Effective compound for inhibiting hemolysis cardiolipin acyltransferase as well as preparation method and application thereof

Abstract

The invention discloses a compound shown as a formula (I) or pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or isotope isomer of the compound. A ring A and a ring B jointly form a fused ring. Ring A and ring B are independently selected from 5-10-membered aromatic rings and saturated or unsaturated aliphatic rings; the aromatic ring and the saturated or unsaturated aliphatic ring contain 0-3 O, N, S or carbonyl groups; the ring A and the ring B are optionally substituted by 0-3 Q1; q1 is defined in the specification; l is-CONH <->,-SO2NH <->,-NHCO <-> or NHSO2 <->; r1 and R2 are defined in the specification. A compound shown as a formula (I) or a pharmaceutically acceptable salt, a solvate, a hydrate, a stereoisomer or an isotope isomer thereof has excellent inhibitory activity on hemolytic cardiophosphatidyltransferase (ALCAT1), and can be used for preparing drugs for preventing or treating diseases related to the activity of the hemolytic cardiophosphatidyltransferase.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medical compounds, in particular to a lysocardilin acyltransferase inhibiting effective compound and a preparation method and application thereof. BACKGROUND

[0002] With the improvement of people's living standards, changes in daily dietary structure and the arrival of social aging, the incidence of aging and age-related diseases is increasing year by year. Age-related diseases include hyperlipidemia, fatty liver, type 2 diabetes, diabetic complications (nephropathy, retinopathy and cardiomyopathy), cardiovascular disease, obesity, nervous system disease (Parkinson's disease and Alzheimer's disease) and the like.

[0003] There are views that the causes of aging and age-related diseases are related to mitochondrial dysfunction. Lysocardilin acyltransferase (ALCAT1) belongs to the endoplasmic reticulum membrane multi-channel transmembrane protein, mediates the remodeling of mitochondrial specific phospholipid cardiolipin (CL), and under physiological conditions, the enzyme takes linoleoyl coenzyme A (C18:2) as the main acyl donor, catalyzes the acylation of substrate monolysocardiolipin (MLCL) to generate cardiolipin. The C18:2 composition in cardiolipin helps to fold into a ridge structure, binds to downstream transport proteins with high affinity, and ensures mitochondrial oxidative phosphorylation. When genetic genetic variation or environmental factors change (such as nutrient abundance) after birth, the metabolic pressure in cells is enhanced, and the expression of ALCAT1 is up-regulated. ALCAT1 transfers super-long chain polyunsaturated fatty acids such as C22:6 docosahexaenoic acid and C20:4 arachidonic acid to cardiolipin, resulting in cardiolipin isacylation, increased sensitivity to oxidative stress damage, and further triggering cardiolipin peroxidation, mitochondrial dysfunction, and energy metabolism-induced dysfunction.

[0004] In mouse models of oxidative stress, obesity, type 2 diabetes, fatty liver, coronary heart disease, etc., the expression level of ALCAT1 is up-regulated, the remodeling of cardiolipin abnormal acylation, mitochondrial fragmentation, autophagy defects, liver steatosis, etc. Coronary heart disease, as one of the complications of diabetic cardiovascular disease, is prone to occur on the basis of myocardial metabolic disorder and arterial vascular disease, and is closely related to oxidative stress caused by chronic abnormal glucose and lipid metabolism. Scientists take rheumatic heart disease, coronary heart disease and patients with diabetes combined with heart surgery as research objects, and analyze the mRNA and protein levels of ALCAT1 in myocardial cells of different diseases. The results show that the mRNA level of ALCAT1 in patients with coronary heart disease is higher than that in patients with rheumatic coronary heart disease, and the mRNA level of ALCAT1 in patients with diabetes is higher than that in patients without diabetes. In the mouse models of the above-mentioned various diseases, the mitochondrial autophagy, mitochondrial structure, mtDNA fidelity and oxidative phosphorylation can be restored by knocking out ALCAT1 by siRNA, the expression of genes related to de novo lipogenesis (PPARγ, SREBP1c, FAS1 and ACC1) can be significantly reduced, and the triglyceride can be significantly reduced, thereby preventing the occurrence of liver steatosis and fatty liver disease.

[0005] Dafaglitapin (Dafa) is an effective and selective ALCAT1 inhibitor reported in a patent (US202 / 089582A1). Dafa can effectively inhibit the activity of ALCAT1 in various mouse models, and improve cardiolipin remodeling and mitochondrial function. In addition, the mitochondrial targeting peptide Elamipretide currently in phase III clinical study can indirectly inhibit the transcription level of ALCAT1. In a dog model of heart failure, the mRNA of ALCAT1 is up-regulated by 3.56 times, and the 18:2 cardiolipin is significantly reduced. After subcutaneous injection of Elamipretide (0.5mg / kg / d) for 3 months, the mRNA level of ALCAT1 is down-regulated to the normal animal level, and the cardiolipin remodeling is restored. Therefore, ALCAT1 can be used as a new drug target for delaying aging and improving age-related diseases. SUMMARY

[0006] The present application provides a compound as shown in formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or isotopologue thereof, which has excellent inhibitory activity on lysocardiolipin acyltransferase (ALCAT1) and can be used for preparing a drug for preventing or treating diseases related to the activity of lysocardiolipin acyltransferase.

[0007] The technical scheme of the present application is as follows:

[0008] In the first aspect, the present application provides a compound as shown in formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or isotopologue thereof:

[0009]

[0010] wherein ring A and ring B together form a fused ring group; ring A and ring B are independently selected from a 5-10 membered aromatic ring, a saturated or unsaturated aliphatic ring; said aromatic ring, saturated or unsaturated aliphatic ring contains 0-3 O, N, S or carbonyl;

[0011] said ring A and ring B are optionally substituted with 0-3 Q1; Q1 is selected from halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, C1-C10 alkoxy, C1-C10 haloalkoxy, C1-C10 alkylthio, C1-C10 haloalkylthio, hydroxy, cyano, trifluoromethyl;

[0012] L is selected from -CONH-, -SO2NH-, -NHCO- or NHSO2-;

[0013] R1, R2 are independently selected from a 5-12 membered aryl group, a saturated or unsaturated cycloalkyl group; said aryl group, saturated or unsaturated cycloalkyl group contains 0-3 O, N, S or carbonyl;

[0014] one or more hydrogen atoms on said R1, R2 are replaced by a substituent selected from the group consisting of cyano, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, C1-C10 alkoxy, C1-C10 haloalkoxy, halogen, hydroxy, hydroxymethyl, carboxyl (-COOH), C1-C10 aldehyde, C2-C10 acyl, C2-C10 ester, amino, phenyl, benzyl; said phenyl, benzyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, C1-C10 alkyl, cyano, OH, nitro, C3-C10 cycloalkyl, C1-C10 alkoxy, amino.

[0015] Preferably, Selected from substituted or unsubstituted quinoxalinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted cyclolinyl, substituted or unsubstituted indoleyl, substituted or unsubstituted isoyindolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted indazoleyl, substituted or unsubstituted imidazole[1,2-a]pyridyl, substituted or unsubstituted imidazole[1,5-a]pyridyl, substituted or unsubstituted imidazole[1,2-a][1,3,5]triazinyl Substituted or unsubstituted imidazo[4,5-b]pyridyl, substituted or unsubstituted benzo[b][1,4]oxazonylheptyl, substituted or unsubstituted [1,2,4]triazolo[1,5-a]pyrazinyl, substituted or unsubstituted pteridinyl, substituted or unsubstituted purine, substituted or unsubstituted imidazo[4,5-b]pyrazinyl, substituted or unsubstituted 3,7-dihydro-6H-purine-6-one, substituted or unsubstituted 2λ 2 -Inzol-3(1H)-keto, substituted or unsubstituted 6λ 2 -pyrrolo[3,4-b]pyrazine-5(7H)-keto, substituted or unsubstituted 1H-imidazo[4,5-b]pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzofuranyl;

[0016] Wherein, the hydrogen atom on the substituent group is substituted by 1, 2 or 3 substituents selected from the group consisting of: F, Cl, Br, I, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, and C1-C6 haloalkylthio.

