Peptide-like diaryl substituted pyrazole compound as well as preparation method and application thereof

Abstract

The invention relates to the field of medicinal chemistry, and relates to a preparation method and application of a diaryl substituted pyrazole compound. Specifically, the invention relates to a peptidoid diaryl substituted pyrazole compound as well as a preparation method and application thereof. The invention relates to a peptidoid diaryl substituted pyrazole compound which is shown in a general formula (I), and a racemate, an optical isomer, a pharmaceutically acceptable salt or a solvate thereof: # imgabs0. The invention provides a compound of a combined amino acid or a similar structure, and the compound has ALK5 inhibition capability and can be used for inhibiting ALK5. A new medicine can be provided for treating or preventing diseases related to a TGF-beta signal channel, and meanwhile, the medicine solubility and the cell membrane permeability are improved.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and relates to a preparation method and application of a bi-aryl-substituted pyrazole compound. Specifically, the present invention relates to a peptide-like bi-aryl-substituted pyrazole compound, a preparation method and application thereof. Background Art

[0002] The tumor microenvironment (TME) refers to the noncancerous cells and components present in tumors, as well as the factors they produce and release. The interaction between tumor cells and the TME plays a crucial role in tumor development, progression, metastasis, and therapeutic response. Numerous studies have revealed that dysregulation of the transforming growth factor-β (TGF-β) signaling pathway within the TME is directly associated with cancer development and metastasis. Signaling by members of the TGF-β superfamily requires two related transmembrane heteromeric serine / threonine kinase receptors: Type I receptors (TGFβ-RI or ALKs (activin receptor-like kinases)) and Type II receptors. Currently, seven Type I receptors have been discovered: ALK1-7, with the ALK5 isoform playing a crucial role in TGF-β signaling. Blocking the binding of ALK5 to its substrates smad2 / smad3 or inhibiting ALK5's phosphorylation of its substrates smad2 / smad3 can cut off the transmission of TGF-β signals to the cell nucleus, blunting the transcriptional regulation of target genes, thereby achieving the goal of treating related diseases. Given the important role of ALK5 in TGF-β signaling, it has always been one of the most popular anti-tumor targets.

[0003] The immune-related TGF-β / TGF-βR / Smad pathway has been extensively researched globally. To block TGF-β, the fusion protein luspatercept has been approved for the treatment of transfusion-dependent β-thalassemia and myelodysplastic syndrome (MDS). Regarding antibodies, the most popular candidates currently include Fresolimumab (monoclonal antibody), SAR439459 (monoclonal antibody), and M7824 (bispecific antibody).

[0004] The development of small molecule inhibitors for ALK5 is in full swing. Currently, many small molecule inhibitors have entered the clinical research stage, such as Galunisertib, Vactosertib, LY3200882, TP-0184, PF-06952229, YL-13027, etc. In addition, a number of potent and well-defined ALK5 inhibitors have been reported, such as GW788388, an effective and selective ALK5 inhibitor with IC 50 The concentration of β-actin is 21.4 nM, which also inhibits the activity of TGF-β type II receptor and activin type II receptor, but does not inhibit BMP type II receptor. Summary of the Invention

[0005] The purpose of the present invention is to develop a peptide-like bi-aryl-substituted pyrazole compound with ALK5 inhibitory ability, a preparation method thereof, and an application thereof in drugs for treating or preventing diseases related to the TGF-β signaling pathway.

[0006] To achieve the above purpose, the specific technical solutions of the present invention are as follows:

[0007] A peptide-like biaryl-substituted pyrazole compound, the compound is represented by general formula (I), its racemate, optical isomers, and pharmaceutically acceptable salts or solvates:

[0008]

[0009] In formula (I), R1 is selected from an amino acid ester residue lacking an N-terminal amino group, an amino alcohol residue lacking an N-terminal amino group, a C5-C8 membered heterocycle which is unsubstituted or substituted with at least one of the following groups, wherein the following groups are amino, a cinnamoyl group which is unsubstituted or substituted with a benzene ring; R2 is hydrogen, a C1-C6 alkyl group, or a C1-C6 alkoxy group;

[0010] Wherein, the amino acid ester is methyl ester or ethyl ester.

[0011] Preferably, the compound is represented by general formula (I), its racemate, optical isomer, or pharmaceutically acceptable salt or solvate:

[0012] In formula (I),

[0013] R1 is selected from an amino acid ester residue lacking an N-terminal amino group, an amino alcohol residue lacking an N-terminal amino group, a C5-C7 membered heterocycle which is unsubstituted or substituted with at least one of the following groups, wherein the following groups are amino, a cinnamoyl group which is unsubstituted or substituted with a benzene ring; R2 is hydrogen, a C1-C4 alkyl group or a C1-C4 alkoxy group;

[0014] Wherein, the amino acid ester is methyl ester or ethyl ester.

[0015] The heteroatom in the above-mentioned heterocyclic ring may be N, O or S, and the substitution on the heterocyclic ring may be on the heteroatom or H atom in the ring.

[0016] More preferably, the compound is represented by general formula (I), its racemate, optical isomer, or pharmaceutically acceptable salt or solvate:

[0017] In formula (I), R1 is phenylalanine methyl ester, phenylalanine ethyl ester; alanine methyl ester, alanine ethyl ester; proline methyl ester, proline ethyl ester; aspartic acid dimethyl ester, aspartic acid diethyl ester; glutamate dimethyl ester, glutamate diethyl ester; methionine methyl ester, methionine ethyl ester; valine methyl ester, valine ethyl ester; leucine methyl ester, leucine ethyl ester; glycine methyl ester, glycine ethyl ester; tyrosine methyl ester, tyrosine ethyl ester; phenylalaninol; phenylglycinol; alaninol; 4-aminopiperidine, N-substituted-4-aminopiperidine, wherein the N-substituent is cinnamoyl and cinnamoyl substituted with a phenyl ring;

[0018] R2 is hydrogen, C1-C2 alkyl or methoxy.

[0019] More preferably, the compound is the following compound, its racemate, its S optical isomer, its R optical isomer, or a pharmaceutically acceptable salt or solvate thereof;

[0020] The following compounds are

[0021] N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-phenylalanine methyl ester

[0022]

[0023] N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-phenylalanine methyl ester

[0024]

[0025] N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-alanine methyl ester

[0026]

[0027] Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-alaninate

[0028]

[0029] Dimethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate

[0030]

[0031] Dimethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate

[0032]

[0033] Dimethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid ester

[0034]

[0035] Dimethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid ester

[0036]

[0037] Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-methionine

[0038]

[0039] Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-methionine

[0040]

[0041] Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-valine

[0042]

[0043] Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-valine

[0044]

[0045] Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-leucinate

[0046]

[0047] Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-leucinate

[0048]

[0049] N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-glycine methyl ester

[0050]

[0051] N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-tyrosine methyl ester

[0052]

[0053] Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-tyrosine

[0054]

[0055] N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-proline methyl ester

[0056]

[0057] N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-proline methyl ester

[0058]

[0059] (S)-N-(1-Hydroxy-3-phenylpropan-2-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide

[0060]

[0061] (R)-N-(1-Hydroxy-3-phenylpropan-2-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide

[0062]

[0063] (S)-N-(1-Hydroxypropan-2-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide

[0064]

[0065] N-(1-Cinnamoylpiperidin-4-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide

[0066]

[0067] (E)-N-(1-(3-(4-methoxyphenyl)acryloyl)piperidin-4-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide

[0068]

[0069] (E)-N-(1-(3-(4-bromophenyl)acryloyl)piperidin-4-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide

[0070]

[0071] N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-phenylalanine methyl ester

[0072]

[0073] Methyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-phenylalaninate

[0074]

[0075] Dimethyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate

[0076]

[0077] Dimethyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate

[0078]

[0079] Dimethyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid ester

[0080]

[0081] Dimethyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid ester

[0082]

[0083] Dimethyl N-(4-(4-(3-(6-ethylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate

