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

Abstract

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

Description

[0001] This patent application is a divisional application of patent application number 2025102190668, filed on February 26, 2025, entitled "Pyranopyridine Compounds, Preparation Methods Thereof, Pharmaceutical Compositions and Applications". Technical Field

[0002] This invention belongs to the pharmaceutical field, specifically relating to pyranopyridine compounds, their preparation methods, pharmaceutical compositions, and applications. Background Technology

[0003] Aldosterone is a key downstream regulatory molecule in the renin-angiotensin-aldosterone system (RAAS), a core regulatory system for blood flow, blood pressure, and water-electrolyte balance in the human body. Aldosterone is a steroid hormone (a member of the mineralocorticoid family) that promotes renal reabsorption of water and sodium by binding to and activating mineralocorticoid receptors (MR) in distal renal tubular and collecting duct epithelial cells, while simultaneously inducing potassium and hydrogen ion excretion, thus maintaining water and electrolyte balance and participating in maintaining appropriate blood pressure, vascular tone, and tissue perfusion. Furthermore, recent studies have shown that aldosterone can upregulate AT1R expression on vascular smooth muscle cells, altering vascular smooth muscle tone, response to vasoconstrictive signals, and arterial wall structure. It also increases the vascular pressor response to norepinephrine, leading to increased blood pressure, vascular smooth muscle cell proliferation, vascular wall thickening, and hyalinization.

[0004] Under normal circumstances, plasma aldosterone concentration is regulated by related stimulating factors such as the renin-angiotensin-aldosterone system (RAAS), serum potassium levels, and adrenocorticotropic hormone (ACTH). Elevated aldosterone levels can induce blood pressure abnormalities, cause inflammation, vascular remodeling, and tissue fibrosis associated with cardiometabolic diseases, ultimately leading to organ dysfunction, cardiovascular complications, advanced kidney disease, and an increased risk of death. Therefore, combating the harmful effects of excessive aldosterone in patients has been a targeted clinical strategy for many years.

[0005] For cardiovascular and renal diseases associated with aldosterone and its receptors, blocking the effects of aldosterone is an effective treatment. Aldosterone 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 aldosterone action by competitively binding to mineralocorticoid receptors, while RAS inhibitors (such as angiotensin II receptor blockers) indirectly reduce aldosterone levels by blocking the upstream stimulation of angiotensin II. Clinically, on the one hand, MRAs can over-antagonize receptor effects (aldosterone receptors can also be stimulated by estrogen) and have off-target side effects from androgen receptor antagonism; on the other hand, RAS inhibitors do not completely inhibit excessive aldosterone, leading to drug resistance issues. Therefore, specific inhibitors (ASIs) that directly inhibit aldosterone synthase (AS) can completely reduce aldosterone production without producing additional effects and can serve as a superior alternative to MRAs and RAS inhibitors.

[0006] Aldosterone synthase (encoded by the CYP11B2 gene) controls aldosterone synthesis, catalyzing the final step in the conversion of cholesterol into aldosterone, and has been a pharmacological target for treating hypertension for decades. Potassium ions, angiotensin II, and leptin can all activate the production of CYP11B2, leading to aldosterone synthesis. Importantly, CYP11B2 is the only enzyme that catalyzes the final oxidation to aldosterone, and it is primarily expressed in the glomerular zona glomeruli of the adrenal glands; it is largely absent in other parts of the body, thus off-target effects are not expected.

[0007] Because the enzymes that produce aldosterone and cortisol are 93% identical (CYP11B1, or cortisol synthase, the final enzyme in the cortisol synthesis pathway), this high degree of similarity 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 a current challenge and a major challenge.

[0008] LCI699 was the first orally active aldosterone synthase inhibitor to enter clinical trials for the treatment of essential aldosteronism. Oral administration of LCI699 resulted in decreased plasma aldosterone levels and lower blood pressure. However, LCI699 exhibited poor selectivity for CYP11B2 and CYP11B1, with a stronger inhibitory effect on cortisol synthase, leading to additional side effects and necessitating a shift in development towards the treatment of Cushing's disease. Subsequently, a new generation of highly selective ASI inhibitors was developed, but currently only a few products have entered clinical trials.

