Composition for use in the treatment of APOL1-related diseases

Abstract

This provides a composition for use in the treatment of APOL1-related diseases. [Solution] In some embodiments, the present invention relates to the field of compositions and / or pharmaceutical compositions comprising one or more biologically active compounds, and methods of using them, such as for treating a target ApoL1-related disease or disorder. The present invention generally relates to the field of compositions comprising one or more quinazolindione derivatives, and methods of using them for treating a disease or disorder.

Description

Technical Field

[0001] Cross-references to related applications This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 021,222, filed May 7, 2020, entitled "COMPOSITION FOR USE IN THE TREATMENT OF APOL1-ASSOCIATED DISEASE", the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention generally relates to the field of compositions, particularly compositions containing one or more quinazolinone derivatives, and to methods of using them for treating a disease or disorder.

Background Art

[0003] Apolipoprotein L1 (ApoL1) is a minor apolipoprotein component of high-density lipoprotein (HDL) and is also synthesized in the liver and in many other tissues including the pancreas, kidney, and brain. It is well known that ApoL1 plays a role in innate immunity by protecting humans against Trypanosoma parasite infections. Recently, it has been reported that high-frequency variant forms of ApoL1 designated as G1 and G2 (in contrast to the ancestral version designated as G0) are highly associated with kidney disease in humans with African ancestry. Many African Americans have a high prevalence of ApoL1 risk alleles as well as ApoL1-related kidney disease. Since the discovery of the potential risks of the ApoL1 variants G1 and G2, researchers have attempted to elucidate the cellular mechanisms of ApoL1 toxicity and have tried to develop potential drug candidates for treating or preventing ApoL1-related kidney disease.

Summary of the Invention

Means for Solving the Problems

[0004] The following embodiments and aspects are described and illustrated in conjunction with the systems, tools, and methods, but these are illustrative and explanatory and not limiting in scope.

[0005] In one aspect of the present invention, one or more of the following compounds:

[0006] [ka]

[0007] There are compounds that contain a salt thereof.

[0008] In another aspect of the present invention, there is a pharmaceutical composition comprising (i) a compound of the present invention, a pharmaceutically acceptable salt thereof, or both, and (ii) a pharmaceutically acceptable carrier.

[0009] In another aspect of the present invention, the compound represented by formula 1:

[0010] [ka]

[0011] or compounds represented by formula 1A:

[0012] [ka]

[0013] In the formula, each of R, R1 and R2 independently contains or does not contain alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydrogen, C1-C10 branched alkyl, haloalkyl, mercaptoalkyl, heteroatom, hydroxyalkyl, aminoalkyl, nitroalkyl, alkyl sulfate, C1-C10 alkyl, or substituted C1-C10 alkyl; or R1 and R2 are interconnected to form a cyclic ring; each X1 independently contains methylene, heteroatom, -OR, -NRR, -SR, cyano, alkyl, carboxyl derivative, nitro, sulfonate, sulfonyl, or hydrogen; each X independently contains or does not contain methylene or heteroatom;

[0014] [ka]

[0015] There are pharmaceutical compositions comprising a single or double bond, where n is 0-10 or a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable carrier for use in inhibiting or reducing ApoL1-associated cytotoxicity.

[0016] In one embodiment, the compound is represented by formula 1C.

[0017] [ka]

[0018] In one embodiment, the compound comprises the following:

[0019] [ka]

[0020] In one embodiment, the compound is represented by formula 2:

[0021] [ka]

[0022] In the formula, R3 represents a substituent that independently contains at least one of the following: C1-C10 alkyl, C1-C10 branched alkyl, substituted C1-C10 alkyl, halo, hydroxy, amino, mercapto, cyano, carboxylic acid derivative, nitro, guanidine, aryl, heteroaryl, benzyl, alkalyl, cycloalkyl, heterocyclyl, heteroatom, or hydrogen, or it may not exist.

[0023] In one embodiment, the compound is represented by formula 3.

[0024] [ka]

[0025] In one embodiment, the compound is represented by formula 4:

[0026] [ka]

[0027] In the formula, n is between 0 and 5, and each R3 independently represents a substituent containing the following,

[0028] [ka]

[0029] or absent, where A represents an optionally substituted aliphatic (C3-C20) ring, an optionally substituted aromatic (C5-C20) ring, or is absent; each R4 represents a substituent independently comprising hydrogen, a C1-C10 alkyl, a C1-C10 branched alkyl, a substituted C1-C10 alkyl, a halo, nitro, hydroxy, mercapto, amino, cyano, and carboxyl derivative, or any combination thereof.

[0030] In one embodiment, each R3 is independently selected from the group including the following:

[0031] [ka]

[0032] In one embodiment, the compound is represented by any of formulas 7A to 7C: Formula 7A:

[0033] [ka]

[0034] Formula 7B:

[0035] [ka]

[0036] Formula 7C:

[0037] [ka]

[0038] In the formula, each X2 is independently selected from the group comprising methylene, heteroatom, alkyl, halo, alkoxy, hydroxy, amino, thioalkoxy, mercapto, cyano, carboxylic acid derivatives, nitro, guanidine, heteroatom, aryl, heteroaryl, benzyl, alkylaryl, cycloalkyl, heterocyclyl, bond, and hydrogen, or any combination thereof.

[0039] In one embodiment, each X1 independently contains a heteroatom, and each X is independently selected from the group containing -N-, -NH, -O-, and -S-.

[0040] In one embodiment, the substituted C1-C10 alkyl group comprises substituents selected from the group including halo, mercapto, hydroxy, amino, carboxyl derivatives, cyano, nitro, sulfonate, and sulfonyl, or any combination thereof.

[0041] In one embodiment, the compound comprises any of the following:

[0042] [ka]

[0043] In one embodiment, inhibition or reduction of ApoL1-related cytotoxicity includes the prevention or treatment of ApoL1-related kidney disease.

[0044] In one embodiment, ApoL1-related cytotoxicity is ApoL1 mutant-related cytotoxicity.

[0045] In another aspect of the present invention, there is a method for inhibiting or reducing ApoL1-related cytotoxicity in a target where it is needed, and this involves a compound represented by formula 1:

[0046] [ka]

[0047] or compounds represented by formula 1A:

[0048] [ka]

[0049] During the ceremony, Each of R, R1, and R2 independently contains or does not contain alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydrogen, C1-C10 branched alkyl, haloalkyl, mercaptoalkyl, heteroatom, hydroxyalkyl, aminoalkyl, nitroalkyl, alkyl sulfate, C1-C10 alkyl, or substituted C1-C10 alkyl; or R1 and R2 are interconnected to form a cyclic ring; each X1 independently contains methylene, heteroatom, -OR, -NRR, -SR, cyano, alkyl, carboxyl derivative, nitro, sulfonate, sulfonyl, or hydrogen; each X independently contains or does not contain methylene or heteroatom;

[0050] [ka]

[0051] The method comprises administering a pharmaceutical composition comprising a single or double bond, where n is 0 to 10, or a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable carrier, thereby inhibiting or reducing ApoL1-related cytotoxicity in the subject.

[0052] In one embodiment, inhibiting or reducing ApoL1-related cytotoxicity includes preventing or treating ApoL1-related kidney disease.

[0053] In one embodiment, ApoL1-related cytotoxicity is ApoL1 mutant-related cytotoxicity.

[0054] In addition to the exemplary embodiments and models described above, further embodiments and models will become apparent by reference to the figures and by consideration of the following detailed description. [Brief explanation of the drawing]

[0055] [Figure 1A]Figures 1A to 1C are bar graphs showing the viability of T-REx-293 cells and untreated controls after 16 hours of incubation with exemplary compounds of the present invention at various concentrations. Black bars represent the number of cells expressing ApoL1 G1 (activated by doxycycline). White bars represent the number of cells expressing wild-type ApoL1. Figure 1A: Incubation at various concentrations of compound 1 (0, 0.08, 0.156, 0.3, 0.6, 1.25, 2.5, 5, and 10 μM). [Figure 1B] Figure 1B: Incubation of compound 3 at various concentrations (0, 0.08, 0.156, 0.3, 0.6, 1.25, 2.5, 5, and 10 μM). [Figure 1C] Figure 1C: Incubation of compound 7 at various concentrations (0, 0.156, 0.313, 0.625, 1.25, 2.5, 5, and 10 μM). [Figure 2] Figure 2 is a bar graph showing the survival rates of T-REx-293 cells and untreated controls (as negative controls) after 16 hours of incubation with an exemplary compound of the present invention (KS-1, KS-2, or KS-8 at a concentration of 10 μM). The Y-axis represents the number of cells. [Modes for carrying out the invention]

[0056] In one aspect of the present invention disclosed herein, a compound, a salt, or a derivative thereof is provided, wherein the compound is of formula 1.2:

[0057] [ka]

[0058] represented by, wherein each X is independently methylene, contains a heteroatom, or is absent; each R’ is independently (C0-C6) alkyl-aryl, (C0-C6) alkyl-heteroaryl, (C0-C6) alkyl-(C3-C8) cycloalkyl, optionally substituted C3-C8 heterocyclyl, halogen, -NO2, -CN, -OH, -CONH2, -CONR”2, -CNNR”2, -CSNR”2, -CONH-OH, -CONH-NH2, -NHCOR”, -NHCSR”, -NHCNR”, -NC(=O)OR”, -NC(=O)NR”, -NC(=S)OR”, -NC(=S)NR”, -SO2R”, -SOR”, -SR”, -SO2OR”, -SO2N(R)2, -NHNR2, -NNR, C1-C 10 haloalkyl, optionally substituted C1-C 10 alkyl, -NH2, -NH(C1-C 10 alkyl), -N(C1-C 10 alkyl)2, C1-C 10 alkoxy, C1-C 10 haloalkoxy, hydroxy(C1-C 10 alkyl), hydroxy(C1-C 10 alkoxy), alkoxy(C1-C 10 alkyl), alkoxy(C1-C 10 alkoxy), C1-C 10 alkyl-NR”2, C1-C 10 alkyl-SR, -CONH(C1-C 10 alkyl), -CON(C1-C 10 alkyl)2, -CO2H, -CO2R”, -OCOR”, -OCOR”, -OC(=O)OR”, -OC(=O)NR”, -OC(=S)OR”, -OC(=S)NR”, any combination thereof, wherein R” is optionally substituted C1-C 10 alkyl and hydrogen.

[0059] In some embodiments, the heteroatom is independently selected from the group consisting of O, N, NH, and S. In some embodiments, the heteroatom is N.

[0060] In some embodiments, the compound of the present invention is of formula 1.2A:

[0061] [ka]

[0062] Or formula 1.3:

[0063] [ka]

[0064] This is expressed by the formula, where X and R' are as described above.

[0065] In some embodiments, the compounds of the present invention are: or include the following:

[0066] [ka]

[0067] This compound (also referred to as Compound 7 in this specification) may optionally include any salt or any derivative thereof.

