Pyranopyridine compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a pyranopyridine compound as well as a preparation method, a pharmaceutical composition and application thereof. The invention provides a compound as shown in a formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, and the compound has a relatively strong inhibition effect on aldosterone synthetase, almost has no influence on cortisol synthetase, has high selectivity and relatively high safety, and can be used for preventing and / or treating various diseases related to aldosterone. # imgabs0 #

Description

[0001] This application claims the priority of Chinese Patent Application No. 2024102347458 with an application date of March 1, 2024. This application incorporates the entire text of the above-mentioned Chinese patent application by reference. Technical Field

[0002] The present invention belongs to the field of medicine, and particularly relates to pyrano[2,3-d]pyridine compounds, their preparation methods, pharmaceutical compositions and uses. Background Art

[0003] Aldosterone is a core regulatory system for human blood pressure and water-salt balance in the renin-angiotensin-aldosterone system (RAAS), and aldosterone is a key regulatory molecule downstream of this system. Aldosterone is a steroid hormone (member of the mineralocorticoid family), which promotes the reabsorption of water and sodium in the kidneys by binding to and activating mineralocorticoid receptors (MRs) in the epithelial cells of the distal renal tubules and collecting ducts, while inducing the excretion of potassium and hydrogen ions, maintaining water and electrolyte balance, and participating in maintaining appropriate blood pressure, vascular tone and tissue perfusion. In addition, the latest research shows 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 vasoconstrictive signals and the arterial wall structure, increase the pressor response of blood vessels to norepinephrine, and cause elevated blood pressure, proliferation of vascular smooth muscle cells, thickening of the vascular wall and hyaline degeneration.

[0004] Under normal circumstances, plasma aldosterone concentration is regulated by relevant stimulating factors such as RAAS, blood potassium concentration, adrenocorticotropic hormone (ACTH), etc. Elevated aldosterone levels can induce blood pressure disorders, cause inflammation, vascular remodeling and tissue fibrosis related to cardiac metabolic diseases, and ultimately lead to organ function decline, cardiovascular complications, advanced kidney diseases, and increase the risk of death. Therefore, counteracting the harmful effects of excessive aldosterone in patients has been a targeted clinical strategy for many years.

[0005] For cardio-renal system diseases related to aldosterone and its receptors, blocking the effects of aldosterone is an effective treatment method. Mineralocorticoid receptor antagonists (MRAs) and renin-angiotensin-aldosterone system antagonists (RAS inhibitors) are currently the clinical therapies used to antagonize aldosterone. MRAs (such as spironolactone) inhibit the action of aldosterone by competitively binding to the mineralocorticoid receptor, while RAS inhibitors (such as sartans) indirectly reduce aldosterone levels by blocking the upstream stimulatory effect of angiotensin II. Clinically, on the one hand, MRAs can over-antagonize the receptor effect (the aldosterone receptor can also be activated by estrogen), and there are off-target side effects of androgen receptor antagonism. On the other hand, RAS inhibitors do not completely inhibit excessive aldosterone, and there is a problem of drug resistance clinically. Therefore, specific inhibitors (ASIs) that directly inhibit aldosterone synthase (AS) can completely reduce the production of aldosterone without additional effects and can be used as superior iterative products of MRAs and RAS inhibitors.

[0006] Aldosterone synthase (encoded by the CYP11B2 gene), which controls the synthesis of aldosterone and catalyzes the final step in the synthesis of aldosterone from cholesterol, has been a pharmacological target for treating hypertension for decades. Potassium ions, angiotensin II, leptin, etc. can all 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 zona glomerulosa of the adrenal gland, and this enzyme is basically not produced in other parts of the body, so off-target effects are not expected to occur.

[0007] Since 93% of the enzymes that produce aldosterone and the enzymes that produce cortisol are the same (CYP11B1 is the 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, developing a drug that can both inhibit the production of aldosterone and have no effect on cortisol is the current difficulty and pain point.

