Use of heterocyclic compound in preparation of drug for preventing and / or treating kidney disease

Abstract

A use of a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof in preparation of a drug for treating and / or preventing a kidney disease, wherein the compound of formula (I) is as follows: (I).

Description

Use of heterocyclic compounds in preparing drugs for preventing and / or treating kidney diseases

[0001] This application claims priority to a prior application with patent number 202311217283.0 filed with the State Intellectual Property Office of China on September 20, 2023, a prior application with patent number 202311217299.1 filed with the State Intellectual Property Office of China on September 20, 2023, and a prior application with patent number 202411281982.6 filed with the State Intellectual Property Office of China on September 12, 2024. The entire contents of each of the aforementioned applications are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medicine, and particularly relates to the use of heterocyclic compounds in preparing medicines for preventing and / or treating kidney diseases. Background Art

[0003] Diabetic kidney disease (DKD), also known as diabetic nephropathy, is a chronic kidney disease (CKD) caused by diabetes mellitus (DM). It has a complex pathogenesis and is clinically characterized by persistent increased albuminuria and / or a progressive decrease in glomerular filtration rate (GFR), ultimately leading to end-stage renal disease (ESRD).

[0004] DKD is primarily characterized by a urine albumin to creatinine ratio (UACR) ≥ 30 mg / g or a urine albumin excretion rate (UAER) ≥ 30 mg / 24 hours, with two or more of the three repeated UACR or UAER measurements within three to six months reaching or exceeding the critical value; the exclusion of other confounding factors, such as infection; and / or an estimated glomerular filtration rate (eGFR) < 60 ml·min-1·(1.73 m-1)-1 for more than three months. DKD is renal damage caused by chronic hyperglycemia, which can affect the entire kidney (including glomeruli, renal tubules, renal interstitium, and renal blood vessels). Podocytes are located on the epithelial surface of the glomerulus and filter molecules below 60 kDa. Effacement of podocyte foot processes is associated with proteinuria and the development of nephrotic syndrome. Podocyte foot process reduction and enlargement are seen in early DKD, while podocyte loss occurs in late DKD. Late DKD is often accompanied by heavy, often nephrotic-level proteinuria, highlighting the critical role of podocytes in DKD. Podocytes are terminally differentiated cells that are unable to proliferate, and loss of more than 20% of podocytes is an irreversible step in the pathogenesis of DKD, leading to glomerular scarring and the development of end-stage renal disease.

[0005] According to the 2021 "Chinese Guidelines for the Clinical Diagnosis and Treatment of Diabetic Kidney Disease," existing treatments for diabetic kidney disease can be summarized as follows: lifestyle management, blood sugar control, blood pressure and proteinuria control, lipid regulation, and uric acid control. Existing DKD treatments lack high-quality, evidence-based medical data demonstrating their effectiveness. Developing new, effective treatments to meet the clinical needs of DKD patients is of vital social and practical significance.

[0006] Lupus nephritis (LN) is the most common and important renal complication of systemic lupus erythematosus (SLE), with a complex pathogenesis. SLE is the most common systemic autoimmune disease in my country. The kidney is the organ most commonly affected by SLE.

[0007] The clinical manifestations of lupus nephritis vary, ranging from asymptomatic proteinuria and / or hematuria in mild cases to nephrotic syndrome or rapidly progressive glomerulonephritis in severe cases. Persistent and recurrent disease can lead to chronic renal insufficiency or even renal failure. Patients may experience abnormal urine output (oliguria or increased nocturia), hematuria, foamy urine, edema, and hypertension. Most patients have microscopic hematuria. Proteinuria is the most common symptom, with varying severity. Patients may experience elevated blood pressure, which is more pronounced when combined with renal vascular disease.

[0008] Summary of the Invention

[0009] In order to improve the above technical problems, the present invention provides a use of a heterocyclic compound in preparing a medicament for treating and / or preventing kidney diseases, wherein the kidney diseases are diabetic nephropathy and lupus nephritis.

[0010] The present invention provides a use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing kidney disease, wherein the kidney disease is diabetic nephropathy and lupus nephritis.

[0011] in,

[0012] R 1 Selected from halogen, OH, CN, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 3-10 Cycloalkyloxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0013] R 2 Selected from H, halogen, OH, CN, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0014] R 3 Selected from H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy, NH2, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0015] R 4 Selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0016] R 5 Selected from H, halogen and C 1-6 alkyl;

[0017] R 6 Selected from H, halogen, OH, CN, and C 1-6 alkyl;

[0018] R 7 is selected from -COOH and 5-membered heteroaryl;

[0019] R 8 Selected from H, halogen, OH, CN, and C 1-6 alkyl;

[0020] R 9 Selected from H, halogen, OH, CN, C 1-6 Alkyl and C 1-6 haloalkyl; or any two R 9 Together they form C 1-6 alkylene;

[0021] R 10 and R 11 The same or different, independently selected from H, halogen, OH, CN, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy and 3-10 membered heterocyclyloxy, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy and 3-10 membered heterocyclyloxy are optionally substituted by one or more R a replace;

[0022] R a Selected from halogen, OH, CN, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group and C 1-6 Alkoxy, the C 1-6 Alkyl, C 3- 10 Cycloalkyl, 3-10 membered heterocyclic group and C 1-6 Alkoxy is optionally selected from halogen, OH, CN and C 1-6 The alkyl group is substituted by one or more substituents;

[0023] n is selected from 0, 1, 2, 3 or 4;

[0024] m is selected from 0, 1, 2, 3, 4, 5 or 6.

[0025] In some embodiments of the present invention, R 10 Selected from H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-6 Alkoxy, C 3-6-membered cycloalkyloxy and 3-6-membered heterocyclyloxy, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy and 3-6 membered heterocyclyloxy are optionally substituted with one or more R a replace;

[0026] R 11 Selected from H, halogen and C 1-6 alkyl;

[0027] R a Selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, the C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally selected from halogen, OH, CN and C 1-6 The alkyl group is substituted by one or more substituents.

