Use of molecular glue compound in preparing medicament for preventing and / or treating iga nephropathy

Abstract

The present application relates to use of a molecular glue compound or a pharmaceutically acceptable salt thereof in preparing a medicament for treating and / or preventing IgA nephropathy.

Description

Use of molecular colloidal compounds in the preparation of drugs for the prevention and / or treatment of IgA nephropathy

[0001] Cross-reference to related applications

[0002] This application is based on and claims priority to CN application No. 202411925198.4 filed on December 25, 2024, and CN application No. 202511902747.0 filed on December 16, 2025, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This invention belongs to the field of medicine, specifically relating to the use of molecular gel compounds in the preparation of drugs for the prevention or treatment of IgA nephropathy. Background Technology

[0004] VAV1 is a member of the VAV family, a group of signal transduction proteins that act as phosphorylation-dependent GDP / GTP exchange factors (GEFs) and adaptor molecules for Rho subfamily GTPases. In vertebrates, this family consists of three members: VAV1, VAV2, and VAV3. VAV1 primarily encodes and expresses GEFs in human hematopoietic stem cells, including T cells, B cells, monocytes, natural killer (NK) cells, granulocytes, and dendritic cells, while family members VAV2 and VAV3 are more commonly expressed. The VAV protein family is crucial for the homeostasis of the central nervous system, cardiovascular system, and immune system, and is involved in the development and progression of diseases such as autoimmune diseases, transplant rejection, and cancer.

[0005] VAV1 possesses multiple domains, determining its dual function as a GEF (gastrointestinal fibroblast) and scaffold protein. In its resting state, unphosphorylated VAV1 exhibits a closed, inactive conformation: the N-terminal CH-AC domain and the C-terminal SH3 domain fold inwards to bind to the catalytic core (DH-PH-ZF domain), simultaneously inhibiting GEF activity and adaptor protein function. When the AC structure of VAV1 is phosphorylated, the inhibitory folds within the protein are released, forming an open, active conformation, enabling it to perform both GEF and adaptor protein functions. The primary substrate for VAV1's GEF function is Rac1, which participates in regulating actin dynamics signaling pathways and cytoskeleton remodeling, facilitating immune cell migration, adhesion, and immune synapse formation. As a scaffold protein, it interacts with various protein complexes to form the TCR / BCR proximal complex, performing adaptor protein function and regulating T cell and B cell receptor activation signal transduction.

[0006] IgA nephropathy (IgAN) is a complex, immune-related primary glomerulonephritis characterized by the deposition of IgA or predominantly IgA-based immune complexes in the glomeruli, accompanied by various pathological damage. In China, IgA nephropathy accounts for nearly half of all primary glomerulonephritis cases. It is most common in adolescents and is one of the most frequent causes of end-stage renal disease. Compared to conventional nephritis, such as glomerulonephritis, IgA nephropathy has a higher clinical incidence, more complex treatment, faster disease progression, and a worse prognosis. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides the use of a molecular gel compound in the preparation of a medicament for treating and / or preventing IgA nephropathy.

[0008] Specifically, on the one hand, the present invention provides the use of a compound of Formula I or a stereoisomer thereof, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate in the preparation of a medicament for treating and / or preventing IgA nephropathy;

[0009] Meanwhile, the present invention also provides a method for treating and / or preventing IgA nephropathy in a subject in need, comprising administering to the subject an effective amount of a compound of formula I or a stereoisomer thereof, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate thereof.

[0010] Furthermore, the present invention also provides a compound of Formula I or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, for the treatment and / or prevention of IgA nephropathy;

[0011] in:

[0012] R 1 Selected from

[0013] R 2 R 3 R 4 R 5 R 6 and R 7 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C3-C6 cycloalkyl;

[0014] R a R b R c and R dEach is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C3-C6 cycloalkyl;

[0015] n can be 0, 1, 2, 3, or 4.

[0016] In some embodiments of the present invention, R 1 for

[0017] In some embodiments of the present invention, R 1 Selected from

[0018] In some embodiments of the present invention, R 1 for

[0019] In some embodiments of the present invention, R 2 It is a halogen or a C1-C6 haloalkyl group.

