TRPC6 inhibitors for treatment of focal segmental glomerulosclerosis

Abstract

Disclosed are methods for treating focal segmental glomerulosclerosis (FSGS) comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula (I) wherein R1 to R7, A, L, and Y are as defined herein. Also disclosed are pharmaceutical compositions comprising the compounds of formula (I) and their use for the treatment of FSGS.

Description

Technical Field

[0001] This invention relates to an inhibitor of transient receptor potential C6 ion channel (TRPC6) for the treatment of patients with focal segmental glomerulosclerosis (FSGS).

[0002] Existing technology In the United States, focal segmental glomerulosclerosis (FSGS) is the leading glomerular cause of end-stage renal disease (ESKD). FSGS refers to a histological pattern characterized by potentially different underlying etiologies, but sharing the common features of podocyte damage and depletion. See Rosenberg AZ and Kopp JB, “Focal segmentalglomerulosclerosis” Clin J Am Soc Nephrol 2017;12(3):502-517.

[0003] Unlike a specific disease, FSGS is characterized by histological abnormalities. FSGS is a pathophysiological entity that typically explains the onset of nephrotic syndrome in adults or pediatric patients. Assessed by microscopic examination of kidney biopsy, the histological abnormalities contain focal (some) segmental (partial) sclerosis of the glomeruli.

[0004] FSGS is a common histopathological finding in adults with nephrotic syndrome, accounting for 35% of all cases in the United States and >50% in African Americans. See Haas M et al., “Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997”, Am J Kidney Dis 1997;30(5):621-631 and Kitiyakara C et al., “Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States”, Am J Kidney Dis 2004;44(5):815-825.

[0005] As defined below, FSGS are classified into specific categories based on various etiologies: Primary (idiopathic) FSGS: often expressed as nephrotic syndrome.

[0006] Secondary FSGS (sFSGS), also known as adaptive FSGS, typically presents as non-nephrotic proteinuria and is usually accompanied by some degree of renal impairment. This category is a common adaptive response to conditions characterized by hyperfiltration or glomerular hypertrophy and renal vasodilation and / or reduced kidney mass (e.g., unilateral renal hypoplasia). Other causes of sFSGS include drug or toxin-induced pathologies (e.g., heroin, interferon, pamidronate) and viral-induced pathologies (especially HIV).

[0007] Hereditary (familial) FSGS: It usually manifests as parenchymal nephrotic syndrome and proteinuria in early childhood, or less severe proteinuria in adolescence or adulthood.

[0008] FSGS classification will depend on a variety of assessments, including clinical history, laboratory tests, renal biopsy, and, in some cases, genetic testing. While considerable progress has been made in the clinical understanding of FSGS, further research is needed to identify plasma factors considered to cause primary FSGS, assess the clinical applicability of routine genetic testing, and identify more effective and safer therapeutic interventions for FSGS. See Rosenberg AZ and Kopp JB, “Focal segmentalglomerulosclerosis”, Clin J Am Soc Nephrol 2017;12(3):502-517.

[0009] One potentially important mechanism associated with glomerular dysfunction in proteinuria is podocyte calcium overload. Increased podocyte foot process separation and loss have been observed in subjects with TRPC6 mutations due to disruption of the glomerular filtration barrier. (Jiang L et al., “Over-expressing transient receptor potential cation channel 6 in podocytes induces cytoskeleton rearrangement through increases of intracellular Ca2+ and RhoA activation”, Exp Biol Med (Maywood) 2011;236:184-193 and Tian D et al., “Antagonistic regulation of actin dynamics and cellmotility by TRPC5 and TRPC6 channels”, Sci Signal 2010;3(145):ra77). It is hypothesized that increased TRPC6 activity may be a major mechanism driving the progression of proteinuria-related kidney disease to ESKD. Therefore, using TRPC6 inhibitors to restrict TRPC6 channel activity in the presence of pathological Ca2+ intrusion could be a novel therapeutic option that should preserve podocyte function while reducing podocyte loss.

[0010] FSGS is one of the most common forms of acquired glomerular disease leading to ESKD and is one of the most important causes of acquired chronic kidney disease in children and adults. (Kiffel J et al., “Focal segmental glomerulosclerosis and chronic kidney disease in pediatric patients,” AdvChronic Kidney Dis 2011;18(5):332-338). Based on the clear biological association between FSGS and TRPC6 gain-of-function mutations in this disease, and the mechanism of TRPC6 inhibition, it is expected that treatment with TRPC6 inhibitors can reduce proteinuria in FSGS, thereby reducing disease burden and potential progression.

[0011] TRPC6 is expressed in several kidney cell types, including podocytes, which are key cells for glomerular filtration function. Multiple gain-of-function mutations in TRPC6 have been shown to cause FSGS by increasing intracellular calcium concentration in podocytes and inducing cytoskeletal rearrangement. This is associated with podocyte apoptosis, foot process separation, and podocyte loss, leading to disruption of the glomerular filtration barrier. Therefore, regulation of TRPC6 activity should have the potential to improve podocyte function and survival in proteinuric glomerular diseases, particularly FSGS. Summary of the Invention

[0012] In one embodiment (Embodiment 1), the present invention relates to a method for reducing proteinuria and / or maintaining renal function in a patient with focal segmental glomerulosclerosis (FSGS), comprising administering to the patient in need a pharmaceutically effective amount of a compound of formula (I). (I) in L is absent or is methylene or ethylene; Y is either CH or N; A is CH or N; R 1 Choose from the following groups: C can be substituted by one to three groups independently selected from the following groups. 1-6 Alkyl group: halogenated group, C 3-6 cycloalkyl and OC 3-6 cycloalkyl; Phenyl groups optionally substituted with one to three groups independently selected from the following groups: CF3, halogen, C 3-6 cycloalkyl, OC 3-6 cycloalkyl and OC 1-6 Alkyl; wherein the OC 1-6 Alkyl groups may be optionally substituted with one to three halogen groups; and C can be substituted by one to three groups independently selected from the following groups. 3-6 Cycloalkyl: halogenated groups and C groups optionally substituted with 1 to 3 halogenated groups 1-6 alkyl; R 2 Choose from the following groups: H, C 1-6 Alkyl, OCF3, C 3-6 cycloalkyl, OC 1-6 Alkyl and OC 3-6 cycloalkyl; R 3 Choose from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl and OC 3-6cycloalkyl; wherein the R 3 The C of the group 1-6 Alkyl, C 3-6 cycloalkyl or OC 3-6 Each of the cycloalkyl groups may be independently substituted by one to three groups, each independently selected from the group consisting of: halogen, OH, OC. 1-6 Alkyl, SC 1-6 Alkyl and N(C) 1-6 alkyl)2; and wherein the R 3 The C of the group 1-6 One to three carbon atoms of an alkyl group may be optionally partially substituted by one or two groups selected from the following: NH, N(C 1-6 Alkyl groups), O, and S; R 4 and R 5 Each independently chooses H and C. 1-6 Groups composed of alkyl groups; or R 3 and R 4 Together with the atoms they are attached to, they can connect to form a 3-membered carbon ring; or R 3 and R 5 Together with the atoms to which it is attached, it can be linked to form 3- to 9-membered bicyclic rings, wherein the 3- to 9-membered bicyclic rings may optionally contain one to three heteroatoms selected from the groups of N, O and S; R 6 Choose from the following groups: H, C 1-6 Alkyl, CN, CF3, OCF3, C 3-6 cycloalkyl, OC 1-6 Alkyl and OC 3-6 cycloalkyl; R 7 Choose freely between H and OC 1-6 Groups composed of alkyl groups; Or its pharmaceutically acceptable salt.

[0013] In another embodiment (Embodiment Two), the present invention relates to a method as described in Embodiment One, wherein R 1 Choose from the following groups: C can be substituted by one to three groups independently selected from the following groups. 1-6 Alkyl groups: halogens and C 3-6 cycloalkyl; Phenyl groups optionally substituted with one to three groups independently selected from the following groups: CF3, halogen, OC. 3-6 cycloalkyl and OC 1-6 Alkyl; wherein the OC 1-6Alkyl groups may be optionally substituted with one to three halogen groups; and C10 ... 3-6 cycloalkyl; R 2 For OC 1-6 alkyl; R 3 Choose from the following groups: H and any group consisting of OH or OC. 1-6 Alkyl-substituted C 1-6 alkyl, R 4 For H; R 5 For H; or R 3 and R 4 Together with the atoms they are attached to, they can connect to form a 3-membered carbon ring; or R 3 and R 5 Together with the atoms they are attached to, they can be linked to form 3- to 9-membered bicyclic rings, wherein the 3- to 9-membered bicyclic rings may optionally contain one to three heteroatoms selected from the groups of N and O; R 6 Choose from the following groups: H, C 1-6 Alkyl, OC 1-6 Alkyl and OC 3-6 cycloalkyl; and R 7 Choose freely between H and OC 1-6 Groups composed of alkyl groups; Or its pharmaceutically acceptable salt.

[0014] In another embodiment (Embodiment Three), the present invention relates to the method according to Embodiment One, wherein A is CH and Y is N; or A is CH and Y is CH; or A is N and Y is CH; Or its pharmaceutically acceptable salt.

[0015] In another embodiment (Embodiment Four), the present invention relates to the method according to Embodiment One, wherein R 1 A phenyl group that is optionally substituted with a group belonging to the following groups: CF3, halogen, OC. 3-6 cycloalkyl and OC 1-6 Alkyl; wherein the OC 1-6 Alkyl groups may be optionally substituted with one to three halogen groups; R 2 For OC 1-6 alkyl; R 3Choose from the following groups: H and any group consisting of OH or OC. 1-6 Alkyl-substituted C 1-6 alkyl; R 4 For H; R 5 For H; or R 3 and R 4 It can connect with the atoms it is attached to to form a 3-membered carbon ring, or R 3 and R 5 Together with the atoms they are attached to, they can be linked to form 3- to 9-membered bicyclic rings, wherein the 3- to 9-membered bicyclic rings may optionally contain one to three heteroatoms selected from the groups of N and O; R 6 Choose from the following groups: H, C 1-6 Alkyl, OC 1-6 Alkyl and OC 3-6 cycloalkyl; R 7 Choose freely between H and OC 1-6 Groups composed of alkyl groups; Or its pharmaceutically acceptable salt.

[0016] In another embodiment (Embodiment Five), the present invention relates to the method according to Embodiment One, wherein R 1 A phenyl group that is optionally substituted with a group selected from the group consisting of: CF3, OCF3, F, and methoxy; R 2 The group is selected from those composed of methoxy or ethoxy groups; R 3 The groups to be selected are H, C. 1-6 Alkyl, 2-hydroxymethyl, methoxymethyl, and 1-hydroxyethyl; R 4 For H; R 5 For H; or R 3 and R 5 Together with the atoms to which it is attached, it can be linked to form 3- to 9-membered bicyclic rings, wherein the 3- to 9-membered bicyclic rings may optionally contain one to three heteroatoms selected from the groups of N, O and S; R 6 The group selected is composed of: H, methyl, methoxy, ethoxy, propoxy, and cyclopropyloxy; and R 7 The group selected is composed of H and methoxy groups; Or its pharmaceutically acceptable salt.

[0017] In another embodiment (Embodiment Six), the present invention relates to the method according to Embodiment One, wherein R 1 Together with L, it represents a group selected from the group consisting of: phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-difluoromethoxyphenyl, 4-cyclopropyloxyphenyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, 2-fluorobenzyl, and phenylethyl; and R 2 It is methoxy or ethoxy; Or its pharmaceutically acceptable salt.

[0018] In another embodiment (Concept Seven), the present invention relates to the method according to Embodiment One, wherein Y is CH and A is N; R 1 Together with L, it represents a group selected from the following groups: phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-difluoromethoxyphenyl, 4-cyclopropoxyphenyl, benzyl, 2-fluorobenzyl, and phenylethyl; R 2 It is methoxy or ethoxy; R 3 R 4 and R 5 Each is H; R 6 It is H, methyl, methoxy, or ethoxy; and R 7 For H; Or its pharmaceutically acceptable salt.

[0019] In another embodiment (Embodiment Eight), the present invention relates to the method according to Embodiment One, wherein Y is CH and A is CH; R 1 Together with L, it represents a group selected from the following groups: phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, cyclopentyl, cyclohexyl, benzyl, 2-fluorobenzyl, and phenylethyl; R 2 It is methoxy or ethoxy; R 3 R 4 and R 5 Each is H; R 6 H, methyl, methoxy, or ethoxy; and R 7For H; Or its pharmaceutically acceptable salt.

[0020] In another embodiment (Concept Nine), the present invention relates to the method according to Embodiment One, wherein Y is N and A is CH; R 1 Together with L, it represents a group selected from the following groups: phenyl and 4-fluorophenyl; R 2 It is a methoxy group; R 3 The group consisting of H, 2-hydroxymethyl, and hydroxyethyl is selected. R 4 For H; R 5 For H; or R 3 and R 5 Together with the atoms to which it is attached, it can be linked to form 3- to 9-membered bicyclic rings, wherein the 3- to 9-membered bicyclic rings may optionally contain one to three heteroatoms selected from the groups of N, O and S; R 6 Choose from groups composed of H and methoxy groups; and R 7 For H; Or its pharmaceutically acceptable salt.

[0021] In another embodiment (Embodiment Ten), the present invention relates to the method according to Embodiment One, wherein R 1 C is a C that is optionally substituted by one to three groups independently selected from the group consisting of the following groups. 1-6 Alkyl groups: halogens and C 3-6 cycloalkyl; R 2 For OC 1-6 alkyl; R 3 R 4 and R 5 Each is H; R 6 Choose from the following groups: H, C 1-6 Alkyl and OC 1-6 Alkyl groups; and R 7 For H; Or its pharmaceutically acceptable salt.

[0022] In another embodiment (Embodiment Eleven), the present invention relates to the method according to Embodiment One, wherein R 1Together with L, it represents a group selected from the group consisting of: ethyl, propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 2,2-dimethylpropyl, 1-methylcyclopropylmethyl, 1-fluoromethylcyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclobutylmethyl, 3,3-difluorocyclobutylmethyl, 3-(trifluoromethyl)cyclobutylmethyl, and 3,3,3-trifluoro-2-methylpropyl; R 2 It is a methoxy group; R 3 R 4 and R 5 Each is H; R 6 Selected from the group consisting of H, methyl, and methoxy groups; and R 7 For H; Or its pharmaceutically acceptable salt.

[0023] In another embodiment (Embodiment Twelve), the present invention relates to the method according to Embodiment One, wherein Y is CH and A is N; R 1 Together with L, it represents a group selected from the following group: propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 2,2-dimethylpropyl, 1-cyclopropylethyl, and 2-cyclopropylethyl; R 2 It is a methoxy group; R 3 R 4 and R 5 Each is H; R 6 Selected from the group consisting of H, methyl, and methoxy groups; and R 7 For H; Or its pharmaceutically acceptable salt.

[0024] In another embodiment (Embodiment Thirteen), the present invention relates to the method according to Embodiment One, wherein Y is CH and A is CH; R 1 Together with L, it represents a group selected from the group consisting of: ethyl, propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 2,2-dimethylpropyl, 1-methylcyclopropylmethyl, 1-fluoromethylcyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclobutylmethyl, 3,3-difluorocyclobutylmethyl, 3-(trifluoromethyl)cyclobutylmethyl, and 3,3,3-trifluoro-2-methylpropyl; R2 It is a methoxy group; R 3 R 4 and R 5 Each is H; R 6 Selected from the group consisting of H, methyl, and methoxy groups; and R 7 For H; Or its pharmaceutically acceptable salt.

[0025] In another embodiment (Embodiment Fourteen), the present invention relates to the method according to Embodiment One, wherein R 3 and R 5 Together with the atoms they are attached to, they form 3- to 9-membered bicyclic rings, wherein the 3- to 9-membered bicyclic rings may optionally contain one or two heteroatoms independently selected from the groups of N and O. Or its pharmaceutically acceptable salt.