[0017] Preferably, R1 is a substituted or unsubstituted furan cyclogroup, a substituted or unsubstituted thiophene cyclogroup, a substituted or unsubstituted pyrrole cyclogroup, or a substituted or unsubstituted oxadiazole cyclogroup;

[0018] In R1, substitution refers to substitution by 1 to 3 groups selected from the following group: halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, hydroxymethyl, trifluoromethyl, trifluoromethoxy.

[0019] Preferably, R2 is a substituted or unsubstituted 5-6 membered aromatic ring group containing 0-3 atoms selected from O, N or S atoms;

[0020] In R2, substitution refers to substitution by 1 to 3 groups selected from the following group: halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, hydroxymethyl, trifluoromethyl, trifluoromethoxy, C1-C4 acyl, amide.

[0021] In a preferred embodiment, R1 is a substituted or unsubstituted furan ring group, a substituted or unsubstituted thiophene ring group, a substituted or unsubstituted pyrrole ring group, or a substituted or unsubstituted oxadiazole ring group; R2 is a substituted or unsubstituted phenyl group;

[0022] In R1, the substitution means being substituted by 1-3 groups selected from halogen, C1-C3 alkyl group;

[0023] In R2, the substitution means being substituted by 1-3 groups selected from halogen, C1-C3 alkyl group, C1-C3 alkoxy group, trifluoromethyl group, trifluoromethoxy group.

[0024] Further preferably, the ring A is a benzene ring; the ring B is a 5-membered aromatic heterocycle containing 2 atoms selected from O, N or S;

[0025] The ring A and the ring B are optionally substituted by 0-2 Q1; Q1 is selected from halogen or C1-C6 alkyl group;

[0026] R1 is a substituted or unsubstituted furan ring group, a substituted or unsubstituted thiophene ring group, a substituted or unsubstituted pyrrole ring group, or a substituted or unsubstituted oxadiazole ring group;

[0027] R2 is a substituted or unsubstituted phenyl group;

[0028] In R1, the substitution means being substituted by 1-3 groups selected from halogen, C1-C3 alkyl group;

[0029] In R2, the substitution means being substituted by 1-3 groups selected from halogen, C1-C3 alkyl group, C1-C3 alkoxy group, trifluoromethyl group, trifluoromethoxy group.

[0030] Further preferably, the compound represented by formula (I) is selected from:

[0031]

[0032]

[0033]

[0034] In a second aspect, the present application provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or isotopologue thereof, and a pharmaceutically acceptable excipient.

[0035] In a third aspect, the present application provides a lysocardiin inhibitor, the active ingredient of which comprises a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or isotopologue thereof.

[0036] In a fourth aspect, the present application also provides a use of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or isotopologue thereof in the manufacture of a medicament for preventing or treating a disease associated with lysocardiphospholipase activity.

[0037] In a fifth aspect, the present application also provides a use of the pharmaceutical composition in the manufacture of a medicament for preventing or treating a disease associated with lysocardiphospholipase activity.

[0038] The disease associated with lysocardiphospholipase activity includes hyperlipidemia, fatty liver, type 2 diabetes, diabetic complications (such as nephropathy, retinopathy and cardiomyopathy), cardiovascular disease, obesity, nervous system diseases (such as Parkinson's disease and Alzheimer's disease), etc.

[0039] Compared with the prior art, the present application has the following beneficial effects:

[0040] The inhibitory activity of the compound provided by the present application at the enzyme level and the triglyceride-lowering activity at the cell level are comparable to or better than those of the positive compound Dafa, indicating that the compound of the present application has good inhibition on ALCAT1 and can exert the function after inhibiting ALCAT1. DETAILED DESCRIPTION

[0041] The compounds described herein will be better understood in connection with the following representative synthetic schemes, which illustrate methods of making the compounds of the present disclosure, which are intended merely to be illustrative and not limiting of the scope of the present disclosure. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and can be made without departing from the spirit and scope of the present disclosure, including but not limited to changes and modifications relating to the chemical structures, substituents, derivatives, formulations, and / or methods of the present disclosure.

[0042] I. Synthetic Methods

[0043] (1) Synthetic Route 1

[0044] Take the synthesis of 2-ethoxy-5-ethyl-N-(2-(furan-2-yl)-1H-benzo[d]imidazol-5-yl)benzamide (5) as an example. Starting from 4-nitro-1,2-diphenylamine a1 and furfural b1, it is prepared through condensation cyclization, nitro reduction and amide condensation.

[0045]

[0046] In a 100 mL round bottom flask, 4-nitro-o-phenylenediamine a1 (2 g, 13.07 mmol), furfural b1 (1.082 mL, 13.07 mmol), sodium metabisulfite (9.937 g, 52.27 mmol) were added. A solution of EtOH:H2O = 9:1 (10 mL) was added, and the reaction was carried out at 50-80 °C for 5-12 h (TLC monitoring). After the reaction was completed, the reaction solution was poured into ice water, and the filtrate was dried to obtain the target crude product 2-(furan-2-yl)-5-nitro-1H-benzo[d]imidazole c1. Yellow solid.

[0047] In a 100 mL round bottom flask, 2-(furan-2-yl)-5-nitro-1H-benzo[d]imidazole c1 (2 g, 8.73 mmol), tetrahydroxydiboron (2.35 g, 26.2 mmol), N,N-dimethylformamide (50 mL), and finally 4,4'-dipyridine (6.8 mg, 0.04 mmol) were added. The reaction was carried out at room temperature for 5-10 min (TLC monitoring). After the reaction was completed, the reaction solution was quenched with water, extracted with ethyl acetate three times, washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. The crude product 2-(furan-2-yl)-1H-benzo[d]imidazole-5-amine d1 was obtained by concentration under reduced pressure. Brown solid.

[0048] In a 100 mL round bottom flask, 2-ethoxy-5-ethylbenzoic acid f1 (470 mg, 2.42 mmol) was added, and 5 mL of thionyl chloride and one drop of DMF were added. The reaction was carried out at 50-80 °C for 5 h (TLC monitoring). After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 2-ethoxy-5-ethylbenzoyl chloride as a white solid. In a 50 mL round bottom flask, 2-(furan-2-yl)-1H-benzo[d]imidazole-5-amine d1 (322 mg, 1.62 mmol) was added, and anhydrous dichloromethane (5 mL) and anhydrous triethylamine (337 μL, 2.42 mmol) were added under nitrogen protection. 2-Ethoxy-5-ethylbenzoyl chloride was dissolved in anhydrous dichloromethane, and the solution was slowly added dropwise on an ice-water mixture. The reaction was carried out at room temperature for 2 h (TLC monitoring). After the reaction was completed, the crude product was purified by column chromatography (PE:EA = 3:1) to obtain the target product 2-ethoxy-5-ethyl-N-(2-(furan-2-yl)-1H-benzo[d]imidazol-5-yl)benzamide 19. White solid.

[0049] (2) Synthesis route 2

[0050]

[0051] In a 100 mL three necked flask was charged with a solution of 2-amino-4-nitrophenol a2 (500 mg, 3.24 mmol) in dry xylene (10 mL), under an oxygen atmosphere was added furfural b1 (347 mg, 3.23 mmol) and Darco KB (600 mg). The solution was stirred at 100-120 °C for 4-6 hours (TLC monitoring). After completion of the reaction, the reaction mixture was cooled to room temperature and filtered over celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography, acetate / n-hexane (50:50) to give 2-(furan-2-yl)-5-nitrobenzo[d]oxazole c2 as a yellow solid.

[0052] Subsequent steps are synthesized with reference to Scheme 1.

[0053] (3) Synthesis Scheme 3

[0054]

[0055] Furoyl chloride b3 (2.43 g, 18.71 mmol) was added dropwise by syringe to a solution of 2-bromo-5-nitroaniline a3 (3.83 g, 17.72 mmol) in dry pyridine (7.5 mL) and the reaction mixture formed a precipitate of N-(2-bromo-5-nitrophenyl)furan-2-carboxamide c3 under nitrogen protection. More pyridine (7.5 mL) was added and the mixture was stirred overnight. The reaction mixture was poured into water. The precipitated product was recrystallized from EtOH as white crystals.