[0020] In some embodiments of the present invention, R 2 It is a halogen.

[0021] In some embodiments of the present invention, R 2 It is chlorine.

[0022] In some embodiments of the present invention, R 3 R 4 R 5 R 6 and R 7 Each is independently selected from hydrogen and C1-C6 alkyl groups.

[0023] In some embodiments of the present invention, R 3 R 4 R 5 R 6 and R 7 It is hydrogen.

[0024] In some embodiments of the present invention, R a R b R c and R d Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.

[0025] In some embodiments of the present invention, R a R b R c and R d Each is independently selected from hydrogen, fluorine, methyl, methoxy, -CF3 and -CHF2.

[0026] In some embodiments of the present invention, R a R b R c and R d Both are hydrogen.

[0027] In some embodiments of the present invention, n is 0.

[0028] On the other hand, the present invention provides the use of compound A or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate (preferably compound A or its pharmaceutically acceptable salt) in the preparation of a medicament for treating and / or preventing IgA nephropathy.

[0029] In addition, the present invention also provides a method for treating and / or preventing IgA nephropathy in a subject in need, comprising administering to the subject an effective amount of compound A or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate.

[0030] Furthermore, the present invention also provides a compound A or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate, for the treatment and / or prevention of IgA nephropathy.

[0031] In some embodiments of the present invention, compound A is selected from compound A-1, compound A-2, or a mixture of compound A-1 and compound A-2 in any proportion.

[0032] In some embodiments of the present invention, the IgA nephropathy includes primary IgA nephropathy and secondary IgA nephropathy.

[0033] In some embodiments of the present invention, the primary IgA nephropathy includes primary IgA nephropathy caused by genetic factors or abnormal autoimmune regulation.

[0034] In some embodiments of the present invention, the primary IgA nephropathy is characterized by an eGFR ≥ 30 mL / min / 1.73 m 2 “eGFR” refers to glomerular filtration rate.

[0035] In some embodiments of the present invention, the secondary IgA nephropathy includes diseases secondary to allergic purpura, viral hepatitis, cirrhosis, systemic lupus erythematosus, ankylosing spondylitis, rheumatoid arthritis, mixed connective tissue disease, polyarteritis nodosa, erythema nodosa, psoriasis, ulcerative colitis, Crohn's disease, tumors, or AIDS.

[0036] In some embodiments of the present invention, the IgA nephropathy is IgA nephropathy caused by glomerular lesions; the glomerular lesions are preferably one or more of the following: abnormal urinary albumin concentration, abnormal urinary albumin amount (e.g., total 24-hour urinary albumin), abnormal urinary albumin-to-creatinine ratio, IgA deposition, and C3 deposition; the abnormal urinary albumin amount is preferably ≥0.75g / 24h urinary protein during the screening period (24-hour urine sample) and / or ≥0.75g / 24h urinary protein level before the first administration of the study drug.

[0037] In some embodiments of the present invention, the IgA nephropathy is IgA nephropathy caused by glomerular lesions; the glomerular lesions are preferably C3 deposition and / or C5b-9 deposition.

[0038] In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, stearate, laurate, p-toluenesulfonate, methanesulfonate, fumarate, hydroxyethylsulfonate, maleate, malate, tartrate, citrate, oxalate, benzoate, bis(hydroxynaphthyl)ate, salicylate, vanillate, and succinate.

[0039] In some embodiments of the present invention, the drug or the compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate are presented in oral or injectable dosage forms.

[0040] In some embodiments of the present invention, the drug or the compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate are presented in an oral dosage form.

