Methods for treating C3 nephropathy

Abstract

To treat a human suffering from or susceptible to C3 glomerulopathy.SOLUTION: The present invention discloses a method comprising administering to a human an effective amount of a C5aR antagonist.SELECTED DRAWING: Figure 1

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. § 119(e) to 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, each of which is incorporated by reference herein in its entirety for all purposes.

[0002] Declaration of Rights in Inventions Made Under Federally Sponsored Research and Development Not applicable

[0003] Reference to a "Sequence Listing" or table or computer program listing submitted on a compact disc Not applicable

[0004] C3 nephropathy (C3G) is a rare disease of the kidney (the prevalence of C3G is estimated at 2–3 cases per million population). C3G is characterized by the deposition of a protein known as C3 (a component of the body's complement system) within the kidney's filtering units (glomeruli), suggesting complement involvement in causing kidney damage. C3 nephropathy is characterized by evidence based on intraglomerular C3 deposition, which results in alternative complement activation. Two forms of the disease exist: dense deposition disease (DDD, formerly called membranoproliferative glomerulonephritis type II [MPGN]) and C3 glomerulonephritis (C3GN, formerly called idiopathic MPGN). Genetic lesions leading to defective complement regulation, including mutations in complement factor H (CFH), have been reported in these patients. Patients with C3 nephropathy often present with proteinuria and progressive deterioration of renal function. There are no approved treatments for patients with C3 nephropathy (including C3GN). Because there is no treatment for C3G, it inevitably leads to kidney failure, and kidney transplantation is often the only option. Even after transplant, the new kidney often fails due to recurrence of the disease. Summary of the Invention

[0005] The present disclosure relates to a method of treating a human suffering from or susceptible to C3 nephropathy, comprising administering to the human an effective amount of a C5aR antagonist.

[0006] In one embodiment, the C5aR antagonist has formula (I): [ka] or a pharmaceutically acceptable salt thereof, provided that in this formula: C 1 is any one to three R 1 is a phenyl substituted with a substituent; C 2 is any one to three R 2 is a phenyl substituted with a substituent; C3 is C 3-8 selected from the group consisting of cycloalkyl and phenyl; 3 is any one to three R 3 substituted with a substituent; Each R 1 are independently 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 , -S(O)NR a R b wherein each R is selected from the group consisting of a and R b are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R c are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R a , R b , R c The aliphatic and cyclic portions of the formula (I) are optionally substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, or dialkylamino groups; and optionally two R 1 When substituents are present on adjacent atoms, they may be combined to form a fused 5- or 6-membered carbocyclic ring; Each R 2are independently 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 , -S(O)NR d R e wherein each R is selected from the group consisting of d and R e are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R f are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R d , R e , R f wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen groups, hydroxy groups, methyl groups, amino groups, alkylamino groups, or dialkylamino groups; Each R 3 are independently halogen, -CN, -R i , -CO2R g , -CONR g R h , C(O)R g , -OC(O)NR g R h , -NR hC(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)NR 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 , -NHCH2R j wherein X is selected from the group consisting of 4 is C 1-4 alkylene; each R g and R h are independently hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combined with the nitrogen atom to form a 5- or 6-membered ring containing as members thereof 0 to 2 additional heteroatoms selected from N, O, and S, and optionally substituted by 1 or 2 oxo; each R i are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j is C 3-6 R is selected from the group consisting of cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl; g , R h , R i , R jwherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen, methyl, CF3, hydroxy, amino, alkylamino, or dialkylamino groups; X is hydrogen or CH3).

[0007] In some embodiments, the C5aR antagonist has the formula: [ka] It is a compound having the formula: [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 depicts the estimated glomerular filtration rate (eGFR) of patients before and after treatment with Compound 1.

[0009] [Figure 2] FIG. 2 depicts the histopathological improvement after treatment with Compound 1.

[0010] Detailed Description of the Invention Abbreviations and definitions The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms (i.e., C1-8 means 1 to 8 carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, s-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term "alkenyl" refers to unsaturated alkyl groups having one or more double bonds. Similarly, the term "alkynyl" refers to unsaturated alkyl groups having one or more triple bonds. Included in such unsaturated alkyl groups are vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl, 3-propynyl, 3-butynyl, and higher homologs and isomers. The term "cycloalkyl" refers to a group having a specified number of atoms in the ring (e.g., C 3-6 "Cycloalkyl" refers to 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 carbocycles, such as bicyclo[2.2.1]heptane and bicyclo[2.2.2]octane. The term "heterocycloalkyl" refers to a cycloalkyl group containing 1 to 5 heteroatoms selected from N, O, and S (the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized). Heterocycloalkyls can be monocyclic, bicyclic, or polycyclic ring systems. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc. A heterocycloalkyl group can be attached to the remainder of the molecule through a carbon or heteroatom of the ring.

[0011] The term "alkylene" by itself or as part of another substituent refers to a divalent group derived from an alkane, such as -CHCHCHCH-. Typically, alkyl (or alkylene) groups have from 1 to 24 carbon atoms, although groups having 10 or fewer carbon atoms are preferred in this disclosure. A "lower alkyl" or "lower alkylene" is a shorter alkyl or alkylene group, generally having four or fewer carbon atoms. Similarly, "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene," having a double or triple bond, respectively.

[0012] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched hydrocarbon radical or cyclic hydrocarbon radical, or combination thereof, consisting of the specified number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si, and S, wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The O, N, and S heteroatoms may be placed at any position within the heteroalkyl group. The Si heteroatom may be placed at any position within the heteroalkyl group, including the position at which the alkyl group is attached to the remainder 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, -CH=CH-N(CH3)-CH3. Up to two heteroatoms can be consecutive, for example, -CH2-NH-OCH3 or -CH2-O-Si(CH3)3. Similarly, the terms "heteroalkenyl" and "heteroalkynyl," by themselves or in combination with other terms, mean, unless otherwise stated, an alkenyl or alkynyl group, respectively, containing the specified number of carbon atoms and having from 1 to 3 heteroatoms selected from the group consisting of O, N, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The O, N, and S heteroatoms can be placed at any position within the heteroalkyl group.

[0013] The term "heteroalkylene" by itself or as part of another substituent means a saturated, monounsaturated, or polyunsaturated divalent radical derived from heteroalkyl, examples of which are -CH-CH-S-CHCH-, -CH-S-CH-CH-NH-CH-, -O-CH-CH=CH-, -CH-CH=C(H)CH-O-CH-, and -S-CH-C≡C-. In heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).

[0014] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense to refer to an alkyl group attached to the remainder of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. In addition, in a dialkylamino group, the two alkyl moieties may be the same or different and may form a 3- to 7-membered ring with the nitrogen atom to which they are attached. Thus, NR a R b is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, and the like.

[0015] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, fluorine, chlorine, bromine, or iodine. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C1-4 haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0016] The term "aryl," unless otherwise specified, refers to a polyunsaturated (typically aromatic) hydrocarbon group. The hydrocarbon group can be monocyclic or multiple rings (up to three rings) fused or covalently linked to each other. The term "heteroaryl" refers to an aryl group (or aryl ring) containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, and non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, and isobenzofuryl. Examples include isoindolyl, indolizinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0017] For brevity, the term "aryl," when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl), includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is meant to include groups in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.).

[0018] The above terms (e.g., "alkyl," "aryl," and "heteroaryl"), in some embodiments, include both saturated and unsaturated forms of the indicated radical. Preferred substituents for each type of radical are provided below. For simplicity, the terms aryl and heteroaryl refer to either substituted or unsubstituted versions, as indicated below, while the term "alkyl" and its related aliphatic groups refer to unsubstituted versions unless indicated to be substituted.

[0019] A wide variety of groups are possible as substituents on alkyl groups (including those often referred to as alkylene, alkenyl, alkynyl, and cycloalkyl), and the selection of groups varies depending on the group: -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)R', -S(O)NR'R", -NR'S(O)R", -CN, and -NO, which range from 0 to (2m'+1), where m' is the total number of carbon atoms in such groups. R', R", and R"' each independently represent hydrogen, unsubstituted C alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1 to 3 halogens, unsubstituted C alkoxy, unsubstituted C thioalkoxy, or unsubstituted aryl-C alkyl. When R' and R" are attached to the same nitrogen atom, R' and R" can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl. The term "acyl" by itself or as part of another substituent means an alkyl group in which two substituents on the carbon nearest to the point of attachment of the group are replaced with the substituent =O (e.g., -C(O)CH, -C(O)CHCHOR', etc.).

[0020] Similarly, substituents on the aryl and heteroaryl groups vary and generally include -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' and R', R", and R"' are independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, unsubstituted aryl, unsubstituted heteroaryl, (unsubstituted aryl)-C1-4 alkyl, and unsubstituted aryloxy-C1-4 alkyl. Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene bridge of 1 to 4 carbon atoms.

[0021] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -TC(O)-(CH) q It can be substituted with a substituent of -U- (wherein T and U are independently -NH-, -O-, -CH2- or a single bond, and q is an integer of 0 to 2).

[0022] Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring optionally have the formula -A-(CH2) rA and B may be substituted with a substituent of the formula -B- (where A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 3). One of the single bonds in the new ring thus formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a group of the formula -(CH2) s -X-(CH2) t - (wherein s and t are independently integers of 0 to 3, and X is any of -O-, -NR'-, -S-, -S(O)-, -S(O)2-, and -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen and unsubstituted C1-6 alkyl.

[0023] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0024] The term "ionic liquid" refers to any liquid that contains primarily ions. In the present disclosure, "ionic liquid" preferably refers to a salt that has a relatively low melting point (e.g., less than 250°C). Non-limiting examples of ionic liquids include 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 tetrafluoroborate, 1-hexyl-3-methylimidazolium bromide, and the like.

[0025] As used herein, the term "treat" or "treatment" encompasses both disease-altering and symptomatic treatment, either of which can be prophylactic (i.e., treatment before symptoms appear and to prevent, delay, or reduce the severity of symptoms) or therapeutic (i.e., treatment after symptoms appear and to reduce the severity and / or duration of symptoms). Treatment methods provided herein generally involve administering to a patient an effective amount of one or more compounds provided herein. Suitable patients include those suffering from or likely to suffer from a disorder or disease identified herein (i.e., prophylactic treatment). Typical patients for the treatments described herein include mammals, particularly primates, and especially humans. Other suitable patients include domesticated pet animals (e.g., dogs, cats, horses, etc.) and livestock (e.g., cows, pigs, sheep, etc.).