[0009] Lorundrostat (Mineralys) is a highly selective aldosterone synthase inhibitor that inhibits aldosterone synthase CYP11B2, lowering aldosterone levels in the body without inhibiting CYP11B1. Another new drug is Baxdrostat (CinCor Pharma / AstraZeneca). Phase I clinical trials of Baxdrostat showed that its inhibitory effect on aldosterone synthase is 100 times greater than its inhibitory effect on cortisol synthesis, classifying it as a highly selective aldosterone synthesis inhibitor that can dose-dependently reduce plasma aldosterone levels by >70%.

[0010] Although two clinical trial products exist, it remains unclear whether they will ultimately prove safe and effective in large-scale Phase III clinical trials. Therefore, highly selective aldosterone synthase inhibitors with better selectivity, safety, and efficacy remain in demand by patients. Summary of the Invention

[0011] The technical problem to be solved by this invention is to provide a highly selective aldosterone synthase inhibitor with a novel structure. This invention aims to provide a pyranopyridine compound, its preparation method, pharmaceutical composition, and applications. This type of compound has a strong inhibitory effect on aldosterone synthase but almost no effect on cortisol synthase, exhibiting high selectivity and high safety, and shows great promise for the prevention and / or treatment of various aldosterone-related diseases.

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

[0013] This invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0014] ;

[0015] in, The carbon atom is labeled as the S configuration, R configuration, or a mixture thereof;

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

[0017] R 2 It is an H, D, C1-C6 alkyl group, with one, two or three R radicals. 2-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, "5-10 membered heteroaryl groups selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", surrounded by one, two, or three R 2-2The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 5-10 membered heteroaryl group with one, two, or three heteroatoms; it is a C3-C6 cycloalkyl group; it is substituted with one, two, or three R atoms. 2-3 Substituted C3-C6 cycloalkyl or NR 2-4 R 2 -5 ;

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

[0019] R 2-2 and R 2-3 Halogens are independent of each other;

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

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

[0022] R 4 It is a C1-C6 alkyl group.

[0023] In certain preferred embodiments of the present invention, certain groups in the compound represented by Formula I, its pharmaceutically acceptable salt or its stereoisomer are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention").

[0024] In one embodiment of the present invention, the C1-C6 alkyl group and the C1-C6 alkyl group of each of the substituted C1-C6 alkyl groups are independently methyl, ethyl, propyl, butyl or hexyl; preferably methyl or ethyl.

[0025] In one embodiment of the present invention, each of the C1-C6 haloalkyl groups is independently a halomethyl, haloethyl, halopropyl, halobutyl, or halohexyl group, wherein the halogenation is fluorinated, chlorinated, brominated, or iodinated.

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

[0027] 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.

[0028] In one embodiment of the present invention, each of the C1-C6 haloalkoxy groups is independently a halomethoxy, haloethoxy, halopropoxy, haloisopropoxy, halobutoxy, haloisobutoxy, halosec-butoxy, or halotert-butoxy; the halogenation is fluorinated, chlorinated, brominated, or iodinated.

[0029] In one embodiment of the present invention, the C3-C6 cycloalkyl group and the substituted C3-C6 cycloalkyl group are all cyclopropyl groups.

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

[0031] In one aspect 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 aspect of the present invention, the... The carbon atom is labeled as the R configuration.

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

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

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

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

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

[0038] In one aspect of the present invention, R 2 for , or Preferred or Further preferred .

[0039] In one aspect of the present invention, the R 3 It can be H or D; H is preferred.

[0040] In one aspect of the present invention, the R 4 It is a methyl group.

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

[0042] Among them, R 1 R 2 R 3 and R 4 The definition is as described in any of the claims of this invention.

