Aldosterone synthase inhibitors for treating chronic kidney disease - Patents.com

Abstract

The present invention relates to a compound comprising Cy, R 1 and R 2 The present invention relates to the treatment of chronic kidney disease by administering to a patient in need thereof a compound of formula (I) and its pharma- ceutical acceptable salts, wherein: TIFF2025500826000045.tif2835(I)

Description

[Technical field]

[0001] The present invention relates to the use of certain aldosterone synthase inhibitors for the treatment of certain disorders, including diabetic and non-diabetic chronic kidney disease. The present invention further relates to the use of aldosterone synthase inhibitors in combination with sodium glucose cotransporter-2 (SGLT2) inhibitors. [Background technology]

[0002] Chronic kidney disease (CKD) is the leading cause of kidney damage and end-stage renal disease (ESRD). The 5-year survival rate for dialysis patients is 35%, dropping to only 25% for diabetic dialysis patients. As a result, CKD represents a significant burden on healthcare systems worldwide, with an annual cost per patient in the United States of over $75,000. In addition to its direct consequences on the kidney, reduced kidney function is also a major trigger of cardiovascular events. Overall, about 12% of the European population has CKD stages 3-5, with a high degree of variability between countries, ranging from 4.1% to 25.5%.

[0003] Diabetes is the leading cause of CKD in most countries, accounting for more than 40% of new cases. Mortality increases linearly as glomerular filtration rate (GFR) declines, with a GFR >60 mL / min / 1.73 m 2 compared with patients with a GFR < 45 mL / min / 1.73 m 2 The incidence of diabetes is increased 2-5 fold in patients with diabetes. Decreased renal function is associated with an increased risk of coronary heart disease, stroke, and heart failure. Diabetic nephropathy is the leading cause of kidney damage and end-stage renal disease (ESRD) and accounts for >40% of patients undergoing dialysis. The 5-year survival rate for patients undergoing dialysis is 35%, whereas the 5-year survival rate for diabetic patients undergoing dialysis is only 25%.

[0004] Currently, only a limited number of treatment options are available to slow renal decline in patients with CKD. Angiotensin-converting enzyme (ACE) inhibitors (ACEi) and angiotensin receptor blockers (ARBs) can reduce albuminuria and slow the rate of progression of proteinuric nephropathy. However, clinical trials in patients with diabetic nephropathy have only moderately reduced the relative risk of the combined primary endpoint of all-cause mortality, ESRD, and doubling of serum creatinine in the trials (16% in the RENAAL trial and 19% in the IDNT trial). Recently, the sodium glucose cotransporter-2 (SGLT2) inhibitor empagliflozin has been shown to reduce the risk of renal disease progression in people with type 2 diabetes. An exploratory analysis of the EMPA-REG OUTCOME trial showed that empagliflozin reduced the incidence of the combined outcome of doubling of creatinine, need for initiation of renal replacement therapy, or renal death by 46% (HR 0.54, 95% CI 0.40-0.75). These benefits were similar regardless of baseline ACEi or ARB use, with no evidence of increased risk of hyperkalemia or acute kidney injury. (See Wanner C, et al, EMPA-REG OUTCOME Investigators; Empagliflozin and progression of kidney disease in type 2 diabetes. New England Journal of Medicine, published June 14, 2016, p. 323-334.) In the EMPEROR-Reduced study conducted in patients with heart failure and reduced ejection fraction, empagliflozin reduced the risk of an exploratory composite renal endpoint (chronic dialysis, kidney transplant, or persistent decline in eGFR) by 50% across the study population. This was consistent in patients with and without baseline CKD. The cardiorenal benefits of empagliflozin are currently being investigated in patients with CKD and at high risk of progression in the ongoing EMPA-KIDNEY study.(See Herrington WG, et al., The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study. Clinical Kidney Journal, Published: 25 October 2018.)

[0005] Growing evidence indicates that SGLT2 inhibitors may be a new treatment option for patients across a broad range of CKD phenotypes. The SGLT2 inhibitor canagliflozin has received FDA approval for the treatment of patients with diabetic kidney disease. In the CREDENCE trial, canagliflozin provided a 30% relative risk reduction for the composite endpoint of doubling serum creatinine, ESRD, or renal / CV death on top of standard of care. A large clinical outcomes trial evaluating the SGLT2 inhibitor dapagliflozin in patients with CKD (with or without type 2 diabetes) (DAPA-CKD) was stopped early due to underwhelming efficacy. Data reported in August 2020 showed that dapagliflozin provided a 39% relative risk reduction (RRR) for the composite primary endpoint (≥50% eGFR decline / ESKD / renal or CV death). Dapagliflozin also resulted in a 39% RRR for the composite secondary endpoint of CV death and HF hospitalization and a 31% RRR for all-cause mortality.

[0006] Current guidelines have begun to incorporate this new evidence by recommending SGLT2 inhibitors, with their demonstrated benefits, as an integral part of the treatment regimen for type 2 diabetes patients with CKD or CV risk. (See de Boer IH, Caramori L, Chan JCN, et al. KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int Suppl 2020. 98:S1-S115.) Recommendations for nondiabetic kidney disease are likely to follow shortly in light of the upcoming new evidence. Despite this progress, patients' residual renal and cardiovascular risk remains unacceptably high for CKD patients, especially those at substantial risk (GFR decline >3 mL / min / 1.73 m 2 Rapidly progressive patients (those with ≥ 1 year of disease) require continuing efforts to provide new treatments.

[0007] Empagliflozin is an orally available SGLT2 inhibitor indicated for lowering blood glucose in patients with Type 2 Diabetes Mellitus (T2DM) and for reducing the risk of cardiovascular (CV) death in patients with T2DM and pre-existing CV disease. Recently, empagliflozin has been shown to reduce the risk of kidney disease progression in people with T2DM. An exploratory analysis of the EMPAREG OUTOCOME trial showed that empagliflozin reduced the incidence of the composite outcome of doubling of creatinine, need for initiation of renal replacement therapy, or renal death by 46% (HR 0.54, 95% CI 0.40 to 0.75). These benefits were similar regardless of baseline ACEi or ARB use, with no evidence of increased risk of hyperkalemia or acute kidney injury. Empagliflozin is currently being investigated for the treatment of CKD in the ongoing EMPA-KIDNEY renal outcomes trial. Despite the marked improvement in clinical outcomes with SGLT2i treatment, CKD patients remain at high risk for further progression. In particular, persistent rapidly progressive patients are at disproportionate risk for poor clinical outcomes and there is a high unmet need for additional treatment options that are safe and effective when added on top of standard therapies (i.e., RAAS inhibitors and SGLT2i). In particular, persistent rapidly progressive patients are at disproportionate risk for poor clinical outcomes and there is a high unmet need for additional treatment options that are safe and effective when added on top of standard therapies (i.e., RAASi and SGLT2i). New treatments are needed for CKD patients at high risk for disease progression, especially those with rapid progression (eg, eGFR decline >3 ml / min / year). Summary of the Invention

[0008] The present invention relates to a method of treating CKD comprising administering to a patient in need thereof a therapeutically effective amount of an aldosterone synthase inhibitor ("AS inhibitor"), optionally in combination with an SGLT2 inhibitor ("method of the invention").

[0009] WO2016 / 014736 and WO2016 / 061161 describe oral small molecule inhibitors of human aldosterone synthase. Inhibition / blockade of aldosterone is reported to be useful in reducing renal fibrosis and improving glomerular filtration rate and albuminuria in models of chronic kidney disease (CKD) and diabetic nephropathy. In one embodiment of the invention, the AS inhibitor used in the methods of the invention is a compound of formula (I) or a salt thereof.

[0010] [ka] (I) (In the formula, Cy is C 3-10 a mono- or bicyclic ring system selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Said C 3-10Each of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be selected from the group consisting of halogen, -C 1-3 -Alkyl, -OC 1-3 -Alkyl, -CF 3 , cyano, oxo, -N(C 1-3 -alkyl) 2 , -NH(C 1-3 -alkyl), -NHCOC 1-3 -Alkyl, -C(O)C 1-3 -Alkyl, -C(O)OC 1-3 Alkyl, Hydroxy C 1-3 optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, heteroaryl, R 1 and R 2 is H, C 1-3 Alkyl, Hydroxy C 1-3 Alkyl, -CH 2 NHC(O)OC 1-4 Alkyl, -CH 2 O.C.(O)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, -C(O)H, -COOH, -C(O)NHC 1-4 Alkyl and C(O)N(C 1-4 Alkyl) 2 or R 1 and R 2 Let's get together and 3-6 Cycloalkyl or C 3-6 forming a heterocyclyl) Unless otherwise stated, the terms "compounds of formula (I)" and "AS inhibitors of the present invention" are used interchangeably.