[0026] Brief description of the attached figures Figure 1 The study design for a clinical trial demonstrating the use of the exemplary compound (compound 17) of the present invention for the treatment of FSGS is shown. Detailed Implementation

[0027] abbreviation: ACE angiotensin-converting enzyme AE adverse events AESI-related adverse events of particular concern AHR aryl hydrocarbon receptor ALT alanine aminotransferase ANOVA analysis of variance ARB angiotensin II receptor blockers AST aspartate aminotransferase Area under the AUC plasma concentration curve AUC 0-∞ The area under the plasma concentration curve from 0 to ∞ AUC t1-t2 The area under the plasma concentration curve from t1 to t2 AUC t1-t2,ss The area under the plasma concentration curve from t1 to t2 under steady-state conditions Boehringer Ingelheim (BI) BMI (Body Mass Index) CA authorities CAR constitutive androstane receptor CKD (Chronic Kidney Disease) CKD-EPI Chronic Kidney Disease Epidemiology Collaboration C max Maximum plasma concentration C max,ss Maximum plasma concentration under steady-state conditions C pre,ss Plasma concentration before administration under steady-state conditions C trough,ss trough plasma concentration under steady state COVID-19 (Coronavirus Disease 2019) CRA Clinical Research Specialist Contract Research Organization (CRO) CSA cyclosporine CT Manager Clinical Trial Manager CTL Clinical Trial Leader CYP3A4 cytochrome P450 3A4 DCT decentralized clinical trials Drug-Drug Interactions in DDI DEX Dexamethasone DILI-induced liver injury DMC Data Monitoring Committee EC Ethics Committee ECG (electrocardiogram) eCRF Electronic Medical Record Form EDC Electronic Data Acquisition eGFR (estimated glomerular filtration rate) The EoS study has ended (corresponding to the conclusion of the experiment). EoT treatment completed ES Input Sets ESKD (End-stage renal disease) EudraCT European Clinical Trials Database FAS Full Analysis Collection FDA (Food and Drug Administration) FSGS (focal segmental glomerulosclerosis) FUP1 Follow-up First Visit GCP Good Clinical Practice gCV geometric coefficient of variation GGTγ-glutamyltransferase GI gastrointestinal gMean Geometric Mean HA Health Authority HR heart rate IB Researchers' Handbook Intercurrent Event (ICE) ICF Informed Consent Form ICH International Coordinating Council IEC Independent Ethics Committee IgA Immunoglobulin A IRB Institutional Review Committee IRT Interactive Reaction Technology ISF Researcher Site Documentation DILI-induced liver injury DMC Data Monitoring Committee EC Ethics Committee ECG (electrocardiogram) eCRF Electronic Medical Record Form EDC Electronic Data Acquisition eGFR (estimated glomerular filtration rate) The EoS study has ended (corresponding to the conclusion of the experiment). EoT treatment completed ES Input Sets ESKD (End-stage renal disease) EudraCT European Clinical Trials Database FAS Full Analysis Collection FDA (Food and Drug Administration) FSGS (focal segmental glomerulosclerosis) FUP1 Follow-up First Visit GCP Good Clinical Practice gCV geometric coefficient of variation GGTγ-glutamyltransferase GI gastrointestinal gMean Geometric Mean HA Health Authority HR heart rate IB Researchers' Handbook Intercurrent Event (ICE) ICF Informed Consent Form ICH International Coordinating Council IEC Independent Ethics Committee IgA Immunoglobulin A IRB Institutional Review Committee IRT Interactive Reaction Technology ISF Researcher Site Documentation K-EDTA potassium ethylenediaminetetraacetate LOCS III Lens Opacity Classification System III The last patient in LPLT received their last treatment. MATE1 Multidrug and Toxin Extruder 1 MATE2 multidrug and toxin extrudate 2 MedDRA Medical Dictionary for Drug Regulatory Activities MMF Mycophenolate Mofetil MRN Mobile Research Nurse milliseconds mRNA messenger RNA NEPTUNE Nephrotic Syndrome Research Network NFAT activates T cell nuclear factors No adverse effects were observed with NOAEL. OCT2 organic cation transporter 2 P-gp glycoprotein penetration PD pharmacodynamics PE physical examination PK pharmacokinetics Oral administration (PO) qd once a day (once a day) The time between the start of the Q wave and the end of the T wave in a QT electrocardiogram QTc refers to the QT interval for heart rate correction. QTcF uses the Fridricia method to target the heart rate-corrected QT interval. RA regulators SAE Serious Adverse Events SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) Secondary focal segmental glomerulosclerosis (sFSGS) SGLT2 sodium-glucose cotransporter-2 Standard Operating Procedures (SOP) SULT sulfotransferase SUSAR suspected unforeseen serious adverse reaction TS Treatment Collection TRPC6 transient acceptor potential, cation subfamily C6 member. TSAP Trial Statistical Analysis Plan t 1 / 2 Terminal half-life of the analyte t max Time to reach maximum plasma concentration UACR (Urine Albumin-Cretin Ratio) UGT uridine diphosphate glucuronyl transferase ULN normal upper limit UNephCR urine nephropathy protein-creatinine ratio UPCR urine protein-creatinine ratio UPNR urine protein ratio in nephropathy UPodCR urine podoprotein creatinine ratio WOCBP Women of Childbearing Age As mentioned above, the present invention relates to a method for treating a patient with FSGS, comprising administering to the patient a pharmaceutically effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0028] The method of the present invention also relates to compounds of formula (I) as defined above, and therefore pharmaceutically acceptable salts for the treatment of patients with FSGS.

[0029] As used herein, the term "compound of the present invention" or "compound of the present invention" refers to any compound included in formula (I) as defined above and below in Table 1, and its pharmaceutically acceptable salts.

[0030] In one embodiment, the present invention relates to a method for reducing proteinuria in patients with FSGS, comprising administering to the patient a pharmaceutically effective amount of the compound of the present invention.

[0031] In another embodiment, the present invention relates to a method for reducing proteinuria in patients with FSGS, wherein the method reduces the patient’s 24-hour urinary protein-to-creatinine ratio (UPCR) by at least 25% relative to baseline at week 12.

[0032] In another embodiment, the present invention relates to a method for maintaining renal function in a patient with FSGS, comprising administering to the patient a pharmaceutically effective amount of the compound of the present invention.

[0033] In another embodiment, the present invention relates to a method for maintaining renal function in a patient with FSGS, wherein the method enables the patient to maintain an estimated glomerular filtration rate (eGFR). In another embodiment, the eGFR is based on serum cystatin C levels.

[0034] In another embodiment, the present invention relates to a method for reducing proteinuria and maintaining renal function in patients with FSGS, comprising administering to the patient a pharmaceutically effective amount of the compound of the present invention.

[0035] In one embodiment, the present invention relates to a compound of the present invention for treating a patient with FSGS.

[0036] In another embodiment, the present invention relates to a compound of the present invention for reducing proteinuria in patients with FSGS.

[0037] In another embodiment, the present invention relates to a compound of the present invention for reducing proteinuria in patients with FSGS, wherein the method reduces the 24-hour urinary protein-creatinine ratio (UPCR) of the patient at week 12 by at least 25% relative to baseline.

[0038] In another embodiment, the present invention relates to a compound for maintaining renal function in patients with FSGS. In another embodiment, renal function maintenance is defined as an improvement in eGFR in patients from the second visit (before the first dose) to week 12 and / or week 13, as determined by efficacy analysis using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula based on serum cystatin C.

[0039] In another embodiment, the present invention relates to a compound of the present invention for reducing proteinuria and maintaining renal function in patients with FSGS, comprising administering a pharmaceutically effective amount of the compound of the present invention to the patient.

[0040] Table 1 shows specific compounds of the present invention that can be used according to the method of the present invention.

[0041] Table 1. In one embodiment, the present invention relates to any of the methods described herein, wherein the compounds of the present invention are selected from any of compounds 1 to 95 depicted in Table 1 above and their pharmaceutically acceptable salts.

[0042] In another embodiment, the present invention relates to any of the methods described herein, wherein the compounds of the present invention are selected from any of the compounds 6, 16, 17, 33, 34, 40, 41, 44, 54, 57, 80, 83 and 88 depicted in Table 1 above, and their pharmaceutically acceptable salts.

[0043] In another embodiment, the present invention relates to any of the methods described herein, wherein the compounds of the present invention are selected from any of compounds 29, 31, 49, 56, 66, 85, 87 and 90 depicted in Table 1 above, and their pharmaceutically acceptable salts.

[0044] In another embodiment, the present invention relates to any of the methods described herein, wherein the compound of the invention is selected from the group consisting of: [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[5-(4-isopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone; [4-(6-amino-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methyl ketone; [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone; [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)pyridin-2-yl]-methyl ketone; [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[5-(4-chloro-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone; [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[5-(4-cyclopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone; [4-(6-amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-benzoxy)-4-methoxy-pyridin-2-yl]-methyl ketone; [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)pyridin-2-yl]-methyl ketone; [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[5-(4-difluoromethoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone; [4-(6-amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(2-fluoro-benzoxy)-4-methoxy-pyridin-2-yl]-methyl ketone; [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethoxy-phenoxy)pyridin-2-yl]-methyl ketone; [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[5-(phenoxy)-4-ethoxy-pyridin-2-yl]-methyl ketone; and [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-ethoxy-pyridin-2-yl]-methyl ketone; Or its pharmaceutically acceptable salt.

[0045] In another embodiment, the present invention relates to any of the methods described herein, wherein the compound of the invention is selected from the group consisting of: [4-(6-amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone, [4-(6-amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methyl ketone, [4-(6-amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone, [4-(6-amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2-yl]-methyl ketone, [4-(6-amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methyl ketone, [4-(6-amino-4-ethoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(phenoxy)-pyridin-2-yl]-methyl ketone, 5-Ethoxy-6-(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)pyridazine-3-amine, and 6-(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5-methylpyridazine-3-amine, Or its pharmaceutically acceptable salt.

[0046] In another embodiment, the invention relates to any of the methods described herein, wherein the compound of the invention is [4-(6-amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone (compound 17 depicted in Table 1); and a pharmaceutically acceptable salt thereof.

[0047] In another embodiment, the invention relates to any of the methods described herein, wherein the compound of the invention is 6-(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridin-2-carbonyl}piperidin-4-yl)-5-methylpyridazine-3-amine (compound 90 depicted in Table 1); and a pharmaceutically acceptable salt thereof.

[0048] The terms "treatment" and "treating" encompass therapeutic treatment of a patient who has developed one of the conditions described herein, particularly in an overt form. Therapeutic treatment can be symptomatic to alleviate symptoms of a specific indication, or etiological treatment to reverse or partially reverse the condition of an indication, or to halt or slow disease progression. Therefore, the compositions and methods of the present invention can be used, for example, as therapeutic treatments for a period of time and long-term treatment.

[0049] The TRPC6 inhibitor of the present invention can be prepared according to the method described in WO2019081637.

[0050] General definition Terms not specifically defined herein shall be given the meaning that a person skilled in the art would interpret based on the disclosure and context. However, unless otherwise stated, as used herein, the following terms shall have specified meanings and shall be subject to the following conventions.

[0051] In the definition of a group, radical, or part below, the number of carbon atoms is usually specified before the group name; for example, C1-6 alkyl refers to an alkyl group or alkyl radical having 1 to 6 carbon atoms. Typically, in groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, and F3C, those skilled in the art can identify the group junction point of the molecule from the group's free valence. For composite groups containing two or more daughter groups, the last named daughter group is the group junction point; for example, the substituent "aryl-C..." 1-3 "alkyl" refers to a compound with C 1-3 alkyl-bonded aryl group, the C 1-3 Alkyl groups are bonded to the core or to substituents.

[0052] In cases where compounds are described by their chemical names and chemical formulas, the chemical formula shall prevail in the event of any discrepancy.

[0053] As used herein, the term “substituted” means that any one or more hydrogen atoms on a specified atom are replaced by a group from which the indicated selection is made, provided that the substitution does not exceed the normal valence of the specified atom and that the substitution produces a stable compound.

[0054] Unless specifically instructed otherwise, throughout this specification and the appended claims, the given chemical formula or name will cover 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 proportions of individual enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers are present, and their salts (including pharmaceutically acceptable salts) and their solvates (such as hydrates), including solvates of the free compound or solvates of salts of the compound.

[0055] The phrase “pharmaceutically acceptable” in this article refers to compounds, materials, compositions, and / or dosage forms that are suitable for contact with human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that meet a reasonable benefit / risk ratio.

[0056] As used herein, “pharmaceutically acceptable salt” means a derivative of the disclosed compound in which the parent compound is modified by producing its acidic or basic salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues of amines; alkali metal or organic salts of acidic residues of carboxylic acids; and so on.

[0057] For example, such salts include acetates, ascorbic acid salts, benzenesulfonates, benzoates, besylates, bicarbonates, tartrates, bromides / hydrobromates, ethylenediaminetetraacetate, dextrorotatory camphor sulfonates, carbonates, chlorides / hydrochlorides, citrates, ethanedisulfonates, ethanedisulfonates, propionates, dodecyl sulfate, ethanesulfonates, fumarates, glucohepanoates, glucuronates, glutamates, glycolates, glycolamides, hexylresorcinol salts, hydrabamine, hydroxycis-butenedioic acid salts, hydroxynaphthylcarboxylate, iodides, isothiosulfates, lactates, lactobionates, malates, and maleic acid salts. Diasterates, mandelates, methanesulfonates, methyl bromide, methyl nitrates, methyl sulfates, mucates, naphthalenesulfonates, nitrates, oxalates, dihydroxynaphthalate, pantothenates, phenylacetate, phosphates / bisphosphonates, polygalacturonic acid salts, propionates, salicylates, stearates, hypoacetate, succinates, thioamides, sulfates, tannates, tartrates, teoclates, toluenesulfonates, triethyl iodide, trifluoroacetate, ammonium salts, benzathine, chloroprocaine, choline, diethanolamine salts, ethylenediamine salts, meglumine salts, and procaine. Other pharmaceutically acceptable salts may be formed from cations derived from metals such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and their analogues (see also Pharmaceutical Salts, Birge, SM et al., J. Pharm. Sci., (1977), 66, 1-19) or from cations derived from ammonia, L-arginine, calcium, 2,2'-iminodiethanol, L-lysine, magnesium, N-methyl-D-glucosamine, potassium, sodium and tris(hydroxymethyl)-aminomethane.

[0058] The term halogen generally refers to fluorine, chlorine, bromine, and iodine.

[0059] Term "C" 1-n "alkyl", where n is an integer selected from the group consisting of 2, 3, 4, 5 or 6, preferably 4 or 6, alone or in combination with another group, represents an acyclic, saturated, branched or straight-chain hydrocarbon group having 1 to n C atoms. For example, the term C 1-5Alkyl groups include: H3C, H3C CH2, H3C CH2CH2, H3CCH(CH3), H3CCH2CH2CH2, H3CCH2CH(CH3), H3CCH(CH3)CH2, H3CC(CH3)2, H3CCH2CH2CH2CH2, H3CCH2CH2CH(CH3), H3CCH2CH(CH3)CH2, H3CCH(CH3)CH2CH2, H3CCH2C(CH3)2, H3CC(CH3)2CH2, H3CCH(CH3)CH(CH3), and H3CCH2CH(CH2CH3).

[0060] The term "C" refers to integers from 4 to n. 3-n "Cycloalkyl" alone or in combination with another group refers to a cyclic, saturated, unbranched hydrocarbon group having 3 to n carbon atoms. For example, the term C 3-7 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0061] The term "halogen" added to "alkyl," "alkylene," or "cycloalkyl" (saturated or unsaturated) refers to an alkyl or cycloalkyl group in which one or more hydrogen atoms are replaced by a halogen atom selected from fluorine, chlorine, or bromine, preferably fluorine and chlorine, and especially preferably fluorine. Examples include: H2FC-, HF2C-, F3C-. Similarly, the term "halogen" added to an aryl group (e.g., phenyl) refers to one or more hydrogen atoms replaced by a halogen atom selected from fluorine, chlorine, or bromine, preferably fluorine and chlorine, and especially preferably fluorine.

[0062] The term "carbocyclic group," used alone or in combination with another group, refers to a monocyclic, bicyclic, or tricyclic structure consisting of 3 to 9 carbon atoms and heteroatoms optionally selected from the group consisting of N, O, and S. The term carbocyclic group refers to a fully saturated ring system and encompasses fused, bridged, and spirocyclic systems.

[0063] Many of the terms given above can be used repeatedly to define chemical formulas or groups, and in each case, each has one of the meanings given above independently.

[0064] Unless specifically indicated, throughout this specification and the accompanying claims, the given chemical formula or name will cover tautomers and all stereo, optical and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and their racemates, as well as mixtures of individual enantiomers in different proportions, mixtures of diastereomers, or mixtures containing any of the foregoing forms of such isomers and enantiomers, and their salts (including pharmaceutically acceptable salts) and their solvates (such as hydrates), including solvates of the free compound or solvates of salts of the compound.

[0065] Some of the compounds in Table 1 can exist in more than one tautomer form. This invention includes methods using all such tautomers.

[0066] Additionally, within the scope of this invention is the use of prodrugs of TRPC6 inhibitors in the treatment methods of this invention. Prodrugs include compounds that have been modified following a simple chemical transformation to produce the compounds of this invention. Simple chemical transformations include hydrolysis, oxidation, and reduction. In particular, when administered to a patient, the prodrug can be converted into the compounds disclosed above, thereby imparting the desired pharmacological action.

[0067] For all compounds disclosed above in this application, in the event of a conflict between nomenclature and structure, it should be understood that the compound is defined by its structure.

[0068] Dosage form and application Conventional dosage forms typically include a pharmaceutically acceptable carrier suitable for the chosen specific dosage form. Routes of administration include (but are not limited to) intravenous, intramuscular, subcutaneous, intrasynovial, infusion, sublingual, transdermal, oral, local, or inhalation. Preferred administration methods are oral and intravenous.

