Application of heterocyclic compound in preparation of medicine for preventing and / or treating kidney diseases

Abstract

The invention relates to application of a compound shown in a formula (I) or pharmaceutically acceptable salt thereof to preparation of medicine for treating and / or preventing kidney diseases. The compound shown in the formula (I) is as follows: # imgabs0 #.

Description

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

[0002] The present invention belongs to the field of medicine, and in particular 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 excretion and / or a progressive decrease in glomerular filtration rate (GFR), eventually developing into end-stage renal disease (ESRD).

[0004] DKD mainly includes urine albumin to creatinine ratio (UACR) ≥ 30mg / g or urine albumin excretion rate (UAER) ≥ 30mg / 24h, and repeated UACR or UAER within 3 to 6 months, reaching or exceeding the critical value 2 out of 3 times; excluding other interfering factors such as infection; and (or) estimated glomerular filtration rate (eGFR) < 60ml·min-1·(1.73m2)-1, and lasting for more than 3 months. DKD is renal damage caused by chronic hyperglycemia, and the lesions can affect the whole kidney (including glomeruli, renal tubules, renal interstitium and renal blood vessels); podocytes are located on the epithelial surface of the glomerulus, and molecules below 60kda are filtered through them. The disappearance of podocyte foot processes is associated with the occurrence of proteinuria and nephrotic syndrome. Podocyte foot process reduction and enlargement are seen in early DKD, while podocyte loss is seen in advanced DKD. Advanced DKD is often accompanied by massive, often nephrotic levels of 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 Clinical Diagnosis and Treatment of Diabetic Kidney Disease", the existing treatments for diabetic kidney disease can be summarized into the following categories: lifestyle management, blood sugar control, blood pressure and urine protein control, blood lipid regulation, uric acid control, etc. Existing DKD treatments lack high-quality evidence-based medical data to prove the effectiveness of existing treatments. The development of new effective therapeutic drugs to meet the clinical needs of DKD patients is of great social and practical significance.

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

[0007] LN has various clinical manifestations, ranging from asymptomatic proteinuria and / or hematuria in mild cases to nephrotic syndrome or rapidly progressive glomerulonephritis in severe cases. Persistent and recurrent lesions can also lead to chronic renal insufficiency or even renal failure. Patients may experience abnormal urine volume (oliguria or increased nocturia), hematuria, foamy urine, edema, and hypertension. Most have microscopic hematuria. Proteinuria is the most common, with varying degrees of severity. Patients may experience increased blood pressure, which is more significant when combined with renal vascular disease. Summary of the invention

[0008] 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.

[0009] The present invention provides a use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in preparing a medicament for treating and / or preventing kidney disease, wherein the kidney disease is diabetic nephropathy and lupus nephritis.

[0010]

[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 Haloalkyl;

[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 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;

[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 The alkoxy group 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 3-6Cycloalkyloxy 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 by 1 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 group, 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 with 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 by 1 or more R a Replacement; R 11 H; 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 1-6The 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. 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 they 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 the following formula (II):

[0034]

[0035] 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 group, the C 1-6 Alkyl, C 3-6 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 are as defined in the compound represented by the above formula (I).

[0036] In some embodiments of the present invention, each group in the compound of formula (II) has the following definitions:

[0037] 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 C1-6 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.

[0038] 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),

[0039]

[0040] 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 the above formula (I).

[0041] In some embodiments of the present invention, the compound represented by formula I can be selected from the following structures:

[0042]

[0043]

[0044]

[0045] In some embodiments of the present invention, the compound represented by formula (I) is compound A, and the structural formula of compound A is

[0046]

[0047] 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.

[0048] In some embodiments of the present invention, the pharmaceutically acceptable salt is a hydrochloride salt.

[0049] In some embodiments of the invention, the pharmaceutically acceptable salt is a monohydrochloride salt.

[0050] In some embodiments of the present invention, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound B,

[0051] In some embodiments of the present invention, the kidney disease is diabetic nephropathy.

[0052] 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.

[0053] 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 decrease in glomerular filtration rate (GFR) in a subject with diabetic nephropathy.

[0054] On the other hand, 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 the urine albumin to creatinine ratio (UACR) of a subject suffering from diabetic nephropathy.