[0011] In another embodiment, the method of the invention comprises the use of a compound of formula (I) as described according to the above embodiment, Cy is a phenyl, cyclohexyl, indanyl, 2,3-dihydrobenzofuranyl or tetrahydroquinolinyl group, each of which is -Cl, -F, -C 1-3 optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, oxo and CN; R 1 and R 2 H, C 1-3 Alkyl, Hydroxy C 1-3 Alkyl, -CH 2 NHC(O)OC 1-4 Alkyl, -C(O)N(C 1-4 Alkyl) 2 and -CH 2 O.C.(O)C 1-4 independently selected from alkyl, Regarding use.

[0012] In another embodiment, the method of the invention comprises the use of a compound of formula (I) according to any of the above embodiments, Cy is -Cl, -F, C 1-3 phenyl optionally substituted with 1, 2 or 3 substituents independently selected from alkyl and CN; Regarding use.

[0013] In another embodiment, the method of the invention comprises the use of a compound of formula (I) as described according to any of the above embodiments, Cy is -Cl, -F, C 1-3 phenyl substituted with 1, 2 or 3 substituents independently selected from alkyl and CN; Regarding use. In another embodiment, the method of the invention comprises the use of a compound of formula (I) as described according to any of the above embodiments, Cy is substituted with CN, Cl, -F and C 1-3 phenyl, optionally substituted with 1 or 2 additional groups independently selected from alkyl; Regarding use.

[0014] In another embodiment, the method of the invention comprises the use of a compound of formula (I) as described according to any of the above embodiments, R 1 Ga-CH 3 and R 2 Ga-CH 3or -CH 2 OH, Regarding use. In another embodiment, the method of the invention comprises the use of a compound of formula (I) as described according to any of the above embodiments, R 1 Ga-CH 3 and R 2 Ga-CH 2 OH, Regarding use.

[0015] In another embodiment, the method of the invention comprises the use of a compound of formula (I) as described according to any of the above embodiments, R 1 Ga-CH 3 and R 2 Ga-CH 3 That is, Regarding use. Table 1 provides representative compounds of the invention that can be used according to the methods of the invention.

[0016] [Table 1] TIFF2025500826000004.tif240170 TIFF2025500826000005.tif244165 TIFF2025500826000006.tif247170 TIFF2025500826000007.tif250164 TIFF2025500826000008.tif248170 TIFF2025500826000009.tif243170 TIFF2025500826000010.tif249170 TIFF2025500826000011.tif231170 TIFF2025500826000012.tif102169

[0017] In one embodiment, the methods of the present invention relate to the use of compounds 1-46, and pharma- ceutically acceptable salts thereof, as set forth in Table 1 above. In another embodiment, the method of the present invention relates to the use of compounds 1-11, 13, 15, 18, 19, 22, 23, 26, 28, 29A, 29B, 30-33, 35, 39, 41, 42, 45 and 46 shown in Table 1 above, and pharma- ceutically acceptable salts thereof.

[0018] In one embodiment, the SLGT inhibitor used in the methods of the invention is selected from the group consisting of empagliflozin, dapagliflozin and canagliflozin. In another embodiment, the SLGT inhibitor used in the methods of the invention is empagliflozin.

[0019] In another embodiment, the present invention relates to a method for treating CKD comprising administering to a patient in need thereof a therapeutically effective amount of an AS inhibitor of the present invention or a pharma- ceutically acceptable salt thereof, optionally in combination with empagliflozin. In another embodiment, the present invention relates to a method of treating CKD comprising administering a therapeutically effective amount of an AS inhibitor of the present invention, or a pharma- ceutically acceptable salt thereof, in combination with empagliflozin to a patient in need thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Abbreviation [Table 2]

[0021] Unless specifically indicated, throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers and all stereo, optical and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and their racemates, as well as mixtures of different ratios of the separate enantiomers, mixtures of diastereomers or any of the aforementioned forms in which such isomers and enantiomers exist, as well as salts, including pharma- ceutically acceptable salts thereof, and solvates thereof, such as, for example, hydrates, including solvates of the free compounds or solvates of the salts of the compounds.

[0022] Some of the compounds of formula (I) may exist in more than one tautomeric form and the present invention includes methods of using all such tautomers. The compounds of formula (I) also include their isotopically labeled forms.Isotopically labeled forms of the active agents of the combination of the present invention are identical to said active agents, except for the fact that one or more atoms of said active agents are replaced with atoms having different atomic masses or mass numbers from the atomic masses or mass numbers of said atoms normally found in nature.Examples of isotopes that are already commercially available and can be incorporated into the active agents of the combination of the present invention according to well-established procedures include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, respectively. 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 Cl is included. Active agents of the combinations of the invention, their prodrugs or pharma- ceutically acceptable salts that contain one or more of the aforementioned isotopes and / or other isotopes of other atoms are contemplated to be within the scope of the invention.

[0023] The method of the present invention also includes pharma- ceutically acceptable derivatives of the compounds of formula (I). "Pharmaceutically acceptable derivatives" refers to any pharma- ceutically acceptable salt or ester, or any other compound that, upon administration to a patient, is capable of providing (directly or indirectly) a compound useful in the present invention, or a pharmacologically active metabolite or pharmacologically active residue thereof. A pharmacologically active metabolite shall be understood to mean any compound of the present invention that can be enzymatically or chemically metabolized. This includes, for example, hydroxylated or oxidized derivative compounds of formula (I).

[0024] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by making its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. For example, such salts include acetate, ascorbate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide / hydrobromide, edetate, camsylate, carbonate, chloride / hydrochloride, citrate, and the like. Salts (citrates), edisylates, ethane disulfonates, estolates, esylates, fumarates, gluceptates, gluconates, glutamates, glycolates, glycollylarsnilates, hexylresorcinols, The following salts are available: hexylresorcinates, hydrabamine, hydroxymaleates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates ethanesulfonates), methyl bromides, methyl nitrates, methyl sulfates, mucates, napsylates, nitrates, oxalates, pamoates, pantothenates, phenylacetates,These include phosphates / diphosphates, polygalacturonates, propionates, salicylates, stearates, subacetates, succinates, sulfamides, sulfates, tannates, tartrates, teoclates, toluenesulfonates, triethiodides, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, and procaine. Further pharma- ceutically acceptable salts can be formed with cations derived from metals such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc. (see also Pharmaceutical salts, Birge, SM et al., J. Pharm. Sci., (1977), 66, 1-19).

[0025] The pharma- ceutically acceptable salts of the compounds of formula (I) can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a sufficient amount of an appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Salts of acids other than those mentioned above, which are useful, for example, for purifying or isolating the compounds of the invention (eg, trifluoroacetates), also form part of the invention. In addition, the use of prodrugs of the compounds of formula (I) is within the scope of the present invention. Prodrugs include compounds that can be modified by simple chemical transformation to produce the compounds of the present invention. Simple chemical transformations include hydrolysis, oxidation, and reduction. Specifically, prodrugs, when administered to a patient, can be converted to the compounds disclosed herein above, thereby imparting the desired pharmacological effect. The compounds of formula (I) are the only compounds contemplated to be "chemically stable" as will be understood by those of skill in the art. For example, peroxides or compounds with "dangling valences" or "carbanions" are not compounds contemplated by the inventive methods disclosed herein.

[0026] For all compounds disclosed hereinabove in this application, in the event that the nomenclature conflicts with the structural formula, it shall be understood that the compound is defined by the structural formula. All terms used herein are to be understood in their ordinary sense as known in the art unless otherwise specified. For example, "C 1-4 "Alkyl" refers to a monovalent saturated aliphatic hydrocarbon group containing 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, or t-butyl. 1-4 "Alkoxy" refers to C alkyl groups with terminal oxygen such as methoxy, ethoxy, propoxy, and butoxy. 1-4 Alkyl. All alkyl, alkenyl and alkynyl groups, where structurally possible, are understood to be branched or unbranched, cyclic or acyclic, unless otherwise specified. Other more specific definitions are as follows.

[0027] "C 1-n The term "alkyl", alone or in combination with another group, denotes an acyclic, saturated, branched or straight-chain hydrocarbon group having 1 to n C atoms. For example, C 1-5 The term alkyl refers to the group H 3 C-, H 3 C-CH 2 -, H 3 C-CH 2 -CH 2 -, H 3 C-CH(CH 3 )-, H 3 C-CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH(CH 3 )-, H 3C-CH(CH 3 )-CH 2 -, H 3 CC(CH 3 ) 2 -, H 3 C-CH 2 -CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH 2 -CH(CH 3 )-, H 3 C-CH 2 -CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -CH 2 -, H 3 C-CH 2 -C(CH 3 ) 2 -, H 3 CC(CH 3 ) 2 -CH 2 -, H 3 C-CH(CH 3 )-CH(CH 3 )- and H 3 C-CH 2 -CH(CH 2 CH 3 )-Inclusive.