[0069] The compounds of the present invention can be administered alone or in combination with adjuvants and their analogues (including other active ingredients), wherein the adjuvants enhance the stability of the inhibitor, in some embodiments facilitate administration of the pharmaceutical composition containing the adjuvant, provide increased solubility or dispersion, increase inhibitory activity, and provide adjuvant therapy. For example, in one embodiment, multiple compounds of the present invention can be administered. Advantageously, such combination therapies use lower doses of conventional therapeutic agents, thus avoiding the potential toxicity and adverse side effects that may occur when these agents are used as monotherapy. The compounds of the present invention can be physically combined with conventional therapeutic agents or other adjuvants in a single pharmaceutical composition. Advantageously, the compounds can then be administered together in a single dosage form. In some embodiments, the pharmaceutical composition comprising such combinations of compounds contains at least about 5%, but more preferably at least about 20%, of the compounds of the present invention (w / w) or combinations thereof. The optimal percentage (w / w) of the compounds of the present invention can vary and is within the scope of those skilled in the art. Alternatively, the compounds of the present invention and conventional therapeutic agents or other adjuvants can be administered alone (continuously or simultaneously). Single administration allows for greater flexibility in dosing regimens.

[0070] As mentioned above, the dosage forms of the compounds of the present invention may include pharmaceutically acceptable carriers and adjuvants known to those skilled in the art and suitable for such dosage forms. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffers, water, salts or electrolytes, and cellulose-based substances. Preferred dosage forms include tablets, capsules, pouches, liquids, solutions, suspensions, emulsions, lozenges, syrups, reconstituteable 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 edition, Lea and Febbiger (1990)). The dosage content and requirements of the compounds of the present invention may be selected by those skilled in the art based on available methods and techniques suitable for a particular patient. In some embodiments, the dosage content for a 70 kg patient is in the range of about 1 to 1000 mg / dose. Although once-daily dosing may be sufficient, up to five doses per day may be given. For oral doses, up to 2000 mg / day may be required. As those skilled in the art will understand, lower or higher doses may be required depending on specific factors. For example, a particular dose and treatment regimen will depend on factors such as the patient's general health condition, the severity and duration of the patient's illness or its treatment, and the judgment of the treating physician.

[0071] The compounds of the present invention can be used alone or in combination with one or more additional therapeutic agents. Non-limiting examples of additional therapeutic agents may include: Adrenocorticotropic hormone (ACTH); Aldosterone inhibitors, such as those described in WO 2016 / 014736; Angiotensin-converting enzyme (ACE) inhibitors, such as cilazapril, enalapril, captopril, benazepril, or lisinopril; Antihypertensive agents, such as reserpine, hydralazine, or prazosin; Angiotensin II receptor blockers (ARBs): such as candastartan, irbesartan, or losartan; Calcineurin inhibitors (CNIs), such as cyclosporine tacrolimus; Calcium channel blockers or inhibitors, such as isradipine; CD20 monoclonal antibodies, such as rituximab; Corticosteroid therapy, such as prednisone or dexamethasone (including high-dose dexamethasone); Cytotoxic agents, such as cyclophosphamide or chlorambucil; Diuretics, such as furosemide; Immunosuppressants, such as mycophenolate mofetil (MMF), prednisolone, methylprednisolone, corticosteroids, cyclosporine, cyclosporine A, or adalimumab. Mineral corticosteroid receptor antagonists, such as finerenone; Renin-angiotensin-aldosterone system (RAAS) mediators / inhibitors; and SGLT2i, such as empagliflozin, dapagliflozin, or canagliflozin; Description of the design and experimental population The use of the compounds of the present invention for the treatment of FSGS can be demonstrated in the clinical trials described below.

[0072] The applicant found that a higher proportion of patients treated with TRPC6 inhibition using compound 17 showed a reduction in proteinuria of more than 25% from baseline compared to patients treated with placebo.

[0073] 1.1 Overall Experimental Design This multicenter, randomized, double-blind, parallel-group study will evaluate, compared with placebo, three doses of the TRPC6 inhibitor of the present invention administered orally once daily for 12 weeks in patients with primary or TRPC6 monogenic FSGS.

[0074] After completing all screening procedures, eligible patients will be randomly assigned to one of four stratified treatment groups using corticosteroids, with treatment lasting 12 weeks. Approximately 15 patients are planned to be randomly assigned to each treatment group. A follow-up visit will be conducted on day 7 after the end of treatment. A second follow-up visit will be scheduled by telephone 30 days after the end of treatment. An eye examination will be performed at the second follow-up visit. Figure 1 A schematic illustration of the experimental design is presented.

[0075] 1.2 Discussion of experimental design, including the selection of the control group. This study employs a randomized, double-blind, placebo-controlled design. In the early development phases of the study, the standard protocol was to use a placebo as a control group to assess efficacy, safety, and tolerability. This short-term primary clinical study will test a range of established standard care modalities, including conservative management and steroid-based immunosuppressive regimens.

[0076] Most FSGS studies on glomerular diseases use different measures of proteinuria, including UPCR. In this study, UPCR in 24-hour urine will be measured.

[0077] This study analyzed the reduction rates of UPCR achieved by cyclosporine A (CSA) and mycophenolate mofetil / dexamethasone (MMF / DEX) (tracked against baseline) in adults and children with steroid-resistant FSGS. (Gipson DS et al., “Clinical trial of focal segmental glomerulosclerosis in children and young adults”, Kidney Int 2011;80(8):868-878). At week 8, CSA and MMF / DEX reduced UPCR by approximately 65% ​​and 50%, respectively. Therefore, a 12-week course of treatment to identify UPCR reduction should be sufficient to demonstrate the efficacy in this study. Furthermore, efficacy will be further evaluated in this study by assessing UACR and 24-hour proteinuria as secondary endpoints.

[0078] 1.3 Selection of the experimental group This study will randomize approximately 60 patients with primary FSGS or those with TRPC6 mutations that cause FSGS. The study is planned to be conducted at approximately 55 sites in multiple countries. A sufficient number of patients will be screened to meet the randomization target.

[0079] Research sites in the selected countries will be able to integrate decentralized clinical trial (DCT) models, where research visits are conducted outside of dedicated healthcare or research facilities. This will allow patients to participate in trials remotely and complete the study in their own homes or residences. DCT models can be implemented in patients' homes via telemedicine, smartphone devices, and the deployment of mobile research nurses (MRNs). MRNs will visit patients at their homes and collaborate with the site's principal investigators and research staff to complete the trial procedures.

[0080] Sites participating in the DCT model will continue to recruit patients using traditional site-based methods, with patients attending at the designated time points specified in the protocol. Sites with DCT integration may also allow actively participating patients to switch to remote participation. Additional operational guidelines will be provided in a separate DCT Operations Manual. A copy of the Operations Manual will be available in the ISF.

[0081] Patient recruitment for this trial is competitive, meaning that once a sufficient number of patients have been screened, screening at all sites will cease simultaneously. Researchers will be notified that screening is complete, and no further screening of additional patients will be permitted. If patients already screened at this point meet the eligibility criteria, they may be allowed to proceed with randomization.

[0082] Records of all patients enrolled in the trial (i.e., those who have signed informed consent forms, including those who signed screening consent forms or provided non-written consent forms) will be retained in the ISF, regardless of whether the patients were treated with the investigational drug. If, in retrospect, it is discovered that a patient was incorrectly randomized (not meeting all inclusion criteria or one or more exclusion criteria), the sponsor or commissioning party should be contacted immediately. The decision to continue participation in the trial will be based on an individual benefit-risk assessment.

[0083] 1.3.1 Main diagnostic criteria for entering the trial The study will include patients with primary FSGS and patients with monogenic FSGS caused by TRPC6 mutations.

[0084] 1.3.2 Inclusion Criteria 1. Informed consent forms were signed and dated in accordance with ICH-GCP and local regulations before the study began.

[0085] 2. Male and female patients aged 18 to 75 years (inclusive) on the day they sign the informed consent form.

[0086] 3. Patients diagnosed with primary FSGS by biopsy or with a documented TRPC6 gene mutation causing FSGS prior to the screening visit.

[0087] 4. Based on the first morning urine sample during the screening period, UPCR ≥ 1000 mg / g.

[0088] 5. Patients treated with corticosteroids must maintain a stable dose for at least 4 weeks prior to the screening visit and are not scheduled to change the dose until the end of the trial treatment.

[0089] 6. Patients treated with ACE inhibitors, ARBs, finerenone, aldosterone inhibitors, or SGLT2 inhibitors should maintain a stable dose for at least 4 weeks prior to the screening visit and no dose change is planned until the end of the trial treatment.

[0090] 7. Body Mass Index (BMI) ≤ 40 kg / m² at the time of screening visit. 2 .

[0091] 8. Women of childbearing potential (WOCBP) 1 Individuals must be willing and able to use highly effective birth control methods according to ICH M3 (R2) that, when used consistently and appropriately, have a low annual failure rate of less than 1%. A list of contraceptive methods that meet these guidelines is provided in the informed consent form (ICF) and as described herein.

[0092] 1.3.3 Exclusion Criteria 1. Clinical or histological evidence of known monogenic (other than TRPC6 gene mutation) or secondary FSGS.

[0093] 2. Recorded cases of Alport syndrome, nail-patella syndrome, diabetic nephropathy, IgA-nephropathy, lupus nephritis, or monoclonal gamma globulinopathy (e.g., multiple myeloma).

[0094] 3. Genitourinary malformation, accompanied by cystic ureteral reflux or renal hypoplasia.

[0095] 4. History of organ transplantation or planned transplantation during the research process.

[0096] 5. Uncontrolled hypertension at the screening visit, defined as a mean resting systolic blood pressure >160 mmHg, calculated from the last two of three repeated seated blood pressure measurements. This may include patients with a documented history of white coat hypertension.

[0097] 6. Use a calcineurin inhibitor concurrently for 5 half-lives prior to the screening visit.

[0098] 7. Concomitant therapy with a cytotoxic agent (cyclophosphamide, chlorambucil) or a CD20 monoclonal antibody (e.g., rituximab) for five half-lives prior to the screening visit. Note: Other immunosuppressive therapies considered standard care may be used as long as the patient maintains a stable dose throughout the study.

[0099] 8. Treat with metformin or dofetilide (MATE1 or OCT2 substrates) for 5 half-lives prior to the screening visit; or dabigatran or digoxin (P-gp substrates with a narrow therapeutic window).

[0100] 9. Treat with a potent inhibitor or inducer of CYP3A for one week or five half-lives (whichever is longer) prior to the screening visit.

[0101] 10. Estimated glomerular filtration rate (eGFR) at the screening visit <30 mL / min / 1.73 m 2 (CKD-EPI formula based on serum creatinine and cystatin C).

[0102] 11. During screening visits, alanine aminotransferase (ALT) / aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN).

[0103] 12. Clinically significant laboratory abnormalities or medical conditions observed during screening visits, which researchers believe pose a safety risk to the patient or may interfere with the trial objectives (excluding deviations in renal function tests or clinical laboratory values ​​related to FSGS).

[0104] 13. At the screening visit, the QTc interval (QTcF) is greater than 450 ms for men or greater than 470 ms for women, or any other clinically relevant ECG result (at the researcher's discretion).

[0105] 14. History of congenital long QT syndrome, previous drug-induced QT prolongation or other risk factors for torsade depointes (e.g., hypokalemia, bradycardia, heart failure).

[0106] 15. Cataract grade Detected by LOCS III during slit-lamp ophthalmology at the screening visit was higher than NC1 / NO1, C0, P0. Cataract surgery was planned during the study period. Patients with cataracts who had previously undergone lens replacement surgery were not excluded.

[0107] 16. A history of gastrointestinal (GI) surgery or GI-related conditions that researchers believe may interfere with the absorption of the investigational drug.

[0108] 17. Major surgery performed or planned within 6 months of enrollment in the study (major surgery performed based on the researcher's assessment, such as hip replacement) has been performed 3 months prior to the screening visit.

[0109] 18. Any documented active or suspected malignant tumor or history of malignant tumor within 5 years prior to the screening visit, except for basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been appropriately treated.

[0110] 19. A history of relevant allergic or hypersensitivity reactions based on the researcher’s clinical judgment (e.g., systemic hypersensitivity reactions, including systemic allergic reactions and anaphylactic reactions to excipients or any other systemically administered drug).

[0111] 20. Patients who require the use of restricted medications (see Other Treatments, Emergency Procedures, Restrictions) or any medications deemed likely to interfere with the safe conduct of the study (e.g., medications with known QT prolongation effects).

[0112] 21. Patients who are not expected to comply with protocol requirements or are not expected to complete the study as planned (e.g., chronic alcoholism or substance abuse, or any other condition that researchers believe would make the patient an unreliable study participant).

[0113] 22. Patients who have previously been enrolled in this trial, or are currently participating in another investigational device or drug study, or who have not completed another investigational drug study for at least 30 days or 5 times the half-life of the investigational drug (whichever is longer), will not be excluded. Patients participating in observational studies will not be excluded.

[0114] 23. Women who are pregnant, breastfeeding, or planning to become pregnant at the time of this study.

[0115] 24. During the screening period and up to randomization, the SARS-CoV-2 test was positive.

[0116] 1.3.4 Patient discontinuation of treatment or evaluation Patients may discontinue trial treatment or withdraw their consent for the entire trial (“Withdrawal Consent”), the consequences of which are vastly different (see Patient Discontinuation of Treatment or Assessment). Every effort should be made to retain patients in the trial. Measures to control withdrawal rates include careful patient selection, appropriate explanation of trial requirements and procedures before participation, and explanation of the consequences of withdrawal. The decision to discontinue trial treatment or withdraw consent for participation, along with the reasons, must be documented in the patient’s file and electronic case report form (eCRF). Where applicable, consider the requirements for AE collection and reporting (see the Adverse Event Assessment section below).

[0117] Stop experimental treatment Individual patients will discontinue trial treatment in the following circumstances: ● The patient wishes to discontinue the trial treatment. An explanation will be requested, but the patient has the right to refuse to answer.

[0118] ● It has been repeatedly demonstrated that the patients do not meet the important trial procedures, and the safety of the patients cannot be guaranteed in the view of the researchers and the organizers, because they are unwilling or unable to comply with the trial requirements in the future.

[0119] ● Patients may require concomitant medications, which may increase the risk of adverse effects or interfere with the investigational drug (see Other Treatments, Emergency Procedures, and Limitations below). In cases where the anticipated treatment is temporary (short-term), the situation should be discussed with the sponsor, who will determine whether the investigational drug may be restarted.

[0120] ● The patient is no longer able to receive the trial treatment for medical reasons (such as surgery, severe or serious drug-induced liver injury attributable to the investigational drug (see Adverse Event Assessment below), other AEs, other diseases, or pregnancy).

[0121] ● The patient experienced a confirmed QT prolongation of more than 500 ms or an increase of more than 60 ms in the QTcF interval compared to baseline (defined as measured at the second visit, before medication).

[0122] ● The patient has a clinically relevant conduction disorder (e.g., AV block ≥ grade 2, bundle branch block).

[0123] ● During the study treatment, the patient was diagnosed with cataracts (LOCS III grade higher than NC1 / NO1, C0, P0).

[0124] ● eGFR below 25 mL / min / 1.73 m 2 (CKD-EPI formula based on serum cystatin C), and it was not improved by addressing transient events (e.g., dehydration).

[0125] According to the researchers' clinical judgment and / or according to the modified Kidney Disease: Improving Global Outcomes (KDIGO) definition, the patient experienced acute kidney injury. See “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 and adapted for cystatin C as opposed to serum creatinine. Inker LA et al., “CKD-EPI Investigators. Estimating glomerular filtration rate from serum creatinine and cystatin C,” N Engl J Med 2012;367(1):20-29 and Levey AS et al., “Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review,” JAMA 2015;313(8):837-846.

[0126] An increase in cystatin C to ≥1.5 times the baseline value is provided that it is known or assumed to have occurred within the first 7 days.

[0127] ● Patients diagnosed with severe COVID-19 (e.g., requiring hospitalization, supplemental oxygen, or impaired lung function). If a patient has mild illness, the decision to continue the trial is at the researcher's discretion. SARS-CoV-2 infection testing must be conducted locally, not in a central laboratory. Positive tests should be reported as adverse events (AEs), and, if applicable, the reason for premature withdrawal should be recorded as "other AEs."

[0128] If new efficacy / safety information becomes available, the benefit-risk assessment will be reviewed, and if necessary, trial treatment for all patients will be paused or stopped, or any other appropriate action will be taken to ensure the safety of trial patients.

[0129] If the trial treatment is permanently discontinued, the patient should complete the EoT, follow-up (FUP1), and EoS visits outlined in the study procedures in Table 2.

[0130] Table 2. Research Procedure footnote: 1. For patients participating remotely via a distributed clinical trial (DCT) model, study visits can be conducted at the patient's home. All trial procedures performed in the clinic can be completed at the patient's home by a mobile research nurse (MRN). For eye examinations (see footnotes 11 and 12).

[0131] 2. End of Treatment (EoT) Visit. Patients who prematurely discontinue trial treatment should undergo the End of Treatment (EoT) visit procedure as soon as possible.

[0132] 3. End of Study (EoS) is a synonym for the end of the trial. EoS will be conducted via telephone visit. For eye examinations at EoS, see footnote 12. Patients who prematurely discontinue trial treatment should complete a follow-up visit (FUP1) and an EoS visit. Study site staff will conduct EoS visits to all patients by telephone.

[0133] 4. The screening period can be shorter than 30 days. If necessary, the screening period can be extended.

[0134] 5. Number of days after the first administration of the investigational drug. Randomization was completed before the second visit, and the investigational drug was delivered directly to the patients.