[0041] In some embodiments of the present invention, the dosage (calculated per active ingredient) of the drug or the compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate is any value or combination of the ranges of 0.1-1000 mg, 0.1-200 mg, 1-50 mg, or 1-20 mg.For example, 0.5mg, 1mg, 1.5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg... g, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 100mg, 150mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230 mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 33 0mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 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, 515mg, 520mg, 525m The dosages listed are as follows: g, 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, 755mg, 760mg, 765mg, 770mg, 775mg, 780mg, 785mg, 790mg, 795mg, 800mg, 850mg, 900mg, 950mg, 1000mg. The dosage referred to here is the total amount of active ingredient administered within a single dosing cycle.

[0042] In some embodiments of the present invention, the dosage (calculated per active ingredient) of the drug or the compound or its stereoisomers, its prodrugs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates is 0.1 mg / kg to 300 mg / kg, preferably any value from 4 mg / kg to 20 mg / kg or any combination of values ​​within the range, such as 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. g, 16mg / kg, 17mg / kg, 18mg / kg, 19mg / kg, 20mg / kg, 21mg / kg, 22mg / kg, 23mg / kg, 24mg / kg, 25mg / kg, 26mg / kg, 27mg / kg, 28mg / kg, 29mg / kg, 30mg / k g, 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 / k g, 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, 17 0mg / kg, 175mg / 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, 240mg / 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.

[0043] In some embodiments of the present invention, a unit dose of the drug comprises the compound or its stereoisomers, prodrugs, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, within the range of any value or combination of 0.1-1000 mg, 0.1-200 mg, 1-50 mg, 1-20 mg, or 50 mg-1000 mg. Alternatively, the compound or its stereoisomers, prodrugs, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof are formulated as a unit dose formulation comprising the compound or its stereoisomers, prodrugs, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, within the range of any value or combination of 0.1-1000 mg, 0.1-200 mg, 1-50 mg, 1-20 mg, or 50 mg-1000 mg.For example, it contains 0.5mg, 1mg, 1.5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, etc. mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 100mg, 150mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 23 0mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 3 30mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 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, 515mg, 520mg, 525m g, 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, 755mg, 760mg, 765mg, 770mg, 775mg, 780mg, 785mg, 790mg, 795mg, 800mg, 850mg, 900mg, 950mg, 1000mg. Those skilled in the art will understand that a unit dose of drug refers to a pre-packaged, individually packaged drug containing a single-dose dose.For example, for tablets, the common unit dose is one tablet in a blister pack, but a unit dose may also consist of multiple tablets to meet the total amount of active ingredient required for a single administration.

[0044] In some embodiments of the present invention, the frequency of administration of the drug or the compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate may 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 every three weeks, once every four weeks, etc., preferably once a day or twice a day.

[0045] In some embodiments of the present invention, the medicament further comprises one or more pharmaceutically acceptable carriers.

[0046] In some embodiments of the present invention, the weight ratio of the compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate in the medicament is 1-99% or 65-99% or any value therein or any combination of values ​​within the range, for example 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90%.

[0047] In some embodiments of the present invention, the drug is used in combination with one or more other therapeutic agents selected from glucocorticoids and angiotensin receptor blockers.

[0048] On the other hand, the present invention provides the use of a pharmaceutical composition in the preparation of a medicament for treating and / or preventing IgA nephropathy, said pharmaceutical composition comprising an effective amount (e.g., a therapeutically effective amount) of the compound or its stereoisomer as described above, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate (preferably said compound or its pharmaceutically acceptable salt), and one or more pharmaceutically acceptable carriers.

[0049] Meanwhile, the present invention also provides the use of a unit dose pharmaceutical composition in the preparation of a medicament for treating and / or preventing IgA nephropathy, wherein each unit dose contains 50 mg to 1000 mg of the compound or its stereoisomer as described above, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate, and one or more pharmaceutically acceptable carriers.

[0050] Furthermore, the present invention also provides a pharmaceutical composition for treating and / or preventing IgA nephropathy, the pharmaceutical composition comprising an effective amount of the compound or its stereoisomer as described above, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate, and one or more pharmaceutically acceptable carriers.

[0051] In addition, the present invention also provides a unit dose pharmaceutical composition for treating and / or preventing IgA nephropathy, each unit dose comprising 50 mg to 1000 mg of the compound or its stereoisomer as described above, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate, and one or more pharmaceutically acceptable carriers.

