Methods of treating c3 glomerulopathy

Abstract

Provided are methods of treating a human having or susceptible to C3 glomerulopathy, comprising administering to the human an effective amount of a C5aR antagonist.

Description

[0001] Cross-reference to related applications

[0002] This application is an application for priority of U.S. Provisional Application No. 62 / 278,788, filed January 14, 2016; U.S. Provisional Application No. 62 / 280,346, filed January 19, 2016; U.S. Provisional Application No. 62 / 347,450, filed June 8, 2016; and U.S. Provisional Application No. 62 / 397,527, filed September 21, 2016, filed pursuant to 35 U.SC §119(e), the entire contents of which are incorporated herein by reference.

[0003] Declaration of rights to inventions made under federally funded research and development projects

[0004] not applicable.

[0005] The "sequence list" submitted on the hard drive, or a reference to a table or computer program list appendix.

[0006] not applicable. Background Technology

[0007] C3 glomerulonephropathy (C3G) is a rare kidney disease (estimated prevalence of 2–3 cases per 1,000,000 people). C3G is characterized by the deposition of a protein called C3 (a component of the body's complement system) in the filtration units of the kidneys (glomeruli), indicating that complement involvement contributes to kidney damage. C3 glomerulonephropathy is characterized by evidence of alternative complement activation based on C3 deposition in the glomeruli. The disease has two forms: dense deposition disease (DDD, formerly known as membranoproliferative glomerulonephritis [MPGN] type II) and C3 glomerulonephritis (C3GN, formerly known as idiopathic MPGN). Genetic abnormalities leading to complement regulation defects have been described in these patients, including mutations in complement factor H (CFH). Patients with C3 glomerulonephropathy typically have high proteinuria and progressive deterioration of kidney function. There is no approved treatment for patients with C3 glomerulonephropathy, including C3GN. Without treatment, C3G inevitably leads to kidney failure, and kidney transplantation is often the only option. Even after transplantation, the new kidney can frequently fail due to disease recurrence. Summary of the Invention

[0008] This article relates to methods for treating people who have or are susceptible to C3 glomerulonephropathy, including administering an effective dose of a C5aR antagonist.

[0009] In one embodiment, the C5aR antagonist is a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0010]

[0011] in,

[0012] C 1 It is optional to be 1-3 Rs 1 Substituent-substituted phenyl groups;

[0013] C 2 It is optional to be 1-3 Rs 2 Substituent-substituted phenyl groups;

[0014] C 3 Selected from C 3-8 Cycloalkyl and phenyl, and each C 3 Optional land is covered by 1-3 R 3 Substituent substitution;

[0015] Each R 1 Independently selected from halogen, -CN, -R c -CO2R a -CONR a R b -C(O)R a -OC(O)NR a R b -NR b C(O)R a -NR b C(O)2R c -NR a C(O)NR a R b -NR a R b -OR a and -S(O)2NR a R b ; where each R a and R b Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0 to 2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R c Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the R of the aliphatic and cyclic moiety a R b and R c Optionally further substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups; optionally, when two R groups are substituted... 1When substituents are on adjacent atoms, they combine to form fused five- or six-membered carbon rings;

[0016] Each R 2 Independently selected from halogen, -CN, -R f -CO2R d -CONR d R e -C(O)R d -OC(O)NR d R e -NR e C(O)R d -NR e C(O)2R f -NR d C(O)NR d R e -NR d C(O)NR d R e -NR d R e -OR d and -S(O)2NR d R e ; where each R d and R e Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0-2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R f Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R d R e and R f The aliphatic and cyclic moieties are optionally further replaced by one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino and dialkylamino groups;

[0017] Each R 3 Independently selected from halogen, -CN, -R i -CO2R g -CONR g R h -C(O)R g -OC(O)NR g R h -NR h C(O)R g -NRh C(O)2R i -NR g C(O)NR g R h -NR g R h -OR g -S(O)2NR g R h -X 4 -R j -X 4 -NR g R h -X 4 -CONR g R h -X 4 -NR h C(O)R g -NHR j and -NHCH2R j , where X 4 It is C 1-4 Alkylene; each R g and R h Independently selected from hydrogen and C 1-8 Alkyl, C 3-6 cycloalkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms, wherein the additional heteroatoms as ring members are selected from N, O, or S, and optionally substituted with one or two oxygen groups; each R i Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j Selected from C 3-6 Cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and R g R h R i and R j The aliphatic and cyclic moieties may optionally be further substituted with 1 to 3 halogen, methyl, CF3, hydroxyl, amino, alkylamino, and dialkylamino groups; and

[0018] X is hydrogen or CH3.

[0019] In some implementations, the C5aR antagonist is a compound having the following formula:

[0020]

[0021] Brief description of the attached figures

[0022] Figure 1 shows the estimated glomerular filtration rate (eGFR) of patients before and after treatment with compound 1.

[0023] Figure 2 shows the improvement in histopathology after treatment with compound 1. Detailed Implementation

[0024] Abbreviations and Definitions

[0025] Unless otherwise stated, the term "alkyl" on its own or as part of another substituent refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms (i.e., C64 ... 1-8 This means 1 to 8 carbons. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and more advanced homologues and isomers. The term "cycloalkyl" refers to a cycloalkyl group having a specified number of ring atoms (e.g., C1, C2, C3, C4, C5, C6, C6, C7, C8, C9 ... 3-6 A cycloalkyl group is a hydrocarbon ring that is fully saturated or has no more than one double bond between the ring vertices. "Cycloalkyl" also refers to bicyclic and polycyclic hydrocarbon rings, such as bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, etc. The term "heterocyclic alkyl" refers to a cycloalkyl group containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and one or more nitrogen atoms are optionally quaternized. Heterocyclic alkyl groups can be monocyclic, bicyclic, or polycyclic. Non-limiting examples of heterocyclic alkyl groups include pyrrolidine, imidazoline, pyrazolidine, butyrolactam, valproic acid, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrrolidine, thiaran, pyranone, tetrahydrofuran, tetrahydrothiophene, quinine ring, etc. Heterocyclic alkyl groups can be attached to the rest of the molecule via a cyclic carbon or heteroatom.

[0026] The term "alkylene" itself, or as part of another substituent, refers to a divalent group derived from an alkane, such as -CH2CH2CH2CH2-. Typically, the alkyl (or alkylene) group will have 1 to 24 carbon atoms, and in this invention, those groups having 10 or fewer carbon atoms are preferred. "Lower alkyl" or "lower alkylene" refers to a shorter-chain alkyl or alkylene group, typically having four or fewer carbon atoms. Similarly, "alkenyl" and "alkynyl" refer to the unsaturated form of an alkylene group having a double or triple bond, respectively.

[0027] Unless otherwise stated, the term "heteroalkyl" on its own or in combination with another term refers to a stable straight-chain or branched, or cyclic, hydrocarbon group, or a combination thereof, consisting of a specified number of carbon atoms and one to three heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Heteroatoms O, N, and S may be located at any internal position of the heteroalkyl group. Heteroatoms Si may be located at any position of the heteroalkyl group, including positions where the alkyl group is attached to the rest of the molecule. Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. The two heteroatoms can be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, unless otherwise stated, the terms "heteroalkenyl" and "heteroyneyl" on their own or in combination with another term refer to an alkenyl or ynyl group containing a specified number of carbon atoms and having 1-3 heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, and S can be located at any internal position of the heteroalkyl group.

[0028] The term "heteroalkylene" itself, or as part of another substituent, refers to a saturated, unsaturated, or polyunsaturated divalent group derived from a heteroalkyl group, such as -CH2-CH2-S-CH2CH2- and -CH2-S-CH2-CH2-NH-CH2-, -O-CH2-CH=CH-, -CH2-CH=C(H)CH2-O-CH2-, and -S-CH2-CH≡C-. For heteroalkylene, the heteroatom may also occupy any one or both of the chain ends (e.g., alkeneoxy, alkenedioxy, alkyleneamino, alkylenediamino, etc.).

[0029] The terms "alkoxy," "alkylamino," and "alkathio" (or thioalkoxy) are used in their conventional sense and refer to alkyl groups connected to the rest of the molecule via an oxygen, amino, or sulfur atom, respectively. Additionally, for dialkylamino groups, the alkyl moiety can be the same or different, and can also combine with each attached nitrogen atom to form a 3-7 membered ring. Therefore, it is represented as -NR. a R b The groups are intended to include piperidinyl, pyrrolidinyl, morpholinyl, azacyclic butyl, etc.

[0030] Unless otherwise stated, the terms "halogenated" or "halogen" on their own or as part of another substituent refer to a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "halogenated alkyl" are intended to include both monohalogenated and polyhalogenated alkyl groups. For example, the term "C 1-4 "Halogenated alkyl" refers to compounds including trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0031] Unless otherwise stated, the term "aryl" refers to a polyunsaturated, typically aromatic, hydrocarbon group, which can be a monocyclic or multiple rings fused together or covalently linked (up to three rings). The term "heteroaryl" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and one or more nitrogen atoms are optionally quaternized. Heteroaryl groups can be attached to the rest of the molecule via heteroatoms. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyrazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cyclophosphinyl, phthalazinyl, benzotriazinyl, purineyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoisoxazoleyl, isobenzofuranyl, isoindolyl, indazinyl, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothiaenyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxaconyl, isoxazolyl, thiadiazolyl, pyrroleyl, thiazolyl, furanyl, thiopheneyl, etc. The substituents for each of the above aryl and heteroaryl ring systems are selected from the following acceptable substituents.

[0032] For the sake of brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthiooxy, arylalkyl) includes aryl and heteroaryl rings as defined above. Therefore, the term "arylalkyl" is intended to include those groups in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.).

[0033] In some embodiments, the terms above (e.g., "alkyl," "aryl," and "heteroaryl") will include substituted and unsubstituted forms of the specified group. Preferred substituents for each type of group are provided below. For brevity, the terms aryl and heteroaryl refer to the substituted or unsubstituted forms provided below, while the terms "alkyl" and the associated aliphatic group refer to the unsubstituted form unless specified otherwise.

[0034] The substituents of the alkyl group (including those commonly referred to as alkylene, alkenyl, ynyl, and cycloalkyl) can be a variety of groups selected from the group consisting of: -halogen, -OR", -NR"R", -SR", -SiR"R"R", -OC(O)R", -C(O)R", -CO2R", -CONR"R", -OC(O)NR"R", -NR"C(O)R", -NR"-C(O)NR"R", -NR" C(O)2R”, -NH-C(NH2)=NH, -NR”C(NH2=NH, -NH-C(NH2)=NR”, -S(O)R”, -S(O)2R”, -S(O)2NR”R”, -NR”S(O)2R”, -CN and -NO2, in quantities from 0 to (2m'+1), where m' is the total number of carbon atoms in the group. R”, R” and R”” each independently represent hydrogen, and unsubstituted C 1-8 Alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C 1-8 Alkyl, C 1-8 Alkoxy or C 1-8 Thioalkoxy or unsubstituted aryl-C 1-4 Alkyl groups. When R” and R” are attached to the same nitrogen atom, they can combine with the nitrogen atom to form 3-, 4-, 5-, 6-, or 7-membered rings. For example, -NR”R” is intended to include 1-pyrrolidinyl and 4-morpholinyl. The term “acyl” itself or as part of another group refers to the two substituents on the carbon of that group closest to the group's attachment point being replaced by substituent =O (e.g., -C(O)CH3, -C(O)CH2CH2OR', etc.).

[0035] Similarly, the substituents of aryl and heteroaryl groups are varied and are generally selected from: -halogen, -OR", -OC(O)R", -NR"R", -SR", -R", -CN, -NO2, -CO2R", -CONR"R", -C(O)R", -OC(O)NR"R", -NR"C(O)R", -NR"C(O)2R", -NR"-C(O)NR"R", -NH-C( NH2)=NH, -NR”C(NH2)=NH, -NH-C(NH2)=NR”, -S(O)R”, -S(O)2R”, -S(O)2NR”R”, -NR”S(O)2R”, -N3, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, ranging from zero to the total number of open valences on the aromatic ring system; and wherein R”, R” and R”” are independently selected from hydrogen, C 1-8 Alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 Alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4 Alkyl and unsubstituted aryloxy-C 1-4 Alkyl groups. Other suitable substituents include each of the above aryl substituents attached to the ring atom via an alkylene chain of 1-4 carbon atoms.

[0036] The two substituents on adjacent atoms of the aryl or heteroaryl ring can optionally be of the formula -TC(O)-(CH2). q -U- substituent substitution, where T and U are independently -NH-, -O-, -CH2- or single bonds, and q is an integer from 0 to 2.

