Pyrano-pyridine compound, preparation method therefor, pharmaceutical composition thereof and use thereof

Abstract

Disclosed in the present invention are a pyrano-pyridine compound, a preparation method therefor, a pharmaceutical composition thereof and the use thereof. Provided in the present invention are a compound as shown in formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof. These compounds have a stronger inhibitory effect on aldosterone synthetase, but have almost no influence on cortisol synthetase, have high selectivity and higher safety, and can be used for preventing and / or treating various diseases related to aldosterone.

Description

Pyranopyridine compounds, preparation methods, pharmaceutical compositions and applications thereof

[0001] This application claims priority to Chinese Patent Application No. 2024102347458 filed on March 1, 2024, and Chinese Patent Application No. 2025102190668 filed on February 26, 2025. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to pyranopyridine compounds, preparation methods, pharmaceutical compositions and applications thereof. Background Art

[0003] Aldosterone is a key regulator of blood flow, blood pressure, and water-salt balance in the human body, and the renin-angiotensin-aldosterone system (RAAS) is a key downstream regulatory molecule. Aldosterone is a steroid hormone (mineralocorticoid family) that binds to and activates mineralocorticoid receptors (MRs) in the epithelial cells of the distal renal tubules and collecting ducts, promoting renal reabsorption of water and sodium while inducing the excretion of potassium and hydrogen ions, maintaining water and electrolyte balance and participating in the maintenance of appropriate blood pressure, vascular tone, and tissue perfusion. Furthermore, recent studies have shown that aldosterone can also upregulate AT1R expression on vascular smooth muscle cells, altering vascular smooth muscle tone, responses to vasoconstrictor signals, and arterial wall structure. It also increases the vascular pressor response to norepinephrine, leading to elevated blood pressure, vascular smooth muscle cell proliferation, vascular wall thickening, and hyaline degeneration.

[0004] Under normal circumstances, plasma aldosterone concentration is regulated by stimulatory factors such as the RAAS, serum potassium concentration, and adrenocorticotropic hormone (ACTH). Elevated aldosterone levels can induce blood pressure disorders and trigger inflammation, vascular remodeling, and tissue fibrosis associated with cardiometabolic diseases, ultimately leading to decreased organ function, cardiovascular complications, advanced renal disease, and an increased risk of death. Therefore, counteracting the deleterious effects of excess aldosterone in patients has been a targeted clinical strategy for many years.

[0005] Blocking the effects of aldosterone is an effective treatment for cardiovascular and renal diseases associated with aldosterone and its receptors. Aldosterone receptor antagonists (MRAs) and renin-angiotensin-aldosterone system antagonists (RAS inhibitors) are currently used clinically to antagonize aldosterone. MRAs (such as spironolactone) inhibit aldosterone action by competitively binding to the mineralocorticoid receptor, while RAS inhibitors (such as sartans) indirectly reduce aldosterone levels by blocking the upstream stimulation of angiotensin II. Clinically, MRAs can excessively antagonize receptor effects (aldosterone receptors can also be stimulated by estrogen) and have off-target side effects of androgen receptor antagonism. RAS inhibitors, on the other hand, incompletely inhibit excess aldosterone, leading to drug resistance in clinical practice. Therefore, specific inhibitors (ASIs) that directly inhibit aldosterone synthase (AS) can completely reduce aldosterone production without causing additional side effects, and can serve as an effective alternative to MRAs and RAS inhibitors.

[0006] Aldosterone synthase (encoded by the CYP11B2 gene) controls aldosterone synthesis, catalyzing the final step in the synthesis of aldosterone from cholesterol. For decades, it has been a pharmacological target for the treatment of hypertension. Potassium ions, angiotensin II, and leptin can all activate CYP11B2, which in turn synthesizes aldosterone. Importantly, CYP11B2 is the only enzyme that catalyzes the final oxidation to aldosterone and is primarily expressed in the zona glomerulosa of the adrenal gland. This enzyme is largely absent in other parts of the body, thus minimizing the potential for off-target effects.

[0007] Because the enzymes that produce aldosterone and cortisol are 93% identical (CYP11B1, or cortisol synthase, is the final enzyme in the cortisol synthesis pathway), this high degree of similarity has led to cross-reactivity and inhibition of cortisol synthesis by early aldosterone synthase inhibitors. Therefore, developing a drug that can inhibit aldosterone production without affecting cortisol is currently a difficult and painful issue.

[0008] LCI699 is the first orally active aldosterone synthase inhibitor to enter clinical trials for the treatment of primary aldosteronism. Oral administration of LCI699 has been shown to reduce plasma aldosterone levels and blood pressure. However, LCI699 exhibits poor selectivity for CYP11B2 and CYP11B1, with a greater inhibitory effect on cortisol synthase, resulting in additional side effects, necessitating its development into the treatment of Cushing's disease. Subsequently, a new generation of highly selective ASI inhibitors has been developed, with only a few currently in clinical trials.