[0026] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Examples of salts derived from pharmaceutically acceptable organic bases include salts of primary amines, secondary amines, and quaternary amines (including substituted amines, cyclic amines, and naturally occurring amines), specifically, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperazine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present disclosure contains a rather basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid (neat or in a suitable inert solvent). Pharmaceutically acceptable acid addition salts include those derived from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, phosphorous acid, and the like) and those derived from relatively non-toxic organic acids (e.g., propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like).Also included are salts of amino acids (e.g., alginate) and organic acids (e.g., glucuronic acid and galacturonic acid) (see, e.g., Berge, SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, Vol. 66, pp. 1-19). Some particular compounds of the present disclosure contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.

[0027] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent forms differ from the various salt forms in some physical properties (e.g., solubility in polar solvents), but are otherwise equivalent to the parent forms for purposes of this disclosure.

[0028] The compounds described in the following embodiments can be obtained according to the methods described in WO 2010 / 075257, WO 2011 / 163640, WO 2016 / 053890.

[0029] Implementation The present disclosure relates to a method of treating a human suffering from or susceptible to suffering from complement 3 nephropathy, comprising administering to the human a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: C 1 is any one to three R 1 is a phenyl substituted with a substituent; C 2 is any one to three R 2 is a phenyl substituted with a substituent; C 3 is C 3-8 selected from the group consisting of cycloalkyl and phenyl; 3 is any one to three R3 substituted with a substituent; Each R 1 are independently 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 , -S(O)NR a R b wherein each R is selected from the group consisting of a and R b are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R c are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R a , R b , R c The aliphatic and cyclic portions of the formula (I) are optionally substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, or dialkylamino groups; and optionally two R 1 When substituents are present on adjacent atoms, they may be combined to form a fused 5- or 6-membered carbocyclic ring; Each R 2 are independently halogen, -CN, -R f , -CO2R d , -CONR d R e , C(O)Rd , -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 , -S(O)NR d R e wherein each R is selected from the group consisting of d and R e are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R f are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R d , R e , R f wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen groups, hydroxy groups, methyl groups, amino groups, alkylamino groups, or dialkylamino groups; Each R 3 are independently 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 Rh , -NR g R h , -OR g , -S(O)NR 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 , -NHCH2R j wherein X is selected from the group consisting of 4 is C 1-4 alkylene; each R g and R h are independently hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combined with the nitrogen atom to form a 5- or 6-membered ring containing as members thereof 0 to 2 additional heteroatoms selected from N, O, and S, and optionally substituted by 1 or 2 oxo; each R i are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j is C 3-6 R is selected from the group consisting of cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl; g , R h , R i , R j wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen, methyl, CF3, hydroxy, amino, alkylamino, or dialkylamino groups; X is hydrogen or CH3.

[0030] In some embodiments, the compound has Formula (Ia): [ka] have.

[0031] In some embodiments, the compound has formula (Ib): [ka] However, in this formula, X 1 CH and CR 1 selected from the group consisting of: The subscript n is an integer between 0 and 2; X 2 CH and CR 2 selected from the group consisting of: The subscript m is an integer between 0 and 2.

[0032] In some embodiments, the compound has formula (Ic): [ka] However, in this formula, X 1 CH and CR 1 selected from the group consisting of: The subscript n is an integer between 0 and 2; X 2 CH and CR 2 selected from the group consisting of: The subscript m is an integer between 0 and 2.

[0033] In some embodiments, the compound is (Id): [ka] However, in this formula, The subscript p is an integer between 0 and 3; X 1 CH and CR 1 selected from the group consisting of: The subscript n is an integer between 0 and 2; X 2 CH and CR 2 selected from the group consisting of: The subscript m is an integer between 0 and 2.

[0034] In some embodiments, the compound is (Ie): [ka] where p is either 0, 1, or 2.

[0035] In some embodiments, the compound is [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0037] A method of slowing the rate of decline in estimated glomerular filtration rate (eGFR) in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: C 1 is any one to three R 1 is a phenyl substituted with a substituent; C 2 is any one to three R2 is a phenyl substituted with a substituent; C 3 is C 3-8 selected from the group consisting of cycloalkyl and phenyl; 3 is any one to three R 3 substituted with a substituent; Each R 1 are independently 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 , -S(O)NR a R b wherein each R is selected from the group consisting of a and R b are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R c are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R a , R b , R c The aliphatic and cyclic portions of the formula (I) are optionally substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, or dialkylamino groups; and optionally two R 1When substituents are present on adjacent atoms, they may be combined to form a fused 5- or 6-membered carbocyclic ring; Each R 2 are independently 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 , -S(O)NR d R e wherein each R is selected from the group consisting of d and R e are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R f are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R d , R e , R f wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen groups, hydroxy groups, methyl groups, amino groups, alkylamino groups, or dialkylamino groups; Each R 3 are independently halogen, -CN, -R i , -CO2R g , -CONR g Rh , 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)NR 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 , -NHCH2R j wherein X is selected from the group consisting of 4 is C 1-4 alkylene; each R g and R h are independently hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combined with the nitrogen atom to form a 5- or 6-membered ring containing as members thereof 0 to 2 additional heteroatoms selected from N, O, and S, and optionally substituted by 1 or 2 oxo; each R i are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j is C 3-6 R is selected from the group consisting of cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl; g , R h , Ri , R j wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen, methyl, CF3, hydroxy, amino, alkylamino, or dialkylamino groups; X is hydrogen or CH3.

[0038] In some embodiments, the compound has formula (Ie): [ka] where p is either 0, 1, or 2.

[0039] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0040] A method of reducing glomerulonephritis in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: C 1 is any one to three R 1 is a phenyl substituted with a substituent; C 2 is any one to three R 2 is a phenyl substituted with a substituent; C 3 is C 3-8 selected from the group consisting of cycloalkyl and phenyl; 3 is any one to three R 3 substituted with a substituent; Each R 1 are independently halogen, -CN, -R c , -CO2R a , -CONR aR 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 , -S(O)NR a R b wherein each R is selected from the group consisting of a and R b are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R c are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R a , R b , R c The aliphatic and cyclic portions of the formula (I) are optionally substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, or dialkylamino groups; and optionally two R 1 When substituents are present on adjacent atoms, they may be combined to form a fused 5- or 6-membered carbocyclic ring; Each R 2 are independently 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 , -S(O)NR d R e wherein each R is selected from the group consisting of d and R e are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R f are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R d , R e , R f wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen groups, hydroxy groups, methyl groups, amino groups, alkylamino groups, or dialkylamino groups; Each R 3 are independently 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)NR g R h , -X 4 -Rj , -X 4 -NR g R h , -X 4 -CONR g R h , -X 4 -NR h C(O)R g , -NHR j , -NHCH2R j wherein X is selected from the group consisting of 4 is C 1-4 alkylene; each R g and R h are independently hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combined with the nitrogen atom to form a 5- or 6-membered ring containing as members thereof 0 to 2 additional heteroatoms selected from N, O, and S, and optionally substituted by 1 or 2 oxo; each R i are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j is C 3-6 R is selected from the group consisting of cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl; g , R h , R i , R j wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen, methyl, CF3, hydroxy, amino, alkylamino, or dialkylamino groups; X is hydrogen or CH3.

[0041] In some embodiments, the compound has formula (Ie): [ka] have.

[0042] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0043] A method of reducing C3 and / or C5b-9 deposits in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: C 1 is any one to three R 1 is a phenyl substituted with a substituent; C 2 is any one to three R 2 is a phenyl substituted with a substituent; C 3 is C 3-8 selected from the group consisting of cycloalkyl and phenyl; 3 is any one to three R 2 substituted with a substituent; Each R 1 are independently 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 , -S(O)NR a R b wherein each R is selected from the group consisting ofa and R b are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R c are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R a , R b , R c The aliphatic and cyclic portions of the formula (I) are optionally substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, or dialkylamino groups; and optionally two R 1 When substituents are present on adjacent atoms, they may be combined to form a fused 5- or 6-membered carbocyclic ring; Each R 2 are independently 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 , -S(O)NR d R e wherein each R is selected from the group consisting of d and R e are independently hydrogen, C 1-8 Alkyl, C 1-8haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R f are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R d , R e , R f wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen groups, hydroxy groups, methyl groups, amino groups, alkylamino groups, or dialkylamino groups; Each R 3 are independently 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)NR 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 , -NHCH2R j wherein X is selected from the group consisting of 4 is C 1-4 alkylene; each R g and Rh are independently hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combined with the nitrogen atom to form a 5- or 6-membered ring containing as members thereof 0 to 2 additional heteroatoms selected from N, O, and S, and optionally substituted by 1 or 2 oxo; each R i are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j is C 3-6 R is selected from the group consisting of cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl; g , R h , R i , R j wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen, methyl, CF3, hydroxy, amino, alkylamino, or dialkylamino groups; X is hydrogen or CH3.

[0044] In some embodiments, the compound has formula (Ie): [ka] where p is either 0, 1, or 2.

[0045] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the human is suffering from complement 3 glomerulonephritis. In some embodiments, the human is suffering from progressive complement 3 glomerulonephritis. In some embodiments, the human is suffering from recurrent complement 3 glomerulonephritis after kidney transplantation. In some embodiments, the human is suffering from dense deposit disease.

[0047] A method for eliminating glomerular endocapillary proliferation in a human suffering from or susceptible to C3 nephropathy is provided, the method comprising administering to the human a compound of the general formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: C 1 is any one to three R 1 is a phenyl substituted with a substituent; C 2 is any one to three R 2 is a phenyl substituted with a substituent; C 3 is C 3-8 selected from the group consisting of cycloalkyl and phenyl; 3 is any one to three R 3 substituted with a substituent; Each R 1 are independently 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 , -S(O)NR a R bwherein each R is selected from the group consisting of a and R b are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R c are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R a , R b , R c The aliphatic and cyclic portions of the formula (I) are optionally substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, or dialkylamino groups; and optionally two R 1 When substituents are present on adjacent atoms, they may be combined to form a fused 5- or 6-membered carbocyclic ring; Each R 2 are independently 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 , -S(O)NR d R e wherein each R is selected from the group consisting of d and R e are independently hydrogen, C 1-8 Alkyl, C 1-8haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R f are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R d , R e , R f wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen groups, hydroxy groups, methyl groups, amino groups, alkylamino groups, or dialkylamino groups; Each R 3 are independently 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)NR 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 , -NHCH2R j wherein X is selected from the group consisting of 4 is C 1-4 alkylene; each R g and Rh are independently hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combined with the nitrogen atom to form a 5- or 6-membered ring containing as members thereof 0 to 2 additional heteroatoms selected from N, O, and S, and optionally substituted by 1 or 2 oxo; each R i are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j is C 3-6 R is selected from the group consisting of cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl; g , R h , R i , R j wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen, methyl, CF3, hydroxy, amino, alkylamino, or dialkylamino groups; X is hydrogen or CH3.