[0055] In some embodiments of the invention, the subject suffers from type 2 diabetes.

[0056] 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.

[0057] In some embodiments of the present invention, the kidney disease is lupus nephritis.

[0058] In some embodiments of the present invention, the lupus nephritis includes mesangial mild 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).

[0059] In some embodiments of the present invention, the lupus nephritis is focal LN (type III) or diffuse LN (type IV).

[0060] In some embodiments of the present invention, the lupus nephritis is a first attack or a relapse of lupus nephritis.

[0061] In some embodiments of the present invention, the recurrent lupus nephritis is lupus nephritis that relapses after treatment with cyclophosphamide or mycophenolate mofetil (MMF).

[0062] In some embodiments of the present invention, the patient with lupus nephritis suffers from systemic lupus erythematosus (SLE).

[0063] 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 the urine albumin to creatinine ratio (UACR) of a subject suffering from lupus nephritis.

[0064] In some embodiments of the present invention, the drug is in the form of an oral dosage form or an injection dosage form.

[0065] In some embodiments of the present invention, the drug is in an oral dosage form.

[0066] 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 any combination of 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, 315 mg, 320 mg, 330 mg, 345 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 490 mg, 415 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 490 mg, 495 mg, 400 mg, 410 mg, 415 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 490 mg 15mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg , 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450 mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 5 20mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg , 590mg, 595mg, 600mg, 705mg, 710mg, 715mg, 720mg, 725mg, 730mg, 735mg, 740mg, 745mg, 750mg, 755 mg, 760mg, 765mg, 770mg, 775mg, 780mg, 785mg, 790mg, 795mg, 800mg, 850mg, 900mg, 950mg, 1000mg.

[0067] 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 ​​in 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.

[0068] 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, once every other day, once a week, twice a week, three times a week, once every other week, once every two weeks, once three weeks, once every four weeks, etc., preferably once a day or twice a day.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] In some embodiments of the present invention, the dosage of the drug (calculated as active ingredient) is 4 mg / kg to 20 mg / kg, and the frequency of administration can be once a day or twice a day.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] In some embodiments of the invention, the drug is administered at a daily dose of 400 mg / day, 600 mg / day, 800 mg / day or 1200 mg / day.

[0082] 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.

[0083] 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 the preparation of a medicament for treating and / or preventing kidney diseases, wherein the kidney diseases are diabetic nephropathy and lupus nephritis.

[0084] 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.

[0085] In some embodiments of the present invention, the administration is selected from simultaneous administration, independently formulated and co-administered, or independently formulated and sequentially administered.

[0086] 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.

[0087] Definition of terms

[0088] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0089] The term "alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical. 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.

[0090] 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-, having 1, 2, 3, 4, 5 or 6 carbon atoms; for example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, etc. or their isomers.

[0091] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein the alkyl group is as defined above.

[0092] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

[0093] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein the alkoxy group is as defined above.

[0094] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0095] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two H 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-), etc. The alkylene group may be substituted or unsubstituted.

[0096] 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 The term "Cycloalkyl" 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]nonanyl, 2,6-diazaspiro[3,4]octanyl, or a tricyclic hydrocarbon group such as adamantyl.

[0097] The term "heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, such as a 3-10 membered heterocyclyl, which is a 3-, 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9- or 10-membered bicyclic ring (such as a fused ring, a bridged ring, a spiro ring), 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- states. 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.

[0098] The term "cycloalkyloxy" refers to a cycloalkyl-O- group wherein the cycloalkyl group is as defined above.

[0099] The term "heterocyclyloxy" refers to heterocyclyl-O- wherein the heterocyclyl group is as defined above.

[0100] The term "diabetic nephropathy (DKD)" is a chronic kidney disease caused by diabetes. The cause of the disease is renal damage caused by chronic hyperglycemia. The lesions can affect the entire kidney (including glomeruli, tubules, renal interstitium and renal blood vessels, etc.), and the clinical characteristics are persistent increased urinary albumin excretion and (or) progressive decrease in glomerular filtration rate (GFR). For example, the clinical characteristics of DKD are increased urinary albumin excretion, decreased glomerular filtration rate, and obvious histopathological changes, including thickening of the glomerular basement membrane, mesangial expansion, tuberous sclerosis, interstitial fibrosis and tubular atrophy, as well as interstitial infiltration and vascular lesions. The deposition of C3a and C5b-9 in the glomeruli and tubulointerstitium of DKD patients is significantly higher than that in healthy subjects.