[0008] LCI699 is the first orally active aldosterone synthase inhibitor to enter clinical trials for the treatment of primary aldosteronism. After oral administration of LCI699, it was found that the aldosterone level in the plasma decreased and the blood pressure decreased. However, LCI699 has poor selectivity for CYP11B2 and CYP11B1 and has a greater inhibitory effect on cortisol synthase, so it brings additional side effects and has to turn to the research and development for the treatment of Cushing's disease. Subsequently, a new generation of highly selective ASI inhibitors has been developed one after another, 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 and reduces the aldosterone level in the body without inhibiting CYP11B1. Another new drug is Baxdrostat (CinCor Pharma / AstraZeneca). The phase I clinical study of Baxdrostat showed that the inhibitory effect of Baxdrostat on aldosterone synthase is 100 times that on cortisol synthesis, belonging to a highly selective aldosterone synthesis inhibitor, which can dose-dependently reduce the plasma aldosterone level by >70%.

[0010] Although there are already two clinical research products, it is still unclear whether they are ultimately proven safe and effective in large-scale clinical phase III trials. Therefore, highly selective aldosterone synthase inhibitors with better 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 new structure. The present invention aims to provide a pyrano[2,3 - d]pyridine compound, a preparation method thereof, a pharmaceutical composition, and an application. This type of compound has a strong inhibitory effect on aldosterone synthase but has little effect on cortisol synthase, has high selectivity, and has high safety, and has good application prospects in the prevention and / or treatment of various diseases related to aldosterone.

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

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

[0014] ;

[0015] wherein, The marked carbon atom is in the 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 by 1, 2, or 3 R 2-1 groups, C1 - C6 alkoxy, C1 - C6 haloalkoxy, "a 5 - 10 - membered heteroaryl in which the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the number of heteroatoms is 1, 2, or 3", C1 - C6 alkyl substituted by 1, 2, or 3 R 2-2"The substituted "heteroatom is selected from one, two or three of N, O and S, and the 5-10 membered heteroaryl having one, two or three heteroatoms", C3-C6 cycloalkyl, substituted by one, two or three R 2-3 substituted C3-C6 cycloalkyl or NR 2-4 R 2 -5 ;

[0018] R 2-1 is independently hydroxy or halogen;

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

[0020] R 2-4 and R 2-5 are independently H, C1-C6 alkyl or C1-C6 haloalkyl;

[0021] R 3 is H, D, C1-C6 alkyl or C1-C6 haloalkyl;

[0022] R 4 is C1-C6 alkyl.

[0023] In certain preferred embodiments of the present invention, some groups in the compounds, their pharmaceutically acceptable salts or their stereoisomers represented by Formula I are defined as follows, and the groups not mentioned are the same as those described in any embodiment of the present invention (abbreviated as "in a certain embodiment of the present invention").

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

[0025] In a certain embodiment of the present invention, each of the C1-C6 haloalkyl groups is independently halo-methyl, halo-ethyl, halo-propyl, halo-butyl or halo-hexyl, and the halogen is fluoro, chloro, bromo or iodo.

[0026] In a certain embodiment of the present invention, each of the halogens is independently fluorine, chlorine, bromine or iodine; preferably fluorine.

[0027] In a certain 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.

[0028] In one embodiment of the present invention, each of the C1-C6 haloalkyloxy groups is independently halo-methoxy, halo-ethoxy, halo-n-propoxy, halo-isopropoxy, halo-n-butoxy, halo-isobutoxy, halo-sec-butoxy or halo-tert-butoxy; the halo is fluoro, chloro, bromo or iodo.

[0029] In one embodiment of the present invention, each of the C3-C6 cycloalkyl groups and each of the C3-C6 cycloalkyl groups in the substituted C3-C6 cycloalkyl groups is independently cyclopropyl.

[0030] In one embodiment of the present invention, each of the 5-10 membered heteroaryl groups and each of the 5-10 membered heteroaryl groups in the substituted 5-10 membered heteroaryl groups is independently a 5-6 membered monocyclic heteroaryl group.

[0031] In one embodiment of the present invention, 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, .