[0084]

[0085] Dimethyl N-(4-(4-(3-(6-ethylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate

[0086]

[0087] Dimethyl N-(4-(4-(3-(6-ethylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid ester

[0088]

[0089] Dimethyl N-(4-(4-(3-(6-ethylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid ester

[0090]

[0091] Dimethyl N-(4-(4-(3-(6-methoxypyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate

[0092]

[0093] Dimethyl N-(4-(4-(3-(6-methoxypyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate

[0094]

[0095] Dimethyl N-(4-(4-(3-(6-methoxypyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid ester

[0096]

[0097] Dimethyl N-(4-(4-(3-(6-methoxypyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid ester

[0098]

[0099] Diethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate

[0100]

[0101] Diethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate

[0102]

[0103] N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid diethyl ester

[0104]

[0105] N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid diethyl ester

[0106]

[0107] The present invention further provides methods for preparing some of the above compounds, but is not limited to the following methods:

[0108] Using 2-bromo-4-methylpyridine as the starting material, a strong base such as KHMDS, LDA, and n-BuLi is used to remove the hydrogen proton from the methyl group. The reaction is then carried out with a substituted ethyl pyridine-2-carboxylate at room temperature for a period of time, preferably 50-80 hours, more preferably 40-60 hours, to obtain compound 1. Compound 1 is then reacted with hydrazine hydrate under an acidic environment to complete the pyrazole formation, yielding compound 2. Acids used include 0.5N hydrochloric acid, acetic acid, 10% sulfuric acid, and trifluoroacetic acid. The pyrazole nitrogen atom in compound 2 is protected with triphenylmethane to yield compound 3. Compound 3 is then coupled with 4-methoxycarbonylphenylboronic acid via a Suzuki reaction using a palladium catalyst, including tetrakistriphenylphosphine palladium, ferrocene palladium, and palladium acetate. Compound 4 can be hydrolyzed to yield compound 5. Hydrolysis conditions include lithium hydroxide / THF, aqueous sodium hydroxide solution, and aqueous potassium hydroxide solution. Then, under the action of different condensing agents, the target molecules are generated by condensation with different amino acid esters, amino alcohols and heterocyclic compounds.

[0109] The condensing agents include: CDI, DCC, EDCI, etc.

[0110]

[0111] A pharmaceutical composition comprising the compound represented by general formula (I), its racemate, optical isomer, or pharmaceutically acceptable salt or solvate.

[0112] One application is the use of the compound represented by general formula (I), its racemate, optical isomer, pharmaceutically acceptable salt or solvate, or the pharmaceutical composition in the preparation of a drug for treating or preventing diseases mediated by the TGF-β signaling pathway.

[0113] The drug is an ALK5 kinase inhibitor.

[0114] The advantages of the present invention are:

[0115] The present invention provides a plexed amino acid or a similar structural compound, which has ALK5 inhibitory ability and can provide a new drug for treating or preventing diseases related to the TGF-β signaling pathway, while also improving the drug solubility and cell membrane permeability. DETAILED DESCRIPTION

[0116] The following is a detailed description of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-mentioned content of the present invention fall within the scope of the present invention.

[0117] Example 1: General Method for the Preparation of N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-phenylalanine Methyl Ester

[0118] Step 1:

[0119] Dissolve 1 mL (8.98 mmol) of 2-bromo-4-methylpyridine in 20 mL of dry tetrahydrofuran, cool to -50°C, and slowly add 10.90 mL (10.90 mmol) of a 1.0 mol / L solution of KHMDS in tetrahydrofuran dropwise. Incubate for 30 minutes. Dilute 1.35 mL (9.84 mmol) of ethyl pyridine-2-carboxylate with 20 mL of dry tetrahydrofuran and slowly add dropwise to the reaction solution. After the addition is complete, slowly warm to room temperature and continue the reaction for 16 hours. After the reaction is complete, pour the reaction solution into 10 mL of saturated citric acid solution. Remove the tetrahydrofuran under reduced pressure, and extract the remaining aqueous layer with 40 mL of dichloromethane. Wash the organic layer once with 15 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a black, viscous oil. Silica gel column chromatography (ethyl acetate:petroleum ether = 1:50 v / v) yields 1.99 g of a white solid (80% yield). 1 H NMR (400MHz, CDCl3) δ8.65 (ddd, J=4.8, 1.8, 0.9Hz, 1H), 8.23 (dd, J=5.0, 0.7Hz, 1H), 8.00 (dt, J=7.8, 1.1Hz,1H),7.80(td,J=7.7,1.7Hz,1H),7.49-7.39(m,2H),7.17(dd,J=5.0,1.5Hz,1H),4.46(s,2H).

[0120] Step 2:

[0121] Compound 1 (1.99 g, 7.21 mmol) was dissolved in 10 mL of anhydrous DMF. Glacial acetic acid (0.99 mL) was added and stirred for 10 minutes. DMF-DMA (1.44 mL, 10.82 mmol) was slowly added and the mixture was allowed to react at room temperature for 1.5 hours. Under an ice bath, 80% hydrazine hydrate (2.74 mL) was added dropwise. The mixture was reacted at 50°C under argon for 2 hours, then gradually cooled to room temperature and continued to react for 5 hours. After the reaction was complete, the entire reaction solution was poured into a separatory funnel, diluted with 150 mL of dichloromethane, washed five times with 30 mL of water, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (ethyl acetate:dichloromethane = 1:20 v / v) to yield 1.69 g of a light red oil with a yield of 78%. 1HNMR (400MHz, CDCl3) δ8.61 (ddd, J=4.9, 1.8, 1.0Hz, 1H), 8.25 (dd, J=5.1, 0.7Hz, 1H), 7.69 (s, 1H), 7. 62(td,J=7.8,1.8Hz,1H),7.48(dd,J=1.5,0.7Hz,1H),7.41(dt,J=8.0,1.1Hz,1H),7.26-7.19(m,2H).

[0122] Step 3:

[0123] Compound 2 (1.69 g, 5.61 mmol), DIPEA (1.39 mL), and triphenylmethane (2.33 g, 8.41 mmol) were dissolved in tetrahydrofuran (40 mL) and refluxed for 5 hours. After the reaction, the tetrahydrofuran was removed under reduced pressure, and the remaining oil was diluted with an appropriate amount of dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (acetone:dichloromethane = 1:100 v / v) to obtain 2.22 g of a yellow solid with a yield of 73%. 1 H NMR (400MHz, CDCl3) δ8.12 (dd, J=5.1, 0.7Hz, 1H), 7.68 (dt, J=8.0, 1.2Hz, 1H), 7.61 (td, J=7. 7,1.8Hz,1H),7.49(s,1H),7.45(dd,J=1.6,0.6Hz,1H),7.29-7.25(m,9H),7.19-7.12(m,9H).

[0124] Step 4:

[0125] Compound 3 (2.22 g (4.09 mmol)) and tetrakistriphenylphosphine palladium (0.33 mmol) were dissolved in dichloromethane and stirred at room temperature under argon for 30 minutes. 4-Methoxycarbonylphenylboronic acid (1.99 g (11.04 mmol)) and potassium carbonate (2.17 g) were dissolved in 30 mL of toluene and 20 mL of water, respectively, and added all at once to the reaction solution. The mixture was refluxed under argon for 3 hours. After the reaction, the toluene was removed under reduced pressure, and the remaining oil was diluted with 120 mL of dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on a silica gel column (ethyl acetate:dichloromethane = 1:45 v / v) to yield 1.47 g of a white solid (60% yield). 1HNMR (400MHz, CDCl3) δ8.52-8.43(m,2H),8.05-7.99(m,2H),7.92-7.87(m,2H),7.82(dd,J=1.7,0.8Hz,1H),7.70(dt,J =7.9,1.2Hz,1H),7.62(td,J=7.7,1.8Hz,1H),7.55(s,1H),7.27(dp,J=3.9,2.1Hz,9H),7.21-7.13(m,8H),3.85(s,3H).