[0056] A mixture of N-(2-bromo-5-nitrophenyl)furan-2-carboxamide c3 (3.36 g, 10.85 mmol), sodium sulfide nonahydrate (2.96 g, 12.34 mmol) and sulfur (397 mg, 12.37 mmol) in EtOH (100 mL) was refluxed for 2.5 hours. The cooled reaction mixture was evaporated under reduced pressure, diluted with 1 M HC1 (100 mL) and extracted into EtOAc. The product was purified on a silica gel column eluted in DCM and then recrystallized from EtOH to give white needles d3.

[0057] Subsequent steps are synthesized with reference to Scheme 1.

[0058] (4) Synthesis Scheme 4

[0059]

[0060] In a 100 mL round bottom flask, 4-nitro-l,3,5-triazin-2-amine a4 (2 g, 14.18 mmol), 2-acetylfuran b4 (2 g, 14.18 mmol), sodium bicarbonate (1.21 g, 14.18 mmol) and I2 (7.2 g, 28.35 mmol) were added, about 20 mL of toluene was added, and the reaction was carried out at 130 °C. The reaction progress was monitored by TLC (dichloromethane:methanol = 10:1), and after the reaction was completed, it was cooled to room temperature, and 10% Na2S2O3 was added to quench the reaction. Dichloromethane (50 mL x 4) was extracted, and anhydrous sodium sulfate was dried. Column chromatography was used for separation, and gradient elution (dichloromethane:methanol = 100:1→15:1) was used to obtain 7-(furan-2-yl)-2-nitroimidazo[l,2-a][l,3,5]triazine c4.

[0061] The subsequent steps were synthesized according to Route 1.

[0062] (5) Synthesis Route 5

[0063]

[0064] In a 50 mL round bottom flask, 2-amino-5-fluoro-4-nitrophenol a5 (1 g, 9.16 mmol), 3-(furan-2-yl)propynal b5 (2.22 g, 18.33 mmol) were added, 1,4-dioxane 15 mL was added, and the reaction was carried out at 100 °C for 19 h. The reaction progress was monitored by TLC (dichloromethane:methanol = 10:1), and after the reaction was completed, the solvent was removed under reduced pressure. Dichloromethane (20 mL x 4) was extracted, and anhydrous sodium sulfate was dried. Column chromatography was used for separation, and gradient elution (dichloromethane:methanol = 100:1→20:1) was used to obtain 8-fluoro-3-(furan-2-yl)-7-nitrobenzo[b][l,4]oxazepine c5.

[0065] The subsequent steps were synthesized according to Route 1.

[0066] (6) Synthesis Route 6

[0067]

[0068] In a 50 mL round bottom flask, 2-nitro-lH-imidazo[4,5-b]pyridine a6 (1 g, 6.10 mmol) was added, dibromofuran b6 (890 mg, 6.10 mmol), tin tetrachloride (798 mg, 3.05 mmol) was added, and the reaction was carried out in dichloromethane solvent at 0°C for 5 hours. The reaction progress was monitored by TLC (dichloromethane:methanol = 20:1), and after the reaction was completed, the solvent was removed under reduced pressure. Extraction was carried out with dichloromethane (20 mL x 4), and drying was carried out with anhydrous sodium sulfate. Column chromatography was used for separation, and gradient elution was used to obtain the target compound 5-(furan-2-yl)-2-nitro-lH-imidazo[4,5-b]pyridine c6.

[0069] (7) Synthetic Route 7

[0070]

[0071] In a 100 mL round bottom flask, 2,4-diamino-6-hydroxy-5-nitro pyrimidine a7 (2 g, 11.69 mmol) was dissolved in tetrahydrofuran, potassium carbonate (3.3 g, 35.07 mmol) was added at 25°C, and the flask was placed on ice. Furoyl chloride b3 (1.83 g, 14.03 mmol) was dissolved in dichloromethane and added to the flask. After the reaction was completed, the reaction solution was poured into ice water, and the filter cake was filtered to obtain the crude target product N-(2-amino-5-nitro-6-oxo-3,6-dihydropyrimidin-4-yl)furan-2-formamide c7.

[0072] In a 100 mL round bottom flask, N-(2-amino-5-nitro-6-oxo-3,6-dihydropyrimidin-4-yl)furan-2-formamide c7 (2 g, 7.5 mM) was dissolved in o-xylene, PPh3 (4.33 g, 15 mM) and Bu3P (7.7 g, 15 mM) were added, and the reaction was carried out at room temperature for 2 hours (TLC monitoring). After the reaction was completed, the reaction solution was quenched with water, extracted with ethyl acetate three times, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 2-amino-8-(furan-2-yl)-3,7-dihydro-6H-purin-6-one d7.

[0073] The subsequent steps were synthesized with reference to Synthetic Route 1.

[0074] (8) Synthetic Route 8

[0075]

[0076] In 100 mL round bottom flask was taken methyl 2-fluoro-4-nitrobenzoate a8 (2 g, 10.05 mmol), 2-furanhydrazine b8 (985.9 mg, 10.05 mmol). Added EtOH 50 ml, gradually warmed from 20 °C to 120 °C refluxed the reaction for 2 h (TLC monitoring), on completion of the reaction, cooled to room temperature, concentrated under reduced pressure to get the target crude 2-(furan-2-yl)-5-nitro-1,2-dihydro-3H-indazol-3-one c8. Yellow solid.

[0077] Subsequent steps were synthesized with reference to synthetic route 1.

[0078] All compounds were synthesized with reference to routes 1-8, compounds of formula (I) wherein L is sulfonamide chain were prepared by condensation of benzene sulfonyl chloride instead of benzoic acid in route 1-8 with aniline.

[0079] Example 1

[0080]

[0081] 5-chloro-N-(7-(furan-2-yl)imidazo[1,2-a][1,3,5]triazin-2-yl)-2-methoxybenzamide (Compound 1)

[0082] Synthesized with reference to route 4 by replacing f1 with 5-chloro-2-methoxybenzoic acid.

[0083] 1H NMR (500 MHz, Chloroform-d) δ 9.41 (s, 1H), 8.32 (s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.66 (t, J = 1.5 Hz, 1H), 7.46 (dd, J = 8.6, 2.4 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.00 (dd, J = 5.8, 1.7 Hz, 1H), 6.93 (dd, J = 5.8, 1.2 Hz, 1H), 3.92 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 17 H 13 ClN5O3] + : 370.7700, Found: 370.7773.

[0084] Example 2

[0085]

[0086] 5-chloro-N-(6-fluoro-2-(furan-2-yl)imidazo[1,2-a]pyridin-7-yl)-2-methoxybenzamide (Compound 2)

[0087] Synthesized according to Scheme 4 by replacing a4 with 5-fluoro-4-nitro-2-aminopyridine, f1 with 4-chloro-2-methoxybenzoic acid, followed by substitution with iodomethane.

[0088] 1H NMR (500 MHz, Chloroform-d) δ 9.86 (s, 1H), 8.61 (d, J = 8.0 Hz, 1H), 8.46 (s, 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.74 (d, J = 5.1 Hz, 1H), 7.65 (t, J = 1.5 Hz, 1H), 7.46 (dd, J = 8.6, 2.4 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 6.97 (dd, J = 5.8, 1.7 Hz, 1H), 6.93 (dd, J = 5.7, 1.3 Hz, 1H), 3.92 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 19 H 14 ClFN3O3] + : 386.7800, Found: 386.7853.

[0089] Example 3

[0090]

[0091] 5-chloro-N-(5-fluoro-2-(furan-2-yl)-l-methyl-lH-indol-6-yl)-2-methoxybenzamide (Compound 3)

[0092] Synthesized according to Scheme 4 by replacing a4 with 4-fluoro-3-nitroaniline, f1 with 4-chloro-2-methoxybenzoic acid, followed by substitution with iodomethane.

[0093] 1H NMR (500 MHz, Chloroform-d) δ 9.96 (s, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 5.3 Hz, 1H), 7.61 (t, J = 1.5 Hz, 1H), 7.54 (dd, J = 7.9, 2.2 Hz, 1H), 7.46 (dd, J = 8.6, 2.4 Hz, 1H), 7.20 (s, 1H), 6.97 (dd, J = 4.0, 1.6 Hz, 1H), 6.59 (dd, J = 4.2, 1.3 Hz, 1H), 6.39 (d, J = 2.2 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 21 H 17 ClFN2O3] +: 399.8200, Found: 399.8283.