[0028] In some embodiments of the present invention, each group in the compound of formula (I) has the following definitions:

[0029] R 1 C 1-6 Alkoxy; R 2 H; R 3 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 3-10 Cycloalkyl; R 4 H; R 5 is H or halogen; R 6 H; R 7 is -COOH; R 8 Selected from H, halogen and C 1-6 Alkyl; R 9 Selected from H, halogen and C 1-6 Alkyl; R 10 Selected from C 1-6 Alkoxy, C 3-6 Cycloalkyloxy and 3-6 membered heterocyclyloxy, wherein the C 1-6 Alkoxy, C 3-6 Cycloalkyloxy and 3-6 membered heterocyclyloxy are optionally substituted with one or more R a Replacement; R 11 H; R a Selected from halogen, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, the C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally selected from halogen, OH, CN and C 1-6is substituted by one or more substituents in the alkyl group; n is selected from 0, 1 or 2; m is selected from 0, 1 or 2. In some embodiments of the present invention, each group in the compound of formula (I) has the following definitions:

[0030] R 1 C 1-6 Alkoxy; R 2 H; R 3 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 3-6 Cycloalkyl; R 4 H; R 5 is H or halogen; R 6 H; R 7 is -COOH; R 8 Selected from H, halogen and C 1-6 Alkyl; R 9 Selected from H, halogen and C 1-6 Alkyl; R 10 Selected from C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally substituted by one or more R a Replacement; R 11 H; R a Halogen or C 1-6 alkyl; n is selected from 0, 1 or 2; m is selected from 0, 1 or 2.

[0031] In some embodiments of the present invention, each group in the compound of formula (I) has the following definitions:

[0032] R 1 C 1-6 Alkoxy; R 2 H; R 3 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 3-6 Cycloalkyl; R 4 H; R 5 is H or halogen; R 6 H; R 7 is -COOH; R 8 Selected from H, halogen and C 1-6 Alkyl; any two R 9 Together form -CH2- or -CH2CH2-; R 10 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally substituted by one or more R a Replacement; R 11 is H, halogen or C 1-6 Alkyl; R a Selected from halogen, C 1-6 Alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; n is selected from 0, 1, 2, 3 or 4; m is 2.

[0033] In some embodiments of the present invention, the compound represented by formula (I) is a compound represented by formula (II) below,

[0034] Where: R 9 Selected from H, halogen and C 1-6 Alkyl; R 12 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, the C 1-6 Alkyl, C 3- 6-membered cycloalkyl and 3-6-membered heterocyclic groups are optionally substituted by one or more R a Replacement; R a Selected from halogen, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, the C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally selected from halogen, OH, CN and C 1-6 The alkyl group is substituted by one or more substituents; R 1 -R 8 , n and m are as defined in the compound represented by formula (I) above.

[0035] In some embodiments of the present invention, each group in the compound of formula (II) has the following definitions:

[0036] R 1 C 1-6 Alkoxy; R 2 H; R 3 Selected from C 1-6 Alkyl; R 4 H; R 5 is H or halogen; R 6 H; R 7 is -COOH; R 8 Selected from H, halogen and C 1-6 Alkyl; R 9 Selected from H, halogen and C 1-6 Alkyl; R 12 C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more Ra Replacement; R a Selected from halogen, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, the C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally selected from halogen, OH, CN and C 1-6 The alkyl group is substituted by one or more substituents; n is selected from 0, 1 or 2; m is selected from 0, 1 or 2.

[0037] In some embodiments of the present invention, the compound represented by formula (I) is a compound represented by formula (III-1), formula (III-2), formula (III-3) or formula (III-4),

[0038] Wherein: T is -CH2- or -CH2CH2-; R 10 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally substituted by one or more R a Replacement; R 11 is H, halogen or C 1-6 Alkyl; R 1 -R 8 , n and m are as defined in the compound represented by formula (I) above.

[0039] In some embodiments of the present invention, the compound represented by Formula I can be selected from the following structures:

[0040] In some embodiments of the present invention, the compound represented by formula (I) is compound A, and the structural formula of compound A is

[0041] In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from hydrochloride, phosphate, hydrogen phosphate, sulfate, bisulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, stearate, laurate, p-toluenesulfonate, methanesulfonate, fumarate, isethionate, maleate, malate, tartrate, citrate, oxalate, benzoate, pamoate, salicylate, vanillate or succinate.

[0042] In some embodiments of the present invention, the pharmaceutically acceptable salt is hydrochloride.

[0043] In some embodiments of the present invention, the pharmaceutically acceptable salt is a monohydrochloride salt.

[0044] In some embodiments of the present invention, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound B,

[0045] In some embodiments of the present invention, the kidney disease is diabetic nephropathy.

[0046] In another aspect, the present invention provides a use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for delaying progressive renal function decline in a subject with diabetic nephropathy.

[0047] In another aspect, the present invention provides a use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for delaying the progressive decline in glomerular filtration rate (GFR) in a subject with diabetic nephropathy.

[0048] In another aspect, the present invention provides a use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving the urine protein to creatinine ratio (UPCR) and / or urine albumin to creatinine ratio (UACR) in subjects with diabetic nephropathy.

[0049] In some embodiments of the invention, the subject suffers from type 2 diabetes.

[0050] In some embodiments of the present invention, the urine albumin to creatinine ratio (UACR) of the diabetic nephropathy subject is ≥300 mg / g and <1500 mg / g.

[0051] In some embodiments of the present invention, the kidney disease is lupus nephritis.

[0052] In some embodiments of the present invention, the lupus nephritis includes minimal mesangial lesion LN (type I), mesangial proliferative LN (type II), focal LN (type III), diffuse LN (type IV), membranous LN (type V), and sclerosing LN (type VI).

[0053] In some embodiments of the present invention, the lupus nephritis is focal LN (type III) or diffuse LN (type IV).

[0054] In some embodiments of the present invention, the lupus nephritis is a first-onset or recurrent lupus nephritis.

[0055] In some embodiments of the present invention, the relapsed lupus nephritis is lupus nephritis that relapses after treatment with cyclophosphamide or mycophenolate mofetil (MMF).

[0056] In some embodiments of the present invention, the patient with lupus nephritis suffers from systemic lupus erythematosus (SLE).

[0057] In another aspect, the present invention provides a use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving the urine protein to creatinine ratio (UPCR) and / or urine albumin to creatinine ratio (UACR) in a subject with lupus nephritis.

[0058] In some embodiments of the present invention, the drug is in the form of an oral dosage form or an injection dosage form.

[0059] In some embodiments of the present invention, the drug is in an oral dosage form.

[0060] In some embodiments of the present invention, the dosage of the drug (calculated as active ingredient) is 0.1-1000 mg, or 0.1-800 mg, or 100-800 mg, or any value in the range of 200-600 mg, or a range formed by a combination of any values ​​in the range. For example, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380 mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515m g, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585 mg, 590mg, 595mg, 600mg, 705mg, 710mg, 715mg, 720mg, 725mg, 730mg, 735mg, 740mg, 745mg, 750mg, 75 5mg, 760mg, 765mg, 770mg, 775mg, 780mg, 785mg, 790mg, 795mg, 800mg, 850mg, 900mg, 950mg, 1000mg.