[0126] Step 5:

[0127] Compound 4 (1.47 g, 2.45 mmol) was dissolved in 120 mL of methanol. 0.98 g of lithium hydroxide (24.50 mmol) and 15 mL of water were added and refluxed for 1 hour. The reaction system gradually became clear. After the reaction, ethanol was removed under reduced pressure, and 60 mL of water was added for redissolution. 1% hydrochloric acid solution was slowly added dropwise to adjust the pH to 6. A large amount of solid precipitated, which was filtered under reduced pressure to obtain 0.94 g of a gray solid with a yield of 65%.

[0128] Step 6: General method for the preparation of N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-phenylalanine methyl ester

[0129] Compound 5 584 mg (1 mmol) and EDCI . Dissolve 248 mg (1.3 mmol) of HCl in 40 mL of dichloromethane and stir for 30 minutes until the solution becomes clear. Add 1.3 mmol of L-phenylalanine methyl ester in dichloromethane dropwise and allow to react at room temperature for 5 hours. After the reaction, perform silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 v / v) to obtain a white solid. Add 20 mL of a 2.0 mol / L hydrogen chloride / ethyl acetate solution and stir at room temperature overnight. After the reaction, remove the ethyl acetate under reduced pressure, dissolve the remaining solid in 30 mL of dichloromethane and 10 mL of water, and adjust the pH to 8 with triethylamine in an ice bath. Transfer the reaction mixture to a separatory funnel and allow the liquid to stand. Wash the organic layer with water, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and chromatograph on a silica gel column (ethyl acetate:dichloromethane = 1:20 v / v) to obtain a colorless oil. ESI-MS (m / z): 526.35 [M+Na] + ; 1H NMR (400MHz, CDCl3) δ8.56-8.67(m,2H),7.94(d,J=8.5Hz,2H),7.69-7.77(m,4H),7.57(td,J=7.7,1.7Hz,1H),7.42(dt,J=7.9,1.1Hz,1H),7. 1-7.28(m,4H),7.17(s,1H),7.05-7.09(m,2H),6.66(d,J=7.6Hz,1H), 5.04(dt,J=7.6,5.7Hz,1H),3.70(s,3H),3.20(qd,J=13.8,5.7Hz,2H). 13 CNMR(100MHz, CDCl3)δ171.06,165.38,155.49,149.08,148.80,141.43,141.21,135.96,134.77,133.13, 128.32×2,127.63×2,126.53×2,126.21,126.09×2,122.49,121.62,120.69,119.85,52.56,51.47,36.87.

[0130] Example 2: Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-phenylalaninate

[0131] Synthesis Method: Refer to Example 1. Substitute D-phenylalanine methyl ester for L-phenylalanine methyl ester in equal moles to obtain the target compound with a yield of 82.2%. ESI-MS (m / z): 526.33 [M+Na] + ; 1 HNMR (400MHz, CDCl3) δ8.62(dd,J=15.2,4.9Hz,2H),7.95(d,J=8.4Hz,2H),7.67-7.82(m,4H),7.58(td,J=7.8,1.7Hz,1H),7.42(d,J=8.0Hz, 1H),7.24(m,4H),7.07(dd,J=7.9,1.6Hz,2H),6.62(d,J=7.6Hz,1H),5.05(dt,J=7.6,5.6Hz,1H),3.71(s,3H),3.21(qd,J=13.8,5.6Hz,2H).

[0132] Example 3: N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-alanine methyl ester

[0133] Synthesis Method: Refer to Example 1. Substitute L-alanine methyl ester for L-phenylalanine methyl ester in equal moles to obtain the target compound with a yield of 80.9%. ESI-MS (m / z): 450.29 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.67-8.58(m,2H),7.97(d,J=8.4Hz,2H),7.83(d,J=8 .4Hz,2H),7.77(d,J=0.8Hz,1H),7.73(s,1H),7.58(td,J=7.7,1.8Hz,1H), 7.43(d,J=7.8Hz,1H),7.27(dd,J=5.0,1.6Hz,1H),7.20-7.24(m,1H),6.81 (d,J=7.3Hz,1H),4.77(p,J=7.2Hz,1H),3.74(s,3H),1.48(d,J=7.2Hz,3H).

[0134] Example 4: Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-alaninate

[0135] Synthesis Method: Refer to Example 1. Substitute D-alanine methyl ester for L-phenylalanine methyl ester in equal moles to obtain the target compound with a yield of 83.1%. ESI-MS (m / z): 450.31 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.62(t,J=5.4Hz,2H),7.96(d,J=7.9Hz,2H),7.78(dd,J=30.3,10.9Hz,4H),7.58(t,J=7.8Hz,1H),7. 43(d,J=8.0Hz,1H),7.26(d,J=5.1Hz,2H),6.86(d,J=7.3Hz,1H),4.77(p,J=7.1Hz,1H),3.73(s,3H),1.48(d,J=7.1Hz,3H).

[0136] Example 5: Dimethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate

[0137] Synthesis Method: Refer to Example 1. Substitute L-aspartic acid dimethyl ester for L-phenylalanine methyl ester in equal moles to obtain the target compound with a yield of 81.6%. ESI-MS (m / z): 508.33 [M+Na] + ;1 HNMR (400MHz, CDCl3) δ8.55-8.71(m,2H),7.98(d,J=8.4Hz,2H),7.84(d,J=8 .4Hz,2H),7.79(d,J=0.9Hz,1H),7.74(s,1H),7.59(td,J=7.8,1.8Hz,1H),7. 44(d,J=8.0Hz,1H),7.21-7.32(m,3H),5.03(dt,J=8.3,4.4Hz,1H),3.74(s, 3H), 3.65 (s, 3H), 3.10 (dd, J=17.4, 4.3Hz, 1H), 2.95 (dd, J=17.3, 4.5Hz, 1H).

[0138] Example 6: Dimethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate

[0139] Synthesis Method: Refer to Example 1. Substitute an equal molar amount of D-aspartic acid dimethyl ester for L-phenylalanine methyl ester as described in Step 6 to obtain the target compound in 89.0% yield. ESI-MS (m / z): 508.30 [M+Na] + ; 1 HNMR (400MHz, CDCl3) δ8.63-8.78(m,2H),8.04(d,J=7.9Hz,2H),7.90(d,J=8.1Hz,2H),7.85(d,J=10.4Hz,2H),7.67(t,J=7.8Hz,1H),7.53(d,J=7 .8Hz,1H),7.38(dd,J=14.2,6.4Hz,2H),7.30(s,2H),4.97-5.28(m,1H), 3.81(s,3H),3.72(s,3H),3.17(d,J=16.3Hz,1H),3.02(d,J=16.4Hz,1H).

[0140] Example 7: Dimethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid ester

[0141] The synthesis method was similar to that described in Example 1. The target compound was obtained by replacing L-phenylalanine methyl ester with L-glutamic acid dimethyl ester in equal moles. The yield was 84.3%. ESI-MS (m / z): 522.29 [M+Na] + ; 1H NMR (400MHz, CDCl3) δ8.59-8.68(m,2H),7.98(d,J=8.5Hz,2H),7.85(d,J=8.5Hz,2H),7.78(d, J=0.8Hz,1H),7.73(s,1H),7.58(td,J=7.8,1.8Hz,1H),7.43(d,J=8.0Hz,1H),7.28(dd,J=5.1 ,1.6Hz,1H),7.21-7.24(m,1H),7.12(d,J=7.5Hz,1H),4.78(td,J=7.8,4.9Hz,1H),3.73(s,3H ),3.59(s,3H),2.36-2.53(m,2H),2.28(dt,J=14.2,4.9Hz,1H),2.11(dt,J=14.2,7.0Hz,1H).