[0048] In some embodiments, the compound has formula (Ie): [ka] where p is either 0, 1, or 2.

[0049] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0050] A method of reducing glomerulonephritic macrophages in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of the general formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: C 1 is any one to three R 1 is a phenyl substituted with a substituent; C 2 is any one to three R 2 is a phenyl substituted with a substituent; C 3 is C 3-8 selected from the group consisting of cycloalkyl and phenyl; 3 is any one to three R 3 substituted with a substituent; Each R 1 are independently 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 , -S(O)NR a R b wherein each R is selected from the group consisting of a and R b are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R c are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R a , R b , R c The aliphatic and cyclic portions of the formula (I) are optionally substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, or dialkylamino groups; and optionally two R 1 When substituents are present on adjacent atoms, they may be combined to form a fused 5- or 6-membered carbocyclic ring; Each R 2 are independently 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 , -S(O)NR d R e wherein each R is selected from the group consisting of d and R e are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R f are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R d , R e , R fwherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen groups, hydroxy groups, methyl groups, amino groups, alkylamino groups, or dialkylamino groups; Each R 3 are independently 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)NR 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 , -NHCH2R j wherein X is selected from the group consisting of 4 is C 1-4 alkylene; each R g and R h are independently hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combined with the nitrogen atom to form a 5- or 6-membered ring containing as members thereof 0 to 2 additional heteroatoms selected from N, O, and S, and optionally substituted by 1 or 2 oxo; each R i are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C3-6 selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j is C 3-6 R is selected from the group consisting of cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl; g , R h , R i , R j wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen, methyl, CF3, hydroxy, amino, alkylamino, or dialkylamino groups; X is hydrogen or CH3.

[0051] In some embodiments, the compound has formula (Ie): [ka] where p is either 0, 1, or 2.

[0052] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0053] A method of reducing proteinuria in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of the general formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: C 1 is any one to three R 1 is a phenyl substituted with a substituent; C 2 is any one to three R 2 is a phenyl substituted with a substituent; C 3is C 3-8 selected from the group consisting of cycloalkyl and phenyl; 3 is any one to three R 3 substituted with a substituent; Each R 1 are independently 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 , -S(O)NR a R b wherein each R is selected from the group consisting of a and R b are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R c are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R a , R b , R c The aliphatic and cyclic portions of the formula (I) are optionally substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, or dialkylamino groups; and optionally two R 1 When substituents are present on adjacent atoms, they may be combined to form a fused 5- or 6-membered carbocyclic ring; Each R 2 are independently halogen, -CN, -Rf , -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 , -S(O)NR d R e wherein each R is selected from the group consisting of d and R e are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R f are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R d , R e , R f wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen groups, hydroxy groups, methyl groups, amino groups, alkylamino groups, or dialkylamino groups; Each R 3 are independently 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)NR 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 , -NHCH2R j wherein X is selected from the group consisting of 4 is C 1-4 alkylene; each R g and R h are independently hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combined with the nitrogen atom to form a 5- or 6-membered ring containing as members thereof 0 to 2 additional heteroatoms selected from N, O, and S, and optionally substituted by 1 or 2 oxo; each R i are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j is C 3-6 R is selected from the group consisting of cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl; g , R h , R i , R jwherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen, methyl, CF3, hydroxy, amino, alkylamino, or dialkylamino groups; X is hydrogen or CH3.

[0054] In some embodiments, the compound has formula (Ie): [ka] have.

[0055] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the human has complement 3 glomerulonephritis. In some embodiments, the human has progressive complement 3 glomerulonephritis. In some embodiments, the human has recurrent complement 3 glomerulonephritis after kidney transplant. In some embodiments, the human has dense deposit disease. In some embodiments, the human has disease resistant to immunosuppressants.

[0057] A method of treating a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of formula (Ie): [ka] or a pharmaceutically acceptable salt thereof, wherein: Each R 1 are independently halogen, -CN, -R c , -CO2R a , -CONR a R b , C(O)R a , -OC(O)NR a R b , -NR b C(O)Ra , -NR b C(O)2R c , -NR a C(O)NR a R b , -NR a R b , -OR a , -S(O)NR a R b wherein each R is selected from the group consisting of a and R b are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R c are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R a , R b , R c The aliphatic and cyclic portions of the formula (I) are optionally substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, or dialkylamino groups; and optionally two R 1 When substituents are present on adjacent atoms, they may be combined to form a fused 5- or 6-membered carbocyclic ring; Each R 2 are independently 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 Re , -NR d R e , -OR d , -S(O)NR d R e wherein each R is selected from the group consisting of d and R e are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combine with the nitrogen atom to form a 5- or 6-membered ring containing 0 to 2 additional heteroatoms selected from N, O, and S as members of the ring; each R f are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R d , R e , R f wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen groups, hydroxy groups, methyl groups, amino groups, alkylamino groups, or dialkylamino groups; Each R 3 are independently 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)NR 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 , -NHCH2R j wherein X is selected from the group consisting of 4 is C 1-4 alkylene; each R g and R h are independently hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combined with the nitrogen atom to form a 5- or 6-membered ring containing as members thereof 0 to 2 additional heteroatoms selected from N, O, and S, and optionally substituted by 1 or 2 oxo; each R i are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j is C 3-6 R is selected from the group consisting of cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl; g , R h , R i , R j wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen, methyl, CF3, hydroxy, amino, alkylamino, or dialkylamino groups; p is either 0, 1, or 2.

[0058] In some embodiments, Each R 1 are independently halogen, -CN, -R c , -NR a R b , -OR a wherein each R is selected from the group consisting of a and R b are independently hydrogen, C 1-8 Alkyl, C 1-8haloalkyl, or when attached to the same nitrogen atom, combine with the nitrogen atom to form a pyrrolidine ring; each R c are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 cycloalkyl; R a , R b , R c The aliphatic and cyclic portions of the formula (I) are optionally substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, or dialkylamino groups; and optionally two R 1 When substituents are present on adjacent atoms, they may be combined to form a fused 5- or 6-membered carbocyclic ring; Each R 2 are independently halogen, -R f , -OR d wherein each R is selected from the group consisting of d are independently hydrogen, C 1-8 Alkyl, C 1-8 haloalkyl, and each R f are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, and heteroaryl; R d and R f wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen groups, hydroxy groups, methyl groups, amino groups, alkylamino groups, or dialkylamino groups; Each R 3 are independently halogen, -R i , -CO2R g , -CONR g R h , -NR h C(O)R g , -NR h C(O)2R i , -NR g R h , -OR g , -X 4 -R j , -X 4 -NR g Rh , -X 4 -CONR g R h , -X 4 -NR h C(O)R g , -NHR j , -NHCH2R j wherein X is selected from the group consisting of 4 is C 1-4 alkylene; each R g and R h are independently hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 1-8 haloalkyl, or, when attached to the same nitrogen atom, combined with the nitrogen atom to form a 5- or 6-membered ring containing as members thereof 0 to 2 additional heteroatoms selected from N, O, and S, and optionally substituted by 1 or 2 oxo; each R i are independently, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each R j is C 3-6 R is selected from the group consisting of cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl; g , R h , R i , R j wherein the aliphatic and cyclic portions are optionally further substituted with 1 to 3 halogen, methyl, CF3, hydroxy, amino, alkylamino, or dialkylamino groups; p is 1.

[0059] In some embodiments, Each R 1 are independently, C 1-8 Alkyl and C 1-8 haloalkyl; Each R 2 are independently halogen and C 1-8 selected from the group consisting of alkyl; Each R 3 Ha-NR g R h and each R g and R h are independently hydrogen and C 3-6 cycloalkyl; p is 1.

[0060] In some embodiments, Each R 1 are independently, C 1-3 Alkyl and C 1-3 haloalkyl; Each R 2 are independently halogen and C 1-3 selected from the group consisting of alkyl; Each R 3 Ha-NR g R h and each R g and R h are independently hydrogen and C 4-6 cycloalkyl; p is 1.

[0061] In some embodiments, the compound is [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the disclosed methods include one or more of slowing the rate of decline in estimated glomerular filtration rate (eGFR) in a human, alleviating glomerulonephritis in a human, eliminating glomerular endocapillary proliferation in a human, reducing glomerulonephritic macrophages in a human, reducing proteinuria in a human, slowing the progression of kidney disease in a human, halting the progression of kidney disease in a human, delaying end-stage kidney disease in a human, improving kidney histology in a human, and slowing the increase in proteinuria in a human. In some embodiments, the improvement can be supported by a kidney biopsy.

[0065] A method of slowing the rate of decline in estimated glomerular filtration rate (eGFR) in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a dose of a compound according to the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0066] A method of slowing the rate of decline in estimated glomerular filtration rate (eGFR) in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a dose of a compound according to the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0067] A method of reducing glomerulonephritis in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0068] A method of reducing glomerulonephritis in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0069] A method of reducing C3 and / or C5b-9 deposition in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0070] A method of reducing C3 and / or C5b-9 deposition in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0071] A method of eliminating glomerular endocapillary proliferation in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0072] A method of eliminating glomerular endocapillary proliferation in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0073] A method of reducing glomerulonephritic macrophages in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0074] A method of reducing glomerulonephritic macrophages in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0075] A method of reducing proteinuria in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0076] A method of reducing proteinuria in a human suffering from or susceptible to C3 nephropathy is provided, comprising administering to the human a compound of the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the human is suffering from complement 3 glomerulonephritis. In some embodiments, the human is suffering from progressive complement 3 glomerulonephritis. In some embodiments, the human is suffering from recurrent complement 3 glomerulonephritis after kidney transplantation. In some embodiments, the human is suffering from dense deposit disease.