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

[0044] Among them, R 1 R 2 R 3 and R 4 The definition is as described in any of the claims of this 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 shown in formula (I), which includes the following steps: preparing the compound shown in formula (I) from compounds II and III in a solvent, in the presence of a base and a catalyst;

[0048] ;

[0049] in, R 1 R 2 R 3 and R 4 The definition is as described in any of the claims of this 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 alkali is an inorganic alkali; 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 comprising:

[0053] (1) The compound shown in formula (I) above, its pharmaceutically acceptable salt or its stereoisomer; and

[0054] (2) Pharmaceutically acceptable excipients.

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

[0056] The present invention also provides the compound shown in formula (I), its pharmaceutically acceptable salt or stereoisomer, and the use of the above pharmaceutical composition in the preparation of a medicament for the treatment and / or prevention of chronic kidney disease, congestive heart failure, hypertension or primary aldosteronism; preferably hypertension; preferably, the compound shown in formula (I) is not... , or .

[0057] definition

[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 pertains. Furthermore, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe this invention.

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

[0060] The term "alkyl" refers to a straight-chain or branched 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, etc.

[0061] The term "halogenated alkyl" refers to a halogen-substituted alkyl group, wherein the halogen and alkyl are the same as those defined above.

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

[0063] The term "haloalkoxy" refers to a halogen-substituted alkoxy group, where the halogen and alkoxy group are the same as those defined above.

[0064] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one, two, or three of N, O, and S), which can be monocyclic or polycyclic, and each ring is aromatic (conforming to Hückel's rule). Heteroaryl groups are attached to the rest of the molecule via carbon atoms or heteroatoms; they are attached to the rest of the molecule via rings with or without heteroatoms. Heteroaryl groups include, but are 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, etc.

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

[0066] The term "pharmaceutically acceptable salt" includes "pharmaceutically acceptable salt formed with organic or inorganic acids" and "pharmaceutically acceptable salt formed with organic or inorganic bases".

[0067] The term “stereoisomer” includes configurational isomers, which primarily include optical isomers, such as enantiomers, diastereomers or mixtures thereof.

[0068] The term "pharmaceuticalally acceptable excipient" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative excipients include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals.

[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, intended for administration to mammals, such as humans, in need of such treatment.

[0070] The term “treatment” refers to reversing, alleviating, inhibiting, or preventing the progression of an obstacle or condition to which the term applies, or one or more symptoms of such an obstacle or condition. As used herein, the term “treatment” refers to the action of the verb “to treat,” as previously defined.

[0071] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

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

[0073] The positive and progressive effects of this invention are as follows: This invention discloses a pyranopyridine compound, its preparation method, pharmaceutical composition, and application. It provides a class of selective aldosterone synthase inhibitors with structures different from previously reported or disclosed compounds: the compounds of this invention exhibit a selectivity fold of 50-220 for hCYP11B 1 / 2; excellent pharmacokinetic properties: 12 hours after administration, the plasma aldosterone concentration is 85-220 pg / mL, the plasma corticosterone concentration is 350-1000 pg / mL, the maximum plasma concentration (Cmax) is 8-25 ng / mL, and the plasma exposure (AUC0-24h) is 150-2200 h·ng / mL; it also exhibits in vitro inhibitory activity >50 μM against common CYP450 enzymes and has high safety. Attached Figure Description

[0074] Figure 1 The concentration of aldosterone in plasma at different time points after drug administration.

[0075] Figure 2 The concentration of cortisol in plasma at different time points after drug administration. Detailed Implementation

[0076] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0077] The raw materials or reagents used in this article are commercially available or prepared by synthetic methods generally 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 hours. 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, washed with acetonitrile (200 mL), and the solid was collected and dried to give compound 2 (45.0 g, 87%) as a white solid.

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

[0083] Step 2

[0084] Compound 2 (40.0 g, 133.38 mmol) was dissolved in tetrahydrofuran (400 mL), and 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 azodicarbonate (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, 65% yield) as a yellow oil.