[0142] Example 8: Dimethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid ester

[0143] Synthesis Method: Refer to Example 1. Substitute an equal molar amount of D-glutamic acid dimethyl ester for L-phenylalanine methyl ester as described in Step 6 to obtain the target compound with a yield of 84.9%. ESI-MS (m / z): 522.25 [M+Na] + ; 1 H-NMR (400MHz, CDCl3) δ8.72(d,J=5.0Hz,1H),8.63(d,J=4.5Hz,1H),8.06(d,J=8.0Hz,2 H),7.95-8.01(m,1H),7.91(d,J=8.1Hz,2H),7.85(d,J=7.8Hz,1H),7.67(s,1H),7.51(s ,1H),7.34(s,2H),7.14(d,J=7.5Hz,1H),4.80-4.90(m,1H),3.80(s,3H),3.66(s,2H),2 .51(dt,J=13.8,7.2Hz,1H),2.36(dt,J=13.5,6.4Hz,1H),2.19(dt,J=14.5,7.2Hz,1H).

[0144] Example 9: Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-methionine

[0145] The synthesis method was similar to that described in Example 1. The target compound was obtained by replacing L-phenylalanine methyl ester with L-methionine methyl ester in equal moles, yielding 77.6%. ESI-MS (m / z): 488.34 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ8.63 (dd, J=12.2, 5.0Hz, 2H), 7.98 (d, J=8.2Hz, 2H), 7.84 (d, J=8.4Hz,2H),7.71-7.80(m,2H),7.57(dd,J=7.7,1.7Hz,1H),7.44(d,J=8.0Hz,1H) ,7.28(dd,J=5.1,1.6Hz,1H),7.23(t,J=4.1Hz,1H),7.04(d,J=7.6Hz,1H),4.90(td ,J=7.2,5.1Hz,1H),3.74(s,3H),2.49-2.62(m,2H),2.08-2.31(m,2H),2.05(s,3H).

[0146] Example 10: Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-methionine

[0147] The synthesis method was similar to that described in Example 1. The method described in Step 6 was modified by replacing L-phenylalanine methyl ester with D-methionine methyl ester in equal moles to obtain the target compound with a yield of 78.8%. ESI-MS (m / z): 488.29 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ8.61-8.65(m,2H),8.03(d,J=8.2Hz,2H),7.93(d,J=8.3Hz ,2H),7.73-7.83(m,2H),7.55(dd,J=7.6,1.7Hz,1H),7.43(d,J=8.1Hz,1H),7.30 (dd,J=5.2,1.7Hz,1H),7.22(t,J=4.1Hz,1H),7.02(d,J=7.7Hz,1H),4.92(td,J= 7.2,5.1Hz,1H),3.74(s,3H),2.47-2.61(m,2H),2.07-2.30(m,2H),2.04(s,3H).

[0148] Example 11: N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-valine methyl ester

[0149] Synthesis Method: Refer to Example 1. Substitute L-valine methyl ester for L-phenylalanine methyl ester in equal moles to obtain the target compound with a yield of 93.1%. ESI-MS (m / z): 478.36 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.59-8.72(m,2H),7.96-8.04(m,2H),7.77-7.88(m, 3H),7.74(s,1H),7.59(td,J=7.8,1.8Hz,1H),7.41-7.47(m,1H),7.30(dd ,J=5.0,1.6Hz,1H),7.21-7.26(m,1H),6.64(d,J=8.6Hz,1H),4.75(dd,J= 8.6, 4.9Hz, 1H), 3.73 (s, 3H), 2.23 (d, J = 6.9Hz, 1H), 0.95 (t, J = 8.2Hz, 6H).

[0150] Example 12: Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-valine

[0151] Synthesis Method: Refer to Example 1. Substitute an equal molar amount of D-valine methyl ester for L-phenylalanine methyl ester as described in Step 6 to obtain the target compound in 90.3% yield. ESI-MS (m / z): 478.36 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.62-8.76(m,2H),8.01-8.07(m,2H),7.79-7.88(m, 3H),7.76(s,1H),7.62(td,J=7.9,2.1Hz,1H),7.43-7.49(m,1H),7.33(dd ,J=5.1,1.8Hz,1H),7.24-7.28(m,1H),6.67(d,J=8.7Hz,1H),4.77(dd,J= 8.6, 4.9Hz, 1H), 3.75 (s, 3H), 2.25 (d, J = 7.0Hz, 1H), 0.97 (t, J = 8.2Hz, 6H).

[0152] Example 13: Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-leucinate

[0153] Synthesis Method: Refer to Example 1. Substitute L-leucine methyl ester for L-phenylalanine methyl ester in equal moles to obtain the target compound with a yield of 91.3%. ESI-MS (m / z): 492.38 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.62(t,J=5.1Hz,2H),7.95(d,J=8.1Hz,2H),7.75-7.82(m,4H),7.57(td,J=7.8,1.7Hz,1H),7.43(d,J=8.0Hz ,1H),7.21-7.30(m,2H),6.71(d,J=8.3Hz,1H),4.82(td,J=7.8,4.5Hz,1H),3.71(s,3H),1.59-1.76(m,3H),0.92(t,J=6.5Hz,6H).

[0154] Example 14: Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-leucinate

[0155] Synthesis Method: Refer to Example 1. Substitute D-leucine methyl ester for L-phenylalanine methyl ester in equal moles to obtain the target compound with a yield of 92.1%. ESI-MS (m / z): 492.40 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.65(m,2H),7.98(d,J=8.1Hz,2H),7.78-7.82(m,4H),7.59(m,1H),7.46(d,J=8.0Hz,1H),7.23- 7.34(m,2H),6.73(d,J=8.3Hz,1H),4.83(td,J=7.8,4.5Hz,1H),3.73(s,3H),1.60-1.79(m,3H),0.92(t,J=6.5Hz,6H).

[0156] Example 15: N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-glycine methyl ester

[0157] Synthesis Method: Refer to Example 1. Substitute glycine methyl ester for L-phenylalanine methyl ester in equal moles to obtain the target compound with a yield of 84.5%. ESI-MS (m / z): 436.29 [M+Na] + ; 1H NMR (400MHz, CDCl3) δ8.62(dd,J=8.7,5.1Hz,2H),7.96(d,J=8.1Hz,2H),7.83(d,J=8.0Hz,2H),7.75(d,J=15.5Hz,2 H),7.59(td,J=7.3,1.8Hz,1H),7.42-7.46(m,1H),7.21-7.29(m,2H),6.82(s,1H),4.17-4.23(m,2H),3.74(s,3H).

[0158] Example 16: N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-tyrosine methyl ester

[0159] The synthesis method was similar to that described in Example 1. The target compound was obtained by replacing L-phenylalanine methyl ester with L-tyrosine methyl ester in equal moles, yielding 87.2%. ESI-MS (m / z): 542.30 [M+Na] + ; 1 H NMR (400MHz, DMSO-d6) δ9.20 (s, 1H), 8.90 (d, J = 7.7Hz, 1H), 8.53-8.78 (m, 2H), 8.34 (s, 1H), 7.80-8.21 (m, 7H), 7.3 6-7.55(m,2H),7.06-7.17(m,2H),6.66-6.78(m,2H),4.60(dd,J=9.7,7.7Hz,1H),3.67(s,3H),2.95-3.18(m,2H).

[0160] Example 17: Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-tyrosine

[0161] The synthesis method was similar to that described in Example 1. The target compound was obtained by replacing L-phenylalanine methyl ester with D-tyrosine methyl ester in equal moles, yielding 85.4%. ESI-MS (m / z): 542.29 [M+Na] + ; 1H NMR (400MHz, DMSO-d6) δ9.22 (s, 1H), 8.88 (d, J = 7.7Hz, 1H), 8.51-8.75 (m, 2H), 8.32 (s, 1H), 8.20-7.78 (m, 7H), 7.3 5-7.49(m,2H),7.04-7.16(m,2H),6.61-6.74(m,2H),4.58(dd,J=9.7,7.7Hz,1H),3.65(s,3H),2.91-3.16(m,2H).

