Pyranopyridine compounds, methods of making, pharmaceutical compositions, and uses thereof

Abstract

The application discloses a pyrano pyridine compound, a preparation method, a pharmaceutical composition and application thereof. The application provides a compound as shown in formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, the compounds have a strong inhibitory effect on aldosterone synthase, have little influence on cortisol synthase, have high selectivity and high safety, and can be used for preventing and / or treating various diseases related to aldosterone.

Description

[0001] This application claims priority to Chinese patent application 2024102347458 with the filing date of 2024 / 3 / 1. This application incorporates the entire text of the above-mentioned Chinese patent application. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and specifically relates to pyrano pyridine compounds, a preparation method, a pharmaceutical composition and application thereof. BACKGROUND

[0003] The renin-angiotensin-aldosterone system (RAAS) is the core regulatory system of blood pressure and water-salt balance in the human body, and aldosterone is a key regulatory molecule downstream of the system. Aldosterone is a kind of steroid hormone (mineralocorticoid family), which promotes the reabsorption of water and sodium in the distal tubule and collecting duct epithelial cells by binding and activating the mineralocorticoid receptor (MR), while inducing the excretion of potassium and hydrogen ions, maintaining the balance of water and electrolytes, and participating in the maintenance of proper blood pressure, vascular tension and tissue perfusion. In addition, recent studies have shown that aldosterone can also up-regulate the expression of AT1R on vascular smooth muscle cells, change the tension of vascular smooth muscle, the response to vasoconstrictor signals and the structure of the arterial wall, increase the pressure response of blood vessels to norepinephrine, and cause blood pressure to rise, vascular smooth muscle cell proliferation, vascular wall thickening and hyalinization.

[0004] Under normal circumstances, the plasma aldosterone concentration is regulated by related stimulating factors such as RAAS, blood potassium concentration, adrenocorticotropic hormone (ACTH). Elevated aldosterone levels can induce blood pressure disorders, cause inflammation, vascular remodeling and tissue fibrosis related to cardiac metabolic diseases, ultimately leading to decreased organ function, cardiovascular complications, end-stage kidney disease, and increased risk of death. Therefore, for many years, it has been a targeted clinical strategy to counteract the harmful effects of excess aldosterone in the body of patients.

[0005] For aldosterone and its receptor related cardio-renal system diseases, blocking the effect of aldosterone is an effective treatment method. Aldosterone receptor antagonists (MRA) and renin-angiotensin-aldosterone system antagonists (RAS inhibitors) are currently used in clinical therapy to antagonize aldosterone. MRA (such as spironolactone) inhibits the effect of aldosterone by competitive binding to the mineralocorticoid receptor, while RAS inhibitors (such as sartan drugs) indirectly reduce aldosterone levels by blocking the upstream stimulation of angiotensin II. Clinically, on the one hand, MRA can over-antagonize the receptor effect (the aldosterone receptor can also be stimulated by estrogen), and there is an off-target side effect of antagonizing the androgen receptor, and on the other hand, RAS inhibitors are not completely inhibited by excessive aldosterone, and there are drug resistance problems in clinical practice. Therefore, specific inhibitors of aldosterone synthase (ASI) that directly inhibit the synthesis of aldosterone can completely reduce the production of aldosterone while not producing additional effects, and can be an efficient iteration of MRA and RAS inhibitors.

[0006] Aldosterone synthase (encoded by the CYP11B2 gene) controls the synthesis of aldosterone, catalyzes the last step of synthesizing aldosterone from cholesterol, and has been a pharmacological target for treating hypertension for decades. Potassium ions, angiotensin II, and leptin can activate the production of CYP11B2, and then synthesize aldosterone. Importantly, CYP11B2 is the only enzyme that catalyzes the final oxidation to produce aldosterone, and is mainly expressed in the glomerular zone of the adrenal gland, and is basically not produced in other parts of the body, so it is expected that there will be no off-target effects.

[0007] Because the enzyme that produces aldosterone and the enzyme that produces cortisol are 93% identical (CYP11B1 is a cortisol synthase, which is the final enzyme in the cortisol synthesis pathway), this high degree of similarity leads to cross-reaction and inhibition of cortisol synthesis by early aldosterone synthase inhibitors. Therefore, it is currently difficult and painful to develop a drug that can inhibit the production of aldosterone without affecting cortisol.

[0008] LCI699 is the first aldosterone synthase inhibitor with oral activity and enters the clinical trial for the treatment of primary aldosterone hyperplasia. After oral administration of LCI699, the plasma aldosterone level is found to be reduced, and the blood pressure is reduced. However, LCI699 has poor selectivity for CYP11B2 and CYP11B1, and has more inhibitory effect on cortisol synthase, so it brings additional side effects, and has to be diverted to the development of Cushing's disease treatment. Thereafter, a new generation of highly selective ASI inhibitors is developed, and currently only a few products have entered the clinic.

[0009] Lorundrostat (Mineralys) is a highly selective aldosterone synthase inhibitor that inhibits aldosterone synthase CYP11B2, reduces the level of aldosterone in the body, and does not inhibit CYP11B1. Another new drug is Baxdrostat (CinCor Pharma / AstraZeneca), and the phase I clinical study of Baxdrostat shows that the inhibition of Baxdrostat on aldosterone synthase is 100 times that of cortisol synthesis, which is a highly selective aldosterone synthesis inhibitor and can dose-dependently reduce the plasma aldosterone level by > 70%.

[0010] Although there are two clinical research products, it is not yet clear whether they will ultimately prove safe and effective in large clinical phase III. Therefore, a highly selective aldosterone synthase inhibitor with better selectivity, higher safety and better effectiveness is still needed by patients. SUMMARY

[0011] The technical problem to be solved by the present application is to provide a highly selective aldosterone synthase inhibitor with a new structure. The present application aims to provide a pyrano pyridine compound, a preparation method thereof, a pharmaceutical composition and an application. The compound has a strong inhibitory effect on aldosterone synthase and almost no effect on cortisol synthase, has high selectivity, and has high safety, and has a good application prospect in the prevention and / or treatment of various diseases related to aldosterone.

[0012] The present application solves the above technical problems through the following technical solutions.

