Methods for treating APOL-1-dependent focal segmental glomerulosclerosis

Abstract

This application describes methods for inhibiting APOL1 and treating APOL1-mediated diseases, comprising administering Compound I and / or a pharmaceutically acceptable salt thereof. This application also describes pharmaceutical compositions comprising Compound I and / or a pharmaceutically acceptable salt thereof. JPEG2023515668000016.jpg5256

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 986,096, filed March 6, 2020, the contents of which are incorporated by reference in their entirety. The present disclosure is directed to methods of treating APOL1-mediated diseases, including APOL1-mediated kidney diseases such as APOL1-mediated focal segmental glomerulosclerosis (FSGS) and / or APOL1-mediated non-diabetic kidney disease (NDKD), comprising administering Compound I, a pharmaceutically acceptable salt thereof, and / or a deuterated derivative of Compound I or its salt. The present disclosure also provides pharmaceutical compositions comprising therapeutic dosages of Compound I, a deuterated derivative of Compound I, and a pharmaceutically acceptable salt of Compound I or its deuterated derivative. [Background technology]

[0002] NDKD is a kidney disease involving damage to podocytes or the glomerular vascular bed that is not attributable to diabetes. FSGS is a rare kidney disease with an estimated global incidence of 0.2–1.1 / 100,000 / year. FSGS and NDKD are caused by damage to podocytes, which are part of the glomerular filtration barrier, resulting in proteinuria. Patients with proteinuria are at high risk for developing end-stage kidney disease (ESKD) and proteinuria-related complications, such as infection or thromboembolic events. There are no standardized treatment regimens or approved medications for FSGS or NDKD. Current treatment options for patients with FSGS and proteinuria include high-dose corticosteroids, which induce remission of proteinuria in a minority of patients. Current treatment options for NDKD are fixed on blood pressure control and blockade of the renin-angiotensin system.

[0003] FSGS and NDKD can be divided into distinct subpopulations based on the underlying etiology. One homogeneous subpopulation of FSGS is characterized by independent common sequence variants in the apolipoprotein L1 (APOL1) gene, designated G1 and G2, which are referred to as "APOL1 risk alleles." G1 encodes a correlated pair of nonsynonymous amino acid changes (S342G and I384M), G2 encodes a two-amino acid deletion (N388del:Y389del) near the C-terminus of the protein, and G0 is the ancestral (low-risk) allele. Distinct NDKD phenotypes are also observed in patients with APOL1 genetic risk variants. In both APOL1-mediated FSGS and NDKD, higher levels of proteinuria and more accelerated loss of renal function occur in patients with two risk alleles compared to patients with the same disease who have no or only one APOL1 genetic risk variant.

[0004] The APOL1 gene is expressed in multiple organs in humans, including the liver and kidney. APOL1 protects against parasitic infection with Trypanosoma brucei brucei (Tbbrucei). APOL1 is endocytosed by Tbbrucei and transported to lysosomes, where it inserts into the lysosomal membrane, forming a pore that leads to the swelling and death of the parasite. The ability to lyse Tbbrucei is shared by all three APOL1 variants (G0, G1, and G2). APOL1 G1 and G2 variants confer additional protection against parasite species that have evolved serum resistance-associated proteins (SRA) that inhibit APOL1 G0, while these species cause sleeping sickness. The G1 and G2 variants escape inhibition by SRA, with G1 conferring additional protection against Tbgambiense (which causes West African sleeping sickness) and G2 conferring additional protection against Tbrhodesiense (which causes East African sleeping sickness).

[0005] In the kidney, APOL1 is expressed in podocytes, endothelial cells (including glomerular endothelial cells), and some tubular cells. Podocyte-specific expression of APOL1 G1 or G2 (but not G0) in transgenic mice induces structural and functional changes, including albuminuria, decreased renal function, podocyte abnormalities, and glomerular sclerosis. Consistent with these data, APOL1 G1 and G2 variants play a causative role in inducing FSGS and accelerating its progression in humans. Individuals with APOL1 risk alleles (i.e., homozygous or compound heterozygous for the APOL1 G1 or APOL1 G2 allele) are at increased risk of developing FSGS and, if they do develop FSGS, are at risk for a rapid decline in renal function. Therefore, inhibition of APOL1 may have a positive effect in individuals carrying the APOL1 risk allele. Summary of the Invention [Means for solving the problem]

[0006] 3-[5,7-Difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide (Compound I) is a small molecule inhibitor of APOL1-induced cell death and lysis of Tbbrucei. Compound I can be depicted as having the following structure: [ka]

[0007] Compound I, its method of preparation, and physicochemical data are disclosed (as "Compound 2") in co-pending U.S. Application No. 16 / 717,099 and PCT International Application No. PCT / US2019 / 066746, both of which are incorporated herein by reference for this disclosure.

[0008] The present disclosure provides methods for inhibiting APOL1-induced cell death and treating APOL1-mediated diseases, including, for example, APOL1-mediated renal diseases such as FSGS and / or NDKD, by administering a therapeutically effective amount of Compound I, a deuterated derivative of Compound I, and / or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound I or a deuterated derivative of Compound I. The methods and pharmaceutical compositions disclosed herein provide treatment for individuals who have APOL1-mediated renal diseases associated with one or more APOL1 risk alleles and who may or may not have proteinuria (i.e., a protein-to-creatinine ratio of greater than 3 g / g for individuals with nephrotic-range proteinuria; a protein-to-creatinine ratio of greater than 0.15 g / g to less than 3.0 g / g for individuals with sub-nephrotic-range proteinuria). The methods and pharmaceutical compositions disclosed herein provide treatment for individuals with APOL1-mediated kidney disease associated with one or more APOL1 risk alleles, with or without nephrotic syndrome-range proteinuria.

[0009] In some embodiments, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative of Compound I.

[0010] In some embodiments, the present disclosure relates to pharmaceutical compositions comprising Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative of Compound I, which may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier. In some embodiments, the present disclosure provides methods of treating APOL1-mediated kidney disease, including FSGS and / or NDKD, comprising administering Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative of Compound I, optionally as part of a pharmaceutical composition comprising at least one additional active ingredient, to a subject in need thereof. [Brief explanation of the drawings]

[0011] [Figure 1] 1 depicts the XRPD diffractogram of Compound I Form A. [Figure 2] 1 depicts the solid state 13C NMR spectrum of Compound I Form A. DETAILED DESCRIPTION OF THE INVENTION

[0012] definition As used throughout this disclosure, "Compound I" refers to 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide, which can be depicted as having the following structure: [ka] Compound I can be in the form of a deuterated derivative, or a pharmaceutically acceptable salt of the compound or deuterated derivative. In some embodiments, Compound I is administered in crystalline or substantially pure crystalline Form A.