[0101] 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.

[0102] The term "effective amount" or "therapeutically effective amount" refers to the 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 intended application (in vitro or in vivo), or the subject and the disease condition to be treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be easily determined by a person of ordinary skill in the art. The specific dosage will vary depending on the following factors: the specific compound selected, the dosage regimen relied on, 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 carried.

[0103] 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.

[0104] The term "lupus nephritis (LN)" refers to a renal complication caused by systemic lupus erythematosus (SLE). For example, the clinical manifestations of LN are abnormally elevated urine protein, and the plasma levels of C3a, C5a, and soluble C5b-9 in patients with active lupus nephritis are significantly elevated.

[0105] Currently, according to pathological classification, it is divided into mild mesangial lesion LN (type I), mesangial hyperplastic LN (type II), focal LN (type III), diffuse LN (type IV), membranous LN (type V), and sclerosing LN (type VI).

[0106] 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.

[0107] Mesangial proliferative LN (type II): Light microscopy shows simple mesangial cell proliferation to varying degrees or accompanied by increased mesangial matrix and immune complex deposition in the mesangial area; immunofluorescence and electron microscopy show a small amount of subepithelial or subendothelial immune complex deposition.

[0108] Focal LN (type III): divided into active (A) or inactive (C) lesions, showing focal (affecting <50% of glomeruli), segmental or spherical intraglomerular proliferation, membrane proliferation and moderate to severe mesangial proliferation or with crescent formation, typical focal subendothelial immune complex deposition, with or without mesangial changes. III (A): Active lesions: focal proliferative lupus nephritis. III (A / C): Active and chronic lesions: focal proliferative and sclerosing lupus nephritis. III (C): Chronic inactive lesions with glomerular sclerosis: focal sclerosing lupus nephritis.

[0109] Diffuse LN (Type IV): active or inactive lesions. Diffuse (≥50% of affected glomeruli) segmental or spherical glomerular capillary proliferation, membrane proliferation and moderate to severe mesangial proliferation, or crescentic glomerulonephritis, typical diffuse subendothelial immune complex deposition, with or without mesangial lesions. Type IV lupus nephritis is divided into two subtypes: IV-S lupus nephritis: segmental lesions in more than 50% of glomeruli; IV-G lupus nephritis: spherical lesions in more than 50% of glomeruli. If diffuse "platinum ear-like" lesions occur, even mild or non-cellular lupus nephritis is classified as type IV diffuse lupus nephritis.

[0110] Membranous LN (type V): diffuse thickening of the glomerular basement membrane, diffuse or segmental subepithelial immune complex deposition, with or without mesangial lesions. Type V membranous lupus nephritis may be combined with type III or type IV lesions, and a composite diagnosis should be made, such as type V + type III, type V + type IV, etc., and may progress to type VI sclerosing lupus nephritis.

[0111] 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

[0112] Attached Figure 1 : 24-hour urine albumin content at the end point of the study in the SD rat nephropathy model induced by BSA / LPS / CCL4;

[0113] Attached Figure 2 :Deposition of C3 in glomeruli in the SD rat nephropathy model induced by BSA / LPS / CCL4;

[0114] Attached Figure 3 :Deposition of C5b-9 in glomeruli in SD rat nephropathy model induced by BSA / LPS / CCL4.

[0115] Beneficial effects:

[0116] The compound of the present invention has therapeutic effects on diabetic nephropathy and lupus nephritis. DETAILED DESCRIPTION

[0117] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions 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 included in the scope that the present invention is intended to protect.

[0118] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0119] Preparation Example 1: Preparation of Compound A

[0120] Reaction formula for the synthesis of compound A and intermediate b

[0121]

[0122] Preparation of intermediate b

[0123] In a 250mL single-mouth bottle, dichloromethane (50mL), 5-methoxy-7-methyl-1H-indole (3g), Boc anhydride (5.68g), 4-dimethylaminopyridine (227mg) and triethylamine (2.26g) were added in sequence, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched by adding saturated ammonium chloride solution (5mL), extracted with dichloromethane (20mL) three times, and the combined organic phase was washed with water (5mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain intermediate a (4.6g, yield: 94%). MS m / z (ESI): 262.0 [M+1].