[0078] In some embodiments, the complement 3 nephropathy is resistant to treatment. In some embodiments, the complement 3 glomerulonephritis is resistant to other treatments. In some embodiments, the human has disease resistant to immunosuppressants. In some embodiments, the human has disease resistant to one or more of rituximab, cyclophosphamide, mycophenolate mofetil, tacrolimus, and steroids. In some embodiments, the human has disease resistant to one or more of rituximab, cyclophosphamide, mycophenolate mofetil, tacrolimus, and glucocorticosteroids. In some embodiments, the human has an improvement in health-related quality of life. In some embodiments, the health-related quality of life is based on a Short Form-36 version 2 (SF-36 v2) assessment or a EuroQOL-5D-5L (EQ-5D-5L) assessment. In some embodiments, the health-related quality of life is based on a Short Form-36 version 2 (SF-36 v2) assessment. In some embodiments, health-related quality of life is based on the EuroQOL-5D-5L (EQ-5D-5L) assessment.

[0079] 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 once every two days. In some embodiments, the compound is administered once every three days. In some embodiments, the compound is administered three times daily. In some embodiments, the compound is administered four times daily.

[0080] In some embodiments, the human takes 30 mg of the compound daily. In some embodiments, the human takes 20 mg of the compound daily. In some embodiments, the human takes 10 mg of the compound daily. In some embodiments, the human takes 40 mg of the compound daily. In some embodiments, the human takes 60 mg of the compound daily. In some embodiments, the human takes 50 mg, or 70 mg, or 80 mg, or 90 mg, or 100 mg, or 150 mg, or 200 mg of the compound daily.

[0081] In some embodiments, the human takes 30 mg of the compound twice daily. In some embodiments, the human takes 20 mg of the compound twice daily. In some embodiments, the human takes 10 mg of the compound twice daily.

[0082] In some embodiments, the compound is administered orally.

[0083] In some embodiments, the human has a complement factor H-related protein 5 (CFHR5) mutation.

[0084] In some embodiments, the human receives treatment for 12 weeks. In some embodiments, the human receives treatment for 26 weeks. In some embodiments, the human receives treatment for 52 weeks. In some embodiments, the human receives long-term treatment. In some embodiments, the human receives continuous treatment.

[0085] In some embodiments, the methods of the disclosure include administering to a human a therapeutically effective amount of one or more additional therapeutic agents, which in some embodiments are administered sequentially, simultaneously in the same composition, or simultaneously in different compositions.

[0086] In some embodiments, the one or more additional therapeutic agents are selected from an immunosuppressant, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II type 1 receptor blocker (ARB), and a corticosteroid.

[0087] In some embodiments, the 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, corticotropin, CDX-1135, ramipril, perindopril, lisinopril, perindopril arginine, captopril, spirapril, quinapril, enalapril, imidapril, fosinopril, zofenopril, benazepril, trandolapril, verapamil, benazepril, azathioprine, amitriptyline ... In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of mulodipine, trandolapril, P-003, cilazapril, delapril, moexipril, temocapril, losartan, candesartan, irbesartan, telmisartan, olmesartan, valsartan, azilsartan, fimasartan, EMA-401, azilsartan medoxomil potassium, sparsentan, candesartan cilexetil, olmesartan medoxomil, TRV-027, losartan potassium, YH-22189, azilsartan trimethylethanolamine, allisartan isoproxil, and eprosartan. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of cyclophosphamide, mycophenolate mofetil, rituximab, eculizumab, and tacrolimus.

[0088] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of a corticosteroid, a steroid, an immunosuppressant, an immunoglobulin G agonist, a dipeptidyl peptidase IV inhibitor, a lymphocyte function antigen-3 receptor antagonist, an interleukin-2 ligand, an interleukin-1 beta ligand inhibitor, an IL-2 receptor alpha subunit inhibitor, an HGF gene stimulator, an IL-6 antagonist, an IL-5 antagonist, an alpha 1 antitrypsin stimulator, a cannabinoid receptor antagonist, a histone deacetylase inhibitor, an AKT protein kinase inhibitor, a CD20 inhibitor, an Abl tyrosine kinase inhibitor, a JAK tyrosine kinase inhibitor, a TNF alpha ligand inhibitor, a hemoglobin modulator, a TNF antagonist, a proteasome inhibitor, a CD3 modulator, an Hsp 70 family inhibitors, immunoglobulin agonists, CD30 antagonists, tubulin antagonists, sphingosine-1-phosphate receptor-1 agonists, connective tissue growth factor ligand inhibitors, caspase inhibitors, adrenocorticotropic hormone ligands, Btk tyrosine kinase inhibitors, complement C1 minor component inhibitors, erythropoietin receptor agonists, B-lymphocyte stimulating 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 C1s minor component inhibitors, thymidine kinase modulators, cytotoxic T-lymphocyte protein-4 modulators, angiotensin II receptor antagonists, angiotensin II receptor modulators, TNF Superfamily receptor 12A antagonist, CD52 antagonist, adenosine deaminase inhibitor, T cell differentiation antigen CD6 inhibitor, FGF-7 ligand, dihydroorotate dehydrogenase inhibitor, CCR5 chemokine antagonist, CCR2 chemokine antagonist, Syk tyrosine kinase inhibitor, interferon type I receptor antagonist, interferon α ligand inhibitor, macrophage migration inhibitory factor inhibitor, integrin α-V / β-6 antagonist, cysteine ​​protease stimulator, p38MAP kinase inhibitors, TP53 gene inhibitors, Shiga-like toxin I inhibitors, fucosyltransferase 6 stimulators, interleukin-22 ligands, CXCR 1 The therapeutic agent is selected from the group consisting of chemokine antagonists, CXCR4 chemokine antagonists, IRS1 gene inhibitors, protein kinase C stimulators, protein kinase C alpha inhibitors, CD74 antagonists, immunoglobulin gamma Fc receptor IIB antagonists, T cell antigen CD7 inhibitors, CD95 antagonists, N-acetylmannosamine kinase stimulators, cardiotrophin-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.

[0089] In some embodiments, the one or more additional therapeutic agents selected are obinutuzumab, rituximab, ocrelizumab, cyclophosphamide, prednisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone ribonucleotides, ... Sodium phosphate, Fluocortolone, Hydrocortisone 17-valerate, Halometasone, Alclometasone Dipropionate, Beclomethasone, Betamethasone Valerate, Betamethasone Dipropionate, Prednicarbate, Clobetasone 17-butyrate, Clobetasol 17-propionate, Fluocortolone Caproate, Fluocortolone Pivalate, Fluprednidene Acetate, Hydrocortisone 17-butyrate, Hydrocortisone 17-aceponate, Hydrocortisone-17-buteprate, Ciclesonide and Prednicarbate, GB-0998, immuglo, Bege Romab, alefacept, aldesleukin, gevokizumab, daclizumab, basiliximab, inolimomab, beperminogen perplasmid, sirukumab, tocilizumab, clazakizumab, mepolizumab, fingolimod, panobinostat, triciribine, nilotinib, imatinib, tofacitinib, momelotinib, peficitinib, itacitinib, infliximab, PEG-bHb-CO, etanercept, ixazomib, bortezomib, muromonab, otelixizumab, gusperimus, brentuximab vedotin, ponesimod, KRP-203, FG-3019, Emricasan, corticotropin, ibrutinib, cinryze, conestat, methoxypolyethylene glycol-epoetin beta, belimumab, blissibimod, atacicept, seliciclib, neiflizumab, everolimus, sirolimus, denileukin diftitox, LMB-2, natalizumab, catridecacog, cyclosporine, tacrolimus, voclosporin, canakinumab, mycophenolate, mizoribine, CE-1145, TK-DLI, abatacept, belatacept, olmesartan medoxomil, sparsentan,TXA-127, BIIB-023, alemtuzumab, pentostatin, itolizumab, palifermin, leflunomide, PRO-140, cenicriviroc, fostamatinib, anifrolumab, sifalimumab, BAX-069, BG-00011, rosmapimod, QPI-1002, Shiga mAbs, TZ-101, F-652, reparixin, ladalixin, PTX-9908, aganirsen, APH-703, sotrastaurin, milatuzumab, SM-101, T-guard, APG-101, DEX-M74, cardiotrophin-1, tiplerestat, ASKP-1240, BMS-986004, HPH-116, KD-025, OPN-305 , TOL-101, defibrotide, pomalidomide, thymoglobulin, laquinimod, remestemcel-L, equine antithymic immunoglobulin, stempeucel, LIV-γ, octagam 10%, t2c-001, 99mTc-sestamibi, ClairYg, Prosolva, pomalidomide, teplizumab, FCRx, solnatide, foralumab, ATIR-101, BPX-501, ACP-01, ALLO-ASC-DFU, irbesartan + propagermanium, ApoCell, cannabidiol, RGI-2001, Saratin, anti-CD3 bivalent antibody-diphtheria toxin conjugate, OMS-721, eculizumab, covelcin, ACH-4471, ALN-CC5, AMY-101, IFX-1, IFX-2, IFX-3, LFG316, Verinert, CB 2782, ANX005, APL-2, APL-1, PEG-Cp40, ALXN1007, bicasinomab, NOX-D20, NOX-D19, OMS906, Mvozina, ALXN1210, Ruconest, TNT009, SOBI005, SHP623, lampalizumab, regenemab, RA101495, RA101295, Zimra, NOX-100, LT-1951, CD4, + CD25 + This is done from a group of regulatory T cells.

[0090] Some compounds of the present disclosure can exist in unsolvated and solvated forms (including hydrated forms). In general, solvated forms are equivalent to unsolvated forms and are intended to be within the scope of the present disclosure. Some compounds of the present disclosure can exist in polycrystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0091] Some compounds of the present disclosure have asymmetric carbons (optical centers) or double bonds. All racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separate enantiomers) are intended to be encompassed within the scope of the present disclosure. The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain radioactive isotopes (e.g., tritium ( 3 H), iodine-125( 125 I), carbon-14( 14 C)) can be radiolabeled. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0092] The compounds disclosed herein are also meant to include all pharmaceutically acceptable compounds of Formula (I), (Ia), (Ib), (Ic), (Id), and (Ie), and Compound 1, that are isotopically enriched by having one or more atoms replaced with an atom of a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35S, 18 F, 36 Cl, 123 I, 125 I. These radiolabeled compounds may be useful in determining and measuring the efficacy of compounds, for example, by characterizing the site or mode of action or by characterizing the binding affinity to a pharmacologically useful site of action. Isotopically labeled compounds of formula (I), (Ia), (Ib), (Ic), (Id), and (Ie) and Compound 1 (e.g., compounds incorporating a radioisotope) are useful in studying drug and / or substrate distribution to tissues. The radioisotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) is particularly useful for this purpose given the ease of incorporation and the provision of detection means.