[0037] Alternatively, the two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -A-(CH2). r The substituents of -B- are substituted, where A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR”- or single bonds, and r is an integer from 1 to 3. One of the single bonds in the newly formed ring may optionally be substituted with a double bond. Alternatively, the two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with the formula -(CH2). s -X-(CH2) t The substituent R” in -NR”- and -S(O)2NR”- is selected from hydrogen or unsubstituted C. 1-6 alkyl.

[0038] As used in this article, the term “heteroatoms” is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0039] The term "ionic liquid" refers to any liquid that primarily contains ions. Preferably, in this invention, "ionic liquid" refers to a salt with a relatively low melting point (e.g., below 250°C). Examples of ionic liquids include, but are not limited to, 1-butyl-3-methylimidazolium tetrafluoroborate, 1-hexyl-3-methylimidazolium tetrafluoroborate, 1-octyl-3-methylimidazolium tetrafluoroborate, 1-nonyl-3-methylimidazolium tetrafluoroborate, 1-decyl-3-methylimidazolium tetrafluoroborate, 1-hexyl-3-methylimidazolium hexafluorophosphate, and 1-hexyl-3-methylimidazolium bromide, etc.

[0040] As used herein, the term "treatment" or "curative therapy" includes both disease-modulating treatment and symptomatic treatment, either of which can be preventative (i.e., prior to the onset of symptoms to prevent, delay, or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms to reduce the severity and / or duration of symptoms). The treatments described herein typically involve administering an effective amount of one or more of the compounds described herein to a patient. Suitable patients include those who have or are susceptible to (i.e., for preventative treatment) the condition or disease referred to herein. Typical patients for treatment as described herein include mammals, particularly primates, especially humans. Other suitable patients include domesticated companion animals such as dogs, cats, horses, etc., or livestock such as cattle, pigs, sheep, etc.

[0041] The term "pharmaceutically acceptable salt" refers to salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds provided herein contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base in a pure or suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese sulfide, potassium, sodium, zinc, and others. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, halogenamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds provided herein contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired acid, which can be pure or in a suitable inert solvent. Pharmaceutically acceptable examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfide, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, succinic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Salts of amino acids such as arginine and salts of organic acids such as glucuronic acid or galacturonic acid are also included (see, for example, Berge, SM, et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 1977, 66, 1-19). Some specific compounds described herein contain both basic and acidic functional groups, allowing the compounds to be converted into either basic or acid addition salts.

[0042] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties, such as solubility in polar solvents, but for the purposes of this invention, the salt is otherwise equivalent to the parent form of the compound.

[0043] The compounds described in the following embodiments can be obtained according to the methods described in WO2010 / 075257, WO2011 / 163640 and WO2016 / 053890.

[0044] Implementation Plan

[0045] This disclosure relates to methods for treating persons with or susceptible to complement 3 glomerulonephropathy, including administering to a person an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0046]

[0047] in,

[0048] C 1 It is optional to be 1-3 Rs 1 Substituent-substituted phenyl groups;

[0049] C 2 It is optional to be 1-3 Rs 2 Substituent-substituted phenyl groups;

[0050] C 3 Selected from C 3-8 Cycloalkyl and phenyl, and each C 3 Optional land is covered by 1-3 R 3 Substituent substitution;

[0051] Each R 1 Independently selected from halogen, -CN, -R c -CO2R a -CONR a R b -C(O)R a -OC(O)NR a R b -NR b C(O)R a -NR b C(O)2R c -NR a C(O)NR a R b -NR a R b -OR a and -S(O)2NR a R b ; where each R a and R b Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0 to 2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R c Selected independently from C 1-8 Alkyl, C1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R a R b and R c The aliphatic and cyclic moieties are optionally further substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups; optionally, when two R groups are substituted, the aliphatic and cyclic moieties are substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups. 1 When substituents are on adjacent atoms, they combine to form fused five- or six-membered carbon rings;

[0052] Each R 2 Independently selected from halogen, -CN, -R f -CO2R d -CONR d R e -C(O)R d -OC(O)NR d R e -NR e C(O)R d -NR e C(O)2R f -NR d C(O)NR d R e -NR d C(O)NR d R e -NR d R e -OR d and -S(O)2NR d R e ; where each R d and R e Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0-2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R f Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R d R e and R f The aliphatic and cyclic moieties are optionally further replaced by one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino and dialkylamino groups;

[0053] Each R 3Independently selected from halogen, -CN, -R i -CO2R g -CONR g R h -C(O)R g -OC(O)NR g R h -NR h C(O)R g -NR h C(O)2R i -NR g C(O)NR g R h -NR g R h -OR g -S(O)2NR g R h -X 4 -R j -X 4 -NR g R h -X 4 -CONR g R h -X 4 -NR h C(O)R g -NHR j and -NHCH2R j , where X 4 It is C 1-4 Alkylene; each R g and R h Independently selected from hydrogen and C 1-8 Alkyl, C 3-6 cycloalkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms, wherein the additional heteroatoms as ring members are selected from N, O, or S, and optionally substituted with one or two oxygen groups; each R i Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j Selected from C 3-6 Cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and R g R h R i and R jThe aliphatic and cyclic moieties may optionally be further substituted with 1 to 3 halogen, methyl, CF3, hydroxyl, amino, alkylamino, and dialkylamino groups; and

[0054] X is hydrogen or CH3.

[0055] In some embodiments, the compound has formula (Ia):

[0056]

[0057] In some embodiments, the compound has the formula (Ib):

[0058]

[0059] in,

[0060] X 1 Selected from CH and CR 1 ;

[0061] The subscript n is an integer from 0 to 2;

[0062] X 2 Selected from CH and CR 2 ;as well as

[0063] The subscript m is an integer from 0 to 2.

[0064] In some embodiments, the compound has the formula (Ic):

[0065]

[0066] in,

[0067] X 1 Selected from CH and CR 1 ;

[0068] The subscript n is an integer from 0 to 2;

[0069] X 2 Selected from CH and CR 2 ;as well as

[0070] The subscript m is an integer from 0 to 2.

[0071] In some embodiments, the compound has the formula (Id):

[0072]

[0073] in,

[0074] The subscript p is an integer from 0 to 3;

[0075] X 1 Selected from CH and CR1 ;

[0076] The subscript n is an integer from 0 to 2;

[0077] X 2 Selected from CH and CR 2 ;as well as

[0078] The subscript m is an integer from 0 to 2.

[0079] In some embodiments, the compound has the formula (Ie):

[0080]

[0081] Where p is 0, 1 or 2.

[0082] In some embodiments, the compound is selected from:

[0083]

[0084]

[0085] Or its pharmaceutically acceptable salt.

[0086] In some embodiments, the compound is

[0087]

[0088] Or its pharmaceutically acceptable salt.

[0089] A method is provided to slow the estimated rate of decline in glomerular filtration rate (eGFR) in individuals with or susceptible to C3 glomerular disease, comprising administering to the individual an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0090]

[0091] in,

[0092] C 1 It is optional to be 1-3 Rs 1 Substituent-substituted phenyl groups;

[0093] C 2 It is optional to be 1-3 Rs 2 Substituent-substituted phenyl groups;

[0094] C 3 Selected from C 3-8 Cycloalkyl and phenyl, and each C 3 Optional land is covered by 1-3 R 3 Substituent substitution;

[0095] Each R 1 Independently selected from halogen, -CN, -R c -CO2R a -CONR a R b -C(O)R a -OC(O)NR a R b -NR b C(O)R a -NR b C(O)2R c -NR a C(O)NR a R b -NR a R b -OR a and -S(O)2NR a R b ; where each R a and R b Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0 to 2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R c Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R a R b and R c The aliphatic and cyclic moieties are optionally further substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups; optionally, when two R groups are substituted, the aliphatic and cyclic moieties are substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups. 1 When substituents are on adjacent atoms, they combine to form fused five- or six-membered carbon rings;

[0096] Each R 2 Independently selected from halogen, -CN, -R f -CO2R d -CONR d R e -C(O)R d -OC(O)NR d R e -NR e C(O)R d -NR e C(O)2R f-NR d C(O)NR d R e -NR d C(O)NR d R e -NR d R e -OR d and -S(O)2NR d R e ; where each R d and R e Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0-2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R f Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R d R e and R f The aliphatic and cyclic moieties are optionally further replaced by one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino and dialkylamino groups;

[0097] Each R 3 Independently selected from halogen, -CN, -R i -CO2R g -CONR g R h -C(O)R g -OC(O)NR g R h -NR h C(O)R g -NR h C(O)2R i -NR g C(O)NR g R h -NR g R h -OR g -S(O)2NR g R h -X 4 -R j -X 4 -NR g R h -X 4 -CONR gR h -X 4 -NR h C(O)R g -NHR j and -NHCH2R j , where X 4 It is C 1-4 Alkylene; each R g and R h Independently selected from hydrogen and C 1-8 Alkyl, C 3-6 cycloalkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms, wherein the additional heteroatoms as ring members are selected from N, O, or S, and optionally substituted with one or two oxygen groups; each R i Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j Selected from C 3-6 Cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and R g R h R i and R j The aliphatic and cyclic moieties may optionally be further substituted with 1 to 3 halogen, methyl, CF3, hydroxyl, amino, alkylamino, and dialkylamino groups; and

[0098] X is hydrogen or CH3.

[0099] In some embodiments, the compound has the formula (Ie):

[0100]

[0101] Where p is 0, 1 or 2.

[0102] In some embodiments, the compound is

[0103] Or its pharmaceutically acceptable salt.

[0104] A method for reducing glomerular inflammation in individuals with or susceptible to C3 glomerular disease is provided, comprising administering to a person an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0105]

[0106] in,

[0107] C1 It is optional to be 1-3 Rs 1 Substituent-substituted phenyl groups;

[0108] C 2 It is optional to be 1-3 Rs 2 Substituent-substituted phenyl groups;

[0109] C 3 Selected from C 3-8 Cycloalkyl and phenyl, and each C 3 Optional land is covered by 1-3 R 3 Substituent substitution;

[0110] Each R 1 Independently selected from halogen, -CN, -R c -CO2R a -CONR a R b -C(O)R a -OC(O)NR a R b -NR b C(O)R a -NR b C(O)2R c -NR a C(O)NR a R b -NR a R b -OR a and -S(O)2NR a R b ; where each R a and R b Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0 to 2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R c Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R a R b and R c The aliphatic and cyclic moieties are optionally further substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups; optionally, when two R groups are substituted, the aliphatic and cyclic moieties are substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups. 1 When substituents are on adjacent atoms, they combine to form fused five- or six-membered carbon rings;

[0111] Each R 2 Independently selected from halogen, -CN, -R f -CO2R d -CONR d R e -C(O)R d -OC(O)NR d R e -NR e C(O)R d -NR e C(O)2R f -NR d C(O)NR d R e -NR d C(O)NR d R e -NR d R e -OR d and -S(O)2NR d R e ; where each R d and R e Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0-2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R f Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R d R e and R f The aliphatic and cyclic moieties are optionally further replaced by one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino and dialkylamino groups;

[0112] Each R 3 Independently selected from halogen, -CN, -R i -CO2R g -CONR g R h -C(O)R g -OC(O)NR g R h -NR h C(O)R g -NR h C(O)2R i -NRg C(O)NR g R h -NR g R h -OR g -S(O)2NR g R h -X 4 -R j -X 4 -NR g R h -X 4 -CONR g R h -X 4 -NR h C(O)R g -NHR j and -NHCH2R j , where X 4 It is C 1-4 Alkylene; each R g and R h Independently selected from hydrogen and C 1-8 Alkyl, C 3-6 cycloalkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms, wherein the additional heteroatoms as ring members are selected from N, O, or S, and optionally substituted with one or two oxygen groups; each R i Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j Selected from C 3-6 Cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and R g R h R i and R j The aliphatic and cyclic moieties may optionally be further substituted with 1 to 3 halogen, methyl, CF3, hydroxyl, amino, alkylamino, and dialkylamino groups; and

[0113] X is hydrogen or CH3.

[0114] In some embodiments, the compound has the formula (Ie):

[0115]

[0116] In some embodiments, the compound is

[0117]

[0118] Or its pharmaceutically acceptable salt.

