result, the heart-to-body weight ratio, heart-to-tibia ratio and other parameters of C57 mice with myocardial hypertrophy and myocardial injury are close to the level of the normal control group. This shows that the 3-trifluoromethyl-substituted pyrazole compound of the present invention can effectively treat myocardial hypertrophy.

[0205] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof, characterized in that, The 3-trifluoromethyl-substituted pyrazole compound is one of the compounds shown in the following structural formulas: 。 2. The method for preparing the 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that, Includes the following steps: (1) In the presence of sodium ethoxide, aryl ketones react with ethyl trifluoroacetate to form aryl diketone intermediates; (2) The aryl dione intermediate undergoes a condensation and ring-closing reaction with an aromatic hydrazine compound to form a pyrazole intermediate with a 3-trifluoromethyl substituted phenolic hydroxyl group protected; (3) The pyrazole intermediate containing phenolic hydroxyl groups protected by 3-trifluoromethyl substituted pyrazole intermediate is obtained by deprotection of the protecting group; (4) Reaction of pyrazole intermediates containing phenolic hydroxyl 3-trifluoromethyl substituted with 2-bromomethylquinoline compounds yields 3-trifluoromethyl substituted pyrazole compounds; Among them, the aryl ketone compounds are The aryl diketone intermediate is ; The aromatic hydrazine compound is The 3-trifluoromethyl-substituted pyrazole intermediate containing a phenolic hydroxyl group protection is... The pyrazole intermediate containing a phenolic hydroxyl group substituted with a 3-trifluoromethyl group is... The 2-bromomethylquinoline compound is ; The X, R3, and R2 refer to the corresponding groups of the 3-trifluoromethyl-substituted pyrazole compounds according to claim 1; R is a phenolic hydroxyl protecting group.

3. The method for preparing the 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof as described in claim 2, characterized in that, In step (4), after the pyrazole intermediate containing phenolic hydroxyl 3-trifluoromethyl substituted reacts with the 2-bromomethylquinoline compound, it also includes a saponification hydrolysis reaction and an amide condensation reaction.

4. The method for preparing the 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof as described in claim 3, characterized in that, The alkali used in the saponification and hydrolysis reaction is LiOH; the reagent used in the amide condensation reaction is selected from 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, and N,N-dimethylformamide.

5. The method for preparing the 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof as described in claim 3, characterized in that, The process includes saponification hydrolysis and amide condensation followed by removal of Boc protecting groups.

6. The method for preparing the 3-trifluoromethyl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof as described in claim 5, characterized in that, The reagents used in the deprotection treatment of Boc groups are selected from trifluoroacetic acid and dichloromethane.

7. The use of the 3-trifluoromethyl-substituted pyrazole compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the treatment and / or prevention of diseases caused by PDE10A.

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