[0028] "C 1-n The term "alkylene", alone or in combination with another group, refers to a divalent acyclic, straight or branched chain alkyl group containing 1 to n carbon atoms. For example, C 1-4 The term alkylene is -(CH 2 )-, -(CH 2 -CH 2 )-, -(CH(CH 3 ))-, -(CH 2 -CH 2 -CH 2 )-, -(C(CH 3 ) 2 )-, -(CH(CH 2 CH 3))-, -(CH(CH 3 )-CH 2 )-, -(CH 2 -CH(CH 3 ))-, -(CH 2 -CH 2 -CH 2 -CH 2 )-, -(CH 2 -CH 2 -CH(CH 3 ))-, -(CH(CH 3 )-CH 2 -CH 2 )-, -(CH 2 -CH(CH 3 )-CH 2 )-, -(CH 2 -C(CH 3 ) 2 )-, -(C(CH 3 ) 2 -CH 2 )-, -(CH(CH 3 )-CH(CH 3 ))-, -(CH 2 -CH(CH 2 CH 3 ))-, -(CH(CH 2 CH 3 )-CH 2 )-, -(CH(CH 2 CH 2 CH 3 ))-, -(CHCH(CH 3 ) 2 )- and -C(CH 3 )(CH 2 CH 3 )-Includes.

[0029] "C 3-n The term "cycloalkyl", alone or in combination with another group, denotes a cyclic, saturated, unbranched hydrocarbon group having 3 to n C atoms. For example, C 3-7 The term cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. As used herein, the term "heteroatom" shall be understood to mean atoms other than carbon, such as O, N, S and P. In any alkyl group or carbon chain, one or more carbon atoms may be replaced with a heteroatom O, S or N, where if N is unsubstituted it is understood to be NH, and it is understood that the heteroatom may replace either a terminal or internal carbon atom in a branched or unbranched carbon chain. Such groups may be substituted as described herein above with groups such as oxo to provide definitions such as, but not limited to, alkoxycarbonyl, acyl, amido and thioxo.

[0030] The term "aryl" as used herein, alone or in combination with another group, refers to a carbocyclic aromatic monocyclic group containing 6 carbon atoms, which may be further fused to a second 5- or 6-membered carbocyclic group, which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

[0031] The term "heteroaryl" means an aromatic 5-6 membered monocyclic heteroaryl or an aromatic 7-11 membered bicyclic heteroaryl ring in which at least one of the rings is aromatic, the heteroaryl ring containing 1-4 heteroatoms such as N, O and S. Non-limiting examples of 5-6 membered monocyclic heteroaryl rings include furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, tetrazolyl, triazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, and purinyl. Non-limiting examples of 7-11 membered heteroaryl bicyclic heteroaryl rings include benzimidazolyl, quinolinyl, dihydro-2H-quinolinyl, tetrahydroquinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl, benzofuranyl, dihydrobenzofuranyl, benzopyranyl, benzodioxolyl, benzoxazolyl, and benzothiazolyl.

[0032] The term "heterocyclyl" refers to a stable non-aromatic 4-8 membered monocyclic heterocyclic group or a stable non-aromatic 6-11 membered fused bicyclic, bridged bicyclic or spirocyclic heterocyclic group. The 5-11 membered heterocyclic ring consists of carbon atoms and one or more, preferably 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. The heterocyclic ring may be saturated or partially unsaturated. Non-limiting examples of non-aromatic 4-8 membered monocyclic heterocyclic groups include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, 1,1-dioxo-1λ ... 6 -thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl and azepinyl. Non-limiting examples of non-aromatic 6- to 11-membered fused bicyclic groups include octahydroindolyl, octahydrobenzofuranyl and octahydrobenzothiophenyl. Non-limiting examples of non-aromatic 6- to 11-membered bridged bicyclic groups include 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl and 3-azabicyclo[3.2.1]octanyl. Non-limiting examples of non-aromatic 6- to 11-membered spirocyclic heterocyclic groups include 7-azaspiro[3,3]heptanyl, 7-spiro[3,4]octanyl and 7-azaspiro[3,4]octanyl. The term "heterocyclyl" is intended to include all possible isomeric forms.

[0033] The term "halogen" as used herein shall be understood to mean bromine, chlorine, fluorine or iodine. The definitions "halogenated", "partially or fully halogenated", partially or fully fluorinated, "substituted with one or more halogen atoms" include, for example, mono-, di- or trihalo derivatives on one or more carbon atoms. A non-limiting example for alkyl is -CH 2 CHF 2 , -CF 3 etc. It is to be understood that each alkyl, cycloalkyl, heterocycle, aryl or heteroaryl, or the like, described herein may be partially or fully halogenated. As used herein, "nitrogen" or N and "sulfur" or S include all oxidized forms of nitrogen and sulfur and the quaternized form of any basic nitrogen. For example, -SC 1-6 For an alkyl group, unless otherwise specified, this is -S(O)-C 1-6 Alkyl and S(O) 2 -C 1-6 Similarly, -SR a is R a is phenyl, then phenyl-S(O) m -, where m is 0, 1 or 2.

[0034] Basic synthesis method Compounds of formula (I) for use in the methods of the present invention may be prepared by the methods and examples described in WO2016 / 014736. Therapeutic uses Unless otherwise defined herein, the term "chronic kidney disease" or "CKD" refers to either renal impairment of at least 3 months duration or a reduced glomerular filtration rate (GFR) of less than 60 mL / min / 1.73 m2. The stage or severity of CKD is based on GFR values ​​as follows: Stage 1: Renal impairment with normal or increased GFR (>90 mL / min / 1.73 m2) Stage 2: Mildly decreased GFR (60-89mL / min / 1.73m2) Stage 3a: Moderately decreased GFR (45-59 mL / min / 1.73 m2) Stage 3b: Moderately decreased GFR (30-44 mL / min / 1.73 m2) Stage 4: Severely reduced GFR (15-29 mL / min / 1.73 m2) Stage 5: Renal failure (GFR<15mL / min / 1.73m2 or dialysis)

[0035] As used herein, the term "end stage renal disease" refers to either a decline in kidney function below an eGFR of <15 mL / min / 1.73 m2 and / or the need for renal replacement therapy by kidney transplant or dialysis. In one embodiment, the patient has stage 1 CKD, or stage 2 CKD, or stage 3 CKD, or stage 4 CKD, or stage 5 CKD. In another embodiment, the patient has end stage renal disease. In one embodiment, the invention relates to a method of treating, preventing and / or reducing the risk of chronic kidney disease progression, end stage renal disease, renal death or cardiovascular death in adult CKD patients at high risk of disease progression, including rapidly progressing patients (e.g. eGFR decline >3 ml / min / year), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof, optionally in combination with empagliflozin. In another embodiment, the CKD patient has or is at risk for an eGFR decline of >3 ml / min / year.

[0036] In another embodiment, the present invention relates to a method of treating, preventing, and / or reducing the risk of chronic kidney disease progression, end stage renal disease, renal death or cardiovascular death in an adult patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, optionally in combination with empagliflozin.

[0037] Direct inhibition of AS has the potential to reduce the deleterious effects due to both MR-dependent and MR-independent actions of aldosterone. AS inhibitors affect MR-dependent actions, so there is a potential risk of hyperkalemia. Therefore, another aspect of the clinical trial is related to the treatment of CKD with AS inhibitors in combination with the SGLT2 inhibitor empagliflozin. Combination treatment with SGLT2 inhibitors reduces the hyperkalemia of some AS inhibitors, thereby allowing high doses of AS inhibitors with balanced safety against hyperkalemia. This dual mechanism is also expected to provide a higher therapeutic advantage than mineralocorticoid receptor (MR) antagonists, as efficacy should be exerted at doses with less impact on MR-dependent electrolyte regulation, and with a lower risk of hyperkalemia. In one embodiment, the SGLT2 inhibitor is empagliflozin.

[0038] In one embodiment, the invention relates to a method of treating, preventing, and / or reducing the risk of renal disease progression, end stage renal disease, renal death or cardiovascular death in an adult patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof in combination with empagliflozin. In another embodiment, the present invention relates to a method for treating, preventing and / or reducing the risk of renal disease progression, end stage renal disease, renal death or cardiovascular death in adult patients with uncontrolled CKD progression (eGFR decline >3 mL / min / 1.73 m2 / year), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmacologic acceptable salt thereof in combination with empagliflozin. In another embodiment, the invention relates to a method of treating, preventing and / or reducing the risk of renal disease progression, end stage renal disease, renal death or cardiovascular death in an adult patient, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I) or a pharma- ceutical acceptable salt thereof in combination with empagliflozin, wherein treatment with empagliflozin reduces the risk of hyperkalemia compared to a patient treated without empagliflozin.

