N-(benzothiazole-2-yl) benzamide compound or derivative and application thereof

Abstract

The invention discloses an N-(benzothiazole-2-yl) benzamide compound or a derivative of the N-(benzothiazole-2-yl) benzamide compound and application of the N-(benzothiazole-2-yl) benzamide compound. The compound has a TRPC ion channel inhibition effect and can block opening of an intracellular calcium ion channel, so that the compound has a potential treatment value in various diseases. The preparation method is simple, the synthetic route is simple, the operation is convenient, and the yield is higher. The compound provided by the invention can be used as a TRPC antagonist and is used for preparing anti-renal fibrosis drugs, anti-renal injury drugs, anti-pulmonary hypertension drugs and anti-tumor drugs. In addition, the compound can be administered in various ways, including oral administration, subcutaneous injection, intraperitoneal injection and intratumor injection. Experimental data show that the compound disclosed by the invention shows a strong inhibition effect in a cellular level anti-fibrosis model and has no obvious toxicity to cells. Therefore, the invention provides a new drug choice for the treatment of related diseases, and has a wide application prospect.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly relates to an N-(benzothiazol-2-yl)benzamide compound or its derivative and its application. Background Art

[0002] Renal fibrosis is a hallmark pathological process in the progression of chronic kidney disease (CKD) and end-stage renal disease (ESRD), which is characterized by the excessive accumulation of extracellular matrix in the renal tubulointerstitium, ultimately leading to the loss of renal function. The canonical transient receptor potential (TRPC) channel family consists of calcium-permeable non-selective cation channels, which play a key role in sensing cellular and environmental stimuli and are involved in regulating the progression of kidney diseases. According to sequence homology and functional characteristics, the mammalian TRPC subfamily contains seven transmembrane proteins and can be divided into four subgroups: TRPC1, TRPC2, TRPC4 / 5, and TRPC3 / 6 / 7. The TRPC1 / 4 / 5 homotetrameric or heterotetrameric channels are activated through the G-protein-coupled phospholipase C (PLC) signaling pathway, resulting in the hydrolysis of phosphatidylinositol bisphosphate (PIP2). This process generates inositol trisphosphate (IP3), which binds to the IP3 receptor on the endoplasmic reticulum and promotes extracellular Ca 2+ influx through store-operated calcium entry (SOCE). In contrast, the TRPC3 / 6 / 7 channels are activated by the PIP2 hydrolysis product diacylglycerol (DAG) and belong to receptor-operated calcium entry (ROCE) channels. TRPC channels are widely expressed in various tissues and play a key role in physiological and pathological processes, highlighting their importance as potential therapeutic targets for disease prevention and treatment.

[0003] Among the TRPC channels, TRPC3 / 6 / 7 are widely expressed in tissues such as the lung, kidney, and brain and are involved in various physiological functions. Among them, TRPC6 is highly expressed in podocytes and is a key component of the glomerular slit diaphragm, which forms the renal filtration barrier. Gain-of-function mutations in the TRPC6 gene can enhance calcium signal transduction and are associated with hereditary focal segmental glomerulosclerosis (FSGS) - a kidney disease characterized by podocyte damage and progression to end-stage renal failure. Renal fibrosis, as a typical pathological change in end-stage chronic kidney disease (including diabetic nephropathy, hypertensive nephropathy, and IgA nephropathy), is characterized by the progressive loss of renal function, excessive deposition of renal interstitial tissue, and abnormal accumulation of extracellular matrix (ECM). Studies have shown that the expression of TRPC6 is increased in a unilateral ureteral obstruction (UUO)-induced fibrosis model, and interstitial fibrosis can be significantly reduced and the upregulation of fibrosis-related gene expression can be inhibited by gene knockout or drug inhibition of TRPC6. The abnormal expression of the TRPC6 channel may be an important pathogenic factor in kidney diseases, but its clinical application still requires further research. Summary of the Invention

[0004] In view of the deficiencies of the above prior art, the present invention provides the following, which is specifically realized through the following technologies.

[0005] An N-(benzothiazol-2-yl)benzamide compound or a derivative thereof, the structure of the compound being as shown in Formula 1:

[0006] Formula 1

[0007] Wherein R1-R2 are each independently selected from at least one of: hydrogen, aldehyde group, carboxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamino group;

[0008] Or R1-R2 are each independently selected from: an alkane chain containing a primary amine, an alkane chain containing a secondary amine, an alkane chain containing a tertiary amine;

[0009] Or R1-R2 are connected through at least one of a heterocycle containing a primary amine, a heterocycle containing a secondary amine, a heterocycle containing a tertiary amine, a saturated ring containing a primary amine, a saturated ring containing a secondary amine, a saturated ring containing a tertiary amine, a saturated ring to form a cyclic structure;

[0010] The number n of the side chains is each independently 1-6;

[0011] Preferably, the number n of the side chains is each independently 1-4;

[0012] The R3 groups are each independently selected from the following groups, the wavy line represents the bonding position;

[0013]

[0014] R4, R5, R6, R7 are each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, alkylamino, cycloalkyl, nitro, trifluoromethyl, amino, ester group, cyano group;

[0015] Preferably, R4 is selected from methoxy;

[0016] Preferably, R5, R6, R7 are each independently selected from hydrogen;

[0017] The structure shown in Formula 1 does not include the structure shown in Formula 2;

[0018] Formula 2.

[0019] Preferably, R1-R2 are each independently selected from: C1-C3 alkyl group, C1-C3 alkoxy group, C1-C3 alkylamino group.

[0020] Preferably, R1-R2 are each independently selected from: hydrogen, methyl, ethyl, , , ;

[0021] Or R1-R2 form a cyclic structure, and the structure is selected from any one of the following groups:

[0022] .

[0023] According to the above technical features, the most preferred compound structure obtained by the present invention is selected from:

[0024] ;

[0025] In the above structures, Me represents: methyl, Et represents: ethyl, and Bco represents: tert-butoxycarbonyl.

[0026] According to the above technical features, the compound or its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its solvates or its hydrates.

[0027] According to the above technical features, the salt is a salt formed by the compound and an alkali metal.

[0028] According to the above technical features, the number of crystal water molecules of the hydrate is any integer from 1 to 16.

[0029] A pharmaceutical composition comprising a therapeutically effective amount of an N-(benzothiazol-2-yl)benzamide compound or its derivative and a pharmaceutically acceptable pharmaceutical excipient.

[0030] According to the above technical features, the application of an N-(benzothiazol-2-yl)benzamide compound or its derivative in the preparation of an anti-renal fibrosis drug, an anti-renal injury drug, an anti-pulmonary hypertension drug, and an anti-tumor drug.

[0031] According to the above technical features, the dosage form prepared by the drug is: oral preparation, injection, tablet.

[0032] The compound involved in the present invention can be synthesized according to the following reaction route:

[0033] According to the above technical features, the synthesis route of an N-(benzothiazol-2-yl)benzamide compound or its derivative:

[0034] ;

[0035] Reaction conditions: (Ⅰ), HBTU, HOBT, DIPEA, DMF, 25 °C, overnight reaction;

[0036] (Ⅱ), K2CO3, DMF, 60 °C, overnight reaction;

[0037] (Ⅲ), DMP, DCM, 25 °C, overnight reaction;

[0038] (Ⅳ), NaBH3CN, MeOH, DCM, 25 °C, overnight reaction.