[0013] The present application provides a compound as shown in formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,

[0014] ;

[0015] wherein, the marked carbon atom is in S configuration, R configuration or a mixture thereof;

[0016] R 1 is H, D, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0017] R 2 is H, D, C1-C6 alkyl, C1-C6 alkyl substituted with 1, 2 or 3 R 2-1 , C1-C6 alkoxy, C1-C6 haloalkoxy, "5-10 membered heteroaryl with 1, 2 or 3 heteroatoms selected from N, O and S, and 1, 2 or 3 heteroatoms", C1-C6 alkyl substituted with 1, 2 or 3 R 2-2substituted "5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, the number of heteroatoms being 1, 2, or 3," C3-C6cycloalkyl, substituted C3-C6cycloalkyl, or NR 2-3 substituted C3-C6cycloalkyl or NR 2-4 R 2 -5 ;

[0018] R 2-1 independently hydroxyl or halogen;

[0019] R 2-2 and R 2-3 independently halogen;

[0020] R 2-4 and R 2-5 independently H, C1-C6alkyl, or C1-C6haloalkyl;

[0021] R 3 is H, D, C1-C6alkyl, or C1-C6haloalkyl;

[0022] R 4 is C1-C6alkyl.

[0023] In certain preferred embodiments of the application, certain groups in the compounds of Formula I, pharmaceutically acceptable salts thereof, or stereoisomers thereof, are defined as follows, and any group not mentioned is as described in any embodiment of the application (referred to as "in an embodiment of the application").

[0024] In an embodiment of the application, each C1-C6alkyl and each C1-C6alkyl in substituted C1-C6alkyl is independently methyl, ethyl, propyl, butyl, or hexyl; preferably methyl or ethyl.

[0025] In an embodiment of the application, each C1-C6haloalkyl is independently halomethyl, haloethyl, halopropyl, halobutyl, or halohexyl, the halo being fluoro, chloro, bromo, or iodo.

[0026] In an embodiment of the application, each halogen is independently fluoro, chloro, bromo, or iodo; preferably fluoro.

[0027] In an embodiment of the application, each C1-C6alkoxy is independently methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy.

[0028] In a certain embodiment of the present application, each of said C1-C6haloalkoxy is independently halomethoxy, haloethoxy, halonormalpropoxy, haloisopropoxy, halonormalbutoxy, haloisobutoxy, halosecondarybutoxy or halotert-butoxy; said halo is fluoro, chloro, bromo or iodo.

[0029] In a certain embodiment of the present application, each of said C3-C6cycloalkyl and each of said substituted C3-C6cycloalkyl is independently C3-C6cycloalkyl.

[0030] In a certain embodiment of the present application, each of said 5-10 membered heteroaryl and each of said substituted 5-10 membered heteroaryl is independently 5-6 membered monocyclic heteroaryl.

[0031] In a certain embodiment of the present application, each of said 5-10 membered heteroaryl and each of said substituted 5-10 membered heteroaryl is independently 5-6 membered monocyclic heteroaryl. .

[0032] In a certain embodiment of the present application, said R is marked in R configuration.

[0033] In a certain embodiment of the present application, said R 1 is H or halogen.

[0034] In a certain embodiment of the present application, said R 2 is C1-C6alkyl or NR 2-4 R 2-5 ; preferably C1-C6alkyl.

[0035] In a certain embodiment of the present application, said R 2-4 is H or C1-C6alkyl; preferably C1-C6alkyl.

[0036] In a certain embodiment of the present application, said R 2-5 is independently C1-C6alkyl.

[0037] In a certain embodiment of the present application, R 1 is H or fluoro.

[0038] In a certain embodiment of the present application, R 2 is , or ; preferably or ; further preferably .

[0039] In a certain embodiment of the present application, said R 3 is H or D; preferably H.

[0040] In some embodiments, the compound of formula (I) is a compound of formula (I-1): 4 is methyl.

[0041] In some embodiments, the compound of formula (I) is a compound of formula (I-2):

[0042] ; wherein R 1 , R 2 , R 3 and R 4 are as defined in any embodiment herein.

[0043] In some embodiments, the compound of formula (I) is a compound of formula (I-2):

[0044] ; wherein R 1 , R 2 , R 3 and R 4 are as defined in any embodiment herein.

[0045] In some embodiments, the compound of formula (I) is any one of the following compounds: ; preferably, , , , , , , or .

[0046] In some embodiments, the compound of formula (I) is not , , , , , , , , , , , , , or .

[0047] The present application also provides a method for preparing the compound of formula (I), comprising the step of preparing the compound of formula (I) from compound II and compound III in the presence of a base and a catalyst in a solvent;

[0048] ; wherein R 1 , R 2 , R 3 and R 4 are as defined in any embodiment herein.

[0049] wherein, , R 1 , R 2 , R 3 and R 4 are defined as in any one of the present application.

[0050] In some embodiments, the solvent is an organic solvent and / or water; preferably an organic solvent and water; the organic solvent can be an alcoholic solvent; for example, ethanol.

[0051] In some embodiments, the base is an inorganic base; preferably potassium carbonate and / or sodium carbonate.

[0052] In some embodiments, the catalyst is a palladium catalyst; preferably palladium tetra-triphenylphosphine. The present application also provides a pharmaceutical composition comprising:

[0053] (1) the above-mentioned compound represented by formula (I), pharmaceutically acceptable salt thereof or stereoisomer thereof; and

[0054] (2) a pharmaceutically acceptable excipient.

[0055] The present application also provides the use of the above-mentioned compound represented by formula (I), pharmaceutically acceptable salt thereof or stereoisomer thereof, the above-mentioned pharmaceutical composition in the preparation of aldosterone synthase inhibitors.

[0056] The present application also provides the use of the above-mentioned compound represented by formula (I), pharmaceutically acceptable salt thereof or stereoisomer thereof, the above-mentioned pharmaceutical composition in the preparation of a medicament for treating and / or preventing chronic kidney disease, congestive heart failure, hypertension or primary aldosteronism; preferably hypertension; preferably, the compound represented by formula (I) is not , or .

[0057] Definitions

[0058] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Furthermore, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the application.

[0059] The term "halogen" means fluorine, chlorine, bromine, or iodine.

[0060] The term "alkyl" means a straight or branched chain alkyl group having the indicated number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, s-butyl, n-pentyl, n-hexyl, and the like.

[0061] The term "haloalkyl" refers to an alkyl group substituted with halogen, wherein halogen and alkyl are as defined above.