[0032] In one embodiment of the present invention, the labeled carbon atom is in the R configuration.

[0033] In one embodiment of the present invention, the R 1 is H or a halogen.

[0034] In one embodiment of the present invention, the R 2 is a C1-C6 alkyl group or NR 2-4 R 2-5 ; preferably a C1-C6 alkyl group.

[0035] In one embodiment of the present invention, the R 2-4 is H or a C1-C6 alkyl group; preferably a C1-C6 alkyl group.

[0036] In one embodiment of the present invention, the R 2-5 is independently a C1-C6 alkyl group.

[0037] In one embodiment of the present invention, R 1 is H or fluorine.

[0038] In one embodiment of the present invention, R 2 is , or ; preferably or ; more preferably .

[0039] In one embodiment of the present invention, the R 3 is H or D; preferably H.

[0040] In one embodiment of the present invention, the R 4 is methyl.

[0041] In one embodiment of the present invention, the compound represented by formula (I) is the compound represented by the following formula (I-1),

[0042] ; wherein the definitions of R 1 , R 2 , R 3 and R 4 are as described in any one of the present invention.

[0043] In one embodiment of the present invention, the compound represented by formula (I) is the compound represented by the following formula (I-2),

[0044] ; wherein the definitions of R 1 , R 2 , R 3 and R 4 are as described in any one of the present invention.

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

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

[0047] The present invention also provides a method for preparing the compound represented by formula (I), which comprises the following steps of preparing the compound represented by formula (I) from compound II and compound III in a solvent in the presence of a base and a catalyst;

[0048] ;

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

[0050] 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.

[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 tetrakis(triphenylphosphine)palladium. The present invention also provides a pharmaceutical composition, which comprises:

[0053] (1) The compound represented by formula (I) as described above, its pharmaceutically acceptable salt or its stereoisomer; and

[0054] (2) Pharmaceutically acceptable excipients.

[0055] The present invention also provides the use of the compound represented by formula (I) as described above, its pharmaceutically acceptable salt or its stereoisomer, and the above pharmaceutical composition in the preparation of an aldosterone synthase inhibitor.

[0056] The present invention also provides the use of the compound represented by formula (I) as described above, its pharmaceutically acceptable salt or its stereoisomer, and the above pharmaceutical composition in the preparation of a drug for treating and / or preventing chronic kidney disease, congestive heart failure, hypertension or primary aldosteronism; preferably hypertension; more preferably, the compound represented by formula (I) as described above 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 invention belongs. In addition, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the present invention.

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

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

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

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

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

[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 is aromatic (complies with Hückel'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 a heteroatom or a ring not having a heteroatom. Heteroaryl groups include, but are not limited to, furan ring, pyrrole ring, thiophene ring, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, pyridine ring, pyrimidine ring, indole ring, benzopyrrole ring, and the like.

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

[0066] 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".

[0067] The term "stereoisomer" includes configurational isomers, and configurational isomers mainly include optical isomers, for example, enantiomers, diastereomers, or mixtures thereof.

[0068] The term "pharmaceutically acceptable excipient" refers to any preparation 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 is non-toxic and has no side effects on the host or patient. Representative excipients include water, oils, vegetables and minerals, paste bases, lotion bases, ointment bases, and the like. These bases include suspending agents, thickening agents, transdermal promoters, and the like. Their preparations are well known to those skilled in the art of the cosmetic field or the topical drug field.

[0069] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, which is prepared for administration to a mammal in need thereof, such as a human.

[0070] The term "treatment" refers to reversing, alleviating, inhibiting the progression of, or preventing a disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. As used herein, the noun "treatment" refers to the action of the verb "treat", which is defined as above.

[0071] Without departing from the common sense in the art, on the basis of the above preferred conditions, any combination can be made to obtain various preferred examples of the present invention.

[0072] The reagents and raw materials used in the present invention are all commercially available.