[0135] 6. To allow for the collection of first morning urine samples to determine if a patient's UPCR meets the protocol inclusion criteria prior to the first visit, the patient may sign a separate screening consent form (or verbal consent). Patients eligible based on their UPCR results must sign a primary consent form before proceeding with additional screening procedures. Once a patient consents to the collection of their first morning urine sample, that patient is considered a participant in the trial and must be enrolled in the IRT.

[0136] 7. Height measurements are collected only during screening visits.

[0137] 8. Physical examinations will be conducted on patients participating in the trial remotely via telemedicine.

[0138] 9. ECGs will be recorded at the screening visit. Two ECGs will be recorded from the first administration visit (second visit) to the EoT visit: before administration and 1 to 2 hours after administration. One ECG record will be taken at the FUP1 visit. See the section for additional guidance on ECG recording.

[0139] a. The ECG during the screening visit will be recorded three times (three individual ECGs recorded within 180 seconds). The average of the three readings will be used to determine eligibility.

[0140] b. The ECG during the screening visit will be recorded three times (three individual ECGs recorded within 180 seconds). The average of the three readings will be used to determine eligibility.

[0141] c. For patients participating in the trial remotely, the MRN will complete the ECG procedure at the patient's home.

[0142] 10. Serum pregnancy test at the screening visit (test performed in the central laboratory), and urine pregnancy test at other visits at the study site (excluding the third visit and telephone visit). Menstrual cycle status (no delayed or missing periods) should be checked before the first dose (second visit). Applicable only to women of childbearing age.

[0143] 11. Eye examinations should be performed at the study site or another healthcare or eye care facility. If a documented history of cataract surgery in both eyes is available at screening, an eye assessment is not required for this trial.

[0144] 12. If cataract surgery in both eyes is confirmed through the eye examination during screening, the patient does not need to complete the eye examination during EoT and EoS.

[0145] 13. Patients will receive instructions on urine collection, storage, and returning samples to the study site. If possible, patients should be reminded (e.g., by telephone) to collect a 24-hour urine sample during screening and before the applicable visit.

[0146] 14. Two separate 24-hour urine samples should be collected on different days prior to the second visit. The 24-hour urine samples should only be collected after confirming that the patient meets all eligibility criteria for the trial, and collection should be as close as possible to the second visit. If UPCR data cannot be obtained from at least one 24-hour urine sample, the second visit must be rescheduled.

[0147] 15. A 24-hour urine sample should be collected before the third visit.

[0148] 16. A 24-hour urine sample should be collected before the EoT visit. If a 24-hour urine sample cannot be collected for UPCR measurement, the EoT visit must be rescheduled.

[0149] 17. A 24-hour urine sample will be collected prior to FUP1. For information and collection timing, see section 6.1.

[0150] 18. Single-point urine samples will be collected for UACR and UPCR calculations. Urine samples for this purpose cannot be obtained from 24-hour urine samples.

[0151] 19. Single-point urine samples for biomarkers will be collected during the study visit. Serum and plasma blood samples for biomarkers will be collected at the same time as the first PK sample is drawn. Urine samples for this purpose cannot be obtained from 24-hour urine samples. If the visit is conducted remotely, urine biomarker samples will not be collected.

[0152] 20. A blood sample for pharmacogenomics will be collected at the second visit. If no sample is collected at the second visit, it may be collected at a later visit.

[0153] 21. For the planned PK sampling schedule, see Table 6. The date and exact time of administration of the investigational drug will be recorded in the eCRF along with the date and exact time of PK sampling.

[0154] 22. Additional PK samples will be collected during the FUP1 visit.

[0155] 23. Randomization will be conducted using the IRT platform at least one week prior to the planned second visit date. Randomization is only mandatory after patient eligibility (including UPCR criteria, eye examination) has been confirmed and UPCR data from the central laboratory is available from at least one 24-hour urine sample during the screening period. Unless local / site regulations prohibit it, the investigational drug will be delivered directly to the patient from the central warehouse via courier. The first dose will be administered at the second visit. Telephone calls (and video calls if possible) from the site to the patient should occur within approximately 24 hours (or the next business day) of the site receiving delivery notification from the courier.

[0156] 24. A medication diary (paper) will be provided to the patient. The patient should record the date and time of any medication intake at home for the first 3 days of the EoT and the day before all other clinical visits. The patient should bring the diary to the clinic for review. For more information, see section 4.1.4. If possible, the patient should be reminded (e.g., by telephone) a few days before the visit to complete the medication diary and not to take the study medication on the day of the study visit.

[0157] 25. Patients will bring all investigational medications received directly from the central repository to their clinic for their second visit (first dosing visit). Site staff will check all investigational medications and provide patients with instructions on how to administer the medication at home and how to bring it to their clinic visit. The site will open the first vial for clinical administration of the first dose. When contacting patients after delivery of the investigational medication to their homes (see footnote 23), patients should be reminded to bring the investigational medication to their clinic for their second visit. If possible, patients should be reminded (e.g., by telephone) to bring the investigational medication to their clinic before each visit. If the investigational medication is unavailable during the applicable visit, the study visit must be rescheduled. For information on how investigational medications will be handled during the trial, see section 4.1.4.

[0158] 26. A separate eCRF will be used to collect specific data related to acute kidney injury. From the FUP1 visit until the end of the individual patient's trial, only new histological cancers and progression of existing cancers will be collected for all investigational drug-related SAEs and all investigational drug-related AESIs.

[0159] 27. Medication adherence will be checked by research site staff based on capsule counts. Information regarding medication returns.

[0160] 28. Assessment of uncontrolled hypertension should be completed only during the first visit. After the patient has rested at rest and remained seated for at least 5 minutes, three blood pressure measurements should be taken approximately 2 minutes apart. The average of the last two systolic blood pressure measurements should be <160 mmHg to assess exclusion criterion 5 during the screening visit.

[0161] Withdrawal of consent form to participate in the trial Patients may withdraw their consent to participate in the trial at any time without having to explain the decision.

[0162] If a patient wishes to withdraw their consent, researchers should engage in a discussion with the patient and explain the difference between discontinuing the trial treatment and withdrawing the consent form. Researchers should also explain the option of continued follow-up after the trial treatment is discontinued.

[0163] The organizers stopped the trial. BI reserves the right to suspend the trial at any time or at any particular test site for the following reasons: 1. Failed to meet the expected selection criteria at all or at specific test sites.

[0164] 2. New efficacy or safety information renders early positive benefit-risk assessments ineffective.

[0165] 3. Deviations from Good Clinical Practice (GCP), trial protocols, or contracts that impair the normal conduct of the trial.

[0166] If the trial is terminated, the researchers / trial site will receive reasonable compensation (except in the case of the third reason).

[0167] 2. Treatment 2.1 Research-based treatment 2.1.1 The status of research-based medical products General descriptions of investigational test products are shown in Table 3 (TRPCi drug products) and Table 4 (placebo).

[0168] Table 3. Drug test TRPC1 test product compound 17 (product 1). substance: The TRPC6 inhibitor of the present invention Drug formulation: capsule Unit strength: Low-dose (20 mg), intermediate-dose (40 mg), and high-dose (80 mg) TRPC6 inhibitors Dosimetry: Once a day Application mode: Oral (po) Table 4. Matched placebo test product 2. substance: Placebo matching the TRPC6 inhibitor of this invention Drug formulation: capsule Unit strength: not applicable Dosimetry: Once a day Application mode: Oral (po) 2.1.2 Dosage selection in the experiment The recommended dose of TRPC6 inhibitors is 1 to 100 mg.

[0169] In one implementation, the TRPC inhibitor is administered to the patient in the following amounts: 10 mg, or 12.5 mg, or 15 mg, or 17.5 mg, or 20 mg, or 22.5 mg, or 25 mg, or 27.5 mg, or 30 mg, or 32.5 mg, or 35 mg, or 37.5 mg, or 40 mg, or 42.5 mg, or 45 mg, or 47.5 mg, or 50 mg, or 52.5 mg, or 55 mg, or 57.5 mg, or 60 mg, or 62.5 mg, or 65 mg, or 67.5 mg, or 70 mg, or 72.5 mg, or 75 mg, or 77.5 mg, or 80 mg, or 82.5 mg, or 85 mg, or 87.5 mg, or 90 mg.

[0170] In another implementation, the TRPC inhibitor is administered to the patient in doses of 20 mg, 40 mg, or 80 mg.

[0171] In some implementations, recommended dosages may include low-dose, moderate-dose, and / or high-dose treatment regimens.

[0172] In one embodiment, the amount of the low-dose TRPC6 inhibitor is 1 to 30 mg. In another embodiment, the amount of the low-dose TRPC6 inhibitor is 5 to 30 mg. In another embodiment, the amount of the low-dose TRPC6 inhibitor is 10 to 25 mg. In another embodiment, the amount of the low-dose TRPC6 inhibitor is 15 to 25 mg.

[0173] In another embodiment, the amount of the low-dose TRPC6 inhibitor is 10 mg or 12.5 mg or 15 mg or 17.5 mg or 20 mg or 22.5 mg or 25 mg or 27.5 mg or 30 mg.

[0174] In another embodiment, the amount of a moderate dose of the TRPC6 inhibitor is 32.5 to 60 mg. In another embodiment, the amount of a moderate dose of the TRPC6 inhibitor is 35 to 45 mg.

[0175] In another embodiment, the amount of a moderate dose of the TRPC6 inhibitor is 32.5 mg or 35 mg or 37.5 mg or 40 mg or 42.5 mg or 45 mg or 47.5 mg or 50 mg or 52.5 mg or 55 mg or 57.5 mg or 60 mg.

[0176] In another embodiment, the amount of the high-dose TRPC6 inhibitor is 62.5 to 100 mg. In another embodiment, the amount of the high-dose TRPC6 inhibitor is 70 to 90 mg. In another embodiment, the amount of the high-dose TRPC6 inhibitor is 75 to 85 mg.

[0177] In another embodiment, the amount of the high-dose TRPC6 inhibitor is 62.5 mg, or 65 mg, or 67.5 mg, or 70 mg, or 72.5 mg, or 75 mg, or 77.5 mg, or 80 mg, or 82.5 mg, or 85 mg, or 87.5 mg, or 90 mg, or 92.5 mg, or 95 mg, or 97.5 mg, or 100 mg.

[0178] In another embodiment, the amount of the intermediate-dose TRPC6 inhibitor is 1.25 times that of the low-dose inhibitor, and the amount of the high-dose TRPC6 inhibitor is 2.5 times that of the low-dose inhibitor. In another embodiment, the amount of the intermediate-dose TRPC6 inhibitor is 1.5 times that of the low-dose inhibitor, and the amount of the high-dose TRPC6 inhibitor is 3 times that of the low-dose inhibitor. In another embodiment, the amount of the intermediate-dose TRPC6 inhibitor is 2 times that of the low-dose inhibitor, and the amount of the high-dose TRPC6 inhibitor is 4 times that of the low-dose inhibitor. In another embodiment, the amount of the intermediate-dose TRPC6 inhibitor is 2.25 times that of the low-dose inhibitor, and the amount of the high-dose TRPC6 inhibitor is 4.5 times that of the low-dose inhibitor. In another embodiment, the amount of the intermediate-dose TRPC6 inhibitor is 2.5 times that of the low-dose inhibitor, and the amount of the high-dose TRPC6 inhibitor is 5 times that of the low-dose inhibitor.

[0179] In another embodiment, the low, medium, and high doses are 10 mg, 20 mg, and 30 mg, respectively. In another embodiment, the low, medium, and high doses are 15 mg, 30 mg, and 45 mg, respectively. In another embodiment, the low, medium, and high doses are 20 mg, 40 mg, and 60 mg, respectively. In another embodiment, the low, medium, and high doses are 10 mg, 20 mg, and 40 mg, respectively. In another embodiment, the low, medium, and high doses are 20 mg, 40 mg, and 80 mg, respectively. In another embodiment, the low, medium, and high doses are 10 mg, 25 mg, and 50 mg, respectively. In another embodiment, the low, medium, and high doses are 20 mg, 50 mg, and 100 mg, respectively.

[0180] In one embodiment, the TRPC6 inhibitor is administered to the patient once daily. In another embodiment, the TRPC6 inhibitor is administered to the patient twice daily. In yet another embodiment, the TRPC6 inhibitor is administered to the patient three times daily.

[0181] In another embodiment, the TRPC6 inhibitor is administered to the patient at a total daily dose of 20 mg. In another embodiment, the TRPC6 inhibitor is administered to the patient at a total daily dose of 40 mg. In another embodiment, the TRPC6 inhibitor is administered to the patient at a total daily dose of 80 mg.

[0182] In one embodiment, the therapeutic dose of the TRPC6 inhibitor of the present invention is between 20 and 40 mg. However, in the absence of the possibility of assessing targeted binding in humans and considering the uncertainty of provable pharmacokinetic effects based solely on in vitro dose estimates, higher exposures (IC50) may be required. 90 The therapeutic response in the body is observed by multiples thereof.

[0183] From an efficacy perspective, this mechanistic study investigates high doses of the present invention's TRPC6 inhibitor (above the expected therapeutic dose) to explore whether TRPC6 inhibition induces a clinically meaningful UPCR response in patients with primary or TRPC6 monogenic FSGS. In addition to establishing clinical proof of principle, a key objective of this trial, future studies, including a dedicated Phase 2 dose-finding trial, will be able to thoroughly investigate the therapeutic dose and establish the minimum effective dose.

[0184] 2.1.3 Methods for assigning patients to treatment groups After evaluating all inclusion and exclusion criteria, eligible patients will be randomly assigned to one of the treatment groups in a 1:1:1:1 ratio according to the randomization plan using interactive response technology (IRT). Randomization will be stratified using corticosteroids.

[0185] It should be noted that the investigational drug number is different from the patient number (the latter is generated via the IRT system during screening). A total of 60 patients will be randomized, with approximately 15 patients in each treatment group. Patients who are incorrectly randomized and do not receive any investigational drug may be replaced.

[0186] 2.1.4 Drug distribution and dosage administration for each patient Table 5 shows the timeline of trial drug administration for each treatment group.

[0187] Table 5. TRPC6 inhibitor and placebo treatment of the present invention Dosage group substance Drug formulation Unit strength Number of capsules to be administered each time Total daily dose 1 TRPC6 inhibitors capsule 20 mg One capsule, once daily for 12 weeks. 20 mg 2 TRPC6 inhibitors capsule 40 mg One capsule, once daily for 12 weeks. 40 mg 3 TRPC6 inhibitors capsule 80 mg One capsule, once daily for 12 weeks. 80 mg 1-3 Placebo* capsule -- Matched with a placebo, for 12 weeks -- *Subjects receiving the placebo were evenly distributed across all three treatment groups.

[0188] After patient eligibility is confirmed during the screening period, patients will be randomized on the IRT platform at least 7 days prior to their scheduled second visit. Randomization will initiate direct delivery of the investigational drug to the patient. Each patient will receive the investigational drug from an external repository contracted by the sponsor. The sponsor will not have access to the patient's name or address. Patients will receive adequate amounts of the investigational drug throughout the entire 12-week treatment period.

[0189] Before delivering the investigational drug, research site staff will train patients on the handling, storage, and use of the investigational drug. Site staff should contact patients by telephone (or video call if possible) within approximately 24 hours (or the next business day) of receiving delivery notification. During this contact, the site should remind patients of the correct storage requirements for the medication. Patients should also be instructed not to open the investigational drug package and to bring all medication to their clinic for their second visit.

[0190] During the second visit, the patient will be administered medication using one of the bottles. Site staff will check the delivery to ensure the patient has received all medication. All investigational medications (except the capsules used for administration during the second visit) will be returned to the patient along with instructions for home use.

[0191] ● Patients will administer the investigational drug at home. On the study visit day, after the pre-dosing PK sample is collected, patients must receive the dose during the study visit (at the clinic or at home).

[0192] ● Patients should take one capsule daily, either with or without food, preferably at the same time in the morning.

[0193] ● If the dose is administered before 6:00 PM, the next dose should be given the following morning (followed by the next morning dose).

[0194] ● If the dose is taken before midnight, the next dose should be taken around noon the following day (followed by the morning dose).

[0195] ● If a dose is not taken on a particular day (until midnight), the next dose should be taken the following morning.

[0196] The route of administration is through the mouth (oral). The trial treatment can be restarted after a temporary cessation. Dosage reduction or increase is not permitted.

[0197] On the study visit day, the investigational drug will be administered at the designated time (see Table 6).

[0198] Table 6. Schedule of PK blood sampling during treatment 1 ECG should be performed at least 10 minutes before or after the PK blood sample.

[0199] 2 At the selected site, additional PK samples will be collected at planned times of 673:00, 1343:55, and 2022:00 and acidified for CD 7949 quantification. Details regarding the handling and acidification of these specific samples will be provided in the laboratory manual.

[0200] 3 For post-drug administration sample collection, + / - 15 minutes.

[0201] Patients should be instructed to bring all used and unused vials to the clinic for each study visit. Site staff will check all investigational medications and also calculate adherence based on capsule counts. The site will destroy any recorded empty vials at each study visit and redistribute any remaining medication to the patient. At the EoT visit, all remaining used and unused vials containing the investigational medication will be collected from the patient. If the investigational medication cannot be administered to the patient after obtaining the pre-dose PK sample, the study visit should be rescheduled.