[0039] The calculated amount of benzothiazol-2-amine (Compound A), HBTU, HOBT, DIPEA and benzoic acid compounds (Compound B) were stirred overnight at 25 °C in DMF, and N-(benzothiazol-2-yl)benzamide (Compound C) was obtained through an amide condensation reaction; Compound C, Compound D and anhydrous potassium carbonate were weighed and stirred overnight at 60 °C in DMF, and Compound E was obtained through a nucleophilic substitution reaction; Compound D was reacted with Dess-Martin periodinane (DMP) to obtain Compound F; Compound F was obtained through a reductive amination reaction to obtain Compound H.

[0040] According to the above technical features, when N-(benzothiazol-2-yl)benzamide compounds or their derivatives are used as TRPC inhibitors, they block the opening of intracellular calcium channels.

[0041] Compared with the prior art, the advantages of the present invention are as follows:

[0042] 1. The N-(benzothiazol-2-yl)benzamide compounds or their derivatives of the present invention have an inhibitory effect on TRPC ion channels, thereby inhibiting calcium influx, reducing oxidative stress, regulating neuronal excitability, vasoconstriction and immune cell activation, and have potential therapeutic value in various diseases.

[0043] 2. The preparation method of the present invention is simple, the synthetic route is concise, the operation method is convenient, and the yield is relatively high.

[0044] 3. The N-(benzothiazol-2-yl)benzamide compounds or their derivatives of the present invention can be used as TRPC antagonists for preparing anti-renal fibrosis drugs, anti-renal injury drugs, anti-pulmonary arterial hypertension drugs and anti-tumor drugs. Brief Description of the Drawings

[0045] Figure 1 Compound X26 dose-dependently reduced the expression of fibrosis-related genes in TGF-β-induced HK-2 cells.

[0046] Figure 2 Immunofluorescence experiments showed that Compound X26 reduced the expression of the fibrosis-related protein α-SMA.

[0047] Figure 3 Detection of the contents of serum creatinine and blood urea nitrogen in mice.

[0048] Figure 4 Detection of the expression level of the TRPC6 gene in mouse kidney tissues.

[0049] Figure 5Detection of the expression levels of α-SMA and Fibronectin, genes related to renal fibrosis in mice.

[0050] Figure 6 HE staining, Masson staining and IHC analysis of α-SMA staining of mouse kidney tissue. Detailed implementation manners

[0051] The technical solutions of the present invention will be described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0052] All reagents used in the present invention are commercially available. Unless otherwise specified, the purity of substances is analytical pure and they are used directly without purification; anhydrous solvents (such as dichloromethane, tetrahydrofuran) are prepared and stored according to standard operating procedures; thin-layer chromatography silica gel (GF254, Qingdao Ocean Chemical Industry) is selected for preparing thin-layer chromatography, and silica gel (H, 200 - 300 / 100 - 200 mesh, Qingdao Ocean Chemical Industry) is selected for column chromatography. Nuclear magnetic resonance spectra Figure 1 1H-NMR (400 MHz) and 13C-NMR (100 / 150 MHz) are both measured using a Bruker Avance-400 / 600 type nuclear magnetic resonance tester. The solvents used for nuclear magnetic resonance spectrum testing are DMSO-d6 or CDCl3 (with an internal standard of 0.03% TMS). ppm represents the chemical shift, and the peak shapes of nuclear magnetic resonance spectra are represented by singlet (s), doublet (d), doublet of doublets (dd), triplet (t), quartet (q), multiplet (m), etc. High-resolution mass spectrometry (HRMS) is measured using an Agilent 6530 accurate-mass Q-TOF LC-MS system (ESI).

[0053] Example 1: Preparation of Compound F1

[0054]

[0055] Weigh the calculated amount of 5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (1.0 eq.) (Compound A), HBTU (1.5 eq.), HOTB (1.5 eq.), DIPEA (4.0 eq.) and 4-methoxybenzo[d]thiazol-2-amine (1.2 eq.) (Compound B1) in DMF, and stir the mixture overnight at 25 °C. After monitoring the reaction by TLC until completion, add saturated brine and ethyl acetate for extraction three times. After the collected organic phase is washed with saturated brine three times, it is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of petroleum ether / ethyl acetate (40:1, v / v) to obtain the white solid Compound C1.

[0056] Weigh the calculated amount of N-(4-methoxybenzo[d]thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound C1), 4-bromobutan-1-ol (3.0 eq.) (Compound D1) and anhydrous potassium carbonate (3.0 eq.) in DMF, and stir the mixture overnight at 65 °C. After monitoring the reaction by TLC until completion, add saturated brine and ethyl acetate for extraction three times. After the collected organic phase is washed with saturated brine three times, it is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of petroleum ether / ethyl acetate (40:1, v / v) to obtain the white solid Compound E1.

[0057] Weigh the calculated amount of N-(4-hydroxybutyl)-N-(4-methoxybenzo[d]thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound E1), Dess-Martin periodinane (3.0 eq.) in DCM, and stir the mixture overnight at 25 °C. After monitoring the reaction by TLC until completion, concentrate the reaction solution and then subject it to silica gel column chromatography with a mobile phase of petroleum ether / ethyl acetate (30:1, v / v) to obtain the white solid Compound F1.

[0058] Example 2: Preparation of Compound X1

[0059]

[0060] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(3-oxopropyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F3), dimethylamine (3.0 eq.), and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract three times with dichloromethane. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain the white solid Compound X1.

[0061] 1 H NMR (600 MHz, DMSO-d6) δ 7.95 (dd, J = 10.6, 2.8 Hz, 2H), 7.47 (dd, J = 7.8, 0.8 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.17 (d, J = 8.1 Hz, 2H), 4.84 - 4.81 (m, 2H), 3.98 (s, 3H), 2.79 (d, J = 9.0 Hz, 4H), 2.43 (t, J = 6.5 Hz, 2H), 2.21 (s, 6H), 1.97 - 1.92 (m, 2H), 1.78 - 1.75 (m, 4H). 13 C NMR (151 MHz, DMSO-d6) δ 173.64, 166.17, 147.09, 141.25, 136.46, 133.75, 129.70, 128.92, 127.51, 126.13, 125.28, 124.73, 115.19, 110.39, 56.53, 56.45, 47.08, 45.01, 28.97, 28.87, 26.88, 22.64, 22.51.

[0062] HRMS (ESI) calcd for C 24 H 29 N3O2S [M + H] + 424.1980, found 424.2047.

[0063] Example 3: Preparation of Compound X2

[0064]

[0065] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(4-oxobutyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F4), dimethylamine (3.0 eq.), and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract with dichloromethane three times. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain the white solid Compound X2.

[0066] 1 H NMR (600 MHz, DMSO-d6) δ 7.97 - 7.92 (m, 2H), 7.47 (dd, J = 7.8, 0.8 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.2 Hz, 2H), 4.83 - 4.78 (m, 2H), 3.97 (s, 3H), 2.81 - 2.76 (m, 4H), 2.28 (t, J = 7.2 Hz, 2H), 2.10 (s, 6H), 1.81 (q, J = 7.5 Hz, 2H), 1.78 - 1.74 (m, 4H), 1.52 (p, J = 7.3 Hz, 2H). 13 C NMR(151 MHz, DMSO-d6) δ 173.56, 147.05, 141.20, 136.45, 133.73, 129.66, 128.87, 127.49, 126.12, 125.20, 124.72, 115.17, 110.37, 58.52, 56.39, 48.18, 44.98, 28.94, 28.89, 26.90, 24.20, 22.61, 22.50.