[0162] Example 18: N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-proline methyl ester

[0163] Synthesis Method: Refer to Example 1. Substitute L-proline methyl ester for L-phenylalanine methyl ester in equal moles to obtain the target compound with a yield of 72.1%. ESI-MS (m / z): 476.37 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.54-8.63(m,2H),7.84-7.95(m,2H),7.71-7.80(m,2H),7.38-7.61(m,4H),7.25-7.31(m,2H), 4.63(dd,J=8.4,5.1Hz,1H),3.71(s,3H),3.53-3.62(m,1H),3.46-3.51(m,1H),1.94-2.34(m,1H),1.85-1.98(m,3H).

[0164] Example 19: N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-proline methyl ester

[0165] The synthesis method was similar to that described in Example 1. The target compound was obtained by replacing L-phenylalanine methyl ester with D-proline methyl ester in equal moles, yielding 73.7%. ESI-MS (m / z): 476.33 [M+Na] + ; 1H NMR (400MHz, CDCl3) δ9.59-8.67(m,2H),7.90-7.99(m,2H),7.72-7.81(m,2H),7.40-7.63(m,4H),7.23-7.35(m,2H), 4.64(dd,J=8.4,5.1Hz,1H),3.72(s,3H),3.57-3.66(m,1H),3.51-3.55(m,1H),1.91-2.33(m,1H),1.83-1.94(m,3H).

[0166] Example 20: (S)-N-(1-hydroxy-3-phenylpropan-2-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide

[0167] Synthesis Method: Refer to Example 1. Substitute (S)-phenylpropanol in an equal molar ratio for L-phenylalanine methyl ester to obtain the target compound in 80.1% yield. ESI-MS (m / z): 474.63 [MH] - ; 1 H NMR(400MHz,MeOD)δ8.41-8.45(m,2H),8.14(s,1H),7.50-7.87(m,7H),7.36(dd,J=7.6,4.9Hz,1H),7.14-7.28(m,5H),7.05 -7.11(m,1H),4.27(dq,J=8.5,5.7Hz,1H),3.57(d,J=5.5Hz,2H),2.94(dd,J=13.7,6.1Hz,1H),2.78(dd,J=13.8,8.5Hz,1H).

[0168] Example 21: (R)-N-(1-hydroxy-3-phenylpropan-2-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide

[0169] The synthesis method was similar to that described in Example 1. The method described in Step 6 was modified by replacing L-phenylalanine methyl ester with (R)-phenylpropanol in equal moles to obtain the target compound in 82.8% yield. ESI-MS (m / z): 474.65 [MH] - ; 1H NMR (400MHz, MeOD) δ8.35-8.59(m,2H),8.09(s,1H),7.51-7.85(m,7H),7.35(ddd,J=7.6,5.0,1.2Hz,1H),7.13-7.26(m,5H),7.07(ddt ,J=8.6,6.1,1.8Hz,1H),4.27(dq,J=8.5,5.7Hz,1H),3.57(d,J=5.5Hz,2H),2.93(dd,J=13.7,6.1Hz,1H),2.78(dd,J=13.7,8.5Hz,1H).

[0170] Example 22: (S)-N-(1-hydroxypropan-2-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide

[0171] Synthesis Method: Refer to Example 1. Substitute (S)-phenylglycine for L-phenylalanine methyl ester in an equal molar ratio using (S)-phenylglycine alcohol to obtain the target compound in 87.6% yield. ESI-MS (m / z): 460.44 [MH] - ; 1 H NMR (400MHz, DMSO-d6) δ8.80(d,J=8.1Hz,1H),8.57(s,2H),8.01-8.15(m,5H),7.78-7.98(m,2H),7.62(d,J=10.7Hz,1H),7.37 -7.47(m,4H),7.34(t,J=7.6Hz,2H),7.20-7.28(m,1H),5.11(td,J=8.1,5.4Hz,1H),4.97(t,J=5.9Hz,1H),3.64-3.80(m,2H).

[0172] Example 23: N-(1-cinnamoylpiperidin-4-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide

[0173] Synthesis Method: Referring to Example 1, the method described in Step 6 was modified, substituting 1-(4-aminopiperidin-1-yl)-3-phenylprop-2-en-1-one in equal moles for L-phenylalanine methyl ester to obtain the target compound in a 77.2% yield. ESI-MS (m / z): 553.50 [MH] - ; 1H NMR (400MHz, CDCl3) δ8.57(m,2H),7.91(d,J=8.3Hz,2H),7.82(d,J=8.4Hz,2 H),7.68-7.75(m,2H),7.51-7.59(m,2H),7.35-7.47(m,3H),7.16-7.30(m,7H ),6.70-6.87(m,2H),4.65(d,J=13.3Hz,1H),3.99-4.29(m,2H),3.20(t,J=12 .7Hz,1H),2.79(t,J=12.7Hz,1H),1.95-2.18(m,2H),1.42(d,J=12.2Hz,2H).

[0174] Example 24: (E)-N-(1-(3-(4-methoxyphenyl)acryloyl)piperidin-4-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide

[0175] Synthesis Method: Referring to Example 1, the method described in Step 6 was modified, substituting 1-(4-aminopiperidin-1-yl)-3-(4-methoxyphenyl)prop-2-en-1-one in equal moles for L-phenylalanine methyl ester to obtain the target compound in a 72.5% yield. ESI-MS (m / z): 583.68 [MH] - ; 1 H NMR (400MHz, CDCl3) δ8.59(m,2H),7.94(d,J=8.1Hz,2H),7.82(d,J=8.2Hz,2H),7.73(d, J=14.4Hz,2H),7.49-7.60(m,2H),7.44(d,J=8.0Hz,1H),7.31-7.39(m,2H),7.22-7.27( m,1H),6.75-6.83(m,2H),6.70(d,J=15.4Hz,1H),6.56(d,J=7.8Hz,1H),4.66(s,1H),4. 01-4.28(m,2H),3.74(s,3H),3.20(s,1H),2.80(s,1H),2.06(m,2H),1.37-1.50(m,2H).

[0176] Example 25: (E)-N-(1-(3-(4-bromophenyl)acryloyl)piperidin-4-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide

[0177] Synthesis Method: Referring to Example 1, the method described in Step 6 was modified by replacing L-phenylalanine methyl ester with 1-(4-aminopiperidin-1-yl)-3-(4-bromophenyl)prop-2-en-1-one in equal moles to obtain the target compound in a 75.6% yield. ESI-MS (m / z): 631.410 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ8.62(t,J=5.1Hz,2H),8.34-8.50(m,2H),8.17(s,1H),8.13-8.06(m,2H) ,7.92-8.01(m,3H),7.80(d,J=7.9Hz,1H),7.68-7.75(m,2H),7.58-7.66(m,2H),7.43-7.53(m,3 H),7.38(d,J=15.4Hz,1H),4.47(d,J=13.0Hz,1H),4.34(d,J=13.5Hz,1H),4.13(qt,J=7.0,5.2, 3.8Hz,1H),3.20-3.31(m,1H),2.85(t,J=12.3Hz,1H),1.85-1.98(m,2H),1.50(t,J=13.4Hz,2H).

[0178] Example 26: Methyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-phenylalaninate

[0179] Synthesis Method: Refer to Example 1. Substitute 6-methylpyridine-2-carboxylic acid ethyl ester for ethyl pyridine-2-carboxylate in equal moles to obtain the target compound in 72.1% yield. ESI-MS (m / z): 540.20 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.45-8.57(m,2H),7.82(d,J=8.5Hz,2H),7.60-7.72(m,4H),7.51-7.56(m,1H),7.37-7.42(m,1H),7.22-7 .28(m,4H),7.05-7.12(m,3H),6.66(d,J=7.6Hz,1H),4.98-5.04(m,1H),3.73(s,3H),3.20(dd,J=13.8,5.7Hz,2H),2.69(s,3H).