[0068] In another aspect of the present invention, Formula 1:

[0069] [ka]

[0070] Compounds represented by the formula are provided, where each of R, R1 and R2 independently contains or does not contain alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydrogen, C1-C10 branched alkyl, haloalkyl, mercaptoalkyl, heteroatom, hydroxyalkyl, aminoalkyl, nitroalkyl, alkyl sulfate, or optionally substituted C1-C10 alkyl; or R1 and R2 are interconnected to form a cyclic ring; each X1 independently contains methylene, heteroatom, -OR'', -NR''R'', -SR'', cyano, alkyl, carboxyl derivative, nitro, sulfonate, sulfonyl, or hydrogen; R'' is as described herein, and each X independently contains or does not contain CH, CH2, or heteroatom;

[0071] [ka]

[0072] represents a single bond or a double bond; and each n is between 0 and 10.

[0073] In some embodiments, each n independently represents an integer in the range of 0 to 10, 0 to 1, 1 to 2, 2 to 4, 4 to 6, or 6 to 10, and includes any range in between.

[0074] In some embodiments, the heteroatom is independently selected from the group consisting of O, N, NH, and S. In some embodiments, the heteroatom is N.

[0075] In some embodiments, each of R1 and R2 independently comprises R' or H, where R' is as described herein. In some embodiments, each of R1 and R2 independently comprises optionally substituted C1-C10 alkyl, halo, sulfonate, sulfonyl, nitro, hydroxy, mercapto, amino, cyano, carboxyl derivatives, alkylhydroxy, aminoalkyl, mercaptoalkyl, CONH2, -CONR”2, -CNNR”2, -CSNR”2, -CONH-OH, -CONH-NH2, -NHCOR”, -NHCSR”, -NHCNR”, -NC(=O)OR”, -NC(=O)NR”, -NC(=S)OR”, -NC(=S)NR”, -CO2H, -CO2R”, -OCOR”, -OCOR”, -OC(=O)OR”, -OC(=O)NR”, -OC(=S)OR”, -OC(=S)NR” or hydrogen, any combination thereof or any salt thereof.

[0076] In some embodiments, each of R1 and R2 independently comprises a C1-C10 alkyl group optionally containing H or one or more substituents selected from the group consisting of halo, sulfonate, sulfonyl, nitro, hydroxy, mercapto, amino, cyano, carboxyl derivatives, alkylhydroxy, aminoalkyl, mercaptoalkyl, or any combination thereof. In some embodiments, each of R1 and R2 independently comprises a C1-C10 alkyl group optionally substituted with H or one or more R'. In some embodiments, each of R1 and R2 independently comprises or is absent alkyl, hydrogen, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0077] In some embodiments, the cyclic ring is an aliphatic cycloalkyl, aliphatic heterocyclyl, an aromatic ring, a heteroaromatic ring, or a combination thereof. In some embodiments, the cyclic ring is a fusion ring. In some embodiments, the cyclic ring is a bicyclic ring. In some embodiments, the ring comprises one or more substituents, the substituents as described herein.

[0078] In some embodiments, the compounds of the present invention are

[0079] [ka]

[0080] It can be expressed by one of the following, where X, X1, R, R1, R2, and n are as described above.

[0081] In some embodiments, the compounds of the present invention are represented by formula 1C, where each R independently comprises a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; X is N or CH; and X1 is O or OH. In some embodiments, the substitution is by one or more (e.g., 1, 2, 3, 4)R'.

[0082] In some embodiments, the compound of the present invention is of formula 1D:

[0083] [ka]

[0084] Represented by formula 1D, where each R1 is independently a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, hydrogen, a haloalkyl, a mercaptoalkyl, a heteroatom, a hydroxyalkyl, an aminoalkyl, a nitroalkyl, an alkyl sulfate, a substituted or unsubstituted C1-C10 alkyl, or any combination thereof; where R1, R'n, and X are as described herein. In some embodiments, the compounds of the present invention are represented by formula 1D, where each R1 is a substituted or unsubstituted C1-C10 alkyl, where n is independently 0 to 5 (e.g., selected from 0, 1, 2, and 3), and where each R' is a halogen or absent.

[0085] In some embodiments, the compounds of the present invention are: or include the following:

[0086] [ka]

[0087] In this specification, this is also referred to as Compound 1, and optionally includes any salt or any derivative thereof.

[0088] In some embodiments, the compound of the present invention is represented by formula 2:

[0089] [ka]

[0090] Represented by the formula, where R3 represents or is absent a substituent independently comprising alkyl, halo, alkoxy, hydroxy, amino, thioalkoxy, mercapto, cyano, carboxylic acid derivatives, nitro, guanidine, heteroatom, aryl, heteroaryl, benzyl, alkaryl, cycloalkyl, heterocyclyl, or hydrogen; where X, X1, R, and n are as described above. In some embodiments, R3 represents or is absent a substituent independently comprising at least one of C1-C10 alkyl, C1-C10 branched alkyl, substituted C1-C10 alkyl, halo, hydroxy, amino, mercapto, cyano, carboxylic acid derivatives, nitro, guanidine, aryl, heteroaryl, benzyl, alkaryl, cycloalkyl, heterocyclyl, heteroatom, or hydrogen.

[0091] In some embodiments, the compounds of the present invention are

[0092] [ka]

[0093] It is expressed by one of the following, where X, X1, R, R1, R2, R3 and n are as described above.

[0094] In some embodiments, the compounds of the present invention are of formulas 3A to 3D:

[0095] [ka]

[0096] Selected from the above, where X, X1, R, R3, and n are as described above.

[0097] In some embodiments, the compounds of the present invention are

[0098] [ka]

[0099] It can be expressed by one of the following, where X, X1, R, R3, and n are as described above.

[0100] In some embodiments, R3 is hydrogen. In some embodiments, each R3 independently

[0101] [ka]

[0102] The formula comprises any of the following, where a dashed line represents a single or double bond; where each X2 independently comprises at least one of methylene, heteroatom, alkyl, halo, alkoxy, hydroxy, amino, thioalkoxy, mercapto, cyano, carboxylic acid derivative, nitro, guanidine, heteroatom, aryl, heteroaryl, benzyl, alkylaryl, cycloalkyl, heterocyclyl, bond, or hydrogen; where each A independently represents an optionally substituted aliphatic (C3-C20) ring, an optionally substituted aromatic (C5-C20) ring, or is absent; and where X and n are as described above.

[0103] In some embodiments, the dashed line represents a single bond, and each X2 independently contains at least one of alkyl, halo, alkoxy, hydroxy, amino, thioalkoxy, mercapto, cyano, carboxylic acid derivative, nitro, guanidine, heteroatom, aryl, heteroaryl, benzyl, alkalyl, cycloalkyl, heterocyclyl, bond, and hydrogen.

[0104] In some embodiments, the dashed line represents a double bond, and each X2 independently contains at least one of methylene, a heteroatom, a cycloalkyl, and a heterocyclyl. In some embodiments, the dashed line represents a double bond, and each X2 independently contains a heteroatom. In some embodiments, X2 represents a bond.

[0105] In some embodiments, R3 is hydrogen or

[0106] [ka]

[0107] The formula includes, where X is a heteroatom or is absent; A represents an optionally substituted aliphatic (C3-C20) ring or an optionally substituted aromatic (C5-C20) ring; where n is between 0 and 5.

[0108] In some embodiments, A represents an optionally substituted aliphatic (C5-C7) ring, an optionally substituted heterocyclic aliphatic (C5-C7) ring, an optionally substituted aromatic (C5-C6) ring, or an optionally substituted heteroaromatic (C5-C6) ring. In some embodiments, A represents an optionally substituted bicyclic aliphatic (C6-C15) ring, an optionally substituted bicyclic aromatic (C6-C15) ring, or an optionally substituted fusion (C6-C15) ring. In some embodiments, A represents an optionally substituted aliphatic (C5-C7) ring or an optionally substituted aromatic (C5-C6) ring.

[0109] In some embodiments, the compounds of the present invention are of formula 4:

[0110] [ka]

[0111] This is expressed as follows, where X1, R and R3 are as described above, n is between 0 and 5, and R4 is as described below.

[0112] In some embodiments, each X1 independently represents a heteroatom or methylene group. In some embodiments, the dashed bond is a double bond.

[0113] In some embodiments, R3 is hydrogen or

[0114] [ka]

[0115] In the formula, X and R are as described above. In some embodiments, each X is independently selected from -NH, -O-, and -S-, or is absent.

[0116] In some embodiments, R3 is hydrogen or

[0117] [ka]

[0118] And in the formula, X and A are as described above.

[0119] In some embodiments, R3 is hydrogen or

[0120] [ka]

[0121] And in the formula, R is as described above.

[0122] In some embodiments, R3 is hydrogen. In some embodiments, each R3 independently is:

[0123] [ka]

[0124] R4 is selected from the group consisting of hydrogen, alkyl, C1-C10 branched alkyl, haloalkyl, mercaptoalkyl, heteroatom, hydroxyalkyl, aminoalkyl, nitroalkyl, alkyl sulfate, optionally halo, nitro, hydroxy, mercapto, amino, cyano, carboxyl derivative, alkylhydroxy, aminoalkyl, mercaptoalkyl, or any combination thereof, where X and X1 are as described above. In some embodiments, R3 represents one or more substituents. In some embodiments, each X1 is independently selected from N and CH. In some embodiments, each X is independently selected from the group consisting of -N-, -NH, -O-, and -S-.

[0125] In some embodiments, the compound of the present invention is represented by formula 5:

[0126] [ka]

[0127] It is expressed as follows, where X1 is selected from the group including O, S, and NH, and where R, R3, and n are as described above.

[0128] In some embodiments, the compounds of the present invention are

[0129] [ka]

[0130] Represented by one of the following formulas, where R, R3, n, and X1 are as described herein, and where R4 is as described above. In some embodiments, R4 is hydrogen or a C1-C10 alkyl group. In some embodiments, R4 is hydrogen.

[0131] In some embodiments, the compound of the present invention is represented by formula 4.1:

[0132] [ka]

[0133] It is expressed by the equation, where n is between 0 and 5; each R3 is independent,

[0134] [ka]

[0135] R3 represents a substituent containing or is absent; where A represents an optionally substituted aliphatic (C3-C20) ring, an optionally substituted aromatic (C5-C20) ring, or H; R4 independently represents a substituent containing hydrogen, a C1-C10 alkyl, a C1-C10 branched alkyl, a substituted C1-C10 alkyl, a halo, nitro, hydroxy, mercapto, amino, cyano, and carboxyl derivative, or any combination thereof. In some embodiments, each X is independently selected from the group containing -N-, -NH, -O-, and -S-.

[0136] In some embodiments, the compounds of the present invention are: or include the following:

[0137] [ka]

[0138] In this specification, this is also referred to as compound 3, and optionally includes any salt or any derivative thereof.