[0119] A method for reducing C3 deposits and / or C5b-9 deposits in individuals with or susceptible to C3 glomerulonephropathy is provided, comprising administering to the individual an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0120]

[0121] in,

[0122] C 1 It is optional to be 1-3 Rs 1 Substituent-substituted phenyl groups;

[0123] C 2 It is optional to be 1-3 Rs 2 Substituent-substituted phenyl groups;

[0124] C 3 Selected from C 3-8 Cycloalkyl and phenyl, and each C 3 Optional land is covered by 1-3 R 3 Substituent substitution;

[0125] Each R 1 Independently selected from halogen, -CN, -R c -CO2R a -CONR a R b -C(O)R a -OC(O)NR a R b -NR b C(O)R a -NR b C(O)2R c -NR a C(O)NR a R b -NR a R b -OR a and -S(O)2NR a R b ; where each R a and R b Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0 to 2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R cSelected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R a R b and R c The aliphatic and cyclic moieties are optionally further substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups; optionally, when two R groups are substituted, the aliphatic and cyclic moieties are substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups. 1 When substituents are on adjacent atoms, they combine to form fused five- or six-membered carbon rings;

[0126] Each R 2 Independently selected from halogen, -CN, -R f -CO2R d -CONR d R e -C(O)R d -OC(O)NR d R e -NR e C(O)R d -NR e C(O)2R f -NR d C(O)NR d R e -NR d C(O)NR d R e -NR d R e -OR d and -S(O)2NR d R e ; where each R d and R e Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0-2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R f Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R d R e and R f The aliphatic and cyclic moieties are optionally further replaced by one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino and dialkylamino groups;

[0127] Each R 3 Independently selected from halogen, -CN, -R i -CO2R g -CONR g R h -C(O)R g -OC(O)NR g R h -NR h C(O)R g -NR h C(O)2R i -NR g C(O)NR g R h -NR g R h -OR g -S(O)2NR g R h -X 4 -R j -X 4 -NR g R h -X 4 -CONR g R h -X 4 -NR h C(O)R g -NHR j and -NHCH2R j , where X 4 It is C 1-4 Alkylene; each R g and R h Independently selected from hydrogen and C 1-8 Alkyl, C 3-6 cycloalkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms, wherein the additional heteroatoms as ring members are selected from N, O, or S, and optionally substituted with one or two oxygen groups; each R i Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j Selected from C 3-6 Cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and R g R h R i and R jThe aliphatic and cyclic moieties may optionally be further substituted with 1 to 3 halogen, methyl, CF3, hydroxyl, amino, alkylamino, and dialkylamino groups; and

[0128] X is hydrogen or CH3.

[0129] In some embodiments, the compound has the formula (Ie):

[0130]

[0131] Where p is 0, 1 or 2.

[0132] In some embodiments, the compound is

[0133]

[0134] Or its pharmaceutically acceptable salt.

[0135] In some embodiments, the person has complement 3 glomerulonephritis. In some embodiments, the person has progressive complement 3 glomerulonephritis. In some embodiments, the person has recurrent complement 3 glomerulonephritis after kidney transplantation. In some embodiments, the person has dense deposit disease.

[0136] A method for clearing intraglomerular capillary proliferation in individuals with or susceptible to C3 glomerular disease is provided, comprising administering to the individual an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0137]

[0138] in,

[0139] C 1 It is optional to be 1-3 Rs 1 Substituent-substituted phenyl groups;

[0140] C 2 It is optional to be 1-3 Rs 2 Substituent-substituted phenyl groups;

[0141] C 3 Selected from C 3-8 Cycloalkyl and phenyl, and each C 3 Optional land is covered by 1-3 R 3 Substituent substitution;

[0142] Each R 1 Independently selected from halogen, -CN, -R c -CO2R a -CONR a R b -C(O)R a-OC(O)NR a R b -NR b C(O)R a -NR b C(O)2R c -NR a C(O)NR a R b -NR a R b -OR a and -S(O)2NR a R b ; where each R a and R b Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0 to 2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R c Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R a R b and R c The aliphatic and cyclic moieties are optionally further substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups; optionally, when two R groups are substituted, the aliphatic and cyclic moieties are substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups. 1 When substituents are on adjacent atoms, they combine to form fused five- or six-membered carbon rings;

[0143] Each R 2 Independently selected from halogen, -CN, -R f -CO2R d -CONR d R e -C(O)R d -OC(O)NR d R e -NR e C(O)R d -NR e C(O)2R f -NR d C(O)NR d R e -NR d C(O)NR d R e -NR d R e -ORd and -S(O)2NR d R e ; where each R d and R e Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0-2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R f Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R d R e and R f The aliphatic and cyclic moieties are optionally further replaced by one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino and dialkylamino groups;

[0144] Each R 3 Independently selected from halogen, -CN, -R i -CO2R g -CONR g R h -C(O)R g -OC(O)NR g R h -NR h C(O)R g -NR h C(O)2R i -NR g C(O)NR g R h -NR g R h -OR g -S(O)2NR g R h -X 4 -R j -X 4 -NR g R h -X 4 -CONR g R h -X 4 -NR h C(O)R g -NHR j and -NHCH2R j , where X 4 It is C 1-4Alkylene; each R g and R h Independently selected from hydrogen and C 1-8 Alkyl, C 3-6 cycloalkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms, wherein the additional heteroatoms as ring members are selected from N, O, or S, and optionally substituted with one or two oxygen groups; each R i Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each Rj is selected from C 3-6 Cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and R g R h R i The aliphatic and cyclic moieties of Rj may optionally be further substituted with 1 to 3 halogen, methyl, CF3, hydroxyl, amino, alkylamino, and dialkylamino groups; and

[0145] X is hydrogen or CH3.

[0146] In some embodiments, the compound has the formula (Ie):

[0147]

[0148] Where p is 0, 1 or 2.

[0149] In some embodiments, the compound is

[0150] Or its pharmaceutically acceptable salt.

[0151] A method for reducing glomerular inflammatory macrophages in individuals with or susceptible to C3 glomerular disease is provided, comprising administering to a person an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0152]

[0153] in,

[0154] C 1 It is optional to be 1-3 Rs 1 Substituent-substituted phenyl groups;

[0155] C 2 It is optional to be 1-3 Rs 2 Substituent-substituted phenyl groups;

[0156] C 3 Selected from C3-8 Cycloalkyl and phenyl, and each C 3 Optional land is covered by 1-3 R 3 Substituent substitution;

[0157] Each R 1 Independently selected from halogen, -CN, -R c -CO2R a -CONR a R b -C(O)R a -OC(O)NR a R b -NR b C(O)R a -NR b C(O)2R c -NR a C(O)NR a R b -NR a R b -OR a and -S(O)2NR a R b ; where each R a and R b Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0 to 2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R c Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R a R b and R c The aliphatic and cyclic moieties are optionally further substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups; optionally, when two R groups are substituted, the aliphatic and cyclic moieties are substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups. 1 When substituents are on adjacent atoms, they combine to form fused five- or six-membered carbon rings;

[0158] Each R 2 Independently selected from halogen, -CN, -R f -CO2R d -CONR d R e -C(O)R d -OC(O)NR d R e -NRe C(O)R d -NR e C(O)2R f -NR d C(O)NR d R e -NR d C(O)NR d R e -NR d R e -OR d and -S(O)2NR d R e ; where each R d and R e Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0-2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R f Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R d R e and R f The aliphatic and cyclic moieties are optionally further replaced by one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino and dialkylamino groups;

[0159] Each R 3 Independently selected from halogen, -CN, -R i -CO2R g -CONR g R h -C(O)R g -OC(O)NR g R h -NR h C(O)R g -NR h C(O)2R i -NR g C(O)NR g R h -NR g R h -OR g -S(O)2NR g R h -X 4 -R j -X 4-NR g R h -X 4 -CONR g R h -X 4 -NR h C(O)R g -NHR j and -NHCH2R j , where X 4 It is C 1-4 Alkylene; each R g and R h Independently selected from hydrogen and C 1-8 Alkyl, C 3-6 cycloalkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms, wherein the additional heteroatoms as ring members are selected from N, O, or S, and optionally substituted with one or two oxygen groups; each R i Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j Selected from C 3-6 Cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and R g R h R i and R j The aliphatic and cyclic moieties may optionally be further substituted with 1 to 3 halogen, methyl, CF3, hydroxyl, amino, alkylamino, and dialkylamino groups; and

[0160] X is hydrogen or CH3.

[0161] In some embodiments, the compound has the formula (Ie):

[0162]

[0163] Where p is 0, 1 or 2.

[0164] In some embodiments, the compound is

[0165]

[0166] Or its pharmaceutically acceptable salt.

[0167] A method for reducing proteinuria in individuals with or predisposed to C3 glomerulonephropathy is provided, comprising administering to the individual an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0168]

[0169] in,

[0170] C 1 It is optional to be 1-3 Rs 1 Substituent-substituted phenyl groups;

[0171] C 2 It is optional to be 1-3 Rs 2 Substituent-substituted phenyl groups;

[0172] C 3 Selected from C 3-8 Cycloalkyl and phenyl, and each C 3 Optional land is covered by 1-3 R 3 Substituent substitution;

[0173] Each R 1 Independently selected from halogen, -CN, -R c -CO2R a -CONR a R b -C(O)R a -OC(O)NR a R b -NR b C(O)R a -NR b C(O)2R c -NR a C(O)NR a R b -NR a R b -OR a and -S(O)2NR a R b ; where each R a and R b Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0 to 2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R c Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R a R b and R cThe aliphatic and cyclic moieties are optionally further substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups; optionally, when two R groups are substituted, the aliphatic and cyclic moieties are substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups. 1 When substituents are on adjacent atoms, they combine to form fused five- or six-membered carbon rings;

[0174] Each R 2 Independently selected from halogen, -CN, -R f -CO2R d -CONR d R e -C(O)R d -OC(O)NR d R e -NR e C(O)R d -NR e C(O)2R f -NR d C(O)NR d R e -NR d C(O)NR d R e -NR d R e -OR d and -S(O)2NR d R e ; where each R d and R e Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0-2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R f Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R d R e and R f The aliphatic and cyclic moieties are optionally further replaced by one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino and dialkylamino groups;

[0175] Each R 3 Independently selected from halogen, -CN, -R i -CO2R g -CONR g R h -C(O)R g-OC(O)NR g R h -NR h C(O)R g -NR h C(O)2R i -NR g C(O)NR g R h -NR g R h -OR g -S(O)2NR g R h -X 4 -R j -X 4 -NR g R h -X 4 -CONR g R h -X 4 -NR h C(O)R g -NHR j and -NHCH2R j , where X 4 It is C 1-4 Alkylene; each R g and R h Independently selected from hydrogen and C 1-8 Alkyl, C 3-6 cycloalkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms, wherein the additional heteroatoms as ring members are selected from N, O, or S, and optionally substituted with one or two oxygen groups; each R i Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j Selected from C 3-6 Cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and R g R h R i and R j The aliphatic and cyclic moieties may optionally be further substituted with 1 to 3 halogen, methyl, CF3, hydroxyl, amino, alkylamino, and dialkylamino groups; and

[0176] X is hydrogen or CH3.

[0177] In some embodiments, the compound has the formula (Ie):

[0178]

[0179] In some embodiments, the compound is

[0180]

[0181] Or its pharmaceutically acceptable salt.

[0182] In some embodiments, the person has complement 3 glomerulonephritis. In some embodiments, the person has progressive complement 3 glomerulonephritis. In some embodiments, the person has recurrent complement 3 glomerulonephritis after kidney transplantation. In some embodiments, the person has dense deposit disease. In some embodiments, the person has immunosuppressive drug refractory disease.

[0183] Methods for treating individuals with or susceptible to complement 3 glomerulonephropathy are provided, including administering an effective amount of a compound having formula (Ie) or a pharmaceutically acceptable salt thereof.

[0184]

[0185] in

[0186] Each R 1 Independently selected from halogen, -CN, -R c -CO2R a -CONR a R b -C(O)R a -OC(O)NR a R b -NR b C(O)R a -NR b C(O)2R c -NR a C(O)NR a R b -NR a R b -OR a and -S(O)2NR a R b ; where each R a and R b Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0 to 2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each Rc Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R a R b and R c The aliphatic and cyclic moieties are optionally further substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups; optionally, when two R groups are substituted, the aliphatic and cyclic moieties are substituted with one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups. 1 When substituents are on adjacent atoms, they combine to form fused five- or six-membered carbon rings;

[0187] Each R 2 Independently selected from halogen, -CN, -R f -CO2R d -CONR d R e -C(O)R d -OC(O)NR d R e -NR e C(O)R d -NR e C(O)2R f -NR d C(O)NR d R e -NR d C(O)NR d R e -NR d R e -OR d and -S(O)2NR d R e ; where each R d and R e Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring with 0-2 additional heteroatoms, the additional heteroatoms being selected from N, O, or S; each R f Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R d R e and R f The aliphatic and cyclic moieties are optionally further replaced by one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino and dialkylamino groups;

[0188] Each R 3 Independently selected from halogen, -CN, -R i -CO2R g -CONR g R h -C(O)R g -OC(O)NR g R h -NR h C(O)R g -NR h C(O)2R i -NR g C(O)NR g R h -NR g R h -OR g -S(O)2NR g R h -X 4 -R j -X 4 -NR g R h -X 4 -CONR g R h -X 4 -NR h C(O)R g -NHR j and -NHCH2R j , where X 4 It is C 1-4 Alkylene; each R g and R h Independently selected from hydrogen and C 1-8 Alkyl, C 3-6 cycloalkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms, wherein the additional heteroatoms as ring members are selected from N, O, or S, and optionally substituted with one or two oxygen groups; each R i Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j Selected from C 3-6 Cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and R g R h R i and R jThe aliphatic and cyclic moieties may optionally be further substituted with 1 to 3 halogen, methyl, CF3, hydroxyl, amino, alkylamino, and dialkylamino groups; and

[0189] p is 0, 1, or 2.