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

[0086] Step 3

[0087] Compound 3 (30.7 g, 1.0 eq) was dissolved in N,N-dimethylformamide (300 mL), followed by the sequential addition of 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). After the addition was complete, 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 that the starting material was completely consumed. After cooling the reaction solution, quenching was performed by adding 300 mL of hydrochloric acid aqueous solution (4 M), followed by extraction with ethyl acetate (300 mL × 2). The organic phase was washed with 200 mL of hydrochloric acid aqueous solution (4 M), and the aqueous phase was collected. The pH was adjusted to greater than 7 with 2 M sodium hydroxide aqueous solution, and then extracted with ethyl acetate (300 mL × 200 mL). The organic phase was washed with saturated sodium chloride solution (300 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a 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 then purged with ozone while stirring 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 cooled to room temperature, quenched with saturated sodium sulfite aqueous solution (300 mL), and extracted with dichloromethane (200 mL × 2). 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 and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 5 (13.0 g, yield 86%) as a yellow solid.

[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 the addition was complete, 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 that the starting material was completely consumed. After cooling, water (100 mL) and ethyl acetate (200 mL, 150 mL) were added to the reaction mixture 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 give compound 6 (800 mg, yield 18.4%) as a yellow solid.

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

[0095] Step 6

[0096] Compound 6 (218 mg, 1.0 eq) was dissolved in methanol (10.0 mL), and sodium borohydride (75 mg, 3.0 eq) was added at -50 °C. After the addition was complete, the mixture was stirred at this temperature for 2 hours. TLC (dichloromethane / methanol = 20 / 1, product: Rf = 0.2, feed: Rf = 0.4) showed that the feed was completely consumed. The reaction was quenched by adding 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, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 15 / 1) to give a 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 in hydrochloric acid (0.45 mL, 4 M, 3.0 eq) was added. After the addition was complete, 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 that the starting material was completely consumed. Diethyl ether (6.0 mL) was added to the reaction mixture, and a solid precipitated out. The solid was filtered, collected, and dried to give a yellow solid compound 8 (140 mg, crude product).

[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 was complete, 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 that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give a yellow solid intermediate (80 mg, yield 53.6%).

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

[0104] Intermediate 2

[0105]

[0106] Intermediate 2 was synthesized by using the same experimental method as intermediate 1, but replacing propionyl chloride in step 8 with N,N-dimethylacetyl chloride.

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

[0108] Intermediate 3

[0109]

[0110] Using the same experimental method as intermediate one, intermediate three was synthesized by replacing NaBH4 in step 6 with NaBD4.

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

[0112] Intermediate four

[0113]

[0114] Using the same experimental method as intermediate one, intermediate four was synthesized by replacing NaBH4 in step 6 with NaBD4 and propionyl chloride in step 8 with N,N-dimethylacetyl chloride.

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

[0116] Intermediate 5

[0117]

[0118] Step 1

[0119] Compound 11 (10 g, 44.23 mmol) was dissolved in DMF (200 mL). Potassium tert-butoxide (9.92 g, 88.47 mmol) was added at 0 °C, and the mixture was stirred for half an hour. Iodomethane (8.16 g, 57.50 mmol) was added dropwise, and the mixture was stirred overnight. Iodomethane (2.5 g, 17.69 mmol) was added as a supplement, and the reaction mixture was heated to 40 °C and stirred for 5 hours. TLC showed that the starting material was completely consumed. 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 give compound 12 (8.9 g, yield 83.8%) as a white solid.

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

[0121] Step 2

[0122] Compound 12 (2.1 g, 8.75 mmol) was dissolved in dioxane (20 mL), 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 the addition was complete, the reaction mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. TLC showed that the starting material was completely consumed. After the reaction mixture was cooled, water (20 mL) and ethyl acetate (40 mL) were added for extraction. The organic phase was washed with saturated sodium chloride solution (20.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give intermediate five (1.6 g, yield 63.7%), a light brownish-red solid.

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

[0124] Intermediate 6

[0125]

[0126] Step 1

[0127] 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 mixture was stirred at 20 °C for 2 hours. TLC showed complete consumption of the starting material. The reaction was quenched by adding saturated sodium bicarbonate (100 mL), and extracted with dichloromethane (100 mL, 50 mL). 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 give compound 14 (28.7 g, 79% yield) as a white solid.