[0139] In some embodiments, the compounds of the present invention are

[0140] [ka]

[0141] It is expressed by one of the following, where R4, X2, A, X1 and n are as described above, where,

[0142] [ka]

[0143] represents a single bond or a double bond. In some embodiments, the compounds of the present invention are represented by any one of formulas 7A to 7C, where each X2 is independently selected from the group comprising methylene, heteroatom, alkyl, halo, alkoxy, hydroxy, amino, thioalkoxy, mercapto, cyano, carboxylic acid derivatives, nitro, guanidine, heteroatom, aryl, heteroaryl, benzyl, alkylaryl, cycloalkyl, heterocyclyl, bond, and hydrogen, or any combination thereof; where each X1 is O. In some embodiments, R4 is hydrogen or a C1-C10 alkyl.

[0144] In some embodiments, the compounds of the present invention are of formula 8A:

[0145] [ka]

[0146] Or formula 8B:

[0147] [ka]

[0148] Or formula 8C:

[0149] [ka]

[0150] It is expressed by the formula, where R4, X2, A, X1 and n are as described above, where,

[0151] [ka]

[0152] This represents a single bond or a double bond.

[0153] In some embodiments, X1 is oxygen. In some embodiments, each X2 is independently selected from methylene, -N-, -NH, -O-, and -S-.

[0154] In some embodiments, the compounds of the present invention are of formulas 9A to 9F:

[0155] [ka]

[0156] It is expressed by one of the following, where R4, R3, X2, and A are as described above.

[0157] In some embodiments, the compounds of the present invention are of formula 9G:

[0158] [ka]

[0159] In the formula, R4, R', and X2 are as described above, where R4' is either a C1-C10 alkyl group or absent. In some embodiments, the compounds of the present invention are represented by formula 9G, where X2 is methylene or N.

[0160] In some embodiments, the compound of the present invention is of formula 6D:

[0161] [ka]

[0162] Represented by the formula, where R' and n are as described above; where X is CH or N; each A independently represents a (C3-C20)cycloalkyl, a (C3-C20)heterocyclyl (optionally containing an unsaturated bond), an aryl, or a heteroaryl, where at least one A is a (C3-C20)heterocyclyl or heteroaryl. In some embodiments, each A is (C0-C6)alkyl-aryl, (C0-C6)alkyl-heteroaryl, (C0-C6)alkyl-(C3-C8)cycloalkyl, optionally substituted C3-C8 heterocyclyl, halogen, -NO2, -CN, -OH, -CONH2, -CONR”2, -CNNR”2, -CSNR”2, -CONH-OH, -CONH-NH2, -NHCOR”, -NHCSR”, -NHCNR”, -NC(=O)OR”, -NC(=O)NR”, -NC(=S)OR”, -NC(=S)NR”, -SO2R”, -SOR”, -SR”, -SO2OR”, -SO2N(R)2, -NHNR2, -NNR, C1-C 10 Haloalkyl, optionally substituted C1-C 10 Alkyl, -NH2, -NH(C1-C 10 Alkyl), -N(C1-C 10 Alkyl)2, C1-C 10 Alkyl, C1-C 10 Haloalkoxy, Hydroxy(C1-C) 10 Alkyl), Hydroxy(C1-C 10 Alkoxy), Alkoxy (C1-C 10 Alkyl), alkoxy (C1-C 10 Alkyl(alkoxy), C1-C 10 Alkyl-NR"2, C1-C 10 Alkyl-SR,-CONH(C1-C 10 Alkyl), -CON(C1-C 10It is optionally substituted by one or more R's, including alkyl)2, -CO2H, -CO2R'', -OCOR'', -OCOR'', -OC(=O)OR'', -OC(=O)NR'', -OC(=S)OR'', or -OC(=S)NR'', or any combination thereof.

[0163] In some embodiments, the compounds of the present invention are of formula 6E:

[0164] [ka]

[0165] Represented by the formula, where X, n, and R' are as described herein, where X' is N or CH, and at least one X' is N. In some embodiments, both X' are N.

[0166] In some embodiments, the compounds of the present invention are as follows:

[0167] [ka]

[0168] It is any of the following, any salt thereof, and / or any derivative thereof.

[0169] In some embodiments, the compounds of the present invention are as follows:

[0170] [ka]

[0171] It is any of the following, any salt thereof, and / or any derivative thereof.

[0172] As used herein, the term “stereoisomer” refers to an enantiomer or diastereomer of a compound.

[0173] In some embodiments, the term “derivative” refers to a prodrug of a compound such as an ester; a tautomer of a compound such as a keto-enol tautomer, an imine-enamine tautomer, an amide-iminol tautomer, or any combination thereof. In some embodiments, the term “derivative” refers to a compound substituted with one or more (e.g., 2, 3, 4, or 5) substituents, optionally any one of which substituents independently is R', where R' is as described herein.

[0174] In some embodiments, compositions comprising one or more compounds of the present invention, including any salt thereof (e.g., a pharmaceutically acceptable salt), any tautomer, and / or any stereoisomer, are provided herein. In some embodiments, the compounds described above constitute the sole active ingredient in a composition of the present invention (e.g., a pharmaceutical composition).

[0175] In some embodiments, the composition of the present invention is a pharmaceutical composition comprising at least one compound of the present invention and a pharmaceutically acceptable carrier. In some embodiments, the composition of the present invention is a pharmaceutical composition comprising at least one compound of the present invention as a first active ingredient and an additional active ingredient.

[0176] In some embodiments, the pharmaceutical composition is in the form of a combination or a kit of components. In some embodiments, the pharmaceutical composition of the present invention is intended for use as a pharmaceutical agent. Treatment method In another embodiment, a method is provided for inhibiting or reducing ApoL1-related cytotoxicity in a subject requiring it, the method comprising administering the pharmaceutical composition or compound of the present invention to the subject. In some embodiments, the administration is by oral administration, systemic administration, or a combination thereof.

[0177] In some embodiments, the method is for preventing or treating ApoL1-related diseases or disorders. In some embodiments, the method is for preventing or treating diseases or disorders associated with the expression of ApoL1 mutant alleles within a subject. In some embodiments, the method is for preventing or treating diseases or disorders associated with the overexpression of ApoL1 (mutant and / or wild-type) within a subject. In some embodiments, overexpression includes increasing the intracellular concentration of ApoL1.

[0178] In some embodiments, ApoL1-related cytotoxicity includes ApoL1-induced endolysosome dysfunction, ApoL1-induced mitochondrial dysfunction (such as a decrease in mitochondrial respiration rate), ApoL1-induced increased potassium efflux, inflammasome activation, protein aggregation, protein-protein interactions, unfold protein responses, pyroptosis, necroptosis, feroptosis, autophagy inhibition, or any combination thereof.

[0179] In some embodiments, ApoL1 is an ApoL1 variant (such as ApoL1 G1 and / or ApoL1 G2). The sequences of the ApoL1 G1 / G2 variant alleles are well known in the art.

[0180] In some embodiments, the method of the present invention includes the steps of: determining whether the expression level of at least one ApoL1 gene is increased beyond a predetermined threshold (e.g., at least 10%, at least 50%, at least 100%, at least 200%, at least 300%, at least 1000%, or any range in between) in a sample obtained from or derived from a subject; administering a therapeutically effective amount of the compound of the present invention to a subject in which the expression level of at least one ApoL1 gene is determined to be increased beyond the predetermined threshold; and thereby treating an ApoL1-related disease or disorder in the subject. In some embodiments, the ApoL1-related disease or disorder is or includes a disease or disorder associated with overexpression of the ApoL1 gene in the subject. In some embodiments, the ApoL1 gene is a wild-type gene or a mutant gene (G1 and / or G2).

[0181] In some embodiments, the method of the present invention involves the G1 mutation (S 342 >G and / or I 384 The method comprises determining whether a G1 or G2 mutation (e.g., 6bp deletion N388del:Y389del), or both, is present in the ApoL1 gene of a target cell (e.g., kidney cell), administering a therapeutically effective dose of the compound of the present invention to a target determined to have cells containing the G1 and / or G2 mutation in the ApoL1 gene, thereby treating an ApoL1-related disease or disorder in the target. In some embodiments, the ApoL1-related disease or disorder is or includes a disease or disorder related to the expression of an ApoL1 mutant allele (e.g., G1 and / or G2) in the target.

[0182] In some embodiments, the cells are kidney cells (e.g., podocytes) or vascular cells (e.g., endothelial cells). In some embodiments, the cells contain a mutant ApoL1 allele, the mutant ApoL1 being as described herein. In some embodiments, the cells are characterized by overexpression of ApoL1 (mutant and / or wild-type). In some embodiments, the cells contain an ApoL1 G1 mutant, an ApoL1 G1 mutant, or both. In some embodiments, the cells selectively express a single ApoL1 mutant (either G1 or G2). In some embodiments, the cells express multiple ApoL1 mutants. In some embodiments, the wild-type ApoL1 has the same sequence as NCBI gene ID 8542.

[0183] In some embodiments, selective expression includes the expression of at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, and at least 99% of a single ApoL1 variant, where the expression rate is related to the proportion of ApoL1 variants in the total ApoL1 protein content.

[0184] In some embodiments, the method of the present invention includes selectively inhibiting or reducing ApoL1 G1-related cytotoxicity. In some embodiments, the method of the present invention includes selectively inhibiting or reducing ApoL1 G2-related cytotoxicity. In some embodiments, the method of the present invention includes inhibiting or reducing ApoL1 G1 and ApoL1 G2-related cytotoxicity.

[0185] In some embodiments, the method is for preventing or treating a kidney disease or disorder. In some embodiments, the method is for preventing or treating an ApoL1-related kidney disease or disorder. In some embodiments, ApoL1-related kidney diseases include hypertensive kidney disease, sickle cell nephropathy, focal segmental glomerulosclerosis (FSGS), primary non-idiopathic FSGS, HIV-related nephropathy, lupus nephritis, end-stage renal disease (ESRD), diabetic ESRD, albuminuria, or any combination thereof. In some embodiments, the method is for preventing or treating an ApoL1-related cardiovascular disease. In some embodiments, ApoL1 is an ApoL1 variant (such as ApoL1 G1 and / or ApoL1 G2).

[0186] In some embodiments, the method includes administering the pharmaceutical composition of the present invention at least once a day, at least twice a day, at least three times a day, at least four times a day, at least five times a day, at least seven times a day, or at least ten times a day, or any value and range therebetween. Each possibility represents a separate embodiment of the present invention. In some embodiments, the method includes administering the composition or combination of the present invention once to twice a day, once to three times a day, once to four times a day, once to five times a day, once to seven times a day, twice to three times a day, twice to four times a day, twice to five times a day, three times to four times a day, three times to five times a day, or five times to seven times a day. Each possibility represents a separate embodiment of the present invention.