[0073] The positive and progressive effects of the present invention are as follows: The present invention discloses a pyrano[2,3-c]pyridine compound, a preparation method thereof, a pharmaceutical composition and an application. A class of selective aldosterone synthase inhibitors with different structures from the reported or disclosed compounds is provided: the selectivity multiple of the compounds of the present invention for hCYP11B1 / 2 is 50 - 220; excellent pharmacokinetic properties: the concentration of aldosterone in plasma is 85 - 220 pg / mL 12 hours after administration of the compounds of the present invention, the concentration of corticosterone in plasma is 350 - 1000 pg / mL 12 hours after administration, the maximum plasma drug concentration (Cmax) is 8 - 25 ng / mL, and the plasma exposure (AUC0-24h) is 150 - 2200 h·ng / mL; the in vitro inhibitory activity against common CYP450 enzymes > 50 μM and has high safety. Brief Description of the Drawings

[0074] Figure 1 It is the concentration of aldosterone in plasma at different time points after administration.

[0075] Figure 2 It is the concentration of cortisol in plasma at different time points after administration. Detailed Description of the Invention

[0076] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. The experimental methods without specific conditions noted in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

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

[0078] Intermediate 1

[0079]

[0080] Step 1

[0081] 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 h. TLC (dichloromethane / methanol = 10 / 1, product: Rf = 0.1, starting material: Rf = 0.2) showed that the starting material was completely consumed. The reaction mixture was filtered while hot, rinsed with acetonitrile (200 mL), and the collected solid was dried to obtain 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. After the addition was complete, the reaction mixture was stirred at room temperature for 0.5 h, cooled to 0 °C, and diisopropyl azodicarboxylate (29.7 g, 146.72 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at 65 °C for 12 h under a nitrogen atmosphere. 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 mixture was concentrated under reduced pressure, and column chromatography (petroleum ether / ethyl acetate = 20 / 1) gave compound 3 (30.7 g, yield 65%) 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). 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 the addition, the reaction mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. 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 mixture was cooled, it was quenched by adding aqueous hydrochloric acid solution (300 mL, 4 M), and extracted with ethyl acetate (300 mL×2). The organic phase was washed with aqueous hydrochloric acid solution (200 mL, 4 M), and then the aqueous phase was collected, adjusted to a pH value greater than 7 with 2 M aqueous sodium hydroxide solution, and extracted again 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%).

[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 a nitrogen atmosphere, and ozone was introduced. The mixture was stirred at this temperature for 2 hours. TLC (petroleum ether / ethyl acetate = 4 / 1, product: Rf = 0.3, starting material: Rf = 0.4) showed complete consumption of the starting material. The reaction mixture was transferred to room temperature, quenched by adding saturated aqueous sodium sulfite solution (300 mL), and extracted with dichloromethane (200 mL×2). The combined organic phases were washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, 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). Tetraisopropyl titanate (9.3 g, 2.5 eq) was added under a nitrogen atmosphere. After addition, the reaction mixture 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 the reaction mixture was cooled, water (100 mL) and ethyl acetate (200 mL, 150 mL) were added 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 yellow solid compound 6 (800 mg, yield 18.4%).

[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). 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) showed complete consumption of the starting material. The reaction was quenched by adding saturated sodium bicarbonate (10.0 mL), and extraction was carried out 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, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 15 / 1) to obtain yellow solid intermediate 7 (195 mg, yield 89.0%).

[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), and a dioxane solution of hydrochloric acid (0.45 mL, 4 M, 3.0 eq) was added. After the 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. Ether (6.0 mL) was added to the reaction mixture, and a solid precipitated. The solid was collected by filtration, and yellow solid compound 8 (140 mg, crude product) was obtained after drying.

[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), and propionyl chloride (59 mg, 0.63 mmol) and triethylamine (106 mg, 1.05 mmol) were added. After the 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 obtain yellow solid intermediate 1 (80 mg, yield 53.6%).

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

[0104] Intermediate 2

[0105]

[0106] Using the same experimental method as for intermediate 1, N,N-dimethylacetyl chloride was used instead of propionyl chloride in step 8 to synthesize intermediate 2.