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

[0129] Step 5

[0130] Compound 14 (5 g, 24.80 mmol) was added to aluminum trichloride (11.6 g, 86.79 mmol). After the addition was complete, the reaction mixture was transferred to 120 °C and stirred for 3 hours. TLC showed that the starting material was completely consumed. After cooling the reaction system, the reaction was quenched with ice water, and extracted with dichloromethane (10.0 mL, 5.0 mL). 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 give a 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), and sodium hydride (60%, 727 mg, 18.16 mmol) was added under ice bath conditions. After the addition was complete, the reaction mixture was stirred at 20 °C for 0.5 h. Then, iodomethane (2.1 g, 14.53 mmol) was added to the reaction mixture, and after the addition was complete, the reaction mixture was stirred at 20 °C for 2 h. TLC showed that the starting material was completely consumed. The reaction was quenched by adding water (10 mL), and extracted with ethyl acetate (20 mL, 10 mL). 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 give compound 16 (1.8 g, yield 82.9%) as a white solid.

[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), and then 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. The reaction was quenched by adding water (10 mL), and extracted with ethyl acetate (20 mL × 2). 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 give compound 17 (1.4 g, yield 57.2%) as a white solid.

[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), and pinacol diboronate (2.4 g, 9.30 mmol), potassium acetate (2.3 g, 23.25 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (283.5 mg, 0.39 mmol) were added. After the addition was complete, the reaction mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. TLC showed that the starting material was completely consumed. 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 give a white solid intermediate 6 (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-pyran[3,2-c]pyridin-4-yl)propionamide

[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 tetraphenylphosphine palladium (16 mg, 14 μmol) were added sequentially. 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 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-pyran[3,2-c]pyridin-4-yl-4-D)propionamide

[0147] The same experimental method as in Example 1 was used to synthesize the intermediate through the coupling reaction of intermediates three and five.

[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-pyran[3,2-c]pyridin-4-yl)urea

[0152] The same experimental method as in Example 1 was used to synthesize the intermediate through a coupling reaction of intermediate 2 and intermediate 5.

[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-pyran[3,2-c]pyridin-4-yl-4-d)propionamide

[0157] The same experimental method as in Example 1 was used to synthesize the intermediate through a coupling reaction of intermediate tri and intermediate hexa.

[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-pyran[3,2-c]pyridin-4-yl-4-d)urea

[0162] The same experimental method as in Example 1 was used to synthesize the intermediate through the coupling reaction of intermediate four and intermediate five.

[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-pyran[3,2-c]pyridin-4-yl)-1,1-dimethylurea

[0167] The same experimental method as in Example 1 was used to synthesize the intermediate through a coupling reaction of intermediate 2 and intermediate 6.

[0168]

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

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

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

[0172] The same experimental method as in Example 1 was used to synthesize the intermediate through a coupling reaction of intermediate tetra and intermediate hexa.

[0173]

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

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

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

[0177] The same experimental method as in Example 1 was used to synthesize the intermediate through the coupling reaction of intermediate one and intermediate six.

[0178]

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

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

[0181] Experimental Example 1: Inhibitory activity of the compound against hCYP11B2 / hCYP11B1

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

[0183] The above-mentioned high-expression stable transgenic strains were constructed based on the human adrenal leiomyosarcoma cell line G-402, and artificial lentiviruses were introduced into human CYP11B2 (NM_000498.3) and CYP11B1 (NM_000497.4), 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% FBS filtered with activated carbon (S11695, R&D).

[0187] 2. Experimental steps:

[0188] Seeding: After cell resuscitation, culture in maintenance medium until suitable conditions are reached, at a concentration of 1×10⁻⁶. 4 / 100μL / well (Unified details) (cell mass)96-well flat-bottomed plates were cultured using seed plates.