[0062] The term "alkoxy" refers to the group R Z -O-, wherein R Z is alkyl as defined above.

[0063] The term "haloalkoxy" refers to an alkoxy group substituted with halogen, wherein halogen and alkoxy are as defined above.

[0064] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one, two, or three of N, O, and S), which is monocyclic or polycyclic, and each ring has aromaticity (complying with Huckel's rule). The heteroaryl is attached to the rest of the molecule through a carbon atom or a heteroatom; the heteroaryl is attached to the rest of the molecule through a ring having a heteroatom or a ring not having a heteroatom. Heteroaryl includes, but is not limited to, furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, thiazole, pyridine, pyrimidine, indole, benzopyrrole, and the like.

[0065] The term "cycloalkyl" refers to a saturated monocyclic ring group consisting of only carbon atoms having a specified number of carbon atoms (e.g., C3-C6). Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0066] The term "pharmaceutically acceptable salt" includes "a pharmaceutically acceptable salt formed with an organic or inorganic acid" and "a pharmaceutically acceptable salt formed with an organic or inorganic base".

[0067] The term "stereoisomer" includes configurational isomers, wherein configurational isomers include optically active isomers, e.g., enantiomers, diastereomers, or mixtures thereof.

[0068] The term "pharmaceutically acceptable excipient" refers to any formulation or carrier medium that can deliver an effective amount of active substance of the present application, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative excipients include water, oil, vegetable and mineral, cream bases, lotion bases, ointment bases, and the like. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, and the like. Their formulation is well known to those skilled in the art of cosmetics or topical medicine.

[0069] The term "pharmaceutical composition" means a mixture or solution of a therapeutically effective amount of an active pharmaceutical ingredient with a pharmaceutically acceptable excipient, which is ready for administration to a mammal, e.g., a human, in need thereof.

[0070] The term "treatment" relates to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein relates to the act of treating as defined before.

[0071] The above-mentioned preferred conditions can be combined in any way, without departing from the scope of the present application, to provide various preferred embodiments of the present application.

[0072] The reagents and materials used in the present application are commercially available.

[0073] The positive progress effect of the present application is that the present application discloses a pyrano pyridine compound, a preparation method, a pharmaceutical composition and an application thereof. A selective aldosterone synthase inhibitor with a structure different from the reported or disclosed compounds is provided: the selectivity of the compound of the present application to hCYP11B 1 / 2 is 50-220; the pharmacokinetic property is excellent: the aldosterone concentration in the plasma 12 hours after administration of the compound of the present application is 85-220 pg / mL, the corticosterone concentration in the plasma 12 hours after administration is 350-1000 pg / mL, the maximum blood drug concentration (Cmax) is 8-25 ng / mL, and the plasma exposure amount (AUC0-24h) is 150-2200 h·ng / mL; the in vitro inhibition activity of common CYP450 enzymes is >50 μM and has high safety. BRIEF DESCRIPTION OF DRAWINGS

[0074] Figure 1 Aldosterone concentration in the plasma at different time points for administration.

[0075] Figure 2 Cortisol concentration in the plasma at different time points for administration. DETAILED DESCRIPTION

[0076] The present application will be further described by way of examples, but the present application is not limited to the examples described. The experimental methods in the following examples, for which no specific conditions are indicated, are selected according to conventional methods and conditions, or according to the instructions of the commercial product.

[0077] The starting materials or reagents used herein are commercially available or prepared by synthetic methods generally known in the art

[0078] Intermediate I

[0079]

[0080] Step 1

[0081] Compound 1 (30.0 g, 172.42 mmol) was dissolved in acetonitrile (300 mL), N-iodosuccinimide (46.5 g, 206.90 mmol) was added, and the reaction was stirred at 80 °C for 2.5 h. TLC (dichloromethane / methanol = 10 / 1, product: Rf = 0.1, starting material: Rf = 0.2) showed complete consumption of starting material. The reaction was filtered hot, rinsed with acetonitrile (200 mL), and the solid was collected and dried to give compound 2 (45.0 g, 87%) as a white solid.

[0082] LCMS (ESI) m / z: 299.8 [M+H]+.

[0083] Step 2

[0084] Compound 2 (40.0 g, 133.38 mmol) was dissolved in tetrahydrofuran (400 mL), 3-buten-1-ol (9.85 g, 136.60 mmol) and triphenylphosphine (42.0 g, 160.06 mmol) were added, and the reaction was stirred at room temperature for 0.5 h, cooled to 0 °C, and diisopropyl azodicarboxylate (29.7 g, 146.72 mmol) was added dropwise. The reaction was stirred at 65 °C under a nitrogen atmosphere for 12 h. TLC (petroleum ether / ethyl acetate = 10 / 1, product: Rf = 0.8, starting material: Rf = 0.02) showed complete consumption of starting material. The reaction was concentrated under reduced pressure, and column chromatography (petroleum ether / ethyl acetate = 20 / 1) gave compound 3 (30.7 g, 65% yield) as a yellow oil.

[0085] LCMS (ESI) m / z: 353.9 [M+H]+.

[0086] Step 3

[0087] Compound 3 (30.7 g, 1.0 eq) was dissolved in N,N-dimethylformamide (300 mL), and triphenylphosphine (4.55 g, 17.35 mmol), tetraethylammonium chloride (14.4 g, 86.73 mmol), palladium acetate (1.95 g, 8.67 mmol) and potassium acetate (21.3 g, 216.82 mmol) were added successively. After addition, the reaction solution was stirred at 80 °C under nitrogen atmosphere for 1 hour. TLC (petroleum ether / ethyl acetate = 5 / 1, product: Rf = 0.4, starting material: Rf = 0.78) showed that the starting material was consumed completely. After the reaction solution was cooled, hydrochloric acid aqueous solution (300 mL, 4 M) was added to quench the reaction, and ethyl acetate (300 mL x 2) was used for extraction. After the organic phase was washed with hydrochloric acid aqueous solution (200 mL, 4 M), the aqueous phase was collected, adjusted to pH greater than 7 with 2 M sodium hydroxide aqueous solution, and extracted with ethyl acetate (300 mL, 200 mL). After the organic phase was washed with saturated sodium chloride solution (300 mL), anhydrous sodium sulfate was added for drying, filtered, and the filtrate was concentrated under reduced pressure to obtain yellow solid compound 4 (20.0 g, yield 76.5%).