[0202] If local regulations or site procedures prevent direct delivery of the investigational drug to the patient, the drug may be delivered to the study site. Randomization will still be completed at least 7 days prior to the planned second visit date to initiate delivery of the investigational drug to the site. Site staff will administer the investigational drug to the patient.

[0203] The research site can initiate unplanned investigational drug supplies within the IRT. Patients should contact the site if additional drug supplies are needed.

[0204] Paper diaries will be allocated and collected at the time points shown in Table 2. Patients will record the date and time of their investigational drug intake in their diaries 3 days before their EoT visit and the day before all other visits. Patients should be instructed to bring their completed diaries for review by site staff. The dates and times of medication intake for the 3 days before the EoT and the day before all other visits will be entered into the eCRF. The dates and times of medication intake during study visits will also be entered into the eCRF. Copies of the paper diaries will be placed in the ISF.

[0205] For patients participating in the trial remotely via the DCT model, the MRN will conduct a study visit to the patient's home to complete the trial procedures, including checking the investigational drug, providing instructions for home administration, administering the investigational drug at the prescribed times during the study visit, and reviewing the paper diary. Additional instructions for remote study visits will be provided in a separate PCT operating manual, which will include instructions for disposing of empty vials and unused investigational drug.

[0206] COVID-19 Pandemic - Contingency Plan: During the COVID-19 pandemic, it may be necessary to limit on-site visits (for patients not participating in the DCT model) to ensure patient safety. Researchers may still decide to continue the trial treatment based on a comprehensive assessment of the benefits and risks, after discussion with the sponsoring organization.

[0207] 2.1.5 Blinding and Unblinding Procedures Blinding The trial is double-blind. The randomization protocol and the list of medication kits (i.e., treatment information) will be handled in accordance with the sponsor's standard operating procedures (SOP).

[0208] The following (Table 7) provides an overview of the role / function and timing of unblinding. Table 7. Unblinding Scheme Function / Effect The timing of deblinding / Access to treatment information (including basic principles) Subjects / participants, researchers / site staff This trial will be blinded to both the subjects / participants and the researchers / site staff. Treatment information for the subjects / participants will be provided to the site upon completion of the study. Organizer - Clinical Trial and Project Team. As needed, additional safety, efficacy, and pharmacokinetic / pharmacodynamic (PK / PD) analyses may be performed during the trial without blinding the database. Selected members of the trial / project team will have access to treatment information for participating patients. In-process evaluation of the trial data will support the clinical development of TRPC6 inhibitors. For rules regarding the unblinding and unblinding of procedural codes in emergency situations targeting subjects or all patients, refer to the guidelines on unblinding and unblinding procedural codes.

[0209] Unblocking and cracking program code Emergency unblinding will be available to researchers via IRT. It must only be used in emergency situations where researchers need to be aware of the investigational drug's identity to provide appropriate medical treatment or otherwise ensure the safety of trial participants. The reason for unblinding must be documented in the source document and / or the appropriate CRF page. If researchers fail to blind a patient, the patient must be discontinued from the trial. Discontinued patients will undergo EoT and follow-up visits.

[0210] Because of the need to report suspected unintended serious adverse events (SUSARs), representatives from the pharmacovigilance group at BI may need to obtain the randomization procedure code for individual patients during the trial. This procedure code is only provided to authorized pharmacovigilance representatives for processing in the PV database system and will not be shared further.

[0211] 2.1.6 Packaging, Marking and Resupply Investigational drug products will be supplied by BI or a designated contract research organization (CRO). They will be packaged and labeled according to Good Manufacturing Practice (GMP) principles. Resupply will be managed through the IRT system (where necessary). For details regarding packaging and labeling, please refer to the ISF.

[0212] 2.1.7 Storage conditions Medication supplies will be kept in their original packaging according to the recommended storage conditions on the medication label. Patients will be instructed to store the medication in a safe area. Site staff will train patients on the storage conditions. Patient temperature records will not be maintained.

[0213] If the investigational drug needs to be transported to the site, the site should store the drug in a secure, limited-access storage area according to the storage conditions recommended on the drug label, and maintain temperature records until the drug is dispensed to a patient. If storage conditions are found to be outside the prescribed range, the procedures described in the ISF must be followed, and the Clinical Research Associate (CRA) should be contacted immediately.

[0214] 2.1.8 Drug Liability Patients will receive investigational drugs delivered by the sponsor when the research site meets the following requirements: ● The clinical trial protocol must be approved by the Institutional Review Board (IRB) / Ethics Committee; ● Provide a dated clinical trial contract signed between the organizer or representative and the research site. ● Approval / notification from regulatory agencies (e.g., competent authorities), ● Provide the CVs of the key researchers; ● Provide a signed and dated clinical trial protocol. ● Provide proof of the principal investigator's medical license. ● Provide FDA Form 1572 (if applicable). ● The research site has obtained signed informed consent forms from patients.

[0215] Investigational drugs are not permitted to be used outside of this protocol. They must not be transferred to other researchers or clinics. Patients should be instructed to return all unused investigational drugs.

[0216] Researchers or designated personnel must maintain records of product delivery to patients, patient use, and return to the sponsor or warehouse / distribution center, or alternative disposal of unused products. Where applicable, the sponsor or warehouse / distribution center will maintain disposal records. These records will include the date, quantity, batch / serial number, expiry date (“Expiration Date”), and a unique procedure code number assigned to the investigational drug product and the trial patient. Researchers or designated personnel will maintain adequate records of the dosage provided to patients according to the clinical trial protocol and will coordinate all investigational drug products received by patients from the sponsor. Upon return to the sponsor and / or designated CRO, researchers or designated personnel must verify that all unused or partially used drug supplies have been returned by the patient and that researchers retain no remaining supplies.

[0217] 2.2 Other treatments, emergency procedures, and restrictions 2.2.1 Other treatments and emergency procedures There are no special emergency procedures to follow in this trial.

[0218] 2.2.2 Restrictions Table 8 shows the limitations regarding concomitant treatments.

[0219] Table 8. Pharmaceuticals or pharmaceutical categories Limitations on demand and time Potent inhibitors and potent inducers of CYP3A4 / 5; immunosuppressants; drugs with UGT1A4 activity; drugs known as P-gp substrates with narrow therapeutic windows; and OCT2, MATE1, or MATE2-K substrates. Randomization is not permitted 1 week prior to randomization or 5 half-lives (whichever is longer) until 5 days after EOT. Research devices or drugs Randomization is not permitted for 30 days prior to randomization or for 5 half-lives (whichever is longer) until 5 days after EOT. Known agents that prolong the QT interval Randomization is not permitted 1 week prior to randomization or 5 half-lives (whichever is longer) until 5 days after EOT. Systemic corticosteroids The dosage must be maintained consistently for at least 4 weeks prior to the screening visit. The dosage should not be changed during the screening and treatment period unless the researchers deem it necessary to ensure patient safety. The ISF provides additional information on the following drug categories, including a list of drugs to be avoided: immunosuppressants, potent inhibitors / inducers of CYP3A4 / 5, UGT1A4, drugs known as P-gp substrates with narrow therapeutic windows, and OCT2, MATE1, or MATE2-K substrates, as well as drugs known to prolong the QT interval.

[0220] Medications listed under the exclusion criteria are not permitted during the trial. Where possible, the use of restricted medications and their impact on treatment discontinuation should be discussed with the host organization. There are no restrictions on trial participants receiving COVID-19 vaccinations during or after the study period.

[0221] Dietary and lifestyle restrictions Patients should avoid high-protein and high-salt diets. It is especially important to avoid dietary protein loads and strenuous exercise in the 24 hours before starting and until the completion of 24-hour urine collection.

[0222] Contraception requirements female patients WOCBP participants and their male partners must use two medically approved methods of contraception during the treatment period and for at least five days after the last intake of the test drug. Male partners of WOCBP trial participants who are fertile must use condoms.

[0223] WOCBP (Trial Participant) must use a highly effective method of birth control according to ICH M3 (R2) such that, when used consistently and appropriately, the annual failure rate is less than 1%. As indicated by the asterisk (*) below, a method of birth control with low user dependence is preferred.

[0224] ● Hormonal contraception that avoids ovulation (containing estrogen and progesterone) (oral, intravaginal, percutaneous) ● Ovulation-avoiding progestin-only contraception (oral, injectable, implantable) * ) ● Intrauterine device (IUD) * Or intrauterine hormone-releasing system (IUS) * ● Bilateral fallopian tube occlusion* Acceptable methods of contraception would include abstinence from male-to-female sexual intercourse or the removal of the vas deferens by the partner, subject to the following conditions: the participant in the WOCBP trial has a single sexual partner, and the partner who has had the vas deferens removed has undergone a medical evaluation of the success of the surgery.

[0225] Abstinence from male-to-female sexual activity is defined as consistent with the patient's preferred and common lifestyle. This includes regular abstinence, such as the calendar method, ovulation method, symptom-basal body temperature method, or post-ovulation method; a declaration of abstinence for the duration of exposure to the study drug; and non-retraction.

[0226] Since TRPC6 inhibitors are not expected to cause a clinically relevant reduction in oral contraceptive exposure due to enzyme-induced metabolic increases, oral contraceptives are permitted in this trial.

[0227] 2.3 Treatment adherence During the visit, patients are asked to bring all remaining trial medication, including empty vials. Treatment adherence will be calculated based on capsule count as shown in the following formula. Adherence will be verified by the sponsor or a CRA authorized by their representative. The target for medication adherence should be 100%. If a patient does not adhere, site staff will explain the importance of treatment adherence to the patient. Randomized patients will not be discontinued from the trial due to poor medication adherence without prior discussion with the sponsor-designated clinical trial manager (CT manager).

[0228] For patients participating in the trial remotely via the DCT model, adherence will be calculated by the MRN, and all used investigational medications and empty vials will be collected by the MRN and returned to the study site or alternative site for disposal. Delivery schedules and guidelines will be described in the DCT Operations Manual. Researchers or designated personnel must verify that all unused investigational medications have been returned by the patients and that no remaining medication supplies remain at the patients' homes.

[0229] 3. Assessment 3.1 Efficacy Evaluation 3.1.1 Measurement of proteinuria The primary endpoint was a reduction of at least 25% in the patient's UPCR relative to baseline, as determined by 24-hour urine after 12 weeks of treatment. Baseline UPCR was calculated as the average of two 24-hour urine samples collected prior to the second visit.

[0230] Secondary endpoints and other endpoints are listed below, and these endpoints and other endpoints will be evaluated as follows: ● Changes in UPCR at week 12 relative to the third visit: Samples will be taken from 24-hour urine samples collected at the third and twelfth visits.

[0231] ● Changes in UPCR at week 13 relative to baseline: Samples will be 24-hour urine samples collected at baseline and week 13.

[0232] ● Changes in 24-hour urinary protein secretion relative to baseline at week 12.

[0233] ● Changes in UACR relative to baseline (second visit, first dose) at weeks 4, 8, 12 and 13: This analysis will be performed using single-point urine samples.

[0234] ● Changes in UPCR at weeks 4, 8, 12 and 13 relative to baseline (second visit, first dose): This analysis will be performed using single-point urine samples.

[0235] For additional information on urine sample collection and timing, please refer to the visit schedule and Table 2.

[0236] 3.1.2 eGFR Assessment To assess other endpoints, eGFR measurements collected at the second visit (before the first dose) will be used as baseline and compared with measurements at weeks 12 and 13. The Chronic Kidney Disease-Epidemiological Collaboration (CKD-EPI) formula based on serum cystatin C will be used for efficacy analysis.

[0237] 3.2 Security Assessment 3.2.1 Physical Examination A full physical examination will be conducted at the time points specified in Table 2. This examination will include at least a general appearance, neck, lungs, cardiovascular system, abdomen, limbs, and skin. Height and weight will be measured at the time points specified in Table 2. Results must be included in the source documents available on the site.

[0238] For patients participating in the trial remotely via DCT model, a physical examination will be conducted at the patient's home at the time points specified in the study protocol. The physical examination will be remotely supervised by a researcher or designated personnel (as indicated in the site trial staff list). MRNs will assist with the physical examination at the patient's home.

[0239] For patients participating in the trial remotely, if in-person follow-up is deemed necessary during the physical examination (PE) or at any time during the trial, the patient will be advised to visit the research site or their healthcare provider or local facility for consultation. Where applicable, research site staff will contact the local healthcare facility to obtain medical records.

[0240] 3.2.2 Vital signs Prior to blood sampling, vital signs will be assessed at the time points specified in Table 2. This includes measuring systolic and diastolic blood pressure and pulse rate (electronically or by palpation for 1 minute) after a 5-minute rest. Assessment of uncontrolled hypertension should only be performed on the first visit. Three blood pressure measurements should be taken approximately 2 minutes apart after the patient has rested at rest and remained seated for at least 5 minutes. For screening visits excluding assessments according to criterion 5, the average of the last two systolic blood pressure measurements should be <160 mmHg. For subsequent visits, three measurements are only required if the first reading is >160 mmHg, and the average of the last two readings is used as the final reading. Results must be included in the source documents available on the site.

[0241] 3.2.3 Safety Laboratory Parameters Table 9 lists the laboratory parameters for the safety to be evaluated. Sampling time points are provided in Table 2.

[0242] All analyses will be conducted in the central laboratory, and the corresponding reference ranges will be provided in the laboratory manual. The laboratory manual provides instructions on sample collection, sample handling, processing, and transportation.

[0243] If central laboratory services or reagent kits provided by a central laboratory are not available at the research site, a safety laboratory may be established at a local laboratory. The results of laboratory tests should be entered into the eCRF. Note that a local laboratory should only be used when necessary, and the CT administrator should be notified.

[0244] For patients participating in the trial remotely via the DCT model, laboratory kits will be provided at their homes for appropriate home visits. The MRN will collect, process, and transport laboratory samples to the central laboratory or research site (where applicable). Additional information will be provided in the DCT Operation Manual.

[0245] Patients can undergo blood sampling in the safety laboratory without fasting.

[0246] The central laboratory will send laboratory reports to researchers. Researchers are responsible for evaluating these reports. Clinically relevant abnormalities as determined by researchers will be reported as adverse events (AEs).

[0247] If the liver injury criteria are met, several additional measurements will be performed (see the definition of AE and the DILI checklist provided in the Electronic Data Acquisition (EDC) system). Due to this additional sampling for DILI assessment, the amount of blood collected from the patient of interest will increase. The central laboratory will periodically transmit the data to the organizers.

[0248] For the assessment of the eGFR exclusion criteria, the CKD-EPI formula based on serum creatinine and serum cystatin C will be used. The CKD-EPI formula based on serum cystatin C will be used to calculate eGFR in efficacy assessment. For sensitivity analysis, the CKD-EPI formula based on serum creatinine will also be used to calculate eGFR. Inker LA et al., “CKD-EPI Investigators. Estimating glomerular filtration rate from serum creatinine and cystatin C,” N Engl J Med 2012;367(1):20-29.

[0249] Table 9. Safety Laboratory Tests. Functional Laboratory Group Test Name hematology Hematocrit, heme, red blood cells (RBC), white blood cells (WBC), platelet count, MCVMCH, MCHCRDW Automatic WBC Differences (Relative and Absolute) Total neutrophils, total lymphocytes, eosinophils, basophils, monocytes, lymphocytes Manually differ WBC (if automatic WBC differencing is abnormal). Polymorphonuclear neutrophils (SEGS), banded neutrophils (Stabs), eosinophils, basophils, monocytes, and lymphocytes Blood clotting Activated partial thromboplastin time (aPTT), prothrombin time (PT), international normalized ratio (INR) enzymes <![CDATA[Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), Gamma-glutamyltransferase (GGT), Creatine kinase (CK), Creatine kinase-MB fraction (CK-MB 1 ) Lactate dehydrogenase, Lipase, Amylase, Troponin I 1 <!-- 43 -->]]> Substrate <![CDATA[Glucose HbA1c (at screening and EoT) Creatinine (enzymatic method) 2 Cystatin C eGFR - CKD-EPI formula based on serum creatinine and cystatin C 3 eGFR - CKD-EPI based on serum creatinine CKD-EPI based on serum cystatin C 4 Urea Uric acid Total bilirubin Direct bilirubin Total protein Triglyceride Albumin Globulin Albumin / Globulin ratio C-reactive protein (CRP) Total cholesterol]]> <![CDATA[Infectious serology 5 > Hepatitis B surface antigen, hepatitis C antibody, HIV-1 / 2 combination electrolytes Calcium, sodium, potassium, magnesium chloride, phosphate, bicarbonate (calculated) anion gap Urine sample analysis Urine nitrite, urine protein, urine glucose, urine ketones, urine bilirubin, urine blood, urine leukocyte esterase, urine pH, specific gravity, urine drug screening (screening visit only): cannabis, cocaine, benzodiazepines, amphetamines, barbiturates, methadone, opiates. Urinary sediments (microscopic examination is required if there are abnormalities in red blood cells, white blood cells, nitrates, or proteins in the urine). Only positive findings (such as the presence of bacteria in sediment, casts, squamous epithelial cells, erythrocytes, and leukocytes) will be reported. A serum pregnancy test was performed at the first visit (only for female participants of childbearing age), and a urine pregnancy test was performed at other visits to determine if the result was positive. Human serum human chorionic gonadotropin Urine pregnancy test Human serum human chorionic gonadotropin 1. If the initial CK level is elevated, retest CK using CK-MB and troponin I.