[0124] In a 250mL single-mouth bottle, dichloromethane (80mL), N-methylformanilide (3.8g) and oxalyl chloride (3.6g) were added in sequence, and the reaction was stirred at room temperature for 3 hours. Then the reaction temperature was lowered to -14°C, and intermediate a (2.5g) 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 (100mL), extracted with dichloromethane (100mL) three times, and the combined organic phase was washed twice with water (10mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain intermediate b (1.3g, yield: 47%).

[0125] MS m / z(ESI):290.0[M+1]. 1 H NMR (400MHz, CDCl3) δ10.65 (s, 1H), 7.65 (d, J = 3.4Hz, 1H), 7.49 (d, J

[0126] =3.4Hz,1H),6.76(s,1H),3.98(s,3H),2.70(s,3H),1.65(s,9H).

[0127] Preparation of Compound A

[0128] first step:

[0129] In a 3L three-necked flask, tetrahydrofuran (150mL) and 4-bromobenzonitrile (50g) were added in sequence, and isopropylmagnesium chloride lithium chloride complex (1.3M, 210mL) was slowly added to the reaction system under nitrogen protection, and the reaction was carried out at room temperature for 2 hours. Then anhydrous tetrahydrofuran (500mL) was added to the reaction system for dilution and the temperature was lowered to -5°C, 4-methoxypyridine (25mL) was added, and benzyl chloroformate (35mL) was slowly added dropwise (maintaining the system temperature below 0°C), and the reaction was stirred at 0°C for 2 hours after the addition was completed, and then the temperature was raised 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), extracted twice with ethyl acetate (500 mL), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The crude product obtained after concentration of the filtrate was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1-1: 1) to obtain compound 1 (23 g, yield: 23%).

[0130] MS m / z(ESI):333.0[M+1].

[0131] Step 2:

[0132] 46g of compound 1 prepared in the first step and the second batch were taken out (28g), zinc powder (55g) and acetic acid (200mL) were added to a 500mL single-mouth bottle in sequence, and the reaction was heated to 100°C and stirred at this temperature for 16 hours. After the reaction was completed, the mixture was filtered, the filtrate was diluted with water (500mL), extracted with ethyl acetate (500mL), the organic phase was washed twice with saturated sodium bicarbonate aqueous solution (500mL), washed once with saturated brine (100mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2 (26g, yield: 73%).

[0133] MS m / z(ESI):334.8[M+1].

[0134] Step 3:

[0135] In a 500mL single-mouth bottle, tetrahydrofuran (100mL), ethanol (100mL) and compound 2 (26g) were added in sequence, and then sodium borohydride (2g) was added in batches, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the system was cooled to 0°C, saturated aqueous ammonium chloride solution (30mL) was added until the temperature no longer increased, water (500mL) was added to dilute, and extracted twice with ethyl acetate (200mL); the combined organic phase was washed with saturated brine (500mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3 (25g, yield: 76%).

[0136] MS m / z(ESI):336.9[M+1].

[0137] Step 4:

[0138] Dichloromethane (200 mL) was added to a 500 mL single-mouth bottle, and then compound 3 (25 g), imidazole (6.6 g) and tert-butyldiphenylsilyl chloride (25 g) were added in sequence, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was washed with water (500 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. 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).

[0139] MS m / z(ESI):597.0[M+23].

[0140] Step 5:

[0141] 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, water (100 mL) was added for dilution, and ethyl acetate (50 mL) was used for extraction three times. The combined organic phase was 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 subjected to chiral separation 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%).

[0142] MS m / z(ESI):358.8[M+23].

[0143] Step 6:

[0144] To a solution of compound 5 (1200 mg) in N,N-dimethylformamide (10 mL), imidazole (486 mg) and tert-butyldimethylsilyl chloride (593 mg) were added, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL), the organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was directly concentrated to obtain compound 6 (600 mg, yield: 90%).

[0145] MS m / z(ESI):472.8[M+23].