[0088] LCMS (ESI) m / z: 226.0 [M+H]+.

[0089] Step 4

[0090] Compound 4 (15.0 g, 1.0 eq) was dissolved in dichloromethane (600 mL), cooled to -50 °C under nitrogen atmosphere, and ozone was introduced while stirring for 2 hours. TLC (petroleum ether / ethyl acetate = 4 / 1, product: Rf = 0.3, starting material: Rf = 0.4) showed that the starting material was consumed completely. After the reaction solution was removed to room temperature, saturated sodium sulfite aqueous solution (300 mL) was added to quench the reaction, and dichloromethane (200 mL x 2) was used for extraction. After the organic phase was washed with saturated sodium chloride solution (150 mL), anhydrous sodium sulfate was added for drying, filtered, and the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain yellow solid compound 5 (13.0 g, yield 86%).

[0091] LCMS (ESI) m / z: 227.9 [M+H]+.

[0092] Step 5

[0093] Compound 5 (3.0 g, 1.0 eq) and S-tert-butylsulfinamide (1.91 g, 1.2 eq) were dissolved in toluene (100 mL), and tetraisopropyl titanate (9.3 g, 2.5 eq) was added under a nitrogen atmosphere. After the addition was complete, the reaction solution was stirred at 100 °C for 1 hour. TLC (petroleum ether / ethyl acetate = 2 / 1, product: Rf = 0.3, starting material: Rf = 0.4) showed that the starting material was completely consumed. After the reaction solution was cooled, water (100 mL) and ethyl acetate (200 mL, 150 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 6 (800 mg, yield 18.4%) as a yellow solid.

[0094] LCMS (ESI) m / z: 331.0 [M+H]+.

[0095] Step 6

[0096] Compound 6 (218 mg, 1.0 eq) was dissolved in methanol (10.0 mL), and sodium borohydride (75 mg, 3.0 eq) was added at -50 °C. After the addition was complete, the temperature was maintained and stirring was performed for 2 hours. TLC (dichloromethane / methanol = 20 / 1, product: Rf = 0.2, starting material: Rf = 0.4) showed that the starting material was completely consumed. Saturated sodium bicarbonate solution (10.0 mL) was added to the reaction solution to quench the reaction, and dichloromethane (20.0 mL, 10.0 mL) was added for extraction. The organic phase was washed with saturated sodium chloride solution (20.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 15 / 1) to obtain intermediate 7 (195 mg, yield 89.0%) as a yellow solid.

[0097] LCMS (ESI) m / z: 333.0 [M+H]+.

[0098] Step 7

[0099] Compound 7 (195 mg, 1.0 eq) was dissolved in dioxane (3.0 mL), hydrochloric acid in dioxane (0.45 mL, 4 M, 3.0 eq) was added, and the reaction was stirred at room temperature for 4 hours. TLC (dichloromethane / methanol = 20 / 1, product: Rf = 0.05, starting material: Rf = 0.2) showed complete consumption of the starting material. Ethyl ether (6.0 mL) was added to the reaction, and a solid precipitated. The solid was collected by suction filtration and dried to give yellow solid compound 8 (140 mg, crude).

[0100] LCMS (ESI) m / z: 229.0 [M+H]+.

[0101] Step 8

[0102] Compound 8 (120 mg, 0.52 mmol) was dissolved in dichloromethane (10.0 mL), propionyl chloride (59 mg, 0.63 mmol) and triethylamine (106 mg, 1.05 mmol) were added, and the reaction was stirred at room temperature for 1 hour. TLC (dichloromethane / methanol = 10 / 1, product: Rf = 0.4, starting material: Rf = 0.3) showed complete consumption of the starting material. The reaction was concentrated under reduced pressure to give yellow solid intermediate one (80 mg, 53.6% yield).

[0103] LCMS (ESI) m / z: 285.0 [M+H]+.

[0104] Intermediate two

[0105]

[0106] Intermediate two was synthesized using the same experimental procedure as for intermediate one, using N,N-dimethylacetyl chloride instead of propionyl chloride in step 8.

[0107] LCMS (ESI) m / z: 300 [M+H]+

[0108] Intermediate three

[0109]

[0110] Intermediate three was synthesized using the same experimental procedure as for intermediate one, using NaBD4 instead of NaBH4 in step 6.

[0111] LCMS (ESI) m / z = 286 [M+H]+

[0112] Intermediate four

[0113]

[0114] Using the same experimental procedure as for Intermediate One, Intermediate Four was synthesized by replacing NaBH4 in Step 6 with NaBD4 and replacing propionyl chloride in Step 8 with N,N-dimethylacetyl chloride.

[0115] LCMS (ESI) m / z: 301 [M+H]+.

[0116] Intermediate Five

[0117]

[0118] Step 1

[0119] Compound 11 (10 g, 44.23 mmol) was dissolved in DMF (200 mL), potassium tert-butoxide (9.92 g, 88.47 mmol) was added at 0 °C, stirred for half an hour, iodomethane (8.16 g, 57.50 mmol) was added dropwise, stirred overnight, iodomethane (2.5 g, 17.69 mmol) was added, the reaction solution was warmed to 40 °C and stirred for 5 hours. TLC showed that the starting material was completely consumed. After the reaction solution was cooled, water (50 mL) and ethyl acetate (100 mL) were added for extraction, the organic phase was washed with saturated sodium chloride solution (20.0 mL), then anhydrous sodium sulfate was added for drying, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain white solid compound 12 (8.9 g, yield 83.8%).

[0120] LCMS (ESI) m / z: 241 [M+H]+.

[0121] Step 2

[0122] Compound 12 (2.1 g, 8.75 mmol) was dissolved in dioxane (20 mL), bis(pinacolato)diboron (2.67 g, 10.50 mmol), potassium acetate (2.58 g, 26.24 mmol), Pd(dppf)Cl2 (320 mg, 0.44 mmol) were added, the reaction solution was warmed to 80 °C and stirred for 12 hours. TLC showed that the starting material was completely consumed. After the reaction solution was cooled, water (20 mL) and ethyl acetate (40 mL) were added for extraction, the organic phase was washed with saturated sodium chloride solution (20.0 mL), then anhydrous sodium sulfate was added for drying, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain light brown-red solid compound Intermediate Five (1.6 g, yield 63.7%).