[0094] Example 4

[0095]

[0096] 5-Chloro-N-(8-fluoro-3-(furan-2-yl)benzo[b][l,4]oxazinan-7-yl)-2- methoxybenzamide (Compound 4)

[0097] Synthesized by following Route 5 with 5-chloro-2-methoxybenzoic acid instead of f1.

[0098] 1H NMR (500 MHz, Chloroform-d) δ 8.50 (d, J = 1.4 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 4.9 Hz, 1H), 7.69 (t, J = 1.6 Hz, 1H), 7.46 (dd, J = 8.6, 2.4 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 6.98 - 6.92 (m, 3H), 6.74 (dd, J = 5.2, 1.7 Hz, 1H), 6.52 (dd, J = 5.3, 1.6 Hz, 1H), 3.92 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 21 H 15 ClFN2O4] + : 413.8000, Found: 413.8103.

[0099] Example 5

[0100]

[0101] 5-Chloro-N-(2-(furan-2-yl)-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-2- methoxybenzamide (Compound 5)

[0102] Synthesized by following Route 4 with furan-2-carboxamide instead of a4 and 5-chloro-2-methoxybenzoic acid instead of f1.

[0103] 1H NMR (500 MHz, Chloroform-d) δ 8.88 (d, J = 7.7 Hz, 1H), 7.87-7.82 (m, 2H), 7.46 (dd, J = 8.6, 2.4 Hz, 1H), 7.23-7.16 (m, 4H), 6.74 (dd, J = 6.6, 1.3 Hz, 1H), 3.92 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 17 H 13 ClN5O3] + :370.7700, Found:370.7743.

[0104] Example 6

[0105]

[0106] 5-Chloro-N-(5-(furan-2-yl)-lH-imidazo[4,5-b]pyridin-2-yl)-2-methoxybenzamide (Compound 6)

[0107] Synthesized by following Route 6 with 5-chloro-2-methoxybenzoic acid instead of fl.

[0108] 1 H NMR (500 MHz, Chloroform-d) δ 7.91 (d, J = 9.2 Hz, 1H), 7.88-7.82 (m, 3H), 7.64 (t, J = 1.5 Hz, 1H), 7.46 (dd, J = 8.6, 2.4 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.10-7.05 (m, 1H), 6.86 (dd, J = 5.7, 1.1 Hz, 1H), 3.92 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 18 H 14 ClN4O3] + :369.7800, Found:369.7893.

[0109] Example 7

[0110]

[0111] 5-Chloro-N-(2-(furan-2-yl)-7H-purin-8-yl)-2-methoxybenzamide (Compound 7)

[0112] Synthesized by following Route 6 with 8-nitro-7H-urea instead of a6 and 5-chloro-2-methoxybenzoic acid instead of fl.

[0113] 1 H NMR (500 MHz, Chloroform-d) δ 8.80 (s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.76 (t, J = 1.5 Hz, 1H), 7.46 (dd, J = 8.6, 2.4 Hz, 1H), 7.24 - 7.16 (m, 3H), 6.73 (dd, J = 6.6, 1.3 Hz, 1H), 3.92 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 17 H 13 ClN5O3] + : 370.0629, Found: 370.0631.

[0114] Example 8

[0115]

[0116] 5-Chloro-N-(5-(furan-2-yl)-lH-imidazo[4,5-b]pyrazin-2-yl)-2-methoxybenzamide (Compound 8)

[0117] Synthesized by following Route 6 by replacing a6 with 2-nitro-lH-imidazo[4,5-b]pyrazine, f1 with 5-chloro-2-methoxybenzoic acid.

[0118] 1 H NMR (500 MHz, Chloroform-d) δ 8.83 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 7.40 (dd, J = 7.5, 2.0 Hz, 1H), 7.20 (s, 1H), 7.16 (s, 1H), 6.59 (s, 1H), 3.97 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 16 H 10 Cl2N5O2] + : 370.0629, Found: 370.0631.

[0119] Example 9

[0120]

[0121] 5-Chloro-N-(2-(furan-2-yl)quinolin-7-yl)-2-methoxybenzamide (Compound 9)

[0122] Synthesized by following Route 6 by replacing a6 with 7-nitroquinoline, f1 with 5-chloro-2-methoxybenzoic acid.

[0123] 1 H NMR (500 MHz, Chloroform-d) δ 9.87 (s, 1H), 8.29 (d, J = 7.3 Hz, 2H), 8.22 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.40 (dd, J = 7.5, 2.0 Hz, 1H), 7.22 - 7.14 (m, 2H), 6.65 (s, 1H), 3.97 (s, 3H). LC-HRMS (ESI) calcd for [M+H, C 21 H 15 ClN2O3] + : 379.0844, Found: 379.0846.

[0124] Example 10

[0125]

[0126] 5-Chloro-N-(7-(furan-2-yl)pteridin-2-yl)-2-methoxybenzamide (Compound 10)

[0127] Synthesized according to Scheme 6 by replacing a6 with 2-nitropteridine, f1 with 5-chloro-2-methoxybenzoic acid.

[0128] 1 H NMR (500 MHz, Chloroform-d) δ 9.01 (s, 1H), 8.70 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 7.40 (dd, J = 7.5, 2.0 Hz, 1H), 7.20 (s, 1H), 7.16 (s, 1H), 6.59 (s, 1H), 3.97 (s, 3H). LC-HRMS (ESI) calcd for [M+H,

[0129] C 18 H 12 ClN5O3] + : 382.0702, Found: 382.0704.

[0130] Example 11

[0131]

[0132] 5-Chloro-N-(8-(furan-2-yl)-6-oxo-6,7-dihydro-3H-purin-2-yl)-2-methoxybenzamide (Compound 11)

[0133] Synthesized by following Route 7 by replacing f1 with 5-chloro-2-methoxybenzoic acid.

[0134] 1 H NMR (500 MHz, Chloroform-d) δ 7.95 (d, J = 1.9 Hz, 1H), 7.76 (s, 1H), 7.40 (dd, J = 7.5, 2.0 Hz, 1H), 7.15 - 7.07 (m, 2H), 6.58 (s, 1H), 3.97 (s, 3H). LC-HRMS (ESI) calcd for [M+H, C 17 H 12 ClN5O4] + : 386.0651, Found: 386.0653.

[0135] Example 12

[0136]

[0137] 5-chloro-N-(8-(furan-2-yl)-7-methyl-6-oxo-6,7-dihydro-3H-purin-2-yl)-2- methoxybenzamide (Compound 12)

[0138] Synthesized by following Route 7 by replacing f1 with 5-chloro-2-methoxybenzoic acid, substitution reaction of d7 with iodomethane.

[0139] 1 H NMR (500 MHz, Chloroform-d) δ 7.95 (d, J = 1.9 Hz, 1H), 7.76 (s, 1H), 7.40 (dd, J = 7.5, 2.0 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.04 (s, 1H), 6.58 (s, 1H), 3.97 (s, 3H), 3.91 (s, 3H). LC-HRMS (ESI) calcd for [M+H,

[0140] C 18 H 14 ClN5O4] + : 400.0807, Found: 400.0809.

[0141] Example 13

[0142]

[0143] 5-chloro-N-(2-(furan-2-yl)-3-oxo-2,3-dihydro-1H-indazol-6-yl)-2- methoxybenzamide (Compound 13)

[0144] Synthesized by following Route 8 with 5-chloro-2-methoxybenzoic acid instead of f1.

[0145] 1 H NMR (500 MHz, Chloroform-d) δ 9.87 (s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.89 (dd, J = 7.5, 2.0 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.40 (dd, J = 7.5, 2.0 Hz, 1H), 7.24 - 7.17 (m, 2H), 6.60 (s, 1H), 3.97 (s, 2H). LC-HRMS (ESI) calcd for [M+H, C 19 H 14 ClN3O4] + : 384.0746, Found: 384.0748.

[0146] Example 14

[0147]

[0148] 5-chloro-N-(3-fluoro-6-(furan-2-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-2-yl)-2-methoxybenzamide

[0149] (Compound 14)

[0150] Synthesized by following Route 8 with N-methylfuran-2-amine instead of b8 and 5-chloro-2-methoxybenzoic acid instead of f1.