[0013] As used herein, the term "APOL1" refers to the apolipoprotein L1 protein, and the term "APOL1" refers to the apolipoprotein L1 gene.

[0014] As used herein, the term "FSGS" means focal segmental glomerulosclerosis, a disease of podocytes (glomerular visceral epithelial cells) that causes proteinuria and progressive decline in kidney function and is associated with two common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del).

[0015] As used herein, the term "NDKD" refers to non-diabetic kidney disease, which is a kidney disease associated with damage to the podocyte or glomerular vascular bed that is not caused by diabetes and is associated with two common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del). This includes, but is not limited to, hypertensive kidney disease, lupus, minimal change, membranous nephropathy, steroid-resistant or steroid-sensitive nephrotic syndrome, and renal allograft dysfunction. In some embodiments, it includes chronic kidney disease in non-diabetic patients with hypertension and proteinuria of 0.2 g / g or greater, but without chronic kidney disease caused by infection, malignancy, obstruction, or autoimmune disorders.

[0016] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0017] As used herein, the terms "treatment," "treating," and the like generally refer to the improvement of APOL1-mediated renal diseases, including, but not limited to, FSGS and / or NDKD, or APOL1-mediated diseases, including one or more symptoms, and / or the reduction of the severity of FSGS and / or NDKD or one or more symptoms thereof in a subject. As used herein, "treatment" and its cognates include, but are not limited to, complete or partial remission, a lower risk of renal failure (e.g., ESRD), and disease-related complications (e.g., edema, susceptibility to infection, or thromboembolic events). The improvement or reduction of the severity of any of these symptoms can be easily assessed according to methods and techniques known in the art or subsequently developed.

[0018] As used herein, a "therapeutically effective" amount of Compound I refers to the amount of Compound I, a deuterated derivative of Compound 1, or a pharmaceutically acceptable salt of Compound I or its deuterated derivative that produces the desired effect (e.g., amelioration of symptoms of APOL1-mediated kidney disease, reduction of the severity of APOL1-mediated kidney disease or symptoms of APOL1-mediated kidney disease, and / or reduction of the progression of APOL1-mediated kidney disease or symptoms of APOL1-mediated kidney disease, amelioration of symptoms of FSGS and / or NDKD, reduction of the severity of FSGS and / or NDKD or symptoms of FSGS and / or NDKD, and / or slowing or reducing the progression of FSGS and / or NDKD or symptoms of FSGS and / or NDKD). The exact amount of a therapeutically effective dose depends on the purpose of the treatment and can be ascertained by one skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding). In some embodiments, the therapeutically effective dose of Compound I is between 2 mg and 250 mg. Other suitable therapeutically effective doses are disclosed herein.

[0019] As used herein, "ULN" means "upper normal limit."

[0020] As used herein, the term "in combination with," when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of the two or more compounds, agents, or active pharmaceutical ingredients to a patient before, simultaneously with, or after each other.

[0021] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having the same chemical structure unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that isotopic variation may exist among the constituent atoms of the molecule. Thus, it will be apparent to one of skill in the art that a compound represented by a particular chemical structure containing a deuterium atom as shown also contains a lesser amount of isotopologues bearing hydrogen atoms at one or more of the designated deuterium positions in the structure. The relative amount of such isotopologues in the compounds of the present disclosure will depend on several factors, including the isotopic purity of the reagents used to make the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as noted above, the relative amount of such isotopologues overall will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitution overall will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0022] As used herein, the terms "crystalline form" and "form" refer interchangeably to a crystal structure (or polymorph) having a specific molecular packing arrangement within a crystal lattice. Crystalline forms can be identified and distinguished from one another by one or more characterization techniques, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, and solid-state nuclear magnetic resonance (SSNMR). Thus, as used herein, the term "crystalline Form A of Compound I" refers to a unique crystalline form that can be identified and distinguished from other forms by one or more characterization techniques, including, for example, XRPD, single crystal X-ray diffraction, and SSNMR. In some embodiments, Compound I crystalline Form A is characterized by an X-ray powder diffractogram having one or more signals at one or more specific 2-theta values ​​(°2θ).

[0023] As used herein, the term "SSNMR" refers to the analytical characterization method of solid-state nuclear magnetic resonance. SSNMR spectra can be recorded at ambient conditions on any magnetically active isotope present in the sample. Typical examples of active isotopes for small molecule active pharmaceutical ingredients include: 1 H, 2 H, 13 C. 19 F, 31 P, 15 N, 14 N, 35 Cl, 11 B. 7 Li, 17 O. 23 Na, 79 Br, and 195 Contains Pt.

[0024] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded at ambient conditions in transmission or reflection geometry using a diffractometer.

[0025] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," and "XRPD pattern" refer interchangeably to an experimentally obtained pattern that plots signal position (on the abscissa) against signal intensity on the ordinate. For amorphous materials, the X-ray powder diffractogram may include one or more broad signals; for crystalline materials, the X-ray powder diffractogram may include one or more signals, each identified by its angular value, measured in degrees 2θ (°2θ), depicted on the abscissa of the X-ray powder diffractogram, which may be expressed as "signal at ... degrees 2-theta," "signal at a 2-theta value of ...," and / or "signal at at least ... 2-theta values ​​selected from ...."

[0026] As used herein, a "signal" or "peak" refers to a point in an XRPD pattern where the intensity, as measured in counts, is at a local maximum. Those skilled in the art will recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may not be apparent to the naked eye, for example. Indeed, those skilled in the art will recognize that several art-recognized methods are capable and suitable for determining whether a signal is present in a pattern, such as Rietveld refinement.

[0027] As used herein, "signal at ... degrees 2-theta," "signal at a 2-theta value [ ] of ...," and / or "signal at at least ... 2-theta values ​​selected from ..." refer to the X-ray reflection positions measured and observed in an X-ray powder diffraction experiment (°2θ).

[0028] The reproducibility of the angle values ​​is within ±0.2 degrees 2-theta, i.e., the angle value can be at the listed angle value +0.2 degrees 2-theta, angle value -0.2 degrees 2-theta, or any value between those two endpoints (angle value +0.2 degrees 2-theta and angle value -0.2 degrees 2-theta).

[0029] The terms "signal intensity" and "peak intensity" refer interchangeably to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect relative signal intensity or peak intensity include sample thickness and preferred orientation (e.g., crystalline particles are not randomly distributed).