[0180] Example 27: Methyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-phenylalaninate

[0181] The synthesis method was similar to that described in Example 1. The method described in step 1 was modified by replacing ethyl pyridine-2-carboxylate with an equal molar amount of ethyl 6-methylpyridine-2-carboxylate. The method described in step 6 was modified by replacing L-phenylalanine methyl ester with an equal molar amount of D-phenylalanine methyl ester to obtain the target compound in a 70.2% yield. ESI-MS (m / z): 540.22 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.46-8.59(m,2H),7.84(d,J=8.5Hz,2H),7.60-7.75(m,4H),7.53-7.56(m,1H),7.38-7.43(m,1H),7.22-7 .28(m,4H),7.05-7.12(m,3H),6.65(d,J=7.6Hz,1H),4.98-5.06(m,1H),3.74(s,3H),3.22(dd,J=13.8,5.7Hz,2H),2.71(s,3H).

[0182] Example 28: Dimethyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate

[0183] The synthesis method was similar to that described in Example 1. The method described in step 1 was modified by replacing ethyl pyridine-2-carboxylate with an equal molar amount of ethyl 6-methylpyridine-2-carboxylate. The method described in step 6 was modified by replacing methyl L-phenylalaninate with an equal molar amount of dimethyl L-aspartate. The target compound was obtained in a yield of 75.2%. ESI-MS (m / z): 522.17 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.76(d,J=5.1Hz,1H),8.73(d,J=5.1Hz,1H),8.08(d,J=8.5Hz,2H ),7.94(s,1H),7.92(d,J=8.3Hz,2H),7.84(s,1H),7.73(d,J=2.9Hz,1H),7.59(s,1H),7 .41(s,1H),7.33(d,J=10.6Hz,1H),7.29(d,J=4.0Hz,1H),7.22(s,1H),5.40-5.30(m,1 H),3.82(s,3H),3.72(s,3H),3.15(d,J=4.2Hz,1H),3.04(d,J=4.5Hz,1H),2.67(s,3H).

[0184] Example 29: Dimethyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate

[0185] The synthesis method was similar to that described in Example 1. The method described in step 1 was modified by replacing ethyl pyridine-2-carboxylate with an equal molar amount of ethyl 6-methylpyridine-2-carboxylate. The method described in step 6 was modified by replacing L-phenylalanine methyl ester with an equal molar amount of dimethyl D-aspartate. The target compound was obtained in a yield of 76.2%. ESI-MS (m / z): 522.17 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.75(d,J=5.1Hz,1H),8.72(d,J=5.1Hz,1H),8.10(d,J=8.5Hz,2H ),7.92(s,1H),7.90(d,J=8.3Hz,2H),7.85(s,1H),7.73(d,J=2.9Hz,1H),7.60(s,1H),7 .43(s,1H),7.33(d,J=10.6Hz,1H),7.27(d,J=4.0Hz,1H),7.22(s,1H),5.40-5.32(m,1 H),3.81(s,3H),3.70(s,3H),3.15(d,J=4.2Hz,1H),3.05(d,J=4.5Hz,1H),2.67(s,3H).

[0186] Example 30: Dimethyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid ester

[0187] The synthesis method was similar to that described in Example 1. The method described in step 1 was modified by replacing ethyl pyridine-2-carboxylate with an equal molar amount of ethyl 6-methylpyridine-2-carboxylate. The method described in step 6 was modified by replacing methyl L-phenylalanine with dimethyl L-glutamate. The target compound was obtained in a 73.0% yield. ESI-MS (m / z): 536.19 [M+Na] + ; 1H NMR (400MHz, CDCl3) δ8.74(d,J=5.0Hz,1H),8.61(d,J=4.9Hz,1H),8.12(d,J=3.7Hz,2H),8.06(d,J= 2.1Hz,1H),8.04(d,J=3.1Hz,2H),7.98(d,J=6.1Hz,1H),7.87(s,1H),7.71(d,J=1.5Hz,1H),7.54(t ,J=7.8Hz,1H),7.36(dd,J=5.1,1.5Hz,1H),7.30(s,1H),7.18(dd,J=6.4,2.2Hz,1H),5.27-5.43(m, 1H),3.98(s,3H),3.95(s,3H),2.48(s,3H),2.18-2.27(m,1H),1.97-2.07(m,1H),1.59-1.71(m,2H).

[0188] Example 31: Dimethyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid ester

[0189] The synthesis method was similar to that described in Example 1. The method described in step 1 was modified by replacing ethyl pyridine-2-carboxylate with an equal molar amount of ethyl 6-methylpyridine-2-carboxylate. The method described in step 6 was modified by replacing L-phenylalanine methyl ester with an equal molar amount of dimethyl D-glutamate. The target compound was obtained in a yield of 76.5%. ESI-MS (m / z): 536.17 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.72(d,J=5.1Hz,1H),8.06(d,J=8.5Hz,2H),7.92(d,J=8.5Hz ,2H),7.87(s,1H),7.80(s,1H),7.54(t,J=7.8Hz,1H),7.37(dd,J=5.1,1.6Hz,1H),7 .30(d,J=7.8Hz,1H),7.15(d,J=7.7Hz,2H),4.85(td,J=7.7,4.9Hz,1H),3.80(s,3H) ,3.67(s,3H),2.61(s,3H),2.41-2.59(m,2H),2.28-2.42(m,1H),2.12-2.27(m,1H).

[0190] Example 32: Dimethyl N-(4-(4-(3-(6-ethylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate

[0191] The synthesis method was similar to that described in Example 1. The method described in step 1 was modified by replacing ethyl pyridine-2-carboxylate with an equal molar amount of ethyl 6-ethylpyridine-2-carboxylate. The method described in step 6 was modified by replacing L-phenylalanine methyl ester with an equal molar amount of dimethyl L-aspartate. The target compound was obtained in a yield of 76.6%. ESI-MS (m / z): 538.17 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.70(m,1H),8.65(d,J=5.1Hz,1H),7.95(d,J=8.5Hz,2H),7.88(s,1H), 7.79(d,J=8.3Hz,2H),7.64(s,1H),7.59(d,J=2.9Hz,1H),7.50(s,1H),7.33(s,1H),7.21(d, J=10.6Hz,1H),7.17(d,J=4.0Hz,1H),7.07(s,1H),5.21-5.32(m,1H),3.76(s,3H),3.64(s,3 H), 3.05 (d, J = 4.2Hz, 1H), 2.97 (d, J = 4.5Hz, 1H), 2.62 (q, J = 7.2Hz, 2H), 1.17 (t, J = 7.2Hz, 3H).

[0192] Example 33: Dimethyl N-(4-(4-(3-(6-ethylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate

[0193] The synthesis method was similar to that in Example 1. The method described in step 1 was modified by replacing ethyl pyridine-2-carboxylate with an equal molar amount of ethyl 6-ethylpyridine-2-carboxylate. The method described in step 6 was modified by replacing L-phenylalanine methyl ester with an equal molar amount of dimethyl D-aspartate. The target compound was obtained in a yield of 74.3%. ESI-MS (m / z): 538.18 [M+Na] + ; 1H NMR (400MHz, CDCl3) δ8.73(m,1H),8.66(d,J=5.1Hz,1H),7.97(d,J=8.5Hz,2H),7.90(s,1H), 7.80(d,J=8.3Hz,2H),7.65(s,1H),7.61(d,J=2.9Hz,1H),7.51(s,1H),7.34(s,1H),7.21(d, J=10.6Hz,1H),7.18(d,J=4.0Hz,1H),7.09(s,1H),5.21-5.30(m,1H),3.77(s,3H),3.64(s,3 H), 3.04 (d, J = 4.2Hz, 1H), 2.96 (d, J = 4.5Hz, 1H), 2.66 (q, J = 7.2Hz, 2H), 1.15 (t, J = 7.2Hz, 3H).