[0190] In some implementations...

[0191] Each R 1 Independently selected from halogen, -CN, -R c -NR a R b and -OR a ; where each R a and R b Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a pyrrolidine ring; each R c Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 cycloalkyl, wherein R a R b and R c The aliphatic and cyclic moieties are optionally further substituted with one to three groups selected from hydroxyl, methyl, amino, alkylamino, and dialkylamino groups; optionally, when two R groups are substituted, the aliphatic and cyclic moieties are substituted with the cyclic moieties. 1 When substituents are on adjacent atoms, they combine to form fused five- or six-membered carbon rings;

[0192] Each R 2 Independently selected from halogens, -R f and -OR d ; where each R d Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 Halogenated alkyl groups, each R f Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, and heteroaryl, wherein R d and R f The aliphatic and cyclic moieties are optionally further replaced by one to three groups selected from halogen, hydroxyl, methyl, amino, alkylamino and dialkylamino groups;

[0193] Each R 3 Independently selected from halogens, -R i -CO2R g -CONR g R h -NRh C(O)R g -NR h C(O)2R i -NR g R h -OR g -X 4 -R j -X 4 -NR g R h -X 4 -CONR g R h -X 4 -NR h C(O)R g -NHR j and -NHCH2R j , where X 4 It is C 1-4 Alkylene; each R g and R h Independently selected from hydrogen and C 1-8 Alkyl, C 3-6 cycloalkyl and C 1-8 Halogenated alkyl groups, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms, wherein the additional heteroatoms as ring members are selected from N, O, or S, and optionally substituted with one or two oxygen groups; each R i Selected independently from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j Selected from C 3-6 Cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and R g R h R i and R j The aliphatic and cyclic moieties may optionally be further substituted with 1 to 3 halogen, methyl, CF3, hydroxyl, amino, alkylamino, and dialkylamino groups; and

[0194] p is 1.

[0195] In some implementations...

[0196] Each R 1 Selected independently from C 1-8 Alkyl and C 1-8 Halogenated alkyl groups;

[0197] Each R 2 Independently selected from halogens and C1-8 alkyl;

[0198] Each R 3 For -NR g R h , where each R g and R h Independently selected from hydrogen and C 3-6 cycloalkyl; and

[0199] p is 1.

[0200] In some implementations...

[0201] Each R 1 Selected independently from C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0202] Each R 2 Independently selected from halogens and C 1-3 alkyl;

[0203] Each R 3 For -NR g R h , where each R g and R h Independently selected from hydrogen and C 4-6 cycloalkyl; and

[0204] p is 1.

[0205] In some embodiments, the compound is selected from...

[0206]

[0207]

[0208]

[0209] Or its pharmaceutically acceptable salt.

[0210] In some embodiments, the compound is

[0211]

[0212] Or its pharmaceutically acceptable salt.

[0213] In some embodiments, the compound is

[0214]

[0215] Or its pharmaceutically acceptable salt.

[0216] In some embodiments, the method includes one or more of the following: slowing the rate of decline in estimated glomerular filtration rate (eGFR), reducing glomerular inflammation, clearing intraglomerular capillary proliferation, reducing inflammatory macrophages in the glomeruli, reducing proteinuria, slowing the progression of kidney disease, halting the progression of kidney disease, delaying the progression of end-stage renal disease, improving kidney histology, reducing proteinuria, and slowing the increase in proteinuria. In some embodiments, a kidney biopsy may support this improvement.

[0217] A method is provided for slowing the estimated rate of decline in glomerular filtration rate (eGFR) in individuals with or susceptible to C3 glomerular disease, the method comprising administering to the individual an effective amount of a compound having the following formula:

[0218]

[0219] Or its pharmaceutically acceptable salt.

[0220] A method is provided for slowing the estimated rate of decline in glomerular filtration rate (eGFR) in individuals with or susceptible to C3 glomerular disease, the method comprising administering to the individual an effective amount of a compound having the following formula:

[0221]

[0222] Or its pharmaceutically acceptable salt.

[0223] A method for alleviating glomerular inflammation in individuals with or predisposed to C3 glomerulonephropathy is provided, comprising administering to the person an effective amount of a compound having the following formula:

[0224]

[0225] Or its pharmaceutically acceptable salt.

[0226] A method for alleviating glomerular inflammation in individuals with or predisposed to C3 glomerulonephropathy is provided, comprising administering to the person an effective amount of a compound having the following formula:

[0227]

[0228] Or its pharmaceutically acceptable salt.

[0229] A method for reducing C3 deposits and / or C5b-9 deposits in individuals with or susceptible to C3 glomerulonephropathy is provided, comprising administering to the individual an effective amount of a compound having the following formula:

[0230]

[0231] Or its pharmaceutically acceptable salt.

[0232] A method for reducing C3 deposits and / or C5b-9 deposits in individuals with or susceptible to C3 glomerulonephropathy is provided, comprising administering to the individual an effective amount of a compound having the following formula:

[0233]

[0234] Or its pharmaceutically acceptable salt.

[0235] A method for clearing intraglomerular capillary proliferation in individuals with or susceptible to C3 glomerulonephropathy is provided, comprising administering to a person an effective amount of a compound having the following formula:

[0236]

[0237] Or its pharmaceutically acceptable salt.

[0238] A method for clearing intraglomerular capillary proliferation in individuals with or susceptible to C3 glomerulonephropathy is provided, comprising administering to a person an effective amount of a compound having the following formula:

[0239]

[0240] Or its pharmaceutically acceptable salt.

[0241] A method for reducing inflammatory macrophages in the glomeruli of individuals with or susceptible to C3 glomerulonephropathy is provided, comprising administering to the individual an effective amount of a compound having the following formula:

[0242]

[0243] Or its pharmaceutically acceptable salt.

[0244] A method for reducing inflammatory macrophages in the glomeruli of individuals with or susceptible to C3 glomerulonephropathy is provided, comprising administering to the individual an effective amount of a compound having the following formula:

[0245]

[0246] Or its pharmaceutically acceptable salt.

[0247] This invention provides a method for reducing proteinuria in individuals with or susceptible to C3 glomerulonephropathy, the method comprising administering to the individual an effective amount of a compound having the following formula:

[0248]

[0249] Or its pharmaceutically acceptable salt.

[0250] This invention provides a method for reducing proteinuria in individuals with or susceptible to C3 glomerulonephropathy, the method comprising administering to the individual an effective amount of a compound having the following formula:

[0251]

[0252] Or its pharmaceutically acceptable salt.

[0253] In some embodiments, the person has complement 3 glomerulonephritis. In some embodiments, the person has progressive complement 3 glomerulonephritis. In some embodiments, the person has recurrent complement 3 glomerulonephritis after kidney transplantation. In some embodiments, the person has dense deposit disease.

[0254] In some embodiments, complement 3-glomerulonephropathy is unresponsive to treatment. In some embodiments, complement 3-glomerulonephropathy is unresponsive to other treatments. In some embodiments, the person has immunosuppressive drug-resistant disease. In some embodiments, the person has one or more of the following drug-resistant diseases: rituximab, cyclophosphamide, mycophenolate mofetil, tacrolimus, and steroids. In some embodiments, the person has one or more of the following drug-resistant diseases: rituximab, cyclophosphamide, mycophenolate mofetil, tacrolimus, and glucocorticoids. In some embodiments, the person exhibits an improvement in health-related quality of life. In some embodiments, the health-related quality of life is assessed based on Short Form-36 version 2 (SF-36v2) or EuroQOL-5D-5L (EQ-5D-5L). In some embodiments, the health-related quality of life is assessed based on Short Form-36 version 2 (SF-36v2). In some embodiments, the health-related quality of life is assessed based on EuroQOL-5D-5L (EQ-5D-5L).

[0255] In some embodiments, the compound is administered twice daily. In some embodiments, the compound is administered once daily. In some embodiments, the compound is administered every other day. In some embodiments, the compound is administered every three days. In some embodiments, the compound is administered three times daily. In some embodiments, the compound is administered four times daily.

[0256] In some embodiments, a person receives 30 mg of the compound daily. In some embodiments, a person receives 20 mg of the compound daily. In some embodiments, a person receives 10 mg of the compound daily. In some embodiments, a person receives 40 mg of the compound daily. In some embodiments, a person receives 60 mg of the compound daily. In some embodiments, a person receives 50 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, or 200 mg of the compound daily.

[0257] In some embodiments, a person receives 30 mg of the compound twice daily. In some embodiments, a person receives 20 mg of the compound twice daily. In some embodiments, a person receives 10 mg of the compound twice daily.

[0258] In some embodiments, the compound is administered orally.

[0259] In some implementations, the human has a complement factor H-related protein 5 (CFHR5) mutant.

[0260] In some implementations, the person receives treatment for 12 weeks. In some implementations, the person receives treatment for 26 weeks. In some implementations, the person receives treatment for 52 weeks. In some implementations, the person receives chronic treatment. In some implementations, the person receives continuous treatment.

[0261] In some embodiments, the method further includes administering a therapeutically effective amount of one or more additional therapeutic agents to a person. In some embodiments, the one or more additional therapeutic agents are administered sequentially or simultaneously in the same or different compositions.

[0262] In some embodiments, one or more additional therapeutic agents are selected from immunosuppressive drugs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II type 1 receptor blockers (ARBs), and corticosteroids.

[0263] In some embodiments, one or more additional therapeutic agents are selected from the group consisting of: cyclophosphamide, mycophenolate mofetil, rituximab, eculizumab, tacrolimus, belimumab, OMS721, ACH-4471, AMY-101, Acthar Gel, SAND-5, adrenocorticotropic hormone, CDX-1135, ramipril, perindopril, lisinopril, perindopril arginine, captopril, spiropril, quinapril, enalapril, imidapril, fosinopril, zoflurazole, benazepril, quinapril, verapamil, benazepril, amlodipine, quinapril, P-003, cilazapril, delapril, moxipril, and quinapril. Fosinopril, temopril, losartan, candesartan, irbesartan, telmisartan, olmesartan, valsartan, azilsartan, telmisartan, femasartan, EMA-401, azilsartan medoxomil potassium, sparsentan, candesartan medoxomil, olmesartan medoxomil, TRV-027, losartan potassium, YH-22189, azilsartan trimethylethanolamine, alisartan medoxomil, and eprosartan. In some embodiments, one or more additional therapeutic agents are selected from the group consisting of cyclophosphamide, mycophenolate mofetil, rituximab, eculizumab, and tacrolimus.