[0067] HRMS (ESI) calcd for C 25 H 31 N3O2S [M + H] + 438.2137, found 438.2202.

[0068] Example 4: Preparation of Compound X3

[0069]

[0070] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(4-oxobutyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F5), dimethylamine (3.0 eq.), and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract with dichloromethane three times. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain the white solid Compound X3.

[0071] 1 H NMR (400 MHz, Chloroform-d) δ 8.05 (d, J = 8.1 Hz, 2H), 7.24 (s,1H), 7.18 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.90 (d, J = 7.8 Hz,1H), 4.90 - 4.79 (m, 2H), 3.95 (s, 3H), 2.86 - 2.77 (m, 4H), 2.31 - 2.27 (m, 2H),2.22 (s, 6H), 1.88 (p, J = 7.5 Hz, 2H), 1.83 - 1.77 (m, 4H), 1.57 (p, J = 7.1Hz, 2H), 1.45 (p, J = 7.2 Hz, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 175.36,167.25, 147.46, 141.68, 137.02, 134.39, 130.49, 129.11, 129.08, 126.72,126.19, 124.34, 115.38, 109.43, 59.82, 56.21, 48.84, 45.46, 29.86, 29.71,29.64, 27.42, 24.95, 23.37, 23.28.

[0072] HRMS (ESI) calcd for C 26 H 33 N3O2S [M + H] + 452.2293, found 452.2372.

[0073] Example 5: Preparation of Compound X4

[0074]

[0075] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(3-oxopropyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F3), diethylamine (3.0 eq.), and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract three times with dichloromethane. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain the white solid compound X4.

[0076] 1 H NMR (600 MHz, DMSO-d6) δ 7.95 (d, J = 4.5 Hz, 2H), 7.53 - 7.40 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 (dd, J = 8.0, 6.3 Hz, 2H), 4.83 - 4.76 (m, 2H), 3.97 (s, 3H), 3.17 (s, 2H), 2.78 (d, J = 6.6 Hz, 4H), 2.66 (s, 2H), 2.57 (s, 4H), 1.99 - 1.93 (m, 2H), 1.78 - 1.73 (m, 4H), 0.98 (t, J = 7.1 Hz, 6H). 13 CNMR (151 MHz, DMSO-d6) δ 173.60, 166.17, 147.06, 141.26, 136.48, 133.74, 129.67, 128.87, 127.52, 126.13, 125.28, 124.73, 115.20, 110.39, 56.45, 49.39, 48.60, 47.18, 46.12, 28.96, 28.88, 22.64, 22.51.

[0077] HRMS (ESI) calcd for C 26 H 33 N3O2S [M + H] + 452.2293, found 452.2364.

[0078] Example 6: Preparation of Compound X5

[0079]

[0080] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(4-oxobutyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F4), diethylamine (3.0 eq.) and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1, and stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract with dichloromethane three times. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain the white solid compound X5.

[0081] 1 H NMR (600 MHz, DMSO-d6) δ 7.94 (d, J = 9.6 Hz, 2H), 7.47 (dd, J = 7.8, 0.9 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.18 - 7.15 (m, 2H), 4.83 - 4.78 (m, 2H), 3.97 (s, 3H), 2.80 - 2.76 (m, 4H), 2.42 (q, J = 7.2 Hz, 6H), 1.82 (p, J = 7.5 Hz, 2H), 1.76 (q, J = 3.0 Hz, 4H), 1.52 (p, J = 7.4 Hz, 2H), 0.90 (t, J = 7.1 Hz, 6H). 13 C NMR (151 MHz, DMSO-d6) δ 173.59, 166.21, 147.07, 141.19, 136.45, 133.76, 129.65, 128.84, 127.49, 126.10, 124.73, 115.18, 110.40, 56.40, 51.92, 48.29, 46.22, 41.74, 28.94, 28.90, 27.07, 24.04, 22.61, 22.50, 11.89, 11.62.

[0082] HRMS (ESI) calcd for C 27 H 35 N3O2S [M + H] + 466.2450, found 466.2519.

[0083] Example 7: Preparation of Compound X6

[0084]

[0085] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(4-oxobutyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F5), diethylamine (3.0 eq.) and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract three times with dichloromethane. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain the white solid compound X6.

[0086] 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (d, J = 8.2 Hz, 2H), 7.24 (s, 1H), 7.19 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 4.89 - 4.81 (m, 2H), 3.95 (s, 3H), 2.87 - 2.79 (m, 4H), 2.55 (q, J = 7.1 Hz, 4H), 2.49 - 2.43 (m, 2H), 1.89 (p, J = 7.6 Hz, 2H), 1.81 (s, 4H), 1.57 (p, J = 7.6 Hz, 2H), 1.46 - 1.39 (m, 2H), 1.02 (t, J = 7.1 Hz, 6H). 13 C NMR (151 MHz, Chloroform-d) δ 175.27, 167.17, 147.39, 141.61, 136.94, 134.33, 130.43, 129.02, 128.99, 126.66, 126.09, 124.31, 115.26, 109.37, 56.15, 52.84, 48.79, 46.86, 29.80, 29.66, 29.64, 26.48, 25.07, 23.31, 23.22, 11.35.

[0087] HRMS (ESI) calcd for C 28 H37 N3O2S [M + H] + 480.2606, found 480.2683.

[0088] Example 8: Preparation of Compound X7

[0089]

[0090] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(3-oxopropyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F3), piperidine (3.0 eq.), and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract three times with dichloromethane. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain the white solid Compound X7.

[0091] 1 H NMR (600 MHz, DMSO-d6) δ 7.95 (d, J = 7.9 Hz, 1H), 7.91 (s, 1H), 7.48 - 7.44 (m, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 4.85 - 4.81 (m, 2H), 3.96 (s, 3H), 2.79 (dd, J = 8.9, 5.0 Hz, 4H), 2.42 (t, J = 6.5 Hz, 2H), 2.26 (s, 4H), 1.95 (t, J = 7.2 Hz, 2H), 1.78 - 1.74 (m, 4H), 1.44 - 1.40 (m, 4H), 1.33 (s, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 173.59, 166.32, 147.10, 141.21, 136.51, 133.81, 129.61, 128.86, 127.56, 126.12, 125.43, 124.66, 115.13, 110.31, 56.41, 56.27, 54.02, 47.44, 28.96, 28.91, 25.95, 25.53, 24.15, 22.64, 22.52.

[0092] HRMS (ESI) calcd for C 27 H 33 N3O2S [M + H] + 464.2293, found 464.2358.

[0093] Example 9: Preparation of Compound X8

[0094]

[0095] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(4-oxobutyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F4), piperidine (3.0 eq.) and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract three times with dichloromethane. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain a pale yellow solid compound X8.

[0096] 1 H NMR (600 MHz, DMSO-d6) δ 7.94 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 7.8 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 (dd, J = 7.8, 4.1 Hz, 2H), 4.84 - 4.77 (m, 2H), 3.97 (s, 3H), 2.82 - 2.75 (m, 4H), 2.40 - 2.19 (m, 6H), 1.83 (q, J = 7.4 Hz, 2H), 1.76 (p, J = 3.2 Hz, 4H), 1.54 (p, J = 7.3 Hz, 2H), 1.45 - 1.39 (m, 4H), 1.34 (d, J = 14.5 Hz, 2H). 1313C NMR (151 MHz, DMSO-d6) δ 173.60, 166.21, 141.19, 136.46, 129.66, 128.86, 127.48, 126.09, 125.22, 124.73, 115.18, 110.39, 57.99, 56.40, 53.91, 48.23, 41.53, 28.94, 28.90, 27.06, 25.46, 24.06, 23.53, 22.62, 22.51, 11.46.