[0151] 1 H NMR (500 MHz, Chloroform-d) δ 7.95 (d, J = 2.0 Hz, 1H), 7.60 (s, 1H), 7.40 (dd, J = 7.5, 2.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 6.83 (s, 1H), 6.47 (s, 1H), 5.31 (s, 1H), 5.26 (s, 1H), 3.97 (s, 3H). LC-HRMS (ESI) calcd for [M+H, C 18 H 12 ClFN4O4] + : 403.0604, Found: 403.0606.

[0152] Example 15

[0153]

[0154] 5-chloro-N-(2-(furan-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)-2-methoxybenzamide (Compound 15)

[0155] Synthesized by following Route 1 by replacing a1 with 6-nitropyridine-2,3-diamine and f1 with 5-chloro-2-methoxybenzoic acid.

[0156] 1 H NMR (500 MHz, Chloroform-d) δ 7.88 - 7.82 (m, 3H), 7.75 (t, J = 1.5 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.46 (dd, J = 8.6, 2.4 Hz, 1H), 7.21 - 7.14 (m, 3H), 6.72 (dd, J = 5.5, 1.3 Hz, 1H), 3.92 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 18 H 14 ClN4O3] + : 369.0749, Found: 369.0742.

[0157] Example 16

[0158]

[0159] 5-chloro-N-(2-(furan-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)-2-methoxybenzamide (Compound 15)

[0160] Synthesized by following Route 1 by replacing a1 with 6-nitropyridine-2,3-diamine and f1 with 5-chloro-2-methoxybenzoic acid.

[0161] 1 H NMR (500 MHz, Chloroform-d) δ 8.68 (s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.77 (t, J = 1.5 Hz, 1H), 7.46 (dd, J = 8.6, 2.4 Hz, 1H), 7.21 - 7.15 (m, 3H), 6.76 (dd, J = 5.5, 1.3 Hz, 1H), 3.92 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 17 H 13 ClN5O3] + : 370.0702, Found: 370.0709.

[0162] Example 17

[0163]

[0164] 5-Chloro-N-(8-(furan-2-yl)-7H-purin-2-yl)-2-methoxybenzamide (Compound 17)

[0165] Synthesized by following Route 1 with a1 replaced by 6-nitro pyrimidine-2,3-diamine, f1 replaced by 5-chloro-2-methoxybenzoic acid.

[0166] 1 H NMR (500 MHz, Chloroform-d) δ 8.70 (s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.75 (t, J = 1.5 Hz, 1H), 7.46 (dd, J = 8.6, 2.4 Hz, 1H), 7.21 - 7.14 (m, 3H), 6.72 (dd, J = 5.5, 1.3 Hz, 1H), 3.92 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 17 H 13 ClN5O3] + : 370.0702, Found: 370.0709.

[0167] Example 18

[0168]

[0169] N-(2-(4-Bromofuran-2-yl)-1H-benzo[d]imidazol-5-yl)-5-chloro-2-methoxybenzamide (Compound 18)

[0170] Synthesized by following Route 1 with b1 replaced by 4-bromofuran-2-carbaldehyde, f1 replaced by 5-chloro-2-methoxybenzoic acid.

[0171] 1 H NMR (500 MHz, Chloroform-d) δ 8.12 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.58 (dd, J = 7.8, 1.9 Hz, 1H), 7.49 - 7.42 (m, 4H), 7.19 (d, J = 8.6 Hz, 1H), 3.92 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 19 H 14 BrClN3O3] + : 445.9902, Found: 445.9907.

[0172] Example 19

[0173]

[0174] 2-ethoxy-5-ethyl-N-(2-(furan-2-yl)-1H-benzo[d]imidazol-5-yl)benzamide (Compound 19)

[0175] Synthetic procedure is referred to Route 1.

[0176] 1 H NMR (500 MHz, Chloroform-d) δ 9.74 (s, 1H), 8.16 (s, 1H), 7.77 - 7.71 (m, 2H), 7.64 (s, 1H), 7.55 (s, 1H), 7.16 (ddt, J = 7.5, 2.0, 1.1 Hz, 1H), 7.09 (s, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.59 (s, 1H), 4.22 (s, 2H), 2.69 (t, J = 1.0 Hz, 2H), 1.27 (s, 2H). LC-HRMS (ESI) calculated for [M+H, C 22 H 22 N3O3] + : 376.1656, Found: 376.1654.

[0177] Example 20

[0178]

[0179] 5-chloro-N-(6-fluoro-2-(4-methylfuran-3-yl)-1H-benzo[d]imidazol-5-yl)-2- methoxybenzamide (Compound 20)

[0180] Synthetic procedure is referred to Route 1 with 4-methylfuran-3-carbaldehyde instead of b1, 5-chloro-2-methoxybenzoic acid instead of f1.

[0181] 1 H NMR (500 MHz, Chloroform-d) δ 8.11 (d, J = 5.0 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.46 (dd, J = 8.6, 2.4 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.29 (q, J = 0.9 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 3.92 (s, 3H), 2.37 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 20 H 16ClFN3O3] + :400.0859, Found:400.0852.

[0182] Example 21

[0183]

[0184] 5-Chloro-2-methoxy-N-(2-(thiophen-2-yl)-1H-benzo[d]imidazol-5-yl)benzamide (Compound 21)

[0185] Synthesized by following Route 1 by replacing b1 with 2-thiophenecarboxaldehyde and f1 with 5-chloro-2-methoxybenzoic acid.

[0186] 1 H NMR (500 MHz, Chloroform-d) δ 9.88 (s, 1H), 8.16 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 17.2 Hz, 2H), 7.54 (d, J = 17.4 Hz, 2H), 7.40 (dd, J = 7.5, 2.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.10 (s, 1H), 3.97 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 19 H 15 ClN3O2S] + :400.0859, Found:400.0852.

[0187] Example 22

[0188]

[0189] 2-Methoxy-N-(2-(thiophen-2-yl)-1H-benzo[d]imidazol-5-yl)-5-(trifluoromethyl)benzamide (Compound 22)

[0190] Synthesized by following Route 2 by replacing b2 with 2-thiophenecarboxaldehyde and f1.

[0191] 1H NMR (500 MHz, Chloroform-d) δ 9.89 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.16 (s, 1H), 7.66 (d, J = 17.2 Hz, 2H), 7.57 (dd, J = 7.5, 2.0 Hz, 1H), 7.56 (s, 1H), 7.52 (s, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.10 (s, 1H), 3.97 (s, 2H). LC-HRMS (ESI) calculated for [M+H, C 20 H 15 F3N2O4S + : 435.0621, Found: 435.0623.

[0192] Example 23

[0193]

[0194] N-(2-(Furan-2-yl)benzo[d]thiazol-5-yl)-2-methoxy-5-(trifluoromethoxy)benzamide (Compound 23)

[0195] Synthesized by following Route 1 and 3 by replacing f1 with 2-methoxy-5- trifluoromethoxybenzoic acid.

[0196] 1 H NMR (500 MHz, Chloroform-d) δ 9.90 (s, 1H), 8.27 (s, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.43 (s, 1H), 7.16 - 7.06 (m, 3H), 6.55 (s, 1H), 3.92 (s, 3H).

[0197] LC-HRMS (ESI) calculated for [M+H, C 20 H 14 F3N2O4S + : 435.0621, Found: 435.0623.

[0198] Example 24

[0199]

[0200] 5-Chloro-N-(2-(furan-2-yl)benzo[d]oxazol-5-yl)-2-(trifluoromethoxy)benzamide (Compound 24)

[0201] Synthesized by following Route 2 and 1 by replacing f1 with 5-chloro-2- trifluoromethoxybenzoic acid.

[0202] 1 H NMR (500 MHz, Chloroform-d) δ 9.82 (s, 1H), 8.23 (s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.80 (s, 1H), 7.65 (d, J = 0.8 Hz, 2H), 7.37 (dd, J = 7.5, 2.0 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.15 (s, 1H), 6.62 (s, 1H). LC-HRMS (ESI) calculated for [M+H, C 19 H 11 ClF3N2O4] + : 423.0354, Found: 423.0352.

[0203] Example 25

[0204]

[0205] 2-Methoxy-N-(2-(thiophen-2-yl)benzo[d]thiazol-5-yl)-5- (trifluoromethyl)benzamide (Compound 25)

[0206] Synthesized according to Scheme 3 by replacing b3 with 2-thiophenecarbonyl chloride and f1 with 2-methoxy-5-trifluoromethoxybenzoic acid.