[0030] As used herein, the term "X-ray powder diffractogram with signals at ... 2-theta values" refers to an XRPD pattern containing X-ray reflection positions (°2θ) as measured and observed in an X-ray powder diffraction experiment.

[0031] As used herein, an X-ray powder diffractogram is substantially similar to one in a particular view if at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms overlap. In determining "substantial similarity," one skilled in the art will understand that even with the same crystalline form, there may be variations in intensity and / or signal positions in XRPD diffractograms. Thus, one skilled in the art will understand that a signal maximum (in degrees two-theta (°2θ) as referred to herein) in an XRPD diffractogram generally means that the reported value is ±0.2 degrees two-theta, an art-recognized variance of the reported value.

[0032] As used herein, an SSNMR spectrum is "substantially similar to that in a particular figure" if at least 90% of the signals in the two overlapping spectra overlap, such as at least 95%, at least 98%, or at least 99%. In determining "substantial similarity," those skilled in the art will understand that even for the same crystalline form, there may be variations in the intensity and / or signal position of SSNMR spectra. Thus, those skilled in the art will understand that the signal maxima in SSNMR spectra (in ppm) referred to herein generally mean that the reported values ​​are within ±0.2 ppm of the reported value, subject to art-recognized variances.

[0033] As used herein, a crystalline form is "substantially pure" if it accounts for 90% or more by weight of the sum of all solid forms in a sample, as determined by methods known in the art, such as quantitative XRPD. In some embodiments, a solid form is "substantially pure" if it accounts for 95% or more by weight of the sum of all solid forms in a sample. In some embodiments, a solid form is "substantially pure" if it accounts for 99% or more by weight of the sum of all solid forms in a sample.

[0034] As used herein, the term " pharmaceutically acceptable salt " refers to the salt form of the compound of the present disclosure, wherein the salt is non-toxic.The pharmaceutically acceptable salt of the compound of the present disclosure includes those derived from suitable inorganic and organic acids and bases.Pharmaceutically acceptable salts are well known in the art.For example, S.M. Berge, et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19.

[0035] Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of that article, reproduced below, provides the following pharmaceutically acceptable salts: [Table 1]

[0036] Non-limiting examples of pharmaceutically acceptable acid salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; and salts formed by using other methods used in the art, such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1~4(Alkyl) 4 salts are also included. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable, non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0037] As used herein, "deuterated derivative of Compound I" refers to a form of Compound I in which at least one hydrogen atom is replaced by a deuterium atom. It will be recognized that some variation in natural isotopic abundance occurs in synthesized compounds depending on the origin of the chemicals used in synthesis. Despite this variation, the concentration of naturally abundant stable hydrogen isotopes is small and immaterial compared to the degree of stable isotopic substitution of the deuterated derivatives described herein. Therefore, unless otherwise stated, when referring to a "deuterated derivative" of a compound of the present invention, at least one hydrogen atom is replaced with deuterium in an amount significantly exceeding its natural isotopic abundance (typically about 0.015%). In some embodiments, deuterated derivatives of the present disclosure have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation).

[0038] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0039] In some embodiments, the present disclosure is also directed to methods of treatment using isotopically labeled compounds of Compound I, which in some embodiments are referred to as Compound I or a pharmaceutically acceptable salt thereof, the formulas and variations of such compounds and salts being each and independently as described above or any other embodiment described above, provided that one or more atoms therein are replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the normally naturally occurring atom (isotopically labeled). Examples of isotopes that are commercially available and suitable for the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Contains Cl.

[0040] Isotopically labeled compounds and salts can be used in a number of beneficial ways. They can be suitable for various types of assays, such as drug and / or substrate tissue distribution assays. For example, tritium ( 3 H) and / or carbon-14 ( 14 C) labeled compounds are particularly useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability. For example, deuterium ( 2 H) Labeled items are 2 H-labeled compounds are therapeutically useful with potential therapeutic advantages over non-H-labeled compounds. 2H) Labeled compounds and salts can have higher metabolic stability than non-isotopically labeled compounds due to the kinetic isotope effect described below. Higher metabolic stability directly translates into increased in vivo half-life or lower dosage, which may be desired. Typically, isotopically labeled compounds and salts can be prepared by following the procedures disclosed in the synthetic schemes and related descriptions in the exemplary and preparation sections of this text, replacing non-isotopically labeled reactants with readily available isotopically labeled reactants.

[0041] In some embodiments, isotopically labeled compounds and salts contain deuterium ( 2 In some particular embodiments, isotopically labeled compounds and salts are deuterium (H) labeled compounds. 2 H) labeled in which one or more hydrogen atoms have been replaced by deuterium. In chemical structures, deuterium is represented as "D."

[0042] deuterium( 2 H) labeled compounds and salts are labeled with deuterium ( 2 H) can undergo altered oxidative metabolic rates relative to unlabeled compounds. The primary kinetic isotope effect is a change in the rate of a chemical reaction resulting from the exchange of isotopes, which in turn is caused by a change in the ground state energy required for covalent bond formation after this isotope exchange. Exchange of a heavier isotope usually results in a lowering of the ground state energy of the chemical bond, thus reducing the rate-limiting bond breaking. If bond breaking occurs at or near a saddle point region along the coordination of a multi-product reaction, the product distribution ratio can be substantially altered. For example, if deuterium is attached to a carbon atom at a non-exchangeable position, k M / k DA rate difference of 2 to 7 is typical. For further explanation, see S.L. Harbeson and R.D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, which is incorporated herein by reference.

[0043] The terms "about" and "approximately," when used in conjunction with a dose, amount, or weight percent of a component of a composition or dosage form, include a particular dose, amount, or weight percent value, or a range of doses, amounts, or weight percents, recognized by one of ordinary skill in the art, that provides a pharmacological effect comparable to that obtained by the particular dose, amount, or weight percent. The terms "about" and "approximately" can also refer to an acceptable error for a particular value determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In some embodiments, the terms "about" and "approximately" mean within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range.

[0044] Those skilled in the art will recognize that when an amount of "a compound or a deuterated derivative thereof, or a pharmaceutically acceptable salt of the compound or a deuterated derivative thereof" is disclosed, the amount of a pharmaceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. Note that the disclosed amounts of compounds or their pharmaceutically acceptable salts herein are based on their free base form. For example, "100 mg of at least one compound selected from Compound I and a pharmaceutically acceptable salt thereof" includes 100 mg of Compound I and a concentration of a pharmaceutically acceptable salt of Compound I equivalent to 100 mg of Compound I.