[0093] Heavier isotopes (e.g., deuterium, i.e. 2 Substitution with H may offer several therapeutic advantages due to greater metabolic stability, such as a longer in vivo half-life or a reduced dose requirement, and therefore in some situations heavier isotopes may be preferable.

[0094] Positron-emitting isotopes ( 11 C. 18 F, 15 O. 13 Substitution with N may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I), (Ia), (Ib), (Ic), (Id), and (Ie) and compound 1 can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples below, substituting the appropriate isotopically labeled reagent for the unlabeled reagent previously used.

[0095] The methods, compositions, kits, and articles of manufacture provided herein utilize or include compounds in which one to n hydrogen atoms bonded to a carbon atom can be replaced with deuterium atoms, i.e., D (e.g., (I), (Ia), (Ib), (Ic), (Id), and (Ie) and Compound 1), or pharmaceutically acceptable salts, prodrugs, and solvates thereof, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds can increase resistance to metabolism and, therefore, may be useful for increasing the half-life of the compound or its pharmaceutically acceptable salts, prodrugs, and solvates when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Drug Metabolism Studies," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds can be synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0096] The methods of treatment provided herein generally involve administering an effective amount of a compound provided herein to a patient. Suitable patients include those suffering from C3 glomerulonephritis or those at risk of developing C3 glomerulonephritis (i.e., prophylactic treatment).

[0097] In general, the treatment methods provided herein comprise administering to a patient an effective amount of a compound provided herein. In a preferred embodiment, the compounds of the present disclosure are preferably administered orally or topically to a patient (e.g., a human). In another embodiment, the compounds of the present disclosure are administered systemically (intravenously or subcutaneously) to a patient (e.g., a human). An effective amount can be an amount sufficient to alter the activity of the C5a receptor and / or to reduce or alleviate symptoms in the patient. The amount administered is an amount sufficient to achieve a plasma concentration of the compound (or, if the compound is a prodrug, its active metabolite) that allows for in vitro detection of chemotactic inhibition of white blood cells (e.g., neutrophils). Treatment regimens may vary depending on the compound used and the specific disease being treated. For the treatment of most diseases, a dosing frequency of four times per day or less is preferred. Generally, a twice-daily dosing regimen is more preferred, with once-daily administration being particularly preferred. It will be understood, however, that specific dosage levels and treatment regimens for any particular patient will depend on a variety of factors (e.g., the activity of the specific compound used, the patient's age, body weight, general health, sex, diet, timing of administration, route of administration, rate of excretion, drug combinations (i.e., other drugs being administered to the patient), and the severity of the particular condition being treated), as well as the judgment of the prescribing physician. In general, it is preferable to use the lowest dose sufficient to provide effective treatment. Patients may generally be monitored for therapeutic effectiveness using medical or veterinary standards appropriate to the condition being treated or prevented.

[0098] Dosage levels of about 0.1 mg to about 140 mg per kg of body weight per day are useful for treating or preventing diseases involving pathological D5a activity (about 0.5 mg to about 7 g per day in human patients). The amount of active ingredient that can be combined with a carrier material to produce a unit dosage form will vary depending on the host treated and the particular mode of administration. Unit dosage forms will generally contain from about 1 mg to about 500 mg of active ingredient. For compounds administered orally, transdermally, intravenously, or subcutaneously, it is preferred to administer an amount of compound sufficient to achieve a serum concentration of 5 ng (nanograms) to 10 μg (micrograms) per ml of serum, more preferably 20 ng to 1 μg per ml of serum, and most preferably 50 ng to 200 ng per ml of serum. For direct injection into the synovium (for the treatment of arthritis), sufficient compound should be administered to achieve a local concentration of about 1 micromolar.

[0099] The frequency of administration may vary depending on the compound used and the specific disease being treated. However, for the treatment of most diseases, a dosing regimen of four times a day, three times a day, or less frequently is preferred, with once a day or twice a day being particularly preferred. However, it will be understood that the specific dosage level for a particular patient will depend on a variety of factors (e.g., the activity of the specific compound used, age, body weight, general health, sex, diet, timing of administration, route of administration, excretion rate, drug combinations (i.e., other drugs being administered to the patient), and the severity of the specific disease being treated), as well as other factors (e.g., the judgment of the prescribing medical professional).

[0100] Pharmaceutical Composition The compounds presented herein can be administered as a composition which will typically contain a pharmaceutical carrier or diluent.

[0101] As used herein, the term "composition" is intended to encompass products containing the specified ingredients in the specified amounts, as well as any product resulting directly or indirectly from combining the specified amounts of the specified ingredients.

[0102] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents.

[0103] Pharmaceutical compositions for administering the compounds of the present disclosure can be conveniently presented in unit dosage form and can be prepared by any method well known in the art of pharmacy and drug delivery. All methods include the step of combining the active ingredient with a carrier which constitutes one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately combining the active ingredient with a liquid carrier and / or a finely divided solid carrier, and then, if necessary, shaping the product into the desired formulation. The pharmaceutical composition contains the active compound of interest in an amount sufficient to produce the desired effect on the process or condition of a disease.

[0104] Pharmaceutical compositions containing the active ingredient can be in a form suitable for oral use (e.g., tablets, troches, lozenges, aqueous suspensions, oily suspensions, dispersible powders, dispersible granules, emulsions and self-emulsifying liquids described in U.S. Patent Application No. 2002-0012680, hard capsules, soft capsules, syrups, elixirs, solutions, oral patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets). Oral compositions can be prepared according to any method well known for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents selected from sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide an elegant and palatable pharmaceutical composition. Tablets contain the active ingredient mixed with non-toxic excipients that are pharmaceutically acceptable and suitable for the manufacture of tablets. Such excipients can be, for example, inert diluents (e.g., cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, sodium phosphate), granulating and disintegrating agents (e.g., corn starch, alginic acid), binders (e.g., PVP, cellulose, PEG, starch, gelatin, gum arabic), and lubricants (e.g., magnesium stearate, stearic acid, talc). Tablets may be uncoated or enteric-coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, time-retardant materials (e.g., glyceryl monostearate or glyceryl distearate) can be used. Tablets may also be coated by techniques described in U.S. Patents 4,256,108, 4,166,452, and 4,265,874 to form sustained-release therapeutic tablets for controlled release.

[0105] Oral formulations may be presented as hard gelatin capsules containing the active ingredient mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, kaolin), polyethylene glycols (PEG) of various average sizes (e.g., PEG 400, PEG 4000), and several surfactants (e.g., Cremophor and Solutol), or as soft capsules containing the active ingredient mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, olive oil). In addition, emulsions may be prepared using water-immiscible ingredients (e.g., oils), or stabilized with surfactants (e.g., monoglycerides, diglycerides, PEG esters, etc.).

[0106] Aqueous suspensions contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum arabic). Dispersing or wetting agents can include natural phosphatides (e.g., lecithin), condensation products of long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol) with ethylene oxide, condensation products of partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), and condensation products of partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions can also contain one or more preservatives (e.g., ethyl, n-propyl, p-hydroxybenzoates), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (e.g., sucrose and saccharin).

[0107] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions can contain thickening agents (e.g., beeswax, hard paraffin, cetyl alcohol). Sweeteners and flavoring agents, as set forth above, can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant (e.g., ascorbic acid).

[0108] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents have already been exemplified above. Additional excipients, for example sweetening, flavoring, or coloring agents, may also be present.

[0109] The pharmaceutical compositions of the present disclosure can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil (e.g., olive oil or peanut oil), a mineral oil (e.g., liquid paraffin), or a mixture thereof. Suitable emulsifiers include natural gums (e.g., gum arabic, gum tragacanth), natural phosphatides (e.g., soybean lecithin), esters, or esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), or condensation products of such partial esters with ethylene oxide (e.g., polyoxyethylenesorbitan monooleate). The emulsions can also contain sweeteners and flavoring agents.

[0110] Syrups and elixirs can be formulated with sweeteners (e.g., glycerol, propylene glycol, sorbitol, sucrose). Such formulations can also contain demulcents, preservatives, flavorings, and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG, or surfactants.

[0111] The pharmaceutical compositions can be in the form of an injectable aqueous or oleaginous sterile suspension. Suspensions can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents as described above. As a sterile injectable preparation, an injectable sterile solution or suspension in a non-toxic diluent or solvent that is acceptable for parenteral administration (for example, a solution in 1,3-butanediol) can also be used. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or dispersion media. For this purpose, any non-irritating fixed oil (e.g., synthetic monoglycerides, synthetic diglycerides) can be used. In addition, fatty acids (e.g., oleic acid) are used in injectable preparations.

[0112] The compounds of the present disclosure can also be administered in the form of suppositories 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, thereby dissolving and releasing the drug in the rectum. Such materials include cocoa butter and polyethylene glycol. Additionally, the compounds can be administered by delivery to the eye via solutions or ointments. Furthermore, transdermal delivery of the target compounds can be achieved by means of iontophoretic patches and the like. For topical use, creams, ointments, jellies, solutions, suspensions, etc., containing the compounds of the present disclosure are used. As used herein, topical application is meant to include the use of mouthwashes and gargles.

[0113] The compounds of the present disclosure can also be coupled to a substrate, which is a polymer suitable as a drug targeting carrier. Examples of such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, and palmitoyl-substituted polyethylene oxide-polylysine. Furthermore, the compounds of the present disclosure can be coupled to a substrate, which is a class of biodegradable polymers useful for achieving controlled drug release (e.g., polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, crosslinked block copolymers of hydrogels, and amphiphilic block copolymers of hydrogels). The polymer and semipermeable polymer matrix can be formed into shaped articles (e.g., valves, stents, tubes, prostheses, etc.). In one embodiment of the present disclosure, the compounds of the present disclosure are coupled to a polymer or semi-permeable polymer matrix to form a stent or stent-graft device.

[0114] Kits and Packages The terms "kit" and "pharmaceutical kit" refer to a commercially available kit or package containing, in one or more suitable containers, one or more pharmaceutical compositions and instructions for their use. In one embodiment, a kit is provided that includes a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or Compound 1, or a pharmaceutically acceptable salt thereof, and instructions for administering the same. In one embodiment, a kit is provided that includes a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or Compound 1, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, one to three) additional therapeutic agents and instructions for administering the same.