[0009] Lorundrostat (Mineralys) is a highly selective aldosterone synthase inhibitor that inhibits CYP11B2, reducing aldosterone levels in the body without inhibiting CYP11B1. Another new drug is Baxdrostat (CinCor Pharma / AstraZeneca). Phase I clinical studies of Baxdrostat have shown that its inhibitory effect on aldosterone synthase is 100-fold greater than its inhibitory effect on cortisol synthesis, making it a highly selective aldosterone synthesis inhibitor, capable of dose-dependently reducing plasma aldosterone levels by >70%.

[0010] Although there are two clinical research products, it is still unclear whether they will ultimately prove to be safe and effective in large-scale Phase III clinical trials. Therefore, highly selective aldosterone synthase inhibitors with good selectivity, higher safety, and better efficacy are still needed by patients. Summary of the Invention

[0011] The technical problem to be solved by the present invention is to provide a highly selective aldosterone synthase inhibitor with a novel structure. The present invention aims to provide a pyranopyridine compound, a preparation method, a pharmaceutical composition, and applications thereof. These compounds have a strong inhibitory effect on aldosterone synthase but have little effect on cortisol synthase. They exhibit high selectivity and a high safety profile, and have promising application prospects in the prevention and / or treatment of various aldosterone-related diseases.

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

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

[0014] Among them, * marks the carbon atom as S configuration, R configuration or their mixture;

[0015] R 1 is H, D, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0016] 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 1, 2 or 3 heteroatoms selected from N, O and S", 1, 2 or 3 R 2-2Substituted "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 ;

[0017] R 2-1 are independently hydroxy or halogen;

[0018] R 2-2 and R 2-3 are independently halogen;

[0019] R 2-4 and R 2-5 are independently H, C1-C6 alkyl or C1-C6 haloalkyl;

[0020] R 3 is H, D, C1-C6 alkyl or C1-C6 haloalkyl;

[0021] R 4 It is a C1-C6 alkyl group.

[0022] In certain preferred embodiments of the present invention, certain groups in the compound of Formula I, its pharmaceutically acceptable salt or its stereoisomers are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention").

[0023] In a certain embodiment of the present invention, 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; preferably methyl or ethyl.

[0024] In a certain embodiment of the present invention, 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 iodine group.

[0025] In one embodiment of the present invention, each halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine.

[0026] In one embodiment of the present invention, each of the C1-C6 alkoxy groups is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0027] In a certain embodiment of the present invention, each of the C1-C6 haloalkoxy groups is independently a halomethoxy group, a haloethoxy group, a halo-n-propoxy group, a haloisopropoxy group, a halo-n-butoxy group, a haloisobutoxy group, a halo-sec-butoxy group or a halo-tert-butoxy group; and the halo group is a fluoro group, a chloro group, a bromo group or an iodo group.

[0028] In a certain embodiment of the present invention, the C3-C6 cycloalkyl group and the C3-C6 cycloalkyl group in each substituted C3-C6 cycloalkyl group are independently cyclopropyl groups.

[0029] In a certain embodiment of the present invention, the 5-10 membered heteroaryl group in each of the 5-10 membered heteroaryl groups and the 5-10 membered heteroaryl group in each of the substituted 5-10 membered heteroaryl groups is independently a 5-6 membered monocyclic heteroaryl group.

[0030] In one embodiment of the present invention, the heteroatom in each of the 5-10 membered heteroaryl groups and each of the substituted 5-10 membered heteroaryl groups is independently selected from N, and the number of heteroatoms is independently 1; for example,

[0031] In one embodiment of the present invention, the carbon atom marked with * is in R configuration.

[0032] In a certain embodiment of the present invention, the R 1 is H or halogen.

[0033] In a certain embodiment of the present invention, the R 2 is C1-C6 alkyl or NR 2-4 R 2-5 ; preferably a C1-C6 alkyl group.

[0034] In a certain embodiment of the present invention, the R 2-4 is H or C1-C6 alkyl; preferably C1-C6 alkyl.

[0035] In a certain embodiment of the present invention, the R 2-5 are independently C1-C6 alkyl.

[0036] In one embodiment of the present invention, R 1 is H or fluorine.

[0037] In one embodiment of the present invention, R 2 for Preferably More preferably

[0038] In a certain embodiment of the present invention, the R 3 It is H or D; preferably H.

[0039] In a certain embodiment of the present invention, the R 4 It is a methyl group.

[0040] In one embodiment of the present invention, the compound represented by formula (I) is a compound represented by the following formula (I-1):

[0041] Among them, R1 、R 2 、R 3 and R 4 The definition of is as described in any one of the present invention.

[0042] In one embodiment of the present invention, the compound represented by formula (I) is a compound represented by the following formula (I-2):

[0043] Among them, R 1 、R 2 、R 3 and R 4 The definition of is as described in any one of the present invention.