[0264] In some embodiments, one or more additional therapeutic agents are selected from the group consisting of: corticosteroids, steroids, immunosuppressants, immunoglobulin G agonists, dipeptidyl peptidase IV inhibitors, lymphocyte functional antigen-3 receptor antagonists, interleukin-2 ligands, interleukin-1β ligand inhibitors, IL-2 receptor α subunit inhibitors, HGF gene stimulators, IL-6 antagonists, IL-5 antagonists, α1 antitrypsin stimulators, cannabinoid receptor antagonists, histone deacetylase inhibitors, AKT protein kinase inhibitors, CD20 inhibitors, Abl tyrosine kinase inhibitors, JAK tyrosine kinase inhibitors, TNFα ligand inhibitors, hemoglobin modulators, TNF antagonists, proteasome inhibitors, and C. D3 modulators, Hsp70 family inhibitors, immunoglobulin agonists, CD30 antagonists, microtubule antagonists, sphingosine-1-phosphate receptor-1 agonists, connective tissue growth factor ligand inhibitors, caspase inhibitors, adrenocorticotropic hormone ligands, Btk tyrosine kinase inhibitors, complement C1s subfraction inhibitors, erythropoietin receptor agonists, B lymphocyte stimulator ligand inhibitors, cyclin-dependent kinase-2 inhibitors, P-selectin glycoprotein ligand-1 stimulators, mTOR inhibitors, elongation factor 2 inhibitors, cell adhesion molecule inhibitors, factor XIII agonists, calcineurin inhibitors, immunoglobulin G1 agonists, inosine monophosphate dehydrogenase inhibitors, complement C 1S subfraction inhibitors, thymidine kinase modulators, cytotoxic T lymphocyte protein-4 modulators, angiotensin II receptor antagonists, angiotensin II receptor modulators, TNF superfamily receptor 12A antagonists, CD52 antagonists, adenosine deaminase inhibitors, T cell differentiation antigen CD6 inhibitors, FGF-7 ligands, dihydroorotate dehydrogenase inhibitors, CCR5 chemokine antagonists, CCR2 chemokine antagonists, Syk tyrosine kinase inhibitors, interferon type I receptor antagonists, interferon α ligand inhibitors, macrophage migration inhibitory factor inhibitors, integrin α-V / β-6 antagonists, cysteine ​​protease stimulators, p38MAP kinase inhibitors, TP53 gene inhibitors, Shiga-like... Toxin I inhibitors, fucosyltransferase 6 stimulants, interleukin-22 ligands, CXCR1 chemokine antagonists, CXCR4 chemokine antagonists, IRS1 gene inhibitors, protein kinase C stimulants, protein kinase Cα inhibitors, CD74 antagonists, immunoglobulin γFc receptor IIB antagonists, T-cell antigen CD7 inhibitors, CD95 antagonists, N-acetylmannosamine kinase stimulants, myocardial nutrient-1 ligands, leukocyte elastase inhibitors, CD40 ligand receptor antagonists, CD40 ligand modulators, IL-17 antagonists, TLR-2 antagonists, complement factor D inhibitors, complement factor B inhibitors, complement C5 inhibitors, MASP-2 inhibitors, MASP-3 inhibitors.C3 inhibitors, pegylated APL-1, C1s inhibitors, C6 inhibitors, and T-cell receptor antagonists.

[0265] In some embodiments, one or more additional therapeutic agents are selected from the group consisting of: obinutuzumab, rituximab, ocrelizumab, cyclophosphamide, prednisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, tecortisone valerate, prednisolone, methylprednisolone, triamcinolone, triamcinolone acetonide, mometasone, ancinonide, budesonide, desonide, fluocinolone acetonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocinolone, hydrocortisone-17-valerate, halometasone, aclomethasone dipropionate, beclomethasone, betamethasone valerate. Betamethasone dipropionate, prednisone ester, clobetasol-17-butyrate, clobetasol-17-propionate, fluclocolone hexanoate, fluclocolone neopentanoate, fluprednisolone acetate, hydrocortisone-17-butyrate, hydrocortisone-17-ethylpropionate, hydrocortisone-17-butenoate, cyclosonelide and prednisone ester, GB-0998, immuglo antibody, begelomab, alefacept, aldehyde interleukin, gevokizumab, dalizumab, baliximab, enoxaparin, beperminogen plasmid. perplasmid, sirukumab, tocilizumab, clazakizumab, mepolizumab, fingolimod, pabistat, troxilibine, nilotinib, imatinib, tofacitinib, momelotinib, peficitinib, itacitinib, infliximab, PEG-bHb-CO, etanercept, icoxizomib, bortezomib, morosumab, otelixizumab, gusperinmus, brentuximabVedotin), Ponesimod, KRP-203, FG-3019, Enricafen, Adrenocorticotropic hormone, Ibrutinib, Cinryze, Conestat, Methoxy polyethylene glycol-epotetin β, Belimumab, Blisibimod, Asceticip, Seliciclib, Neihulizumab, Everolimus, Sirolimus, Denileukindiftitox, LMB-2, Natalizumab, Catridecacog, Cyclosporine, Tacrolimus, Voclosporin Walkeronine, Conanab, Mycophenolate Mofetil, Imidazolidin, CE-1145, TK-DLI, Abatacept, Beracip, Olmesartan Medoxomil, Sparsentan, TXA-127, BIIB-023, Alemumab, Pentostatin, Itolizumab, Palivmin, Leflunomide, PRO-140, Cenicriviroc, Fostamatinib, Anifrolumab, Sifalimumab, BAX-069, BG-00011, Losmapimod, QPI-1002, ShigamotidineAb), TZ-101, F-652, reparixin, ladarixin, PTX-9908, aganirsen, APH-703, sotrastaurin, milatuzumab, SM-101, T-Guard, APG-101, DEX-M74, cardiac nutrient-1, titrestat, ASKP-1240, BMS-986004, HPH-116, KD-025, OPN-305, TOL-101, defibrotide, pomalidomide, thymoglobin, lamivudine, remestemcel-L, equine anti-thymocyte immunoglobulin, Stempeucel, LIV-γ, and others. Octagam 10%, t2c-001, 99mTc-sestamibi, Clairyg, Prosorba, Pomalidomide, Laquimod, Teplizumab, FCRx, Solnatide, Foralumab, ATIR-101, BPX-501, ACP-01, A LLO-ASC-DFU, Irbesartan + Propaderamer, ApoCell, Cannabidiol, RGI-2001, Orotic Acid (saratin), Anti-CD3 Bivalent Antibody-Diphtheria Toxin Conjugate, OMS-721, Eculizumab, Coversin, ACH-4471, ALN-CC5, AMY-101, IFX-1, IFX-2, IFX-3, LFG316, Berinert, CB 2782, ANX005, APL-2, APL-1, PEG-Cp40, ALXN1007, bikaciomab, NOX-D20, NOX-D19, OMS906, mubodina, ALXN1210, ruconest, TNT009, SOBI005, SHP623, cinryze, lambalizumab, regenemab, RA101495, RA101295, zimura, NOX-100, LT-1951, and CD4+CD25+ regulatory T cells.

[0266] Certain compounds of this invention may exist in both unsolvable and solvable forms, including hydrated forms. Generally, the solvable form is equivalent to the unsolvable form and is intended to be included within the scope of this invention. Certain compounds of this invention may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent to the uses contemplated by this invention and are intended to fall within the scope of this invention.

[0267] Certain compounds of this invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., individual enantiomers) are all intended to be included within the scope of this invention. The compounds of this invention may also contain atomic isotopes in non-natural proportions on one or more atoms constituting these compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium (…). 3 H), Iodine-125 125 I) or carbon-14 ( 14 C). All isotopic variants of the compounds of this invention, regardless of their radioactivity, are included within the scope of this invention.

[0268] The compounds disclosed herein are also intended to include all pharmaceutically acceptable compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), and Compound 1, wherein one or more atoms of said compounds are isotopically labeled by substitution with atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, for example... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. These radiolabeled compounds can be used to help determine or measure the effectiveness of compounds (e.g., by characterizing the site of action or mode of action), or binding affinity to pharmacologically important sites of action. Certain isotope-labeled compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), and Compound 1, such as those doped with radioisotopes, can be used for tissue distribution studies of drugs and / or substrates. Radioisotope tritium (i.e....) 3H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and readily available detection methods.

[0269] Using heavier isotopes such as deuterium (i.e., 2 H) substitution can provide certain therapeutic advantages due to greater metabolic stability. For example, the in vivo half-life may increase or the dosage requirement may decrease. Therefore, in some cases, heavier isotopes may be preferred.

[0270] Using positron emission of isotopes (e.g.) 11 C, 18 F, 15 O and 13 N) substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), and compound 1 can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the examples below, which use suitable isotopically labeled reagents instead of previously used unlabeled reagents.

[0271] The methods, compositions, kits, and articles provided herein use or include compounds (e.g., (I), (Ia), (Ib), (Ic), (Id), (Ie), and compound 1) or pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein one to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. These compounds can increase resistance to metabolism and are therefore used to increase the half-life of the compounds or their pharmaceutically acceptable salts, prodrugs, or solvates when administered to mammals. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci., 5(12): 524-527 (1984). These compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0272] The treatments described in this article typically involve administering an effective amount of the compounds described in this article to the patient. Suitable patients include those who have or are susceptible to (i.e., those receiving prophylactic treatment) C3 glomerulonephritis.

[0273] Typically, the treatment methods provided herein involve administering an effective amount of the compound provided herein to a patient. In a preferred embodiment, the compound of the invention is preferably administered orally or topically to the patient (e.g., a human). In another embodiment, the compound of the invention is administered systemically (intravenously or subcutaneously) to the patient (e.g., a human). An effective amount may be an amount sufficient to modulate C5a receptor activity and / or sufficient to reduce or alleviate the symptoms presented by the patient. Preferably, the amount administered is sufficient to produce a sufficiently high plasma concentration of the compound (or its active metabolite, if the compound is a prodrug) to detectably inhibit the chemotaxis of leukocytes (e.g., neutrophils) in vitro. Treatment regimens may vary depending on the compound used and the specific condition to be treated; for the treatment of most conditions, a dosing frequency of four times daily or less is preferred. Generally, a twice-daily dosing regimen is more preferred, and particularly once-daily dosing is preferred. However, it should be understood that the specific dosage level and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound used, age, weight, general health condition, sex, diet, timing of administration, route of administration, excretion rate, combination of medications (i.e., other medications given to the patient), the severity of the specific disease being treated, and the prescribing physician's judgment. Generally, the minimum dose sufficient to provide effective treatment is preferred. Treatment efficacy can usually be monitored using medical or veterinary standards appropriate for the condition being treated or prevented.

[0274] Dosage levels of approximately 0.1 mg to approximately 140 mg per kilogram of body weight per day can be used to treat or prevent conditions involving pathogenic C5a activity (approximately 0.5 mg to approximately 7 g per person per day). The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host being treated and the specific route of administration. Dosage unit forms typically contain approximately 1 mg to approximately 500 mg of active ingredient. For compounds administered orally, transdermally, intradermally, or subcutaneously, it is preferable to administer an adequate amount of the compound to achieve a serum concentration of 5 ng (nanograms) / mL to 10 μg (micrograms) / mL of serum, more preferably to administer an adequate amount of the compound to achieve a serum concentration of 20 ng to 1 μg / mL of serum, and most preferably to administer an adequate amount of the compound to achieve a serum concentration of 50 ng / mL to 200 ng / mL of serum. For direct injection into the synovium (for the treatment of arthritis), an adequate amount of the compound should be administered to achieve a local concentration of approximately 1 micromolar.

[0275] Dosage frequency may vary depending on the compound used and the specific disease being treated. However, for the treatment of most conditions, a dosage regimen of four times daily, three times daily, or less is preferred, with a particularly preferred regimen of once daily or twice daily. However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, time of administration, route of administration, rate of administration, combination of medications (i.e., other medications given to the patient), the severity of the specific disease being treated, and other factors, including the prescribing physician's judgment.

[0276] Pharmaceutical Composition

[0277] The compounds described herein can be administered in compositions that typically contain a drug carrier or diluent.

[0278] As used herein, the term "composition" is intended to cover products containing specific amounts of specific ingredients, and any products obtained directly or indirectly from a combination of specific amounts of specific ingredients.

[0279] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents.

[0280] Pharmaceutical compositions for administering the compounds of the present invention can be readily available in unit dose form and can be prepared by any method well known in the fields of pharmaceutics and drug delivery. All methods include the step of binding the active ingredient to a carrier constituting one or more excipients. Typically, the preparation of a pharmaceutical composition involves uniformly and tightly binding the active ingredient to a liquid carrier or a finely chopped solid carrier, or both, and then, if desired, shaping the product into a desired formulation. Within the pharmaceutical composition, the amount of the active target compound is sufficient to produce the desired effect against disease progression or symptoms.

[0281] Pharmaceutical compositions containing an active ingredient may be in forms suitable for oral administration, such as tablets, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifiers (as described in U.S. Patent Application 2002-0012680), hard capsules or soft capsules, syrups, elixirs, solutions, oral patches, oral gels, chewing gum, chewable tablets, effervescent powders, and effervescent tablets. Compositions for oral administration may be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide a pharmaceutically aesthetically pleasing and palatable formulation. Tablets contain the active ingredient and, when mixed therewith, non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as cellulose, silica, alumina, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as PVP, cellulose, PEG, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets can be uncoated, or they can be coated by known techniques in an enteric or other manner to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, delay-release materials such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated by techniques described in U.S. Patent Nos. 4,256,108, 4,166,452, and 4,265,874 to form osmotic therapeutic tablets for controlled release.