[0189] Medium change: After the seed plate adheres to the wall overnight (>12 hours), the supernatant is aspirated and washed with 100~150μL / well serum-free medium. After aspiration, 50 μL / well reaction medium is added for later use.

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

[0191] CYP11B2 substrate: 11-deoxycorticosterone (S4243, Selleckchem), with a final reaction concentration of 0.2 μM.

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

[0193] Sample loading: Add the above compound dilution to the cell plate at a rate of 50 μL / well, and set up background wells and control wells at the same time.

[0194] Sample processing and collection: After adding the sample, incubate in a cell culture incubator for 16 hours, then spin each cell plate at 450g for 2 minutes, take 75μL of supernatant and transfer it to a collection plate, freeze at -80°C for later use (or directly detect).

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

[0196] Analysis: The absolute IC50 (Abs IC50) of each compound was calculated using a four-parameter fitting method.

[0197] The experimental results showed that most of the test compounds (Examples 2, 4, 5, and 8) exhibited similar inhibitory activity against CYP11B2 as the reference Baxdrostat, with Examples 2, 6, and 8 showing better selectivity. Unexpectedly, the chiral isomers of the test compounds did not show any inhibitory activity against aldosterone synthase.

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

[0199]

[0200] Experimental Example 2: In vitro inhibitory activity of the test substance against common CYP450 enzymes

[0201] Prepare a working solution of the test compound using dimethyl sulfoxide (DMSO) as the solvent (starting at a final concentration of 50 μM, and diluting 3 times to obtain 7 concentration points).

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

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

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

[0205] Table 2

[0206]

[0207] Table 3

[0208]

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

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

[0211] Table 4

[0212]

[0213] Experiments showed that the test compound did not inhibit any type of CYP450 enzymes, and the risk of drug-drug interaction (DDI) was low. Compared with baxdrostat, the test compound did not inhibit CYP2C19, and the risk of DDI was even lower.

[0214] Example 3: Pharmacokinetic and Pharmacodynamic Tests of the Test Substance in Cynomolgus Monkeys

[0215] Adult cynomolgus macaques (Macaca fascicularis) of suitable weight and age, one male and one female, were selected for the experiment, with an acclimatization period of one week. On the day of the experiment, the monkeys were kept alone in stainless steel mesh cages for testing.

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

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

[0218] At T = +1 hour (i.e., 1 hour after administration), administer an intramuscular injection of 14.5 μg / kg of the aforementioned ACTH working solution.

[0219] Sampling and Testing: Blood samples were collected (in EDTA anticoagulant tubes) before oral administration and at 0.5 h, 1 h, 2 h, 4 h, 6 h, and 12 h after administration for measuring plasma corticosteroid concentrations. Blood was centrifuged at 10,000 rpm for 15 minutes at 4°C, and plasma was then separated and stored at -80°C for further analysis. Analysis was performed using a Roche biochemical analyzer with electrochemiluminescence immunoassay to detect aldosterone and cortisol in plasma. Simultaneously, plasma samples were collected at 0.5 h, 1 h, 2 h, 4 h, 6 h, and 12 h after administration, and an additional 24 h after administration, for LC / MS determination of pharmacokinetic parameters.

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

[0221] Table 5. Plasma aldosterone concentrations at different time points after drug administration

[0222]

[0223] Table 6. Plasma cortisol concentrations at different time points after drug administration

[0224]

[0225] The experiment was repeated, except that: T = 0, and two monkeys in each group were orally administered the compound at a dose of 0.05 mg / kg (the compound was prepared as a suspension using 5% sodium carboxymethyl cellulose aqueous solution as the solvent), with a fixed volume of 2 mL / kg.

[0226] The results of aldosterone detection are shown in Table 7, and the results of cortisol detection are shown in Table 8. The experiment showed that Example 8 significantly inhibited aldosterone synthesis. Example 8 showed the largest change from baseline (-51.05) after 1 hour of ACTH stimulation. Other test substances, including Example 2, did not effectively inhibit aldosterone synthesis at the administered doses. The effectiveness of Example 8 exceeded expectations. All test substances had no effect on cortisol levels.