[0061] In some embodiments of the present invention, the dosage of the drug (calculated as the active ingredient) is 0.1 mg / kg to 300 mg / kg, preferably any value in the range of 4 mg / kg to 20 mg / kg or a range formed by a combination of any values ​​within the range, for example, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg kg, 20mg / kg, 21mg / kg, 22mg / kg, 23mg / kg, 24mg / kg, 25mg / kg, 26mg / kg, 27mg / kg, 28mg / kg, 29mg / kg, 30mg / kg, 31mg / kg, 32mg / kg, 33mg / kg, 34mg / kg, 35mg / kg, 36mg / kg, 37mg / kg, 38mg / kg, 39mg / kg, 40mg / kg, 41mg / kg, 42mg / kg, 43mg / kg, 44mg / kg, 45mg / kg, 46mg / kg, 47mg / kg, 48mg / kg, 49mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, 100mg / kg, 105mg / kg, 110mg / kg, 115mg / kg, 120mg / kg, 125mg / kg, 130mg / kg, 135mg / kg, 140mg / kg, 145mg / kg, 150mg / kg, 155mg / kg, 160mg / kg, 165mg / kg, 170mg / kg, 175 mg / kg, 180mg / kg, 185mg / kg, 190mg / kg, 195mg / kg, 200mg / kg, 205mg / kg, 210mg / kg, 215mg / kg, 220mg / kg, 225mg / kg, 230mg / kg, 235mg / kg, 2 40mg / kg, 245mg / kg, 250mg / kg, 255mg / kg, 260mg / kg, 265mg / kg, 270mg / kg, 275mg / kg, 280mg / kg, 285mg / kg, 290mg / kg, 295mg / kg, 300mg / kg.

[0062] In some embodiments of the present invention, the administration frequency of the drug can be once a day, twice a day, three times a day, every other day, once a week, twice a week, three times a week, every other week, once every two weeks, once three weeks, once four weeks, etc., preferably once a day or twice a day.

[0063] In some embodiments of the present invention, the content of the compound as shown in Formula I or a pharmaceutically acceptable salt thereof in the drug is 50 mg to 800 mg, for example, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg, and the frequency of administration can be once a day or twice a day.

[0064] In some embodiments of the present invention, the content of Compound B in the drug is 100 mg, and the administration frequency is once a day or twice a day.

[0065] In some embodiments of the present invention, the content of Compound B in the drug is 200 mg, and the administration frequency is once a day or twice a day.

[0066] In some embodiments of the present invention, the content of Compound B in the drug is 400 mg, and the administration frequency is once a day or twice a day.

[0067] In some embodiments of the present invention, the content of Compound B in the drug is 400 mg, and the administration frequency is twice a day.

[0068] In some embodiments of the present invention, the content of Compound B in the drug is 600 mg, and the administration frequency is once a day or twice a day.

[0069] In some embodiments of the present invention, the content of Compound B in the drug is 600 mg, and the administration frequency is twice a day.

[0070] In some embodiments of the present invention, the content of Compound B in the drug is 800 mg, and the administration frequency is once a day or twice a day.

[0071] In some embodiments of the present invention, the dosage of the drug (calculated as the active ingredient) is 4 mg / kg to 20 mg / kg, and the administration frequency can be once a day or twice a day.

[0072] In some embodiments of the present invention, the dosage of the drug is 4 mg / kg-6 mg / kg, and the administration frequency is once a day or twice a day.

[0073] In some embodiments of the present invention, the dosage of the drug is 6 mg / kg-8 mg / kg, and the administration frequency is once a day or twice a day.

[0074] In some embodiments of the present invention, the dosage of the drug is 8 mg / kg-10 mg / kg, and the administration frequency is once a day or twice a day.

[0075] In some embodiments of the present invention, the drug is administered at a daily dose of 400 mg / day, 600 mg / day, 800 mg / day, or 1200 mg / day.

[0076] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, for use in the preparation of a medicament for treating and / or preventing kidney diseases, wherein the kidney diseases are diabetic nephropathy and lupus nephritis.

[0077] On the other hand, the present invention provides a unit dose pharmaceutical composition, each unit dose comprising 50 mg to 800 mg of a compound represented by Formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, for use in preparing a medicament for treating and / or preventing kidney diseases, wherein the kidney diseases are diabetic nephropathy and lupus nephritis.

[0078] In some embodiments of the present invention, each unit dose contains, for example, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, for use in the preparation of a medicament for the treatment and / or prevention of kidney disease, wherein the kidney disease is diabetic nephropathy and lupus nephritis.

[0079] In some embodiments of the present invention, the administration is selected from the group consisting of simultaneous administration, independent formulation and co-administration, or independent formulation and sequential administration.

[0080] In some embodiments of the present invention, the administration route is oral administration, parenteral administration or transdermal administration, preferably oral administration. The parenteral administration is selected from injection, including but not limited to intravenous injection, subcutaneous injection or intramuscular injection.

[0081] Definition of terms

[0082] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0083] The term "alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical. For example, "C 1-6The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0084] The term "alkoxy" refers to an alkyl-O- group, wherein the alkyl group is as defined above, for example, "C 1-6 "Alkoxy" means straight-chain and branched alkyl-O- groups having 1, 2, 3, 4, 5 or 6 carbon atoms; for example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, etc. or isomers thereof.

[0085] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein the alkyl group is as defined above.

[0086] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

[0087] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein the alkoxy group is as defined above.

[0088] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0089] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight or branched hydrocarbon group, which may contain 1 to 20 carbon atoms, preferably 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. Non-limiting examples include methylene (-CH2-), ethylene (-CH2CH2-), and the like. The alkylene group may be substituted or unsubstituted.

[0090] The term "cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as fused, bridged, spiro) hydrocarbon ring or tricyclic alkane, preferably "C 3- 10 Cycloalkyl". The term "C 3-10 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (eg bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

[0091] The term "heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, for example a 3- to 10-membered heterocyclyl, which is a 3-, 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9- or 10-membered bicyclic ring (e.g., fused ring, bridged ring, spiro ring) with, for example, 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O)2-. In particular, the heterocyclic group may include, but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused.