[0097] HRMS (ESI) calcd for C 28 H 35 N3O2S [M + H] + 478.2450, found 478.2516.

[0098] Example 10: Preparation of Compound X9

[0099]

[0100] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(4-oxobutyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F5), piperidine (3.0 eq.) and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1, and stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract with dichloromethane three times. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain the pale yellow solid Compound X9.

[0101] 11H NMR (400 MHz, Chloroform-d) δ 8.07 (d, J = 6.7 Hz, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 4.92 - 4.84 (m, 2H), 3.97 (s, 3H), 3.66 (t, J = 6.5 Hz, 2H), 2.87 - 2.80 (m, 4H), 1.95 - 1.89 (m, 2H), 1.83 (q, J = 3.3 Hz, 4H), 1.69 (d, J = 8.0 Hz, 2H), 1.56 - 1.51 (m, 2H), 1.26 (d, J = 12.6 Hz, 8H), 0.89 (dt, J = 13.3, 7.3 Hz, 2H). 13 13C NMR (151 MHz, Chloroform-d) δ 175.19, 167.09, 147.25, 136.85, 134.16, 130.29, 128.93, 128.90, 126.50, 124.16, 115.22, 109.23, 62.79, 56.02, 48.56, 32.33, 29.66, 29.49, 29.23, 23.17, 23.07, 23.03.

[0102] HRMS (ESI) calcd for C 29 H 37 N3O2S [M + H] + 492.2606, found 492.2680.

[0103] Example 11: Preparation of Compound X10

[0104]

[0105] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(4-oxobutyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F4), ammonium acetate (3.0 eq.), and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract three times with dichloromethane. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain the pale yellow solid Compound X10.

[0106] 1 H NMR (600 MHz, DMSO-d6) δ 7.89 (d, J = 7.6 Hz, 2H), 7.46 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 4.75 (t, J = 7.3 Hz, 2H), 3.91 (s, 3H), 2.75 - 2.67 (m, 4H), 2.61 (t, J = 7.2 Hz, 2H), 1.81 - 1.76 (m, 2H), 1.68 (p, J = 3.2 Hz, 4H), 1.50 (q, J = 7.4 Hz, 2H), 1.10 (t, J = 7.1 Hz, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 173.55, 166.19, 147.01, 141.06, 136.36, 133.71, 129.63, 128.77, 127.50, 126.04, 125.17, 124.69, 115.15, 110.33, 56.33, 48.35, 48.00, 42.00, 28.87, 26.87, 22.55, 22.45.

[0107] HRMS (ESI) calcd for C 23 H 27 N3O2S [M + H] + 410.1824, found 410.1884.

[0108] Example 12: Preparation of Compound X11

[0109]

[0110] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(4-oxobutyl)-2,3-dihydro-1H-indene-5-carboxamide (1.0 eq.) (Compound F6), dimethylamine (3.0 eq.) and acetic acid (0.1 eq.) in a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract three times with dichloromethane. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain the white solid compound X11.

[0111] 1 H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 9.1 Hz, 2H), 7.16 (t, J = 7.9 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.89 - 4.82 (m, 2H), 3.93 (s, 3H), 2.92 (q, J = 7.4 Hz, 4H), 2.45 - 2.39 (m, 2H), 2.22 (s, 6H), 2.10 - 2.04 (m, 2H), 1.87 (q, J = 7.5 Hz, 2H), 1.62 (p, J = 7.6 Hz, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 175.43, 167.34, 148.91, 147.43, 144.37, 135.31, 129.06, 128.05, 126.09, 125.54, 124.42, 124.11, 115.38, 109.43, 59.32, 56.21, 48.52, 45.18, 33.21, 32.89, 27.64, 25.69, 24.68.

[0112] HRMS (ESI) calcd for C 24 H 29 N3O2S [M + H] + 424.1980, found 424.2061.

[0113] Example 13: Preparation of Compound X12

[0114]

[0115] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(4-oxobutyl)-2,3-dihydro-1H-indene-5-carboxamide (1.0 eq.) (Compound F6), diethylamine (3.0 eq.), and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract three times with dichloromethane. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with dichloromethane / methanol (100:1, v / v) as the mobile phase to obtain the white solid compound X12.

[0116] 1 H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.25 - 7.22 (m, 2H), 7.18 (t, J = 7.9 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 4.86 (t, J = 7.3 Hz, 2H), 3.94 (s, 3H), 2.92 (q, J = 7.0 Hz, 4H), 2.64 (p, J = 7.1, 6.1 Hz, 6H), 2.08 (q, J = 7.4 Hz, 2H), 1.88 (q, J = 7.4 Hz, 2H), 1.69 (p, J = 7.6 Hz, 2H), 1.04 (t, J = 7.2 Hz, 6H). 13 C NMR (151 MHz, Chloroform-d) δ 171.42 (d, J = 1215.3 Hz), 148.96, 147.45, 144.41, 135.30, 129.04, 128.02, 126.03, 125.50, 124.50, 124.12, 115.38, 109.47, 56.27, 52.47, 48.41, 46.71, 33.22, 32.90, 27.75, 25.71, 10.72.

[0117] HRMS (ESI) calcd for C 26 H 33 N3O2S [M + H] +452.2293, found 452.2363.

[0118] Example 14: Preparation of Compound X13

[0119]

[0120] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-5,5,8,8-tetramethyl-N-(4-oxobutyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F7), dimethylamine (3.0 eq.) and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1, and stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract with dichloromethane three times. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with dichloromethane / methanol (100:1, v / v) to obtain the white solid compound X13.

[0121] 1 H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 1.7 Hz, 1H), 8.10 (dd, J = 8.2, 1.7 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 4.92 - 4.87 (m, 2H), 3.98 (s, 3H), 3.01 (q, J = 7.3 Hz, 2H), 2.58 - 2.50 (m, 2H), 2.31 (s, 6H), 1.97 - 1.91 (m, 2H), 1.71 (s, 4H), 1.34 (s, 6H), 1.31 (s, 6H). 13 C NMR (151 MHz, Chloroform-d) δ 175.05, 167.36, 149.38, 147.28, 144.94, 134.11, 128.75, 127.95, 126.45, 126.43, 125.66, 124.54, 115.24, 109.40, 58.26, 56.18, 47.64, 43.64, 43.63, 34.99, 34.94, 34.63, 34.44, 31.93, 31.76, 29.71, 27.12, 14.14.

[0122] HRMS (ESI) calcd for C 29 H 39 N3O2S [M + H] + 494.2763, found 494.2841.

[0123] Example 15: Preparation of Compound X14

[0124]

[0125] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-5,5,8,8-tetramethyl-N-(4-oxobutyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F7), diethylamine (3.0 eq.) and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1, and stir the reaction solution overnight at 25 °C. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract with dichloromethane three times. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography with dichloromethane / methanol (100:1, v / v) to obtain a pale yellow solid compound X14.