[0052] Furthermore, the present invention also provides a method for treating and / or preventing IgA nephropathy, comprising administering to a subject an effective amount of a pharmaceutical composition comprising an effective amount of the compound or its stereoisomer as described above, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate, and one or more pharmaceutically acceptable carriers.

[0053] Furthermore, the present invention also provides a method for treating and / or preventing IgA nephropathy, comprising administering to a subject a unit dose of a pharmaceutical composition, each unit dose containing 50 mg to 1000 mg of the compound or its stereoisomer as described above, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate, and one or more pharmaceutically acceptable carriers.

[0054] In some embodiments of the present invention, the pharmaceutical composition comprises, by weight, the compound or its stereoisomer as described above, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate, in a range of 1-99% or 65-99% or any combination of values ​​within the range, such as 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90%.

[0055] On the other hand, the present invention provides the use of the compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate as described above, in combination with one or more other therapeutic agents in the preparation of a medicament for treating and / or preventing IgA nephropathy.

[0056] The present invention also provides a method for treating and / or preventing IgA nephropathy, comprising administering to a subject, in combination, an effective amount of the compound or its stereoisomer as described above, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate, and a further therapeutic agent, wherein the further therapeutic agent is selected from one or more glucocorticoids and angiotensin receptor blockers.

[0057] In some embodiments of the present invention, the route of administration is oral, parenteral, or transdermal, with oral administration being preferred. The parenteral administration is selected from injection, including but not limited to intravenous injection, subcutaneous injection, or intramuscular injection.

[0058] In some embodiments of the present invention, the drug or the compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate are used to treat glomerular lesions in subjects with IgA nephropathy. Preferably, the treatment includes reducing proteinuria in the subject; preferably, the treatment includes reducing the urinary albumin-creatinine ratio (ACR) in the subject.

[0059] In some embodiments of the present invention, the drug or the compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate are used to reduce IgA deposition in the kidney tissue of subjects with IgA nephropathy.

[0060] In some embodiments of the present invention, the glucocorticoid drug is selected from prednisone, methylprednisolone, betamethasone, beclomethasone dipropionate, prednisolone, hydrocortisone, dexamethasone, and budesonide.

[0061] In some embodiments of the present invention, the angiotensin receptor blocker is selected from losartan, valsartan, irbesartan, candesartan, telmisartan, olmesartan, and alisartan.

[0062] In this invention, "combination" or "joint administration" refers to the administration of one or more other therapeutic agents when a previously administered therapeutic agent remains effective in the patient. One therapeutic agent and one or more other therapeutic agents may be administered simultaneously, before, or after the patient.

[0063] Terminology Definition

[0064] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar inappropriate reactions, such as gastrointestinal upset, dizziness, etc.

[0065] The term "effective amount" or "therapeutic effective amount" refers to the amount of the compound described in this invention sufficient to achieve the intended application (including, but not limited to, the treatment of diseases as defined below). Therapeutic effective amounts can vary depending on factors such as the intended application (in vitro or in vivo), the subject being treated, and the condition of the disease, such as the subject's weight and age, the severity of the disease, and the route of administration, which can be readily determined by those skilled in the art. Specific dosages will vary depending on factors such as the particular compound selected, the administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which the drug is administered, and the physical delivery system used.

[0066] In this invention, "subject" refers to a vertebrate. In some embodiments, vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In some embodiments, mammal refers to a human.

[0067] The term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antimicrobial agents, antifungal agents), isotonic agents, absorption delay agents, salts, preservatives, pharmaceuticals, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, and the like and combinations thereof, which are considered for use in therapeutic or pharmaceutical compositions unless any conventional carrier is incompatible with the active ingredient.

[0068] In this invention, unless otherwise explicitly stated, the descriptive phrases “...each independently selected from” or “each…independently selected from” used throughout this document are interchangeable. They can mean either that the specific options expressed by the same or different symbols in different groups do not affect each other, or that the specific options expressed by the same or different symbols in the same group do not affect each other.