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

[0108] Intermediate 3

[0109]

[0110] Using the same experimental method as for intermediate 1, NaBD4 was used instead of NaBH4 in step 6 to synthesize intermediate 3.

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

[0112] Intermediate 4

[0113]

[0114] Using the same test method as that for Intermediate I, replace NaBH4 in Step 6 with NaBD4 and replace propionyl chloride in Step 8 with N,N-dimethylacetyl chloride to synthesize Intermediate IV.

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

[0116] Intermediate V

[0117]

[0118] Step 1

[0119] Dissolve Compound 11 (10 g, 44.23 mmol) in DMF (200 mL). Add potassium tert-butoxide (9.92 g, 88.47 mmol) at 0 °C and stir for half an hour. Then add methyl iodide (8.16 g, 57.50 mmol) dropwise and stir overnight. Add additional methyl iodide (2.5 g, 17.69 mmol). Heat the reaction mixture to 40 °C and stir for 5 hours. TLC shows complete consumption of the starting material. After cooling the reaction mixture, add water (50 mL) and ethyl acetate (100 mL) for extraction. Wash the organic phase with saturated sodium chloride solution (20.0 mL), then add anhydrous sodium sulfate for drying, filter, concentrate under reduced pressure, and purify 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] Dissolve Compound 12 (2.1 g, 8.75 mmol) in dioxane (20 mL). Add bis(pinacolato)diboron (2.67 g, 10.50 mmol), potassium acetate (2.58 g, 26.24 mmol), and Pd(dppf)Cl2 (320 mg, 0.44 mmol). After addition, protect the reaction mixture with nitrogen and heat it to 80 °C and stir for 12 hours. TLC shows complete consumption of the starting material. After cooling the reaction mixture, add water (20 mL) and ethyl acetate (40 mL) for extraction. Wash the organic phase with saturated sodium chloride solution (20.0 mL), then add anhydrous sodium sulfate for drying, filter, concentrate under reduced pressure, and purify by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain light brownish-red solid Intermediate V (1.6 g, yield 63.7%).

[0123] LCMS (ESI) m / z: 288 [M+H]+。

[0124] Intermediate Six

[0125]

[0126] Step 1

[0127] Dissolve Compound 13 (20 g, 179.99 mmol) in dichloromethane (200 mL). Under N2 protection, add pyridine (35.6 g, 449.97 mmol) and chloroacetyl chloride (27.5 g, 216.60 mmol). After the addition, stir the reaction mixture at 20 °C for 2 hours. TLC shows that the raw material is completely consumed. Quench the reaction by adding saturated sodium bicarbonate (100 mL) to the reaction mixture, extract with dichloromethane (100 mL, 50 mL), wash the organic phase with saturated sodium chloride solution (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify 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] Add Compound 14 (5 g, 24.80 mmol) to aluminum trichloride (11.6 g, 86.79 mmol). After the addition, transfer the reaction mixture to 120 °C and stir for 3 hours. TLC shows that the raw material is completely consumed. After cooling the reaction system, quench the reaction by adding ice water to the reaction mixture, extract with dichloromethane (10.0 mL, 5.0 mL), wash the organic phase with saturated sodium chloride solution (10.0 mL), dry over anhydrous sodium sulfate, filter, and concentrate 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 an ice bath. After the addition, the reaction mixture was stirred at 20 °C for 0.5 h. Then methyl iodide (2.1 g, 14.53 mmol) was added to the reaction mixture. After the addition, the reaction mixture was stirred at 20 °C for 2 h. TLC showed that the raw material was completely consumed. Water (10 mL) was added to the reaction mixture to quench the reaction, and 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 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 mixture. After the addition, the reaction mixture was stirred at 20 °C for 5 h. TLC showed that the raw material was completely consumed. Water (10 mL) was added to the reaction mixture 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, the filtrate was concentrated, and 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). Bis(pinacolato)diboron (2.4 g, 9.30 mmol), potassium acetate (2.3 g, 23.25 mmol), and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) (283.5 mg, 0.39 mmol) were added. After addition, under nitrogen protection, the reaction mixture was heated to 80 °C and stirred for 12 hours. TLC showed complete consumption of the starting material. After the reaction mixture 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 the white solid intermediate hex (1.3 g, yield 58.4%).