[0092] The term "cycloalkyloxy" refers to a cycloalkyl-O- group wherein the cycloalkyl group is as defined above.

[0093] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein the heterocyclyl group is as defined above.

[0094] The term "diabetic nephropathy (DKD)" refers to a chronic kidney disease caused by diabetes. The cause is renal damage caused by chronic hyperglycemia. The lesions can affect the entire kidney (including the glomeruli, tubules, renal interstitium, and renal blood vessels). Clinically, it is characterized by persistently increased urinary albumin excretion and / or a progressive decrease in glomerular filtration rate (GFR). For example, DKD is clinically characterized by increased urinary albumin excretion, decreased glomerular filtration rate, and significant histopathological changes, including glomerular basement membrane thickening, mesangial dilatation, tuberous sclerosis, interstitial fibrosis, and tubular atrophy, as well as interstitial infiltration and vascular lesions. Deposition of C3a and C5b-9, among other substances, in the glomeruli and tubulointerstitium of DKD patients is significantly higher than in healthy subjects.

[0095] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and generally do not produce allergic or similar untoward reactions, such as gastrointestinal upset, dizziness, and the like, when administered to humans.

[0096] The term "effective amount" or "therapeutically effective amount" refers to an amount of the compound of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below). The therapeutically effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the specific compound selected, the dosing regimen followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system used.

[0097] The term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, etc. and the like, and combinations thereof, unless any conventional carrier is incompatible with the active ingredient, otherwise it is considered for use in the therapeutic or pharmaceutical composition.

[0098] The term "lupus nephritis (LN)" refers to a renal complication caused by systemic lupus erythematosus (SLE). For example, LN is clinically manifested by abnormally elevated urine protein, and patients with active lupus nephritis have significantly elevated plasma levels of C3a, C5a, and soluble C5b-9.

[0099] Currently, according to pathological classification, LN is divided into mild mesangial lesion (type I), mesangial proliferative LN (type II), focal LN (type III), diffuse LN (type IV), membranous LN (type V), and sclerosing LN (type VI).

[0100] Mild mesangial lesion LN (type I): The glomeruli are normal under light microscopy, but immune complex deposition in the mesangial area can be seen under immunofluorescence and / or electron microscopy.

[0101] Mesangial proliferative LN (type II): Light microscopy shows varying degrees of proliferation of simple mesangial cells or increased mesangial matrix, accompanied by immune complex deposition in the mesangial area; immunofluorescence and electron microscopy show a small amount of subepithelial or subendothelial immune complex deposition.

[0102] Focal LN (Type III): Classified as active (A) or inactive (C), these lesions present with focal (affecting <50% of glomeruli), segmental or spherical intraglomerular proliferation, membrane proliferation, and moderate to severe mesangial proliferation, or with crescent formation. They typically include focal subendothelial immune complex deposition, with or without mesangial changes. Type III (A): Active lesions: focal proliferative lupus nephritis. Type III (A / C): Active and chronic lesions: focal proliferative and sclerosing lupus nephritis. Type III (C): Chronic, inactive lesions with glomerulosclerosis: focal sclerosing lupus nephritis.

[0103] Diffuse lupus nephritis (Type IV): Active or inactive lesions. These lesions present as diffuse (affecting ≥50% of glomeruli), segmental or global glomerular capillary proliferation, membrane proliferation, and moderate to severe mesangial proliferation, or crescentic glomerulonephritis, with typical diffuse subendothelial immune complex deposition, with or without mesangial lesions. Type IV lupus nephritis is further divided into two subtypes: IV-S lupus nephritis, which involves segmental lesions in greater than 50% of glomeruli; and IV-G lupus nephritis, which involves global lesions in greater than 50% of glomeruli. If diffuse "platinum ear" lesions are present, even mild or non-cellular lupus nephritis is classified as type IV diffuse lupus nephritis.

[0104] Membranous lupus nephritis (type V): Diffuse thickening of the glomerular basement membrane, with diffuse or segmental subepithelial immune complex deposits, may occur with or without mesangial changes. Type V membranous lupus nephritis may be combined with type III or type IV lesions, resulting in a combined diagnosis (e.g., type V + type III, type V + type IV), and may progress to type VI sclerosing lupus nephritis.

[0105] Sclerosing LN (type VI): More than 90% of the glomeruli show global sclerosis and there are no longer active lesions. BRIEF DESCRIPTION OF THE DRAWINGS

[0106] Figure 1: 24-hour urine albumin content at the end point of the study in the BSA / LPS / CCL4 combined-induced SD rat nephropathy model;

[0107] Figure 2 shows the deposition of C3 in glomeruli in the BSA / LPS / CCL4 combined induced SD rat nephropathy model;

[0108] Figure 3: Deposition of C5b-9 in glomeruli in the BSA / LPS / CCL4 combined-induced SD rat nephropathy model. Beneficial effects:

[0109] The compound of the present invention has therapeutic effects on diabetic nephropathy and lupus nephritis. DETAILED DESCRIPTION

[0110] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0111] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0112] Preparation Example 1: Preparation of Compound A

[0113] Reaction formula for the synthesis of compound A and intermediate b

[0114] Preparation of intermediate b

[0115] To a 250 mL single-necked flask, dichloromethane (50 mL), 5-methoxy-7-methyl-1H-indole (3 g), Boc anhydride (5.68 g), 4-dimethylaminopyridine (227 mg), and triethylamine (2.26 g) were added sequentially. The reaction was allowed to proceed at room temperature for 16 hours. After completion, the reaction mixture was quenched with saturated ammonium chloride solution (5 mL) and extracted three times with dichloromethane (20 mL). The combined organic phases were washed with water (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford Intermediate a (4.6 g, yield: 94%). MS m / z (ESI): 262.0 [M+1].

[0116] In a 250 mL single-necked flask, dichloromethane (80 mL), N-methylformanilide (3.8 g), and oxalyl chloride (3.6 g) were added in sequence and the reaction was stirred at room temperature for 3 hours. The reaction temperature was then lowered to -14°C, and intermediate a (2.5 g) was added. The reaction system was naturally warmed to room temperature and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (100 mL) and extracted three times with dichloromethane (100 mL). The combined organic phases were washed twice with water (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain intermediate b (1.3 g, yield: 47%).

[0117] MS m / z(ESI):290.0[M+1]. 1 H NMR (400MHz, CDCl3) δ 10.65 (s, 1H), 7.65 (d, J = 3.4Hz, 1H), 7.49 (d, J = 3.4Hz, 1H), 6.76 (s, 1H), 3.98 (s, 3H), 2.70 (s, 3H), 1.65 (s, 9H).