[0069] The term "C1-C6 alkyl" refers to any straight-chain or branched group containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-pentyl, n-hexyl, etc., preferably "C1-C4 alkyl".

[0070] The term “C1-C6 alkoxy” refers to any of the above “C1-C6 alkyl” connected to the rest of the molecule by an oxygen atom (-O-), preferably “C1-C4 alkoxy”.

[0071] The term “C1-C6 alkylthio” refers to any of the above “C1-C6 alkyl” linked to the rest of the molecule by a sulfur atom (-S-), preferably “C1-C4 alkylthio”.

[0072] The term "C1-C6 haloalkyl" refers to a group obtained by replacing one or more (e.g., 2 or 3) hydrogen atoms in any of the above "C1-C6 alkyl" with a halogen (preferably fluorine).

[0073] The term "C3-C6 cycloalkyl" refers to a 3- to 6-membered all-carbon saturated monocyclic or polycyclic alkyl group. Examples of C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0074] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0075] The term "stereoisomer" refers to a compound with the same molecular structure as the compound of the present invention but a different spatial configuration. The compounds of the present invention may include one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isolation of individual isomers or the selective synthesis of individual isomers is achieved by applying various methods well known to those skilled in the art. For example, isomers may be isolated from mixtures by methods known to those skilled in the art, including but not limited to: chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. Unless otherwise stated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Unless otherwise stated, the structures described herein also imply all stereochemical forms encompassing that structure; i.e., the (R) and (S) configurations of each asymmetric center. Therefore, those skilled in the art will generally consider that single stereochemical isomers of stable compounds of the present invention, as well as mixtures of enantiomers and diastereomers, are within the scope of the present invention.

[0076] The term "prodrug" refers to a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide the compounds of the present invention. Prodrugs become active compounds only after undergoing the reaction under biological conditions, or they are active in their unreacted forms. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, 5th edition).

[0077] The terms "solvent" or "solvent compound" are used interchangeably to refer to a compound existing in combination with a solvent molecule. This combination may include a stoichiometric amount of a solvent, such as a monohydrate or dihydrate, or may include any amount of water; similarly, methanol or ethanol may form an "alcohol," which may be stoichiometric or non-stoichiometric. As used herein, the term "solvent compound" refers to a solid form, that is, a compound in solution of a solvent that, while solvated, is not a solvate compound as used herein. Beneficial effects:

[0078] The compounds of this invention have therapeutic effects on IgA nephropathy. Attached Figure Description

[0079] Figure 1 shows the 24-hour urinary albumin content in a BSA / LPS / CCL4-induced SD rat nephropathy model.

[0080] Figure 2 shows the ratio of urinary albumin to creatinine in a BSA / LPS / CCL4-induced nephropathy model in SD rats.

[0081] Figure 3 shows the glomerular area ratio of IgA in the BSA / LPS / CCL4-induced nephropathy model of SD rats.

[0082] Figure 4 shows the inhibitory effect of the compound on Gd-IgA1 in R848-stimulated PBMC cells.

[0083] In Figure 1-4, * indicates p < 0.05, ** indicates p < 0.01, *** indicates p < 0.001, and **** indicates p < 0.0001. Detailed Implementation

[0084] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory 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 covered within the scope of protection intended by the present invention.

[0085] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0086] Preparation Example 1: Preparation of Compound A

[0087] Compound A was synthesized according to the method described in Example 24 (Compound 185) on pages 209-210 of the specification WO2024151547A1. MS m / z (ESI): 393.0 [M+1] + .

[0088] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.15(s,1H),7.73(dd,J=6.9,1.6Hz,1H),7.57–7.49(m,5H),7.47–7.35(m,3H),6.51(d,J=9.2Hz,1 H),6.34(dd,J=7.3,6.1Hz,1H),4.37(dd,J=12.2,5.0Hz,1H),2.86–2.76(m,1H),2.59–2.54(m,1H),2.38–2.31(m,1H),2.10–2.02(m,1H).