[0187] In some embodiments, the subject is a mammal. In some embodiments, the subject is an experimental animal. In some embodiments, the subject is a pet. In some embodiments, the subject is a rodent. In some embodiments, the subject is a livestock. In some embodiments, the subject is a human subject.

[0188] In some embodiments, the compositions of the present invention are administered in a therapeutically safe and effective amount. As used herein, the term "safe and effective amount" refers to an amount of a component sufficient to provide a desired therapeutic response without undue harmful side effects, which, when used in the presently described methods, is commensurate with a reasonable benefit / risk ratio, including, but not limited to, toxicities such as calcium toxicity, irritation, or allergic reaction. The actual dosage administered, as well as the rate and duration of administration, depends on the nature and severity of the condition being treated. The determination of the treatment regimen, e.g., dosage, timing, etc., is within the responsibility of the general practitioner or specialist and typically takes into account the disorder being treated, the condition of the individual patient, the site of delivery, the method of administration, and other factors known to the practitioner. Examples of techniques and protocols can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Philadelphia, Pa., (2005).

[0189] In some embodiments, the effective amount or dosage of the active ingredient can first be estimated from in vitro assays. In one embodiment, the dosage can be formulated in animal models, and such information can be used to more accurately determine a useful dosage in humans.

[0190] In one embodiment, the toxicity and therapeutic effects of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell culture, or in experimental animals. In one embodiment, data obtained from these in vitro and cell culture assays as well as animal studies can be used when formulating dose ranges for use in humans. In one embodiment, the dose may vary depending on the dosage form used and the route of administration utilized. In one embodiment, the exact formulation, route of administration, and dose may be selected by the individual physician in consideration of the patient's condition. [See, for example, Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Ed., McGraw-Hill / Education, New York, NY (2017)].

[0191] In some embodiments, subjects suffer from a disease or disorder selected from the group including hypertensive kidney disease, sickle cell nephropathy, and focal segmental glomerulosclerosis (FSGS), primary non-monochromatic FSGS, HIV-associated nephropathy, lupus nephritis, ApoL1-associated cardiovascular disease, end-stage renal disease (ESRD), diabetic ESRD, albuminuria, or any combination thereof.

[0192] In some embodiments, the subjects suffer from ApoL1-related cardiovascular disease or disorder. In some embodiments, the subjects suffer from renal disease or disorder. In some embodiments, the subjects suffer from renal disease or disorder characterized by cells expressing at least one ApoL1 variant. In some embodiments, the ApoL1 variant is the translation product of a mutant ApoL1 gene. In some embodiments, the mutant ApoL1 gene includes ApoL1G1 and / or ApoL1G2 variants.

[0193] In some embodiments, the reduction of ApoL1 cytotoxicity includes a reduction of at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, and at least 99% of cell death (such as by apoptosis, or cellular stress, or protein interactions, or autoaggregation, or aggregate formation), and any value in between. In some embodiments, the compounds of the present invention substantially reduce the mortality rate of cells expressing ApoL1 variants, as shown in Figure 1.

[0194] In some embodiments, the compounds of the present invention are substantially inactive to cells expressing the wild-type ApoL1 gene. In some embodiments, the method is for inhibiting the enzymatic activity of ApoL1 mutants.

[0195] In some embodiments, the compounds of the present invention show increased affinity for ApoL1 variants compared to wild-type ApoL1, as described herein.

[0196] In some embodiments, the compounds of the present invention enhance the cell viability of cells expressing at least one ApoL1 variant. In some embodiments, cell viability is improved by at least 5 times, at least 10 times, at least 15 times, at least 20 times, at least 30 times, at least 30 times, at least 50 times, at least 80 times, at least 100 times, at least 200 times, at least 300 times, at least 400 times, at least 500 times, at least 700 times, at least 1000 times, at least 10,000 times, at least 50,000 times, and at least 100,000 times compared to untreated cells (as shown in Figure 1). In some embodiments, the compounds of the present invention increase the viability of cells expressing at least one ApoL1 variant in a dose-dependent manner (e.g., at concentrations of 0.2 to 10 μM).

[0197] In some embodiments, the compounds of the present invention are substantially nontoxic at concentrations of less than 15 μm, less than 12 μm, less than 11 μm, less than 10 μm, less than 9 μm, less than 8 μm, less than 6 μm, less than 5 μm, less than 3 μm, and less than 1 μm, including any range or value in between.

[0198] In some embodiments, the compounds of the present invention are substantially nontoxic at concentrations of 0.001–15 μm, 0.001–1 μm, 1–5 μm, 5–10 μm, 10–12 μm, and 12–15 μm, including any range or value in between. In some embodiments, the compounds substantially include cell death of less than 20%, less than 17%, less than 15%, less than 13%, less than 10%, less than 8%, and less than 5%, including any range or value in between.

[0199] In some embodiments, ApoL1 gene mutations include ApoL1 G1 point mutations (S342G and / or I384M) and / or APOL1 G2 deletion mutations (Δ388N389Y). In some embodiments, ApoL1 gene mutations are associated with resistance of cells expressing ApoL1 variants to trypanosome infection.

[0200] In another embodiment, a method is provided for preventing or treating proliferative disorders, the method comprising administering a therapeutically effective amount of the pharmaceutical composition or compound of the present invention to a subject. In some embodiments, the administration is by oral administration, topical administration, systemic administration, or a combination thereof. In some embodiments, the administration is as described herein. In some embodiments, the method is for reducing the viability of cancer cells and / or halting their proliferation. In some embodiments, the reduction is at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, and at least 99% of cell viability (e.g., by apoptosis, or cellular stress, or protein interactions, or autoaggregation, or aggregate formation).

[0201] In some embodiments, subjects suffer from a disease or disorder selected from the group including brain cancer, squamous cell carcinoma, bladder cancer, gastric cancer, pancreatic cancer, liver cancer, glioblastoma multiforme, breast cancer, head cancer, neck cancer, esophageal cancer, prostate cancer, colorectal cancer, lung cancer, kidney cancer, renal cancer, ovarian cancer, gynecological cancer, thyroid cancer, non-small cell lung cancer (NSCLC), refractory ovarian cancer, EGFR variant-associated cancer, and head and neck cancer, or any combination thereof. Carrier In some embodiments, the pharmaceutical composition of the present invention comprises a therapeutically effective amount of the compound of the present invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable salt comprises the compound of the present invention and a pharmaceutically acceptable anion. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention as an active ingredient. In some embodiments, the compound of the present invention is the sole active ingredient in the pharmaceutical composition of the present invention.

[0202] Non-limiting examples of pharmaceutically acceptable anions include, but are not limited to, acetates, aspartates, benzenesulfons, benzoates, bicarbonates, carbonates, halides (such as bromides, chlorides, iodides, and fluorides), bitartrates, citrates, salicylates, stearates, succinates, sulfates, tartrates, decanoates, fumarates, glucons, and lactates, or any combination thereof.

[0203] For example, the term "pharmaceutically acceptable" can mean that it has been approved by a federal or state regulatory agency for use in animals, more specifically in humans, or that it is listed in the United States Pharmacopeia or other generally recognized pharmacopoeias.

[0204] In some embodiments, the pharmaceutical compositions described herein are topical compositions. In some embodiments, the pharmaceutical compositions are oral compositions. In some embodiments, the pharmaceutical compositions are injectable compositions. In some embodiments, the pharmaceutical compositions are for systemic use.

[0205] In some embodiments, the pharmaceutical composition is an emulsion, liquid solution, gel, paste, suspension, dispersant, ointment, cream, or foam.

[0206] As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle to which the active ingredient is administered together. Such carriers may be aqueous or oily, e.g., of petroleum, animal, plant, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc., or sterile liquids such as polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents.

[0207] Other non-exclusive examples of carriers include, but are not limited to, cannabis-derived terpenes. Examples include total terpene extracts derived from cannabis plants, terpenes derived from coffee or cocoa, mint extracts, eucalyptus extracts, citrus extracts, tobacco extracts, anise extracts, any vegetable oil, peppermint oil, d-limonene, β-myrcene, α-pinene, linalool, anethole, α-bisabolol, camphor, β-caryophyllene and caryophyllene oxide, 1,8-cineole, citral, citronella, delta-3-carene, farnesol, geraniol, indomethacin, isopulegol, linalool, unalyl acetate, β-myrcene, myrcenol, l-menthol, menthone, menthol and neomenthol, oridonin, α-pinene, diclofenac, nepafenac, bromfenac, phytol, terpineol, terpinen-4-ol, thymol, and thymoquinone. Those skilled in the art will understand that the specific carrier used in the pharmaceutical composition of the present invention may vary depending on the route of administration.

[0208] In some embodiments, the carrier improves the stability of the active ingredient in living organisms. In some embodiments, the carrier improves the stability of the active ingredient in a pharmaceutical composition. In some embodiments, the carrier enhances the bioavailability of the active ingredient.

[0209] Water can be used as a carrier when the active ingredient has sufficient water solubility, such as when it is to be administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be used as liquid carriers, especially for injectable solutions.

[0210] In some embodiments, the carrier is a liquid carrier. In some embodiments, the carrier is an aqueous carrier.

[0211] Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. If desired, the composition can also contain small amounts of wetting or emulsifying agents, or pH buffering agents such as acetates, citrates, or phosphates. Antibacterial agents such as benzyl alcohol or methylparaben, antioxidants such as ascorbic acid or sodium bisulfite, and tonicity modifiers such as sodium chloride or dextrose are also contemplated. The carrier can in total comprise from 0.1 wt% to 99.99999 wt% of the composition or pharmaceutical composition presented herein.

[0212] In some embodiments, the pharmaceutical composition comprises the incorporation of the active ingredient into any one of particulate preparations or particulate modifiers of high molecular weight compounds such as polylactic acid, polyglycolic acid, hydrogels, or into liposomes, microemulsions, micelles, monolayer or multilayer vesicles, erythrocyte ghosts, or spheroplasts. Such compositions can affect the physical state, solubility, stability, in vivo release rate, and in vivo clearance rate.

[0213] In some embodiments, the pharmaceutical composition is a liquid at a temperature of 15–45°C. In some embodiments, the pharmaceutical composition is a solid at a temperature of 15–45°C. In some embodiments, the pharmaceutical composition is a semi-liquid at a temperature of 15–45°C. Naturally, the term “semi-liquid” is intended to mean a material that is fluid under pressure and / or shear force. In some embodiments, semi-liquid compositions include creams, ointments, gel-like materials, and other similar materials. In some embodiments, the pharmaceutical composition is a semi-liquid composition characterized by a viscosity in the range of 31,000–800,000 cps.