[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 1 (80 mg, 0.28 mmol) was dissolved in a mixed solution 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 tetrakis(triphenylphosphine)palladium (16 mg, 14 μmol) were added in sequence. After addition, the reaction mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. 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 by preparative TLC to obtain the white solid compound of Example 1 (50.0 mg, yield 48.8%).

[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] 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

[0147] Synthesized by the coupling reaction of intermediate three and intermediate five using the same test method as in Example 1.

[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] It was synthesized by the coupling reaction of Intermediate II and Intermediate V using the same test method as in Example 1.

[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)propanamide

[0157] It was synthesized by the coupling reaction of Intermediate III and Intermediate VI using the same test method as in Example 1.

[0158]

[0159] LCMS(ESI)m / z=385[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] Synthesized by the coupling reaction of Intermediate Four and Intermediate Five using the same test method as in Example 1.

[0163]

[0164] LCMS(ESI) m / z = 382 [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] Synthesized by the coupling reaction of Intermediate Two and Intermediate Six using the same test method as in Example 1.

[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, 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).

[0171] 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

[0172] It was synthesized by the coupling reaction of Intermediate Four and Intermediate Six using the same test method as in Example 1.

[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 = 8.0 Hz, 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-tetrahydroquinolin-6-yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)propanamide

[0177] It was synthesized by the coupling reaction of Intermediate One and Intermediate Six using the same test method as in Example 1.

[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 against hCYP11B2 / hCYP11B1

[0182] 1. Experimental System: G-402 CYP11B2 or CYP11B1 High-Expression Stable Transfectants

[0183] The above high-expression stable transfectants were constructed based on the human adrenal leiomyoma cell line G-402 and obtained by introducing human CYP11B2 (NM_000498.3) and CYP11B1 (NM_000497.4) into the cells using artificial lentiviruses respectively.

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

[0185] Resuscitation and Seeding 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 Procedures:

[0188] Seeding: After cell resuscitation, the cells were cultured in the maintenance medium until they reached the appropriate state, and then seeded at a density of 1×10 4 / 100 μL / well (Uniform cell count) (Uniform cell count) , inoculate a 96-well flat-bottom plate with a seeded plate medium.

[0189] Medium change: After seeding the plate overnight (>12 hours) and the cells adhering to the wall, aspirate and discard the supernatant, add 100 - 150 μL / well of serum-free medium for washing, and after aspirating it clean, add 50 μL / well of reaction medium for use.

[0190] Preparation: Dilute the compound with the reaction medium containing 0.4 μM substrate (the final experimental concentration is 0.2 μM):

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

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

[0193] Sample addition: Add the above compound dilution to the cell plate at 50 μL / well, and set background wells and control wells simultaneously.

[0194] Treatment and sample collection: After sample addition, culture in a cell incubator for 16 hours, then centrifuge each cell plate at 450 g for 2 minutes, take 75 μL of supernatant and transfer it to a collection plate for storage at -80 °C for use (or directly detect).

[0195] Detection: Use a homogeneous time-resolved fluorescence kit (Cisbio HTRF kit, Cat. 64ALDPEG, Cat.62CRTPEG) to measure the concentration of aldosterone or cortisol in the supernatant.

[0196] Analysis: Use four-parameter fitting to calculate the corresponding absolute IC50 (Abs IC50) of each compound.

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

[0198] Table 1 Inhibitory activities of compounds against hCYP11B2 / hCYP11B1

[0199]

[0200] Experimental Example 2 In vitro inhibitory activities of test substances against common CYP450 enzymes

[0201] Prepare the test compound working solution with dimethyl sulfoxide (DMSO) as the solvent (starting from a final concentration of 50 μM and diluting 7 concentration points by 3-fold).