[0250] 2. Report to researchers only before the second visit.

[0251] 3. eGFR based on serum creatinine and cystatin C will be reported to researchers only before the second visit.

[0252] 4. Starting from the second visit, researchers will be informed of eGFR based on serum cystatin C.

[0253] 5. Only during screening visits.

[0254] 3.2.4 Electrocardiogram Centralized ECG services will be provided by an external vendor. The vendor will provide standardized equipment and quick start guides. ECGs should be collected using the vendor's standardized equipment according to study-specific recommendations.

[0255] A 12-lead ECG will be recorded at the time points shown in Table 2. The ECG should be recorded at least 10 minutes before or after blood sample collection. The patient should remain supine for approximately 5 to 10 minutes before ECG collection. The patient should remain supine but awake during the ECG collection process.

[0256] Following the screening visit, researchers must review the centrally read ECG results to ensure patient eligibility for the study. Starting from the second visit, ECGs will be recorded at two time points during each study visit: before administration and 1 to 2 hours after administration. ECGs may be repeated for quality or safety reasons.

[0257] ECG records will be transmitted electronically to the supplier for central access. ECGs will be centrally evaluated and rated as normal, abnormal, or unevaluable, and the results will be sent to the research site. Researchers are responsible for reviewing reports from central access. If an ECG is rated abnormal, researchers will determine whether the abnormality is clinically significant. If any clinically significant findings are found in the ECG report, researchers will be responsible for following up with the patient.

[0258] During the screening visit, ECGs should be performed three times (three individual ECGs recorded within 180 seconds). The QTcF value used to check eligibility during the screening visit is the average of the three recordings. Any pre-existing conditions should be recorded as baseline conditions.

[0259] Pre-dose ECG at the first dosing visit should be assessed by the researcher before the patient receives the first dose. If the researcher observes abnormal ECG readings at the first dosing visit, the researcher can wait for the central reading results and the first dosing visit can be rescheduled.

[0260] ECG will be taken 1 to 2 hours after the first dose at the second visit. At each of the remaining study visits up to the EoT, ECG will be recorded before and 1 to 2 hours after administration. At the FUP1 visit, ECG will be recorded only once. ECG will not be recorded at the EoS visit.

[0261] If, after a patient receives the first dose, a clinically significant increase in the QTcF interval relative to baseline is identified (defined as measured at the second visit, pre-dose) or any other clinically significant quantitative or qualitative change relative to baseline, the investigator will assess symptoms (e.g., palpitations, near-syncope, or syncope) and determine whether the patient should continue the trial. The investigator must also check that the patient meets any treatment discontinuation criteria. Any new pathological findings (including clinically relevant abnormal ECG findings) or deterioration of previous results observed during the trial will be recorded as an AE or SAE and should be followed up and / or treated as medically appropriate according to local standards.

[0262] Although ECGs are transmitted to the supplier for central reading, researchers are responsible for completing an initial review of the ECG records on the same day as the study visit. At any time during the trial, if any new signs of pathological abnormalities are found in the ECG, researchers may decide to suspend further dosing of the patient, preferably until the results of the central reading are available.

[0263] All ECGs read from the central location will be stored in the supplier's database and will be transmitted to the organizer periodically.

[0264] For patients participating in the trial remotely via DCT, ECGs are performed at the patient's home. The MRN uploads the ECGs to the DCT platform (where applicable), and these ECGs are available for review by researchers or site staff. If necessary, the MRN should consult with the researcher or designated personnel before administering medication to the patient.

[0265] 3.2.5 Other security parameters Eye safety assessment An ophthalmologist or optometrist will perform an eye examination on both eyes during the screening period, including slit-lamp evaluation for cataracts, to assess lens condition and the presence of cataracts. Researchers must obtain the results of the eye examination before patients are randomized in the IRT and before delivery of the investigational drug begins. Eye evaluations will be repeated at the EoT and 30 days after the last dose of the investigational drug (EoS) to monitor eye health and observe any changes relative to baseline.

[0266] Eye examinations do not need to be completed on the same day as the study visit. They can be completed during the screening period upon entry into the study. For EoT and EoS visits, patients should attempt and complete the corresponding eye examination within the protocol-allowed window (±3 days). Eye examinations should be completed at the study site or another healthcare or eye care facility.

[0267] Eye assessments will be conducted according to the eye examination worksheet provided by the organizer. All lenses will be classified using LOCS III. A copy of the worksheet will be available in the ISF. Eye examination results should be entered into a separate eCRF. If applicable, safety-related findings will be reported as AEs. If a history of bilateral cataract surgery is documented at screening, an eye assessment is not required, and the patient will not undergo eye examinations during the screening period, EoT, and EoS. If bilateral cataract surgery is confirmed during the screening visit (via slit-lamp examination), an eye assessment is not required during EoT and EoS.

[0268] Patients participating in the trial remotely via the DCT model will undergo eye examinations at an institution referred by researchers, or at a local medical facility closer to their home. The results of the eye examinations must be sent to the research site.

[0269] 3.2.6 Assessment of Adverse Events Definition of AE 3.2.6.1.1 Adverse Events An AE is defined as any adverse medical event in a patient or clinical trial subject who has received a drug product, and it does not necessarily have to be causally related to the treatment.

[0270] An adverse event (AE) may be any adverse and unexpected sign (including abnormal laboratory findings), symptom, or illness that is temporarily related to the use of the drug product, whether or not it is related to the drug product.

[0271] The following should also be recorded as AEs in the CRF and BI SAE tables (if applicable): ● The underlying disease or other pre-existing condition worsens.

[0272] ● Changes in vital signs, ECG, physical examination, and laboratory test results, if the researchers determine that the changes are clinically relevant.

[0273] If such abnormalities existed prior to trial inclusion, they will be considered baseline conditions and should only be collected in the eCRF.

[0274] 3.2.6.1.2 Serious Adverse Events A serious adverse event (SAE) is defined as any AE that meets at least one of the following criteria: -Causes death -Life-threatening events refer to events in which the patient is at risk of death at the time of the event; they do not refer to events that, hypothetically, could cause death if they were more severe. -Requires hospitalization or extension of existing hospital stay - Leading to persistent or significant disability or loss of working ability, - Congenital abnormalities / birth defects - An event is considered serious for any other reason if, based on appropriate medical judgment, it is a significant medical event that may endanger the patient and may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. Examples of such events include intensive treatment of allergic bronchospasm, cachexia, or seizures in the emergency room or at home that does not result in hospitalization or drug dependence or abuse.

[0275] 3.2.6.1.3 AE, considered "always serious" In accordance with the European Medicines Agency’s initiative on serious medical events, the BI has established a list of other AEs that, by their nature, can always be considered “serious” even if they do not yet meet the SAE criteria defined above.

[0276] The latest list of "Always Severe AEs" can be found in the EDS system. A copy of the latest list of "Always Severe AEs" will be provided upon request. These events should always be reported as SAEs.

[0277] Regardless of how long after medication is discontinued, new histological cancers and the progression of existing cancers must be classified as serious events and must be reported as described in the AE and timeline as collected and reported to the organizer.

[0278] 3.2.6.1.4 Adverse events of special concern The term "Adverse Events of Special Concern (AESI)" refers to any specific AE that has been identified at the program level as requiring special attention for prospective safety monitoring and assessment within this trial, such as based on knowledge of other compounds in the same class that predict the likelihood of an AE. AESIs must be reported to the sponsoring pharmacovigilance department within the same timeframe applicable to the SAE.

[0279] The following are considered AESI: Potential serious DILI Potentially serious drug-induced liver injury (DILI) that needs to be tracked is defined by the following changes in liver laboratory parameters: ● Elevations of AST and / or ALT ≥ 3 times the upper limit of normal (ULN) in the same blood sample or in samples taken within 30 days of each other, combined with an elevation of total bilirubin ≥ 2 times the ULN, or ● ALT and / or AST increase by ≥10 times ULN.

[0280] These laboratory findings constitute an alarm for liver damage, and patients exhibiting abnormalities in these laboratories need to be followed up according to the "DILI Checklist" provided in the EDC.

[0281] In cases presenting with clinical signs of liver injury (jaundice, unexplained encephalopathy, unexplained coagulopathy, right upper quadrant pain, etc.) but without available laboratory results (ALT, AST, total bilirubin), researchers should, if necessary, ensure that these parameters are analyzed in unplanned blood tests. If the results meet the liver injury alert criteria, the procedures described in the DILI checklist should be followed.

[0282] 3.2.6.1.5 Intensity (Severity) of AE The severity of an adverse event (AE) should be determined based on the following: Mild: Noticing signs or symptoms that are easily tolerated.

[0283] Moderate: Discomfort sufficient to interfere with daily activities.

[0284] Severe: Loss of working ability or inability to work or perform daily activities.

[0285] 3.2.6.1.6 Causal Relationship of AE Medical judgment should be used to determine the relationship between adverse events and the investigational compound (BI), taking into account all relevant factors, including response patterns, transient relationships, de-attack or re-attack, confounding factors such as concomitant medications, comorbidities, and relevant medical history.

[0286] Arguments that could reasonably suggest the existence of a causal relationship might include: ● This event is consistent with the known pharmacology of the drug.

[0287] ● The event is known to be caused by or attributed to this drug class.

[0288] ● A seemingly reasonable start time of the event relative to the time of drug exposure.

[0289] ● Evidence suggests that the event was reproducible when the drug was reintroduced.

[0290] ● There is no medically plausible alternative cause to explain the event (e.g., a pre-existing or concomitant disease, or co-administration of medications).

[0291] ● This event is usually drug-related and rarely occurs in the general population who are not exposed to the drug (e.g., Stevens-Johnson syndrome).

[0292] ● Indicator of dose response (i.e., if the dose increases, the effect size is larger; if the dose decreases, the effect size is smaller).

[0293] Arguments that could reasonably suggest the absence of a causal relationship might include: ● There is no apparent reasonable time of onset relative to the time of drug exposure (e.g., pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of drug administration; allergic reactions occurring weeks after discontinuation of the drug of concern).

[0294] ● Given the pharmacological properties of the compound (e.g., after 5 half-lives), the event will continue even after discontinuation of the drug.

[0295] It is worth noting that this guideline may not apply to events where the time course is prolonged despite the elimination of the original triggering factor.

[0296] ● Additional arguments to the previously stated arguments, such as alternative explanations (e.g., situations where other drugs or underlying diseases seem more likely to explain the observed events than the drug of concern).

[0297] ● The event disappeared even if the experimental drug treatment continued or remained unchanged.

[0298] Collection and reporting of adverse events 3.2.6.1.7 AE Collection Researchers should maintain and preserve detailed records of all adverse events (AEs) in patient files.

[0299] Researchers must collect the following and record them on the appropriate CRF: • From the signing of the informed consent form to the follow-up visit: all AEs (serious and non-serious) and all AESIs.

[0300] • From the first follow-up visit until the individual patient completes the trial: new histological cancers and progression of existing cancers, all investigational drug-related SAEs and all investigational drug-related AESIs.

[0301] • After an individual patient completes the trial: Researchers are not required to actively monitor for new AEs in patients. Instead, they should only report any cancer-related and trial-related SAEs and trial-related AESIs that researchers may become aware of through any communication tool (e.g., telephone). These AEs should be reported in the BI SAE form, but not in the CRF form.

[0302] 3.2.6.1.8 Account Executives (AEs) and timelines reporting to the organizer Researchers must report the SAE, AESI, and any non-serious AEs associated with the reported SAE or AESI to the organizer's unique entry point on the BI SAE form within 24 hours of becoming aware of the incident. Country-specific procedures will be specified in the ISF. The same timeline applies if tracking information becomes available. In certain circumstances, researchers may notify the organizer in advance by telephone. This does not supersede the requirement to complete the BI SAE form.

[0303] Upon receiving any further information regarding these events, a follow-up SAE form must be provided. For follow-up information, the same rules and timeline apply as for the initial information. All AEs must be followed, including those persisting after the individual patient's trial ends, until they subside, are assessed as "chronic" or "stable," or no further information becomes available.

[0304] 3.2.6.1.9 Pregnancy In rare cases, pregnancy may occur during clinical trials. Once a patient has been enrolled in a clinical trial and is taking the investigational drug, researchers must immediately (within 24 hours) report any drug exposures during pregnancy to the host’s sole entry point using Part A of the Pregnancy Monitoring Form.

[0305] Pregnancy outcomes related to drug exposure during pregnancy must be tracked and reported to the sole entry point on the Pregnancy Monitoring Form (Part B) for clinical studies. The ISF will include Pregnancy Monitoring Forms (Parts A and B) for clinical studies.

[0306] Since pregnancy itself is not reported as an AE, in the absence of accompanying SAEs and / or AESIs, only the pregnancy monitoring form for clinical studies, not the SAE form, should be completed. If pregnancy-related SAEs and / or AESIs are present, the SAE form must be completed separately.

[0307] 3.2.6.1.10 Additional security monitoring In addition to standard AE and SAE reports, additional information on the following will also be collected in a separate eCRF: ● Acute kidney injury ● Cataracts 3.3 Drug Concentration Measurement and Pharmacokinetics 3.3.1 Pharmacokinetic Assessment Blood samples for PK will be collected according to the planned dates and times provided in Table 6. The dates and times of drug administration and pharmacokinetic sampling will be recorded in the eCRF. The actual sampling time will be used to determine the pharmacokinetic parameters defined in the secondary endpoints. PK samples collected in this study will also be used for population PK and / or PK / PD analysis.

[0308] 3.3.2 Sample collection method To quantify TRPCI plasma concentrations, blood samples will be collected at the time points indicated in Tables 6 and 2. Actual sampling and administration times will be recorded in the eCRF. Additional samples will be collected at selected sites for exploratory metabolite studies. These additional samples will be acidified as described in the laboratory manual.

[0309] Plasma samples should preferably be transported to the central laboratory on the same day they are collected. Samples should be stored at approximately -20°C or lower. Detailed instructions on sampling, preparation, handling, transport, and storage are provided in the laboratory manual.

[0310] Upon completion of the study, plasma samples may be used for further methodological or exploratory studies, such as stability and metabolite testing. However, these additional studies will only generate data related to the analyte and / or its metabolites. Study samples will be discarded after completion of the additional studies, but no later than five years after the final study report is signed.

[0311] 3.3.3 Analytical Determination The concentration of TRPC6 inhibitors in plasma will be determined by validated liquid chromatography-tandem mass spectrometry (LC-MS / MS). All details of the analytical methods will be available prior to sample analysis. The concentrations of metabolites in plasma will be determined by exploratory analysis. Results will be reported separately.

[0312] All samples from subjects receiving the active drug will be analyzed. For subjects receiving a placebo, only one time point will be analyzed to demonstrate the absence of the drug. Where a quantifiable drug concentration is present, all PK samples from the placebo subjects in question will be analyzed.

[0313] The analysis will be conducted under the responsibility of Drug Metabolism and Pharmacokinetics, Boehringer IngelheimPharma GmbH & Co. KG, Biberach, Germany, under a suitable contract research organization. A bioanalyst will unblind the samples during analysis to allow for pharmacokinetic analysis during the trial procedures described herein.

[0314] 3.3.4 Pharmacokinetic-Pharmacodynamic Relationship An exploratory analysis of the PK-PD relationship will use the C-scores of TRPC6 inhibitors. pre,ss C max,ss and AUC 0-6,ss (If feasible; starting from week 12) and the following endpoints / biomarkers, ● The percentage (%) of patients who achieved a 24-hour UPCR reduction of at least 25% relative to baseline by week 12.

[0315] ● Changes in UPCR relative to baseline.

[0316] ● Mechanistic urinary biomarkers reflecting podocyte health: o-podocyte protein [mRNA]-creatinine ratio (UPodCR) o-nephrotic protein [mRNA]-creatinine ratio (UNephCR) The ratio of podocyte protein [mRNA] to nephrotic protein [mRNA] (UPNR) ● Mechanistic urinary biomarkers reflecting drug-targeted regulation: oTPRPC6 mRNA oNFAT mRNA o Other downstream markers in the calcineurin-NFAT pathway.

[0317] In addition, the relationship between TRPC6 inhibitor plasma concentrations and ECG variables (e.g., HR, QTcF, QTc) will be explored. Details will be described in TSAP.

[0318] 3.4 Evaluation of Biomarkers To characterize the role of TRPC6 inhibitors in patients with chronic kidney disease / FSGS, a multi-biomarker set will be analyzed, representing key mechanisms of renal pathophysiology such as inflammation, fibrosis, tubulointerstitial injury, oxidative stress, glomerular injury, and endothelial dysfunction. The results of these measurements are planned to be used to compare TRPC6 inhibitors with other compounds targeting chronic kidney disease, or to data from the literature, or for pharmacometric modeling. Plasma, serum, and urine samples will be collected according to Table 2. A complete list of planned exploratory biomarkers is provided in Table 10.