[0282] Oral formulations can also exist as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), polyethylene glycol (PEG) of various average sizes (e.g., PEG400, PEG4000), and certain surfactants (e.g., cremophor or soluto), or as soft gelatin capsules, in which the active ingredient is mixed with an aqueous or oil medium, such as peanut oil, liquid paraffin, or olive oil. Additionally, emulsions can be prepared with non-aqueous miscible components such as oils and stabilized with surfactants such as mono- or di-glycerides, PEG esters, etc.

[0283] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions mixed with them. Such excipients are suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents can be naturally occurring phospholipids, such as lecithin, or condensation products of alkyl esters and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain aliphatic alcohols, such as heptadecanethoxyhexadecyl alcohol, or condensation products of ethylene oxide and metaesters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide and metaesters derived from fatty acids and hexitan anhydrides, such as polyvinyl sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0284] Oily suspensions can be formulated by suspending the active ingredient in vegetable oils, such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oils such as liquid paraffin. Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as those listed above, and flavoring agents may be added to provide a palatable oral formulation. These compositions can be preserved by adding antioxidants, such as ascorbic acid.

[0285] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide the active ingredient, along with dispersants or wetting agents, suspending agents, and one or more preservatives mixed with it. Suitable dispersants or wetting agents and suspending agents are illustrated by examples mentioned above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0286] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or gum tragali, naturally occurring phospholipids, such as soybean lecithin, and esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate, the condensation product of said metaester with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings.

[0287] Syrups and elixirs can be formulated with sweeteners such as glycerin, propylene glycol, sorbitol, or sucrose. Such formulations may also contain modifiers, preservatives, flavoring agents, and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG, and surfactants.

[0288] Pharmaceutical compositions can be in the form of sterile injectable aqueous or oily suspensions. Such suspensions can be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile, non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic mono- or dianhydride esters. Additionally, fatty acids such as oleic acid can also be used in the preparation of injectable formulations.

[0289] The compounds of the present invention can also be used in suppository form for rectal administration. These compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol. Furthermore, the compound can be administered via ocular delivery in the form of a solution or ointment. Further, transdermal delivery of the compounds of the present invention can be achieved via iontophoresis patches, etc. For topical use, creams, ointments, gels, solutions, or suspensions containing the compounds of the present invention are used. As used herein, topical application is also intended to include the use of mouthwashes and gargles.

[0290] The compounds of the present invention can also be linked to a carrier, which is a suitable polymer as a targeted drug carrier. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl-methacrylamide-phenol, polyhydroxyethyl-asparagine-phenol, or palmitoyl residue-substituted polyethylene oxide-polylysine. Furthermore, the compounds of the present invention can be linked to a carrier that is a class of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly(ε-caprolactone), polyhydroxybutyric acid, poly(oxo-ester), polyacetal, polydihydropyran, polycyanoacrylate, and crosslinked or amphiphilic block copolymers of hydrogels. The polymer and semi-permeable polymer matrix can be processed into molded articles such as valves, stents, catheters, prostheses, etc. In one embodiment herein, the compounds are coupled to a polymer or semi-permeable polymer matrix that can be formed into a scaffold or scaffold-graft device.

[0291] reagent kits and packaging

[0292] The terms "kit" and "drug kit" refer to commercial kits or packages containing one or more pharmaceutical compositions and instructions for use in one or more suitable containers. In one embodiment, a kit is provided comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or compound 1, or a pharmaceutically acceptable salt thereof, and instructions for use thereof. In another embodiment, a kit is provided comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or compound 1, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents (e.g., one, two, three, one or two, or one to three) and instructions for use thereof.

[0293] In one embodiment, the compound of the invention is formulated into a dosing unit packaged in a single package. The single package includes, but is not limited to, bottles, child-safe bottles, ampoules, and tubes. In one embodiment, the compound of the invention and optional additional therapeutic agents are formulated into a dosing unit, and each single dosing unit is packaged separately in a single package. Such individually packaged units may contain any form of pharmaceutical composition, including but not limited to: liquid, solid, powder, granule, effervescent powder or tablet, hard capsule or soft capsule, emulsion, suspension, syrup, suppository, tablet, lozenge, diamond-shaped lozenge, solution, oral patch, film, oral gel, chewable tablet, chewing gum, and disposable syringe. Such individually packaged units may be combined in a package made of one or more types of paper, cardboard, cardboard, metal foil, and plastic foil, such as blister packs. One or more dosing units may be administered once or several times daily. One or more dosing units may be taken three times a day. One or more dosing units may be administered twice a day. One or more dosing units may be administered on the first day, and one or more dosing units may be administered on subsequent days.

[0294]

[0295] Compound 1 has the following formula:

[0296] Example

[0297] Example 1: Study of compound 1 in patients with progressive complement 3 glomerulonephritis

[0298] Patients with C3 glomerulonephritis received oral complement inhibitor compound 1 under the UK Special Needs Scheme (similar to the US Compassionate Use Scheme), following the protocol detailed below. Despite undergoing kidney transplantation and receiving extensive treatment with immunosuppressants including rituximab, cyclophosphamide, mycophenolate mofetil, tacrolimus, and steroids, the patient remained intractable. Kidney allogeneic graft biopsies were performed during treatment, prior to administration, at 2 months, and at 7 months.

[0299] result:

[0300] In response to treatment with compound 1, the patients' conditions improved. The improvements observed in patients treated with compound 1 were based on histological findings from renal biopsies taken during treatment, which showed clearance of intraglomerular capillary proliferation and a significant reduction in glomerular inflammatory macrophages compared to pre-treatment biopsies. Proteinuria decreased by approximately 80% after treatment with compound 1.

[0301] The estimated glomerular filtration rate (eGFR) in the 14 months prior to treatment with compound 1 was:

[0302] 83 mL / min / 1.73 m 2 When treatment with compound 1 was initiated, the estimated glomerular filtration rate (eGFR) decreased to 46 mL / min / 1.73 mcg. 2 Treatment with compound 1 reduced or halted the decline in eGFR.

[0303] One month after treatment, the decline in eGFR had slowed (Figure 1 shows eGFR before and after treatment with compound 1). Repeat biopsies showed regression of excessive intraglomerular capillary cells and a reduction in glomerular macrophages. Compound 1 stabilized eGFR and reduced glomerular inflammation.

[0304] Table 1. Excessive cells in capillaries, immunofluorescence microscopy observation, and CD68 positive cells / glomeruli at different time points.

[0305]

[0306] Figure 2 shows the improvement in histopathology after treatment with compound 1.

[0307] (A) Pretreatment with compound 1 showed fibrinoid necrosis and various inflammatory cells with heme and eosin (H&E) staining.

[0308] (C) Periodic acid-Schiff (PAS) staining after treatment with compound 1 showed a reduction in excessive intravascular capillary cells and a reduction in glomerular inflammation.

[0309] (B) CD68 staining before treatment with compound 1.

[0310] (D) CD68 staining after treatment with compound 1 showed a reduction in glomerular macrophages.

[0311] Research plan:

[0312] Target

[0313] The aim of this study was to evaluate the efficacy, safety, and tolerability of compound 1 in patients with progressive complement 3 (C3) glomerulonephritis.

[0314] Target

[0315] The primary safety objective of this study was to assess the safety and tolerability of compound 1.

[0316] The primary efficacy objective was to assess the efficacy of compound 1 based on baseline changes in eGFR (MDRD, estimated glomerular filtration rate) and proteinuria.

[0317] Secondary objectives of this study include evaluation:

[0318] 1. Baseline changes in pharmacodynamic markers in plasma and urine, such as MCP-1, C3a, C5a, propertin, and sC5b-9;

[0319] 2. Baseline changes in glomerular pathology based on renal biopsy;

[0320] 3. Assessment of plasma concentration of compound 1 in C3 glomerulonephritis.

[0321] method

[0322] This is a clinical study to test the safety, tolerability, and efficacy of compound 1 in patients with recurrent C3GN after kidney transplantation.

[0323] Prior to initiating medication, patients will have a biopsy confirming recurrent C3GN and will be considered eligible based on inclusion and exclusion criteria. The screening procedure will include recording demographic information, medical history, medication history, physical examination and vital signs, serological chemistry, hematology, urinalysis (including UPCR measurements), viral screening (if not performed, within the first 12 weeks), and an estimated glomerular filtration rate (eGFR) assessment based on serum creatinine. A baseline eGFR of at least 25 mL / min / 1.73 mcg is required for study eligibility. 2 .

[0324] On day 1, the patient will begin treatment with compound 1. For the initial 84 days, the patient will take 30 mg of compound 1 orally twice daily. The patient will visit the research center on days 1, 8, 15, 29, 57, and 85. The dosage of compound 1 will be taken in the morning, preferably one hour after breakfast, and in the evening, preferably one hour after dinner. If the patient's clinical condition is stable or improves, and there are no adverse events that would prevent further treatment, the patient may be given an additional 84-day treatment cycle. The 84-day cycle can be repeated according to this protocol, for a maximum of four cycles in total. For the 84-day cycle following the first cycle, the patient will visit the research center every four weeks. There will be a four-week follow-up period after the patient discontinues treatment with compound 1.

[0325] Blood and urine samples will be collected on day 1 and during subsequent study visits for safety, efficacy, and pharmacokinetic measurements. Physical examinations and vital sign assessments will be performed throughout the study. Concomitant medications and adverse events will be assessed at each study visit. If possible, renal biopsies will be performed after an appropriate follow-up period to evaluate renal histological changes.

[0326] No new C3GN treatment may be added during the study period (either during the active treatment period or the follow-up period) unless the subject's condition deteriorates to a level that the investigator deems necessary based on the subject's best interests.

[0327] The duration of treatment with compound 1 is 84 days, with a maximum of 3 repetitions of the 84-day cycle, for a total duration of up to 336 days.

[0328] Follow-up period after treatment with the study drug: 4 weeks.

[0329] At the end of the study, researchers will assess the patients' conditions and provide appropriate care and medical standards as needed.

[0330] Main criteria for selection

[0331] 1. Individuals with biopsy-confirmed C3GN based on renal biopsy within 8 weeks prior to screening;

[0332] 2. eGFR ≥ 25 mL / min / 1.73 m 2 (Through the MDRD equation);

[0333] 3. If there is a couple with fertility potential, adequate contraception must be used throughout the study and for at least 3 months after the completion of administration; adequate contraception is defined as resulting in an annual failure rate of less than 1% (combined estrogen and progestin [oral, vaginal or transdermal], or hormonal contraceptives containing progestin only (oral, injectable or implantable), intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal obstruction, vasectomy, or sexual abstinence).

[0334] 4. Willing and able to provide written informed consent and comply with the requirements of the research protocol; and

[0335] 5. Assess the investigator's health status based on medical history, physical examination, and clinical laboratory evaluation. Clinical laboratory values ​​exceeding normal limits (other than those specified in the exclusion criteria) and / or other abnormal clinical findings deemed clinically insignificant by the investigator are permissible.

[0336] Main criteria for exclusion

[0337] 1. Proteinuria >8 g / day (or >8 g / g creatinine);

[0338] 2. Use of eculizumab within 26 weeks prior to administration;

[0339] 3. History or presence of any form of cancer within 5 years prior to screening, except for resected basal cell or skin squamous cell carcinoma, or carcinoma in situ (such as cervical or breast cancer) that has been completely removed or eradicated without evidence of local recurrence or metastasis.

[0340] 4. Positive HBV, HCV, or HIV virus screening test;

[0341] 5. Any infections requiring antibiotic treatment that have not been cleared before starting compound 1 treatment on day 1;

[0342] 6. White blood cell count less than 4000 / μL, or neutrophil count less than 2000 / μL, or lymphocyte count less than 1000 / μL;

[0343] 7. Hemoglobin levels below 9 g / dL (or 5.56 mmol / L) at the time of screening;

[0344] 8. Evidence of liver disease; AST, ALT, alkaline phosphatase, or bilirubin >3x the upper limit of normal;

[0345] 9. Participated in any clinical study of the investigational product within 30 days prior to screening or within 5 half-lives after the last dose; and

[0346] 10. Any medical condition or illness that the researcher believes could place the subject at an unacceptable risk of participating in the study.

[0347] Duration of treatment and observation

[0348] Patients will be screened no more than 21 days before Day 1. The treatment period for Compound 1 is at least 84 days and at most 336 days, with patients followed up for 4 weeks (28 days) after discontinuation of treatment.

[0349] Where possible, any adverse events deemed relevant to the study drug and ongoing at discharge will be followed up to resolve or until the unresolved events are determined to be stable. At the end of the study, researchers will assess the patient's condition and provide appropriate standard of care as needed.

[0350] Security assessment

[0351] Safety assessment includes adverse events, abnormal physical examination findings, vital signs, and clinical laboratory tests (including blood chemistry, hematology, and urinalysis).