[0123] LCMS (ESI) m / z: 288 [M+H]+.

[0124] Intermediate six

[0125]

[0126] Step 1

[0127] Compound 13 (20 g, 179.99 mmol) was dissolved in dichloromethane (200 mL), under N2protection, pyridine (35.6 g, 449.97 mmol) and chloropropionyl chloride (27.5 g, 216.60 mmol) were added, after addition, the reaction liquid was stirred at 20 °C for 2 hours. TLC showed that the raw material was completely consumed. The reaction was quenched by adding saturated sodium bicarbonate (100 mL), extracted with dichloromethane (100 mL, 50 mL), the organic phase was washed with saturated sodium chloride solution (100 mL), then dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 100~25%) to obtain white solid compound 14 (28.7 g, yield 79%).

[0128] LCMS (ESI) m / z: 202 [M+H]+.

[0129] Step 5

[0130] Compound 14 (5 g, 24.80 mmol) was added to aluminum trichloride (11.6 g, 86.79 mmol), after addition, the reaction liquid was moved to 120 °C and stirred for 3 hours. TLC showed that the raw material was completely consumed. After cooling the reaction system, the reaction was quenched by adding ice water, extracted with dichloromethane (10.0 mL, 5.0 mL), the organic phase was washed with saturated sodium chloride solution (10.0 mL), then dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain white solid compound 15 (2.6 g, yield 63.5%)

[0131] LCMS (ESI) m / z: 166 [M+H]+.

[0132] Step 6

[0133] Compound 15 (2 g, 12.11 mmol) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (60%, 727 mg, 18.16 mmol) was added under ice bath, after addition, the reaction solution was stirred at 20 °C for 0.5 hours. Then iodomethane (2.1 g, 14.53 mmol) was added to the reaction solution, after addition, the reaction solution was stirred at 20 °C for 2 hours. TLC showed that the starting material was completely consumed. Water (10 mL) was added to quench the reaction, ethyl acetate (20 mL, 10 mL) was added for extraction, the organic phase was washed with saturated sodium chloride solution (10 mL), then anhydrous sodium sulfate was added for drying, filtered, concentrated under reduced pressure, and then purified by column chromatography (petroleum ether: ethyl acetate = 100~25%) to obtain white solid compound 16 (1.8 g, yield 82.9%).

[0134] LCMS (ESI) m / z: 180 [M+H]+.

[0135] Step 7

[0136] Compound 16 (1.7 g, 9.49 mmol) was dissolved in N,N-dimethylformamide (10 mL), then N-bromosuccinimide (1.7 g, 9.49 mmol) was added to the reaction solution, after addition, the reaction solution was stirred at 20 °C for 5 hours. TLC showed that the starting material was completely consumed. Water (10 mL) was added to quench the reaction, ethyl acetate (20 mL x 2) was added for extraction, the combined organic phase was washed with saturated sodium chloride solution (10 mL), then anhydrous sodium sulfate was added for drying, filtered, the filtrate was concentrated, and then purified by column chromatography (petroleum ether: ethyl acetate = 100~25%) to obtain white solid compound 17 (1.4 g, yield 57.2%).

[0137] LCMS (ESI) m / z: 259 [M+H]+.

[0138] Step 8

[0139] Compound 17 (2 g, 7.75 mmol) was dissolved in dioxane (20 mL), pinacol diborane (2.4 g, 9.30 mmol), potassium acetate (2.3 g, 23.25 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (283.5 mg, 0.39 mmol) were added, and the reaction was stirred at 80 °C for 12 h under nitrogen. TLC showed that the starting material was consumed completely. After the reaction was cooled, water (5 mL) and ethyl acetate (10 mL) were added for extraction. The organic phase was washed with saturated sodium chloride solution (10.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (PE / EA = 100-25%) to obtain intermediate six (1.3 g, yield 58.4%) as a white solid.

[0140] LCMS (ESI) m / z: 306 [M+H]+.

[0141] Example 1 (R)-N-(8-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3,4- dihydro-2H-pyrano[3,2-c]pyridin-4-yl)propanamide

[0142]

[0143] Intermediate one (80 mg, 0.28 mmol) was dissolved in a mixture of ethanol (7.5 mL) and water (1.5 mL), and intermediate five (97 mg, 0.34 mmol), sodium carbonate (33 mg, 0.31 mmol), and tetrakis triphenylphosphine palladium (16 mg, 14 μmol) were added in sequence. After the addition was completed, the reaction was stirred at 80 °C for 2 h under nitrogen. TLC (dichloromethane / methanol = 15 / 1, product: Rf = 0.1, starting material: Rf = 0.3) showed that the starting material was consumed completely. The reaction was concentrated under reduced pressure, and the product was purified by column chromatography to obtain Example 1 (50.0 mg, yield 48.8%) as a white solid.

[0144] LCMS (ESI) m / z: 366.1 [M+H]+;

[0145] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (d, J = 7.9 Hz, 1 H), 8.26 (s, 1H), 8.22 (s, 1 H), 7.41 (dd, J = 8.3, 2.0 Hz, 1 H), 7.37 (s, 1 H), 7.16 (d, J= 8.4 Hz, 1 H), 5.10 (dd, J = 13.0, 5.8 Hz, 1 H), 4.39 - 4.32 (m, 1 H), 4.31- 4.22 (m, 1 H), 3.29 (s, 3 H), 2.96 - 2.86 (m, 2 H), 2.62 - 2.54 (m, 2 H),2.21 - 2.11 (m, 2 H), 2.11 - 2.04 (m, 1 H), 1.98 - 1.89 (m, 1 H), 1.06 (dd, J= 10.7, 4.4 Hz, 3 H).

[0146] (R) -N- (8- (1-methyl-2-oxo-1, 2, 3, 4-tetrahydroquinoline-6-yl) -3, 4-dihydro-2H- pyran [3, 2-c] pyridine-4-yl) propionamide

[0147] Using the same experimental method as in Example 1, by the coupling reaction of intermediate three and intermediate five, the following compound was synthesized.