[0044] In some embodiments, the compound represented by formula (I) is any of the following compounds: Preferably,

[0045] In some embodiments, the compound represented by formula (I) is not

[0046] The present invention also provides a method for preparing the compound represented by formula (I), which comprises the following steps: in a solvent, in the presence of a base and a catalyst, compound II and compound III are reacted to obtain the compound represented by formula (I);

[0047] Among them, *, R 1 、R 2 、R 3 and R 4 The definition of is as described in any one of the present invention.

[0048] In some embodiments, the solvent is an organic solvent and / or water; preferably an organic solvent and water; the organic solvent may be an alcohol solvent; for example, ethanol.

[0049] In some embodiments, the base is an inorganic base; preferably potassium carbonate and / or sodium carbonate.

[0050] In some embodiments, the catalyst is a palladium catalyst; preferably tetrakistriphenylphosphine palladium. The present invention also provides a pharmaceutical composition, comprising:

[0051] (1) the compound represented by formula (I) above, its pharmaceutically acceptable salt or stereoisomer thereof; and

[0052] (2) Pharmaceutically acceptable excipients.

[0053] The present invention also provides the use of the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, and the pharmaceutical composition in the preparation of aldosterone synthase inhibitors.

[0054] The present invention also provides the use of the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer thereof, and the pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent chronic kidney disease, congestive heart failure, hypertension or primary aldosteronism; preferably hypertension; preferably, the compound represented by formula (I) is not

[0055] definition

[0056] 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 the invention belongs. In addition, the following definitions are set forth to illustrate and limit the meaning and scope of the various terms used to describe the present invention.

[0057] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0058] The term "alkyl" refers to a straight or branched chain alkyl group having a specified number of carbon atoms (e.g., C1-C6). Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0059] The term "haloalkyl" refers to an alkyl group substituted with a halogen, wherein the halogen and alkyl are as defined above.

[0060] The term "alkoxy" refers to a group R Z -O-, where R Z is an alkyl group as defined above.

[0061] The term "haloalkoxy" refers to an alkoxy group substituted with a halogen, wherein the halogen and alkoxy are as defined above.

[0062] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom species (one, two, or three of N, O, and S), which is monocyclic or polycyclic, and each ring is aromatic (in accordance with Huckel's rule). The heteroaryl group is attached to the rest of the molecule through a carbon atom or a heteroatom; the heteroaryl group is attached to the rest of the molecule through a ring having heteroatoms or a ring without heteroatoms. Heteroaryl includes, but is not limited to, furan rings, pyrrole rings, thiophene rings, pyrazole rings, imidazole rings, oxazole rings, thiazole rings, pyridine rings, pyrimidine rings, indole rings, benzopyrrole rings, and the like.

[0063] The term "cycloalkyl" refers to a saturated monocyclic ring group consisting only of 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.

[0064] The term "pharmaceutically acceptable salt" includes "pharmaceutically acceptable salts formed with organic acids or inorganic acids" and "pharmaceutically acceptable salts formed with organic bases or inorganic bases".

[0065] The term "stereoisomer" includes configurational isomers, wherein configurational isomers primarily include optical isomers, for example, enantiomers, diastereomers or mixtures thereof.

[0066] The term "pharmaceutically acceptable excipient" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention, 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, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparation is well known to those skilled in the field of cosmetics or topical medicine.

[0067] The term "pharmaceutical composition" refers to a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, ready for administration to a mammal, such as a human, in need thereof.

[0068] The term "treating" relates to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. The noun "treating" as used herein relates to the action of the verb to treat, which is as defined above.

[0069] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0070] The reagents and raw materials used in the present invention are commercially available.

[0071] The positive progress of the present invention lies in: the present invention discloses a pyranopyridine compound, its preparation method, pharmaceutical composition, and application. It also provides a class of selective aldosterone synthase inhibitors that differ in structure from previously reported or disclosed compounds: the compounds of the present invention exhibit a 50-220-fold selectivity for hCYP11B 1 / 2; they exhibit excellent pharmacokinetic properties: 12 hours after administration, the plasma aldosterone concentration of the compounds of the present invention is 85-220 pg / mL, the plasma corticosterone concentration is 350-1000 pg / mL, the maximum blood concentration (Cmax) is 8-25 ng / mL, and the plasma exposure (AUC0-24h) is 150-2200 h·ng / mL; the compounds of the present invention exhibit in vitro inhibitory activity against common CYP450 enzymes >50 μM and possess a high safety profile. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1 shows the plasma aldosterone concentrations at different time points after administration.

[0073] Figure 2 shows the plasma cortisol concentrations at different time points after administration. DETAILED DESCRIPTION

[0074] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0075] The raw materials and reagents used herein are commercially available or prepared by synthetic methods generally known in the art.