[0039] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof may be used in the preparation of a medicament for treating chronic kidney disease, and in another embodiment the medicament comprises an SGLT2 inhibitor, and in another embodiment the medicament comprises an SGLT2 inhibitor which is empagliflozin. For therapeutic use, each of the compounds of formula (I) and the SGLT2 inhibitors may be administered via a pharmaceutical composition in any conventional pharmaceutical dosage form in any conventional manner. Conventional dosage forms typically include a pharma- ceutically acceptable carrier suitable for the particular dosage form selected. Routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intrasynovial, injection, sublingual, transdermal, oral, topical or inhalation. Preferred modes of administration are oral and intravenous.

[0040] The compounds of formula (I) and optionally the SGLT2 inhibitor may be administered alone or in combination with adjuvants, including other active ingredients, that enhance the stability of the inhibitors, facilitate administration of pharmaceutical compositions containing them in certain embodiments, enhance solubility or dispersibility, enhance inhibitory activity, provide adjunctive therapy, etc. In one embodiment, for example, multiple compounds of the invention may be administered. Advantageously, such combination therapy utilizes lower dosages of conventional therapeutic agents, thus avoiding potential toxic and adverse side effects incurred when these agents are used as monotherapy. The compounds of the invention may be physically combined with conventional therapeutic agents or other adjuvants into a single pharmaceutical composition. Advantageously, the compounds may then be administered together in a single dosage form. In some embodiments, pharmaceutical compositions containing such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of the compound of formula (I) (w / w) or combinations thereof. The optimal percentage (w / w) of the compounds of the invention may vary and is within the skill of the art. Alternatively, the compounds of the invention and the conventional therapeutic agents or other adjuvants may be administered separately (sequentially or concurrently). Separate dosing allows for great flexibility in dosing regimens.

[0041] As mentioned above, each of the dosage forms of the compounds of formula (I) and any SGLT2 inhibitors of the present invention may contain pharma- ceutically acceptable carriers and adjuvants known to those skilled in the art and suitable for the dosage form. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes, and cellulose-based substances. Preferred dosage forms include tablets, capsules, caplets, liquids, solutions, suspensions, emulsions, lozenges, syrups, reconstitutable powders, granules, suppositories, and transdermal patches. Methods for preparing such dosage forms are known (see, for example, HC Ansel and NG Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and requirements of the compounds of the present invention may be selected by those skilled in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1 to 1000 mg / dose for a 70 kg patient. One dose per day may be sufficient, although up to 5 doses per day may be given. For oral doses, up to 2000 mg / day may be required. As one of ordinary skill in the art will appreciate, lower or higher doses may be required depending on certain factors. For example, the specific dosage and treatment regimen will depend on factors such as the patient's general health profile, the severity and course of the patient's disorder or disposition, and the judgment of the attending physician.

[0042] It should be understood that within the scope of the present invention, the combination or combined use of an AS inhibitor and an SGLT2 inhibitor according to the present invention may envisage simultaneous, sequential or separate administration of the therapeutic components. In this context, "combination" or "combined" within the meaning of the present invention may include, but is not limited to, fixed and non-fixed (e.g. free) forms (including kits, or other administration, application or dosage forms) as well as simultaneous, sequential or separate use of, for example, an AS inhibitor and an SGLT2 inhibitor. The combined administration or application of the present invention may be performed by administering the therapeutic components together, e.g., by administering the therapeutic components simultaneously in one single or two separate formulations. Alternatively, administration may be performed by administering the therapeutic components sequentially, e.g., by administering them sequentially in two separate formulations.

[0043] For the combination therapy of the present invention, the therapeutic components may be administered separately (meaning that the therapeutic components are formulated separately) or together (meaning that the therapeutic components are formulated in the same preparation). Thus, the administration of one element of the combination of the present invention may be prior to, simultaneous to, or subsequent to the administration of the other element of the combination. In another embodiment of the present invention, the patient may be treated with a third therapeutic agent.Non-limiting examples of optional third therapeutic agents include ACE inhibitors and ARBs.Non-limiting examples of ACE inhibitors include benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril.Non-limiting examples of ARBs include irbesartan, losartan, telmisartan and valsartan.

[0044] Clinical Trial Protocol The efficacy and safety of the compound of formula (I) alone and in combination with an SGLT2 inhibitor are studied according to the following clinical trial protocol. In summary, patients are administered one of three doses of an AS inhibitor for 14 weeks. In this Phase II dose-finding study, the AS inhibitor is used alone and in combination with empagliflozin in male and female patients with diabetic and non-diabetic CKD.

[0045] Study Evaluation Items The primary endpoint was the change from baseline in log-transformed urinary albumin creatinine ratio (UACR) measured in first morning void after 14 weeks. Secondary endpoints UACR response I, defined as a reduction in absolute change of at least 30% in UACR for first morning void from baseline to week 14 UACR response II, defined as a reduction in absolute change of at least 15% in UACR for first morning void from baseline to week 14

[0046] Test Design A randomized, double-blind, parallel-dose, placebo-controlled Phase II clinical trial to investigate the effects of three doses of an AS inhibitor alone or in combination with empagliflozin over 14 weeks in patients with diabetic and non-diabetic chronic kidney disease. The study included an 8-week 1:1 randomized run-in period with empagliflozin 10 mg / placebo, followed by a 14-week randomized treatment period with AS inhibitor / placebo alone or in combination with empagliflozin. Total number of patients to be randomized: at least 552. Number of patients per treatment group: A minimum of 60 patients per group completed the treatment period, with 480 patients completed overall.

[0047] Diagnosis: Diabetic or non-diabetic chronic kidney disease Main inclusion and exclusion criteria: Inclusion: Male or female patients aged ≥ 18 years at the time of consent eGFR ≥ 30 and < 90 mL / min / 1.73 m 2 UACR ≥ 200 and < 5000mg / g Stable treatment with either an ACEi or an ARB (but not both) Serum potassium ≦4.8mmol / L Exclude: Current or planned SGLT2i / SGLT1 / 2i treatment · type 1 diabetes

[0048] Test products: AS inhibitors and empagliflozin dose: AS inhibitor 3 mg / day (once daily (QD)) or 10 mg / day (once daily (QD)) or 20 mg / day (once daily (QD)) Empagliflozin 10 mg once daily (QD) Mode of administration: Oral (po) (taken by mouth) Comparator products: AS inhibitors and matching placebos for each dose of empagliflozin Dosage: Not applicable Mode of administration: po Treatment duration: 14 weeks (8 weeks run-in with empagliflozin / placebo and 14 weeks treatment with AS inhibitor / placebo alone or in combination with empagliflozin / placebo) Statistical methods: A repeated measures mixed effects model (MMRM) is used to obtain the adjusted mean change from baseline in the treatment effect of continuous endpoints. The MMRM model includes a fixed effect of treatment as a categorical variable and a fixed effect of baseline at each visit as a continuous variable. Visits are considered as repeated measures with an unstructured covariance structure for within-patient variability. For dose selection, the predicted mean responses of each dose group and the estimated covariance matrix from the MMRM are used in a multiple comparison procedure and modeling (MCPMod) analysis. Several possible dose-response patterns are evaluated in the MCPMod to identify the most suitable model and optimal dose for further development.

[0049] The study will compare three doses of an AS inhibitor with placebo in diabetic and non-diabetic CKD patients randomized to empagliflozin or placebo as background therapy (established during randomization run-in). The study will characterize the dose-response curve of an AS inhibitor in diabetic and non-diabetic CKD patients by evaluating three doses and placebo. The response is the change from treatment-period baseline in log-transformed UACR measured in the first morning void after 14 weeks. The primary objectives are (1) to demonstrate that the dose-response curve is not flat, to assess the magnitude of the quantitative treatment effect, and to evaluate the dose-response relationship, and (2) to determine the optimal dose of the AS inhibitor by comparing the change from treatment-period baseline in log-transformed UACR measured in the first morning void after 14 weeks between three doses of the AS inhibitor and placebo. The set of secondary objectives are as above, except in the subpopulations of (1) placebo background therapy (2) empagliflozin background therapy. These analyses included all data before AS inhibitor discontinuation, AS inhibitor down-titration, or death, regardless of changes in concomitant SGLT2 inhibitor use.

[0050] Primary endpoint Change from treatment baseline in log-transformed urinary albumin creatinine ratio (UACR) measured on first morning void after 14 weeks Secondary endpoints UACR response I, defined as a reduction in absolute change of at least 30% in UACR for first morning void from baseline to week 14 of the treatment period UACR response II, defined as a reduction in absolute change of at least 15% in UACR for first morning void from baseline to week 14 of the treatment period Further Objectives Further objectives include the efficacy, safety, PK and PD of three doses of AS inhibitors compared with placebo after 14 weeks of study treatment in CKD patients. Further evaluation items Change from baseline in eGFR after 14 weeks. eGFR gradient Change from baseline in serum potassium after 14 weeks. Change from baseline in blood pressure and pulse rate after 14 weeks. Change from baseline in body weight after 14 weeks.