[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, the corresponding substrate solution, and the HLM working solution, preheat in a 37.0 °C water bath for 10 minutes, then add the NADPH cofactor (BONTAC, Cat No. BT04), continue to mix and incubate in the 37.0 °C water bath for 10 minutes, and then add the 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, and transfer the supernatant to HPLC water and shake well for 10 minutes.

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

[0211] Table 4

[0212]

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

[0214] Pharmacokinetics and Pharmacodynamics Tests of the Test Substance in Cynomolgus Monkeys in Experimental Example 3

[0215] Select adult cynomolgus monkeys (Macaca fascicularis) with appropriate body weight and age, 1 male and 1 female for the experiment, and the adaptation period is 1 week. On the day of the experiment, the monkeys are individually housed in stainless steel wire cages for testing.

[0216] Oral treatment and ACTH working solution (prepared by dissolving Tetracosactrin (HY-P0060, MCE) in ultrapure water and filtering through a 0.22 μm filter, and diluting with a sterile PBS solution to the required concentration of the working solution) were administered according to the following dosing regimen:

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

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

[0219] Sampling and detection: Blood samples (collected in EDTA anticoagulant tubes) were collected before the above oral administration (Pre-dose) and at 0.5 h, 1 h, 2 h, 4 h, 6 h, and 12 h after dosing for measuring the concentration of corticosteroids in plasma. The blood was centrifuged at 10,000 rpm for 15 minutes at 4°C, and then the plasma was separated and stored uniformly at -80°C for further analysis. Aldosterone and cortisol in plasma were detected by electrochemiluminescence using a Roche biochemical analyzer. Meanwhile, part of the plasma (at 0.5 h, 1 h, 2 h, 4 h, 6 h, and 12 h after dosing, and an additional blood sample at 24 h) was taken to determine the pharmacokinetic parameters by LC / MS.

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

[0221] Table 5 Aldosterone concentration in plasma at different time points after dosing

[0222]

[0223] Table 6 Cortisol concentration in plasma at different time points after dosing

[0224]

[0225] The above experiment was repeated, with the difference that: at T = 0, 2 monkeys in each group were orally administered at a dose of 0.05 mg / kg (the compound was formulated as a suspension with 5% sodium carboxymethylcellulose aqueous solution as the solvent), and the fixed volume of administration was 2 mL / kg;

[0226] The aldosterone detection results are shown in Table 7, and the cortisol detection results are shown in Table 8. The experiment shows that Example 8 can significantly inhibit aldosterone synthesis. The maximum relative change from the baseline after 1 hour of ACTH stimulation in Example 8 is the largest (-51.05). Other test substances, including Example 2, have no effective inhibition of aldosterone synthesis at the administered doses. The effectiveness of Example 8 is beyond expectation. All test substances have no effect on cortisol levels.

[0227] Table 7 Aldosterone concentration in plasma at different time points after administration

[0228]

[0229] “ / ” indicates no significant change.

[0230] Table 8 Cortisol concentration in plasma at different time points after administration

[0231]

[0232] 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, while the maximum plasma concentration (C max max) and plasma exposure (AUC) are higher, 2-3 times higher than the reference, showing good pharmacokinetic properties. Unexpectedly, Example 8 has higher (C max max) and (AUC) at the same dose, which are respectively twice that of Example 2 and three times that of baxdrostat.

[0233] Table 9

[0234] 。

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that ； Among them, label the carbon atoms as S configuration, R configuration or a mixture thereof; 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, C1-C6 alkyl substituted by one, two or three R 2-1 substituents, C1-C6 alkoxy, C1-C6 haloalkoxy, "5- to 10-membered heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three", "5- to 10-membered heteroaryl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three" substituted by one, two or three R 2-2 substituents, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by one, two or three R 2-3 substituents or NR 2-4 R 2-5 ; R 2-1 independently is hydroxy or halogen; R 2-2 and R 2-3 are each independently a 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.