[0076] Intermediate 1

[0077] Step 1

[0078] Compound 1 (30.0 g, 172.42 mmol) was dissolved in acetonitrile (300 mL), and N-iodosuccinimide (46.5 g, 206.90 mmol) was added. After the addition was complete, the reaction mixture was stirred at 80°C for 2.5 hours. TLC (dichloromethane / methanol = 10 / 1, product: Rf = 0.1, starting material: Rf = 0.2) showed complete consumption of the starting material. The reaction mixture was filtered while hot and rinsed with acetonitrile (200 mL). The solid was collected and dried to obtain compound 2 (45.0 g, 87%) as a white solid.

[0079] LCMS (ESI) m / z: 299.8 [M+H] +.

[0080] Step 2

[0081] Compound 2 (40.0 g, 133.38 mmol) was dissolved in tetrahydrofuran (400 mL), and 3-butene-1-ol (9.85 g, 136.60 mmol) and triphenylphosphine (42.0 g, 160.06 mmol) were added. After the addition, the reaction solution was stirred at room temperature for 0.5 hours, cooled to 0°C, and diisopropyl azodicarboxylate (29.7 g, 146.72 mmol) was slowly added dropwise. After the addition, the reaction solution was stirred at 65°C under a nitrogen atmosphere for 12 hours. TLC (petroleum ether / ethyl acetate = 10 / 1, product: Rf = 0.8, starting material: Rf = 0.02) showed that the starting material was completely consumed. The reaction solution 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.

[0082] LCMS (ESI) m / z: 353.9 [M+H] +.

[0083] Step 3

[0084] 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 sequentially. After the addition was complete, the reaction solution was stirred at 80°C under a nitrogen atmosphere for 1 hour. TLC (petroleum ether / ethyl acetate = 5 / 1, product: Rf = 0.4, starting material: Rf = 0.78) showed complete consumption of the starting material. After the reaction solution was cooled, aqueous hydrochloric acid solution (300 mL, 4 M) was added to the reaction solution for quenching, and ethyl acetate (300 mL × 2) was used for extraction. The organic phase was washed with aqueous hydrochloric acid solution (200 mL, 4 M), and the aqueous phase was collected and adjusted to a pH greater than 7 with 2 M aqueous sodium hydroxide solution. The mixture was then extracted with ethyl acetate (300 mL, 200 mL). The organic phase was washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain yellow solid compound 4 (20.0 g, yield 76.5%).

[0085] LCMS (ESI) m / z: 226.0 [M+H] +.

[0086] Step 4

[0087] Compound 4 (15.0 g, 1.0 eq) was dissolved in dichloromethane (600 mL), cooled to -50 ° C under a nitrogen atmosphere, and ozone was introduced, and the temperature was maintained and stirred for 2 hours. TLC (petroleum ether / ethyl acetate = 4 / 1, product: Rf = 0.3, raw material: Rf = 0.4) showed that the raw material was completely consumed. The reaction solution was moved to room temperature, quenched with saturated aqueous sodium sulfite solution (300 mL), extracted with dichloromethane (200 mL × 2), and the organic phases were combined, washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 4 / 1) gave compound 5 (13.0 g, yield 86%) as a yellow solid.

[0088] LCMS (ESI) m / z: 227.9 [M+H] +.

[0089] Step 5

[0090] Compound 5 (3.0 g, 1.0 eq) and S-tert-butylsulfenamide (1.91 g, 1.2 eq) were dissolved in toluene (100 mL). Tetraisopropyl titanate (9.3 g, 2.5 eq) was added under a nitrogen atmosphere. After addition, 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 complete consumption of the starting material. After cooling the reaction solution, 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, and concentrated under reduced pressure. Purification by column chromatography afforded Compound 6 (800 mg, 18.4% yield) as a yellow solid.

[0091] LCMS (ESI) m / z: 331.0 [M+H] +.

[0092] Step 6

[0093] 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 addition, the mixture was stirred at this temperature for 2 hours. TLC (dichloromethane / methanol = 20 / 1, product: Rf = 0.2, starting material: Rf = 0.4) indicated complete consumption of the starting material. The reaction mixture was quenched with saturated sodium bicarbonate (10.0 mL), and extracted with dichloromethane (20.0 mL, 10.0 mL). The organic phase was washed with saturated sodium chloride solution (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (dichloromethane / methanol = 15 / 1) afforded intermediate 7 (195 mg, 89.0% yield) as a yellow solid.

[0094] LCMS (ESI) m / z: 333.0 [M+H] +.

[0095] Step 7

[0096] Compound 7 (195 mg, 1.0 eq) was dissolved in dioxane (3.0 mL), and a solution of hydrochloric acid in dioxane (0.45 mL, 4 M, 3.0 eq) was added. After addition, the reaction mixture 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. Diethyl ether (6.0 mL) was added to the reaction mixture, resulting in the precipitation of a solid. The solid was collected by filtration and dried to afford Compound 8 (140 mg, crude) as a yellow solid.

[0097] LCMS (ESI) m / z: 229.0 [M+H] +.