[0146] Step 7:

[0147] At room temperature, 1.2 g of compound 6 from the second batch of the sixth step 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, and then triethylsilane (180 mg) was added. The reaction was naturally warmed to room temperature and continued to stir 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, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain compound 7 (400 mg, yield: 46%).

[0148] MS m / z(ESI):390.9[M+1].

[0149] Step 8:

[0150] Compound 7 (400 mg), isopropanol (2 mL), water (3 mL), and sodium hydroxide (400 mg) were added to a 50 mL single-mouth bottle in sequence, and the reaction mixture was heated to 100° C. and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was added with dilute hydrochloric acid (1 M) to adjust the pH to 5-6 under an ice bath, diluted with water (5 mL), extracted with ethyl acetate (5 mL), and the organic phase was washed once with saturated brine (5 mL), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated at 45° C. to obtain compound 8 (200 mg, yield: 33%).

[0151] MS m / z(ESI):431.8[M+23].

[0152] Step 9:

[0153] Potassium carbonate (135 mg) and iodomethane (140 mg) were added to a solution of compound 8 (200 mg) in acetonitrile (5 mL), and the reaction solution was heated to 50° C. and stirred at this temperature for 16 hours. After the reaction was completed, 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%).

[0154] MS m / z(ESI):445.8[M+23].

[0155] Step 10:

[0156] Palladium / carbon (50 mg) was added to a tetrahydrofuran (3 mL) solution of compound 9 (180 mg), and the reaction solution was subjected to catalytic hydrogenation reaction at room temperature under a hydrogen atmosphere for 2 hours. After the reaction, the reaction solution was filtered and the filtrate was directly concentrated to obtain compound 10 (120 mg, yield: 54%).

[0157] MS m / z(ESI):290.0[M+1].

[0158] Step 11:

[0159] Compound 10 (120 mg) was added to a solution of intermediate b (119 mg) in 1,2-dichloroethane (5 mL), and the reaction was stirred at room temperature for 8 hours, and then sodium acetate borohydride (261 mg) was added and continued to stir at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated, and the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain compound 11 (200 mg, yield: 26%).

[0160] MS m / z(ESI):562.8[M+1].

[0161] Step 12

[0162] Methanol (2 mL), water (2 mL), compound 11 (200 mg) and sodium hydroxide (150 mg) were added to a 50 mL single-mouth bottle in sequence, and the reaction mixture was heated to 75° C. and stirred at this temperature for 3 hours. After the reaction was completed, the reaction solution was added with dilute hydrochloric acid (1 M) in an ice bath to adjust the pH to 7, and then directly concentrated under reduced pressure and purified by Prep-HPLC (chromatographic column: Gemini-C18, 150 x 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-40%) to obtain compound A (30.6 mg, yield: 18%; containing 0.5 equivalents of formic acid).

[0163] MS m / z(ESI):448.9[M+1].

[0164] 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).

[0165] Unless otherwise stated, the compounds A mentioned below were prepared by the above method or by repeating the above method.

[0166] Preparation Example 2 Preparation method of monohydrochloride of compound A

[0167]

[0168] After compound A was prepared in multiple batches, 400 mg of compound A was taken, 8 mL of isopropanol was added, and heated at 50°C to dissolve. Then 460 μL of hydrogen chloride isopropanol solution (concentration was 2 mol / L) was slowly added dropwise, stirred for half an hour, and then 8 mL of n-heptane was added, and stirring was continued for 2 hours. Filter, and the filter cake was dried under reduced pressure at 50°C to obtain 390 mg of monohydrochloride of compound A (compound B), with a yield of 90%.

[0169] Test Example 1. In vitro cell test

[0170] HK-2 cell line was derived from immortalized PTECs from human kidney and purchased from ATCC. HK-2 cells were cultured in DMEM / F12 medium (Gibco, 10565042) containing 10% fetal bovine serum (Gibco, 10099-141C) and 1% penicillin / streptomycin (Gibco, 15140122). HK-2 cells were seeded at a density of 1×105 cells / well in a 6-well plate (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, and then the cells were harvested and used for real-time fluorescence quantitative PCR to analyze the mRNA expression of IL-1β, CFB and TNF-α, respectively. The kit method was used to detect the levels of intracellular ROS (Beyotime Biotechnology, S0033S) and SOD (Beyotime Biotechnology, S0101S). All operations were performed as described in the reagent operating manual.