[0194] Example 34: Dimethyl N-(4-(4-(3-(6-ethylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid ester

[0195] The synthesis method was similar to that described in Example 1. The method described in step 1 was modified by replacing ethyl pyridine-2-carboxylate with an equal molar amount of ethyl 6-ethylpyridine-2-carboxylate. The method described in step 6 was modified by replacing L-phenylalanine methyl ester with an equal molar amount of dimethyl L-glutamate. The target compound was obtained in a 70.0% yield. ESI-MS (m / z): 550.20 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.68-8.73(m,2H),8.01-8.10(m,5H),7.89(d,J=6.1Hz, 1H),7.71-7.87(m,2H),7.47(t,J=7.8Hz,1H),7.30(dd,J=5.1,1.5Hz,1H),7. 18-7.25(m,2H),5.20-5.37(m,1H),3.88(s,3H),3.95(s,3H),2.57(q,J=7.2H z,2H),2.44(s,3H),2.11-2.27(m,1H),1.92-2.07(m,1H),1.41-1.71(m,5H).

[0196] Example 35: Dimethyl N-(4-(4-(3-(6-ethylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid ester

[0197] The synthesis method was similar to that in Example 1. The method described in step 1 was modified by replacing ethyl pyridine-2-carboxylate with an equal molar amount of ethyl 6-ethylpyridine-2-carboxylate. The method described in step 6 was modified by replacing L-phenylalanine methyl ester with an equal molar amount of dimethyl D-glutamate. The target compound was obtained in a 68.5% yield. ESI-MS (m / z): 550.21 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.68-8.73(m,2H),8.01-8.10(m,5H),7.89(d,J=6.1Hz, 1H),7.71-7.87(m,2H),7.474(t,J=7.8Hz,1H),7.30(dd,J=5.1,1.5Hz,1H),7 .18-7.25(m,2H),5.20-5.37(m,1H),3.88(s,3H),3.95(s,3H),2.55(q,J=7.2 Hz,2H),2.43(s,3H),2.13-2.27(m,1H),1.92-2.06(m,1H),1.40-1.71(m,5H).

[0198] Example 36: Dimethyl N-(4-(4-(3-(6-methoxypyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate

[0199] The synthesis method was similar to that in Example 1. The method described in step 1 was modified by replacing ethyl pyridine-2-carboxylate with an equal molar amount of ethyl 6-methoxypyridine-2-carboxylate. The method described in step 6 was modified by replacing L-phenylalanine methyl ester with an equal molar amount of dimethyl L-aspartate. The target compound was obtained in an 80.3% yield. ESI-MS (m / z): 538.17 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.72-8.79 (m, 2H), 8.01 (d, J = 8.5Hz, 2H), 7.88 (s, 1H), 7.80(d,J=8.3Hz,2H),7.76(s,1H),7.59-7.68(m,2H),7.38(s,1H),7.31(d,J =10.6Hz,1H),7.22(d,J=4.0Hz,1H),7.16(s,1H),5.20-5.32(m,1H),3.87(s ,3H),3.82(s,3H),3.72(s,3H),3.13(d,J=4.2Hz,1H),3.03(d,J=4.5Hz,1H).

[0200] Example 37: Dimethyl N-(4-(4-(3-(6-methoxypyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate

[0201] Synthesis was performed using the same method as in Example 1. Equal moles of ethyl 6-methoxypyridine-2-carboxylate were substituted for ethyl pyridine-2-carboxylate in step 1. Equal moles of L-phenylalanine methyl ester were substituted for dimethyl D-aspartate in step 6 to obtain the target compound in 85.8% yield. ESI-MS (m / z): 538.20 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.71-8.75 (m, 2H), 8.02 (d, J = 8.5Hz, 2H), 7.86 (s, 1H), 7.81(d,J=8.3Hz,2H),7.78(s,1H),7.59-7.69(m,2H),7.39(s,1H),7.32(d,J =10.6Hz,1H),7.22(d,J=4.0Hz,1H),7.16(s,1H),5.22-5.31(m,1H),3.88(s ,3H),3.81(s,3H),3.71(s,3H),3.10(d,J=4.2Hz,1H),3.05(d,J=4.5Hz,1H).

[0202] Example 38: Dimethyl N-(4-(4-(3-(6-methoxypyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid ester

[0203] The synthesis method was similar to that described in Example 1. The method described in step 1 was modified by replacing ethyl pyridine-2-carboxylate with an equal molar amount of ethyl 6-methoxypyridine-2-carboxylate. The method described in step 6 was modified by replacing methyl L-phenylalanine with dimethyl L-glutamate. The target compound was obtained in an 82.5% yield. ESI-MS (m / z): 552.18 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.66-8.74(m,2H),8.03-8.11(m,5H),7.88(d,J=6.1Hz,1H),7.70-7.86(m,2H),7.47(m,1H),7.31-7.3 6(m,1H),7.18-7.23(m,2H),5.21-5.36(m,1H),3.95(s,3H),3.88(s,3H),3.82(s,3H),2.15-2.44(m,4H),1.43-2.05(m,6H).

[0204] Example 39: Dimethyl N-(4-(4-(3-(6-methoxypyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid ester

[0205] The synthesis method was similar to that described in Example 1. The method described in step 1 was modified by replacing ethyl pyridine-2-carboxylate with an equal molar amount of ethyl 6-methoxypyridine-2-carboxylate. The method described in step 6 was modified by replacing L-phenylalanine methyl ester with an equal molar amount of dimethyl D-glutamate. The target compound was obtained in an 80.9% yield. ESI-MS (m / z): 552.16 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.65-8.75(m,2H),8.02-8.12(m,5H),7.85(d,J=6.1Hz,1H),7.70-7.82(m,2H),7.45(m,1H),7.31-7.3 4(m,1H),7.18-7.21(m,2H),5.20-5.34(m,1H),3.94(s,3H),3.86(s,3H),3.81(s,3H),2.15-2.43(m,4H),1.43-2.06(m,6H).

[0206] Example 40: Diethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate

[0207] Synthesis Method: Refer to Example 1. Substitute L-aspartic acid diethyl ester for L-phenylalanine methyl ester in equal moles to obtain the target compound with a yield of 81.8%. ESI-MS (m / z): 536.19 [M+Na] + ; 1 HNMR(400MHz, CDCl3)δ8.55-8.70(m,2H),7.97(d,J=8.4Hz,2H),7.85(d,J= 8.4Hz,2H),7.74-7.79(m,2H),7.59(td,J=7.8,1.8Hz,1H),7.42(d,J=8.0Hz ,1H),7.21-7.32(m,3H),5.03(dt,J=8.3,4.4Hz,1H),3.94-4.11(m,4H),3. 10(dd,J=17.4,4.3Hz,1H),2.94(dd,J=17.3,4.5Hz,1H),1.13-1.24(m,6H).

[0208] Example 41: Diethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate

[0209] Synthesis Method: Refer to Example 1. Substitute an equal molar amount of D-aspartic acid diethyl ester for L-phenylalanine methyl ester as described in Step 6 to obtain the target compound with a yield of 83.1%. ESI-MS (m / z): 536.20 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.51-8.68(m,2H),7.91(d,J=8.4Hz,2H),7.80(d,J=8 .4Hz,2H),7.71-7.75(m,2H),7.59(td,J=7.8,1.8Hz,1H),7.40(d,J=8.0Hz ,1H),7.21-7.34(m,3H),5.01(dt,J=8.3,4.4Hz,1H),3.94-4.14(m,4H),3. 11(dd,J=17.4,4.3Hz,1H),2.93(dd,J=17.3,4.5Hz,1H),1.13-1.25(m,6H).

[0210] Example 42: Diethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid ester

[0211] Synthesis Method: Refer to Example 1. Substitute L-phenylalanine methyl ester with L-glutamic acid diethyl ester in equal moles to obtain the target compound with a yield of 84.5%. ESI-MS (m / z): 550.20 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.53-8.61(m,2H),7.92(d,J=8.5Hz,2H),7.80(d,J=8.5Hz,2H),7.71-7 .74(m,2H),7.53(td,J=7.8,1.8Hz,1H),7.41(d,J=8.0Hz,1H),7.22(dd,J=5.1,1.6Hz,1H),7 .19-7.20(m,1H),7.13(d,J=7.5Hz,1H),4.78(td,J=7.8,4.9Hz,1H),3.90-4.16(m,4H),2.33 -2.50(m,2H),2.25(dt,J=14.2,4.9Hz,1H),2.10(dt,J=14.2,7.0Hz,1H),1.18-1.29(m,6H).