[0098] Step 8

[0099] Compound 8 (120 mg, 0.52 mmol) was dissolved in dichloromethane (10.0 mL), and propionyl chloride (59 mg, 0.63 mmol) and triethylamine (106 mg, 1.05 mmol) were added. After addition, the reaction mixture 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 mixture was concentrated under reduced pressure to afford Intermediate 1 (80 mg, 53.6% yield) as a yellow solid.

[0100] LCMS (ESI) m / z: 285.0 [M+H] +.

[0101] Intermediate 2

[0102] Intermediate 2 was synthesized by using the same experimental method as intermediate 1, replacing the propionyl chloride in step 8 with N,N-dimethylacetyl chloride.

[0103] LCMS (ESI) m / z: 300 [M+H]+

[0104] Intermediate 3

[0105] The same experimental method as that of intermediate 1 was used to synthesize intermediate 3 by replacing NaBH4 in step 6 with NaBD4.

[0106] LCMS (ESI) m / z = 286 [M+H] +

[0107] Intermediate 4

[0108] Intermediate 4 was synthesized by using the same experimental method as intermediate 1, replacing NaBH4 in step 6 with NaBD4 and replacing propionyl chloride in step 8 with N,N-dimethylacetyl chloride.

[0109] LCMS (ESI) m / z: 301 [M+H] +.

[0110] Intermediate 5

[0111] Step 1

[0112] 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 and stirred for half an hour. Methyl iodide (8.16 g, 57.50 mmol) was added dropwise and stirred overnight. Additional methyl iodide (2.5 g, 17.69 mmol) was added, and the reaction mixture was heated to 40°C and stirred for 5 hours. TLC indicated complete consumption of the starting material. After cooling, the reaction mixture was extracted with water (50 mL) and ethyl acetate (100 mL). 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 (petroleum ether:ethyl acetate = 4:1) to afford Compound 12 (8.9 g, 83.8% yield) as a white solid.

[0113] LCMS (ESI) m / z: 241 [M+H] +.

[0114] Step 2

[0115] Compound 12 (2.1 g, 8.75 mmol) was dissolved in dioxane (20 mL), and bis-pinacol ester (2.67 g, 10.50 mmol), potassium acetate (2.58 g, 26.24 mmol), and Pd(dppf)Cl2 (320 mg, 0.44 mmol) were added. After addition, the reaction mixture was heated to 80°C and stirred for 12 hours under nitrogen. TLC indicated complete consumption of the starting material. After cooling, the reaction mixture was extracted with water (20 mL) and ethyl acetate (40 mL). 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 (petroleum ether:ethyl acetate = 4:1) to afford Intermediate 5 (1.6 g, 63.7% yield) as a light brownish-red solid.

[0116] LCMS (ESI) m / z: 288 [M+H] +.

[0117] Intermediate 6

[0118] Step 1

[0119] Compound 13 (20 g, 179.99 mmol) was dissolved in dichloromethane (200 mL). Pyridine (35.6 g, 449.97 mmol) and chloropropionyl chloride (27.5 g, 216.60 mmol) were added under N2 protection. After addition, the reaction solution was stirred at 20°C for 2 hours. TLC showed that the starting material was completely consumed. Saturated sodium bicarbonate (100 mL) was added to the reaction solution to quench the reaction. Dichloromethane (100 mL, 50 mL) was added for extraction. The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 100-25%) to obtain compound 14 (28.7 g, 79% yield) as a white solid.

[0120] LCMS (ESI) m / z: 202 [M+H] +.

[0121] Step 5

[0122] Compound 14 (5 g, 24.80 mmol) was added to aluminum chloride (11.6 g, 86.79 mmol). After the addition was complete, the reaction solution was moved to 120°C and stirred for 3 hours. TLC showed that the starting material was completely consumed. After the reaction system was cooled, ice water was added to the reaction solution to quench the reaction. Dichloromethane (10.0 mL, 5.0 mL) was added for extraction. The organic phase was washed with saturated sodium chloride solution (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 15 (2.6 g, yield 63.5%) as a white solid.

[0123] LCMS (ESI) m / z: 166 [M+H] +.

[0124] Step 6

[0125] 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-cooling. After addition, the reaction mixture was stirred at 20°C for 0.5 hours. Methyl iodide (2.1 g, 14.53 mmol) was then added to the reaction mixture. After addition, the reaction mixture was stirred at 20°C for 2 hours. TLC showed that the starting material was completely consumed. Water (10 mL) was added to the reaction mixture 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), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 100-25%) to obtain compound 16 (1.8 g, yield 82.9%) as a white solid.

[0126] LCMS (ESI) m / z: 180 [M+H] +.

[0127] Step 7

[0128] Compound 16 (1.7 g, 9.49 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinimide (1.7 g, 9.49 mmol) was added to the reaction solution. After the addition was complete, 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 the reaction solution to quench the reaction, and ethyl acetate (20 mL × 2) was added for extraction. The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 100-25%) to obtain compound 17 (1.4 g, yield 57.2%) as a white solid.