[0126] 1 H NMR (600 MHz, Chloroform-d) δ 8.28 (d, J = 1.8 Hz, 1H), 8.08 (dd, J = 8.2, 1.8 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.28 (dd, J = 7.9, 1.1 Hz, 1H), 7.24 (t, J = 7.9 Hz, 1H), 6.96 (dd, J = 8.1, 1.1 Hz, 1H), 4.94 (t, J = 7.0 Hz, 2H), 4.01 (s, 3H), 2.92 - 2.88 (m, 2H), 2.81 (q, J = 7.2 Hz, 4H), 2.03 - 1.98 (m, 2H), 1.80 (dt, J = 15.3, 7.6 Hz, 2H), 1.72 (s, 4H), 1.34 (s, 6H), 1.31 (s, 6H), 1.14 (t, J = 7.2 Hz, 6H). 1313C NMR (151 MHz, Chloroform-d) δ 175.06, 167.36, 149.38, 147.29, 144.96, 134.10, 128.70, 127.92, 126.42, 126.40, 125.61, 124.61, 115.20, 109.45, 56.24, 52.11, 47.62, 46.45, 46.01, 34.99, 34.94, 34.63, 34.43, 31.92, 31.76, 29.71, 27.30, 9.22.

[0127] HRMS (ESI) calcd for C 31 H 43 N3O2S [M + H] + 522.3076, found 522.3154.

[0128] Example 16: Preparation of Compound X15

[0129]

[0130] Weigh the calculated amount of tert-butyl (1-(4-(N-(4-methoxybenzothiazol-2-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamido)butyl)piperidin-3-yl)carbamate (1.0 eq.) and trifluoroacetic acid (100 eq.) in DCM, and stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract with dichloromethane three times. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (50:1, v / v) to obtain the light brown solid compound X15.

[0131] 11H NMR (600 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.45 (t, J = 9.0 Hz, 2H), 7.29 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 4.79 (t, J = 7.2 Hz, 2H), 3.96 (s, 3H), 2.86 (s, 1H), 2.73 (s, 1H), 2.46 (d, J = 7.1 Hz, 1H), 2.32 (t, J = 7.1 Hz, 2H), 1.89 (s, 2H), 1.82 (dd, J = 13.1, 6.7 Hz, 2H), 1.75 (d, J = 5.7 Hz, 1H), 1.66 (s, 4H), 1.59 - 1.53 (m, 3H), 1.29 (s, 6H), 1.26 (s, 6H), 0.94 (t, J = 7.1 Hz, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 173.59, 166.10, 148.76, 147.08, 144.19, 133.80, 127.43, 127.17, 126.49, 126.09, 125.23, 124.76, 115.20, 110.44, 57.53, 56.46, 52.61, 48.38, 47.22, 45.66, 34.39, 34.35, 34.24, 33.95, 31.72, 31.41, 27.04, 23.80, 11.45.

[0132] HRMS (ESI) calcd for C 25 H 31 N3O2S [M + H] + 549.3185, found 549.3262.

[0133] Example 17: Preparation of Compound X16

[0134]

[0135] Weigh tert-butyl (1-((4-(N-(4-methoxybenzothiazol-2-yl)-2,3-dihydro-1H-inden-5-carboxamido)butyl)piperidin-3-yl)carbamate (1.0 eq.) and trifluoroacetic acid (100 eq.) in DCM, and stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract with dichloromethane three times. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (50:1, v / v) to obtain the pale yellow solid compound X16.

[0136] 1 H NMR (600 MHz, DMSO-d6) δ 8.08 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.47 - 7.45 (m, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 4.79 (t, J = 7.4 Hz, 2H), 3.96 (s, 3H), 2.91 (q, J = 7.7 Hz, 4H), 2.68 (d, J = 8.8 Hz, 1H), 2.64 - 2.60 (m, 1H), 2.56 (s, 1H), 2.29 (dt, J = 6.9, 3.5 Hz, 2H), 2.07 - 2.03 (m, 2H), 1.85 - 1.77 (m, 4H), 1.70 - 1.62 (m, 2H), 1.53 (p, J = 7.4 Hz, 4H), 1.38 - 1.32 (m, 1H), 0.98 - 0.91 (m, 1H). 13 C NMR(151 MHz, DMSO-d6) δ 173.8, 166.2, 148.4, 147.1, 143.9, 134.8, 127.6, 127.4, 125.2, 124.8, 124.8, 124.0, 115.2, 110.3, 61.7, 57.6, 56.4, 53.1, 48.2, 47.7, 33.0, 32.5, 32.2, 27.1, 25.1, 23.7, 14.8, 8.0.

[0137] HRMS (ESI) calcd for C 27 H 35 N4O2S [M + H] +479.2475, found 479.2489.

[0138] Example 18: Preparation of Compound X17

[0139]

[0140] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(4-oxobutyl)-2,3-dihydro-1H-indene-5-carboxamide (1.0 eq.) (Compound F6), N,N-dimethylpiperidin-4-amine (3.0 eq.), and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract with dichloromethane three times. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain a pale yellow solid compound X17.

[0141] 1 H NMR (400 MHz, Chloroform-d) δ 8.18 (s, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 7.9 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 4.91 - 4.85 (m, 2H), 3.96 (s, 3H), 2.96 (q, J = 7.2 Hz, 6H), 2.45 - 2.38 (m, 2H), 2.30 (s, 6H), 2.24 - 2.19 (m, 1H), 2.14 - 2.08 (m, 2H), 1.89 (dd, J = 14.7, 8.5 Hz, 4H), 1.80 (d, J = 12.3 Hz, 2H), 1.69 - 1.61 (m, 2H), 1.58 - 1.50 (m, 2H). 1313C NMR (151 MHz, Chloroform-d) δ 175.43, 167.27, 148.86, 147.41, 144.33, 135.33, 129.05, 128.03, 126.10, 125.52, 124.38, 124.08, 115.36, 109.42, 62.36, 58.29, 56.20, 53.02, 48.61, 41.41, 33.20, 32.89, 29.88, 27.86, 27.79, 25.70, 24.46.

[0142] HRMS (ESI) calcd for C 29 H 38 N4O2S [M + H] + 507.2715, found 507.2798.

[0143] Example 19: Preparation of Compound X18

[0144]

[0145] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(4-oxobutyl)-2,3-dihydro-1H-indene-5-carboxamide (1.0 eq.) (Compound F6), N,N-dimethylpiperidin-3-amine (3.0 eq.), and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract with dichloromethane three times. Dry the collected organic phase over anhydrous magnesium sulfate, filter, concentrate, and perform silica gel column chromatography with dichloromethane / methanol (100:1, v / v) as the mobile phase to obtain the pale yellow solid Compound X18.

[0146] 11H NMR (600 MHz, Chloroform-d) δ 8.19 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 0.8 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 4.88 (t, J = 6.7 Hz, 2H), 3.96 (s, 3H), 3.03 (d, J = 10.4 Hz, 1H), 2.95 (dd, J = 13.8, 7.1 Hz, 4H), 2.83 (d, J = 11.4 Hz, 1H), 2.48 - 2.45 (m, 2H), 2.29 (s, 6H), 2.13 - 2.09 (m, 2H), 1.96 (d, J = 7.0 Hz, 1H), 1.92 - 1.88 (m, 3H), 1.86 - 1.81 (m, 2H), 1.71 (dt, J = 10.0, 3.3 Hz, 1H), 1.68 - 1.64 (m, 2H), 1.54 (dq, J = 12.6, 4.2, 3.5 Hz, 1H), 1.24 (s, 1H). 13 13C NMR (151 MHz, Chloroform-d) δ 175.41, 167.30, 148.86, 147.42, 144.34, 135.33, 129.07, 128.05, 126.11, 125.53, 124.38, 124.09, 115.37, 109.42, 61.37, 58.82, 56.37, 56.21, 53.72, 48.61, 41.85, 33.20, 32.89, 27.84, 26.79, 25.70, 24.41, 24.26.