[0118] Preparation of Compound A

[0119] first step:

[0120] In a 3L three-necked flask, tetrahydrofuran (150 mL) and 4-bromobenzonitrile (50 g) were added sequentially. Isopropylmagnesium chloride lithium chloride complex (1.3 M, 210 mL) was slowly added to the reaction system under nitrogen protection. The reaction was carried out at room temperature for 2 hours. Anhydrous tetrahydrofuran (500 mL) was then added to the reaction system for dilution and the temperature was lowered to -5°C. 4-Methoxypyridine (25 mL) was added, and benzyl chloroformate (35 mL) was slowly added dropwise (maintaining the system temperature below 0°C). After the addition was complete, the reaction was stirred at 0°C for 2 hours, then warmed to room temperature and the reaction was continued at room temperature for 16 hours. After the reaction, 6 M hydrochloric acid (150 mL) was added, stirred for half an hour, and diluted with water (1000 mL). The mixture was extracted twice with ethyl acetate (500 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1-1:1) to give compound 1 (23 g, yield: 23%).

[0121] MS m / z(ESI):333.0[M+1].

[0122] Step 2:

[0123] 46 g of compound 1 (28 g) prepared in two batches in the first step, zinc powder (55 g), and acetic acid (200 mL) were added sequentially to a 500 mL single-necked flask. The reaction was heated to 100°C and stirred at that temperature for 16 hours. After completion of the reaction, the mixture was filtered, the filtrate diluted with water (500 mL), and extracted with ethyl acetate (500 mL). The organic phase was washed twice with saturated sodium bicarbonate aqueous solution (500 mL) and once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 2 (26 g, yield: 73%).

[0124] MS m / z(ESI):334.8[M+1].

[0125] Step 3:

[0126] In a 500 mL single-necked flask, tetrahydrofuran (100 mL), ethanol (100 mL), and compound 2 (26 g) were added sequentially, followed by the addition of sodium borohydride (2 g) in portions. The reaction was allowed to proceed at room temperature for 2 hours. After the reaction, the system was cooled to 0°C, saturated aqueous ammonium chloride (30 mL) was added until the temperature ceased to rise, the mixture was diluted with water (500 mL), and extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford compound 3 (25 g, yield: 76%).

[0127] MS m / z(ESI):336.9[M+1].

[0128] Step 4:

[0129] Dichloromethane (200 mL) was added to a 500 mL single-necked flask, followed by the addition of compound 3 (25 g), imidazole (6.6 g), and tert-butyldiphenylsilyl chloride (25 g). The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was washed with water (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 4 (5.7 g, yield: 13%, Rf = 0.55; cis-isomer Rf = 0.50).

[0130] MS m / z(ESI):597.0[M+23].

[0131] Step 5:

[0132] In a 250 mL single-necked bottle, compound 4 (5 g) and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 30 mL) were added in sequence, and the reaction was carried out at room temperature for 2 hours. After the reaction, the mixture was diluted with water (100 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1-0:1) to obtain a racemate. The racemate was chirally separated by SFC (Apparatus: SFC Thar prep 80; Column: CHIRALPAK AD-H, 250 mm × 20 mm, 5 μm; Modifier: 35% methanol (0.2% ammonia water); column temperature: 40°C; column pressure: 60 bar; wavelength: 214 / 254 nm; flow rate: 40 g / min; Rt = 4.78 min) to obtain compound 5 (1.2 g, yield: 41%).

[0133] MS m / z(ESI):358.8[M+23].

[0134] Step 6:

[0135] To a solution of compound 5 (1200 mg) in N,N-dimethylformamide (10 mL) were added imidazole (486 mg) and tert-butyldimethylsilyl chloride (593 mg), and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was directly concentrated to give compound 6 (600 mg, yield: 90%).

[0136] MS m / z(ESI):472.8[M+23].

[0137] Step 7:

[0138] At room temperature, 1.2 g of compound 6 from the second batch of step 6 was taken out and compound 6 (700 mg) was added to dichloromethane (10 mL). Under nitrogen protection and -78 ° C, cyclopropylcarboxaldehyde (110 mg) and trimethylsilyl trifluoromethanesulfonate (35 mg) were added to the reaction solution. The reaction system was maintained at -78 ° C and stirred for one hour, then triethylsilane (180 mg) was added. The reaction was naturally warmed to room temperature and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was quenched by adding saturated sodium bicarbonate aqueous solution (20 mL), diluted with water (10 mL), extracted with dichloromethane (10 mL), and the organic phase was washed once with water (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 7 (400 mg, yield: 46%).

[0139] MS m / z(ESI):390.9[M+1].

[0140] Step 8:

[0141] Compound 7 (400 mg), isopropanol (2 mL), water (3 mL), and sodium hydroxide (400 mg) were added sequentially to a 50 mL single-necked flask. The reaction mixture was heated to 100° C. and stirred at this temperature for 16 hours. After the reaction, the reaction solution was adjusted to pH 5-6 by adding dilute hydrochloric acid (1 M) under an ice bath, diluted with water (5 mL), and extracted with ethyl acetate (5 mL). The organic phase was washed once with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated at 45° C. to give compound 8 (200 mg, yield: 33%).

[0142] MS m / z(ESI):431.8[M+23].

[0143] Step 9:

[0144] Potassium carbonate (135 mg) and iodomethane (140 mg) were added to a solution of compound 8 (200 mg) in acetonitrile (5 mL). The reaction solution was heated to 50°C and stirred at this temperature for 16 hours. After the reaction, the reaction solution was directly concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 9 (180 mg, yield: 40%).

[0145] MS m / z(ESI):445.8[M+23].

[0146] Step 10:

[0147] Palladium / carbon (50 mg) was added to a solution of compound 9 (180 mg) in tetrahydrofuran (3 mL), and the reaction solution was subjected to catalytic hydrogenation under a hydrogen atmosphere at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was directly concentrated to obtain compound 10 (120 mg, yield: 54%).

[0148] MS m / z(ESI):290.0[M+1].

[0149] Step 11:

[0150] Compound 10 (120 mg) was added to a solution of intermediate b (119 mg) in 1,2-dichloroethane (5 mL). The reaction was stirred at room temperature for 8 hours, followed by the addition of sodium acetate borohydride (261 mg) and continued stirring at room temperature for 16 hours. After completion of the reaction, the reaction solution was directly concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to provide compound 11 (200 mg, yield: 26%).