[0129] LCMS (ESI) m / z: 259 [M+H] +.

[0130] Step 8

[0131] Compound 17 (2 g, 7.75 mmol) was dissolved in dioxane (20 mL), and diboronic acid pinacol ester (2.4 g, 9.30 mmol), potassium acetate (2.3 g, 23.25 mmol), and 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (283.5 mg, 0.39 mmol) were added. After addition, the reaction mixture was heated to 80°C and stirred for 12 hours under nitrogen. TLC indicated complete consumption of the starting material. After cooling, the reaction mixture was extracted with water (5 mL) and ethyl acetate (10 mL). 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 preparative column chromatography (PE / EA = 100-25%) to obtain intermediate 6 (1.3 g, 58.4% yield) as a white solid.

[0132] LCMS (ESI) m / z: 306 [M+H] +.

[0133] 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

[0134] Intermediate 1 (80 mg, 0.28 mmol) was dissolved in a mixture of ethanol (7.5 mL) and water (1.5 mL). Intermediate 5 (97 mg, 0.34 mmol), sodium carbonate (33 mg, 0.31 mmol), and tetrakistriphenylphosphine palladium (16 mg, 14 μmol) were added sequentially. After addition, the reaction mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. TLC (dichloromethane / methanol = 15 / 1, product: Rf = 0.1, starting material: Rf = 0.3) showed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure and purified on a large plate to obtain Example 1 as a white solid (50.0 mg, 48.8% yield).

[0135] LCMS (ESI) m / z: 366.1 [M+H]+;

[0136] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37(d,J=7.9Hz,1H),8.26(s,1H),8.22(s,1H),7.41(dd,J=8.3,2.0Hz,1H),7. 37(s,1H),7.16(d,J=8.4Hz,1H),5.10(dd,J=13.0,5.8Hz,1H),4.39-4.32(m,1H ),4.31-4.22(m,1H),3.29(s,3H),2.96-2.86(m,2H),2.62-2.54(m,2H),2.21-2 .11(m,2H),2.11-2.04(m,1H),1.98-1.89(m,1H),1.06(dd,J=10.7,4.4Hz,3H).

[0137] Example 2 (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-4-D)propanamide

[0138] The same experimental method as in Example 1 was used to synthesize the compound through coupling reaction of intermediate 3 and intermediate 5.

[0139] LCMS (ESI) m / z = 367 [M+H] +

[0140] 1H NMR (400MHz, DMSO) δ8.38(s,1H),8.25(d,J=17.4Hz,2H),7.45–7.31(m,2H),7.16(d,J=8.4Hz,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=7.6Hz,3H).

[0141] 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

[0142] The same experimental method as in Example 1 was used to synthesize the compound through coupling reaction of Intermediate 2 and Intermediate 5.

[0143] LCMS (ESI) m / z: 381 [M+H]+;

[0144] 1H NMR (400MHz, DMSO) δ8.26(s,1H),8.25(s,1H),7.41(dd,J=8.3,1.9Hz,1H),7.38(s,1H),7.16(d,J=8.4Hz,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=13.0Hz,4H) ,2.94–2.88(m,2H),2.84(s,1H),2.61–2.56(m,2H),2.10–1.93(m,3H).

[0145] 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)propanamide

[0146] The same experimental method as in Example 1 was used to synthesize the compound through coupling reaction of intermediate 3 and intermediate 6.

[0147] LCMS (ESI) m / z = 385 [M+H] +

[0148] 1H NMR (400MHz, DMSO) δ8.40(s,1H),8.23(d,J=32.2Hz,2H),7.32–6.98(m,2H),4.27(d,J=26.3Hz,2H) ,3.27(s,3H),2.88(s,2H),2.58(s,2H),2.16(s,2H),1.99(d,J=51.0Hz,2H)1.06(t,J=7.6Hz,3H).

[0149] 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

[0150] The same experimental method as in Example 1 was used to synthesize the compound through coupling reaction of intermediate 4 and intermediate 5.

[0151] LCMS (ESI) m / z = 382 [M+H] +

[0152] 1H NMR(400MHz,DMSO)δ8.25(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).

[0153] 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

[0154] The same experimental method as in Example 1 was used to synthesize the compound through coupling reaction of intermediate 2 and intermediate 6.

[0155] LCMS (ESI) m / z: 399 [M+H] +;

[0156] 1H NMR(400MHz,DMSO-d6)δppm 1.97-2.09(m,2H),2.56-2.58(m,2H),2.79-2.93(m,8H),2.88(s,3H),4.27-4.32(m,2H),4.99- 5.03(m,1H),6.78-6.80(d,1H),7.07-7.10(d,1H),7.21-7.23(d,1H),8.21(s,1H),8.32(s,1H).

[0157] Example 7 (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-4-d)-1,1-dimethylurea

[0158] The same experimental method as in Example 1 was used to synthesize the compound through coupling reaction of intermediate 4 and intermediate 6.