[0147] HRMS (ESI) calcd for C 29 H 38 N4O2S [M + H] + 507.2715, found 507.2794.

[0148] Example 20: Preparation of Compound X19

[0149]

[0150] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(4-oxobutyl)-2,3-dihydro-1H-indene-5-carboxamide (1.0 eq.) (Compound F6), N,N-diethylpiperidin-4-amine (3.0 eq.) and acetic acid (0.1 eq.) in a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract with dichloromethane three times. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain the pale yellow solid compound X19.

[0151] 1 H NMR (600 MHz, Chloroform-d) δ 8.19 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 4.89 - 4.86 (m, 2H), 3.96 (s, 3H), 2.99 - 2.93 (m, 6H), 2.59 (d, J = 7.2 Hz, 4H), 2.43 - 2.39 (m, 2H), 2.13 - 2.09 (m, 2H), 1.90 (dd, J = 14.3, 8.4 Hz, 4H), 1.74 (d, J = 12.4 Hz, 2H), 1.65 (q, J = 7.7 Hz, 2H), 1.60 - 1.54 (m, 2H), 1.13 - 1.11 (m, 1H), 1.06 (t, J = 7.2 Hz, 6H). 13 C NMR(151 MHz, Chloroform-d) δ 175.42, 167.25, 148.84, 147.41, 144.31, 135.34, 129.06, 128.04, 126.11, 125.52, 124.35, 124.07, 115.35, 109.41, 58.43, 58.31, 56.19, 53.54, 48.64, 43.79, 33.20, 32.88, 28.07, 27.81, 25.69, 24.50, 13.41.

[0152] HRMS (ESI) calcd for C 31 H 42 N4O2S [M + H] + 535.3028, found 535.3107.

[0153] Example 21: Preparation of Compound X20

[0154]

[0155] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(4-oxobutyl)-2,3-dihydro-1H-indene-5-carboxamide (1.0 eq.) (Compound F6), 1-methylpiperidin-4-amine (3.0 eq.) and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1, and stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract with dichloromethane three times. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain the pale yellow solid Compound X20.

[0156] 1 H NMR (600 MHz, Chloroform-d)δ8.15 (s, 1H), 8.13 (d, J = 7.8 Hz,1H), 7.28 (d, J = 7.8 Hz, 1H), 7.23 (dd, J = 7.8, 0.9 Hz, 1H), 7.17 (t, J =7.9 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 4.85 (t, J = 7.2 Hz, 2H), 3.93 (s,3H), 2.96 (dd, J = 15.9, 7.7 Hz, 4H), 2.92 (s, 1H), 2.92-2.87 (m, 2H), 2.84-2.80 (m, 2H), 2.70-2.66 (m, 1H), 2.31 (s, 3H), 2.10 (p, J = 7.5 Hz, 4H), 1.92(q, J = 7.5, 7.1 Hz, 4H), 1.78-1.74 (m, 2H), 1.70-1.65 (m, 2H). 1313C NMR (151 MHz, Chloroform-d) δ 175.41, 167.42, 149.00, 147.38, 144.45, 135.21, 128.92, 128.01, 125.85, 125.48, 124.56, 124.15, 115.29, 109.47, 56.27, 53.62, 47.98, 45.56, 45.13, 33.20, 32.89, 29.88, 29.31, 27.39, 25.67, 25.43.

[0157] HRMS (ESI) calcd for C 28 H 36 N4O2S [M + H] + 493.2559, found 493.2631.

[0158] Example 22: Preparation of Compound X21

[0159]

[0160] Weigh the calculated amount of tert-butyl (1-(2-(N-(4-methoxybenzothiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamido)ethyl)piperidin-3-yl)carbamate (1.0 eq.) and trifluoroacetic acid (100 eq.) in DCM, and stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract three times with dichloromethane. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (50:1, v / v) to obtain the white solid compound X21.

[0161] 11H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 9.0 Hz, 2H), 7.44 (d, J = 7.7 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.13 (dd, J = 7.9, 2.5 Hz, 2H), 4.85 (t, J = 7.0 Hz, 2H), 3.94 (s, 3H), 2.86 (d, J = 8.5 Hz, 1H), 2.76 (d, J = 6.9 Hz, 5H), 2.70 (t, J = 7.1 Hz, 2H), 2.60 (s, 1H), 2.10 (t, J = 9.7 Hz, 1H), 1.90 (t, J = 9.5 Hz, 1H), 1.74 (s, 4H), 1.66 (d, J = 8.8 Hz, 1H), 1.57 - 1.49 (m, 1H), 1.33 (q, J = 8.9, 6.5 Hz, 1H), 1.20 - 1.12 (m, 1H), 1.01 - 0.93 (m, 1H). 13 13C NMR (101 MHz, DMSO-d6) δ 174.05, 166.97, 147.46, 141.65, 136.91, 134.18, 130.13, 129.37, 127.91, 126.48, 125.67, 125.14, 115.60, 110.68, 62.32, 56.86, 56.76, 53.49, 48.22, 45.88, 33.08, 29.43, 29.31, 24.09, 23.11, 22.98.

[0162] HRMS (ESI) calcd for C 26 H 32 N4O2S [M + H] + 465.2246, found 465.2324.

[0163] Example 23: Preparation of Compound X22

[0164]

[0165] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(2-oxoethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F2), N,N-dimethylpiperidin-4-amine (3.0 eq.), and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract three times with dichloromethane. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain the white solid Compound X22.

[0166] 1 H NMR (600 MHz, Chloroform-d) δ 8.04 (d, J = 6.7 Hz, 2H), 7.27 (s, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 5.02 - 4.97 (m, 2H), 3.97 (s, 3H), 3.16 (d, J = 11.6 Hz, 2H), 2.83 (t, J = 7.2 Hz, 6H), 2.67 (t, J = 11.6 Hz, 1H), 2.50 (s, 6H), 2.25 - 2.19 (m, 2H), 1.91 (d, J = 12.1 Hz, 2H), 1.82 (p, J = 3.1 Hz, 4H), 1.58 (tt, J = 11.9, 6.0 Hz, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 175.15, 167.55, 147.15, 141.71, 136.87, 134.02, 130.23, 128.97, 128.80, 126.41, 124.31, 115.25, 109.19, 62.77, 56.33, 55.99, 52.63, 46.97, 45.85, 40.19, 29.66, 29.52, 26.80, 26.29, 23.17, 23.05.

[0167] HRMS (ESI) calcd for C 28 H 36 N4O2S [M + H] +493.2559, found 493.2636.

[0168] Example 24: Preparation of Compound X23

[0169]

[0170] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(2-oxoethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F2), N,N-dimethylpiperidin-3-amine (3.0 eq.) and acetic acid (0.1 eq.) in a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract with dichloromethane three times. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain the pale yellow solid compound X23.