[0151] MS m / z(ESI):562.8[M+1].

[0152] Step 12

[0153] Methanol (2 mL), water (2 mL), compound 11 (200 mg), and sodium hydroxide (150 mg) were added sequentially to a 50 mL single-necked flask. The reaction mixture was heated to 75°C and stirred at this temperature for 3 hours. After completion of the reaction, the reaction solution was adjusted to pH 7 by adding dilute hydrochloric acid (1 M) in an ice bath. The solution was then directly concentrated under reduced pressure and purified by Prep-HPLC (column: Gemini-C18, 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-40%) to afford compound A (30.6 mg, yield: 18%; containing 0.5 equivalents of formic acid).

[0154] MS m / z(ESI):448.9[M+1].

[0155] 1H NMR (400MHz, CD3OD): δ8.18(d,J=7.7Hz,2H),7.69(d,J=7.7Hz,2H),7.32(s,1H),6 .76(s,1H),6.34(s,1H),4.88-4.61(m,1H),4.44-4.07(m,2H),3.95-3.81(m,1H),3 .75(s,3H),3.63-3.47(m,1H),3.46-3.33(m,3H),2.50(s,3H),2.35-2.14(m,2H), 2.13-1.94(m,2H),1.23-1.04(m,1H),0.58(d,J=7.2Hz,2H),0.28(d,J=3.8Hz,2H).

[0156] Unless otherwise stated, the compounds A mentioned below were prepared by the above method or by repeating the above method.

[0157] Preparation Example 2 Preparation Method of Monohydrochloride of Compound A

[0158] After multiple batches of compound A were prepared, 400 mg of compound A was added to 8 mL of isopropanol and heated at 50°C to dissolve. 460 μL of a 2 mol / L hydrogen chloride isopropanol solution was then slowly added dropwise, stirred for half an hour, and then 8 mL of n-heptane was added and stirred for another 2 hours. The mixture was filtered and the filter cake was dried under reduced pressure at 50°C to obtain 390 mg of the monohydrochloride salt of compound A (compound B), with a yield of 90%.

[0159] Test Example 1. In vitro cell test

[0160] HK-2 cell line was derived from immortalized human kidney PTECs and purchased from ATCC. HK-2 cells were cultured in DMEM / F12 medium (Gibco, 10565042) supplemented with 10% fetal bovine serum (Gibco, 10099-141C) and 1% penicillin / streptomycin (Gibco, 15140122). HK-2 cells were seeded at a density of 1×10 5 cells / well in 6-well plates (Corning, 3516). When the cell confluence reached 70%, the cells were stimulated with gradient concentrations of the test compound and High-Glucose (final concentration: 30 mmol / L; MilliporeSigma) for 24 hours. The cells were then harvested and used for real-time fluorescence quantitative PCR to analyze the mRNA expression of IL-1β, CFB, and TNF-α. The levels of intracellular ROS (Beyotime Biotechnology, S0033S) and SOD (Beyotime Biotechnology, S0101S) were detected using kits. All operations were performed according to the reagent operating instructions.

[0161] Total RNA was extracted from cells using the RNA Easy Fast Total RNA Extraction Kit (Tiangen Biotechnology, DP451). Primers used for mRNA detection are shown in the table. 2 μg of total RNA was reverse transcribed into cDNA using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, 4368814). RT-qPCR analysis was performed using a Bio-Rad CFX96. Real-time PCR was performed using SYBR Green Master Mix (Applied Biosystems, A46012).

[0162] RT-qPCR primer sequences

[0163] Test Example 2. In vivo test

[0164] The black-brown short uric acid (BTBR) mouse with leptin deficiency (ob / ob) (BTBR Lepob / ob, hereinafter referred to as BTBR ob / ob) is a DKD model characterized by obesity, hyperglycemia, and dyslipidemia.

[0165] During the study, all male BTBR ob / ob animals were housed under SPF conditions. At 8-12 weeks of age, BTBR ob / ob mice developed proteinuria and glomerular damage. These diseased BTBR ob / ob mice were randomly divided into several groups and given the test compound orally once daily for 4-6 weeks. The experiment was terminated after the end of the treatment period. Before euthanasia, mice were placed in metabolic cages to collect 24-hour urine for assessment of urinary albumin, urinary creatinine, and the urinary albumin to creatinine ratio (UACR). Blood samples were also collected to measure glucose, cholesterol, and triglyceride levels. Mice were euthanized by CO2 inhalation, and kidneys were collected for analysis of renal tissue pathology, including inflammation, glomerular area, podocyte loss, and tubulointerstitial damage.

[0166] Test Example 3. In vivo test

[0167] 3-4 week old male db / db mice were intraperitoneally injected with STZ (50 mg / kg) for 4 consecutive days. One week later, the blood glucose of the mice increased. The test compound was administered orally for 2-6 months. Urine was collected from 2 to 6 months for urine biochemical analysis. The mice were sacrificed and serum, urine and kidney tissue were collected for blood and urine biochemical and renal pathology analysis.

[0168] Conclusion: Compound B can reduce urine albumin, UACR (urine protein to creatinine ratio) and complement deposition in renal tissue of DKD model mice.

[0169] Test Example 4. In vivo test

[0170] 6-9 week old male db / db mice were divided into groups after their blood glucose level increased to 16.7 mmol / L. The test compound was orally administered for 2-6 months. Urine was collected from 2 to 6 months for urine biochemistry analysis. The mice were sacrificed and serum, urine, and kidney tissue were collected for blood and urine biochemistry and renal pathology analysis.

[0171] After compound intervention, the renal function-related urine protein, renal tissue pathology and other indicators of the compound group mice were significantly improved.

[0172] Test Example 5: In vivo test

[0173] This study used spontaneously ill NZBWF1 mice aged 24-26 weeks. The test article was administered orally (PO) once daily (QD or BID) for 8-12 weeks. Body weight, proteinuria, and mortality were recorded weekly during the study. Serum urea nitrogen (BUN) and creatinine levels were measured using an optimized ultraviolet method using an automated analyzer. Total IgG and anti-double-stranded DNA (anti-dsDNA) autoantibodies were measured in serum by ELISA before and every 4 weeks after dosing. Renal tissue pathology was assessed at the study endpoint.