[0207] 1 H NMR (500 MHz, Chloroform-d) δ 9.89 (s, 1H), 8.27 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 7.97 (s, 1H), 7.69 (d, J = 14.8 Hz, 2H), 7.64 (s, 1H), 7.57 (dd, J = 7.5, 2.0 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.16 (s, 1H), 3.97 (s, 2H). LC-HRMS (ESI) calculated for [M+H, C 20 H 14 F3N2O2S2] + : 435.0444, Found: 435.0342.

[0208] Example 26

[0209]

[0210] 5-Chloro-2-ethoxy-N-(2-(5-methylfuran-2-yl)benzo[d]thiazol-5- yl)benzamide (Compound 26)

[0211] Synthesized by following Route 3 by replacing b3 with 5-methyl-2-furoyl chloride, and f1 with 5-chloro-2-ethoxybenzoic acid.

[0212] 1 H NMR (500 MHz, Chloroform-d) δ 9.84 (s, 1H), 8.27 (s, 1H), 7.90 - 7.83 (m, 2H), 7.64 (s, 1H), 7.38 (dd, J = 7.5, 2.0 Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H), 7.07 (s, 1H), 6.23 (s, 1H), 4.21 (s, 2H), 2.44 (s, 2H). LC-HRMS (ESI) calculated for [M+H, C 21 H 18 ClN2O3S] + : 413.0721, Found: 413.0723.

[0213] Example 27

[0214]

[0215] 5-chloro-N-(2-(furan-2-yl)-1H-benzo[d]imidazol-5-yl)-2-methoxybenzenesulfonamide (Compound 27)

[0216] Synthesized by following Route 1 by replacing f1 with 5-chloro-2-methoxybenzenesulfonyl chloride.

[0217] 1 H NMR (500 MHz, Chloroform-d) δ 9.18 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.71 (t, J = 1.5 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.36 (dd, J = 8.2, 2.2 Hz, 1H), 7.20 (dd, J = 5.5, 1.6 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.68 (dd, J = 5.5, 1.3 Hz, 1H), 3.90 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 18 H 15 ClN3O4S] + : 404.0467, Found: 404.0462.

[0218] Example 28

[0219]

[0220] 5-Chloro-N-(2-(furan-2-yl)benzo[d]oxazol-5-yl)-2-methoxybenzenesulfonamide (Compound 28)

[0221] Synthesized by following Route 2 by replacing f1 with 5-chloro-2-methoxybenzenesulfonyl chloride.

[0222] 1 H NMR (500 MHz, Chloroform-d) δ 9.18 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.72 (t, J = 1.5 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.36 (dd, J = 8.2, 2.2 Hz, 1H), 7.13 - 7.01 (m, 3H), 6.67 (dd, J = 7.1, 1.3 Hz, 1H), 3.90 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 18 H 14 ClN2O5S] + : 405.0307, Found: 405.0304.

[0223] Example 29

[0224]

[0225] 5-Chloro-N-(2-(furan-2-yl)benzo[d]thiazol-5-yl)-2-methoxybenzenesulfonamide (Compound 29)

[0226] Synthesized by following Route 3 by replacing f1 with 2-ethoxy-5- ethylbenzenesulfonyl chloride.

[0227] 1 H NMR (500 MHz, Chloroform-d) δ 9.18 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.85 (dd, J = 3.2, 2.0 Hz, 2H), 7.69 (t, J = 1.4 Hz, 1H), 7.37 (ddd, J = 12.3, 8.2, 2.0 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 7.03 (dd, J = 5.5, 1.6 Hz, 1H), 6.68 (dd, J = 5.4, 1.2 Hz, 1H), 3.90 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 18 H 14 ClN2O4S2] + : 421.0078, Found: 421.0076.

[0228] Example 30

[0229]

[0230] N-(5-chloro-2-(trifluoromethyl)phenyl)-2-(furan-2-yl)-1H- benzo[d]imidazole-5-carboxamide (Compound 30)

[0231] Synthesized by following Route 1 with methyl 3,4-diaminobenzoate instead of a1, 5-chloro-2-trifluoromethylaniline instead of f1.

[0232] 1 H NMR (500 MHz, Chloroform-d) δ 9.71 (s, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 7.8, 1.9 Hz, 1H), 7.73 - 7.68 (m, 2H), 7.57 (d, J = 7.3 Hz, 1H), 7.31 (dd, J = 7.1, 2.2 Hz, 1H), 7.21 (dd, J = 5.5, 1.8 Hz, 1H), 6.68 (dd, J = 5.5, 1.3 Hz, 1H). LC-HRMS (ESI) calculated for [M+H, C 19 H 12 ClF3N3O2] + : 406.0565, Found: 406.0563.

[0233] Example 31

[0234]

[0235] N-(2-ethoxy-5-ethylphenyl)-2-(furan-2-yl)-1H-benzo[d]imidazole-5- sulfonamide (Compound 31)

[0236] Synthesized by following Route 1 with 3,4-diaminobenzenesulfonic acid instead of a1, 2-ethoxy-5-ethylphenylamine instead of f1.

[0237] 1H NMR (500 MHz, Chloroform-d) δ 9.10 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.3, 1.9 Hz, 1H), 7.71 (t, J = 1.5 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.30 (dt, J = 2.1, 1.0 Hz, 1H), 7.20 (dd, J = 5.5, 1.6 Hz, 1H), 6.84 (ddt, J = 8.6, 2.1, 1.0 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 6.68 (dd, J = 5.5, 1.3 Hz, 1H), 4.09 (q, J = 6.2 Hz, 3H), 2.67 (qt, J = 7.2, 1.0 Hz, 3H), 1.42 (d, J = 12.5 Hz, 2H), 1.24 (s, 2H), 1.24 (d, J = 14.4 Hz, 2H). LC-HRMS (ESI) calculated for [M+H, C 21 H 22 N3O4S] + :412.1326, Found:412.1324.

[0238] Example 32

[0239]

[0240] N-(2-(1,3,4-oxadiazol-2-yl)-1H-benzo[d]imidazol-5-yl)-5-chloro-2- methoxybenzamide (Compound 32)

[0241] Synthesized according to Route 1 by replacing b1 with 1,3,4-oxadiazole-2- carboxaldehyde and f1 with 5-chloro-2-methoxybenzoic acid.

[0242] 1 H NMR (500 MHz, Chloroform-d) δ 8.86 (s, 1H), 8.13 (d, J = 1.9 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 7.8, 1.9 Hz, 1H), 7.46 (dd, J = 8.3, 2.3 Hz, 2H), 7.19 (d, J = 8.6 Hz, 1H), 3.92 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 17 H 13 ClN5O3] + :370.0702, Found:370.0709.

[0243] Example 33

[0244]

[0245] 2,4-Dichloro-N-(2-(furan-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidine-5- carboxamide (Compound 33)

[0246] Synthesized by replacing f1 with 2,4-dichloro-5-pyrimidinecarboxylic acid chloride, referring to Route 1.

[0247] 1 H NMR (500 MHz, Chloroform-d) δ 9.64 (s, 1H), 8.66 (s, 1H), 8.16 (s, 1H), 7.73 (s, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.09 (s, 1H), 6.59 (s, 1H). LC-HRMS (ESI) calculated for [M+H, C 16 H 10 Cl2N5O2] + : 348.1343, Found: 348.1345.

[0248] Example 34

[0249]

[0250] N-(2-(Furan-2-yl)-1H-benzo[d]imidazol-5-yl)-2-methoxy-5- (trifluoromethyl)benzamide (Compound 34)

[0251] Synthesized by replacing f1 with 2-methoxy-5-trifluoromethylbenzoic acid, referring to Route 1.

[0252] 1 H NMR (500 MHz, Chloroform-d) δ 9.89 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.16 (s, 1H), 7.73 (s, 1H), 7.64 (s, 1H), 7.57 (dd, J = 7.5, 2.0 Hz, 1H), 7.55 (s, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.09 (s, 1H), 6.59 (s, 1H), 3.97 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 20 H 15 F3N3O3] + : 402.1060, Found: 402.1058.