[0214] Non-limiting examples of carriers for pharmaceutical compositions include, but are not limited to, nonionic surfactants (e.g., glyceryl monolinoleate, glyceryl monooleate, glyceryl monostearate, lanolin alcohol, lecithin, monoglycerides and diglycerides, poloxamer polyoxyethylene 50 stearate, and sorbitan trioleate, stearic acid), anionic surfactants (e.g., pharmaceutically acceptable salts of fatty acids such as stearic acid, oleic acid, palmitic acid, and lauric acid), cationic surfactants (e.g., pharmaceutically acceptable quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride), or any combination thereof.

[0215] In some embodiments, the pharmaceutical composition, which is in the form of a cream, further includes a thickening agent.

[0216] Non-limiting examples of thickeners include, but are not limited to, microcrystalline cellulose, starch, modified starch, tragacanth gum, gelatin, and polymeric thickeners (e.g., polyvinylpyrrolidone) or any combination thereof.

[0217] In some embodiments, the pharmaceutical composition comprising the compound of the present invention is in unit dosage form. In some embodiments, the pharmaceutical composition is prepared by any method well known in the art of pharmacy. In some embodiments, the unit dosage form is in the form of a tablet, capsule, lozenge, wafer, patch, ampoule, vial, or pre-filled syringe.

[0218] Furthermore, in vitro assays may optionally be used to determine the optimal dose range. The exact dose adopted for the formulation also depends on the route of administration and the nature of the disease or disorder, and should be determined according to the practitioner's judgment and the circumstances of each patient. The effective dose can be extrapolated from dose-response curves obtained from in vitro or in vivo animal model bioassays or systems. In some embodiments, the effective dose is determined as described above.

[0219] In another embodiment, the pharmaceutical composition of the present invention is administered in any conventional oral, parenteral, or transdermal dosage form.

[0220] As used herein, the terms “administer,” “dosage,” and similar terms refer to any method of delivering a composition containing an activator to a subject in a manner that provides a therapeutic effect in sound medical practice.

[0221] In some embodiments, the pharmaceutical composition is administered via an oral (i.e., enteral), rectal, vaginal, topical, nasal, ocular, transdermal, subcutaneous, intramuscular, intraperitoneal, or intravenous route of administration. The route of administration of the pharmaceutical composition depends on the disease or condition being treated. Preferred routes of administration include, but are not limited to, parenteral injections, e.g., intradermal, intravenous, intramuscular, intrafocal, subcutaneous, intrathecal, and any other injection methods known in the art. Furthermore, it is desirable to introduce the pharmaceutical composition of the present invention by any suitable route, including intraventricular and intrathecal injections, and intraventricular injections can be facilitated, for example, by an intraventricular catheter attached to a reservoir. Lung administration can also be used, for example, by the use of an inhaler or nebulizer.

[0222] In some embodiments, the pharmaceutical composition may be in the form of, for example, an ointment, cream, gel, paste, foam, aerosol, suppository, pad, or gel-like stick.

[0223] In some embodiments, for oral use, the pharmaceutical composition is in the form of a tablet or capsule and may contain any of the following components or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; or flow enhancers such as colloidal silicon dioxide. When the dosage unit form is a capsule, in addition to the above types of materials, it may contain a liquid carrier such as a fatty acid. In addition, the dosage unit form may contain various other materials that modify the physical form of the dosage unit, such as a coating of sugar, shellac, or other enteric solvents. In some embodiments, the tablets of the present invention are further film-coated. In some embodiments, the oral application of the pharmaceutical composition or kit is in the form of a drinkable liquid. In some embodiments, the oral application of the pharmaceutical composition or kit is in the form of an edible product.

[0224] For parenteral administration, solutions in sesame oil or peanut oil, or aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts, can be used. These aqueous solutions may be appropriately buffered as needed, and the liquid diluent may first be isotonic with sufficient saline or glucose. These aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal injection.

[0225] In some embodiments, the subject is a mammal. In some embodiments, the subject is a laboratory animal. In some embodiments, the subject is a pet. In some embodiments, the subject is a rodent. In some embodiments, the subject is livestock. In some embodiments, the subject is a human subject.

[0226] In some embodiments, a composition comprising the formulation of the present invention, formulated on a suitable pharmaceutical carrier, is prepared, placed in a suitable container, and labeled for the treatment of an indicated condition.

[0227] In some embodiments, the composition of the present invention is presented in a pack or dispenser device, such as an FDA-approved kit, containing one or more unit dose forms containing the active ingredient. In some embodiments, the pack includes, for example, metal or plastic foil, such as a blister pack. In some embodiments, the pack or dispenser device is accompanied by instructions for administration. In some embodiments, the pack or dispenser is contained by a notice relating to a form of container prescribed by a government agency that regulates the manufacture, use or sale of a drug, and this notice reflects agency approval of the form of the composition or human or veterinary administration. In some embodiments, such notice is a statement approved by the U.S. Food and Drug Administration for a prescription drug, or a statement in an approved product insert. definition As used herein, the term “alkyl” refers to an aliphatic hydrocarbon containing linear and branched groups. Preferably, alkyl groups have 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms (or C1-C6 alkyl). Thus, short alkyl groups have 20 or fewer main chain carbons. Alkyl groups may be substituted or unsubstituted, as defined herein.

[0228] As used herein, the term “alkyl” also encompasses saturated or unsaturated hydrocarbons, and therefore, the term further encompasses alkenyls and alkynyls. As used herein, the term “C1-C6 alkyl,” including any C1-C6 alkyl-related compound, refers to any linear or branched alkyl chain containing carbon atoms between 1 and 6, between 1 and 2, between 2 and 3, between 3 and 4, between 4 and 5, between 5 and 6, or any range in between. In some embodiments, the C1-C6 alkyl includes any of methyl, ethyl, propyl, butyl, pentyl, isopentyl, hexyl, and tert-butyl, or any combination thereof. In some embodiments, the C1-C6 alkyl described herein further includes an unsaturated bond located at the 1st, 2nd, 3rd, 4th, 5th, or 6th position of the C1-C6 alkyl.

[0229] When used herein, any C1-C6 alkyl-related compound is included. 10 The term "alkyl" refers to any linear or branched alkyl chain containing carbon atoms between 1 and 6, between 1 and 2, between 2 and 3, between 3 and 4, between 4 and 5, between 5 and 6, between 6 and 8, between 8 and 10, or any range in between. In some embodiments, C1-C 10 Alkyl includes methyl, ethyl, propyl, butyl, pentyl, isopentyl, hexyl, nonyl, decyl, ethenyl, propenyl, butenyl, and tert-butyl, or any combination thereof, and each alkyl is optionally substituted with one or more substituents as described herein.

[0230] In some embodiments, C1-C described herein 10 Alkyl groups further contain unsaturated bonds, and these unsaturated bonds are C1-C 10 It is located at the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, or 10th position of the alkyl group.

[0231] The term "alkenyl" as defined herein refers to an unsaturated alkyl group having at least two carbon atoms and at least one carbon-carbon double bond. Alkenyls may be substituted or unsubstituted with one or more substituents, as described above.

[0232] The term "alkynyl" is, as defined herein, an unsaturated alkyl having at least two carbon atoms and at least one carbon-carbon triple bond. Alkynnyls may be substituted or unsubstituted with one or more substituents, as described above.

[0233] The term "cycloalkyl" refers to a whole-carbon monocyclic or fused ring (i.e., a ring sharing an adjacent pair of carbon atoms) group in which one or more rings do not have a fully conjugated pi-electron system. Cycloalkyl groups may be substituted or unsubstituted as shown herein. In some embodiments, the term "cycloalkyl" refers to a C3-C10 cyclic ring. In some embodiments, the term "cycloalkyl" refers to a C3-C10 cyclic ring containing one, two, three, or four heteroatoms (e.g., N, NH, O, or S). (C3-C 10 The ) ring refers to an optionally substituted C3, C4, C5, C6, C7, C8, C9, or C10 ring. In some embodiments, (C3-C 10 The ring may optionally contain substituted cyclopropane, cyclobutene, cyclopentane, cyclohexane, or cycloheptane.

[0234] In some embodiments, the term “cycloalkyl” refers to a group containing a non-aromatic ring, where each atom forming the ring is a carbon atom. Cycloalkyls may be formed by 3, 4, 5, 6, 7, 8, 9, or more than 9 carbon atoms. Cycloalkyls may be optionally substituted. In certain embodiments, cycloalkyls contain one or more unsaturated bonds. Examples of cycloalkyls include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, and cycloheptene.

[0235] In some embodiments, the term “aryl” refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent pairs of carbon atoms) group having a fully conjugated pi-electron system. In some embodiments, the term “aryl” refers to an aromatic (C6-C) group. 12 ) represents a ring. The aryl group may be substituted or unsubstituted as shown herein. In some embodiments, the term "(C6-C 12 The term "(C6-C12) ring" refers to an optionally substituted C6, C7, C8, C9, C10, C11, C12 aromatic ring. In some embodiments, (C6-C 12 The term "aryl" refers to a bicyclic aryl or bicyclic heteroaryl (e.g., a fused ring, a spirocyclic ring, and a biaryl ring). In some embodiments, the term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic system that does not contain a ring heteroatom. If the system is not monocyclic, the term "aryl" includes the saturated (perhydro) or partially unsaturated (e.g., dihydro or tetrahydro) or maximally unsaturated (non-aromatherapy) form for each additional ring. In some embodiments, the term "aryl" refers to a bicyclic radical in which two rings are aromatic, and a bicyclic radical in which only one ring is aromatic. Examples of aryls include phenyl, naphthyl, anthrasyl, indanyl, 1,2-dihydro-naphthyl, 1,4-dihydronaphthyl, indenyl, 1,4-naphthoquinonyl, and 1,2,3,4-tetrahydronaphthyl.

[0236] An aryl ring may be formed by 3, 4, 5, 6, 7, 8, 9, or more than 9 carbon atoms. In some embodiments, aryl refers to a 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14-membered aromatic monocyclic, bicyclic, or tricyclic system. In some embodiments, aryl refers to an aromatic C3-C9 ring. In some embodiments, aryl refers to an aromatic C4-C8 ring. The aryl group may be optionally substituted.

[0237] As used herein, the term “bicyclic heteroaryl” means (C6-C 12 ) refers to a bicyclic heteroaryl ring, and a bicyclic (C6-C 10 The ring is as described herein.

[0238] As used herein, the term “biring aryl” means (C6-C 12 ) refers to a bicyclic aryl ring, and a bicyclic (C6-C 12 The ring is as described herein.

[0239] The term "alkoxy" refers to both O-alkyl groups and -O-cycloalkyl groups as defined herein.

[0240] The term "aryloxy" refers to the -O-aryl compound as defined herein.

[0241] Each of the alkyl, cycloalkyl, and aryl groups in the general formulas herein may be substituted with one or more substituents, so that each substituent, depending on the substituent and its position within the molecule, may independently be, for example, a halide, alkyl, alkoxy, cycloalkyl, nitro, amino, hydroxyl, thiol, thioalkoxy, carboxy, amide, aryl, and aryloxy. Additional substituents are also conceivable.