[0045] As used herein, the administration of a "daily" amount of Compound I or a deuterated derivative or a pharmaceutically acceptable salt thereof refers to the total amount administered in one day, but does not limit the frequency of administration per day. The daily amount administered to a patient can be administered once or multiple times per day, such as twice daily or three times daily (wherein each multiple administration includes administering an amount of Compound I or a deuterated derivative or a pharmaceutically acceptable salt thereof that is less than the "daily" amount, given that the "daily" amount refers to the total amount administered in one day). Each administration of Compound I or a deuterated derivative or a pharmaceutically acceptable salt thereof can consist of administering Compound I or a deuterated derivative or a pharmaceutically acceptable salt thereof in the form of a single composition (e.g., a single dosage, such as a single tablet or a single capsule) or in the form of multiple compositions (e.g., multiple dosages, such as multiple (i.e., two or more) tablets and / or capsules).

[0046] In some embodiments, Compound I used in the methods and compositions of the invention is in crystalline form Form A. In some embodiments, Compound I is in substantially pure crystalline Form A. In some embodiments, Compound I Form A is characterized by an X-ray powder diffractogram substantially similar to that in Figure 1. In some embodiments, Compound I Form A is characterized by an X-ray powder diffractogram having signals at at least two 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 26.3±0.2, 26.7±0.2, and 28.6±0.2. In some embodiments, compound I Form A is characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 26.3±0.2, 26.7±0.2, and 28.6±0.2. In some embodiments, compound I Form A is characterized by an X-ray powder diffractogram having signals at at least four 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 26.3±0.2, 26.7±0.2, and 28.6±0.2. In some embodiments, compound I Form A is characterized by an X-ray powder diffractogram having signals at at least five 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 26.3±0.2, 26.7±0.2, and 28.6±0.2. In some embodiments, compound I Form A is characterized by an X-ray powder diffractogram having signals at at least six 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 26.3±0.2, 26.7±0.2, and 28.6±0.2.In some embodiments, compound I Form A is characterized by an X-ray powder diffractogram having signals at at least seven 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 26.3±0.2, 26.7±0.2, and 28.6±0.2. In some embodiments, compound I Form A is characterized by an X-ray powder diffractogram having signals at at least eight 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 26.3±0.2, 26.7±0.2, and 28.6±0.2. In some embodiments, Compound I Form A is characterized by an X-ray powder diffractogram having signals at the following 2-theta values: 9.5±0.2, 13.2±0.2, 14.4±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 26.3±0.2, 26.7±0.2, and 28.6±0.2.

[0047] In some embodiments, Compound I Form A used in methods and compositions of the invention is characterized by an X-ray powder diffractogram having a signal at at least one 2-theta value selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 16.1±0.2, 17.7±0.2, 18.8±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 20.7±0.2, 21.4±0.2, 21.7±0.2, 22.4±0.2, 22.9±0.2, 23.3±0.2, 24.0±0.2, 26.3±0.2, 26.7±0.2, 27.1±0.2, 27.7±0.2, 28.6±0.2, 29.1±0.2, and 29.5±0.2. In some embodiments, Compound I Form A is characterized by an X-ray powder diffractogram having signals at at least two 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 16.1±0.2, 17.7±0.2, 18.8±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 20.7±0.2, 21.4±0.2, 21.7±0.2, 22.4±0.2, 22.9±0.2, 23.3±0.2, 24.0±0.2, 26.3±0.2, 26.7±0.2, 27.1±0.2, 27.7±0.2, 28.6±0.2, 29.1±0.2, and 29.5±0.2. In some embodiments, Compound I Form A is characterized by an X-ray powder diffractogram having signals at at least three 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 16.1±0.2, 17.7±0.2, 18.8±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 20.7±0.2, 21.4±0.2, 21.7±0.2, 22.4±0.2, 22.9±0.2, 23.3±0.2, 24.0±0.2, 26.3±0.2, 26.7±0.2, 27.1±0.2, 27.7±0.2, 28.6±0.2, 29.1±0.2, and 29.5±0.2.In some embodiments, Compound I Form A is characterized by an X-ray powder diffractogram having signals at at least four 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 16.1±0.2, 17.7±0.2, 18.8±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 20.7±0.2, 21.4±0.2, 21.7±0.2, 22.4±0.2, 22.9±0.2, 23.3±0.2, 24.0±0.2, 26.3±0.2, 26.7±0.2, 27.1±0.2, 27.7±0.2, 28.6±0.2, 29.1±0.2, and 29.5±0.2. In some embodiments, Compound I Form A is characterized by an X-ray powder diffractogram having signals at at least five 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 16.1±0.2, 17.7±0.2, 18.8±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 20.7±0.2, 21.4±0.2, 21.7±0.2, 22.4±0.2, 22.9±0.2, 23.3±0.2, 24.0±0.2, 26.3±0.2, 26.7±0.2, 27.1±0.2, 27.7±0.2, and 28.6±0.2. In some embodiments, Compound I Form A is characterized by an X-ray powder diffractogram having signals at at least six 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 16.1±0.2, 17.7±0.2, 18.8±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 20.7±0.2, 21.4±0.2, 21.7±0.2, 22.4±0.2, 22.9±0.2, 23.3±0.2, 24.0±0.2, 26.3±0.2, 26.7±0.2, 27.1±0.2, 27.7±0.2, and 28.6±0.2.In some embodiments, Compound I Form A is characterized by an X-ray powder diffractogram having signals at at least seven 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 16.1±0.2, 17.7±0.2, 18.8±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 20.7±0.2, 21.4±0.2, 21.7±0.2, 22.4±0.2, 22.9±0.2, 23.3±0.2, 24.0±0.2, 26.3±0.2, 26.7±0.2, 27.1±0.2, 27.7±0.2, and 28.6±0.2. In some embodiments, Compound I Form A is characterized by an X-ray powder diffractogram having signals at at least eight 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 16.1±0.2, 17.7±0.2, 18.8±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 20.7±0.2, 21.4±0.2, 21.7±0.2, 22.4±0.2, 22.9±0.2, 23.3±0.2, 24.0±0.2, 26.3±0.2, 26.7±0.2, 27.1±0.2, 27.7±0.2, and 28.6±0.2. In some embodiments, Compound I Form A is characterized by an X-ray powder diffractogram having signals at at least nine 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 16.1±0.2, 17.7±0.2, 18.8±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 20.7±0.2, 21.4±0.2, 21.7±0.2, 22.4±0.2, 22.9±0.2, 23.3±0.2, 24.0±0.2, 26.3±0.2, 26.7±0.2, 27.1±0.2, 27.7±0.2, and 28.6±0.2.In some embodiments, Compound I Form A is characterized by an X-ray powder diffractogram having signals at at least 10 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 16.1±0.2, 17.7±0.2, 18.8±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 20.7±0.2, 21.4±0.2, 21.7±0.2, 22.4±0.2, 22.9±0.2, 23.3±0.2, 24.0±0.2, 26.3±0.2, 26.7±0.2, 27.1±0.2, 27.7±0.2, and 28.6±0.2.