[0253] Example 35

[0254]

[0255] 5-Chloro-N-(2-(furan-2-yl)-1H-benzo[d]imidazol-5-yl)-2-methoxybenzamide (Compound 35)

[0256] Synthesized by following Route 1 by replacing f1 with 5-chloro-2-methoxybenzoic acid.

[0257] 1 H NMR (500 MHz, Chloroform-d) δ 9.88 (s, 1H), 8.16 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.73 (s, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.40 (dd, J = 7.5, 2.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.09 (s, 1H), 6.59 (s, 1H), 3.97 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 19 H 15 ClN3O3] + : 368.0797, Found: 368.0799.

[0258] Example 36

[0259]

[0260] N-(2-(Furan-2-yl)-1H-benzo[d]imidazol-5-yl)-2-methoxy-5- (trifluoromethoxy)benzamide (Compound 36)

[0261] Synthesized by following Route 1 by replacing f1 with 2-methoxy-5- trifluoromethoxybenzoic acid.

[0262] 1 H NMR (500 MHz, Chloroform-d) δ 9.90 (s, 1H), 8.16 (s, 1H), 7.73 (s, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.16 - 7.07 (m, 3H), 6.59 (s, 1H), 3.92 (s, 3H). LC-HRMS (ESI) calculated for [M+H, C 20 H 15 F3N3O4] + : 418.3515, Found: 418.3517.

[0263] Enzymatic and cellular level activity assay methods

[0264] SF9 eukaryotic cells, which are derived from the ovary tissue of female Spodoptera frugiperda pupae, can be used as a replication baculovirus expression vector and also a suitable transfection host. The Bac-to-Bac expression system, which is commonly used for baculovirus expression, is more efficient and reliable for protein expression in insect cells. The system expresses human ALCAT1 protein with a His tag. Through 3 rounds of virus amplification, high-titer recombinant baculovirus expressing human ALCAT1 protein is obtained. In a 10 cm dish, log phase sf9 cells are plated at 2X106 mL, and 225 μL of P3 virus is added, and the complete medium is supplemented to 10 mL. After static incubation at 28°C for 60 h, ALCAT1 eukaryotic protein expression is completed.

[0265] 1200g centrifugation for 3 min to precipitate cells and cell fragments, and the supernatant is discarded. Add 2 mL of pre-cooled 0.25 mol / L sucrose resuspension buffer to rinse several times, resuspend the cell particles, and put 2 steel balls into the homogenizer. Lysate the cells at 40 Hz for about 20 s. Centrifuge at 4°C, 1000g for 10 min to remove unbroken cells and genomic DNA. Transfer the supernatant to a centrifuge tube and resuspend with about 6 mL of sucrose buffer. Carefully add 1.0 mol / L 1 mL of frozen high-concentration sucrose buffer to the bottom of each ultracentrifuge tube, and centrifuge at 4°C, 38500g for 90 min. Carefully draw out 1 mL of liquid from the bottom of each centrifuge tube. Resuspend the particles with 7 mL of 0.25 mol / L ice-cold sucrose buffer, and transfer the mixture to a clean centrifuge tube. Repeat the centrifugation step, and finally resuspend the cell particles with 5 mL of membrane resuspension buffer. Add the membrane resuspension buffer washed Ni-agrose to the membrane protein extract, shake and incubate for 2 h. Elute the impurities from the affinity chromatography column with 50 mM low-concentration imidazole buffer, and elute the target protein ALCAT1 with 200 mM imidazole buffer. Quickly freeze the prepared membrane fraction in liquid nitrogen and store at -80°C.

[0266] In vitro acyltransferase assay ALCAT1 enzyme activity was measured by the conversion of NBD-palmitoyl-CoA to NBD-1-oleoyl-2-palmitoyl phosphatidic acid with Coenzyme A from NBD- palmitoyl-CoA and 1-oleoyl lysophosphatidic acid in 384-well plates in a 50 mM Tris-HCl (pH 8.0) assay buffer, 200 μΜ oleoyl lysophosphatidic acid solution, 20 μΜ NBD- palmitoyl-CoA, dissolved in 20 mM Tris-HCl (pH 8.0) and 100 μg of protein sample diluted in 50 μL total system. The reaction was incubated at room temperature for 20 min, transferred to an EP tube, and the sample was rotated to extract at room temperature for 6 h. The upper aqueous phase was aspirated, and the organic phase was dried under air, and the lipids were resuspended in 50 μL CHCl3 / methanol (2:1), and the fluorescence intensity was measured under a fluorescence plate reader, with the excitation and emission wavelengths of NBD being 465 nm and 535 nm, respectively. A blue LED laser light source and a 530 BP emission filter were used. The data were expressed in units of NBD-1-oleoyl-2-palmitoyl phosphatidic acid formed per mg of protein per minute (fluorescence intensity).

[0267] Cell-based ALCAT1 inhibitor compound detection experiments were performed on the AML12 cell line. In mouse liver epithelial cells AML12 cells, we found that oleoyl lysophosphatidic acid and palmitoyl-CoA substrate induction caused TG accumulation, and overexpression of ALCAT1. The cells were grown to approximately 70% confluency the day before the experiment, and 15 mL centrifuge tubes were centrifuged at 800 rpm for 3 min, and the supernatant was discarded. The cells were resuspended in F12 complete medium (10% FBS and 1% penicillin-streptomycin F12) and counted. 0.5 mL of cell suspension was seeded into the well plate to achieve a cell density of 1 x 10 5 cells / well, and placed in a 37 °C, 5% CO2 incubator until the next day when the cells reached a stable state.

[0268] The substrate was added at 4 μΜ 1-oleoyl lysophosphatidic acid and 0.4 μΜ palmitoyl-CoA, respectively, and these concentrations were used as the optimal induction conditions for TG accumulation in AML12 cells induced for 12 h. Compound was added at 5 μΜ, and non-induced control, no compound induction, and positive compound groups were set up, with 3 replicates per group.

[0269] At the end of the experiment, the TG content in the cells was determined by extraction. The AML12 cells in the 24-well plate with sufficient treatment time were washed once with PBS, 100 μL of 0.1M KOH (filtered with a 0.45 μM filter) was added to each well, mixed and shaken, collected in a 1.5 mL EP tube, 3 μL was taken from each tube and added to a transparent 96-well plate, 2 replicates for each sample, and water was added to 20 μL. Standard curve wells were added with 20 μL of each standard BSA, 16 μL, 12 μL, 8 μL, 4 μL, 2 μL, 1 μL, 0 μL, and 20 μL was added to make up. 180 μL of Coomassie Brilliant Blue was added to the gun, and the absorbance at 595 nm was measured to calculate the protein concentration of each sample.

[0270] 500 μL of chloroform and 250 μL of anhydrous methanol were added to each tube, and the final volume of liquid in the tube was about 1 mL. First, vortex mixing, then shake vigorously, then extract on the instrument for 12 h at 4°C, centrifuge at 2000 g for 15 min. Take 200 μL of the lower organic layer to another tube, and be careful not to suck the protein in the middle layer. Add 200 μL of 48:47:3 (methanol:water:chloroform) to each tube and wash once, vortex, centrifuge at 4°C, 2000 g for 15 min. Take 200 μL of the lower organic layer to the fume hood and blow off the organic layer under vacuum for about 5 h. Finally, add 100 μL of anhydrous ethanol and shake to dissolve.

[0271] TG detection experiment in a 96-well plate: take 1-5 μL of TG standard, respectively; enzyme reader settings: wavelength difference between 520 and 660, read value, calculate according to the difference between the two absorbances. According to the color comparison, select the appropriate sampling amount. According to the results of the pre-experiment, take 10 μL of each sample, 2 replicates; first add 160 μL of reagent R1 and incubate at 37°C for 5 min, then take 40 μL of reagent R2 and incubate at 37°C for 5 min, and detect the absorbance. Read and export the data, calculate the total cholesterol to total protein ratio TG / Protein (mmol / g), and use Graph Pad (9.0) One way ANOVA for analysis and calculation of significance.

[0272] Small molecule compounds of ALCAT1 enzyme were analyzed by in vitro enzyme method as described above. Before the start of the acyltransferase reaction, the compound inhibitor was added to the enzyme mixture at a concentration of 40 nM, incubated for 1 h, then the fluorescent substrate was added, and the results were compared with the whole enzyme group (without adding small molecule compounds) to obtain the enzyme activity inhibition rate under the condition.