[0148]

[0149] LCMS (ESI) m / z = 367 [M+H]+

[0150] 1H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 8.25 (d, J = 17.4 Hz, 2H),7.45 – 7.31 (m, 2H), 7.16 (d, J = 8.4 Hz, 1H), 4.44 – 4.21 (m, 2H), 3.29 (s,3H), 2.97 – 2.82 (m, 2H), 2.61 – 2.56 (m, 2H), 2.16 (ddd, J = 14.9, 7.4, 4.5Hz, 2H), 2.09 – 2.03 (m, 1H), 2.01 – 1.88 (m, 1H), 1.06 (t, J = 7.6 Hz, 3H).

[0151] Example 3 (R) -1,1-dimethyl-3- (8- (1-methyl-2-oxo-1, 2, 3, 4-tetrahydroquinolin-6-yl) -3, 4-dihydro-2H-pyrano [3, 2-c] pyridin-4-yl) urea

[0152] Using the same experimental method as Example 1, by intermediate two and intermediate five coupling reaction, synthesis was obtained.

[0153]

[0154] LCMS (ESI) m / z: 381 [M+H]+;

[0155] 1H NMR (400 MHz, DMSO) δ 8.26 (s, 1H), 8.25 (s, 1H), 7.41 (dd, J =8.3, 1.9 Hz, 1H), 7.38 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 7.9Hz, 1H), 5.03 – 4.99 (m, 1H), 4.39 – 4.29 (m, 2H), 3.33 – 3.31 (m, 3H), 3.27(d, J = 13.0 Hz, 4H), 2.94 – 2.88 (m, 2H), 2.84 (s, 1H), 2.61 – 2.56 (m, 2H),2.10 – 1.93 (m, 3H).

[0156] Example 4 (R) -N- (8- (7-fluoro-1-methyl-2-oxo-1, 2, 3, 4-tetrahydroquinolin-6-yl) -3, 4-dihydro-2H-pyrano [3, 2-c] pyridin-4-yl-4-d) propionamide

[0157] Using the same experimental method as Example 1, by intermediate three and intermediate six coupling reaction, synthesis was obtained.

[0158]

[0159] LCMS (ESI) m / z: 381 [M+H]+;

[0160] 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.23 (d, J = 32.2 Hz, 2H),7.32 – 6.98 (m, 2H), 4.27 (d, J = 26.3 Hz, 2H), 3.27 (s, 3H), 2.88 (s, 2H),2.58 (s, 2H), 2.16 (s, 2H), 1.99 (d, J = 51.0 Hz, 2H) 1.06 (t, J = 7.6 Hz,3H).

[0161] Example 5 (R) -1,1-dimethyl-3- (8- (1-methyl-2-oxo-1, 2, 3, 4-tetrahydroquinolin-6-yl) -3, 4-dihydro-2H-pyrano [3, 2-c] pyridin-4-yl-4-d) urea

[0162] Using the same experimental method as Example 1, it was synthesized by the coupling reaction of intermediate four and intermediate five.

[0163]

[0164] LCMS (ESI) m / z: 399[M+H]+;

[0165] 1H NMR (400 MHz, DMSO) δ 8.25 (m, 2H), 7.46-7.33 (m, 2H), 7.16 (d,1H),6.75 (s, 1H), 4.36-4.23 (m, 2H), 3.29 (s, 3H), 2.94-2.89 (m, 2H), 2.84(s, 6H), 2.60 – 2.56 (m, 2H), 2.04-1.98 (m, 2H).

[0166] Example 6 (R) -3- (8- (7-fluoro-1-methyl-2-oxo-1, 2, 3, 4-tetrahydroquinolin-6-yl) -3, 4-dihydro-2H-pyrano [3, 2-c] pyridin-4-yl) -1, 1-dimethylurea

[0167] Using the same experimental method as Example 1, it was synthesized by the coupling reaction of intermediate two and intermediate six.

[0168]

[0169] LCMS (ESI) m / z: 399[M+H]+;

[0170] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.97-2.09 (m, 2H), 2.56-2.58(m, 2 H),2.79-2.93(m, 8H), 2.88(s, 3 H), 4.27-4.32(m, 2 H), 4.99-5.03 (m, 1 H), 6.78-6.80 (d, 1 H),7.07-7.10 (d, 1 H), 7.21-7.23(d, 1 H), 8.21(s, 1 H), 8.32(s, 1H)。

[0171] Example 7 (R) -3- (8- (7- fluoro- 1- methyl- 2- oxo- 1, 2, 3, 4- tetrahydroquinoline- 6- yl) -3, 4- dihydro- 2H- pyran [3, 2- c] pyridine- 4- yl- 4- d) -1, 1- dimethylurea

[0172] Using the same experimental method as Example 1, it was synthesized by the coupling reaction of intermediate four and intermediate six.

[0173]

[0174] LCMS (ESI) m / z: 400.2 [M+H]+;

[0175] 1H NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 8.17 (s, 1H), 7.22 (d, J = 8.0Hz, 1H), 7.08 (d, J = 12.0 Hz, 1H), 6.77 (s, 1H), 4.34 – 4.25 (m, 2H), 3.30(d, J = 12.0 Hz, 4H), 2.90 – 2.81 (m, 7H), 2.59 (t, J = 8.0 Hz, 2H), 2.05 –1.96 (m, 2H).

[0176] Example 8 (R) -N- (8- (7- fluoro- 1- methyl- 2- oxo- 1, 2, 3, 4- tetrahydroquinoline- 6- yl) -3, 4- dihydro- 2H- pyran [3, 2- c] pyridine- 4- yl) propionamide

[0177] Using the same experimental method as Example 1, it was synthesized by the coupling reaction of intermediate one and intermediate six.

[0178]

[0179] LCMS (ESI) m / z = 384 [M+H]+

[0180] 1H NMR (400 MHz, DMSO) δ 8.41 (d, J = 7.9 Hz, 1H), 8.25 (m, 2H), 7.22(d, J = 8.0 Hz, 1H), 7.08 (d, J = 11.9 Hz, 1H), 5.12 (m, 1H), 4.39 – 4.15 (m,2H), 3.27 (s, 3H), 2.89 (t, J = 7.3 Hz, 2H), 2.62 – 2.56 (m, 2H), 2.24 – 2.12(m, 2H), 2.09 – 1.89 (m, 2H), 1.06 (t, J = 7.6 Hz, 3H)。

[0181] Experimental Example 1 Inhibitory activity of compounds on hCYP11B2 / hCYP11B1

[0182] 1. Experimental system: G-402 CYP11B2 or CYP11B1 high expression stable strain

[0183] The above high expression stable strain is constructed based on human adrenal leiomyoma cell line G-402, and human CYP11B2 (NM_000498.3) and CYP11B1 (NM_000497.4) are introduced by artificial lentivirus.