[0051] Further endpoints will include changes from baseline in plasma aldosterone, its precursors corticosterone and 11-deoxycorticosterone, cortisol and its precursor 11-deoxycortisol to assess target engagement and target selectivity, including comparison of the time profiles of these markers between selected visits (continuous measurements over 2-3 hours, corresponding primarily to PK sampling time points for AS inhibitors). Further endpoints will also include changes from baseline in biomarkers representing key mechanisms of renal pathophysiology, such as inflammation, fibrosis, tubulointerstitial injury, oxidative stress, glomerular injury and endothelial dysfunction. PK parameters will be evaluated as further endpoints. In relation to the endpoints, the term "baseline" refers to the last observation before first intake of AS inhibitor study medication in the treatment period, excluding first morning void, where baseline is defined as the average of all non-missing assessments from week -2 of the randomized run-in period until first intake of study medication in the treatment period. Baseline does not include UACR measured in spot urine at screening. Further details and additional endpoints may be defined in the Study Statistical Analysis Plan (TSAP).

[0052] Description of Design and Study Population Overall Study Design This study is a multicenter, randomized, double-blind, parallel-dose, placebo-controlled Phase II clinical trial to investigate the effects of three doses of an AS inhibitor alone and in combination with empagliflozin in diabetic and non-diabetic CKD patients receiving background treatment with either an ACEi or an ARB. Use of empagliflozin vs. placebo will be established during a 1:1 randomized run-in period.

[0053] Patients are screened into the study after signing informed consent. Patients undergo a screening period of up to 2 weeks from the time of the first screening assessment. After screening confirms patient eligibility, patients enter the randomized run-in period. Patients are equally randomized in a 1:1 ratio to receive either empagliflozin 10 mg or empagliflozin 10 mg matching placebo and continue to receive the assigned study treatment for 8 weeks. After 8 weeks of treatment in the run-in period, patients enter the treatment period. Patients who received empagliflozin in the run-in period are equally randomized in a 1:1:1:1 ratio to one of four parallel dose arms to receive one of three doses of AS inhibitor (3 mg QD, 10 mg QD, or 20 mg QD) in combination with empagliflozin or empagliflozin alone (empagliflozin plus AS inhibitor matching placebo) (see Figure 3.1:1). Patients who received placebo during the run-in period will be equally randomized in a 1:1:1:1 ratio to one of four parallel dose arms to receive one of three doses of AS inhibitor (3 mg QD, 10 mg QD, or 20 mg QD) or placebo. Patients will continue to receive their assigned treatment for 14 weeks. The study will be blinded to both empagliflozin and the AS inhibitor. The different dose strengths of the AS inhibitor film-coated tablets (3 and 10 mg) and empagliflozin have different sizes to minimize potential observer bias and ensure that the study is blinded across dose groups, so patients will each take four tablets daily for the duration of treatment.

[0054] Eligible patients are randomized to treatment using a stratification algorithm that helps ensure balance between treatment arms with respect to prognostic variables such as prediabetes, eGFR, and UACR. A minimum of 40% of patients must be randomized to each disease type: diabetic kidney disease and non-diabetic kidney disease during the run-in period. Diabetic patients may have diabetic kidney disease, non-diabetic CKD aetiologies, or a combination; for stratification purposes, patients are classified as having diabetic kidney disease. At various time points from the start of screening to the end of the study, patients will collect urine for analysis of UACR. The first morning void will be collected before each day's administration of study medication. At each time point where no physical visit to the site is foreseen, patients will be provided with a urine collection container for sampling urine from the first morning void. To reduce patient burden, if national regulations allow, samples collected at home between visits will be transported from the patient's home to a central laboratory for analysis. If this is not possible, alternatives will be made, such as depositing samples at the investigational site. Samples collected directly at the site before a physical visit will be deposited at the site and processed by site staff.

[0055] In addition to safety analyses, urine and blood samples from this study will serve for biomarker analyses, including UACR. After the treatment period or when the lead-in or treatment period study treatment is permanently discontinued, patients will have an End of Treatment (EoT) visit. This will be followed by a 4-week treatment-free follow-up period. The first follow-up visit (FUp1) at least 7 days later will be considered the end of the Residual Efficacy Period (REP). Until the end of the REP, all AEs and changes to concomitant medications should be collected, documented, and reported. Patients who discontinue early during the lead-in period must participate in at least FUp1. All other patients should be encouraged to complete the entire follow-up period. During the follow-up period, patients will not be treated with study medication, but should continue any background treatments they are receiving, if possible, and additional urine will be collected at home. After the 4-week follow-up period, patients will have a final visit, where blood and urine samples will again be collected. At the end of this visit, each patient's participation in the study will be completed.

[0056] An increase in serum potassium and a decrease in eGFR under treatment with AS inhibitors cannot be excluded. Therefore, patients will be closely monitored (once a week for 2 weeks) after the start of treatment with AS inhibitors or matching placebo, and periodically thereafter. Patients will be asked to voluntarily donate specimens for banking so that future scientific questions can be addressed. If the patient agrees, the banked samples can be used in future biomarker research and drug development projects, for example to identify patients likely to benefit from treatment or likely to experience adverse events (AEs), or to gain a mechanistic or genetic understanding of drug effects, thereby better matching patients to therapy. Historical kidney-related data (including serum creatinine data, eGFR values, and historical AKI data) for 3 years prior to the start of treatment will be collected in the study, which may be used in the future to explore the benefits of AS inhibitors in patients with different classifications of CKD progression rates.

[0057] Study design considerations, including choice of control group This dose-finding study was designed to evaluate the efficacy and safety of AS inhibitors alone and in combination with empagliflozin for potential initiation in clinical practice. The dose-finding study also provides an opportunity to establish optimal doses of AS inhibitors for future development, either by themselves and / or as fixed-dose combinations with empagliflozin. Patients will first start 8 weeks of empagliflozin or placebo in the randomized run-in period, then receive 14 weeks of AS inhibitor or placebo treatment in the treatment period in addition to empagliflozin or placebo treatment. Because both drugs, empagliflozin and AS inhibitor, have potentially similar hemodynamic effects, it is important for patients to first run in empagliflozin before starting treatment with AS inhibitors for safety reasons. We believe that 8 weeks of empagliflozin treatment before starting AS inhibitors is sufficient to reach stable hemodynamic levels.

[0058] A parallel group design was chosen to investigate three different dose regimens of AS inhibitors alone and in combination with empagliflozin. The first parallel group will investigate three different dose regimens of AS inhibitors and placebo. The second parallel group will investigate three different dose regimens of AS inhibitors in combination with empagliflozin versus empagliflozin plus placebo. Placebo will be used to control observer and subject bias, and randomization will be used to control allocation bias. The study design includes two types of randomization. The initial randomization to empagliflozin and placebo is required for two purposes. First, the randomization ensures an equal distribution of the patient population to the empagliflozin and placebo groups, followed by the second randomization to the treatment groups. Second, the alternating approach of initiating empagliflozin during the induction period, followed by subsequent initiation of AS inhibitors, was chosen to enhance patient safety. Both empagliflozin and AS inhibitors have hemodynamic effects that can lead to a rapid decline in eGFR. The alternating treatment initiation is planned to reduce such effects.

[0059] UACR was chosen as the primary endpoint (first morning void collection) and secondary endpoint (responder rate) because it has been shown in previous Phase II studies by others in CKD to be sensitive, distinguish between different doses, have a wide kinetic range, and reach a stable plateau within a reasonable time after treatment initiation. UACR has been accepted by authorities as a dose-finding biomarker in CKD. Furthermore, changes in UACR correlate with long-term clinical and patient-related outcomes.

[0060] Because UACR is a parameter that varies within individuals over time, multiple measurements are required at baseline and during the treatment period, especially toward the end of treatment when a stable response to the drug should be achieved. Therefore, UACR measurements are collected on two consecutive days (total of six measurements) at three time points: weeks -2 to 0 for baseline and weeks 12 to 14 during the treatment period. Serial collection of urine during the 4-week follow-up period can provide exploratory results on response stability and potential rebound effects. To further characterize the hemodynamic effects, serum creatinine will be measured periodically for exploratory analyses. A Data Monitoring Committee (DMC) will be established to regularly review safety data.