[0159] LCMS (ESI) m / z: 400.2 [M+H]+;

[0160] 1H NMR (400MHz, DMSO) δ8.31(s,1H),8.17(s,1H),7.22(d,J=8.0Hz,1H),7.08(d,J=12.0Hz,1H),6.77(s,1H) ,4.34–4.25(m,2H),3.30(d,J=12.0Hz,4H),2.90–2.81(m,7H),2.59(t,J=8.0Hz,2H),2.05–1.96(m,2H).

[0161] Example 8 (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)propanamide

[0162] The same experimental method as in Example 1 was used to synthesize the compound through coupling reaction between intermediate 1 and intermediate 6.

[0163] LCMS (ESI) m / z = 384 [M+H] +

[0164] 1H NMR (400MHz, DMSO) δ8.41(d,J=7.9Hz,1H),8.25(m,2H),7.22(d,J=8.0Hz,1H),7.08(d,J=11.9Hz,1H),5.12(m,1H),4.39–4.1 5(m,2H),3.27(s,3H),2.89(t,J=7.3Hz,2H),2.62–2.56(m,2H),2.24–2.12(m,2H),2.09–1.89(m,2H),1.06(t,J=7.6Hz,3H).

[0165] Experimental Example 1 Inhibitory Activity of Compounds against hCYP11B2 / hCYP11B1

[0166] 1. Experimental system: G-402CYP11B2 or CYP11B1 high-expressing stable transgenic strain

[0167] The above-mentioned high-expression stable strain was constructed based on the human adrenal leiomyoma cell line G-402, and was obtained by introducing human CYP11B2 (NM_000498.3) and CYP11B1 (NM_000497.4) into artificial lentivirus.

[0168] Maintenance medium: McCoy's 5A (modified, #16600082, GIBCO) + 10% FBS (GIBCO) + 1 μg / mL puromycin (A1113803, GIBCO).

[0169] Recovery and plating medium: McCoy's 5A (modified, #16600082, GIBCO) + 10% FBS (GIBCO).

[0170] Reaction medium: DMEM / F12 (#11320033, GIBCO) + 2.5% charcoal-filtered FBS (S11695, R&D).

[0171] 2. Experimental steps:

[0172] Seed plate: After the cells are recovered, they are cultured in maintenance medium until they are in a suitable state. 4 / 100 μL / well (uniform cell amount), seed a 96-well flat-bottom plate with seeding medium.

[0173] Medium change: After the plate is grown overnight (>12 hours) and adhered, aspirate and discard the supernatant, add 100-150 μL / well serum-free medium to wash, aspirate and add 50 μL / well reaction medium for later use.

[0174] Preparation: Dilute compound in reaction medium containing 0.4 μM substrate (final experimental concentration 0.2 μM):

[0175] CYP11B2 substrate: 11-deoxycorticosterone (S4243, selleckchem), the final reaction concentration is 0.2 μM

[0176] CYP11B1 substrate: 11-deoxycortisol (S4775, selleckchem), the final reaction concentration was uniformly set to 0.2 μM.

[0177] Sample addition: Add the above compound dilutions to the cell plate at 50 μL / well, and set up background wells and control wells at the same time.

[0178] Sample collection: After adding the sample, culture in a cell culture incubator for 16 hours, then shake each cell plate at 450g for 2 minutes, take 75μL of supernatant and transfer it to a collection plate and freeze at -80℃ for use (or direct detection).

[0179] Detection: A homogeneous time-resolved fluorescence kit (Cisbio HTRF kit, Cat.64ALDPEG, Cat.62CRTPEG) was used to determine the concentration of aldosterone or cortisol in the supernatant.

[0180] Analysis: Four-parameter fitting was used to calculate the absolute IC50 (Abs IC50) of each compound.

[0181] The test results showed that most of the test compounds (Examples 2, 4, 5 and 8) had similar inhibitory activity against CYP11B2 as the reference compound Baxdrostat, with Examples 2, 6 and 8 showing better selectivity. Unexpectedly, the chiral isomers of the test compounds did not have inhibitory activity against aldosterone synthase.

[0182] Table 1 Inhibitory activity of compounds against hCYP11B2 / hCYP11B1

[0183] Experimental Example 2 In vitro inhibitory activity of the test substance on common CYP450 enzymes

[0184] Prepare the working solution of the test compound using dimethyl sulfoxide (DMSO) as the solvent (starting at a final concentration of 50 μM and diluted 3-fold to 7 concentration points).

[0185] Prepare the corresponding microsomes (CORNING, Cat No. 452117) and the corresponding substrate solution (components see Table 2).

[0186] Prepare HLM working solution (components see Table 3).

[0187] Mix the test compound working solution, corresponding microsomes with the corresponding substrate solution and HLM working solution, preheat in a 37.0°C water bath for 10 minutes, then add NADPH cofactor (BONTAC, Cat No. BT04), continue mixing and incubating in a 37.0°C water bath for 10 minutes, and then add cold stop solution to terminate the reaction.