[0184] Maintenance medium: McCoy's 5A (modified, #16600082, GIBCO) + 10% FBS (GIBCO) + 1 μg / mL puromycin (A1113803, GIBCO).

[0185] Recovery and seed plate medium: McCoy's 5A (modified, #16600082, GIBCO) + 10% FBS (GIBCO).

[0186] Reaction medium: DMEM / F12 (#11320033, GIBCO) + 2.5% activated carbon filtered FBS (S11695, R&D).

[0187] 2. Experimental steps:

[0188] Seeding plate: after cell recovery, culture with maintenance medium to appropriate state, 1 × 10 4 / 100 μL / well (Uniform cell volume)Seeding: Seed 96-well flat bottom plates with plating medium.

[0189] Medium change: After overnight (>12 hours) adhesion, aspirate supernatant, wash with 100-150 μL / well serum-free medium, aspirate and add 50 μL / well reaction medium.

[0190] Preparation: Dilute compounds in reaction medium containing 0.4 μM substrate (final concentration 0.2 μM):

[0191] CYP11B2 substrate: 11-deoxycorticosterone (S4243, selleckchem), final concentration 0.2 μM

[0192] CYP11B1 substrate: 11-deoxycortisol (S4775, selleckchem), final concentration 0.2 μM.

[0193] Addition: Add 50 μL / well of the above dilutions to the cell plates, as well as background and control wells.

[0194] Incubation: Incubate for 16 hours in the cell incubator, then spin the plates at 450g for 2 minutes, and transfer 75 μL of supernatant to collection plates and store at -80°C until use (or directly measure).

[0195] Measurement: Measure the concentration of aldosterone or cortisol in the supernatant using the homogeneous time-resolved fluorescence kit (Cisbio HTRF kit, Cat. 64ALDPEG, Cat. 62CRTPEG).

[0196] Analysis: Calculate the absolute IC50 (Abs IC50) for each compound using a four-parameter fit.

[0197] The results show that most of the tested compounds (Examples 2, 4, 5 and 8) have similar inhibitory activity on CYP11B2 as the reference Baxdrostat, and Examples 2, 6, 8 show better selectivity. Unexpectedly, the chiral isomers of the tested compounds do not have aldosterone synthase inhibitory activity.

[0198] Table 1 Inhibitory activity of compounds on hCYP11B2 / hCYP11B1

[0199]

[0200] Example 2 In vitro inhibitory activity of the tested substances on common CYP450 enzymes

[0201] Prepare the test compound working solution, the solvent is dimethyl sulfoxide (DMSO) (starting with a final concentration of 50 μM, 3-fold dilution of 7 concentration points).

[0202] Prepare the corresponding microsomes (CORNING, Cat No. 452117) and the corresponding substrate solution (components are shown in Table 2).

[0203] Prepare the HLM working solution (components are shown in Table 3).

[0204] Mix the test compound working solution, the corresponding microsomes and the corresponding substrate solution, and the HLM working solution, preheat in a 37.0°C water bath for 10 minutes, then add NADPH cofactor (BONTAC, Cat No. BT04), continue to mix and incubate in a 37.0°C water bath for 10 minutes, then add cold termination solution to terminate the reaction.

[0205] Table 2

[0206]

[0207] Table 3

[0208]

[0209] Centrifuge the sample at 4000 rpm for 20 minutes to precipitate the protein, transfer the supernatant to HPLC water, shake for 10 minutes.

[0210] Finally, perform LC / MS / MS analysis, and the results are shown in Table 4:

[0211] Table 4

[0212]

[0213] The experiment shows that the test compound has no inhibition on each type of CYP450 enzyme, and the risk of drug-drug interaction (DDI) is small. Compared with baxdrostat, the test compound has no inhibition on CYP2C19, and the risk of DDI is lower.

[0214] Pharmacokinetic and pharmacodynamic test of the test substance in cynomolgus monkeys

[0215] Select adult cynomolgus monkeys (Macaca fascicularis) with appropriate body weight and age, one male and one female for the experiment, and adapt for one week. On the day of the experiment, the monkeys were individually housed in stainless steel mesh cages for testing.

[0216] Oral treatment and ACTH working solution (Tetracosactrin (HY-P0060, MCE) dissolved in ultrapure water, filtered through a 0.22 μm filter, and diluted with sterile PBS solution to the required concentration) were administered according to the following dosing schedule:

[0217] At T = 0, two monkeys in each group were orally administered 0.5 mg / kg (the compound was prepared as a suspension in 5% sodium hydroxymethylcellulose aqueous solution as the solvent), with a fixed volume of 2 mL / kg;

[0218] At T = +1 hour (i.e., 1 hour after administration), 14.5 μg / kg of the aforementioned ACTH working solution was injected intramuscularly.

[0219] Sampling and Testing: Blood samples (collected in EDTA-anticoagulant tubes) were collected before oral administration (pre-dose) and 0.5, 1, 2, 4, 6, and 12 hours after administration for measurement of plasma corticosteroid concentrations. Blood was centrifuged at 10,000 rpm for 15 minutes at 4°C, after which plasma was separated and stored at -80°C for further analysis. Plasma aldosterone and cortisol were measured by electrochemiluminescence using a Roche biochemical analyzer. Pharmacokinetic parameters were determined by LC / MS using plasma samples collected simultaneously (0.5, 1, 2, 4, 6, and 12 hours after administration, as well as an additional 24 hours after administration).

[0220] The results of aldosterone test are shown in Table 5 and Figure 1 , cortisol test results are shown in Table 6 and Figure 2 The test showed that the test compound could significantly inhibit aldosterone synthesis and had no effect on cortisol levels.