[0352] Efficacy evaluation

[0353] Efficacy evaluation includes:

[0354] 1. Urine PCR on the morning of the first day;

[0355] 2. eGFR calculated based on the Modified Diet for Kidney Disease (MDRD) equation using serum creatinine;

[0356] 3. Plasma and urine pharmacodynamic markers, such as MCP-1, C3a, C5a, properin, and sC5b-9;

[0357] 4. Follow up on glomerular inflammation (e.g., crescents, inflammatory cell infiltration, intracapillary proliferation) and C3 deposition in renal biopsy samples;

[0358] Pharmacokinetic assessment

[0359] The concentrations of compound 1 and its possible metabolites in plasma were determined on days 8, 15, 29, 57, and 85 from 2 mL blood samples collected from EDTA tubes. The date and time of the last dose of compound 1 were recorded prior to sample collection for measurement. Samples were frozen at -70°C or lower and transported on dry ice for the determination.

[0360] In any subsequent 84-day cycle, plasma samples will continue to be collected every 4 weeks.

[0361] Pharmacodynamic markers

[0362] Plasma samples will be collected on day 1 (before administration) and on days 8, 15, 29, 57, and 85 for the measurement of pharmacodynamic biomarkers, including, for example, complement fragments and levels of inflammatory cytokines and chemokines. Urine samples will also be collected on day 1 (before administration) and on days 8, 15, 29, 57, and 85 for the assessment of biomarkers, including, for example, MCP-1, complement fragments, and levels of inflammatory chemokines and cytokines.

[0363] Plasma and urine samples will continue to be collected every 4 weeks in any subsequent 84-day cycle.

[0364] Kidney histology

[0365] Renal biopsies were analyzed using periodic acid-Schiff (PAS) staining, immunofluorescence staining for C3, C5b-9, and other possible markers. Electron microscopy could also be performed.

[0366] Statistical methods

[0367] Demographic and baseline characteristics

[0368] At the start of the study, all patients’ baseline characteristics and demographic data will be listed (age, sex, race, ethnicity, weight, height, body mass index, smoking status, viral test results, duration of C3GN disease (from the initial diagnosis based on renal biopsy), history of renal transplantation, eGFR, proteinuria (PCR), urine MCP-1:creatinine ratio, physical examination abnormalities, medical history, previous (within 6 months after screening), and concomitant drug treatments (including other treatments for C3GN).

[0369] Security Analysis

[0370] The primary safety endpoint was the incidence of adverse events in patients.

[0371] Other safety endpoints include:

[0372] 1. Baseline variations from all safety laboratory parameters;

[0373] 2. Changes in baseline vital signs.

[0374] List all clinical safety and tolerability data. List treatment-emergent adverse events by systemic tissue class, relevance, and maximum severity. List serious adverse events and adverse events leading to withdrawal. List vital signs and changes from baseline in vital signs, based on study access. List laboratory data (actual values ​​and changes from baseline), based on study access. Mark abnormal laboratory values.

[0375] Efficacy Analysis

[0376] The primary efficacy endpoints were changes in eGFR and changes in urine PCR from baseline during treatment on the first morning of the treatment period.

[0377] Other efficacy endpoints include:

[0378] 1. Percentage changes from baseline in plasma and urine biomarkers, such as MCP-1, C3a, C5a, properdin, and sC5b-9;

[0379] 2. Glomerular inflammation (crescents, inflammatory cell infiltration, and intracapillary proliferation), changes in C3 and C5b-9 deposits from baseline to follow-up biopsy.

[0380] The changes in efficacy parameters and percentage changes during the 4-week follow-up period will also be evaluated to determine the post-treatment effect.

[0381] Pharmacokinetic analysis

[0382] Plasma samples will be collected on days 8, 15, 29, 57, and 85 to determine the plasma concentrations of compound 1 (and its metabolites). Plasma concentrations of compound 1 will be listed and plotted through study visits.

[0383] Example 2. A randomized, double-blind, placebo-controlled phase 2 study to evaluate the safety and efficacy of compound 1 in patients with C3 glomerulonephropathy.

[0384] Research proposal

[0385] Target

[0386] The aim of this study was to evaluate the effect of compound 1 treatment on renal disease activity in patients with complement 3-glomerulonephropathy (C3G). The goal was to treat these patients with compound 1 to slow or improve their renal disease.

[0387] Target

[0388] The primary objective was to evaluate the efficacy of compound 1 compared to placebo based on histological changes in C3G pathology from renal biopsies taken before and during treatment.

[0389] Secondary objectives of this study include evaluation:

[0390] 1. Safety of compound 1 compared to placebo, based on the incidence of adverse events, changes in clinical laboratory measurements and vital signs;

[0391] 2. Changes in nephrological laboratory parameters of compound 1 compared to placebo, including estimated glomerular filtration rate (eGFR), proteinuria, and urinary excretion of monocyte chemoattractant protein-1 (MCP-1);

[0392] 3. Changes in health-related quality of life based on compound 1, Short Form-36 version 2 (SF-36v2) and EuroQOL-5D-5L (EQ-5D-5L), compared to placebo;

[0393] 4. Evaluate the pharmacokinetic characteristics of compound 1 in patients with C3 glomerulonephropathy.

[0394] Additionally, during treatment, baseline changes in markers involved in the alternative complement pathway, such as C3, C3d, C3c, C3adesArg, C5, C5a, C5b-9, C5adesArg, and other inflammatory markers, can be assessed in plasma / serum or urine.

[0395] method

[0396] This is a phase 2 study testing the efficacy, safety, and tolerability of compound 1 in C3G patients (including C3GN and DDD). Eligible patients will be stratified based on the following two factors:

[0397] 1. C3GN or DDD, and

[0398] 2. Had a kidney transplant before being randomly assigned to another group.

[0399] Patients were randomized 1:1 to receive either 30 mg of compound 1 twice daily or a matched placebo in a double-blind, placebo-controlled manner for 26 weeks. Following the 26-week double-blind period, a 26-week treatment period followed, during which all patients received compound 1.

[0400] Patients were selected based on biopsy-confirmed C3 glomerulonephropathy (i.e., C3 staining grade ≥2 higher than any combination of IgG, IgM, IgA, and C1q) and inflammatory evidence based on leukocyte infiltration and / or intracapillary proliferation.

[0401] The screening period is a maximum of 28 days. The screening procedure includes written informed consent, demographics, medical history, medication history, physical examination and vital signs, 12-lead electrocardiogram, serum pregnancy test for women of childbearing age, serum chemistry (including serum creatinine), hematology, urinalysis, urine protein:creatinine ratio (PCR), and screening for viruses and tuberculosis. If the patient has not had a kidney biopsy in the past 12 weeks, a kidney biopsy is required before drug administration. Blood samples will be collected before starting the study of drug treatment for the following measurements to create a baseline profile for all patients:

[0402] 1.C3, C3d, C3c, C3adesArg and C4;

[0403] 2. C3 nephrotic factor;

[0404] 3.C5, C5a, C5b-9, C5adesArg;

[0405] 4. Serum complement factors H and B;

[0406] 5. Serum paraprotein detection;

[0407] 6. Mutation of complement factor H-related protein 5 (CFHR5).

[0408] Patients meeting the inclusion criteria will begin treatment with the study drug on day 1. Patients will take compound 1 (30 mg) orally twice daily, or a matched placebo. The treatment period is 52 weeks (364 days). The study drug will preferably be taken with food in the morning and evening (approximately 12 hours after the morning dose). Patients receiving placebo during the first 26 weeks will receive compound 1 in a blinded crossover. After the 364-day treatment period, all patients will be followed for 8 weeks (56 days) without treatment with the study drug.

[0409] Blood and urine samples will be collected at the study visit following Day 1 for safety, efficacy, and pharmacokinetic and biomarker measurements. Serum pregnancy tests will be performed periodically on women of childbearing potential at the end of the 52-week treatment period and the 8-week follow-up period. Physical examinations and vital sign assessments will be conducted throughout the study. Health-related quality of life, assessed using EQ-5D-5L and SF-36v2, will be evaluated periodically during the study. Study drugs will be dispensed, and drug responsibility will be assigned. Concomitant medication and adverse event assessments will be conducted at each study visit. Follow-up renal biopsies will be performed at the following time points:

[0410] 1. After a 26-week placebo-controlled treatment period;

[0411] 2. If the patient withdraws early in the study, and

[0412] 3. After a 52-week treatment period.

[0413] If a patient is receiving other immunosuppressive therapy at the start of treatment, the dose of that concomitant immunosuppressive therapy may not be increased during the study. Treatment with these other medications may be reduced or discontinued during the study if the patient's condition warrants it. No new treatments may be added during the study (either the active treatment period or the follow-up period) unless the patient's condition worsens to a level that the investigator deems necessary for the patient's best interests. This will be considered treatment failure.

[0414] Patients whose renal function deteriorates due to an unexplained increase in serum creatinine of at least 50% (confirmed by repeat measurement after 2 weeks), or an increase in proteinuria relative to baseline of >3 g / g creatinine, or a level of renal function worsening reaching >8 g / g (confirmed by repeat measurement after 2 weeks) during 52 weeks of treatment, will be withdrawn from the study and their treatment will be decided at the physician's discretion. They will remain in the study for follow-up and outcome recording. These will be considered treatment failures.

[0415] For research centers that have approved enrollment of adolescents (12 to 17 years old), the dosage of compound 1 or placebo will be initially given based on body weight at screening, and the dosage will be adjusted according to the plasma level of compound 1, as shown in the table below.

[0416] In patients aged 12 to 17 years only, blood samples will be collected before and at 0.5, 1, 2, 3, 4, and 6 hours after the first dose of compound 1 on day 1, and plasma samples will be sent to a central laboratory for rapid measurement of compound 1 and its metabolites in these patients. Dosage adjustments will be made based on AUC. 0-6 The results are shown in the table below. These AUCs... 0-6 The threshold will be based on the mean plasma exposure to compound 1 (525 ng·hr / mL) of adult patients from the phase 2 study CL002_168 in AAV and one standard deviation above or below the mean (174 ng·hr / mL).

[0417]

[0418] Patients will visit the research center during the screening period and on day 1 (baseline) and at weeks 1, 2, 4, 8, 12, 16, 20, 26, 32, 38, 44, 52 and 60.

[0419] Duration of double-blind treatment with compound 1 or placebo: 26 weeks.

[0420] Duration of treatment with compound 1 after the double-blind treatment period: 26 weeks.

[0421] Follow-up period after completion of drug treatment: 8 weeks.

[0422] Once all week 60 visits are completed, patients will be withdrawn from the study. At the end of the clinical trial (week 60), investigators will assess patients' conditions and provide appropriate standards of care to all patients as needed.

[0423] Number of patients

[0424] Approximately 44 male or female patients with C3 glomerulonephropathy participated in this study. Patients who withdrew before the week 26 visit could be replaced.

[0425] Main criteria for selection

[0426] 1. Biopsy-confirmed C3 glomerulonephropathy, DDD or C3GN, with a C3 staining degree 2 grades higher than any combination of IgG, IgM, IgA and C1q, and signs of inflammation based on leukocyte infiltration or capillary proliferation observed in a renal biopsy performed within 12 weeks prior to or during screening; kidney transplant patients are eligible to participate in this study;

[0427] 2. Plasma C5b-9 levels were above the upper limit of the central laboratory reference range;

[0428] 3. Male or female patients, aged at least 18 years; adolescents (12-17 years) may enroll with approval; female patients of reproductive potential may participate if they have used adequate contraception during the study and for at least three months after the study; male patients with reproductive potential partners may participate if they have undergone vasectomy at least 6 months prior to randomization and have used adequate contraception during the study and for at least three months after the study; adequate contraception is defined as resulting in an annual failure rate of less than 1% (estrogen and progestin [oral, intravaginal or transdermal], or progestin-only hormonal contraception (oral, injectable or implantable), intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal obstruction, vasectomy partners, or sexual abstinence);

[0429] 4. Willing and able to provide written informed consent and comply with the requirements of the research protocol; written informed consent should be obtained from the legal guardian in accordance with the regional laws or regulations for patients aged 12 to 17; and

[0430] 5. The suitability of an investigator for the study will be determined based on medical history, physical examination, and clinical laboratory assessment. Patients with clinical laboratory values ​​exceeding normal limits (other than those specified in the exclusion criteria) and / or other abnormal clinical findings deemed by the investigator to be of no clinical significance may be enrolled in the study.