[0171] Total RNA was extracted from cells using 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 High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, 4368814), and RT-qPCR analysis was performed using Bio-Rad CFX96, and Real-Time PCR was analyzed using SYBR Green Master Mix (Applied Biosystems, A46012).

[0172] RT-qPCR primer sequences

[0173]

[0174] Test Example 2. In vivo test

[0175] 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.

[0176] During the study, all male BTBR ob / ob animals were housed under SPF conditions. At 8-12 weeks of age, BTBR ob / ob mice had developed proteinuria and glomerular damage. The diseased BTBR ob / ob mice were randomly divided into several groups and given the test compound by gavage once a day for 4-6 weeks. After the end of the administration, the experiment was terminated. Before euthanasia, the mice were placed in metabolic cages to collect 24-hour urine to evaluate urine albumin, urine creatinine, and urine albumin to creatinine ratio (UACR); blood samples were collected to measure indicators such as glucose, cholesterol, and triglyceride levels. Mice were euthanized by CO2 inhalation, and kidneys were collected for renal tissue pathology tests such as renal tissue inflammation, glomerular area, podocyte loss, and tubulointerstitial damage.

[0177] Test Example 3. In vivo test

[0178] 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 orally administered for 2-6 months. Urine was collected from 2 to 6 months for urine biochemical testing. The mice were killed and serum, urine and kidney tissue were collected for blood, urine biochemical and renal pathology testing.

[0179] Conclusion: Compound B can reduce urine albumin, UACR (urine protein to creatinine ratio) and complement deposition in renal tissue of DKD model mice.

[0180] Test Example 4. In vivo test

[0181] After the blood glucose of 6-9 week old male db / db mice increased to 16.7 mmol / L, they were divided into groups and the test compound was orally administered for 2-6 months. Urine was collected from 2 to 6 months for urine biochemical test. The mice were killed and serum, urine and kidney tissue were collected for blood, urine biochemical and kidney pathology tests.

[0182] After compound intervention, the renal function-related urine protein, renal tissue pathology and other indicators of the compound group mice were significantly improved.

[0183] Test Example 5: In vivo test

[0184] This study used spontaneously ill 24-26 week old NZBWF1 mice. The test articles were 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 UV method using a fully automatic analyzer. Total IgG and anti-double-stranded DNA (anti-dsDNA) autoantibodies in serum were measured by ELISA before and every 4 weeks after administration. Renal tissue pathology indicators were detected at the end of the study.

[0185] Test Example 6: In vivo test

[0186] This study used spontaneously ill MRL / lpr mice, and the test article was administered orally (PO) starting from 13-15 weeks of the model. The drug was administered continuously 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 automatic analyzer. Total IgG and anti-double-stranded DNA (anti-dsDNA) autoantibodies in serum were measured by ELISA before and every 4 weeks after administration. Renal tissue pathology indicators were detected at the end of the study.

[0187] Conclusion: Compound B can improve the renal function, urine protein level and renal tissue pathology score of lupus nephropathy mice to a certain extent.

[0188] Test Example 7. In vivo test

[0189] Research method: The pharmacodynamic effect of compound B was evaluated in the SD rat nephropathy model induced by BSA / LPS / CCL4. In the animal nephropathy model induced by BSA (bovine serum albumin) / LPS / CCL4, the urine protein level in the nephropathy animals was significantly increased, and the complement activity was significantly deposited in the renal tissues, such as C5b-9 and C3. These characteristics are consistent with the disease status, characteristics and indicators to be improved of animal DKD and LN. Therefore, the pharmacodynamic effect of compound B of the present invention was evaluated.