[0273] The results are shown in Table 1 below:

[0274] Table 1

[0275] Compound % inhibition at 40 nM Compound % inhibition at 40 nM 1 52.30 19 48.04 2 58.43 20 52.71 3 43.78 21 44.80 4 54.23 22 55.40 5 39.42 23 57.74 6 46.28 24 40.08 7 54.89 25 42.10 8 47.70 26 40.54 9 41.59 27 73.27 10 45.32 28 54.01 11 48.85 29 51.41 12 39.46 30 46.26 13 45.27 31 56.24 14 46.58 32 54.28 15 50.29 33 57.36 16 57.48 34 63.69 17 46.84 35 65.36 18 51.24 36 60.43 Dafa 60.52

[0276] The small molecule compound inhibitors were analyzed by the in vitro cell method TG as described above after the molecular screening of ALCAT1 enzyme. The results are shown in Table 2 below.

[0277] Table 2

[0278]

[0279]

[0280] Some ALCAT1 inhibitors with high activity also underwent IC 50 analysis. IC 50 is the drug concentration that inhibits 50% of the activity of ALCAT1 enzyme. In order to carry out IC 50 analysis, the chemical inhibitors of ALCAT1 enzyme were added at different concentrations of 10000, 2000, 400, 80, 16, 3.2, 0.64 and 0.125 nM respectively and incubated with the enzyme protein. The IC 50 value (N = 3) of each compound was analyzed and calculated by GraphPad software. The IC 50 values of several compounds were determined using the above method. Among them, the IC 50 values of 10 compounds were <500 nM, the IC 50 values of 6 compounds were <200 nM, and the IC 50 values of two compounds were <50 nM. Table 3 below shows the IC 50 results of some compounds of the present application:

[0281] Table 3

[0282]

[0283] Pharmacokinetic study

[0284] Six healthy adult male C57 mice, all animals were fasted overnight (free water), and then administered orally at 20 mg / kg, respectively. At each time point after administration, blood (100 μL) was collected into an anticoagulant tube through the orbit, and the blood sample was centrifuged at 12000 rpm for 10 minutes within one hour to obtain the upper clear liquid, i.e. plasma, which was stored in a -80°C refrigerator for LC-MS / MS analysis.

[0285] Pharmacokinetic parameters of Dafa:

[0286]

[0287] Pharmacokinetic parameters of compound 35:

[0288]

[0289] The compound of the present application is equivalent or superior to Dafa in inhibiting the hemolytic cardiolipin acyltransferase activity, and has high bioavailability. The enzyme activity of the superior compound 35 is 4 times that of Dafa, and the oral plasma exposure is 233 times that of Dafa.

[0290] The above-described embodiments detail the technical solutions and beneficial effects of the present application, and it should be understood that the above-described is only a specific embodiment of the present application and is not intended to limit the present application. Any modification, supplement and equivalent replacement within the principle range of the present application should be included in the protection scope of the present application.

Claims

1. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or isotopic isomer thereof, characterized in that, The structure of the compound is shown in formula (I): In this embodiment, ring A and ring B together form a cyclic ring; ring A and ring B are independently selected from 5- to 10-membered aromatic rings, saturated or unsaturated aliphatic rings; the aromatic rings, saturated or unsaturated aliphatic rings contain 0 to 3 O, N, S or carbonyl groups; The ring A and ring B are optionally substituted with 0 to 3 Q1s; Q1 is selected from halogens, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, C1-C10 alkoxy, C1-C10 haloalkoxy, C1-C10 alkylthio, C1-C10 haloalkylthio, hydroxyl, cyano, and trifluoromethyl. L is selected from -CONH-, -SO2NH-, -NHCO-, or NHSO2-; R1 and R2 are independently selected from 5-12 aryl, saturated or unsaturated cycloalkyl groups; the aryl, saturated or unsaturated cycloalkyl groups contain 0-3 O, N, S or carbonyl groups; One or more hydrogen atoms on R1 and R2 are substituted by substituents selected from the group consisting of: cyano, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, C1-C10 alkoxy, C1-C10 haloalkoxy, halogen, hydroxy, hydroxymethyl, carboxyl, C1-C10 aldehyde, C2-C10 acyl, C2-C10 ester, amino, phenyl, benzyl; wherein the phenyl and benzyl groups are not substituted or are substituted by 1 to 3 substituents selected from the group consisting of: halogen, C1-C10 alkyl, cyano, OH, nitro, C3-C10 cycloalkyl, C1-C10 alkoxy, amino.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or isotopic isomer thereof, characterized in that, Selected from substituted or unsubstituted quinoxalinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted cyclolinyl, substituted or unsubstituted indoleyl, substituted or unsubstituted isoyindolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted indazoleyl, substituted or unsubstituted imidazole[1,2-a]pyridyl, substituted or unsubstituted imidazole[1,5-a]pyridyl, substituted or unsubstituted imidazole[1,2-a][1,3,5]triazinyl Substituted or unsubstituted imidazo[4,5-b]pyridyl, substituted or unsubstituted benzo[b][1,4]oxazonylheptyl, substituted or unsubstituted [1,2,4]triazolo[1,5-a]pyrazinyl, substituted or unsubstituted pteridinyl, substituted or unsubstituted purine, substituted or unsubstituted imidazo[4,5-b]pyrazinyl, substituted or unsubstituted 3,7-dihydro-6H-purine-6-one, substituted or unsubstituted 2λ 2 -Inzol-3(1H)-keto, substituted or unsubstituted 6λ 2 -pyrrolo[3,4-b]pyrazine-5(7H)-keto, substituted or unsubstituted 1H-imidazo[4,5-b]pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzofuranyl; Wherein, the hydrogen atom on the substituent group is substituted by 1, 2 or 3 substituents selected from the group consisting of: F, Cl, Br, I, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, and C1-C6 haloalkylthio.

3. The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or isotopic isomer thereof, characterized in that, R1 is a substituted or unsubstituted furan cyclogroup, a substituted or unsubstituted thiophene cyclogroup, a substituted or unsubstituted pyrrole cyclogroup, or a substituted or unsubstituted oxadiazole cyclogroup; wherein the substitution refers to being substituted by 1 to 3 substituents selected from the group consisting of: halogen, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, hydroxymethyl, trifluoromethyl, and trifluoromethoxy.

4. The compound according to claim 3, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or isotopic isomer thereof, characterized in that, R2 is a substituted or unsubstituted 5-6 membered aromatic ring group containing 0-3 atoms selected from O, N or S; wherein the substitution refers to being substituted by 1-3 substituents selected from the following group: halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, hydroxymethyl, trifluoromethyl, trifluoromethoxy, C1-C4 acyl, amide.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or isotopic isomer thereof, characterized in that, R1 is a substituted or unsubstituted furanyl group, a substituted or unsubstituted thiophene group, a substituted or unsubstituted pyrrole group, or a substituted or unsubstituted oxadiazole group; R2 is a substituted or unsubstituted phenyl group; In R1, substitution means being replaced by 1 to 3 groups selected from the following group: halogen, C1 to C3 alkyl; In R2, substitution refers to substitution by 1 to 3 groups selected from the following group: halogen, C1 to C3 alkyl, C1 to C3 alkoxy, trifluoromethyl, trifluoromethoxy.

6. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or isotopic isomer thereof, characterized in that, The compounds mentioned are selected from:

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a compound of formula (I) as described in any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or isotopic isomer thereof, and a pharmaceutically acceptable excipient.

8. A hemolysinic phosphatidyltransferase inhibitor, characterized in that, The active ingredient of the inhibitor includes a compound of formula (I) as described in any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or isotopic isomer thereof.

9. The use of a compound of formula (I) as described in any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or isotopic isomer thereof, in the preparation of a medicament for the prevention or treatment of diseases related to hemolytic cardiophosphatidyltransferase activity.

10. Use of the pharmaceutical composition of claim 7 in the preparation of a medicament for the prevention or treatment of diseases related to hemolytic cardiophosphatidyltransferase activity.

11. The application according to claim 9 or 10, characterized in that, The diseases associated with hemolytic cardiophosphatidyltransferase activity include hyperlipidemia, fatty liver, type 2 diabetes, diabetic complications, cardiovascular disease, obesity, and neurological diseases.

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