[0171] 1 H NMR (600 MHz, Chloroform-d) δ 8.07 (d, J = 7.4 Hz, 2H), 7.25 (dd, J = 7.8, 0.8 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 5.01 (tdd, J = 12.9, 6.0, 3.2 Hz, 2H), 3.96 (s, 3H), 3.12 - 3.09 (m, 1H), 3.01 (d, J = 10.8 Hz, 1H), 2.90 - 2.86 (m, 1H), 2.83 (dd, J = 11.4, 6.0 Hz, 5H), 2.38 (ddd, J = 10.5, 5.3, 2.8 Hz, 1H), 2.31 (s, 6H), 2.16 (dtd, J = 11.2, 8.3, 7.3, 3.0 Hz, 2H), 1.88 (dd, J = 8.5, 3.8 Hz, 1H), 1.81 (p, J = 3.3 Hz, 4H), 1.75 (dq, J = 9.9, 3.2 Hz, 1H), 1.57 - 1.51 (m, 1H), 1.21 (dd, J = 11.4, 4.0 Hz, 1H). 1313C NMR (151 MHz, Chloroform-d) δ 175.34, 167.49, 147.33, 141.71, 136.96, 134.23, 130.46, 129.05, 128.98, 126.70, 126.04, 124.35, 115.32, 109.29, 61.63, 57.27, 57.10, 56.10, 54.06, 45.88, 42.18, 29.82, 29.65, 26.80, 24.66, 23.34, 23.23.

[0172] HRMS (ESI) calcd for C 28 H 36 N4O2S [M + H] + 493.2559, found 493.2629.

[0173] Example 25: Preparation of Compound X24

[0174]

[0175] Weigh the calculated amount of tert-butyl 4-(((2-(N-(4-methoxybenzo[d]thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamido)ethyl)amino)piperidine-1-carboxylate (1.0 eq.) and trifluoroacetic acid (100 eq.) in DCM, and stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract three times with dichloromethane. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (50:1, v / v) to obtain the white solid compound X24.

[0176] 11H NMR (600 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.3 Hz, 2H), 4.88 (t, J = 6.9 Hz, 2H), 3.96 (s, 3H), 3.03 (d, J = 11.4 Hz, 2H), 2.93 - 2.89 (m, 1H), 2.77 (d, J = 6.2 Hz, 4H), 2.15 (t, J = 11.0 Hz, 2H), 1.82 (d, J = 10.5 Hz, 2H), 1.77 - 1.73 (m, 4H), 1.47 - 1.41 (m, 2H), 1.21 (s, 1H), 1.17 (t, J = 7.3 Hz, 4H). 13 13C NMR (151 MHz, DMSO-d6) δ 166.62, 146.98, 141.19, 136.42, 133.67, 129.65, 128.92, 127.46, 125.96, 125.12, 124.73, 115.16, 110.30, 56.37, 56.13, 51.23, 47.63, 45.45, 45.29, 29.67, 28.94, 28.83, 22.63, 22.50, 8.72.

[0177] HRMS (ESI) calcd for C 26 H 32 N4O2S [M + H] + 465.2246, found 465.2313.

[0178] Example 26: Preparation of Compound X25

[0179]

[0180] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(2-oxoethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F2), 1-methylpiperidin-4-amine (3.0 eq.) and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1. Stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract three times with dichloromethane. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography with dichloromethane / methanol (100:1, v / v) to obtain the white solid compound X25.

[0181] 1 H NMR (600 MHz, Chloroform-d) δ 8.05 (dd, J = 7.9, 1.6 Hz, 1H), 8.03 (s, 1H), 7.27 (d, J = 6.2 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.93 - 6.91 (m, 1H), 4.98 (t, J = 6.6 Hz, 2H), 3.96 (s, 3H), 3.13 (t, J = 6.6 Hz, 2H), 2.83 (d, J = 20.2 Hz, 5H), 2.75 (d, J = 10.1 Hz, 2H), 2.64 (s, 1H), 2.26 (s, 3H), 2.06 (s, 2H), 1.85 (dd, J = 13.4, 3.2 Hz, 2H), 1.82 (p, J = 3.2 Hz, 4H), 1.41 (td, J = 9.6, 6.6 Hz, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 175.30, 167.97, 147.38, 141.89, 137.09, 134.09, 130.40, 129.12, 128.98, 126.73, 126.05, 124.55, 115.42, 109.48, 56.27, 48.59, 46.12, 45.76, 31.94, 29.84, 29.72, 23.32, 23.22.

[0182] HRMS (ESI) calcd for C 27 H 34 N4O2S [M + H]+ 479.2402, found 479.2477.

[0183] Example 27: Preparation of Compound X26

[0184]

[0185] Weigh the calculated amount of tert-butyl 3-((2-(N-(4-methoxybenzo[d]thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamido)ethyl)amino)piperidine-1-carboxylate (1.0 eq.) (Compound X30) and trifluoroacetic acid (100 eq.) in DCM, and stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and dichloromethane for extraction three times. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (50:1, v / v) to obtain a pale yellow solid, Compound X29.

[0186] 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (d, J = 7.9 Hz, 1H), 8.03 (s, 1H), 7.26 - 7.23 (m, 1H), 7.19 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 4.95 (h, J = 6.4 Hz, 2H), 3.96 (s, 3H), 3.12 (tt, J = 7.4, 3.7 Hz, 2H), 3.05 (d, J = 14.1 Hz, 1H), 2.82 (dd, J = 8.9, 5.0 Hz, 4H), 2.64 (dt, J = 8.7, 4.9 Hz, 1H), 2.57 - 2.50 (m, 1H), 2.36 (dd, J = 11.6, 8.7 Hz, 1H), 2.14 (s, 2H), 1.85 (d, J = 13.3 Hz, 1H), 1.83 - 1.79 (m, 4H), 1.66 - 1.60 (m, 1H), 1.42 - 1.34 (m, 1H), 1.27 - 1.17 (m, 2H). 1313C NMR (101 MHz, Chloroform-d) δ 175.16, 167.77, 147.21, 141.66, 136.89, 133.94, 130.23, 128.91, 128.81, 126.57, 125.88, 124.33, 115.20, 109.27, 56.08, 54.20, 52.13, 48.68, 46.47, 46.31, 31.51, 29.67, 29.51, 24.67, 23.16, 23.05.

[0187] HRMS (ESI) calcd for C 26 H 32 N4O2S [M + H] + 465.2246, found 465.2318.

[0188] Example 28: Preparation of Compound X27

[0189]

[0190] Weigh the calculated amount of N-(4-methoxybenzothiazol-2-yl)-N-(2-oxoethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.0 eq.) (Compound F2), tert-butyl 3-aminopiperidine-1-carboxylate (3.0 eq.) and acetic acid (0.1 eq.) into a mixed solvent of DCM:MeOH = 1:1, and stir the reaction solution at 25 °C overnight. After monitoring the reaction by TLC until completion, add saturated sodium bicarbonate solution and extract with dichloromethane three times. The collected organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography with a mobile phase of dichloromethane / methanol (100:1, v / v) to obtain a pale yellow solid compound X30.

[0191] 11H NMR (400 MHz, Chloroform-d) δ 8.06 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H), 4.99 (ddt, J = 42.7, 12.9, 6.4 Hz, 2H), 3.98 (s, 3H), 3.75 (d, J = 13.1 Hz, 1H), 3.27 - 3.10 (m, 2H), 2.86 - 2.81 (m, 4H), 2.64 (d, J = 9.0 Hz, 1H), 1.85 - 1.79 (m, 5H), 1.66 (d, J = 63.7 Hz, 6H), 1.45 (s, 1H), 1.41 (s, 9H). 13 13C NMR (101 MHz, Chloroform-d) δ 175.15, 167.89, 154.91, 147.22, 141.65, 136.89, 133.92, 130.24, 128.93, 128.84, 126.58, 125.89, 124.35, 115.23, 109.29, 79.44, 56.08, 53.48, 48.59, 31.49, 29.68, 29.51, 28.42, 23.18, 23.06.