[0048] In some embodiments, Compound I used in the methods and compositions of the invention is Compound I Form A. In some embodiments, Compound I used in the methods and compositions of the invention is substantially pure Form A.

[0049] In some embodiments, Compound I Form A used in the methods and compositions of the invention has a signal at at least one ppm value selected from 178.7±0.2 ppm, 154.4±0.2 ppm, 127.8±0.2 ppm, 125.2±0.2 ppm, 102.0±0.2 ppm, 59.3±0.2 ppm, 38.9±0.2 ppm, and 24.4±0.2 ppm. 13 In some embodiments, Compound I Form A is characterized by a C NMR spectrum. In some embodiments, Compound I Form A has signals at at least two ppm values ​​selected from 178.7±0.2 ppm, 154.4±0.2 ppm, 127.8±0.2 ppm, 125.2±0.2 ppm, 102.0±0.2 ppm, 59.3±0.2 ppm, 38.9±0.2 ppm, and 24.4±0.2 ppm. 13 In some embodiments, Compound I Form A is characterized by a C NMR spectrum. In some embodiments, Compound I Form A has signals at at least three ppm values ​​selected from 178.7±0.2 ppm, 154.4±0.2 ppm, 127.8±0.2 ppm, 125.2±0.2 ppm, 102.0±0.2 ppm, 59.3±0.2 ppm, 38.9±0.2 ppm, and 24.4±0.2 ppm.13 In some embodiments, Compound I Form A is characterized by a C NMR spectrum. In some embodiments, Compound I Form A has signals at at least four ppm values ​​selected from 178.7±0.2 ppm, 154.4±0.2 ppm, 127.8±0.2 ppm, 125.2±0.2 ppm, 102.0±0.2 ppm, 59.3±0.2 ppm, 38.9±0.2 ppm, and 24.4±0.2 ppm. 13 In some embodiments, Compound I Form A is characterized by a C NMR spectrum having signals at 178.7±0.2 ppm, 154.4±0.2 ppm, 127.8±0.2 ppm, 125.2±0.2 ppm, 102.0±0.2 ppm, 59.3±0.2 ppm, 38.9±0.2 ppm, and 24.4±0.2 ppm. 13 Characterized by C NMR spectrum.

[0050] In some embodiments, Compound I is a substantially crystalline solid. In some embodiments, the crystalline solid consists of 75% to 99% Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 80% to 99% Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 85% to 99% Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 90% to 99% Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 95% to 99% Form A, based on the total weight of the crystalline solid Compound I.

[0051] In some embodiments, the present disclosure provides methods for treating APOL1-mediated diseases with Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or its deuterated derivatives. In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or its deuterated derivatives are administered daily. In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or its deuterated derivatives are administered once daily or multiple times daily, such as twice daily or three times daily. In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or its deuterated derivatives are administered once daily. In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or its deuterated derivatives are administered twice daily. In some embodiments, Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered three times daily.

[0052] In some embodiments, Compound I, Compound I Form A, the deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof are administered as a single composition. In some embodiments, Compound I, Compound I Form A, the deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof are administered in multiple compositions (e.g., multiple tablets and / or multiple pills per single administration). Thus, in some embodiments, Compound I, Compound I Form A, the deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof are administered once daily as a single composition. In some embodiments, Compound I, Compound I Form A, the deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof are administered once daily as multiple compositions administered simultaneously.

[0053] In some embodiments, a therapeutically effective amount of Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered in a daily dosage of 2 mg to 250 mg, 5 mg to 200 mg, 10 mg to 150 mg, 15 mg to 100 mg, 20 mg to 80 mg, or 25 mg to 75 mg. In certain embodiments, a therapeutically effective amount of Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered in a daily dosage of 15 mg to 30 mg, 15 mg to 45 mg, 15 mg to 60 mg, 15 mg to 75 mg, 30 mg to 45 mg, 30 mg to 60 mg, or 30 mg to 75 mg.

[0054] In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or deuterated derivatives thereof are administered once daily, twice daily, or three times daily in a total daily amount of 2 mg to 250 mg, 5 mg to 200 mg, 10 mg to 150 mg, 15 mg to 100 mg, 20 mg to 80 mg, 25 mg to 75 mg, 30 mg to 60 mg, or 15 mg to 45 mg. In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or deuterated derivatives thereof are administered in an amount of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg once daily, twice daily, or three times daily. In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or deuterated derivatives thereof are administered once daily in a daily amount of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 100 mg.In some embodiments, Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered twice daily in a daily amount of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 100 mg, i.e., Compound I, Compound I Form A , deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or its deuterated derivatives are administered in a daily amount (i.e., total daily amount) of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 100 mg in two portions (which may be equal or unequal) during a single day. References to administering Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof in an amount "twice daily" refer to administering that amount of Compound I, Compound I Form A, a deuterated derivative, or a pharmaceutically acceptable salt thereof, twice daily, with each of the two administrations comprising an amount of Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof that is less than the daily amount, but the sum of these amounts administered in one day equals the daily dose.

[0055] In some embodiments, Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered every 8 hours ("q8h"), every 12 hours ("q12h"), or every 24 hours ("q24h"). In some embodiments, Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered every 8 hours (q8h). In some embodiments, Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered every 12 hours (q12h). In some embodiments, Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered every 24 hours (q24h).

[0056] In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or deuterated derivatives thereof are administered every 12 hours (q12h) in an amount of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, or 75 mg.

[0057] In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or deuterated derivatives thereof are administered in an amount of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 100 mg every 24 hours (q24h). In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts thereof are administered in an amount of 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, or 80 mg every 24 hours (q24h).

[0058] In some embodiments, Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered in an amount of 15 mg every 24 hours (q24h). In some embodiments, Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered in an amount of 30 mg every 24 hours (q24h). In some embodiments, Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered in an amount of 45 mg every 24 hours (q24h). In some embodiments, Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered in an amount of 60 mg every 24 hours (q24h). In some embodiments, Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered in an amount of 75 mg every 24 hours (q24h).