[0061] Selection of study population At least 552 patients from approximately 200 centers are expected to be randomized in the randomized run-in period. Investigators are expected to be nephrologists, endocrinologists, or general practitioners. Screening of patients for this study is competitive, i.e., screening of the study will be stopped simultaneously at all centers when a sufficient number of patients have been screened. Investigators will be notified about the completion of screening and will not be allowed to screen additional patients for this study thereafter. Patients already being screened at this point will be allowed to continue randomization if eligible. To maintain power by increasing the sample size, a minimum of 552 patients will be randomized in the run-in period to ensure that at least 480 patients complete the study treatment. During the conduct of the study, if the dropout rate is higher than planned, recruitment may continue until the required number of patients completes treatment. A log of all patients enrolled in the study (i.e., who signed the informed consent) will be kept in the Investigative Site File (ISF), regardless of whether the patient was treated with the investigational drug or not. If a patient is incorrectly randomized (= does not meet all inclusion criteria or meets one or more exclusion criteria), the sponsor or its representative should be contacted immediately. Based on the individual benefit-risk assessment, a decision will be made as to whether continued participation in the study is possible.

[0062] Main diagnosis for study entry chronic kidney disease If the investigator determines that a participant should receive empagliflozin (or any other SGLT-2 or SGLT-1 / 2 inhibitor) in relation to prevailing local, national or international guidelines, the patient should not be included in the study as there is a risk that they may be allocated placebo alone in the study. Potential participants currently being treated with empagliflozin (or other SGLT2 or SGLT-1 / 2 inhibitors) should not discontinue this therapy in order to meet the eligibility criteria.

[0063] Inclusion criteria 1. Sign and date written informed consent in accordance with ICH-GCP and local law prior to study participation. 2. Male or female patients aged ≥18 years at the time of consent. 3. eGFR (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) ≥ 30 and < 90 mL / min / 1.73 m2 at Visit 1 by central laboratory analysis. 4. UACR ≥ 200 and < 5,000 mg / g in spot urine (midstream urine sample) at Visit 1.1 by central laboratory analysis. 5. If patients are taking any of the following medications: antihypertensives, NSAIDs, endothelin receptor antagonists, low-dose systemic steroids (e.g., prednisolone ≦10 mg or equivalent), they should be on a stable dose for at least 4 weeks prior to Visit 1 and until initial randomization prior to the Run-In Phase, without any planned changes in treatment during the study.

[0064] 6. Treatment with a clinically appropriate stable dose of either an ACEi or an ARB (but not both together) for ≥ 4 weeks prior to Visit 1 and until initial randomization, with no planned changes in treatment during the study. 7. In the opinion of the investigator, underlying renal disease due to one or more of the following: Diabetic kidney disease. These patients must have type 2 diabetes and their treatment (including GLP1 receptor agonists) should not be changed or the change should be considered minor (as per the investigator's judgment) within the 4 weeks prior to Visit 1 and until first randomization prior to the Run-In Phase. Hypertensive kidney disease Chronic glomerulonephritis, defined as one of the following: IgA nephropathy, Membranous nephropathy Focal segmental glomerulosclerosis (FSGS) 8. Glycated hemoglobin (HbAlc) < 10.0% at Visit 1 as measured by a central laboratory 9. Serum potassium ≤ 4.8 mmol / L at Visit 1 as measured by a central laboratory 10. Sitting SBP ≥ 110 and ≤ 160 mmHg and DBP ≥ 65 and ≤ 110 mmHg (mean of three BP measurements) at Visit 1 and optimized antihypertensive treatment according to local standard of care and investigator judgment. 11. Body mass index (BMI) ≥ 18.5 and < 50 kg / m2 at Visit 1. 12. Women of childbearing potential 2 (WOCBP) must be willing and able to use highly effective contraceptive methods. Such methods should be used throughout the study. Men must have had a vasectomy or be willing and able to use condoms if their partners are WOCBP.

[0065] Additional inclusion criteria to be assessed prior to second randomization (start of treatment period) 1. Serum potassium ≤ 4.8 mmol / L measured by a local or central laboratory within 7 days prior to randomization through the treatment period 2. eGFR (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) ≥ 20 mL / min / 1.73 m2 measured by a local or central laboratory within 7 days prior to randomization through the treatment period.

[0066] Exclusion criteria 1. Treatment with aldosterone-mediated inhibitors (e.g., mineralocorticoid receptor antagonists such as spironolactone) or taking other potassium-sparing diuretics (e.g., amiloride) within 7 days prior to initial randomization or planned during the study treatment phase. 2. Treatment with other renin angiotensin aldosterone system (RAAS) interventions (apart from either ACEi or ARB) within 4 weeks prior to Visit 1 and scheduled through screening or during the study. Patients who must or wish to continue taking restricted medications or any medications considered that may interfere with the safe conduct of the study will also be excluded. 3. History of type 1 diabetes or other autoimmune diabetes (e.g. LADA) 4. Patients who are at high risk for ketoacidosis in the opinion of the investigator. 5.Currently receiving or scheduled to start an SGLT2 or SGLT1 / 2 inhibitor during the study. 6. Use of biotin (vitamin B7, vitamin H, or coenzyme R) at a dose ≥ 5 mg / day (including dietary supplements) within 72 hours of Visit 1 or scheduled during the study. 7. Absolute cortisol level <18 μg / dL (496.6 nmol / L) 30 minutes (± 5 minutes) after injection of ACTH at Visit 1, measured by local or central laboratory. 8. Known history of severe symptomatic orthostatic dysregulation as determined by the investigator prior to initial randomization. 3 9. Patients with intermittent or persistent second or third degree atrioventricular block, sinus node dysfunction, or clinically significant bradycardia or sinus arrest not treated with a pacemaker

[0067] 10. Serum cortisol < 5 μg / dL (138.0 nmol / L) at Visit 1 or through first randomization or any clinically relevant abnormal laboratory value that, in the investigator's judgment, places the patient at further risk. 11. Any immunosuppressive or immunotherapy in the last 3 months prior to Visit 1. This includes systemic steroids except for oral prednisolone ≤ 10 mg or equivalent. 12. Acute kidney injury (AKI) as defined by Kidney Disease: Improving Global Outcomes (KDIGO) in the 30 days prior to Visit 1 or by initial randomization. 13. End stage renal disease, maintenance dialysis, functioning kidney transplant at Visit 1 or prior to first randomization; scheduled kidney transplant or chronic renal replacement therapy during the study. 14. Patients with heart failure, NYHA III / IV or coronary heart disease not compensated for by medical treatment.

[0068] 15. Active infection with SARS-CoV-2 between Visit 1 and initial randomization, or a positive acute infection-confirmed test within 4 weeks prior to Visit 1. 16. Any documented active or suspected malignancy at screening or history of confirmed malignancy within 2 years prior to Visit 1 (excluding adequately treated basal cell carcinoma of the skin, cervical cancer in situ, and low-grade [T1 or T2] prostate cancer), or treatment for cancer within 2 years prior to Visit 1. 17. Major surgery scheduled during the study (investigator's discretion) 18. History of clinically relevant allergies / hypersensitivities that would prevent study participation, including allergies to the investigational product / placebo / tetracosactide (injectable for ACTH studies) or any of their excipients (e.g., lactose monohydrate). 19. Any other medical condition that, in the opinion of the Investigator, may expose the patient to a safety risk or interfere with the objectives of the study.

[0069] 20. Previous randomization during this study. 21.Currently enrolled in another investigational device or investigational drug trial, or less than 30 days or 5 half-lives (whichever is longer) since completing another investigational device or investigational drug trial or receiving any other investigational treatment until Visit 1. 22. Chronic alcohol or drug abuse, or any condition that, in the opinion of the Investigator, makes the study participant unreliable or less likely to complete the study. 23. Females who are pregnant, breastfeeding or planning to become pregnant during the study.

[0070] Discontinuing Patient Treatment Patients may discontinue study treatment or withdraw consent to participate in the study altogether ("Withdrawal of Consent") if there would be a materially different impact as described below. Every effort should be made to keep patients in the study if operationally feasible. Measures to control withdrawal rates include careful patient selection, adequate explanation of study requirements and procedures prior to study enrolment, and explanation of the consequences of withdrawal. The decision to discontinue study treatment or withdraw consent to participate in the study and the reasons for it must be documented in the patient's file and CRF. Consider adverse event collection reporting requirements, if applicable.

[0071] Discontinuation of study treatment Permanent Discontinuation An individual patient will permanently discontinue all randomized study treatment if: 1. The patient develops acute kidney injury based on clinical judgment by the investigator and / or according to the Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group; KIDGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012; 2(1); 1-138. 2. The patient experiences a decline in eGFR: ≥ 30% during the treatment period and within 1 week of treatment initiation; and / or ≥ 40% at any time point after the start of the treatment period. 3. The patient progresses to end-stage renal disease as defined by either declining renal function below eGFR <15 mL / min / 1.73 m2 and / or the need for renal replacement therapy via kidney transplant or dialysis. 4. The patient wishes to discontinue study treatment. The patient will be asked to explain the reason but has the right to refuse to respond. 5. The patient has repeatedly demonstrated non-compliance with critical study procedures and, in the opinion of both the investigator and sponsor personnel, the patient's safety cannot be assured because the patient is unwilling or unable to comply with future study requirements. 6. The patient needs to take concomitant medications that are not permitted. However, if the patient needs a dose modification and only stable doses are permitted, discontinuation is not automatically required. In this case, the sponsor should be consulted. 7. The patient is no longer able to undergo study treatment for medical reasons such as surgery, severe or severe drug-induced liver injury attributable to the study drug, other adverse events, or other illness. 8. Patient requires treatment for cancer. Some exclusions apply for basal cell carcinoma, for example. Discuss with sponsor. 9. A female patient becomes pregnant. The patient will be followed up until birth or otherwise completion of the pregnancy.