[0190] A total of 60 male Sprague Dawley rats were used in this experiment. The modeling method was to perform BSA / LPS / CCL4 combined induction after unilateral renal resection. The administration method was oral administration: the normal control group group 1 (G1) and the model group group 2 (G2) were given the solvent. Group 3 (G3) was given dexamethasone at a dose of 0.3 mg / kg, gavage, once a day; Group 4 (G4) was given compound B at a dose of 5 mg / kg, gavage, twice a day; Group 5 (G5) was given compound B at a dose of 15 mg / kg, gavage, twice a day; Group 6 (G6) was given compound B at a dose of 50 mg / kg, gavage, twice a day. Administration began four weeks after BSA / LPS / CCL4 combined induction. The administration period was six weeks. Detection indicators: body weight, food intake, urine volume, urine albumin level, pathology and immunofluorescence detection of renal tissue.

[0191] 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; the deposition levels of C3 and C5b-9 in the glomeruli of the model animals were significantly increased.

[0192] Compared with the model group, compound B significantly reduced the urinary albumin concentration of the model animals at the end of the study and the 24-hour urinary albumin level in a dose-dependent manner (see Appendix Figure 1 ), and ACR; significantly reduced the deposition of C3 and C5b-9 in the glomeruli of model animals (see Appendix Figure 2 and attached Figure 3 ).

[0193] Test Example 8. A clinical trial to study the efficacy of the compound of the present invention in patients with diabetic nephropathy

[0194] 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).

[0195] The study drug is compound B:

[0196]

[0197] The dosage is 400mg BID, 600mg QD, 800mg QD or 600mg BID, and it can be taken on an empty stomach or after a meal.

[0198] 2. Research objectives:

[0199] 2.1 Main Purpose:

[0200] 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.

[0201] 2.2 Secondary Purpose

[0202] 2.2.1 The change in morning urine UPCR compared with baseline was used as an indicator to evaluate the efficacy of compound B in patients with diabetic nephropathy at D7, D14, D28, D42, D56, and D70.

[0203] 2.2.2 The change in the urine albumin to creatinine ratio (UACR) in morning urine compared with the baseline was used as an indicator to evaluate the efficacy of compound B in patients with diabetic nephropathy at D7, D14, D28, D42, D56, D70, and D84.

[0204] 2.2.3 Using the change in eGFR compared to baseline as an indicator, the efficacy of compound B in patients with diabetic nephropathy at D28, D56, and D84 was evaluated.

[0205] 3. Inclusion criteria:

[0206] 3.1 T2DKD confirmed by renal biopsy within 1 year before screening. If the last renal biopsy was confirmed more than 1 year ago, renal biopsy can be performed at any time during the screening period to confirm the diagnosis of diabetic nephropathy and help the subject to be selected.

[0207] 3.2 Urine albumin to creatinine ratio (UACR) during the screening period is ≥300 mg / g and <1500 mg / g.

[0208] 4. Exclusion criteria:

[0209] 4.1 eGFR < 30 mL / min / 1.73 m within 4 weeks before screening or during screening 2 .

[0210] 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.

[0211] Test Example 9: A clinical trial to study the efficacy of the compound of the present invention in patients with lupus nephritis

[0212] 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).

[0213] The study drug is compound B:

[0214]

[0215] The dosage is 400mg BID, 600mg QD, 800mg QD or 600mg BID, and it can be taken on an empty stomach or after a meal.

[0216] 2. Research objectives:

[0217] 2.1 Main Purpose:

[0218] 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 lupus nephritis on Day 84.

[0219] 2.2 Secondary Purpose

[0220] 2.2.1 The change in morning urine UPCR compared with baseline was used as an indicator to evaluate the efficacy of compound B in patients with lupus nephritis at D7, D14, D28, D42, D56, and D70.

[0221] 2.2.2 The change in the urine albumin to creatinine ratio (UACR) in morning urine compared with baseline was used as an indicator to evaluate the efficacy of compound B in patients with lupus nephritis at D7, D14, D28, D42, D56, D70, and D84.

[0222] 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.

[0223] 3. Inclusion criteria:

[0224] 3.1 Systemic lupus erythematosus (SLE) was diagnosed according to the 2019 European League Against Rheumatism / American College of Rheumatology (EULAR / ACR) criteria.

[0225] 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 help the subject be selected.

[0226] 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 researchers fully consider the study protocol and believe that there is potential benefit to the patients, and they can be included in this study protocol.

[0227] 4. Exclusion criteria:

[0228] 4.1 Subjects clinically diagnosed with lupus podophyllotocin or lupus TMA.

[0229] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope 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 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.

Images