[0089] Test Example 1. Evaluation of the efficacy of compounds in a BSA / LPS / CCL4-induced SD rat nephropathy model.

[0090] Male Sprague Dawley rats were used in this experiment. The model was established by inducing IgA nephropathy with BSA / LPS / CCL4 after unilateral nephrectomy (for details, see “Tang Ying, Lou Tanqi, Cheng Cailian, et al. Improvement of experimental IgA nephropathy model [J]. Journal of Sun Yat-sen University (Medical Science Edition), 27(2):184-187 (2006)”, or “Jin Di, Zhang Shulin, Zou Di. Research progress of animal model of IgA nephropathy [J]. Journal of Changchun University of Traditional Chinese Medicine; 36(05):1088-1092 (2020)”, the BSA / LPS / CCL4 induced IgA disease model is a commonly used representative model for evaluating the efficacy of IgA nephropathy drugs). All drugs were administered by gavage. The normal control group 1 (G1) and the model group 2 (G2) were given solvent. Group 3 (G3) was administered dexamethasone at a dose of 0.3 mg / kg once daily; Group 4 (G4) was administered compound A at a dose of 15 mg / kg once daily. Administration began four weeks after BSA / LPS / CCL4 combined induction, with a dosing cycle of 4-8 weeks. Detection indicators included: body weight, food intake, urine output, urinary albumin level, and histopathological and immunofluorescence detection of kidney tissue. Detection methods: Urine samples were collected using metabolic cages over a continuous 24-hour period. Urine samples were centrifuged at 4000 rpm for 5 min at 4°C, and the supernatant was collected. Urine samples were frozen at -80°C for urinary albumin detection. Urine albumin (ALB) was detected using an ELISA kit (Nephrat II). At the study endpoint, all rats were euthanized by inhaling excess CO2, and their kidneys were collected and weighed. The left kidney was fixed in 10% formalin, embedded with OCT, and frozen sections were prepared for IgA immunofluorescence staining and analysis.

[0091] The results showed that gavage administration of 15 mpk compound A significantly downregulated urinary albumin, the urinary albumin-to-creatinine ratio (ACR), and the glomerular area ratio of IgA (Table 1-3, Figure 1-3).

[0092] Table 1. Inhibitory effect of compound A on 24-hour total urinary albumin in IgAN rats

[0093] Table 2. Inhibitory effect of compound A on the urinary albumin-creatinine ratio (ACR)

[0094] Table 3. Inhibitory effect of compound A on the percentage of renal IgA deposition in glomerular area.

[0095] Evaluation of the effect of compound 2 in inhibiting R848-induced Gd-IgA1 production in PBMC cells

[0096] PBMC cells (SAILYBIO#SLB-HP100A) were desupernatanted and resuspended in 10% FBS (Gibco#10099-141) in RPMI 1640 (Gibco#22400-089) medium containing 2 mM L-glutamine (Gibco#35050061), 100 mM sodium pyruvate (Gibco#11360070), 1% non-essential amino acids (Gibco#11140050), and 55 μM β-mercaptoethanol (Gibco#21985023). Cells were cultured at a density of 2.5 × 10^5 cells / well in a 37°C, 5% CO2 incubator in 96-well plates (Corning#3599). The 96-well plates were pre-treated with 5 μg / mL anti-IgM (Jackson). ImmunoResearch (#109-005-129) coated cells overnight at 4°C, treated with 20 nM and 200 nM VAV1 inhibitors (compound A), and stimulated with TLR7 / 8 ligand R848 (MCE#HY-13740) for up to 12 days, with a final R848 concentration of 1 μM. After culture, centrifuged at 2000 rpm for 5 minutes, transferred 100 μL of supernatant to a 96-well plate, and stored at -80°C for later use or immediately detected using the Galactose-deficient IgA1 Assay Kit (IBL#:27600).

[0097] The results showed that both 20 nM and 200 nM of compound A significantly inhibited the production of Gd-IgA1 in R848-stimulated PBMC cells (see Table 4 and Figure 4).