[0115] In one embodiment, the compound of the present disclosure is formulated into dosage units and packaged in a single package. Non-limiting examples of single packages include bottles, child-resistant bottles, ampoules, and tubes. In one embodiment, the compound of the present disclosure and any additional therapeutic agents are formulated into dosage units, and all the individual dosage units are packaged individually in a single package. Such individually packaged units can contain the pharmaceutical composition in any form (non-limiting examples include liquid, solid, powder, granular, effervescent powder, effervescent tablet, hard capsule, soft capsule, emulsion, suspension, syrup, suppository, tablet, troche, lozenge, solution, oral patch, thin film, oral gel, chewable tablet, chewing gum, and disposable syringe). Such individually packaged units can be combined in a package (e.g., a blister pack) made of one or more of paper, cardboard, paperboard, metal foil, and plastic foil. One or more dosage units can be administered once or several times daily. One or more dosage units can be administered three times per day. One or more dosage units can be administered twice per day. One or more dosage units can be administered on a first day and one or more dosage units can be administered on subsequent days.

[0116] Compound 1 has the formula: [ka] It has. [Example]

[0117] Example 1: Study of Compound 1 in a patient with advanced complement 3 glomerulonephritis Under the UK's "Special Needs Scheme" (similar to the Compassionate Use protocol in the United States), patients with C3 glomerulonephritis were treated with oral administration of the complement inhibitor compound 1 according to the protocol detailed below. Patients were undergoing kidney transplantation and had resistant disease despite previous treatment with a variety of immunosuppressants: rituximab, cyclophosphamide, mycophenolate mofetil, tacrolimus, and steroids. Transplant kidney biopsies were obtained before treatment and at 2 and 7 months.

[0118] result: The patient's condition improved in response to treatment with Compound 1. The improvement seen in this patient with Compound 1 treatment was based on histological findings from a kidney biopsy performed during treatment, which showed a disappearance of glomerular endocapillary proliferation and a significant reduction in glomerulonephritic macrophages compared to pretreatment. Proteinuria decreased by approximately 80% with Compound 1 treatment.

[0119] The estimated glomerular filtration rate (eGFR) was 83 ml / min / 1.73 m 14 months before treatment with Compound 1. 2 and 46 ml / min / 1.73 m when treatment with Compound 1 was initiated. 2 Treatment with Compound 1 slowed or stopped the deterioration of eGFR.

[0120] After one month of treatment, the deterioration of eGFR had already slowed (Figure 1 shows eGFR before and after treatment with Compound 1). Repeated biopsy samples showed resolution of glomerular endocapillary pleocytosis and a decrease in glomerular macrophages. Compound 1 stabilized eGFR and reduced glomerulonephritis.

[0121] [Table 1]

[0122] FIG. 2 shows the histological improvement after treatment with Compound 1. (A) Hematoxylin and eosin (H&E) staining before treatment with compound 1 shows fibrinoid necrosis and numerous inflammatory cells. (C) Periodic acid-Schiff (PAS) staining after treatment with compound 1 shows a reduction in endocapillary hypercellularity and glomerulonephritis. (B) CD68 staining before treatment with Compound 1. (D) CD68 staining after treatment with Compound 1 shows a reduction in glomerular macrophages.

[0123] Study protocol: the purpose The objective of this study was to evaluate the efficacy, safety, and tolerability of compound 1 in patients with advanced complement 3 (C3) glomerulonephritis.

[0124] the goal The primary safety goal of this study is to evaluate the safety and tolerability of Compound 1.

[0125] The primary efficacy goal is to assess the efficacy of Compound 1 based on the change from baseline in eGFR (MDRD, estimated glomerular filtration rate) and proteinuria.

[0126] Secondary objectives of this study include: 1. Assessment of changes from baseline in plasma and urine pharmacokinetic markers (e.g., MCP-1, C3a, C5a, properdin, sC5b-9); 2. Assessment of changes from baseline in glomerular pathology based on renal biopsy; 3. Evaluation of plasma concentrations of Compound 1 in C3 glomerulonephritis.

[0127] method This is a clinical study to investigate the safety, tolerability, and efficiency of Compound 1 in patients with recurrent C3GN in kidney transplant settings.

[0128] Patients will have biopsy-proven recurrent C3GN before starting medication and will be considered eligible for inclusion based on the inclusion and exclusion criteria. Screening procedures will include recording demographics, medical history, medication history, physical examination, vital signs, serum chemistry, hematology, urinalysis (including UPCR measurement), viral screening (if not performed within the past 12 weeks), and estimated glomerular filtration rate (eGFR) assessment based on serum creatinine. Baseline eGFR must be at least 25 ml / min / 1.73 m to be eligible for inclusion in the study. 2 It must be.

[0129] On Day 1, patients begin treatment with Compound 1. Patients receive 30 mg of Compound 1 orally twice daily for an initial 84-day period. Patients visit the research center on Days 1, 8, 15, 29, 57, and 85. The optimal dose of Compound 1 is taken within one hour of breakfast in the morning and within one hour of dinner in the evening. If the patient's clinical condition stabilizes or improves and there are no adverse events preventing further treatment, the patient may receive treatment for an additional 84-day treatment cycle. The 84-day cycle may be repeated under this protocol for a total of four cycles. During the 84-day cycles following the first cycle, patients visit the research center every four weeks. There is a four-week follow-up period after patients stop treatment with Compound 1.

[0130] Blood and urine samples will be collected on Day 1 and at study center visits after Day 1 to measure safety, efficacy, and pharmacokinetics. Physical examinations and assessment of vital signs will be performed throughout the study. Assessment of concomitant medications and adverse events will be performed at each study center visit. If possible, a kidney biopsy will be performed after an appropriate follow-up period to evaluate changes in kidney histology.

[0131] No new treatments for C3GN could be added during the study period (active treatment period or follow-up) unless the patient's condition deteriorated to the extent that the investigator determined that doing so would be in the patient's best interest.

[0132] Duration of treatment with Compound 1: 84 days, repeated up to three 84-day cycles for a total of up to 336 days.

[0133] Follow-up period after treatment with study drug ends: 4 weeks.

[0134] Patient status will be assessed by the investigator at the end of the study and appropriate standard of care treatment will be provided as needed.

[0135] Main inclusion criteria 1. Proven C3GN based on a renal biopsy performed within the past 8 weeks from the time of screening; 2. eGFR (according to the MDRD formula) is 25 ml / min / 1.73 m 2 Being more than that; 3. If present with a partner of childbearing potential, they must use adequate contraception throughout the study period and for at least 3 months after the end of medication; adequate contraception is defined as a failure rate of less than 1% per year (estrogen and progesterone combination [oral, intravaginal, transdermal] or progesterone-only hormonal contraception [oral, injectable, implantable], intrauterine device, intrauterine hormone-releasing system, tubal ligation, vasectomized partner, abstinence); 4. Willing and able to provide written informed consent and comply with the terms of the research protocol; 5. Otherwise healthy, as determined by the investigator based on medical history, physical examination, and laboratory tests. Laboratory test values ​​outside normal limits (other than those specified in the exclusion criteria) and / or other abnormal clinical findings that are determined by the investigator to be not clinically significant may be acceptable.

[0136] Main exclusion criteria 1. Proteinuria >8 g / day (and >8 g / g creatinine); 2. Use of eculizumab within the past 26 weeks from the time of dosing; 3. History or presence of any form of cancer within the past 5 years from the time of screening (excluding excised basal cell or squamous cell carcinoma of the skin and non-invasive cancers that have been completely excised with no evidence of local recurrence or metastasis (e.g., non-invasive cervical or breast cancers)); 4. Positive screening test for HBC virus, HCV virus, or HIV virus; 5. Any infection that has not resolved and requires antibiotic treatment before starting treatment with Compound 1 on Day 1; 6. WBC count less than 4000 / μl, or neutrophil count less than 2000 / μl, or lymphocyte count less than 1000 / μl; 7. Hemoglobin less than 9 g / dl (or 5.56 mmol / l) at screening; 8. Evidence of liver disease; AST, ALT, alkaline phosphatase, bilirubin >3 times the upper limit of normal; 9. Participation in any clinical trial of an investigational product within the past 30 days from the time of screening or within 5 half-lives of last intake of the drug; 10. History or presence of any medical condition or disease that the investigator determines may pose an unacceptable risk to the patient in participating in the study.

[0137] Treatment and observation period Patients will be screened within no more than 21 days prior to Day 1. Treatment with Compound 1 will last at least 84 days and up to 336 days, with patients being followed up for 4 weeks (28 days) after stopping medication.

[0138] To the extent possible, any adverse events that are deemed related to the study drug and are progressing toward resolution will be tracked until resolved or unresolved events are determined to be stable. The investigator will assess the patient's condition at the end of the study and provide appropriate medical standards of care as needed.

[0139] Safety evaluation Safety assessments included adverse events, physical examination abnormalities, vital signs, and laboratory tests (including blood chemistry, hematology, and urinalysis).

[0140] Efficiency Evaluation The efficiency assessment includes: 1. Morning urine PCR on the first day; 2. eGFR according to the Modification of Diet in Renal Disease (MDRD) formula based on serum creatinine; 3. Plasma and urine pharmacokinetic markers (e.g., MCP-1, C3a, C5a, properdin, sC5b-9); 4. Follow-up renal biopsy specimens show glomerulonephritis (e.g., crescents, inflammatory cell infiltration, endocapillary proliferation) and C3 deposition.

[0141] Pharmacokinetic evaluation Compound 1 concentrations and possible metabolites will be determined in serum from 2 ml blood samples collected in EDTA tubes on days 8, 15, 29, 57, and 85. The date and time of the last Compound 1 dose will be recorded before collecting samples for Compound 1 measurement. Samples will be kept frozen at -70°C or below and shipped on dry ice for assay.

[0142] Plasma samples continue to be collected every 4 weeks for all subsequent 84-day cycles.

[0143] Pharmacokinetic markers Plasma samples will be collected on days 1 (pre-dose), 8, 15, 29, 57, and 85 to measure pharmacokinetic markers (e.g., levels of complement fragments, inflammatory cytokines, and chemokines). Urine samples will also be collected on days 1 (pre-dose), 8, 15, 29, 57, and 85 to assess biomarkers (e.g., levels of MCP-1, complement fragments, inflammatory chemokines, and cytokines).