[0072] Individual patients will permanently discontinue AS inhibitor / placebo if: 1. Patient's serum potassium is measured by a central or any local laboratory to be ≥ 6.0 mmol / L, or ≥ 5.6 mmol / L if tapering is deemed inappropriate. 2. The patient develops Cushing's syndrome, adrenal insufficiency (including cortisol levels <18 μg / dL 30 minutes (± 5 minutes) after ACTH application) or the patient's cortisol levels are <3 μg / dL (82.8 nmol / L) at any time during the study. The patient should be followed according to local guidelines until resolution of the event and the event should be reported to the sponsor. Individual patients will permanently discontinue empagliflozin / placebo if: 1. Ketoacidosis is suspected. 2. Fournier's necrosis is suspected. In these cases, if one of the study medications (either empagliflozin / placebo or AS inhibitor / placebo) is permanently discontinued, the patient may continue treatment with the other study medication.

[0073] Treatment discontinued All randomized study medication must be discontinued if: Severe SARS-COV-2 infection Empagliflozin / placebo must be discontinued if: · Merged UTI Symptomatic volume depletion The AS inhibitor / placebo must be discontinued if: Serum potassium ≥ 5.6mmol / L Serum potassium ≥ 5 mmol / L, if the patient is unable or unwilling to return to the study site In these cases, study treatment may be resumed upon recovery if medically justified.

[0074] Non-Limiting Embodiments of the Invention What is claimed: Embodiment 1. A method of treating diabetic and non-diabetic chronic kidney disease (CKD), comprising administering to a patient in need thereof a pharma- ceutical effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof.

[0075] [ka] I (In the formula, Cy is C 3-10 a mono- or bicyclic ring system selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Said C3-10 Each of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be selected from the group consisting of halogen, -C 1-3 Alkyl, -OC 1-3 Alkyl, -CF 3 , cyano, oxo, -N(C 1-3 Alkyl) 2 , -NH(C 1-3 alkyl), -NHCOC 1-3 Alkyl, -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, Hydroxy C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl or heteroaryl; R 1 and R 2 is H, C 1-3 Alkyl, Hydroxy C 1-3 Alkyl, -CH 2 NHC(O)OC 1-4 Alkyl, -CH 2 O.C.(O)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, -C(O)H, -COOH, -C(O)NHC 1-4 Alkyl and C(O)N(C 1-4 Alkyl) 2 or R 1 and R 2 Let's get together and 3-6 Cycloalkyl or C 3-6 forming a heterocyclyl)

[0076] Embodiment 2. Cy is a phenyl, cyclohexyl, indanyl, 2,3-dihydrobenzofuranyl or tetrahydroquinolinyl group, each of which is selected from the group consisting of -Cl, -F, -C 1-3 optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, oxo and CN; R 1 and R 2 H, C 1-3 Alkyl, Hydroxy C 1-3 Alkyl, -CH 2 NHC(O)OC1-4 Alkyl, -C(O)N(C 1-4 Alkyl) 2 and -CH 2 O.C.(O)C 1-4 independently selected from alkyl, The method of embodiment 1.

[0077] Embodiment 3. Cy is -Cl, -F, -C 1-3 phenyl optionally substituted with 1, 2 or 3 substituents independently selected from alkyl and CN; The method of embodiment 1. Embodiment 4. Cy is substituted with CN and is selected from Cl, -F and C 1-3 phenyl, optionally substituted with 1 or 2 additional groups independently selected from alkyl; R 1 Ga-CH 3 and R 2 Ga-CH 3 or -CH 2 OH The method of embodiment 1.

[0078] Embodiment 5.R 2 Ga-CH 2 OH The method of embodiment 4. Embodiment 6.R 2 Ga-CH 3 is The method of embodiment 4. Embodiment 7. The method of embodiment 1, wherein the compound of formula (I) is selected from the group consisting of compounds 1-46, or a pharma- ceutically acceptable salt thereof. Embodiment 8. The method of embodiment 7, wherein the compound of formula (I) is selected from the group consisting of compound numbers 1-11, 13, 15, 18, 19, 22, 23, 26, 28, 29A, 29B, 30-33, 35, 39, 41, 42, 45 and 46. Embodiment 9. The method of embodiment 7, wherein the compound of formula (I) is:

[0079] [ka] Embodiment 10 The method of embodiment 7, wherein the compound of formula (I) is:

[0080] [ka] Embodiment 11 The method of embodiment 7, wherein the compound of formula (I) is:

[0081] [ka] Embodiment 12 The method of embodiment 7, wherein the compound of formula (I) is:

[0082] [ka] Embodiment 13 The method of embodiment 7, wherein the compound of formula (I) is:

[0083] [ka] Embodiment 14 The method of embodiment 7, wherein the compound of formula (I) is:

[0084] [ka] Embodiment 15 The method of embodiment 7, wherein the compound of formula (I) is:

[0085] [ka] Embodiment 16 The method of embodiment 7, wherein the compound of formula (I) is:

[0086] [ka] Embodiment 17 The method of embodiment 7, wherein the compound of formula (I) is:

[0087] [ka] Embodiment 18 The method of embodiment 7, wherein the compound of formula (I) is:

[0088] [ka] Embodiment 19. The method according to any one of embodiments 1 to 18, wherein the disease is diabetic chronic kidney disease.

[0089] Embodiment 20. The method according to any one of embodiments 1 to 18, wherein the disease is non-diabetic chronic kidney disease. Embodiment 21. The method according to any one of embodiments 1-20, wherein the patient has stage 1 CKD, or stage 2 CKD, or stage 3 CKD, or stage 4 CKD, or stage 5 CKD. Embodiment 22. The method according to any one of embodiments 1 to 21, further comprising administering to the patient a pharma- ceutical effective amount of an SGLT2 inhibitor or a pharma- ceutical acceptable salt thereof. Embodiment 23. A method according to any one of embodiments 1 to 22, wherein the SGLT2 inhibitor is empagliflozin. Embodiment 24. A method according to any one of embodiments 1 to 23, wherein the AS inhibitor is administered in a daily dose of 0.1 to 100 mg, or 0.1 to 30 mg, or 1 mg to 25 mg, or 3 mg to 20 mg.

[0090] Embodiment 25. A method according to any one of embodiments 1 to 24, wherein the AS inhibitor is administered in a daily dose of 3 mg, or 10 mg, or 20 mg. Embodiment 26. The method according to embodiment 23, wherein empagliflozin is administered in a daily dose of 10 mg or 25 mg. Embodiment 27. The method according to embodiment 30, wherein empagliflozin is administered in a daily dose of 10 mg. Embodiment 28. The method according to embodiment 23, wherein the aldosterone synthase inhibitor is administered in an amount of 3 mg, or 10 mg, or 20 mg once per day, and empagliflozin is administered in an amount of 10 mg once per day. Embodiment 29. A method for treating diabetic and non-diabetic chronic kidney disease comprising administering to a patient in need thereof a pharmaceutical composition comprising a pharma- ceutical effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable excipient or carrier.

[0091] [ka] I (In the formula, Cy is C 3-10 a mono- or bicyclic ring system selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Said C 3-10 Each of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be selected from the group consisting of halogen, -C 1-3 -Alkyl, -OC 1-3 -Alkyl, -CF 3 , cyano, oxo, -N(C 1-3 -alkyl) 2 , -NH(C 1-3 -alkyl), -NHCOC 1-3 -Alkyl, -C(O)C 1-3 -Alkyl, -C(O)OC 1-3 Alkyl, Hydroxy C 1-3 optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, heteroaryl, R 1 and R 2 is H, C 1-3 Alkyl, Hydroxy C 1-3 Alkyl, -CH 2 NHC(O)OC 1-4 Alkyl, -CH 2 O.C.(O)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, -C(O)H, -COOH, -C(O)NHC 1-4 Alkyl and C(O)N(C 1-4 Alkyl) 2 or R 1 and R 2 Let's get together and3-6 Cycloalkyl or C 3-6 forming a heterocyclyl)

[0092] Embodiment 30. The method according to embodiment 29, further comprising administering to the patient a pharma- ceutically effective amount of a sodium glucose cotransporter-2 (SGLT2) inhibitor, or a pharma- ceutically acceptable salt thereof. Embodiment 31 The method according to embodiment 30, wherein the SGLT2 inhibitor is empagliflozin.