[0059] In some embodiments, compound I Form A is administered in an amount of 15 mg every 24 hours (q24h). In some embodiments, compound I Form A is administered in an amount of 30 mg every 24 hours (q24h). In some embodiments, compound I Form A is administered in an amount of 45 mg every 24 hours (q24h). In some embodiments, compound I Form A is administered in an amount of 60 mg every 24 hours (q24h). In some embodiments, compound I Form A is administered in an amount of 75 mg every 24 hours (q24h).

[0060] In some embodiments, compound I Form A is administered in an amount of 15 mg to 30 mg every 24 hours (q24h). In some embodiments, compound I Form A is administered in an amount of 30 mg to 45 mg every 24 hours (q24h). In some embodiments, compound I Form A is administered in an amount of 45 mg to 60 mg every 24 hours (q24h). In some embodiments, compound I Form A is administered in an amount of 60 mg to 75 mg every 24 hours (q24h).

[0061] In some embodiments, the present disclosure provides pharmaceutical compositions comprising Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, which may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and at least one pharmaceutically acceptable carrier.

[0062] Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or its deuterated derivatives may be administered in a single pharmaceutical composition or in separate pharmaceutical compositions. Such pharmaceutical compositions may be formulated for once-daily administration (i.e., every 24 hours (q24h)) or multiple daily administrations, such as twice-daily or three-times-daily.

[0063] In some embodiments, Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or its deuterated derivative is administered in combination with one or more other therapeutic agents. In some embodiments, the other therapeutic agents are selected from angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), neprilysin inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, renin inhibitors, immunosuppressants such as tacrolimus, mycophenolate, cyclosporine, or systemic corticosteroids, such as prednisone or prednisone equivalents, and mineralocorticoid receptor antagonists. In some embodiments, the other therapeutic agents are selected from angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, renin inhibitors, neprilysin inhibitors, and systemic corticosteroids (e.g., prednisone or prednisone equivalents). In certain embodiments, Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered in combination with an ACE inhibitor (ACEi) and an ARB. In certain embodiments, Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered in combination with an ACE inhibitor (ACEi), an ARB, and prednisone or a prednisone equivalent.

[0064] As used herein, the term "angiotensin-converting enzyme inhibitors" or "ACE inhibitors" refers to a class of drug treatments, such as small organic chemical compounds (1 kDa or less) or larger biomolecules, such as peptides (e.g., soluble peptides), proteins (e.g., antibodies), nucleic acids (e.g., siRNA), or conjugates combining any two or more of the foregoing, that block the formation of angiotensin I, a natural chemical that narrows blood vessels, thereby causing relaxation of the blood vessels and, in turn, a decrease in blood flow, leading to lower blood pressure and a decrease in oxygen demand from the heart. Non-limiting examples of ACE inhibitors include lisinopril (Prinivil®, Zestril®, Qbrelis®), lisinopril in combination with hydrochlorothiazide (Zestoretic®), benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec®, Epaned®, Enacard®), zofelopril, perindopril (Aceon®), trandolapril (Mavik®), quinapril (Accupril®), and ramipril (ramipril®).

[0065] As used herein, the term "angiotensin receptor blocker" or "ARB" refers to a class of drug treatments, such as substances such as small molecule organic chemical compounds (1 kDa or less) or larger biomolecules, such as peptides (e.g., soluble peptides), proteins (e.g., antibodies), nucleic acids (e.g., siRNA), or conjugates combining any two or more of the foregoing, that block the action (not formation, as it has ACE inhibitors) of the natural chemical angiotensin I, which narrows blood vessels, thereby causing relaxation of blood vessels and, in turn, a decrease in blood flow, leading to lower blood pressure and a decrease in oxygen demand from the heart. Non-limiting examples of ARBs include losartan (Cozaar®), irbesartan (Avapro®), olmesartan (Benicar®), telmisartan (Micardis®), candesartan (Atacand®), valsartan (Diovan®), fimasartan, azilsartan (Edarbi®), elposartan, and iosartan potassium-hydrochloridethiazide (Hyzaar®).

[0066] As used herein, the term "renin inhibitors" refers to a class of drug treatments, such as small organic chemical compounds (1 kDa or less) or large biomolecules, such as peptides (e.g., soluble peptides), proteins (e.g., antibodies), nucleic acids (e.g., siRNA), or conjugates combining any two or more of the foregoing, that slow the production of renin, an enzyme produced by the kidneys that initiates a series of reactions that increase blood pressure, including the production of angiotensin I. The first approved drug in this class is aliskiren (Tekturna®). Due to the risk of serious complications, including stroke, aliskiren cannot be taken without an ACE inhibitor or ARB.

[0067] As used herein, the term "neprilysin inhibitors" refers to a class of drug treatments, such as small organic chemical compounds (1 kDa or less) or larger biomolecules, such as peptides (e.g., soluble peptides), proteins (e.g., antibodies), nucleic acids (e.g., siRNAs), or conjugates combining any two or more of the foregoing, that prevent the activity of neprilysin against signaling peptides, such as enkephalins, substance P, endothelin, and antrial natriuretic peptides. Neprilysin is expressed in many types of tissues, but is particularly abundant in the kidney. It is a zinc-dependent metalloprotease that cleaves and inactivates several peptide hormones, including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin. Non-limiting examples of neprilysin inhibitors include sacubitril / valsartan (Entresto / LCZ696), sacubitril (AHU-377), sacubitrilat (LBQ657), RB-101, UK-414, UK-495, omapatrilat, ecadotril, and candoxatril.

[0068] As used herein, the term "sodium glucose cotransporter 2 inhibitors" or "SGLT2 inhibitors" refers to a class of drug treatments, such as small molecule organic chemical compounds (1 kDa or less) or larger biomolecules, such as peptides (e.g., soluble peptides), proteins (e.g., antibodies), nucleic acids (e.g., siRNA), or conjugates combining any two or more of the foregoing, that possess the activity of sodium-glucose transport protein 2 (SGLT2). Non-limiting examples of SGLT2 inhibitors include epigliflozin (Jardiance®), canagliflozin (Invokana®), dapagliflozin (Farxiga®), remogliflozin (including remogliflozin etabonate BHV091009, ipragliflozin IASP-1941 or Suglat®), HM41322, bexagliflozin, ertugliflozin (Steglatro®), sotagliflozin, luseogliflozin, tofogliflozin (Apleway®, Beberza®), sergliflozin etabonate, or a pharmaceutically acceptable salt of any of the foregoing. Additional examples of SGLT2 inhibitors include WO01 / 027128, WO04 / 013118, WO04 / 080990, EP1852439A1, WO01 / 27128, WO03 / 099836, WO2005 / 092877, WO2006 / 034489, WO2006 / 064033, WO2006 / 117359, WO2006 / 1173 60, WO2007 / 025943, WO2007 / 028814, WO2007 / 031548, WO2007 / 093610, WO2007 / 128749, WO2008 / 049923, WO2008 / 055870, and WO2008 / 055940, each of which is incorporated herein by reference in its entirety.