[0188] Table 2

[0189] Table 3

[0190] The sample was centrifuged at 4000 rpm for 20 minutes to precipitate the protein, and the supernatant was transferred to HPLC water and shaken for 10 minutes.

[0191] Finally, LC / MS / MS analysis was performed, and the calculation results were as shown in Table 4:

[0192] Table 4

[0193] The study showed that the test compound did not inhibit any CYP450 enzymes, minimizing the risk of drug-drug interactions (DDIs). Compared to baxdrostat, the test compound did not inhibit CYP2C19, thus minimizing the risk of DDIs.

[0194] Experimental Example 3 Pharmacokinetic and Pharmacodynamic Studies of the Test Substance in Cynomolgus Monkeys

[0195] Adult cynomolgus monkeys (Macaca fascicularis) of appropriate weight and age were selected for the experiment, one male and one female, with a one-week acclimatization period. On the day of the experiment, the monkeys were individually housed in stainless steel mesh cages for testing.

[0196] 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:

[0197] T = 0, 2 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;

[0198] At T = +1 hour (i.e., 1 hour after administration), 14.5 μg / kg of the aforementioned ACTH working solution was injected intramuscularly.

[0199] Sampling and testing: Blood samples (collected in EDTA anticoagulant tubes) were collected before oral administration (Pre-dose) and 0.5h, 1h, 2h, 4h, 6h and 12h after administration for the measurement of corticosteroid concentrations in plasma. The blood was centrifuged at 10,000 rpm for 15 minutes at 4°C, and then the plasma was separated and stored at -80°C for further analysis. The analysis was performed using a Roche biochemical analyzer by electrochemiluminescence to detect aldosterone and cortisol in plasma. Simultaneously, some plasma was taken (0.5h, 1h, 2h, 4h, 6h and 12h after administration, as well as an additional 24h blood draw) to determine pharmacokinetic parameters by LC / MS.

[0200] The aldosterone test results are shown in Table 5 and Figure 1 , and the 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 the cortisol level.

[0201] Table 5 Plasma aldosterone concentrations at different time points of administration

[0202] Table 6 Plasma cortisol concentrations at different time points of administration

[0203] The above experiment was repeated except that: at T = 0, two monkeys in each group were orally administered a dose of 0.05 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;

[0204] The results of aldosterone testing are shown in Table 7, and the results of cortisol testing are shown in Table 8. The test showed that Example 8 significantly inhibited aldosterone synthesis. Example 8 had the largest change from baseline (-51.05) after 1 hour of ACTH stimulation. The other test substances, including Example 2, did not effectively inhibit aldosterone synthesis at the administered dose. The effectiveness of Example 8 exceeded expectations. All test substances had no effect on cortisol levels.

[0205] Table 7 Plasma aldosterone concentrations at different time points of administration

[0206] “ / ” indicates no significant change.

[0207] Table 8 Plasma cortisol concentrations at different time points of administration

[0208] The pharmacokinetic parameters of the compounds are shown in Table 9. Compared with the reference Baxdrostat, the peak time and half-life of the test compounds are similar, and the maximum blood concentration (C max ) and plasma exposure (AUC) were higher, 2-3 times higher than the reference, showing good pharmacokinetic properties. Unexpectedly, Example 8 had a higher (Cmax ) and (AUC), which were twice as high as those in Example 2 and three times as high as those in baxdrostat, respectively.

[0209] Table 9

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 It is a C1-C6 alkyl group.

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; preferably methyl or ethyl; (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; preferably fluorine; (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; for example, 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 ; Preferably C1-C6 alkyl; (3) R 2-4 is H or C1-C6 alkyl; preferably 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 Preferably More preferably (3) R 3 is H or D; preferably H; 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), Preferably, the compound is as shown in formula (I-2), 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 claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein: The compound represented by formula (I) is any of the following compounds: Preferably, 7. The compound of formula (I) according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound represented by formula (I) is not 8. A method for preparing a compound of formula (I) as claimed in any one of claims 1 to 7, 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 7.

9. The method for preparing the compound of formula (I) as claimed in claim 8, wherein: It meets one or more of the following conditions: (1) The solvent is an organic solvent and / or water; preferably an organic solvent and water; the organic solvent may be an alcohol solvent; for example, ethanol; (2) The base is an inorganic base; preferably potassium carbonate and / or sodium carbonate; The catalyst described in (3) is a palladium catalyst; preferably tetrakistriphenylphosphine palladium.

10. A pharmaceutical composition comprising: (1) a compound of formula (I) according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and (2) Pharmaceutically acceptable excipients.

11. Use of the compound of formula (I) according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and the pharmaceutical composition according to claim 10 in the preparation of an aldosterone synthase inhibitor.

12. Use of the compound of formula (I) according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and the pharmaceutical composition according to claim 10 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

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