[0212] Example 43: Diethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid ester

[0213] Synthesis Method: Refer to Example 1. Substitute an equal molar amount of D-glutamic acid diethyl ester for L-phenylalanine methyl ester as described in Step 6 to obtain the target compound in 87.3% yield. ESI-MS (m / z): 550.21 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ8.51-8.60(m,2H),7.91(d,J=8.5Hz,2H),7.81(d,J=8.5Hz,2H),7.70-7 .74(m,2H),7.52(td,J=7.8,1.8Hz,1H),7.39(d,J=8.0Hz,1H),7.21(dd,J=5.1,1.6Hz,1H),7 .19-7.20(m,1H),7.14(d,J=7.5Hz,1H),4.78(td,J=7.8,4.9Hz,1H),3.91-4.16(m,4H),2.33 -2.51(m,2H),2.24(dt,J=14.2,4.9Hz,1H),2.11(dt,J=14.2,7.0Hz,1H),1.18-1.31(m,6H).

[0214] Example 44: ALK5 enzyme activity test

[0215] Select LanthaScreen TMThe ALK5 inhibitory activity of the synthesized molecules was tested using the Eu Kinase Binding Assay. GW788388 was used as a control. Each compound was prepared into a 10 mM stock solution in dimethyl sulfoxide, diluted 1:3, and stored in 384-PP (LABCYTE, P-05525). Prepare 1X Kinase Buffer A to dilute the following reaction reagents. Using a micropipette (LABCYTE), add 15 nL of compound to a reaction plate (Perkin Elmer). Add 5 μL of ALK5 stock solution (Thermo Scientific Forma) to each well, followed by 5 μL of Eu-Anti-GST Antibody solution (Thermo Scientific Forma) to each well, mix for 15 minutes, and then add 5 μL of KinaseTracer 178 solution (Thermo Scientific Forma) to each well and vortex to mix. The total reaction system contained 50mM Tris (pH 7.5), 150mM NaCl, 0.5mM EDTA, 0.02% Triton X-100, 2mM DTT, 50% Glycerol, 50mM HEPES (pH 7.5), 10mM MgCl2, 1mM EGTA, 0.01% Brij-35, 5nM ALK5, 2nM Eu-Anti-GST Antibody, 20nM Kinase Tracer 178, and 0.1% DMSO. The reaction plate was incubated at 30°C for 50 minutes. The assay was performed using a multi-label microplate reader (purchased from PE). Data were analyzed using GraphPad Prism 5Demo. The IC values of related compounds were calculated using a nonlinear regression model. 50 The results were repeated three times and the average values were taken. All the compounds obtained above had corresponding activities. For details, see Table 1.

[0216] Table 1. Inhibitory activity of compounds against ALK5

[0217]

[0218]

Claims

1. A peptide-like biaryl-substituted pyrazole compound, characterized in that: The compound is represented by the general formula (I), its racemate, optical isomer, and pharmaceutically acceptable salt or solvate: In formula (I), R1 is selected from an amino acid ester residue lacking an N-terminal amino group, an amino alcohol residue lacking an N-terminal amino group, a C5-C8 membered heterocycle which is unsubstituted or substituted with at least one of the following groups, wherein the following groups are amino, a cinnamoyl group which is unsubstituted or substituted with a benzene ring; R2 is hydrogen, a C1-C6 alkyl group, or a C1-C6 alkoxy group; Wherein, the amino acid ester is methyl ester or ethyl ester.

2. The peptoid biaryl-substituted pyrazole compound according to claim 1, characterized in that: The compound is represented by the general formula (I), its racemate, optical isomer, and pharmaceutically acceptable salt or solvate: In formula (I), R1 is selected from an amino acid ester residue lacking an N-terminal amino group, an amino alcohol residue lacking an N-terminal amino group, a C5-C7 membered heterocycle which is unsubstituted or substituted with at least one of the following groups, wherein the following groups are amino, a cinnamoyl group which is unsubstituted or substituted with a benzene ring; R2 is hydrogen, a C1-C4 alkyl group or a C1-C4 alkoxy group; Wherein, the amino acid ester is methyl ester or ethyl ester.

3. The peptoid biaryl-substituted pyrazole compound according to claim 2, characterized in that: The compound is represented by the general formula (I), its racemate, optical isomer, and pharmaceutically acceptable salt or solvate: In formula (I), R1 is phenylalanine methyl ester or phenylalanine ethyl ester; Alanine methyl ester, alanine ethyl ester; Proline methyl ester, proline ethyl ester; aspartic acid dimethyl ester, aspartic acid diethyl ester; Dimethyl glutamate, diethyl glutamate; Methionine methyl ester, methionine ethyl ester; Valine methyl ester, valine ethyl ester; leucine methyl ester, leucine ethyl ester; Glycine methyl ester, glycine ethyl ester; tyrosine methyl ester, tyrosine ethyl ester; phenylalaninol; phenylglycinol; alaninol; 4-aminopiperidine, N-substituted-4-aminopiperidine, wherein the N-substituent is cinnamoyl and cinnamoyl substituted on the benzene ring; R2 is hydrogen, C1-C2 alkyl or methoxy.

4. The peptoid biaryl-substituted pyrazole compound according to claim 3, characterized in that: The compound is the following compound, its racemate, its S optical isomer, its R optical isomer, or its pharmaceutically acceptable salt or solvate; The following compound is N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-phenylalanine methyl ester N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-phenylalanine methyl ester N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-alanine methyl ester Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-alaninate Dimethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate Dimethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate Dimethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid ester Dimethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid ester Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-methionine Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-methionine Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-valine Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-valine Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-leucinate Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-leucinate N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-glycine methyl ester N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-tyrosine methyl ester Methyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-tyrosine N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-proline methyl ester N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-proline methyl ester (S)-N-(1-Hydroxy-3-phenylpropan-2-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide (R)-N-(1-Hydroxy-3-phenylpropan-2-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide (S)-N-(1-Hydroxypropan-2-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide N-(1-Cinnamoylpiperidin-4-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide (E)-N-(1-(3-(4-methoxyphenyl)acryloyl)piperidin-4-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide (E)-N-(1-(3-(4-bromophenyl)acryloyl)piperidin-4-yl)-4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzamide N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-phenylalanine methyl ester Methyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-phenylalaninate Dimethyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate Dimethyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate Dimethyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid ester Dimethyl N-(4-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid ester Dimethyl N-(4-(4-(3-(6-ethylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate Dimethyl N-(4-(4-(3-(6-ethylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate Dimethyl N-(4-(4-(3-(6-ethylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid ester Dimethyl N-(4-(4-(3-(6-ethylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid ester Dimethyl N-(4-(4-(3-(6-methoxypyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate Dimethyl N-(4-(4-(3-(6-methoxypyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate Dimethyl N-(4-(4-(3-(6-methoxypyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid ester Dimethyl N-(4-(4-(3-(6-methoxypyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid ester Diethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-aspartate Diethyl N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-aspartate N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-L-glutamic acid diethyl ester N-(4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)benzoyl)-D-glutamic acid diethyl ester 5. A pharmaceutical composition, characterized in that: A compound represented by the general formula (I) according to claim 1, its racemate, optical isomer, or pharmaceutically acceptable salt or solvate thereof.

6. The use according to claim 1 or 5, characterized in that: Use of the compound represented by general formula (I), its racemate, optical isomer, pharmaceutically acceptable salt or solvate, or the pharmaceutical composition according to claim 5 in the preparation of drugs for treating or preventing diseases mediated by the TGF-β signaling pathway.

7. The use of the compound according to claim 6, characterized in that: The drug is an ALK5 kinase inhibitor.

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