[0144] Plasma and urine samples continue to be collected every 4 weeks for all subsequent 84-day cycles.

[0145] Renal histology Renal biopsy samples are analyzed by periodic acid-Schiff (PAS) staining and immunofluorescence staining for C3, C5b-9, and possibly other markers. Electron microscopy can also be performed.

[0146] statistical methods Demographics and baseline characteristics Baseline characteristics and demographic data for all patients at the time of study entry (age, sex, race, ethnicity, weight, height, body mass index, smoking status, viral test results, duration of C3GN disease (from initial diagnosis based on kidney biopsy), kidney transplant history, eGFR, proteinuria (PCR), urinary MCP-1:creatinine ratio, physical exam abnormalities, medical history, previous (within the past 6 months from the time of screening) and current medications (including other treatments for C3GN)) will be listed.

[0147] Safety analysis The primary safety endpoint is the occurrence of adverse events in patients.

[0148] Other safety endpoints include: 1. Change from baseline in any safety laboratory parameter; 2. Change from baseline in vital signs.

[0149] List all clinical safety and tolerability data. List treatment-emergent adverse events by system organ class, relationship, and maximum severity. List serious adverse events and adverse events leading to withdrawal. List vital signs and changes from baseline in vital signs by study center visit. List laboratory data (actual values ​​and changes from baseline) by study center visit. Flag abnormal laboratory values.

[0150] Efficiency Analysis The primary efficacy endpoints are the change from baseline over the entire treatment period in eGFR and morning urine PCR on the first day.

[0151] Other endpoints of efficiency are 1. Percent change from baseline in plasma and urinary biomarkers (e.g., MCP-1, C3a, C5a, properdin, sC5b-9); 2. Changes from baseline to follow-up biopsy in glomerulonephritis (crescents, inflammatory cell infiltration, endocapillary proliferation), C3 deposits, and C5b-9 deposits.

[0152] Changes and rates of change in efficiency parameters over a 4-week follow-up period will also be assessed to identify off-treatment effects.

[0153] Pharmacokinetic analysis Plasma samples will be collected on days 8, 15, 29, 57, and 85 to determine plasma concentrations of Compound 1 (and metabolites). Plasma concentrations of Compound 1 will be listed and plotted at the time of the research center visit.

[0154] Example 2: A randomized, double-blind, placebo-controlled phase 2 study to evaluate the safety and efficacy of Compound 1 in patients with C3 nephritis Planned study protocol the purpose The purpose of this study was to evaluate the effect of treatment with Compound 1 on kidney disease activity in patients with complement 3 nephritis (C3GN). Treatment with Compound 1 in these patients is intended to slow or reverse kidney disease.

[0155] the goal The primary goal is to compare the efficacy of Compound 1 with placebo based on histological changes in C3G pathology derived from kidney biopsy samples taken before and during treatment.

[0156] Secondary objectives of this study include: 1. Evaluation of the safety of Compound 1 compared with placebo based on the occurrence of adverse events, changes in clinical laboratory measurements, and vital signs; 2. Evaluation of changes in kidney disease laboratory parameters (including estimated glomerular filtration rate (eGFR), proteinuria, and urinary excretion of monocyte chemoattractant protein-1 (MCP-1)) with Compound 1 compared to placebo; 3. Assessment of changes in health-related quality of life based on the Short Form-36 version 2 (SF-36 v2) assessment or EuroQOL-5D-5L (EQ-5D-5L) with Compound 1 compared to placebo; 4. Evaluation of the pharmacokinetic profile of Compound 1 in patients with C3 nephropathy.

[0157] Additionally, changes from baseline in markers of the alternative complement pathway involved (e.g., C3, C3d, C3c, C3adesArg, C5, C5a, C5b-9, C5adesArg) and other inflammatory markers in plasma / serum or urine can be assessed throughout the treatment period.

[0158] method This is a Phase 2 trial to test the efficacy, safety, and tolerability of Compound 1 in patients with C3G (which includes C3GN and DDD). Eligible patients will be selected based on two factors: 1. C3GN or DDD and 2. Whether or not a patient underwent kidney transplantation before randomization Stratify based on:

[0159] Patients will then be randomized 1:1 to receive 30 mg of Compound 1 or a matching placebo twice daily for 26 weeks in a double-blind, placebo-controlled trial. After the 26-week double-blind period, there will be a 26-week period in which all patients will receive treatment with Compound 1.

[0160] Patients will be screened for enrollment based on biopsy-proven C3 nephropathy (i.e., C3 staining greater than two levels above any combination of IgG, IgM, IgA, and C1q) and evidence of inflammation based on leukocyte infiltration and / or endocapillary proliferation.

[0161] The screening period will be up to 28 days. Screening procedures include written informed consent, demographics, medical history, medication history, physical examination, vital signs, 12-lead ECG, serum pregnancy test in women of childbearing potential, serum chemistry (including serum creatinine), hematology, urinalysis, urine protein:creatinine ratio (PCR), and viral and TB screening. Patients will be required to undergo a kidney biopsy prior to dosing if they have not had one within the past 12 weeks. Prior to initiating study drug treatment, blood samples will be collected to measure the following: 1.C3, C3d, C3c, C3adesArg, C4; 2.C3 nephritic factor; 3.C5, C5a, C5b-9, C5adesArg; 4. Complement factor H and factor B in serum; 5. Detection of abnormal proteins in serum; 6. Complement factor H-related protein 5 (CFHR5) mutation to generate a baseline profile for all patients.

[0162] Patients who meet the inclusion criteria will begin study treatment on Day 1. Patients will receive 30 mg of Compound 1 or a matching placebo twice daily. The treatment period will last 52 weeks (364 days). The study medication will preferably be taken in the morning with a meal and in the evening, approximately 12 hours after the morning dose, with a meal. Patients who receive placebo for the first 26 weeks will receive Compound 1 in a double-blind crossover design. After the 364-day treatment period, all patients will be followed for 8 weeks (56 days) without treatment with the study medication.

[0163] Blood and urine samples will be collected at study center visits after Day 1 to measure safety, efficacy, pharmacokinetics, and biomarkers. Serum pregnancy tests will be performed periodically throughout the 52-week treatment period and at the end of the 8-week follow-up period in women of childbearing potential. Physical examinations and vital sign assessments will be performed throughout the study. Health-related quality of life will be assessed periodically throughout the study using the EQ-5D-5L and SF-36 v2 surveys. Study medication will be distributed and a record of investigational drug use will be maintained. Concomitant medication and adverse event assessments will be performed at each study center visit. Follow-up kidney biopsies will be performed at the following time points: 1. After a placebo-controlled treatment period of 26 weeks; 2. If the patient drops out of the study early; After a treatment period of 3.52 weeks.

[0164] If a patient is receiving other immunosuppressive treatment at the time of initiation, the dose of the concomitant immunosuppressant cannot be increased during the study. If the patient's condition permits, treatment with these other drugs may be reduced or stopped during the study. No new treatments will be added during the study unless the patient's condition deteriorates to the point that the investigator determines the patient would benefit from the new treatment. This will be considered a treatment failure.

[0165] During the 52-week treatment period, patients with worsening renal function based on at least a 50% increase in serum creatinine (determined by a repeat measurement after 2 weeks) that cannot be explained by other reasons (e.g., dehydration, administration of new medications) or increasing proteinuria to levels greater than 3 g per g creatinine or greater than 8 g per g creatinine from baseline (determined by a repeat measurement after 2 weeks) will be removed from the treatment phase of the study and treated at the discretion of the treating physician. The patient will remain in the study for follow-up and outcome documentation. The patient will be considered a treatment failure.

[0166] At study centers accepting adolescents (ages 12-17), Compound 1 or placebo will be administered initially based on weight at screening, with doses adjusted based on plasma levels of Compound 1, as shown in the table below.

[0167] Only patients aged 12-17 years will have blood samples taken pre-dose and 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 determination of Compound 1 and its metabolites in these patients. As shown in the table below, AUC 0-6 Dose adjustments are made based on these AUC 0-6 The threshold is based on the mean Compound 1 plasma exposure in adult patients from the Phase 2 AAV study CL002_168 (525 ng h / ml) and ±1 standard deviation of the mean (174 ng h / ml). [Table 2]

[0168] Patients will visit the study center during screening, day 1 (baseline), and weeks 1, 2, 4, 8, 12, 16, 20, 26, 32, 38, 44, 52, and 60.

[0169] Duration of double-blind treatment with Compound 1 or placebo: 26 weeks.

[0170] Duration of treatment with Compound 1 after the double-blind treatment period: 26 weeks.

[0171] Duration of follow-up after treatment with study drug ends: 8 weeks.

[0172] Patients will be released from the study upon completion of all visit procedures at week 60. At the end of the clinical trial (week 60), investigators will assess patient status and provide appropriate standards of medical care treatment to all patients who require it.

[0173] Number of patients Approximately 44 male or female patients with C3 nephropathy will be enrolled in the study. Patients who drop out before the 26-week visit can be replaced.

[0174] Main inclusion criteria 1. Proven C3 nephropathy (DDD or C3GN) based on C3 staining greater than two levels above any combination of IgG, IgM, IgA, and C1q in a renal biopsy sample obtained within the past 12 weeks prior to or during screening, and evidence of inflammation based on leukocyte infiltration or intracapillary proliferation; patients who have undergone kidney transplantation are eligible for inclusion in the study; 2. Plasma C5b-9 above the upper limit of the central laboratory reference range; 3. Male or female patients at least 18 years of age; adolescents (12-17 years of age) may be enrolled if permitted; female patients of childbearing potential may participate if they provide adequate contraception during the study and for at least 3 months after completion of medication; male patients with partners of childbearing potential may participate if they have had a vasectomy at least 6 months before randomization or provide adequate contraception during the study and for at least 3 months after completion of the study; adequate contraception is defined as a failure rate of less than 1% per year (estrogen-progesterone combination [oral, intravaginal, transdermal] or progesterone-only hormonal contraception [oral, injectable, implantable], intrauterine device, intrauterine hormone-releasing system, tubal ligation, vasectomized partner, abstinence); 4. Willing and able to provide written informed consent and comply with the terms of the study protocol; for patients aged 12-17 years, written informed consent must be obtained from a legal guardian in accordance with local laws or regulations; 5. Be judged by the investigator to be otherwise healthy based on medical history, physical examination, and laboratory tests. Patients with laboratory values ​​outside the limits of normal (other than those specified in the exclusion criteria) and / or other abnormal clinical findings judged by the investigator to be not clinically significant may be admitted to the study.