2. The compound of formula (I), its pharmaceutically acceptable salt or its stereoisomer according to claim 1, characterized in that, it satisfies one or more of the following conditions: (1) Each C1-C6 alkyl group and the C1-C6 alkyl group in each substituted C1-C6 alkyl group are independently methyl, ethyl, propyl, butyl or hexyl; preferably methyl or ethyl; (2) Each C1-C6 haloalkyl group is independently halomethyl, haloethyl, halopropyl, halobutyl or halohexyl, and the halogen is fluoro, chloro, bromo or iodo; (3) Each halogen is independently fluorine, chlorine, bromine or iodine; preferably fluorine; (4) Each C1-C6 alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (5) Each C1-C6 haloalkoxy group is independently halo-methoxy, halo-ethoxy, halo-n-propoxy, halo-isopropoxy, halo-n-butoxy, halo-isobutoxy, halo-sec-butoxy or halo-tert-butoxy; the halogen is fluoro, chloro, bromo or iodo; (6) Each C3-C6 cycloalkyl group and the C3-C6 cycloalkyl group in each substituted C3-C6 cycloalkyl group are independently cyclopropyl; (7) Each 5-10 membered heteroaryl group and the 5-10 membered heteroaryl group in each substituted 5-10 membered heteroaryl group are independently a 5-6 membered monocyclic heteroaryl group; (8) In each of the 5- to 10-membered heteroaryls and each of the substituted 5- to 10-membered heteroaryls, the heteroatoms are independently selected from N, and the number of heteroatoms is independently 1; for example, ; and (9) The labeled carbon atom is in the R configuration.

3. The compound of formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof as claimed in claim 1, characterized in that, it satisfies one or more of the following conditions: (1) The R 1 is H or a halogen; (2) The R 2 is a C1-C6 alkyl group or NR 2-4 R 2-5 ; preferably a C1-C6 alkyl group; (3) said R 2-4 is H or a C1-C6 alkyl group; preferably a C1-C6 alkyl group; and (4) The R 2-5 is a C1-C6 alkyl group.

4. The compound represented by formula (I), its pharmaceutically acceptable salt or its stereoisomer according to claim 1, characterized in that, it satisfies one or more of the following conditions: (1) R 1 is H or fluorine; (2) R 2 is , or ; preferably or ; more preferably ; (3)The R 3 is H or D; preferably H; and (4)R 4 is methyl.

5. The compound represented by formula (I), its pharmaceutically acceptable salt or its stereoisomer as claimed in claim 1, characterized in that, The compound represented by formula (I) is a compound represented by formula (I-1), preferably a compound represented by formula (I-2), wherein R 1 , R 2 , R 3 and R 4 are as defined in any one of claims 1-4.

6. The compound represented by formula (I), its pharmaceutically acceptable salt or its stereoisomer according to claim 1, characterized in that The compound of formula (I) is any of the following compounds: ； Preferably, , , , , , , or .

7. The compound represented by formula (I), its pharmaceutically acceptable salt or its stereoisomer according to any one of claims 1-6, characterized in that, The compound of formula (I) is not , , , , , , , , , , , , , or .

8. A method for preparing a compound represented by formula (I) as described in any one of claims 1-7, characterized in that, It includes the following steps: in a solvent, in the presence of a base and a catalyst, compound II and compound III are used to prepare the compound of formula (I); ； Among them, , R 1 , R 2 , R 3 and R 4 are defined as described in any one of claims 1-7.

9. The preparation method of the compound represented by formula (I) as described in claim 8, characterized in that, it satisfies 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 can be an alcohol solvent; for example, ethanol; (2) The base is an inorganic base; preferably potassium carbonate and / or sodium carbonate; and (3) The catalyst is a palladium catalyst; preferably tetrakis(triphenylphosphine)palladium.

10. A pharmaceutical composition, the pharmaceutical composition comprising: (1) A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof as described in any one of claims 1-7; and (2) A pharmaceutically acceptable excipient.

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

12. Use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof as described in any one of claims 1-7, and the pharmaceutical composition as described in claim 10 in the preparation of a drug for treating and / or preventing chronic kidney disease, congestive heart failure, hypertension or primary aldosteronism; preferably hypertension; Preferably, the compound represented by the formula (I) is not , or .

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