[0098] Table 4. Amount of Gd-IgA1 produced by R848-stimulated PBMCs

[0099] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. Use of the compound of Formula I or its stereoisomers, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate in the preparation of medicaments for the treatment and / or prevention of IgA nephropathy. in: R 1 Selected from R 2 R 3 R 4 R 5 R 6 and R 7 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C3-C6 cycloalkyl; R a R b R c and R d Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C3-C6 cycloalkyl; n can be 0, 1, 2, 3, or 4.

2. The use according to claim 1, wherein, R 1 for Preferably, R 1 Selected from Preferably, R 1 for Or, R 2 It is a halogen or a C1-C6 haloalkyl group; Preferably, R 2 It is a halogen; Preferably, R 2 It is chlorine; Or, R 3 R 4 R 5 R 6 and R 7 Each is independently selected from hydrogen and C1-C6 alkyl groups; Preferably, R 3 R 4 R 5 R 6 and R 7 It is hydrogen; Or, R a R b R c and R d Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; Preferably, R a R b R c and R d Each is independently selected from hydrogen, fluorine, methyl, methoxy, -CF3 and -CHF2; Preferably, R a R b R c and R d Both are hydrogen.

3. The use according to claim 1 or 2, wherein, The compound is compound A.

4. The use according to any one of claims 1-3, wherein, The compound is selected from compound A-1, compound A-2, and a mixture of compound A-1 and compound A-2 in any proportion.

5. The use according to any one of claims 1-4, characterized in that, The IgA nephropathy includes primary IgA nephropathy and secondary IgA nephropathy; Preferably, the primary IgA nephropathy includes primary IgA nephropathy caused by genetic factors or abnormal autoimmune regulation; Preferably, the secondary IgA nephropathy includes diseases secondary to allergic purpura, viral hepatitis, cirrhosis, systemic lupus erythematosus, ankylosing spondylitis, rheumatoid arthritis, mixed connective tissue disease, polyarteritis nodosa, erythema nodosa, psoriasis, ulcerative colitis, Crohn's disease, tumors, or AIDS.

6. The use according to claim 1, characterized in that, The pharmaceutically acceptable salts of the compound are selected from hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, stearate, laurate, p-toluenesulfonate, methanesulfonate, fumarate, hydroxyethylsulfonate, maleate, malate, tartrate, citrate, oxalate, benzoate, bis(hydroxynaphthyl)ate, salicylate, vanillate, and succinate.

7. The use according to any one of claims 1-6, characterized in that, The drug is available in oral or injectable dosage form; Alternatively, the dosage of the drug (calculated based on the active ingredient) is 0.1-1000 mg; Alternatively, a unit dose of the drug may contain 0.1-1000 mg of the compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate; Alternatively, the frequency of administration of the drug may 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 every three weeks, or once every four weeks; Alternatively, the drug may also contain one or more pharmaceutically acceptable carriers; Preferably, in the drug, the weight ratio of the compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate is 1-99%.

8. The use according to any one of claims 1-7, characterized in that, The drug can be administered orally, via parenteral administration, or via transdermal administration; 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 1-8, wherein the drug is used to treat glomerular lesions in a subject with IgA nephropathy; Preferably, the treatment includes reducing the subject's proteinuria; Preferably, the treatment includes reducing the subject's urinary albumin-to-creatinine ratio (ACR).

10. The use according to any one of claims 1-9, wherein the drug is used to reduce IgA deposition in the kidney tissue of a subject with IgA nephropathy.

11. The use according to any one of claims 1-10, wherein, The drug is used in combination with one or more other therapeutic agents, wherein the other therapeutic agents are selected from glucocorticoids and angiotensin receptor blockers. Preferably, the glucocorticoid drug is selected from prednisone, methylprednisolone, betamethasone, beclomethasone dipropionate, prednisolone, hydrocortisone, dexamethasone, and budesonide; Preferably, the angiotensin receptor blocker is selected from losartan, valsartan, irbesartan, candesartan, telmisartan, olmesartan, and alisartan.

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