[0069] As used herein, the term "systemic corticosteroid" refers to corticosteroids administered orally or by injection and does not include corticosteroids used in the eye, ear, or nose, or on the skin. Non-limiting examples of systemic corticosteroids include prednisone or prednisone equivalents (e.g., prednisolone, methylprednisolone), beclomethasone, betamethasone, dexamethasone, hydrocortisone, and triamcinolone.

[0070] As used herein, the term "mineralocorticoid receptor antagonist" refers to a class of drug treatments, such as small organic chemical compounds (1 kDa or less) or large biomolecules, such as peptides (e.g., soluble peptides), proteins (e.g., antibodies), nucleic acids (e.g., siRNA), or conjugates combining any two or more of the foregoing, that possess the activity of antagonizing the action of aldosterone (mineralocorticoid) at the mineralocorticoid receptor. Small molecule mineralocorticoid receptor antagonists can be steroidal or non-steroidal compounds, and can be spirolactones, which have the structural feature of a cyclic ester with a spiro attached to another ring system. Non-limiting examples of mineralocorticoid receptor antagonists include spironolactone, eplerenone, canrenone, finerenone, and mexrenone.

[0071] In some embodiments, the disclosure provides a pharmaceutical composition comprising 2 mg to 250 mg of Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises 2 mg to 250 mg, 5 mg to 200 mg, 10 mg to 150 mg, 15 mg to 100 mg, 20 mg to 80 mg, 25 mg to 75 mg, 30 mg to 60 mg, or 15 mg to 45 mg of Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 100 mg of Compound I, a deuterated derivative of Compound I, Compound I Form A, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and optionally at least one pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg of Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and at least one pharmaceutically acceptable carrier.

[0072] In some embodiments, the present disclosure provides a pharmaceutical composition comprising 15 mg of Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising 30 mg of Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising 45 mg of Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising 60 mg of Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising 75 mg of Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and at least one pharmaceutically acceptable carrier.

[0073] In some embodiments, the present disclosure provides a pharmaceutical composition comprising 15 mg of Compound I Form A and at least one pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising 30 mg of Compound I Form A and at least one pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising 45 mg of Compound I Form A and at least one pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising 60 mg of Compound I Form A and at least one pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising 75 mg of Compound I Form A and at least one pharmaceutically acceptable carrier.

[0074] In some embodiments, a patient receiving Compound I, Compound I Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, or a pharmaceutical composition comprising same, is administered and is in a fasted state. As used herein, a patient in a "fasted state" abstains from all food and drink (except water) for at least two hours (e.g., at least four hours) before and at least two hours after administration of Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, or a pharmaceutical composition comprising same.

[0075] In some embodiments, a patient receiving Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, or a pharmaceutical composition comprising the same, is in a fed state. As used herein, a patient in a "fed state" abstains from all food and drink (except water) for at least 8 hours (e.g., at least 10 hours) before the start of a meal, with the intake of a meal initiated within 30 minutes of administration of Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, or a pharmaceutical composition comprising the same, and the entire meal is consumed within 30 minutes. In some embodiments, no additional food is allowed for at least 2 hours (e.g., 4 hours) after administration of Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, or a pharmaceutical composition comprising the same. In some embodiments, water may be consumed without restriction beginning after administration of Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, or a pharmaceutical composition comprising the same. In some embodiments, water may be consumed without restriction beginning at least one hour after administration. In some embodiments, the meal is a high-fat meal, such as a meal containing about 800-1000 total calories and about 500-600 calories from fat and / or 55-65 grams of fat. In some embodiments, the meal is a low-fat meal, such as a meal containing about 500-600 total calories and about 100-125 calories from fat and / or 11-14 grams of fat. In some embodiments, the meal is a medium-fat meal, such as a meal containing about 500-600 total calories and about 30-35% fat and / or about 20g of fat.

[0076] Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or its deuterated derivatives may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the at least one pharmaceutically acceptable is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, or lubricant.

[0077] As used herein, "at least one pharmaceutically acceptable carrier" includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surfactants, isotonicity agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants appropriate for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, disclose various carriers used in formulating pharmaceutical compositions and known techniques for their preparation. The use of any conventional carrier is contemplated within the scope of the present disclosure, except that it is incompatible with the compounds of the present disclosure, for example, by producing any undesirable biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (sodium carboxymethylcellulose, sodium methylcellulose, sodium methylcellulose, sodium methylcellulose), and the like. These include, but are not limited to, starch, cellulose, ethyl cellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0078] The pharmaceutical compositions described herein are useful for treating APOL1-mediated kidney diseases, such as APOL1-mediated diseases, including FSGS and / or NDKD. In some embodiments, the pharmaceutical compositions described herein are useful for treating APOL1-mediated kidney diseases. In some embodiments, the pharmaceutical compositions described herein are useful for treating FSGS. In some embodiments, the pharmaceutical compositions described herein are useful for treating NDKD.

[0079] Any suitable pharmaceutical composition known in the art can be used for compositions comprising Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or its deuterated derivatives. In some embodiments, the pharmaceutical composition used in the treatment of the present disclosure is a tablet. In some embodiments, the tablet is suitable for oral administration.

[0080] In some embodiments, pharmaceutical compositions (including but not limited to tablets) of the present disclosure comprise Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and cellulose. In some embodiments, pharmaceutical compositions (including but not limited to tablets) of the present disclosure comprise Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and croscarmellose sodium. In some embodiments, pharmaceutical compositions (including but not limited to tablets) of the present disclosure comprise Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and sodium stearyl fumarate. In some embodiments, pharmaceutical compositions (including but not limited to tablets) of the present disclosure comprise Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and lactose monohydrate. In some embodiments, pharmaceutical compositions (including but not limited to tablets) of the present disclosure comprise Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, and hypromellose acetate succinate. In some embodiments, pharmaceutical compositions (including but not limited to tablets) of the present disclosure comprise I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, cellulose, and croscarmellose sodium. In some embodiments, pharmaceutical compositions (including but not limited to tablets) of the present disclosure comprise Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, cellulose, croscarmellose sodium, and a pharmaceutically acceptable salt of lactose monohydrate.In some embodiments, pharmaceutical compositions of the present disclosure (including but not limited to tablets) comprise Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, cellulose, croscarmellose sodium, hypromellose acetate succinate, and a pharmaceutically acceptable salt of lactose monohydrate. In some embodiments, pharmaceutical compositions of the present disclosure (including but not limited to tablets) comprise Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, cellulose, croscarmellose sodium, lactose monohydrate, hypromellose acetate succinate, and sodium stearyl fumarate.