[0221] Table 5 Plasma aldosterone concentrations at different time points of administration

[0222]

[0223] Table 6 Plasma cortisol concentrations at different time points of administration

[0224]

[0225] The above experiment was repeated with the following differences: at T = 0, two monkeys in each group were orally administered a dose of 0.05 mg / kg (the compound was suspended in 5% sodium hydroxymethylcellulose aqueous solution as the solvent) at a fixed volume of 2 mL / kg;

[0226] The aldosterone results are shown in Table 7 and the Cortisol results are shown in Table 8. The results demonstrate that Example 8 significantly inhibited aldosterone synthesis and had the largest change from baseline (-51.05) after 1 hour of ACTH stimulation. The other test articles, including Example 2, did not have effective inhibition of aldosterone synthesis at the doses tested. The effectiveness of Example 8 was unexpected. None of the test articles had an effect on Cortisol levels.

[0227] Table 7. Plasma aldosterone concentration at different time points after dosing

[0228]

[0229] "0" indicates no significant change.

[0230] Table 8. Plasma Cortisol concentration at different time points after dosing

[0231]

[0232] The pharmacokinetic parameters of the test compounds are shown in Table 9. Compared to the reference baxdrostat, the test compounds had similar time to peak and half-life, but higher maximum plasma concentration (C max ) and plasma exposure (AUC) that were 2-3 times higher than the reference, demonstrating good pharmacokinetic properties. Unexpectedly, Example 8 had higher (C max ) and (AUC) at the same dose, which were twice as high as Example 2 and three times as high as baxdrostat.

[0233] Table 9

[0234] .

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, characterized in that: Among them, * marks the carbon atom as S configuration, R configuration or their mixture; R 1 is H, D, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R 2 is H, D, C1-C6 alkyl, 1, 2 or 3 R 2-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, "a 5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S", 1, 2 or 3 R 2-2 Substituted "5-10 membered heteroaryl group with 1, 2 or 3 heteroatoms selected from N, O and S", C3-C6 cycloalkyl, 1, 2 or 3 R 2-3 Substituted C3-C6 cycloalkyl or NR 2-4 R 2-5 ; R 2-1 are independently hydroxy or halogen; R 2-2 and R 2-3 are independently halogen; R 2-4 and R 2-5 are independently H, C1-C6 alkyl or C1-C6 haloalkyl; R 3 is H, D, C1-C6 alkyl or C1-C6 haloalkyl; R 4 is a C1-C6 alkyl group; The compound shown in formula (I) is not 2. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein: It meets one or more of the following conditions: (1) The C1-C6 alkyl group in each of the C1-C6 alkyl groups and the C1-C6 alkyl groups in each of the substituted C1-C6 alkyl groups is independently methyl, ethyl, propyl, butyl or hexyl; (2) Each of the C1-C6 haloalkyl groups is independently a halomethyl group, a haloethyl group, a halopropyl group, a halobutyl group or a halohexyl group, and the halo group is a fluoro group, a chloro group, a bromo group or an iodo group; (3) Each of the halogens is independently fluorine, chlorine, bromine or iodine; (4) Each of the C1-C6 alkoxy groups is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (5) Each of the C1-C6 haloalkoxy groups is independently a halomethoxy group, a haloethoxy group, a halo-n-propoxy group, a halo-isopropoxy group, a halo-n-butoxy group, a halo-isobutoxy group, a halo-sec-butoxy group, or a halo-tert-butoxy group; the halo group is a fluoro group, a chloro group, a bromo group, or an iodo group; (6) The C3-C6 cycloalkyl group and the C3-C6 cycloalkyl group in each of the substituted C3-C6 cycloalkyl groups are independently cyclopropyl; (7) The 5-10 membered heteroaryl group in each of the aforementioned 5-10 membered heteroaryl groups and the 5-10 membered heteroaryl group in each of the aforementioned substituted 5-10 membered heteroaryl groups is independently a 5-6 membered monocyclic heteroaryl group; (8) the heteroatoms in each of the 5-10 membered heteroaryl groups and each of the substituted 5-10 membered heteroaryl groups are independently selected from N, and the number of heteroatoms is independently 1; and (9) The carbon atom marked with * is in R configuration.

3. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein: It meets one or more of the following conditions: (1) R 1 is H or halogen; (2) R 2 is C1-C6 alkyl or NR 2-4 R 2-5 ; (3) R 2-4 is H or C1-C6 alkyl; and (4) R 2-5 It is a C1-C6 alkyl group.

4. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein: It meets one or more of the following conditions: (1)R 1 is H or fluorine; (2)R 2 for (3) R 3 is H or D; and (4)R 4 It is a methyl group.

5. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein: The compound represented by formula (I) is a compound represented by formula (I-1), Among them, R 1 、R 2 、R 3 and R 4 The definition as described in any one of claims 1 to 4.

6. The compound of formula (I) according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound represented by formula (I) is not 7. A compound represented by formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, characterized in that: The compound represented by formula (I) is any of the following compounds:

8. The compound of formula (I) according to claim 7, its pharmaceutically acceptable salt or its stereoisomer, wherein: The compound represented by formula (I) is any of the following compounds:

9. A method for preparing a compound of formula (I) as claimed in any one of claims 1 to 8, characterized in that: The method comprises the following steps: preparing a compound represented by formula (I) from compound II and compound III in a solvent in the presence of a base and a catalyst; Among them, *, R 1 、R 2 、R 3 and R 4 The definition as described in any one of claims 1 to 8.

10. The method for preparing the compound of formula (I) as claimed in claim 9, wherein: It meets one or more of the following conditions: (1) The solvent is an organic solvent and / or water; (2) The base is an inorganic base; The catalyst described in (3) is a palladium catalyst.

11. The method for preparing the compound of formula (I) as claimed in claim 10, wherein: It meets one or more of the following conditions: (1) The solvent is an organic solvent and water; (2) the base is potassium carbonate and / or sodium carbonate; and (3) The catalyst is tetrakistriphenylphosphine palladium.

12. The method for preparing the compound of formula (I) as claimed in claim 11, wherein: The organic solvent is an alcohol solvent.

13. The method for preparing the compound of formula (I) as claimed in claim 12, wherein: The organic solvent is ethanol.

14. A pharmaceutical composition comprising: (1) a compound of formula (I) according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and (2) Pharmaceutically acceptable excipients.

15. Use of the compound of formula (I) according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and the pharmaceutical composition according to claim 14 in the preparation of an aldosterone synthase inhibitor.

16. Use of the compound of formula (I) according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating and / or preventing chronic kidney disease, congestive heart failure, hypertension or primary aldosteronism.

17. The use according to claim 16, characterized in that The medicine is used for treating and / or preventing hypertension.

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