[0242] The term "haloalkyl" refers to an alkyl group as defined herein, which is further substituted by one or more halides.

[0243] The term "haloalkoxy" refers to an alkoxy group as defined herein, which is further substituted by one or more halides.

[0244] The term "hydroxyl" or "hydroxy" refers to the -OH group.

[0245] The terms "mercapto" or "thiol" refer to the -SH group.

[0246] The term "thioalkoxy" refers to both -S-alkyl groups and -S-cycloalkyl groups as defined herein.

[0247] The term "thioaryloxy" refers to both -S-aryl and -S-heteroaryl groups, as defined herein.

[0248] The term "amino" represents the -NR'R'' group, where R' and R'' are as described herein.

[0249] As used herein, the term “heterocycle” refers to a ring in which at least one of the ring-forming atoms is a carbon atom and at least one of the ring-forming atoms is a heteroatom. A heterocycle may be formed by 3, 4, 5, 6, 7, 8, 9, or more than 9 atoms. Any number of those atoms may be heteroatoms (i.e., a heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or more than 9 heteroatoms, provided that at least one atom in the ring is a carbon atom). In this specification, whenever the number of carbon atoms in a heterocycle is given (e.g., C1-C6 heterocycle), there must be at least one other atom (heteroatom) in the ring. Designations such as “C1-C6 heterocycle” refer only to the number of carbon atoms in the ring and not to the total number of atoms in the ring. It is understood that a heterocycle may have additional heteroatoms in the ring. The designation "4- to 6-membered heterocycle" refers to the total number of atoms in the ring (i.e., a 4, 5, or 6-membered ring in which at least one atom is a carbon atom, at least one atom is a heteroatom, and the remaining two to four atoms are either carbon atoms or heteroatoms). In a heterocycle containing two or more heteroatoms, those two or more heteroatoms may be identical or different. Heterocycles may be optionally substituted. Bonding to a heterocycle can occur via heteroatoms or through carbon atoms. As used herein, the term "carbocyclic ring" refers to a ring in which each of the ring-forming atoms is a carbon atom. Carbocyclic rings may be formed by 3, 4, 5, 6, 7, 8, 9, or more than 9 carbon atoms. Carbocyclic rings may be optionally substituted.

[0250] As used herein, the term “heteroatom” refers to an atom other than carbon or hydrogen. Heteroatoms are typically selected independently from, but are not limited to, oxygen, sulfur, nitrogen, and phosphorus. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may all be identical to each other, or some or all of the two or more heteroatoms may be different from each other.

[0251] As used herein, the term “bicyclic ring” refers to two rings that are fused together. Examples of bicyclic rings include decalin, pentalene, indene, naphthalene, azulene, heptalene, isobenzofuran, chromene, indidine, isoindole, indole, indoline, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, pteridine, isochromane, chromane, and their various hydrogenated derivatives. The bicyclic ring may be optionally substituted. Each ring is independently aromatic or non-aromatic. In certain embodiments, both rings are aromatic. In certain embodiments, both rings are non-aromatic. In certain embodiments, one ring is aromatic and the other is non-aromatic.

[0252] As used herein, the term “aromatic” refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. Aromatic rings may be formed by 5, 6, 7, 8, 9, or more than 9 atoms. Aromatics may be optionally substituted. Examples of aromatic groups include, but are not limited to, phenyl, tetralinyl, naphthalenyl, phenantrenyl, anthracenyl, fluorenyl, indenyl, and indanyl. Teem aromatics are, for example, linked via one of the ring-forming carbon atoms and optionally include aryl, heteroaryl, cycloalkyl, non-aromatic heterocycles, halo, hydroxy, amino, cyano, nitro, alkylamide, acyl, and C. 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6The aromatic groups include a benzenoide group supporting one or more substituents selected from alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. In certain embodiments, the aromatic group is substituted at one or more of the para, meta, and / or ortho positions. Examples of substituted aromatic groups include, but are not limited to, phenyl, 3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, naphthyl, dimethylphenyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4-morpholine-4-ylphenyl, 4-pyrrolidine-1-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidine-1-yl)phenyl.

[0253] The term "carboxyl" or "carboxyl" represents the -C(O)OR' group, where R' is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (bonded via the ring carbon), or heterocyclyl (bonded via the ring carbon), as defined herein, or where R' is absent, e.g., a carboxylate salt.

[0254] The term "carbonyl" represents the -C(O)R' group, where R' is defined as described above.

[0255] The above terms also include their thio derivatives (thiocarboxy and thiocarbonyl).

[0256] As used herein, the term “carboxylic acid derivative” includes carboxylates, amides, carbonyls, anhydrides, carbonates, and carbamates, as described herein.

[0257] The term "thiocarbonyl" represents the -C(S)R' group, where R' is defined as described above.

[0258] The "thiocarboxyl" group represents the -C(S)OR' group, where R' is defined as described above.

[0259] The "sulfinyl" group represents the -S(O)R' group, where R' is defined as described above.

[0260] The "sulfonyl" or "sulfonate" group represents the -S(O)2R' group, where R' is defined as described above.

[0261] The "carbamoyl" or "carbamate" group represents the -OC(O)NR'R'' group, where R' is as defined herein and R'' is as defined for R'.

[0262] The "nitro" group refers to the -NO2 group.

[0263] In some embodiments, the term “amide” refers to a chemical moiety having the formula -(R)nC(O)NHR' or -(R)n-NHC(O)R', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (linked via ring carbon) and heteroalicyclic (linked via ring carbon), and n is 0 or 1. In certain embodiments, the amide may be an amino acid or a peptide.

[0264] As used herein, the term "amide" encompasses C-amides and N-amides.

[0265] The term "C-amide" refers to a -C(O)NR'R'' terminal group or -C(O)NR'- bond group, as defined above, where R' and R'' are as defined herein.

[0266] The term "N-amide" refers to the -NR''C(O)R' terminal group or -NR'C(O)- bond group, as defined above, where R' and R'' are as defined herein.

[0267] As used herein, the term “carboxylic acid derivative” includes carboxylates, amides, carbonyls, anhydrides, carbonates, and carbamates.

[0268] The "cyano" or "nitrile" group refers to the -CN group.

[0269] The terms "azo" or "diazo" refer to an -N=NR' terminal group or -N=N- bond group, as defined above, where R' is as defined above.

[0270] The term "guanidine" refers to the -R'NC(N)NR''R''' terminal group or -R'NC(N)NR''- bond group, as defined above, where R', R'' and R''' are as defined herein.

[0271] As used herein, the term "alkyl sulfate" means one or more sulfate groups (-OS(=O)2OH and / or (-OS(=O)2O - This refers to alkyl groups as defined herein, which are further substituted by ).

[0272] As used herein, the term "azide" refers to the -N3 group.

[0273] The term "sulfonamide" refers to the -S(O)2NR'R'' group, where R' and R'' are as defined herein.

[0274] The term "phosphonyl" or "phosphonate" represents a -OP(O)-(OR')2 group, where R' is defined as above.

[0275] The term "phosphinyl" represents the -PR'R'' group, where R' and R'' are defined above.

[0276] The term "alkylaryl" refers to an alkyl group as defined herein, substituted with an aryl group as described herein. An exemplary alkylaryl is benzyl.

[0277] As used herein, the term “heteroaryl” refers to an aromatic ring in which at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings can be formed with 3, 4, 5, 6, 7, 8, 9, and more than 9 atoms. Heteroaryl groups may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C atoms containing one oxygen or sulfur atom, or two oxygen atoms, or two sulfur atoms, or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms. 3-8 Examples include heterocyclic groups and their substituted derivatives, as well as benzo- and pyrido-condensed derivatives linked via one of the ring-forming carbon atoms. In certain embodiments, the heteroaryl is selected from oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridadinyl, pyrimidinal, pyrazinyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl.

[0278] In some embodiments, the heteroaryl group is pyrrolyl, furanyl (furyl), thiophenyl (thienyl), imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3-oxazolyl (oxazolyl), 1,2-oxazolyl (isoxazolyl), oxadiazolyl, 1,3-thiazolyl (thiazolyl), 1,2-thiazolyl (isothiazolyl), tetrazolyl, pyridinyl (pyridyl)pyridazinyl, pyrimidinyl, pyrazinyl, 1,2, The heteroaryl group is selected from 3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetradinyl, indazolyl, indolyl, benzothiophenyl, benzofuranil, benzothiazolyl, benzimidazolyl, benzodioxolyl, acridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thienothiophenyl, 1,8-naphthilidinyl, and other naphthilidinyls, pteridinyls, or phenothiazinyls. When a heteroaryl group contains two or more rings, each additional ring can be in a saturated (perhydro) form, a partially unsaturated (e.g., dihydro or tetrahydro) form, or a maximally unsaturated (non-aromatic) form. Thus, the term heteroaryl includes bicyclic radicals in which two rings are aromatic, and bicyclic radicals in which only one ring is aromatic. Examples of heteroaryls include 3H-indolinyl, 2(1H)-quinolinonyl, 4-oxo-1,4-dihydroquinolinyl, 2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, (2H)quinolinyl N-oxide, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 3,4-dihydroisoquinolinyl, chromonyl, 3,4-dihydroisoquinoxalinyl, and 4-(3H)quinazolinyl. L, 4H-clomenyl, 4-clomanonyl, oxyndryll, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, 1H-2,3-dihydroisoindolyl, 2,3-dihydrobenzo[f]isoindolyl, 1,2,3,4-tetrahydrobenzo-[g]isoquinolinyl, 1,2,3,4-tetrahydro-benzo[g]isoquinolinyl, clomanyl, isochromanonyl, 2,3-dihydrochromonyl, 1,4-Benzo-dioxanyl, 1,2,3,4-tetrahydro-quinoxalinyl, 5,6-dihydro-quinolyl, 5,6-dihydroiso-quinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro-1H-benzimidazolyl, 4,5-dihydro-benzoxazolyl, 1,4-naphthoquinolyl, 5,6,7,8-tetrahydro-quinolinyl, 5,6,7,8-tetrahydro-isoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl, 4,5,6,7-tetrahydro Ro-1H-benzimidazolyl, 4,5,6,7-tetrahydro-benzoxazolyl, 1H-4-oxa-1,5-diaza-naphthalene-2-onyl, 1,3-dihydroimidizolo-[4,5]-pyridine-2-onyl, 2,3-dihydro-1,4-dinaphtho-quinonyl, 2,3-dihydro-1H-pyrrole[3,4-b]quinolinyl, 1,2,3,4-tetrahydrobenzo[b]-[1,7]naphthilidinyl, 1,2,3,4-tetrahydrobenz[b][1,6-naphthilidinyl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b] Indolyl, 1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indolyl, 2,3-dihydro-1H-pyrrolo-[3,4-b]indolyl, 1H-2,3,4,5-tetrahydro-azepino[3,4-b]indolyl, 1H-2,3,4,5-tetrahydroazepino-[4,3-b]indolyl, 1H-2,3,4,5-tetrahydro-azepino[4,5-b]indolyl, 5,6,7,8-tetrahydro[1,7]naphthilidinyl, 1,2,3,4-tetrahydro-[2,7]naphthilidyl, 2,3-dihydro[1,4]dioxyno[2 ,3-b]pyridyl, 2,3-dihydro[1,4]-dioxyno[2,3-b]pyridyl, 3,4-dihydro-2H-1-oxa[4,6]diazanaphthalenyl, 4,5,6,7-tetrahydro-3H-imidazo-[4,5-c]pyridyl, 6,7-dihydro[5,8]diazanaphthalenyl, 1,2,3,4-tetrahydro[1,5]-naphthilidinyl, 1,2,3,4-tetrahydro[1,6]naphthilidinyl, 1,2,3,4-tetrahydro[1,7]naphthilidinyl, 1,2,3,4-tetrahydro-[1,8]naphthilidinyl or 1,2,3,It contains 4-tetrahydro[2,6]naphthilidinyl. In some embodiments, the heteroaryl group is optionally substituted. In one embodiment, one or more substituents are independently halo, hydroxy, amino, cyano, nitro, alkylamide, acyl, C, 1-6 -alkyl, C 1-6 -Haloalkyl, C 1-6 -Hydroxyalkyl, C 1-6 -aminoalkyl, C 1-6 - Selected from alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl.