[0319] Table 10. Exploratory Biomarkers category biomarkers Exploratory biomarkers to be evaluated in urine and / or serum by BI or a BI-authorized CRO: Urine: • Creatinine (for normalization) • Nephrotic protein • Podocalyxin • Connective tissue growth factor • Fibronectin • 8-Hydroxyguanosine • Isoprostane • RNA profiling analysis of urinary sediments, including podin, nephrotic protein, TPRPC6, and NFAT mRNA • RNA profiling analysis of urinary extracellular vesicles Serum: • Connective tissue growth factor The plan is to use a custom multianalyte set to evaluate exploratory biomarkers in plasma at BI or a BI-licensed CRO. Due to the analytical format, results may be generated for additional biomarkers that may also be associated with chronic kidney disease / FSGS. Plasma: • Adiponectin • Angiopoietin 2 • C-Reactive Protein • E-Selectin • Fibroblast Growth Factor 2 & 3 • Intercellular Adhesion Molecule 1 • N-terminal pro-hormone of brain natriuretic peptide • Platelet-derived growth factor BB • Tumor necrosis factor receptor 1 • Tumor necrosis factor receptor 2 • Vascular cell adhesion molecule-1 • von Willebrand factor The plan is to use a custom multianalyte set to evaluate exploratory biomarkers in urine at BI or a BI-authorized CRO. Due to the analytical format, results may be generated for additional biomarkers that may also be associated with chronic kidney disease / FSGS. Urine: • Adiponectin • β-2-microglobulin • Cell fibronectin • Collagen IV • C-reactive protein • Cystatin C • Epidermal growth factor • Fatty acid binding protein; Liver: • Blood fibrinogen • Fibroblast growth factor 23 • Growth regulation α protein • Kidney injury molecule-1 • Monocyte chemotactic protein 1 • Neutrophil gelatinase-associated lipotransferase • Tissue inhibitor of metalloproteinase 1 5.4.1 Biochemical biomarkers Sample collection methods The timing and methods for collecting samples for biomarkers are described below. All blood and urine samples will be discarded one year after the last patient completes the trial.

[0320] blood sampling All blood samples used for plasma or serum measurements will be collected at the time points indicated in Table 2, using either an indwelling venous catheter or by venipuncture with a metal needle from the antecubital or forearm vein.

[0321] To measure exploratory biomarkers, blood was drawn into potassium EDTA (K-EDTA) anticoagulant tubes and serum gel tubes at the time points indicated in Table 2. Details of sample handling, including the preparation of aliquots, will be provided in the study-specific laboratory manual.

[0322] Urine sampling For exploratory biomarkers, single-point urine samples will be collected during study visits, as specified in Table 2. If a remote visit is conducted, urine biomarker samples will not be collected. To measure mechanistic biomarkers of podocyte health (such as podocyte protein and nephrotic protein mRNA) and mechanistic biomarkers of drug-targeted regulation (such as TRPC6 mRNA) (see pharmacokinetic endpoints and Table 10), aliquots of urine from single-point urine samples will be centrifuged to obtain urine sediment. The resulting supernatant will be used to isolate extracellular vesicles and perform molecular profiling analysis of their payloads.

[0323] The laboratory manual will describe the details of sample handling, including centrifugation as needed, preparation of aliquots, and the order of aliquot preparation.

[0324] Analytical assay All measurements are considered exploratory biomarkers and are measured using empirically validated methods appropriate to the purpose. In addition to routine central laboratory testing, all analytical methods and measurements will be described in detail in a separate biomarker report.

[0325] All analyses will be performed at a fully accredited CRO such as Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany, or BI.

[0326] 3.4.1 Pharmacogenomic biomarkers Pharmacogenomics studies genetic variations to interpret and predict subject responses to drugs. Therefore, blood samples will be obtained from each subject for pharmacogenomics testing. In cases where variability in PK or PD parameters cannot be explained, DNA can be extracted from these samples for exploratory analysis of variants of genes known to be associated with FSGS, particularly TRPC6, and / or genes involved in drug absorption, distribution, metabolism, and excretion.

[0327] These data are not intended to be included in the clinical trial report. However, they may be included as part of the report if necessary. All DNA samples will be destroyed one year after the last patient completes the trial.

[0328] The laboratory manual will provide detailed instructions on the sampling, handling, and transportation of pharmacogenomics samples.

[0329] Sample collection methods and timing Preferably, during the second visit, a blood sample is collected from the arm vein and placed into the PAXgene blood DNA extraction tube.

[0330] Analytical determination DNA will be extracted from blood samples using standard molecular genetic methods and analyzed using drug-metabolizing enzyme and transporter (DMET) analysis or other standard genotyping techniques.

[0331] 3.5 Biological Repository not applicable.

[0332] 3.6 Other assessments not applicable.

[0333] 3.7 Appropriateness of Measurement Apart from exploratory biomarker measurements performed during this trial, all measurements were standard measurements and will be performed to monitor patient safety and determine pharmacokinetic and pharmacodynamic parameters. Exploratory biomarker sampling carries no additional risk. The risk associated with eye examinations is minimal.

[0334] The planned procedures and measurements will allow for monitoring of changes in vital signs, standard laboratory values, eye health, and ECG parameters that may occur due to administration of the study drug. Safety assessments are standardized and accepted for evaluating safety and tolerability, and are widely used in clinical trials. The outlined pharmacokinetic parameters and measurements are typically used to assess drug exposure. Approximately 200 mL (14 tablespoons) of blood will be collected from the patient during the study.

[0335] 4. Research Programs 4.1 Visit Schedule The trial consists of a screening period, a treatment period, and a follow-up period. After the screening period, patients will be randomly assigned to one of four treatment groups (before the second visit). Following the treatment period is a 30-day follow-up period consisting of two follow-up visits. The second follow-up visit (also known as the EoS visit), in addition to an eye examination, will be conducted by telephone. The visit schedule and trial procedures are provided in Tables 2 and 11. Table 6 presents the PK sampling schedule.

[0336] Table 11. Planned Telephone Visits. footnote: 1. The patient will be contacted by telephone. An unscheduled visit may be arranged if any follow-up is required. The patient should be reminded to adhere to the dosage of the investigational drug.

[0337] 2. Patients should be reminded to collect a 24-hour urine sample before the EOT visit.

[0338] 3. Please see footnote 26 in Table 2.

[0339] Patients should make every effort to complete the trial, including two follow-up visits. Researchers should encourage treatment adherence and compliance with the protocol. All patients should follow the visit schedule outlined in Tables 2 and 11. Any deviations from the planned visit schedule should be recorded.

[0340] All study visits should preferably begin in the morning. Patients should be instructed not to take their investigational drug on the scheduled clinic visit days (from the second visit to the EoT visit). The investigational drug must be administered at the time points specified in Table 6 during the clinical study visits.

[0341] If any visit following the first medication visit (second visit) is rescheduled or missed, subsequent visits should use the original visit dates. The total treatment period (from the second visit to the EoT visit) should be 12 weeks.

[0342] Unscheduled visits may be arranged, and the researchers will decide at their own discretion whether to check for safety or for other reasons.

[0343] ECG should be recorded before collecting blood samples. Post-drug administration ECG should be recorded before collecting PK samples.

[0344] Eye examinations should be performed at a research site or another healthcare facility.

[0345] For patients participating in the trial remotely via a DCT model, study visits and procedures (excluding eye examinations) will be conducted by an MRN deployed by a BI-authorized CRO.

[0346] Home visits can also be conducted by appropriately qualified members of the research site staff (e.g., researchers, research nurses). Research sites may also employ their own mobile research nurses to conduct research visits to patients' homes. Telephone visits should be conducted by site staff.

[0347] Remote visits must follow the visit schedule specified in Table 2. EoS visits conducted by telephone will be conducted by research site staff.

[0348] In the event of force majeure or other disruptive circumstances (e.g., epidemics, war), the investigational program according to this clinical trial protocol may be unfeasible at the site. With the patient's consent, the sponsor and researchers may agree to alternative, backup, or salvage methods, which may include, but are not limited to, virtual patient visits and assessments and home health care nurse visits. The implementation of these measures will depend on patient consent, operational feasibility, and local laws and regulations. If alternative methods are implemented, deviations from the original plan will be accurately documented.

[0349] First morning urine collection: First morning urine samples are collected during the screening period to obtain the UPCR required to determine test eligibility. First morning urine is the urine a patient urinates upon waking to start the day. If a patient urinates in the early morning (e.g., 4 a.m.) and then returns to sleep, this urine does not need to be collected and is not recorded. This also applies to any urination earlier in the night for patients with nocturia. However, if a patient is an early riser and, for example, feels “good” after waking up at 4 a.m., this will be considered their first morning urine. There may be cases where a patient may return to sleep after their usual wake-up time. In those cases, urination after their usual wake-up time constitutes the first morning urine. FMV samples can be brought to the site by the patient or, where possible, delivered to the research site by courier.

[0350] Patients may sign a separate screening consent form to have their first morning urine sample collected during the screening period, or provide verbal consent. The site will process the urine samples and send them to the central laboratory for UPCR analysis. The UPCR value obtained from the first morning urine sample will be used to assess the patient's eligibility for the trial. Site staff should ensure sufficient time to obtain UPCR results from the central laboratory to complete the screening period within the protocol-allowed window. If a patient does not meet the UPCR inclusion criteria starting with their first morning urine sample, the patient may be reassessed, and the UPCR value obtained from the second first morning urine sample can be used to determine study eligibility.

[0351] 24-hour urine collection: Table 2 provides a schedule for 24-hour urine collection and the time points for distributing urine collection containers. The start and end times of the 24-hour urine collection will be recorded. Patients will be asked to empty their bladders from the container before starting sampling and to empty their bladders back into the container during and at the end of the 24-hour collection period. Patients will receive detailed instructions regarding the collection, storage, and transportation of urine samples. The processing and analysis of 24-hour urine samples will be described in the laboratory manual.

[0352] 24-hour urine samples collected starting the day before the study visit should be brought to the clinic by the patient for the corresponding study visit. Other 24-hour urine samples (collected during the screening period) can be brought to the site by the patient or, where possible, delivered to the study site by courier.

[0353] During the screening period, patients will have 24-hour urine samples collected at two separate times. 24-hour urine samples should only be collected after confirming that the patient meets all eligibility criteria for the trial, and collection should be as close as possible to the second visit. If UPCR data cannot be obtained from at least one 24-hour urine sample, the second visit must be rescheduled.

[0354] For the third visit, EoT, and FUP1, a 24-hour urine sample will be collected. Collection should preferably begin one day prior to the relevant study visit and end on the day of the visit.

[0355] If at least one 24-hour urine sample is not collected, a second visit must be rescheduled. If no 24-hour urine sample is collected before the visit, an EoT visit must be rescheduled. Visits must be rescheduled as quickly as possible.

[0356] For patients participating in the trial remotely via the DCT model, urine collection containers for all study visits were delivered to their homes, and urine samples were transported to the study site by courier. If patients lived near the study site, they could also obtain urine collection containers from the study site and bring their 24-hour urine samples to the study site.

[0357] If possible, patients should be reminded (e.g., by telephone) to collect a 24-hour urine sample during the screening period and before the applicable visit.

[0358] Urine samples may be collected repeatedly for logistical reasons (e.g., sample loss or patient inability to complete 24-hour collection) or technical issues (e.g., sample unsuitable for analysis).

[0359] Pregnancy test All WOCBPs will undergo serum pregnancy testing at the screening visit (first visit). Patients testing positive for serum pregnancy will be excluded from the trial. If a patient is a WOCBP, menstrual cycle status should be assessed before administering the first dose of the investigational drug (second visit): in cases of delayed or missing periods, the PI should use their clinical judgment and the pregnancy test results at the second visit to assess the participant's pregnancy status and confirm eligibility before administering the investigational drug.

[0360] Urine pregnancy testing will be performed at all study visits starting from the second visit (except the third visit and telephone visit). If the urine pregnancy test is positive, the investigational drug will be discontinued, and a serum pregnancy test will be performed to confirm pregnancy. If the serum pregnancy test is positive, the patient will be discontinued from the trial. An EoT visit will be scheduled as soon as possible, and the patient should complete an EoS visit. If the serum pregnancy test is negative, the patient can continue the trial and resume treatment with the investigational drug. If the urine pregnancy test is positive at the first administration visit (second visit), the patient should not be given medication unless the serum pregnancy test is negative.

[0361] 4.2 Details of the selected trial procedures during the visit 4.2.1 Filtering and Importing Periods The trial procedures to be performed during the screening period are shown in Table 2. The screening period is defined as the time between the date of informed consent (or screening consent) and the date of the first dose (second visit). Trial procedures should not be performed before the patient consents to participate in the trial. A separate screening consent form will allow the collection of a first morning urine sample to obtain the UPCR required for the eligibility criteria. Each patient will be assigned a unique patient number, and enrollment will be recorded in the eCRF.

[0362] For patients participating in the trial via the DCT model, the consent process can be completed electronically within the DCT platform (via eConsent). Screening consent forms, where applicable, will be issued outside the DCT platform. Prior to initiating the eConsent process, the eligibility of potential patients will be assessed after researchers or site staff review their medical records. Once this preliminary eligibility is confirmed, a discussion of the informed consent form will be arranged. The informed consent form will be presented within the DCT platform. Patients will review the documents and will have the opportunity to discuss the study and answer their questions during a telephone call with a researcher or designated person. If the patient agrees to participate in the trial, they will receive an electronic signature.

[0363] Once a patient consents to have their first morning urine sample collected for screening purposes, the patient is considered enrolled in the trial. The patient should be recorded on the enrollment record and registered with the IRT.

[0364] Baseline condition, medical history, and eligibility criteria will be assessed at the first visit. Concomitant therapies and adverse events (AEs), if present, will be recorded. At the end of the first visit, the patient should receive instructions on the procedures to be followed during the screening period.

[0365] If all eligibility criteria are met, randomization will be completed by calling the IRT. Randomization will initiate delivery of the investigational drug to the patient, and a second visit will be scheduled. More information about drug administration is available.

[0366] For management reasons, the screening period may be extended with the approval of the CT administrator.

[0367] If the screening period exceeds 30 days, researchers should review the laboratory reports from the screening visit (first visit) and determine whether it is necessary to repeat any of the laboratory procedures specified in the protocol before the first dosing visit. If deemed necessary, test samples should be taken and sent to the central laboratory.

[0368] Stop during the screening period If a patient discontinues the trial during the screening period, no additional study visit is required, and the patient will be marked as a screening failure. The patient will be registered as a screening failure in the IRT.

[0369] Re-screening and retesting Patients who fail screening for reversible and resolved reasons or for management reasons (e.g., long-distance travel, life events) may be rescreened once with the approval of the CT administrator or designated personnel.

[0370] If researchers believe that a laboratory test result is due to an error or other mitigating factor, the laboratory test can be repeated once without rescreening the patient.

[0371] 4.2.2 Treatment period. The treatment period will begin at the second visit and will last for 12 weeks. The procedures completed at each study visit are shown in Table 2. There will be three telephone call visits during the treatment period.

[0372] Unscheduled visits may be arranged if necessary. The procedures to be completed during an unscheduled visit will depend on the circumstances of the scheduled visit and will be determined by the researcher.

[0373] If a 24-hour urine sample cannot be collected for UPCR measurement, the EoT must be rescheduled. After the treatment period is completed, the patient will enter a 30-day follow-up period.

[0374] Stop during treatment period For patients who have stopped treatment, an EoT visit must be scheduled as soon as possible. After completing the EoT visit, the patient will complete two follow-up visits (FUP1 and EoS).

[0375] 4.2.3 Follow-up period and completion of the experiment The 30-day follow-up period extends from the EoT visit to the EoS telephone call visit. The FUP1 visit should be scheduled 7 days after the EoT visit, and the EoS telephone call visit should be scheduled 30 days after the EoT visit. The EoS visit will be a telephone visit for all patients. For patients participating remotely in the trial, the EoS visit will be conducted by research site staff over the telephone. The procedures to be completed during follow-up visits are shown in Table 2. Researchers should ensure that eye examinations (if applicable) are completed as part of the EoS visit and that the results are reviewed.

[0376] The final study visit will be the EoS visit, which will mark the end of the observation period and the completion of the trial for the patient.

[0377] 5. Statistical methods and determination of sample size 5.1 Null Hypothesis and Alternative Hypothesis No confirmation tests will be conducted, and therefore no invalid or alternative hypotheses will be defined, as this is a non-confirmatory study.

[0378] 5.2 Analysis of the Plan 5.2.1 General Considerations The following set of analyses will be defined for statistical analysis: ● Input Set (ES): This patient set includes all patients who have signed informed consent forms. The ES will be used to analyze patient configurations.

[0379] ● Randomized Set (RS): This set of patients includes all patients who have signed informed consent forms and have also been randomized, regardless of whether the patients are treated with the investigational drug.

[0380] ● Treatment Collection (TS): This patient collection includes all patients who have received at least one dose of the investigational drug. TS is used for safety analyses and for demographic and baseline characteristics.

[0381] ● Full Analysis Set (FAS): This patient set includes all patients who were randomized and treated, had evaluable UPCR measurements at baseline, and underwent at least one UPCR measurement after the first dose. The FAS is the primary analysis set used to analyze efficacy.