[0175] Main exclusion criteria 1. Being pregnant or breastfeeding; proteinuria of more than 2.8 g / day (and more than 8 g / g of creatinine); 3. >50% interstitial fibrosis on renal histology; 4. Use of eculizumab within the past 26 weeks from the time of dosing; 5. Secondary C3 disease (e.g., infection-related disease) or secondary C3 disease associated with another systemic or autoimmune disease; 6. Currently receiving dialysis or likely to require dialysis within 7 days; 7. History or presence of any form of cancer within the past 5 years from the time of screening (excluding excised basal cell or squamous cell carcinoma of the skin or non-invasive cancers that have been completely excised and have no evidence of local recurrence or metastasis (e.g., non-invasive cervical or breast cancers)); 8. Positive screening test for HBC virus, HCV virus, or HIV virus; 9. Evidence of tuberculosis based on an interferon-gamma release assay (IGRA), or a tuberculin purified protein derivative (PPD) skin test, or chest radiograph performed at screening or within the past 6 weeks from the time of screening; 10. WBC count less than 3500 / μl, or neutrophil count less than 1500 / μl, or lymphocyte count less than 800 / μl before starting medication; 11. Evidence of liver disease; AST, ALT, alkaline phosphatase, bilirubin >3 times the upper limit of normal; 12. Known hypersensitivity to Compound 1 or any of the inactive ingredients; 13. Participation in any clinical trial of an investigational product within the past 30 days from the time of screening or within 5 half-lives of the last drug intake; 14. History or presence of any medical condition or disease that the investigator determines may pose an unacceptable risk to the patient in participating in the study.

[0176] Treatment and observation period Patients will be screened no more than 28 days prior to Day 1. The treatment period will be 52 weeks (364 days), and all patients will be followed for 8 weeks (56 days) after the dosing period.

[0177] To the extent possible, all adverse events that are deemed related to the study drug and are progressing toward resolution will be tracked until resolved or unresolved events are determined to be stable. At the conclusion of the clinical trial, the investigator will evaluate the patient's status and provide appropriate standards of medical care treatment to all patients who require it.

[0178] Safety evaluation Safety assessments included adverse events, physical examination abnormalities, vital signs, and clinical laboratory tests (including blood chemistry, hematology, and urinalysis).

[0179] Efficiency Evaluation The efficiency assessment includes: 1. Renal histology to determine the C3G Histological Index (CHI) for disease activity and chronicity; 2. eGFR calculated from serum creatinine using the Modification of Diet in Renal Disease (MDRD) formula; 3. Morning urine PCR on the first day; 4. Morning urine MCP-1:creatinine ratio on the first day; 5.EQ-5D-5L and SF-36 v2.

[0180] Pharmacokinetic evaluation Calculate the concentrations of compound 1 and metabolites in plasma according to the time-event table.

[0181] Pharmacokinetic markers Plasma / serum samples will be collected according to a time-event schedule to measure pharmacokinetic markers (e.g., complement fragments, inflammatory cytokine and chemokine levels). Urine samples will also be collected according to a time-event schedule to assess biomarkers (e.g., complement fragments, sCD163, inflammatory cytokine and chemokine levels).

[0182] Renal histology To assess eligibility for selection, kidney biopsy samples are evaluated by immunofluorescence staining for C3 and immunoglobulins. Patients must have proven C3 nephropathy (DDD or C3GN) based on C3 staining greater than any combination of IgG, IgM, IgA, and C1q staining by at least two levels in a kidney biopsy sample taken within the past 12 weeks or during screening, and evidence of inflammation based on leukocyte infiltration or intracapillary proliferation.

[0183] All renal biopsy samples will also be analyzed using hematoxylin-eosin (H&E), periodic acid-Schiff (PAS), trichrome, and Jones methenamine silver stains, and will be evaluated from slides or high-resolution electronic images by a central reader blinded to treatment assignment.

[0184] A central reader determines the activity and chronicity of the disease.

[0185] statistical methods Demographics and baseline characteristics Baseline characteristics and demographic data for all patients at study entry (age, sex, race, ethnicity, weight, height, body mass index, smoking status, viral test results, duration of C3 kidney disease (from initial diagnosis based on kidney biopsy), kidney transplant history, eGFR, proteinuria (PCR), urinary MCP-1:creatinine ratio, physical exam abnormalities, medical history, previous (within the past 6 months from the time of screening) medications and concomitant medications (including other treatments for C3 nephropathy)) will also be listed and summarized by study center visit and patient number.

[0186] Efficiency Analysis The primary efficacy endpoint is the percent change from baseline in the C3G histological index (CHI) of disease activity by week 26. Compound 1 and placebo groups will be compared by ANCOVA, with treatment group and randomization strata (C3GN or DDD and kidney transplant status) as factors and baseline as a covariate. Point estimates and corresponding 95% confidence intervals will be estimated for the difference between Compound 1 and placebo groups.

[0187] Because the placebo group receives Compound 1 for the last 26 weeks of the study, the change in CHI from week 26 to week 52 in the placebo control group will be compared to the change from baseline through week 26 in this group. This analysis will be performed by a paired t-test. Point estimates and corresponding 95% confidence intervals will be estimated for the difference between the last 26 weeks (treated with Compound 1) and the first 26 weeks (treated with placebo).

[0188] Changes from baseline through week 52 in CHI will also be compared to changes from baseline at week 26 in the placebo control group using methods similar to those described for the primary efficacy endpoint. Other efficiency endpoints include: 1. Percent change from baseline in CHI for disease chronicity over a 26-week placebo-controlled treatment period; 2. Change and percent change from baseline in eGFR over the 26-week placebo-controlled treatment period; 3. Percent change from baseline in urine PCR over a 26-week placebo-controlled treatment period; 4. Percent change from baseline in urinary MCP-1:creatinine ratio over a 26-week placebo-controlled treatment period; 5. Change from baseline in EQ-5D-5L and SF-36 v2 (domain and component scores) over the 26-week placebo-controlled treatment period.

[0189] Continuous variables (including eGFR, urinary PCR, urinary MCP-1:creatinine ratio, EQ-5D-5L, and SF-36 v2) will be analyzed using mixed-effects models for repeated measures (MMRM), with treatment group, visit, treatment-by-visit interaction, randomization strata (C3GN or DDD and kidney transplant status) as factors, and baseline as a covariate. Patients will be considered as a unit of repeated measures across all visits. Point estimates and corresponding 95% confidence intervals will be estimated for the difference between the Compound 1 and control groups over 26 weeks using simple pairwise comparisons from the model. Similar to the primary endpoint, the second 26 weeks will be compared with the first 26 weeks in the placebo group.

[0190] Changes and rates of change in efficiency parameters during the 8-week follow-up period will also be assessed to identify off-treatment effects.

[0191] Changes from baseline in markers of alternative complement pathway activation are recorded.

[0192] Summary statistics will be calculated for each efficacy endpoint. For continuous variables, counts, means, medians, ranges, standard deviations, standard errors, and 95% confidence intervals will be calculated. Geometric means will be calculated for urine PCR, MCP-1:creatinine ratio, and other measures that are not normally distributed.

[0193] Safety analysis Safety endpoints include: 1. The occurrence of serious adverse events, adverse events, or dropouts due to adverse events in patients resulting from the treatment; 2. Change from baseline and shift from baseline in any safety-related laboratory parameters; 3. Changes in vital signs from baseline.

[0194] All patients who were randomized and received at least one dose of study drug will be included in the safety population.

[0195] All clinical data regarding safety and tolerability will be listed by treatment group, by patient, and summarized by treatment group.

[0196] All reported adverse events will be coded using MedDRA and listed by organ system class, preferred term, and verbatim term.

[0197] Treatment-emergent adverse events will be listed by treatment group, organ system class, relationship, and maximum severity.

[0198] Treatment-emergent serious adverse events and adverse events leading to withdrawal will be summarized by treatment group.

[0199] Individual vital signs and changes from baseline in vital signs will be listed by treatment group, patient, and study center visit and summarized by treatment group.

[0200] List laboratory data (actual values ​​and change from baseline) by treatment group, patient, and study center visit. Mark abnormal laboratory values. Laboratory data will also be summarized by treatment group and study center visit. Create shift tables for each study center visit for shifts in laboratory parameters.

[0201] Analysis of pharmacokinetics and pharmacokinetic markers Plasma samples are collected throughout the study to determine the PK profile of compound 1 (and metabolites). Individual plasma concentrations of compound 1 (and metabolites) are listed, plotted, and summarized textually and graphically. PK parameters are calculated based on the concentration of compound 1 at the time of sample collection relative to the timing of administration of the most recent dose of study drug. PK parameters of important metabolites may also be calculated.

[0202] Plasma and urinary PD markers can be collected and analyzed using similar methods to the efficiency parameters. The following parameters: Cmax maximum plasma concentration tmax Time to maximum plasma concentration AUC 0-6 Area under the plasma concentration-time curve from time 0 to time 6 on day 1 Cmin [ Time Frame: Plasma trough concentration at visits after Day 1 ] is sought in patients aged 12–17 years, if possible.

[0203] The relationship between PK parameters and renal function based on eGFR can be evaluated. The data can also be used to evaluate the PK / PD relationship of treatment with Compound 1. For this purpose, the change and / or percent change from baseline in urinary PCR, eGFR, urinary MCP-1:creatinine ratio, and other biomarkers can be used as PD markers.

Claims

1. 1. A pharmaceutical composition for slowing the rate of decline in estimated glomerular filtration rate (eGFR) in a human suffering from C3 nephropathy, comprising: 【Chemistry 1】 10. A pharmaceutical composition comprising an effective amount of a compound having the formula:

2. The pharmaceutical composition of claim 1, wherein the human is suffering from complement 3 glomerulonephritis.

3. The pharmaceutical composition of claim 1, wherein the human is suffering from a dense deposition disease.

4. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the human has a disease that is resistant to one or more of rituximab, cyclophosphamide, mycophenolate mofetil, tacrolimus, and steroids.

5. 5. The pharmaceutical composition of any one of claims 1 to 4, wherein the human takes the pharmaceutical composition containing 30 mg of the compound twice a day.

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