[0279] Examples of heteroaryl groups include, but are not limited to, unsubstituted and monosubstituted or disubstituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolidine, cinolin, phthalazine, quinazoline and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, OC 1-6 -alkyl, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl and amino-C 1-6 -It is alkyl.

[0280] In some embodiments, the terms “heteroaryl” and “C5-C6 heteroaryl” are used interchangeably herein.

[0281] As used herein, the terms “halo” and “halogenated,” as interchangeable herein, refer to a halogen atom which is fluorine, chlorine, bromine, or iodine, and are also referred to herein as fluoride, chloride, bromide, and iodide.

[0282] The term "haloalkyl" refers to an alkyl group as defined above, which is further substituted by one or more halides.

[0283] As used herein, the term “ring” refers to a structure closed by any covalent bond. Examples of rings include carbocyclic rings (e.g., aryl and cycloalkyl rings), heterocyclic rings (e.g., heteroaryl and non-aromatic heterocyclic rings), aromatic rings (e.g., aryl and heteroaryl rings), and non-aromatic rings (e.g., cycloalkyl and non-aromatic heterocyclic rings). Rings may be optionally substituted. Rings may form part of a ring system.

[0284] As used herein, the term “ring system” refers to two or more rings that are fused together. The term “condensation” refers to a structure in which two or more rings share one or more bonds.

[0285] The terms "substitution" or "substituent" refer to one, two, three, four, or five substituents, each substituent independently of (C0-C6)alkyl-aryl, (C0-C6)alkyl-heteroaryl, (C0-C6)alkyl-(C3-C8)cycloalkyl, optionally substituted C3-C8 heterocyclyl, halogen, NO2, CN, OH, CONH2, CONR2, CNNR2, CSNR2, CONH-OH, CONH-NH2, NHCOR, NHCSR, NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, SO2R, SOR, -SR, SO2OR, SO2N(R)2, -NHNR2, -NNR, C1 -C6 haloalkyl, optionally substituted C1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkylNR2, C1-C6 alkylSR, CONH(C1-C6 alkyl), CON(C1-C6 alkyl)2, CO2H, CO2R, -OCOR, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, and combinations thereof are selected. general Throughout this application, various embodiments of the invention may be presented in range form. Naturally, range form descriptions are merely for convenience and brevity and should not be interpreted as an inflexible limitation on the scope of the invention. Therefore, range descriptions should be considered to specifically disclose all possible subranges and individual numbers within that range. For example, a description such as the range from 1 to 6 should be considered to be a specifically disclosed subrange, such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, and individual numbers within that range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0286] Whenever a numerical range is indicated herein, it is intended that any cited number (decimal or integer) be included within the indicated range. Herein, the term “range” between the first and second indicated numbers is used interchangeably with the term “range” from the first to the second indicated number, and is intended to include the first and second indicated numbers and all decimals and integers between them.

[0287] As used herein, the term “substantially” means at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, at least 99.9%, or any range or value in between. In some embodiments, the terms “substantially” and “essentially” are used interchangeably herein.

[0288] In some embodiments, the terms “treatment” or “to treat” a disease, disorder, or condition encompass substantial relief of at least one symptom, substantial reduction of its severity, or inhibition of its progression, where substantial is as described herein. Treatment does not necessarily mean a complete cure of the disease, disorder, or condition. For a treatment to be useful, the useful compositions herein only need to reduce the severity of the disease, disorder, or condition, reduce the severity of the symptoms associated therewith, or provide an improvement in the quality of life of the patient or subject.

[0289] As used herein, the term “prevention” of a disease, disorder, or condition encompasses delaying, preventing, suppressing, or inhibiting the onset of the disease, disorder, or condition. As used in accordance with the subject matter currently described, the term “prevention” relates to a preventive process in which the subject is exposed to the currently described active ingredient before the induction or onset of the disease / disorder process. This may be done when an individual has a genetic lineage that shows a predisposition to the development of the disease / disorder to be prevented. For example, this may apply to an individual whose ancestors show a predisposition to a particular type of inflammatory disorder.

[0290] The term "suppression" is used to describe a state where a disease / disorder process has already begun, but the obvious symptoms of that condition have not yet manifested. Therefore, an individual's cells may have the disease / disorder, but the external signs of the disease / disorder are not yet clinically recognized. In either case, the term "preventive measures" can be applied to encompass both prevention and suppression.

[0291] Conversely, the term "treatment" refers to the clinical application of an active agent to combat an existing condition in which the clinical symptoms have already manifested in the patient.

[0292] Unless otherwise stated, adjectives such as “substantially” and “about” modifying a condition or relational feature of one or more features of the embodiments of the present invention are understood to mean that the condition or feature is defined within an acceptable tolerance for the operation of the embodiment for its intended use. Unless otherwise suggested, the term “or” in this specification and the claims is considered inclusive, not exclusive, and indicates at least one or any combination of the items it combines.

[0293] Naturally, where used above and elsewhere in this specification, the terms “a” and “an” refer to “one or more” of the enumerated components. To those skilled in the art, it will be obvious that the use of the singular form includes the plural form unless otherwise stated. Thus, the terms “a,” “an,” and “at least one” are used interchangeably in this application.

[0294] For the better understanding of this instruction and to avoid limiting its scope, unless otherwise indicated, all figures representing quantities, percentages, or proportions, and other numerical values ​​used herein and in the claims, should be understood in all cases to be modified by the term “approximately.” Therefore, unless otherwise indicated, the numerical parameters described herein and in the appended claims are approximations and may vary depending on the desired characteristics to be obtained. At a minimum, each numerical parameter should be interpreted in light of the reported number of significant figures and by applying common rounding techniques.

[0295] In the description and claims of this application, each verb, “comprise,” “include,” and “have,” as well as their conjugations, are used to indicate that one or more objects of the verb are not necessarily a complete list of components, elements, or parts of one or more subjects of the verb.

[0296] As used herein, other terms are defined by their meanings, which are well known in the art.

[0297] As used herein, the term "or" is understood to be inclusive unless specifically stated or evident from the context.

[0298] Throughout this specification and the claims, variations of the word “comprise,” such as “comprises,” or “comprising,” indicate that they include any enumerated integer or set of integers, but not any other integer or set of integers.

[0299] When used herein, and throughout this specification and the claims, variations such as "consists essentially of," "consist essentially of," or "consisting essentially of" indicate the inclusion of any enumerated integer or set of integers, and any enumerated integer or set of integers that does not substantially alter the basic or novel properties of the specified method, structure, or composition.

[0300] As used herein, terms such as “comprises,” “comprising,” “containing,” and “having” mean “includes,” “including,” and similarly, “consisting essentially of” or “consists essentially” have the meanings defined in U.S. Patent Law, and these terms are free form, allowing for more than those listed, and excluding embodiments of the prior art, as long as the basic or novel features of the listed do not change as a result of more than those listed. In one embodiment, the terms “comprises,” “comprising,” and “having” are interchangeable with “consisting.”

[0301] While the present invention has been described in relation to its specific embodiments, it is evident that many alternatives, modifications, and variations are obvious to those skilled in the art. Therefore, it is intended to encompass all such alternatives, modifications, and variations, which fall within the spirit and broad scope of the appended claims.

[0302] All publications, patents, and patent applications described herein are incorporated herein by reference in whole to the same extent that individual publications, patents, or patent applications are specifically and individually indicated as being incorporated herein by reference. Furthermore, any citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art of the present invention. Section headings, insofar as they are used, should not necessarily be construed as limiting. [Examples]

[0303] The various embodiments and aspects of the present invention described above and claimed in the following claims are experimentally supported by the following examples. These examples, together with the above description, illustrate some embodiments of the present invention in a non-limiting manner.

[0304] In general, the nomenclature used herein, and the experimental procedures employed in the present invention, include molecular, biochemical, and microbiological techniques. These techniques are thoroughly described in the literature. material and method Compound 1 was purchased from MayBridge (catalog number HTS12305), and compounds 3 and 7 were purchased from ChemBridge (catalog numbers 7990186 and 37031742, respectively). Compound solutions were prepared by diluting the stock solution (10 mM in 100% DMSO) with water to obtain the desired concentration before use.

[0305] ApoL1-G1-induced T-REx-293 stable cell line is a flag-tagged human G1 cell line. The ApoL1 variant DNA (with an African genome sequence background) was introduced into a pcDNA4 / TO plasmid, which was expressed upon doxycycline addition. Cells were cultured at 37°C in DMEM (Gibco, 41965-039) supplemented with 10% FBS and 1% penicillin-streptomycin.

[0306] To estimate the effects of compounds 1, 3, and 7 on ApoL1-induced cells, a cell viability assay was performed as follows: Cells were seeded at a density of 23K cells per well (96-well plate). Before seeding, the wells were treated with fibronectin (Biological The cells were coated at 37°C for 1 hour using (industries, 03-090-1-05). The following day, the cells were switched over for 16 hours to the same growth medium containing 1 ng / ml doxycycline (Sigma, D9891) along with compounds 1, 3, or 7 at different concentrations. Subsequently, the cells were subjected to a viability assay using the CellTiter-Glo luminescent cell viability assay kit (Promega, G7570) according to the manufacturer's instructions. The luminescence of the plates was read using an Infinite 200 PRO to indicate the number of viable cells. Example 1 APOL1-G1-Induced Cell Survival Assay Doxycycline-induced induction of the ApoL1-G1 variant leads to toxicity in the T-REx-293 cell line. To identify potential inhibitors of ApoL1 toxicity, a cell-based high-throughput screening of 200,000 compounds was performed. Cells were incubated with compound solutions (at a concentration of 10 μM). After detailed screening, three compounds (compounds 1, 3, and 7, whose chemical structures are described above) showed the highest cytoprotective effects without significant cytotoxicity.