[0174] Test Example 6: In vivo test

[0175] This study used spontaneously ill MRL / lpr mice and administered the test article orally (PO) starting at 13-15 weeks of model development. Administration continued for 8-12 weeks, and body weight, proteinuria, and mortality were recorded weekly during the study. Serum urea nitrogen (BUN) and creatinine levels were measured using an optimized ultraviolet method using a fully automated analyzer. Total IgG and anti-double-stranded DNA (anti-dsDNA) autoantibodies were measured in serum using an ELISA method before and every 4 weeks after dosing. Renal tissue pathology was performed at the study endpoint.

[0176] Conclusion: Compound B can improve the renal function, urine protein level and renal tissue pathology score of lupus nephropathy mice to a certain extent.

[0177] Test Example 7. In vivo test

[0178] Research Methods: The pharmacological effects of Compound B were evaluated in a BSA / LPS / CCL4 combined induced SD rat nephropathy model. This BSA (bovine serum albumin) / LPS / CCL4 combined nephropathy model demonstrates significantly elevated urinary protein levels and significant renal tissue C5b-9 and C3 deposition, along with elevated complement activity. These findings are consistent with the disease states, characteristics, and indicators for improvement of DKD and LN in these animals. Therefore, this model was used to evaluate the pharmacological effects of Compound B.

[0179] A total of 60 male Sprague Dawley rats were used in this experiment. The model was established by BSA / LPS / CCL4 combined induction after unilateral nephrectomy. All drugs were administered orally: the normal control group (Group 1) (G1) and the model group (Group 2) (G2) were administered with the vehicle. Group 3 (G3) was administered with dexamethasone at a dose of 0.3 mg / kg, administered orally once daily; Group 4 (G4) was administered with compound B at a dose of 5 mg / kg, administered orally twice daily; Group 5 (G5) was administered with compound B at a dose of 15 mg / kg, administered orally twice daily; and Group 6 (G6) was administered with compound B at a dose of 50 mg / kg, administered orally twice daily. Drug administration began four weeks after BSA / LPS / CCL4 combined induction. The administration period was six weeks. Detection indicators included body weight, food intake, urine volume, urine albumin level, and pathological and immunofluorescence examination of renal tissue.

[0180] Research results: Compared with the normal control group, the body weight of rats in the model group was significantly reduced, and the urine albumin concentration, 24-hour urine albumin total and ACR were significantly increased; the percentage of inflammatory infiltration area and the number of glomerular mesangial cells in the renal tissue of the model animals were significantly increased; and the deposition levels of C3 and C5b-9 in the glomeruli of the model animals were significantly increased.

[0181] Compared with the model group, compound B significantly reduced the urine albumin concentration, 24-hour urine albumin total (see Figure 1), and ACR of the model animals in a dose-dependent manner after three weeks of administration and at the end of the study; and significantly reduced the deposition of C3 and C5b-9 in the glomeruli of the model animals (see Figures 2 and 3).

[0182] Test Example 8. A clinical trial to study the efficacy of the compound of the present invention in patients with diabetic nephropathy

[0183] 1. Study design: This study adopted a multicenter, parallel, open-label design and was divided into three phases: screening phase (D-91 to D-1, a total of 13 weeks), efficacy observation phase (D1 to D84, a total of 12 weeks), and follow-up phase (D85 to D112, a total of 4 weeks).

[0184] The study drug is compound B:

[0185] The dosage is 400mg BID, 600mg QD, 800mg QD or 600mg BID, and can be taken on an empty stomach or after a meal.

[0186] 2. Research objectives:

[0187] 2.1 Main Purpose:

[0188] The change in urine protein to creatinine ratio (UPCR) in morning urine compared with baseline was used as an indicator to evaluate the efficacy of compound B in patients with diabetic nephropathy on Day 84.

[0189] 2.2 Secondary Purpose

[0190] 2.2.1 The efficacy of compound B in patients with diabetic nephropathy was evaluated at D7, D14, D28, D42, D56, and D70 using the change in morning urine UPCR compared to baseline as an indicator.

[0191] 2.2.2 The efficacy of compound B in patients with diabetic nephropathy at D7, D14, D28, D42, D56, D70, and D84 was evaluated using the change in the urine albumin to creatinine ratio (UACR) in morning urine compared to baseline.

[0192] 2.2.3 Using the change in eGFR compared to baseline as an indicator, evaluate the efficacy of compound B in patients with diabetic nephropathy at D28, D56, and D84.

[0193] 3. Inclusion criteria:

[0194] 3.1 T2DKD confirmed by renal biopsy within 1 year prior to screening. If the most recent renal biopsy was performed more than 1 year ago, a renal biopsy can be performed at any time during the screening period to confirm the diagnosis of diabetic nephropathy and facilitate subject selection.

[0195] 3.2 Urine albumin to creatinine ratio (UACR) during the screening period is ≥300 mg / g and <1500 mg / g.

[0196] 4. Exclusion criteria:

[0197] 4.1 eGFR < 30 mL / min / 1.73 m within 4 weeks before screening or during the screening period 2 .

[0198] 4.2 Rapidly progressive crescentic glomerulonephritis within 1 year before screening, defined as a 50% decrease in eGFR within 3 months and glomerular crescents in at least 50% of the glomeruli found in renal biopsy.

[0199] Test Example 9: A clinical trial to study the efficacy of the compound of the present invention in patients with lupus nephritis

[0200] 1. Study design: This study adopted a multicenter, parallel, open-label design and was divided into three phases: screening phase (D-91 to D-1, a total of 13 weeks), efficacy observation phase (D1 to D84, a total of 12 weeks), and follow-up phase (D85 to D112, a total of 4 weeks).

[0201] The study drug is compound B:

[0202] The dosage is 400mg BID, 600mg QD, 800mg QD or 600mg BID, and can be taken on an empty stomach or after a meal.

[0203] 2. Research objectives:

[0204] 2.1 Main Purpose:

[0205] The efficacy of compound B in patients with lupus nephritis on Day 84 was evaluated by the change in urine protein to creatinine ratio (UPCR) in morning urine compared with baseline.

[0206] 2.2 Secondary Purpose

[0207] 2.2.1 The efficacy of compound B in patients with lupus nephritis was evaluated at D7, D14, D28, D42, D56, and D70 using the change in morning urine UPCR compared to baseline as an indicator.

[0208] 2.2.2 The efficacy of compound B in patients with lupus nephritis was evaluated on D7, D14, D28, D42, D56, D70, and D84 using the change in the urine albumin-to-creatinine ratio (UACR) in morning urine compared to baseline.