[0227] Table 7. Plasma aldosterone concentrations at different time points after drug administration

[0228]

[0229] " / " indicates no significant change.

[0230] Table 8. Plasma cortisol concentrations at different time points after drug administration

[0231]

[0232] The pharmacokinetic parameters of the compounds are shown in Table 9. Compared with the reference Baxdrostat, the time to peak concentration and half-life of the test compounds were similar, while the maximum plasma concentration (C3) was... max It exhibited higher levels of plasma exposure (AUC), 2-3 times higher than the reference, demonstrating favorable pharmacokinetic properties. Unexpectedly, Example 8 showed a higher AUC at the same dose. max The (AUC) values ​​were twice that of Example 2 and three times that of baxdrostat, respectively.

[0233] Table 9

[0234] .

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, ； in, The carbon atom is labeled as the S configuration, R configuration, or a mixture thereof; R 1 It is H or halogen; R 2 C1-C6 alkyl or NR 2-4 R 2-5 ; R 2-4 It is H or C1-C6 alkyl; R 2-5 It is a C1-C6 alkyl group; R 3 For H or D; R 4 It is a C1-C6 alkyl group; The compound shown in formula (I) is not , , , , , , , , , , , , , and .

2. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, It meets one or more of the following conditions: (1) Each of the C1-C6 alkyl groups is independently methyl, ethyl, propyl, butyl or hexyl; (2) Each of the halogens is independently fluorine, chlorine, bromine, or iodine; and (3) The above The carbon atom is labeled as the R configuration.

3. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, It meets one or two of the following conditions: (1) Each of the C1-C6 alkyl groups is independently methyl or ethyl; (2) Each of the halogens is fluorine.

4. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, It meets one or two of the following conditions: (1) The R 2 It is a C1-C6 alkyl group; (2) The R 2-4 It is a C1-C6 alkyl group.

5. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, It meets one or more of the following conditions: (1) R 1 It is H or fluorine; (2) R 2 for , or ; (3) The R 3 For H; and (4) R 4 It is a methyl group.

6. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, R 2 for or .

7. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, R 2 for .

8. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, The compound shown in formula (I) is the same as the compound shown in formula (I-1). .

9. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, The compound shown in formula (I) is the same as the compound shown in formula (I-2). .

10. A method for preparing a compound of formula (I) as described in any one of claims 1-9, characterized in that, It includes the following steps, in the presence of a base and a catalyst, to prepare the compound shown in formula (I) from compounds II and III; 。 11. The method for preparing the compound of formula (I) as described in claim 10, characterized in that, It meets one or more of the following conditions: (1) The solvent is an organic solvent and / or water; (2) The alkali mentioned is an inorganic alkali; The catalyst mentioned in (3) is a palladium catalyst.

12. The method for preparing the compound as shown in formula (I) as described in claim 10, characterized in that, It meets one or more of the following conditions: (1) The solvent is an organic solvent and water; (2) The alkali is potassium carbonate and / or sodium carbonate; The catalyst mentioned in (3) is tetratriphenylphosphine palladium.

13. The method for preparing the compound as shown in formula (I) as described in claim 10, characterized in that, The solvent is an organic solvent and / or water; the organic solvent is an alcohol solvent.

14. The method for preparing the compound as shown in formula (I) as described in claim 13, characterized in that, The alcohol solvent mentioned is ethanol.

15. A pharmaceutical composition comprising: (1) The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer; (2) Pharmaceutically acceptable excipients.

16. Use of a compound of formula (I) as described in any one of claims 1-9, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition as described in claim 15 in the preparation of an aldosterone synthase inhibitor.

17. Use of a compound of formula (I) as claimed in any one of claims 1-9, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition as claimed in claim 15 in the preparation of a medicament for the treatment and / or prevention of hypertension.

18. The use of a compound of formula (I) as described in any one of claims 1-9, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition as described in claim 15 in the preparation of a medicament for the treatment and / or prevention of chronic kidney disease, congestive heart failure or primary aldosteronism.

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