[0382] ● Pharmacokinetic Analysis Set (PKS): This patient set includes all patients in the TS who provide at least one PK endpoint that has not been excluded due to protocol violation or PK unmeasurability related to PK assessment.

[0383] For efficacy analysis, patients will be analyzed in a randomized manner, without taking into account any changes in treatment.

[0384] 5.2.2 Handling of Intermittent Incidents Intermittent events (ICE) are defined as the following events: ● Stop early, ● Loss to follow-up, or ● Death.

[0385] The strategies used to handle intermittent events in this experiment are as follows: ● Assumptions for estimated results: It is assumed that all subjects will continue to adhere to the prescribed investigational medication and study protocol. This strategy will include all data collected up to the time of ICE.

[0386] ● Treatment strategy estimation results: using all available data, including data collected after ICE.

[0387] 5.2.3 Analysis of Primary Endpoints An exploratory speculative analysis will be conducted to assess the primary endpoint by providing a 95% confidence interval for each treatment group, targeting the proportion of patients achieving a UPCR reduction of at least 25% from baseline at week 12. The primary estimated outcome of interest is the treatment effect assuming all subjects adhere to the prescribed investigational medication and the study protocol using the hypothetical methodology (i.e., taking the investigational medication as directed). This analysis will include all data collected up to the ICE period.

[0388] Additionally, an analysis of variance (ANOVA) model (for changes in UPCR relative to baseline at week 12) will be used to examine differences between groups. Graphical methods can be used to explore dose-response relationships based on UPCR reductions in the logs.

[0389] Sensitivity analysis Sensitivity analyses used to assess the robustness of the main analysis results will be described in the Statistical Analysis Plan for Trials (TSAP).

[0390] Supplementary analysis of the primary endpoint Additional assessment of the primary endpoint, treatment effectiveness / intention, will be conducted using the treatment strategy estimation results. The treatment strategy estimation results will utilize all available data, including data collected after ICE (Intense Efficacy in Treatment). All attempts will be made to collect all data according to the protocol.

[0391] Subgroup analysis Subgroup analysis is not planned.

[0392] 5.2.4 Secondary endpoint analysis Descriptive statistics and figures will be used to analyze all secondary endpoints of TRPC6 inhibitors, excluding pharmacokinetic parameters.

[0393] Further details will be provided in TSAP.

[0394] 5.2.5 Analysis of Other Endpoints Descriptive statistics will be used to describe the following other endpoints.

[0395] ● Changes in eGFR from the second visit to weeks 12 and 13 ● Changes in UACR relative to baseline at weeks 4, 8, 12, and 13 ● Changes in UPCR relative to baseline at weeks 4, 8, 12, and 13.

[0396] If additional statistical analysis is required, methods similar to those described for the primary and secondary analyses will be used. Final details will be provided in TSAP.

[0397] 5.2.6 Security Analysis Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). A standard BI summary table and list will be generated. All adverse events occurring between the start of treatment and the end of the study (including the 5-day period following the last dose of the investigational drug) will be assigned to the treatment period for evaluation.

[0398] All treated patients (i.e., all patients who received at least one dose of the investigational drug) will be included in the safety analysis. Typically, the safety analysis will be descriptive in nature and will be based on BI criteria. Hypothesis testing is not planned.

[0399] Statistical analysis and reporting of adverse events will focus on treatment-induced adverse events, i.e., all adverse events that occurred between the start of treatment and the end of the study. Adverse events that began before the first use of the investigational drug and worsened under treatment will also be considered "treatment-induced".

[0400] The frequency, severity, and causal relationships of adverse events will be determined when the database is locked, coded according to the current version of MedDRA, and categorized by system organ class and preferred item list.

[0401] Laboratory data will be analyzed using both quantitative and qualitative methods. The latter will be accomplished by comparing laboratory data with their reference ranges. Values ​​outside the reference range and those defined as clinically relevant will be summarized. Distribution parameters and the incidence and percentage of patients with outliers or clinically relevant outliers will be compared descriptively across treatment groups.

[0402] To assess potential changes in outcomes compared to those prior to treatment initiation, vital signs, physical examinations, or other safety-related data observed at screening, baseline, during the trial, and at the end of the study will be evaluated.

[0403] 5.2.7 Other analyses Unblinded exploratory data analysis will be conducted on pharmacokinetic, pharmacodynamic, biomarker, and / or other experimental data during the trial.

[0404] 5.2.8 Mid-term Analysis No formal midterm analysis planned 5.3 Handling of Missing Data No missing data will be estimated in UPCR, UACR, and urinary protein secretion analyses. The handling of missing PK data will be in accordance with relevant regulatory procedures. PK parameters that cannot be reasonably calculated based on available drug concentration-time data will not be estimated. Further details will be specified in TSAP.

[0405] 5.4 Random Grouping This study will be conducted in a double-blind design using corticosteroids in a 1:1:1:1 ratio, relative to three different doses of TRPC6 inhibitors and placebo. Patients will be randomly assigned to the double-blind treatment via the IRT system.

[0406] The organizers will arrange for randomization and the packaging and labeling of the investigational drug. The randomization list will be generated using a proven system that employs a pseudo-random number generator and a provided seed number, ensuring that the resulting assignments are both reproducible and unpredictable.

[0407] 5.5 Determination of Sample Size To explore the clinical efficacy of TRPC6 inhibitors, the plan includes a total of 60 FSGS patients. The planned sample size is not based on efficacy calculations. For the primary endpoint, a size of 15 patients per treatment group was considered sufficient to detect differences between the different treatment groups and placebo.

[0408] The goal of the trial is to determine whether the difference in UPCR response between at least one dose and placebo after baseline is greater than 25%. Assuming that approximately 40%, 30%, and 20% of patients in the 80 mg, 40 mg, and 20 mg treatment groups, respectively, achieve a UPCR reduction of at least 25% at week 12, while 9% of patients in the placebo group achieve a 25% UPCR reduction, the suggested sample size provides a 73.4% probability that the difference in the rate of responders between at least one treatment group and placebo is greater than 25%.

Claims

1. A method for reducing the degree of proteinuria and / or maintaining renal function in a patient with focal segmental glomerulosclerosis (FSGS), comprising administering to the patient a pharmaceutically effective amount of a compound of formula (I), (I) in L is absent or is methylene or ethylene; Y is either CH or N; A is CH or N; R 1 Choose from the following groups: C can be substituted by one to three groups independently selected from the following groups. 1-6 Alkyl group: halogenated group, C 3-6 cycloalkyl and OC 3-6 cycloalkyl; Phenyl groups optionally substituted with one to three groups independently selected from the following groups: CF3, halogen, C 3-6 cycloalkyl, OC 3-6 cycloalkyl and OC 1-6 Alkyl; wherein the OC 1-6 Alkyl groups may be optionally substituted with one to three halogen groups; and C can be substituted by one to three groups independently selected from the following groups. 3-6 Cycloalkyl: halogenated groups and C groups optionally substituted with 1 to 3 halogenated groups 1-6 alkyl; R 2 Choose from the following groups: H, C 1-6 Alkyl, OCF3, C 3-6 cycloalkyl, OC 1-6 Alkyl and OC 3-6 cycloalkyl; R 3 Choose from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl and OC 3-6 cycloalkyl; wherein R 3 C of the group 1-6 Alkyl, C 3-6 cycloalkyl or OC 3-6 Each of the cycloalkyl groups may be independently substituted by one to three groups, each independently selected from the group consisting of: halogen, OH, OC. 1-6 Alkyl, SC 1-6 Alkyl and N(C) 1-6 Alkyl)2; and wherein R 3 C of the group 1-6 One to three carbon atoms of an alkyl group may be optionally partially substituted by one or two groups selected from the following: NH, N(C 1-6 Alkyl groups), O, and S; R 4 and R 5 Each independently chooses H and C. 1-6 Groups composed of alkyl groups; or R 3 and R 4 Together with the atoms they are attached to, they can connect to form a 3-membered carbon ring; or R 3 and R 5 Together with the atoms to which it is attached, it can be linked to form a 3- to 9-membered bicyclic ring, wherein the 3- to 9-membered bicyclic ring may optionally contain one to three heteroatoms selected from the groups of N, O and S; R 6 Choose from the following groups: H, C 1-6 Alkyl, CN, CF3, OCF3, C 3-6 cycloalkyl, OC 1-6 Alkyl and OC 3-6 cycloalkyl; R 7 Choose freely between H and OC 1-6 Groups composed of alkyl groups; Or its pharmaceutically acceptable salt.

2. A compound for reducing proteinuria and / or maintaining renal function in patients with focal segmental glomerulosclerosis (FSGS), wherein the compound has formula (I), (I) in L is absent or is methylene or ethylene; Y is either CH or N; A is CH or N; R 1 Choose from the following groups: C can be substituted by one to three groups independently selected from the following groups. 1-6 Alkyl group: halogenated group, C 3-6 cycloalkyl and OC 3-6 cycloalkyl; Phenyl groups optionally substituted with one to three groups independently selected from the following groups: CF3, halogen, C 3-6 cycloalkyl, OC 3-6 cycloalkyl and OC 1-6 Alkyl; wherein the OC 1-6 Alkyl groups may be optionally substituted with one to three halogen groups; and C can be substituted by one to three groups independently selected from the following groups. 3-6 Cycloalkyl: halogenated groups and C groups optionally substituted with 1 to 3 halogenated groups 1-6 alkyl; R 2 Choose from the following groups: H, C 1-6 Alkyl, OCF3, C 3-6 cycloalkyl, OC 1-6 Alkyl and OC 3-6 cycloalkyl; R 3 Choose from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl and OC 3-6 cycloalkyl; wherein R 3 C of the group 1-6 Alkyl, C 3-6 cycloalkyl or OC 3-6 Each of the cycloalkyl groups may be independently substituted by one to three groups, each independently selected from the group consisting of: halogen, OH, OC. 1-6 Alkyl, SC 1-6 Alkyl and N(C) 1-6 Alkyl)2; and wherein R 3 C of the group 1-6 One to three carbon atoms of an alkyl group may be optionally partially substituted by one or two groups selected from the following: NH, N(C 1-6 Alkyl groups), O, and S; R 4 and R 5 Each independently chooses H and C. 1-6 Groups composed of alkyl groups; or R 3 and R 4 Together with the atoms they are attached to, they can connect to form a 3-membered carbon ring; or R 3 and R 5 Together with the atoms to which it is attached, it can be linked to form a 3- to 9-membered bicyclic ring, wherein the 3- to 9-membered bicyclic ring may optionally contain one to three heteroatoms selected from the groups of N, O and S; R 6 Choose from the following groups: H, C 1-6 Alkyl, CN, CF3, OCF3, C 3-6 cycloalkyl, OC 1-6 Alkyl and OC 3-6 cycloalkyl; R 7 Choose freely between H and OC 1-6 Groups composed of alkyl groups; Or its pharmaceutically acceptable salt.

3. The method of claim 1 or the use of claim 2, wherein... R 1 Choose from the following groups: C can be substituted by one to three groups independently selected from the following groups. 1-6 Alkyl groups: halogens and C 3-6 cycloalkyl; Phenyl groups optionally substituted with one to three groups independently selected from the following groups: CF3, halogen, OC. 3-6 cycloalkyl and OC 1-6 Alkyl; wherein the OC 1-6 Alkyl groups may be optionally substituted with one to three halogen groups; and C10 ... 3-6 cycloalkyl; R 2 For OC 1-6 alkyl; R 3 Choose from the following groups: H and any group consisting of OH or OC. 1-6 Alkyl-substituted C 1-6 alkyl, R 4 For H; R 5 For H; or R 3 and R 4 Together with the atoms they are attached to, they can connect to form a 3-membered carbon ring; or R 3 and R 5 Together with the atoms they are attached to, they can be linked to form 3- to 9-membered bicyclic rings, wherein the 3- to 9-membered bicyclic rings may optionally contain one to three heteroatoms selected from the groups of N and O; R 6 Choose from the following groups: H, C 1-6 Alkyl, OC 1-6 Alkyl and OC 3-6 cycloalkyl; and R 7 Choose freely between H and OC 1-6 Groups composed of alkyl groups; Or its pharmaceutically acceptable salt.

4. The method of claim 1 or the use of claim 2, wherein... A is CH and Y is N; or A is CH and Y is CH; or A is N and Y is CH; Or its pharmaceutically acceptable salt.

5. The method of claim 1 or the use of claim 2, wherein... R 1 A phenyl group that is optionally substituted with a group belonging to the following groups: CF3, halogen, OC. 3-6 cycloalkyl and OC 1-6 Alkyl; wherein the OC 1-6 Alkyl groups may be optionally substituted with one to three halogen groups; R 2 For OC 1-6 alkyl; R 3 Choose from the following groups: H and any group consisting of OH or OC. 1-6 Alkyl-substituted C 1-6 alkyl; R 4 For H; R 5 For H; or R 3 and R 4 Together with the atoms they are attached to, they can connect to form a 3-membered carbon ring, or R 3 and R 5 Together with the atoms they are attached to, they can be linked to form 3- to 9-membered bicyclic rings, wherein the 3- to 9-membered bicyclic rings may optionally contain one to three heteroatoms selected from the groups of N and O; R 6 Choose from the following groups: H, C 1-6 Alkyl, OC 1-6 Alkyl and OC 3-6 cycloalkyl; R 7 Choose freely between H and OC 1-6 Groups composed of alkyl groups; Or its pharmaceutically acceptable salt.

6. The method of claim 1 or the use of claim 2, wherein... R 1 A phenyl group that is optionally substituted with a group selected from the group consisting of: CF3, OCF3, F, and methoxy; R 2 The group is selected from those composed of methoxy or ethoxy groups; R 3 The groups to be selected are H, C. 1-6 Alkyl, 2-hydroxymethyl, methoxymethyl, and 1-hydroxyethyl; R 4 For H; R 5 For H; or R 3 and R 5 Together with the atoms to which it is attached, it can be linked to form a 3- to 9-membered bicyclic ring, wherein the 3- to 9-membered bicyclic ring may optionally contain one to three heteroatoms selected from the groups of N, O and S; R 6 The group selected is composed of: H, methyl, methoxy, ethoxy, propoxy, and cyclopropyloxy; and R 7 The group selected is composed of H and methoxy groups; Or its pharmaceutically acceptable salt.

7. The method of claim 1 or the use of claim 2, wherein the compound of formula (I) is selected from the group consisting of: [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[5-(4-isopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone, [4-(6-amino-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methyl ketone, [4-(6-amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone, [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)pyridin-2-yl]-methyl ketone, [4-(6-amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-chloro-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone, [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[5-(4-cyclopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone, [4-(6-amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-benzoxy)-4-methoxy-pyridin-2-yl]-methyl ketone, [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)pyridin-2-yl]-methyl ketone, [4-(6-amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-difluoromethoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone, [4-(6-amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(2-fluoro-benzoxy)-4-methoxy-pyridin-2-yl]-methyl ketone, [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethoxy-phenoxy)pyridin-2-yl]-methyl ketone, [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[5-(phenoxy)-4-ethoxy-pyridin-2-yl]-methyl ketone; and [4-(6-amino-pyridazin-3-yl)piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-ethoxy-pyridin-2-yl]-methyl ketone, Or its pharmaceutically acceptable salt.

8. The method of claim 1 or the use of claim 2, wherein the compound of formula (I) is selected from the group consisting of: [4-(6-amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone, [4-(6-amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methyl ketone, [4-(6-amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methyl ketone, [4-(6-amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2-yl]-methyl ketone, [4-(6-amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methyl ketone, [4-(6-amino-4-ethoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(phenoxy)-pyridin-2-yl]-methyl ketone, 5-Ethoxy-6-(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)pyridazine-3-amine, and 6-(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5-methylpyridazine-3-amine, Or its pharmaceutically acceptable salt.

9. The method of claims 1 and 3 to 8 or the use of claims 2 to 8, wherein the patient's proteinuria is reduced.

10. The method or use of claim 9, wherein at week 12, based on the 24-hour urinary protein-creatinine ratio (UPCR), the patient's proteinuria level is reduced by at least 25% relative to baseline.

11. The method of claims 1 and 3 to 8 or the use of claims 2 to 8, wherein the patient's renal function is preserved.

12. The method or use of claim 11, wherein the patient's estimated glomerular filtration rate (eGFR) is maintained.

13. The method of claims 1 and 3 to 10 or the use of claims 2 to 8, 11 and 12, wherein the TRPC inhibitor is administered to the patient in the following amounts: 10 mg, or 12.5 mg, or 15 mg, or 17.5 mg, or 20 mg, or 22.5 mg, or 25 mg, or 27.5 mg, or 30 mg, or 32.5 mg, or 35 mg, or 37.5 mg, or 40 mg, or 42.5 mg, or 45 mg, or 47.5 mg, or 50 mg, or 52.5 mg, or 55 mg, or 57.5 mg, or 60 mg, or 62.5 mg, or 65 mg, or 67.5 mg, or 70 mg, or 72.5 mg, or 75 mg, or 77.5 mg, or 80 mg, or 82.5 mg, or 85 mg, or 87.5 mg, or 90 mg.

Images