[0093] Embodiment 32. An aldosterone synthase inhibitor or a pharma- ceutically acceptable salt thereof, optionally in combination with a sodium glucose cotransporter-2 (SGLT2) inhibitor, for use in the treatment of diabetic and non-diabetic chronic kidney disease, wherein the aldosterone synthase compound is a compound of formula (I).

[0094] [ka] I (In the formula, Cy is C 3-10 a mono- or bicyclic ring system selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Said C 3-10 Each of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be selected from the group consisting of halogen, -C 1-3 -Alkyl, -OC 1-3 -Alkyl, -CF 3 , cyano, oxo, -N(C 1-3 -alkyl) 2 , -NH(C 1-3 -alkyl), -NHCOC 1-3 -Alkyl, -C(O)C 1-3 -Alkyl, -C(O)OC 1-3 Alkyl, Hydroxy C 1-3 optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, heteroaryl, R 1 and R2 is H, C 1-3 Alkyl, Hydroxy C 1-3 Alkyl, -CH 2 NHC(O)OC 1-4 Alkyl, -CH 2 O.C.(O)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, -C(O)H, -COOH, -C(O)NHC 1-4 Alkyl and C(O)N(C 1-4 Alkyl) 2 or R 1 and R 2 Let's get together and 3-6 Cycloalkyl or C 3-6 forming a heterocyclyl)

Claims

1. A pharmaceutical composition for treating chronic kidney disease (CKD) in a patient having CKD, said pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. I (In the formula, Cy is C 3-10 a monocyclic or bicyclic ring system selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Said C 3-10 Each of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be selected from the group consisting of halogen, —C 1-3 Alkyl, —OC 1-3 Alkyl, —CF 3 , cyano, oxo, -N(C 1-3 alkyl) 2 , —NH(C 1-3 alkyl), -NHCOC 1-3 Alkyl, —C(O)C 1-3 Alkyl, —C(O)OC 1-3 Alkyl, hydroxy C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl or heteroaryl; R 1 and R 2 is H, C 1-3 Alkyl, hydroxy C 1-3 Alkyl, —CH 2 NHC(O)OC 1-4 Alkyl, —CH 2 O.C. (O.C.) 1-4 Alkyl, —C(O)OC 1-4 Alkyl, —C(O)H, —COOH, —C(O)NHC 1-4 Alkyl and C(O)N(C 1-4 alkyl) 2 or R 1 and R 2 Let's get together and C 3-6 Cycloalkyl or C 3-6 forming a heterocyclyl)

2. Cy is a phenyl, cyclohexyl, indanyl, 2,3-dihydrobenzofuranyl, or tetrahydroquinolinyl group, each of which is —Cl, —F, or —C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, oxo, and CN; R 1 and R 2 H, C 1-3 Alkyl, hydroxy C 1-3 Alkyl, —CH 2 NHC(O)OC 1-4 Alkyl, —C(O)N(C 1-4 alkyl) 2 and -CH 2 O.C. (O.C.) 1-4 independently selected from alkyl, The pharmaceutical composition of claim 1.

3. Cy is substituted with CN, and Cl, —F and C 1-3 phenyl, optionally substituted with one or two additional groups independently selected from alkyl; R 1 Ga-CH 3 and R 2 Ga-CH 3 or -CH 2 It is OH The pharmaceutical composition of claim 1.

4. 2. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

5. The compound of formula (I): The pharmaceutical composition of claim 1, wherein 6. The pharmaceutical composition of claim 5, comprising a compound of the following formula in an amount of 3 mg, 10 mg or 20 mg:

7. The pharmaceutical composition according to claim 1 or 5, wherein the disease is diabetic chronic kidney disease.

8. The pharmaceutical composition according to claim 1 or 5, wherein the disease is non-diabetic chronic kidney disease.

9. 10. The pharmaceutical composition of claim 1, wherein the patient has stage 1 CKD, or stage 2 CKD, or stage 3 CKD, or stage 4 CKD, or stage 5 CKD.

10. The pharmaceutical composition of claim 1, wherein the patient has an eGFR of ≥ 30 and < 90 mL / min / 1.73 m 2 .

11. A pharmaceutical composition according to claim 1 or 5, further comprising an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof.

12. 12. The pharmaceutical composition of claim 11, wherein the SGLT2 inhibitor is empagliflozin.

13. The pharmaceutical composition of claim 12, comprising 10 mg of empagliflozin.

14. The pharmaceutical composition of claim 1 for use in combination with an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition of claim 14, comprising a compound of the following formula in an amount of 3 mg, 10 mg, or 20 mg:

16. The pharmaceutical composition described in claim 14, wherein the SGLT2 inhibitor is empagliflozin.

17. The pharmaceutical composition described in claim 15, wherein the SGLT2 inhibitor is 10 mg of empagliflozin.

18. The pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable excipient, carrier, or adjuvant.

19. Use of an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof, optionally in combination with a sodium glucose cotransporter-2 (SGLT2) inhibitor, for the manufacture of a medicament for treating or preventing chronic kidney disease (CKD) in a patient with CKD, wherein the aldosterone synthase inhibitor is a compound of formula (I). I (In the formula, Cy is C 3-10 a monocyclic or bicyclic ring system selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Said C 3-10 Each of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be selected from the group consisting of halogen, —C 1-3 -alkyl, -OC 1-3 -Alkyl, -CF 3 , cyano, oxo, -N(C 1-3 -alkyl) 2 , —NH(C 1-3 -alkyl), -NHCOC 1-3 -alkyl, -C(O)C 1-3 -Alkyl, -C(O)OC 1-3 Alkyl, hydroxy C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, or heteroaryl; R 1 and R 2 is H, C 1-3 Alkyl, hydroxy C 1-3 Alkyl, —CH 2 NHC(O)OC 1-4 Alkyl, —CH 2 O.C. (O.C.) 1-4 Alkyl, —C(O)OC 1-4 Alkyl, —C(O)H, —COOH, —C(O)NHC 1-4 Alkyl and C(O)N(C 1-4 alkyl) 2 or R 1 and R 2 Let's get together and C 3-6 Cycloalkyl or C 3-6 forming a heterocyclyl) 20. Cy is a phenyl, cyclohexyl, indanyl, 2,3-dihydrobenzofuranyl, or tetrahydroquinolinyl group, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from —Cl, —F, C 1-3 alkyl, oxo, and CN; R 1 and R 2 are independently selected from H, C 1-3 alkyl, hydroxyC 1-3 alkyl, —CH 2 NHC(O)OC 1-4 alkyl, —C(O)N(C 1-4 alkyl) 2 and —CH 2 OC(O)C 1-4 alkyl; 20. The use according to claim 19.

21. Cy is phenyl substituted with CN and optionally substituted with one or two additional groups independently selected from Cl, —F, and C 1-3 alkyl; R 1 is —CH 3 , R 2 is —CH 3 or —CH 2 OH 20. The use according to claim 19.

22. The use of claim 19, wherein the compound of formula (I) is selected from the group consisting of:

23. The compound of formula (I):

20. The use according to claim 19, wherein

24. A compound of the following formula:

24. The use according to claim 23, wherein said compound is used once daily in an amount of 3 mg, 10 mg or 20 mg.

25. The use described in claim 19 or 23, wherein the disease is diabetic chronic kidney disease.

26. The use described in claim 19 or 23, wherein the disease is non-diabetic chronic kidney disease.

27. ​​The use of claim 19, wherein the patient has stage 1 CKD, stage 2 CKD, stage 3 CKD, stage 4 CKD, or stage 5 CKD.

28. The use of claim 19, wherein the patient has an eGFR >= 30 and < 90 mL / min / 1.73 m2.

29. The use according to claim 19, wherein an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof is used in combination with an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof.

30. The use described in claim 19 or 29, wherein the SGLT2 inhibitor is empagliflozin.

31. The use of claim 30, wherein empagliflozin is used once a day in an amount of 10 mg.

32. A pharmaceutical composition comprising a compound of the following formula or a pharmaceutically acceptable salt thereof and empagliflozin: The pharmaceutical composition may further comprise a pharmaceutically acceptable excipient, carrier, or adjuvant.

33. The pharmaceutical composition of claim 32, comprising 3 mg, 10 mg, or 20 mg of a compound of the following formula and 10 mg of empagliflozin:

34. A product comprising a compound of the following formula or a pharmaceutically acceptable salt thereof and empagliflozin: The product may further comprise a pharmaceutically acceptable excipient, carrier or adjuvant.

35. The product of claim 34, comprising 3 mg, 10 mg, or 20 mg of a compound of the following formula and 10 mg of empagliflozin:

Images