[0192] HRMS (ESI) calcd for C 31 H 40 N4O4S [M + H] + 565.2770, found 565.2866.

[0193] Drug performance test:

[0194] 1. In vitro TRPC6 inhibition activity test

[0195] Select HEK293T cells stably transfected with TRPC3 / 4 / 5 / 6 / 7, a suitable cell line for the experiment (such as a stable cell line expressing the target receptor). Seed the cells in 96-well or 384-well plates and culture them at 37 °C and 5% CO2 for 24 h. Adjust the appropriate cell density and culture until the appropriate confluence (usually 70% - 90%).

[0196] Prepare a working solution of a calcium indicator dye (such as Fluo-4 AM), which usually contains Pluronic F-127 (to enhance dye solubility) and a HEPES-buffered solution. Add the dye to the cell culture plate, and the volume of the dye is usually 1 / 10 to 1 / 5 of the volume of the culture medium. Incubate at 37°C in the dark for 30 - 60 minutes to allow the dye to enter the cells. Subsequently, wash the cells with a detection buffer (such as HBSS + HEPES) to remove the free dye.

[0197] Record the baseline fluorescence signal (under non-stimulated conditions) in the FLIPR system. Use an automated pipette module to automatically add the drug into the cell wells and capture the change in fluorescence signal over time in real-time. Represent the calcium flux intensity as the peak or area, and process the data using FLIPR software or other analysis tools (such as GraphPad Prism) to extract parameters such as ΔF / F0 (the ratio of fluorescence change).

[0198] 2. Cytotoxicity evaluation

[0199] Adjust the cell concentration to 5 × 10 5 cells / mL and seed them in a 96-well plate, 180 μL per well. Dissolve the compound to be tested in an appropriate amount of DMSO to prepare a stock solution, and then dilute it with an appropriate amount of culture medium respectively. Add 20 μL of the diluted compound solution to each well to make the final volume of each well 200 μL, with the DMSO content being 0.1% and the final concentration of the compound to be tested being 1 μM and 10 μM. Incubate at 37°C and 5% CO2 for 24 h. Add 10 μL of MTS solution to each well and incubate at 37°C and 5% CO2 for 3 h, then measure the absorbance at 492 nm to evaluate the proliferation inhibitory activity of the compound on HK-2 cells.

[0200] 3. Experimental data: Table 1 shows the inhibitory ability of Compounds X1 - X27 at 1 μM on the TRPC6 channel:

[0201] Table 1.

[0202]

[0203]

[0204] Preferably, the activity test of Compound X26 of the present invention in a cell-level anti-fibrosis model:

[0205] Transforming growth factor-β (TGF-β) is widely regarded as a key regulator in the pathogenesis of myofibroblast differentiation. To investigate the anti-fibrotic effect of X26, a TGF-β1-induced HK-2 cell (human renal tubular epithelial cell) model was established. After 24 hours of TGF-β1 stimulation, the expression levels of fibrosis markers, including α-smooth muscle actin (α-SMA), type I collagen (COL1A1), and fibronectin (FN1)), increased by approximately 2 to 4-fold compared to the PBS-treated control group. In addition, TGF-β1 stimulation significantly upregulated the expression of the TRPC6 gene, which was 3.25-fold higher than that of the control group. However, pretreatment with X26 2 hours before TGF-β1 treatment significantly alleviated the above effects in a concentration-dependent manner. Particularly at a concentration of 10 μM, X26 reduced the mRNA expression levels of FN1, α-SMA, and COL1A1 by 2.75-fold, 5.635-fold, and 4.5-fold, respectively. In addition, the results of immunofluorescence staining further confirmed these findings, showing that the fluorescence area of α-SMA (red) decreased significantly with increasing X26 concentration, by 52.0%, 70.1%, and 82.0% at concentrations of 1 μM, 3 μM, and 10 μM, respectively. Importantly, within the effective concentration range, X26 did not show obvious cytotoxicity to HK-2 cells. Taken together, these results indicate that X26 is a potent inhibitor of TGF-β1-induced myofibroblast differentiation.

[0206] The above specific embodiments have described the implementation of the present invention in detail. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the claims and technical concept of the present invention, various simple modifications and changes can be made to the technical solution of the present invention, and these simple variations all belong to the protection scope of the present invention.

Claims

1. An N-(benzothiazol-2-yl)benzamide compound or a derivative thereof, characterized in that: The compound has a structure shown in Formula 1: Formula 1; The structure shown in Formula 1 does not include the structure shown in Formula 2; Formula 2 Wherein R1-R2 are each independently selected from at least one of hydrogen, aldehyde, carboxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino; or R1-R2 are each independently selected from: an alkane chain containing a primary amine, an alkane chain containing a secondary amine, an alkane chain containing a tertiary amine; or R1-R2 are connected by at least one of a primary amine-containing heterocyclic ring, a secondary amine-containing heterocyclic ring, a tertiary amine-containing heterocyclic ring, a primary amine-containing saturated ring, a secondary amine-containing saturated ring, a tertiary amine-containing saturated ring, and a saturated ring to form a ring structure; The R3 group is selected from any one of the following groups, and the wavy line represents the bonding position: ； R4, R5, R6, and R7 are each independently selected from any one of hydrogen, deuterium, halogen, alkyl, alkoxy, alkylamino, cycloalkyl, nitro, trifluoromethyl, amino, ester, and cyano; n is selected from: 1-6.

2. An N-(benzothiazol-2-yl)benzamide compound or a derivative thereof according to claim 1, characterized in that: The R1-R2 are each independently selected from: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino.

3. An N-(benzothiazol-2-yl)benzamide compound or a derivative thereof according to claim 1, characterized in that: The R1-R2 are independently selected from: hydrogen, methyl, ethyl, , , ; Or R1-R2 forms a ring structure, the structure of which is selected from any one of the following groups: .

4. An N-(benzothiazol-2-yl)benzamide compound or a derivative thereof according to claim 1, characterized in that: The n is selected from: 1-4.

5. An N-(benzothiazol-2-yl)benzamide compound or a derivative thereof according to any one of claim 1, characterized in that: The structure of the compound is selected from: 。 6. A stereoisomer of an N-(benzothiazol-2-yl)benzamide compound or a derivative thereof according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

7. An N-(benzothiazol-2-yl)benzamide compound or a derivative thereof according to claim 6, characterized in that: The salt is a salt formed by the compound and an alkali metal.

8. An N-(benzothiazol-2-yl)benzamide compound or a derivative thereof according to claim 6, characterized in that: The number of crystal water of the hydrate is any integer between 1 and 16.

9. A pharmaceutical composition comprising a therapeutically effective amount of an N-(benzothiazol-2-yl)benzamide compound or a derivative thereof selected from any one of claims 1 to 5 and a pharmaceutically acceptable excipient in pharmacy.

10. The use of an N-(benzothiazol-2-yl)benzamide compound or a derivative thereof according to any one of claims 1 to 5, characterized in that: It is used in the preparation of anti-renal fibrosis drugs, anti-renal injury drugs, anti-pulmonary hypertension drugs or anti-tumor drugs.

Images