[0431] Main criteria for exclusion

[0432] 1. Pregnant or breastfeeding;

[0433] 2. Proteinuria >8 g / day (or >8 g / g creatinine);

[0434] 3. More than 50% of renal histology shows interstitial fibrosis;

[0435] 4. Use eculizumab within 26 weeks prior to administration;

[0436] 5. Secondary C3 diseases, such as infection-related diseases, or those associated with other systemic or autoimmune diseases;

[0437] 6. Currently undergoing dialysis or may require dialysis within 7 days;

[0438] 7. History or presence of any form of cancer within 5 years prior to screening, except for resected basal cell or squamous cell carcinoma of the skin, or carcinoma in situ (such as cervical or breast cancer that has been completely removed or eradicated with no evidence of local recurrence or metastasis).

[0439] 8. Positive HBV, HCV, or HIV screening test;

[0440] 9. Evidence of tuberculosis based on interferon-gamma release assay (IGRA), tuberculin purified protein derivative (PPD) skin test, or chest X-ray taken at the time of screening or within 6 weeks prior to screening;

[0441] 10. Before starting administration, the WBC count is less than 3500 / uL, or the neutrophil count is less than 1500 / uL, or the lymphocyte count is less than 800 / uL;

[0442] 11. Evidence of liver disease; AST, ALT, alkaline phosphatase, or bilirubin >3 times the upper limit of normal before starting medication;

[0443] 12. Hypersensitivity to compound 1 or the inactive ingredient is known;

[0444] 13. Participated in any clinical study of the investigational product within 30 days prior to screening or within 5 half-lives after the last dose; and

[0445] 14. Any medical condition or illness that the researcher believes could place the patient at an unacceptable risk of participating in the study, either historically or presently.

[0446] Duration of treatment and observation

[0447] Patients were screened no more than 28 days prior to Day 1. The treatment period was 52 weeks (364 days), and all patients were followed up for 8 weeks (56 days) after the dosing period.

[0448] Where possible, any adverse events deemed relevant to the investigational drug and ongoing at discharge will be followed up to resolve or until the unresolved event is determined to be stable. At the end of the clinical trial, investigators will assess patients' conditions and provide appropriate standards of care to all patients as needed.

[0449] Security assessment

[0450] Safety assessment includes adverse events, abnormal physical examination findings, vital signs, and clinical laboratory tests (including blood chemistry, hematology, and urinalysis).

[0451] Efficacy evaluation

[0452] Efficacy evaluation includes:

[0453] 1. Renal histology determines disease status and chronic C3G histological markers (CHI);

[0454] 2. eGFR calculated using the diet-modification-renal-disease (MDRD) equation derived from serum creatinine;

[0455] 3. Urine PCR on the morning of the first day;

[0456] 4. First morning urine MCP-1:creatinine ratio;

[0457] 5. EQ-5D-5L and SF-36v2.

[0458] Pharmacokinetic assessment

[0459] The concentrations of compound 1 and its metabolites were determined in plasma based on the time and event table.

[0460] Pharmacodynamic markers

[0461] Plasma / serum samples will be collected according to a time and event schedule for pharmacodynamic marker measurements, including, for example, complement fragments and levels of inflammatory cytokines and chemokines. Urine samples will also be collected according to a time and event schedule for biomarker assessment, including, for example, complement fragments, sCD163, and levels of inflammatory chemokines and cytokines.

[0462] Kidney histology

[0463] For eligibility assessment, renal biopsy samples will be evaluated by immunofluorescence staining for C3 and immunoglobulins. Patients must have biopsy-confirmed C3 glomerulonephropathy, DDD, or C3GN, with a C3 staining grade ≥2 higher than any combination of IgG, IgM, IgA, and C1q, and evidence of inflammation based on leukocyte infiltration or intracapillary proliferation observed in renal biopsies performed within 12 weeks prior to or during screening.

[0464] All renal biopsies were analyzed using hematoxylin and eosin (H&E) staining, periodic acid-Schiff (PAS) staining, trichrome staining, and silver agar staining. These biopsies were evaluated by a central reader, and treatment allocation was performed blinded, regardless of whether the images were from slides or high-resolution electronic images.

[0465] The central reader will determine the disease condition and the degree of chronicity.

[0466] Statistical methods

[0467] Demographic and baseline characteristics

[0468] The research center listed all patients' baseline characteristics and demographic data upon entry into the study (age, sex, race, ethnicity, weight, height, body mass index, viral test results, duration of C3 glomerulonephropathy (from the initial diagnosis based on renal biopsy), eGFR, proteinuria (PCR), complement marker levels, urine MCP-1:creatinine ratio, physical examination abnormalities, medical history, past (within 6 months of screening), and concomitant drug treatments (including other treatments for C3 glomerulonephropathy), and also summarized the number of patients.

[0469] Efficacy Analysis

[0470] The primary efficacy endpoint was the percentage change in the C3G histological index (CHI) of disease activity relative to baseline by week 26. Compound 1 and the placebo group were compared using ANCOVA, with the treatment group and randomization layer (C3GN or DDD, and kidney transplantation status) as factors, and baseline as a covariate. Point estimates and corresponding 95% confidence intervals were estimated for differences between the compound 1 and placebo groups.

[0471] Since the placebo group received compound 1 during the second 26-week period of the study, the change in CHI from week 26 to week 52 in the placebo control group will be compared with the change from baseline to week 26 in this group. This analysis will be performed using paired t-tests. Point estimates and corresponding 95% confidence intervals will be estimated for the differences between the second 26-week period (compound 1 treatment) and the first 26 weeks (placebo treatment).

[0472] Changes from baseline to week 52 in the CHI will also be compared with changes from baseline at week 26 in the placebo control group using a method similar to that described for the primary efficacy endpoint.

[0473] Other efficacy endpoints include:

[0474] 1. Percentage change in chronic disease CHI relative to baseline during a 26-week treatment period in a placebo-controlled trial;

[0475] 2. Changes in eGFR relative to baseline and percentage changes during the 26-week treatment period in placebo-controlled trials;

[0476] 3. Percentage change in urine PCR relative to baseline during the 26-week treatment period in placebo-controlled trials;

[0477] 4. Percentage change in urinary MCP-1:creatinine ratio relative to baseline during the 26-week treatment period in a placebo-controlled trial;

[0478] 5. Changes in EQ-5D-5L and SF-36v2 (domain and component scores) relative to baseline during the 26-week treatment period in a placebo-controlled trial.

[0479] For repeated measures (MMRM), a mixed-effects model was used to analyze continuous variables including eGFR, urine PCR, urine MCP-1:creatinine ratio, EQ-5D-5L, and SF-36v2, where treatment group, visits, visit interaction, and randomization layer (C3GN or DDD, and kidney transplantation status) were considered as factors, and baseline was considered as a covariate. Patients were considered as visits-based repeated measures units. Point estimates and corresponding 95% confidence intervals were estimated for the difference between compound 1 group and control group at 26 weeks using simple comparisons from the model. Similar to the primary endpoint, the second 26 weeks were compared with the first 26 weeks in the placebo group.

[0480] The changes in efficacy parameters and percentage changes during the 8-week follow-up period will also be evaluated to determine the post-treatment effect.

[0481] The report will show changes in markers of alternative complement pathway activation relative to baseline.

[0482] Calculate summary statistics for each efficacy endpoint. For continuous variables, calculate the number, mean, median, range, standard deviation, standard error, and 95% confidence interval. Calculate the geometric mean of urinary PCR and MCP-1:creatinine, and other non-normally distributed measurements.

[0483] Security Analysis

[0484] Safety endpoints include:

[0485] 1. Serious adverse events occurring during treatment, incidence of adverse events, and patient withdrawal due to adverse events;

[0486] 2. Variations and offsets of all safety laboratory parameters relative to the baseline;

[0487] 3. Changes in vital signs relative to baseline.

[0488] All patients who are randomly assigned and receive at least one dose of the study drug will be included in the safety population.

[0489] All clinical safety and tolerability data will be listed by treatment group and by patient, and summarized by treatment group.

[0490] All reported adverse events will be coded using MedDRA and listed by system organization category, preferred terminology, and verbatim terminology.

[0491] The treatment team will list and summarize adverse events caused by treatment based on systemic tissue category, relevance, and maximum severity.

[0492] The treatment team will summarize adverse events caused by the treatment and those that led to withdrawal.

[0493] Individual vital signs and baseline changes in vital signs will be listed by treatment group, patient and study visit, and summarized by the treatment group.

[0494] Laboratory data (actual values ​​and baseline changes) will be listed by treatment group, patient, and study visit. Abnormal laboratory values ​​will be flagged. Laboratory data will also be summarized by treatment group and study visit. A moving average table for changes in laboratory parameters will be generated by study visit.

[0495] Pharmacokinetic and pharmacodynamic marker analysis

[0496] Plasma samples are collected during the study to determine the pharmacokinetic (PK) profiles for compound 1 (and its metabolites). Individual plasma concentrations of compound 1 (and its metabolites) are listed, plotted, and summarized in a descriptive and graphical manner. PK parameters are calculated based on the relationship between plasma compound 1 concentrations at sample collection and the time of administration of the most recent dose of the study drug. PK parameters for important metabolites can also be calculated.

[0497] Plasma and urinary PD markers were summarized and analyzed using methods similar to those used for efficacy parameters. Where possible, the following parameters were determined in patients aged 12–17 years:

[0498] Cmax is the maximum plasma concentration.

[0499] Time to maximum plasma concentration (tmax)

[0500] AUC 0-6 Area under the plasma concentration-time curve from time 0 to 6 hours on day 1

[0501] Cmin trough level plasma concentration at day 1 follow-up

[0502] Assess the relationship between eGFR-based PK parameters and renal function. This data can also be used to assess the PK / PD relationship after compound 1 treatment. For this purpose, baseline and / or percentage changes in urinary PCR, eGFR, urinary MCP-1:creatinine ratio, and other biomarkers can be used as PD markers.

Claims

1. The use of an effective amount of a compound having the following structure or a pharmaceutically acceptable salt thereof, characterized in that, Used to prepare pharmaceutical compositions for treating complement 3 glomerulonephropathy. 。 2. The use as described in claim 1, wherein, The person suffers from complement 3 glomerulonephritis.

3. The use as described in claim 1, wherein, The person has progressive complement 3 glomerulonephritis.

4. The use as described in claim 1, wherein, The patient suffers from recurrent complement 3 glomerulonephritis following a kidney transplant.

5. The use as described in claim 1, wherein, The person suffers from dense deposit disease.

6. The use as described in claim 1, wherein, The person suffers from an immunosuppressive disease that is refractory to treatment.

7. The use as described in claim 1, wherein, People with refractory disease to one or more of the following drugs: rituximab, cyclophosphamide, mycophenolate mofetil, tacrolimus, and steroids.

8. The use as described in claim 1, wherein, People showed improvements in health-related quality of life.

9. The use as described in claim 1, wherein, The compound was administered twice daily.

10. The use as described in claim 1, wherein, The compound is administered once daily.

11. The use as described in claim 1, wherein, The compound was administered orally.

12. The use as described in claim 1, wherein, A person takes 30 milligrams of the compound twice a day.

13. The use as described in claim 1, wherein, People take 20 milligrams of the compound twice a day.

14. The use as described in claim 1, wherein, A person receives 10 milligrams of the compound twice a day.

15. The use as described in claim 1, wherein, Humans have a mutant of complement factor H-related protein 5.

16. The use as described in claim 1, wherein, The person received treatment for 12 weeks.

17. The use as described in claim 1, wherein, The person received treatment for 26 weeks.

18. The use as described in claim 1, wherein, The patient received treatment for 52 weeks.

19. The use as described in claim 1, wherein, People receive chronic treatment.

20. The use as described in any one of claims 1-19, wherein, It also includes one or more additional therapeutic agents given to a person in a therapeutically effective amount.

21. The use as described in claim 20, wherein, One or more additional therapeutic agents are selected from immunosuppressive drugs, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, and corticosteroids.

22. The use as described in claim 20, wherein, One or more additional therapeutic agents are selected from cyclophosphamide, mycophenolate mofetil, rituximab, eculizumab, tacrolimus, belimumab, acseregum, adrenocorticotropic hormone, ramipril, perindopril, lisinopril, perindopril arginine, captopril, spiropril, quinapril, enalapril, imidapril, zoflupril, verapamil, benazepril, amlodipine, quindopril, cilazapril, delapril, moxipril, fosinopril, temopril, losartan, candesartan, irbesartan, telmisartan, olmesartan, valsartan, azilsartan, femasartan, azilsartan medoxomil potassium, sparsentan, candesartan medoxomil, olmesartan medoxomil, losartan potassium, azilsartan trimethylethanolamine, alisartan medoxomil, and eprosartan.

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