[0209] 2.2.3 Using the change in eGFR compared to baseline as an indicator, evaluate the efficacy of compound B in patients with lupus nephritis at D28, D56, and D84.

[0210] 3. Inclusion criteria:

[0211] 3.1 Systemic lupus erythematosus (SLE) was diagnosed according to the 2019 European League Against Rheumatism / American College of Rheumatology (EULAR / ACR) criteria.

[0212] 3.2 Active type III or type IV lupus nephritis confirmed by renal biopsy within 3 months before screening, regardless of the coexistence of features of type V lupus nephritis. If the most recent renal biopsy was confirmed more than 3 months ago, a renal biopsy can be performed at any time during the screening period to confirm the diagnosis of LN and assist in the selection of subjects.

[0213] 3.3 For subjects with first-time onset or recurrence of LN, LN recurrence after cyclophosphamide treatment, or LN recurrence after mycophenolate mofetil (MMF) treatment, the investigator, after full consideration of the study protocol, believes that there is potential benefit to the patients and they can be included in this study protocol.

[0214] 4. Exclusion criteria:

[0215] 4.1 Subjects clinically diagnosed with lupus podophyllocytosis or lupus TMA.

[0216] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. Use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing kidney disease, wherein the kidney disease is diabetic nephropathy and lupus nephritis. in, R 1 Selected from halogen, OH, CN, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 3-10 Cycloalkyloxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; R 2 Selected from H, halogen, OH, CN, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; R 3 Selected from H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy, NH2, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; R 4 Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; R 5 Selected from H, halogen and C 1-6 alkyl; R 6 Selected from H, halogen, OH, CN, and C 1-6 alkyl; R 7 is selected from -COOH and 5-membered heteroaryl; R 8 Selected from H, halogen, OH, CN, and C 1-6 alkyl; R 9 Selected from H, halogen, OH, CN, C 1-6 Alkyl and C 1-6 haloalkyl; or any two R 9 Together they form C 1-6 Alkylene; R 10 and R 11 are the same or different and are independently selected from H, halogen, OH, CN, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy and 3-10 membered heterocyclyloxy, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy and 3-10 membered heterocyclyloxy are optionally substituted by one or more R a replace; R a Selected from halogen, OH, CN, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group and C 1-6 Alkoxy, the C 1-6 Alkyl, C 3- 10 Cycloalkyl, 3-10 membered heterocyclic group and C 1-6 The alkoxy group is optionally selected from halogen, OH, CN and C 1-6 The alkyl group is substituted by one or more substituents; n is selected from 0, 1, 2, 3 or 4; m is selected from 0, 1, 2, 3, 4, 5 or 6.

2. The use according to claim 1, wherein the compound represented by formula (I) is a compound represented by the following formula (II), in: R 9 Selected from H, halogen and C 1-6 Alkyl; R 12 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 3- 6-membered cycloalkyl and 3-6-membered heterocyclic groups are optionally substituted by one or more R a Replacement; R a Selected from halogen, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group, the C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally selected from halogen, OH, CN and C 1-6 The alkyl group is substituted by one or more substituents; R 1 -R 8 , n and m as defined in claim 1; preferably, R 1 C 1-6 Alkoxy; R 2 H; R 3 Selected from C 1-6 Alkyl; R 4 H; R 5 is H or halogen; R 6 H; R 7 is -COOH; R 8 Selected from H, halogen and C 1-6 Alkyl; R 9 Selected from H, halogen and C 1-6 Alkyl; R 12 C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more R a Replacement; R a Selected from halogen, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group, the C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally selected from halogen, OH, CN and C 1-6 The alkyl group is substituted by one or more substituents; n is selected from 0, 1 or 2; m is selected from 0, 1 or 2.

3. The use according to any one of claims 1 or 2, characterized in that The compound represented by formula I can be selected from the following structures:

4. The use according to any one of claims 1 to 3, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound A or compound B, 5. The use according to any one of claims 1 to 4, wherein the medicament is used to delay the progressive decline in renal function in a subject with diabetic nephropathy; or to delay the progressive decline in glomerular filtration rate (GFR) in a subject with diabetic nephropathy; or to improve the urine protein to creatinine ratio (UPCR) and / or urine albumin to creatinine ratio (UACR) in a subject with diabetic nephropathy and lupus nephritis; preferably, the subject with diabetic nephropathy suffers from type 2 diabetes; preferably, the urine albumin to creatinine ratio (UACR) of the subject with diabetic nephropathy is ≥300 mg / g and <1500 mg / g.

6. The use according to any one of claims 1 to 5, wherein the lupus nephritis is selected from the group consisting of mesangial mild lesion LN (type I), mesangial proliferative LN (type II), focal LN (type III), diffuse LN (type IV), membranous LN (type V) and sclerotic LN (type VI); or the lupus nephritis is first attack or relapse of lupus nephritis; preferably, the relapsed lupus nephritis is lupus nephritis that relapses after treatment with cyclophosphamide or mycophenolate mofetil (MMF).

7. The use according to any one of claims 1 to 6, characterized in that: The drug is presented in the form of an oral dosage form or an injection dosage form; the dosage of the drug (calculated as active ingredient) is 0.1-1000 mg; preferably 100-800 mg, more preferably 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg; preferably, the administration frequency of the drug is selected from once a day, twice a day, three times a day, once every other day, once a week, twice a week, three times a week, once every two weeks, once every three weeks, once every four weeks; more preferably, the administration frequency of the drug is selected from once a day or twice a day; more preferably, the drug is administered at a daily dose of 400 mg / day, 600 mg / day, 800 mg / day, 1200 mg / day.

8. According to the use according to any one of claims 1 to 7, the drug is a composition, which comprises a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers; preferably, the drug is a unit dose pharmaceutical composition, each unit dose comprising 50 mg to 800 mg, for example, 50 mg, 100 mg, 200 mg, 300 mg or 400 mg of the compound represented by formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers; preferably, the drug is administered in a manner selected from simultaneous administration, independently formulated and co-administered, or independently formulated and administered sequentially; preferably, the drug is administered orally, parenterally or transdermally; the parenteral administration is selected from injection, including but not limited to intravenous injection, subcutaneous injection or intramuscular injection.

9. The use according to any one of claims 1 to 4, wherein the medicament is used to reduce 24-hour urine albumin in subjects with diabetic nephropathy and lupus nephritis.

10. The use according to any one of claims 1 to 4, wherein the medicament is used to reduce the deposition of C3 and / or C5b-9 in glomeruli of subjects with diabetic nephropathy and lupus nephritis.

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