[0307] As shown in Figure 1, compounds 1, 3, and 7 showed a concentration-dependent increase in the viability of ApoL1-G1 expressing cells (orange bars). The blue bars represent the viability of cells expressing wild-type ApoL1. Additional compounds will be tested to evaluate their cytoprotective effects. Example 2 Cell proliferation inhibition induced by exemplary compounds of the present invention The inventors performed cytotoxicity assays to evaluate the potential antiproliferative effects of the exemplary compounds of the present invention.

[0308] T-REx-293 cells were seeded at a density of 25K cells / well on fibronectin in a 96-well plate and grown in DMEM containing 10% FBS and 1% P / S medium. 24 hours after seeding, the medium was replaced with fresh medium containing the test compound (KS-1, KS-2, or KS-8) at a concentration of 5–10 μM. Untreated cells were used as a negative control. After 16 hours, one plate of cells was taken for cell viability testing using the Cell-Titer Glo reagent (Promega). Cells on the other plate were imaged using the Incucyte ZOOM system.

[0309] The exemplary compounds of the present invention that were tested were as follows:

[0310] [ka]

[0311] The results are summarized in Figure 2 (at a concentration of 10 μM). As can be seen from the graph in Figure 2, the cell number determined via the luminescence signal (relative light units, RLU) was lower for cells that proliferated in the presence of compounds KS-1, KS-2, and KS-8. Therefore, the compounds tested significantly reduced the viability and / or proliferation rate of immortalized cells. It is anticipated that the compounds of the present invention can be used as potent antiproliferative agents.

[0312] Although the present invention has been described in particular, those skilled in the art will understand that many variations and modifications are possible. Therefore, the present invention should not be construed as being limited to the embodiments described in particular, and the scope and concepts of the present invention will be more readily understood by referring to the following claims. The present invention provides, for example, the following items: (Item 1) A method for inhibiting or reducing ApoL1-associated cytotoxicity in a subject requiring such inhibition, comprising administering a therapeutically effective amount of a compound comprising any pharmaceutically acceptable salt or tautomer thereof, wherein the compound is of formula 1: [ka] Or formula 1.2: [ka] It is expressed by, in the formula, Each of R, R1, and R2 independently contains or does not contain a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, hydrogen, a haloalkyl, a mercaptoalkyl, a heteroatom, a hydroxyalkyl, an aminoalkyl, a nitroalkyl, an alkyl sulfate, or a substituted or unsubstituted C1-C10 alkyl; Alternatively, R1 and R2 are interconnected to form a ring; Each R' independently corresponds to (C0-C6)alkyl-aryl, (C0-C6)alkyl-heteroaryl, (C0-C6)alkyl-(C3-C8)cycloalkyl, optionally substituted C3-C8 heterocyclyl, halogen, -NO2, -CN, -OH, -CONH2, -CONR”2, -CNNR”2, -CSNR”2, -CONH-OH, -CONH-NH2, -NHCOR”, -NHCSR”, -NHCNR”, -NC(=O)OR”, -NC(=O)NR”, -NC(=S)OR”, -NC(=S)NR”, -SO2R”, -SOR”, -SR”, -SO2OR”, -SO2N(R)2, -NHNR2, -NNR, C1-C 10 Haloalkyl, optionally substituted C1-C 10 Alkyl, -NH2, -NH(C1-C 10 Alkyl), -N(C1-C 10 Alkyl)2, C1-C 10 Alkyl, C1-C 10 Haloalkoxy, Hydroxy(C1-C) 10 Alkyl), Hydroxy(C1-C 10 Alkoxy), Alkoxy (C1-C 10 Alkyl), alkoxy (C1-C 10 Alkyl(alkoxy), C1-C 10Alkyl-NR"2, C1-C 10 Alkyl-SR,-CONH(C1-C 10 Alkyl), -CON(C1-C 10 Includes alkyl)2, -CO2H, -CO2R'', -OCOR'', -OCOR'', -OC(=O)OR'', -OC(=O)NR'', -OC(=S)OR'', -OC(=S)NR'', and any combination thereof; R'' is an optionally substituted C1-C 10 Selected from alkyl and hydrogen; Each X1 independently comprises methylene, heteroatoms, -OR'', -NR''R'', -SR'', cyano, alkyl, carboxyl derivatives, nitro, sulfonate, sulfonyl, or hydrogen; Each X independently contains or does not contain a methylene or heteroatom; [ka] This represents a single bond or a double bond; Each n is between 0 and 10; A method for inhibiting or reducing ApoL1-related cytotoxicity in the subject. (Item 2) The method according to item 1, wherein inhibiting or reducing ApoL1-related cytotoxicity prevents or treats ApoL1-related kidney disease. (Item 3) The method according to either item 1 or 2, wherein the ApoL1-related cytotoxicity is ApoL1 mutant-related cytotoxicity. (Item 4) The method according to any one of items 1 to 3, wherein the heteroatom is independently selected from the group consisting of O, N, NH, and S. (Item 5) The aforementioned compound is given by formula 1C: [ka] It is expressed by, in the formula, Each R independently comprises a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; X is either N or CH; X1 is O or OH, as described in any one of items 1-4. (Item 6) The aforementioned compound is given by formula 1D: [ka] The method according to any one of items 1 to 5, represented by the formula, where each R1 independently comprises a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, hydrogen, a haloalkyl, a mercaptoalkyl, a heteroatom, a hydroxyalkyl, an aminoalkyl, a nitroalkyl, an alkyl sulfate, a substituted or unsubstituted C1-C10 alkyl, or any combination thereof. (Item 7) The method according to item 6, wherein each R1 is a substituted or unsubstituted C1-C10 alkyl group, and each R' is a halogen or absent. (Item 8) The method according to any one of items 1 to 6, wherein the compound is as follows: [ka] (Item 9) The aforementioned compound is given by formula 2: [ka] The method according to any one of items 1 to 5, represented by the formula, where R3 represents a substituent independently comprising at least one of the following: C1-C10 alkyl, C1-C10 branched alkyl, substituted C1-C10 alkyl, halo, hydroxy, amino, mercapto, cyano, carboxylic acid derivative, nitro, guanidine, aryl, heteroaryl, benzyl, alkalyl, cycloalkyl, heterocyclyl, heteroatom, or hydrogen. (Item 10) The method according to any one of items 1 to 5 and 9, wherein the compound is represented by formula 3. [ka] (Item 11) The aforementioned compound is given by formula 4.1: [ka] It is expressed by, in the formula, n is between 0 and 5; Each R3 is [ka] A represents a substituent that independently contains or does not contain R3; where A represents an optionally substituted aliphatic (C3-C20) ring, an optionally substituted aromatic (C5-C20) ring, or H; The method according to any one of items 1-5, 9, and 10, wherein R4 represents a substituent independently comprising hydrogen, a C1-C10 alkyl, a C1-C10 branched alkyl, a substituted C1-C10 alkyl, a halo, nitro, hydroxy, mercapto, amino, cyano, and carboxyl derivative, or any combination thereof. (Item 12) R3 became independent, [ka] The method described in any one of items 9 to 11, selected from the group including, where each X1 is independently selected from N and CH. (Item 13) The method according to item 12, wherein each X is independently selected from the group comprising -N-, -NH, -O-, and -S-. (Item 14) The method according to any one of items 9 to 13, wherein the compound is as follows: [ka] (Item 15) The compound has formulas 7A to 7C: [ka] The method according to any one of items 1 to 5, represented by any one of the formulas, where each X2 is independently selected from the group comprising methylene, heteroatom, alkyl, halo, alkoxy, hydroxy, amino, thioalkoxy, mercapto, cyano, carboxylic acid derivative, nitro, guanidine, heteroatom, aryl, heteroaryl, benzyl, alkylaryl, cycloalkyl, heterocyclyl, bond, and hydrogen, or any combination thereof, where each X1 is O. (Item 16) The method according to item 15, wherein the substituted C1-C10 alkyl comprises a substituent selected from the group comprising halo, mercapto, hydroxy, amino, carboxyl derivatives, cyano, nitro, sulfonate, and sulfonyl, or any combination thereof. (Item 17) The method described in item 1, wherein the compound is represented by formula 1.3. [ka] (Item 18) The method according to item 17, wherein the compound is as follows: [ka] (Item 19) Formula 6D: [ka] A compound represented by the formula, in which, R' represents (C0-C6)alkyl-aryl, (C0-C6)alkyl-heteroaryl, (C0-C6)alkyl-(C3-C8)cycloalkyl, optionally substituted C3-C8 heterocyclyl, halogen, -NO2, -CN, -OH, -CONH2, -CONR”2, -CNNR”2, -CSNR”2, -CONH-OH, -CONH-NH2, -NHCOR”, -NHCSR”, -NHCNR”, -NC(=O)OR”, -NC(=O)NR”, -NC(=S)OR”, -NC(=S)NR”, -SO2R”, -SOR”, -SR”, -SO2OR”, -SO2N(R)2, -NHNR2, -NNR, C1-C 10 Haloalkyl, optionally substituted C1-C 10 Alkyl, -NH2, -NH(C1-C 10 Alkyl), -N(C1-C 10 Alkyl)2, C1-C 10 Alkyl, C1-C 10 Haloalkoxy, Hydroxy(C1-C) 10 Alkyl), Hydroxy(C1-C 10 Alkoxy), Alkoxy (C1-C 10 Alkyl), alkoxy (C1-C 10 Alkyl(alkoxy), C1-C 10 Alkyl-NR"2, C1-C 10 Alkyl-SR,-CONH(C1-C 10 Alkyl), -CON(C1-C 10 Includes alkyl)2, -CO2H, -CO2R'', -OCOR'', -OCOR'', -OC(=O)OR'', -OC(=O)NR'', -OC(=S)OR'', -OC(=S)NR'', and any combination thereof; X is either CH or N; n is between 0 and 10; A compound in which each A independently represents a (C3-C20)cycloalkyl, (C3-C20)heterocyclyl, aryl, or heteroaryl, and at least one A is a (C3-C20)heterocyclyl or heteroaryl. (Item 20) The compound is the compound described in item 19, represented by formula 6E. [ka] (Item 21) Compounds described in either item 19 or 20, one or more of the following compounds: [ka] A compound comprising any salt thereof. (Item 22) (i) a compound described in any one of items 19 to 21, a pharmaceutically acceptable salt thereof, or both, and (ii) a pharmaceutically acceptable carrier, comprising a pharmaceutical composition.

Claims

[Claim 1] The invention described in the present specification.

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