[0081] In some embodiments, tablets comprising Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or deuterated derivatives thereof may optionally further comprise a coating. In some embodiments, tablets comprising Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or deuterated derivatives thereof further comprise a coating, referred to herein as a "non-functional film coating," comprising polyvinyl alcohol (PVA), polyethylene glycol (PEG), titanium dioxide, and talc. An exemplary embodiment of a tablet comprising 250 mg of Compound I, deuterated derivatives of Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or deuterated derivatives thereof, and further comprising a non-functional film coating, is shown in Table 2. The non-functional film coating can be applied to tablets containing Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or its deuterated derivatives using conventional tablet film coating processes. [Table 2]

[0082] In some embodiments, disclosed herein are methods for treating, reducing the severity of, or symptomatically treating an APOL1-mediated disease, such as an APOL1-mediated kidney disease, such as FSGS and / or NDKD, in a patient, comprising administering to the patient suffering from FSGS or NDKD an effective amount of Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, as described herein, or a pharmaceutical composition comprising Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof.

[0083] Non-limiting embodiments of the present disclosure include the following. 1. A method for treating an APOL1-mediated disease, comprising administering to a patient a compound I, [ka] a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, to a patient in need thereof, and in a daily amount of from 2 mg to 100 mg. 2. The method of embodiment 1, wherein the APOL1-mediated disease is an APOL1-mediated renal disease. 3. The method of embodiment 2, wherein the APOL1-mediated kidney disease is APOL1-dependent focal segmental glomerulosclerosis (FSGS). 4. The method of embodiment 2, wherein the APOL1-mediated kidney disease is non-diabetic kidney disease (NDKD). 5. The method of any one of embodiments 1 to 4, wherein the patient has the APOL1 genotype. 6. The method of any one of embodiments 1-4, wherein the patient has nephrotic range proteinuria. 7. The method of any one of embodiments 1-4, wherein the patient does not have proteinuria in the nephrotic syndrome range. 8. The method of any one of embodiments 1-7, wherein Compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered in a daily amount of 5 mg to 200 mg, 10 mg to 150 mg, 15 mg to 100 mg, 20 mg to 80 mg, 25 mg to 75 mg, 30 mg to 60 mg, or 15 mg to 45 mg. 9. The method of any one of embodiments 1-7, wherein Compound I, its deuterated derivative, and / or a pharmaceutically acceptable salt of Compound I or its deuterated derivative is administered in a daily amount of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 100 mg. 10. The method of any one of embodiments 1-9, wherein Compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered in a daily amount of 15 mg or 45 mg. 11. The method of any one of embodiments 1-10, wherein Compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered once daily or multiple times daily. 12. The method of any one of embodiments 1-10, wherein compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of compound I or a deuterated derivative thereof is administered every 24 hours (q24h). 13. The method of any one of embodiments 1-12, wherein the method comprises administering Compound I or a deuterated derivative thereof. 14. The method of any one of embodiments 1-12, wherein the method comprises administering a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof. 15. The method of any one of embodiments 1-14, wherein Compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is comprised in a pharmaceutical composition. 16. The method of embodiment 15, wherein the pharmaceutical composition is a tablet. 17. The method of embodiment 16, wherein the tablet is suitable for oral administration. 18. The method of embodiment 17, wherein the tablet for oral administration contains 15 mg of compound I. 19. The method of any one of embodiments 16-18, wherein the tablet comprises cellulose, croscarmellose sodium, and / or sodium stearyl fumarate. 20. The method of embodiment 19, wherein the tablet further comprises a coating comprising polyvinyl alcohol (PVA), polyethylene glycol (PEG), titanium dioxide, and talc. 21. The method of any one of embodiments 1-20, wherein the patient is in a fasting state. 22. The method of any one of embodiments 1-20, wherein the patient is in a fed state. 23. The method of any one of embodiments 1-22, wherein compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of compound I or a deuterated derivative thereof is administered in combination with one or more therapeutic agents selected from an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a sodium-glucose cotransporter-2 (SGLT2) inhibitor, a renin inhibitor, a neprilysin inhibitor, an immunosuppressant, and a mineralocorticoid receptor antagonist. 23(a) The method of embodiment 23, wherein the immunosuppressant is selected from tacrolimus, cyclosporine, mycophenolate, and systemic corticosteroids. 24. The method of embodiment 23, wherein the systemic corticosteroid is prednisone or a prednisone equivalent. 25. The method of any one of embodiments 1-22, wherein compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of compound I or a deuterated derivative thereof is administered in combination with one or more therapeutic agents selected from an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a renin inhibitor, and a prednisone equivalent. 26. The method of any one of embodiments 1-22, wherein compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of compound I or a deuterated derivative thereof is administered in combination with an ACE inhibitor (ACEi) and an ARB. 27. The method of any one of embodiments 1-22, wherein compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of compound I or a deuterated derivative thereof is administered in combination with an ACEi, an ARB, and prednisone. 28. The method of any one of embodiments 1-27, wherein the patient is not concurrently administered any immunosuppressive agents other than systemic corticosteroids, tacrolimus, cyclosporine, and mycophenolate. 29. The method of any one of embodiments 1-28, wherein compound I is substantially pure crystalline form A. 30. The method of any one of embodiments 1-28, wherein compound I is in crystalline form A. A pharmaceutical composition comprising 31.5 mg to 200 mg, 10 mg to 150 mg, 15 mg to 100 mg, 20 mg to 80 mg, 25 to 75 mg, 30 to 60 mg, or 15 mg to 45 mg of Compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof. 32. The pharmaceutical composition of embodiment 31, wherein the composition comprises 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 100 mg of compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of compound I or a deuterated derivative thereof. 33. The pharmaceutical composition of embodiment 32, wherein the composition comprises 15 mg of compound I. 34. The pharmaceutical composition of embodiment 32, wherein the composition comprises 30 mg of compound I. 35. The pharmaceutical composition of embodiment 32, wherein the composition comprises 45 mg of compound I. 36. The pharmaceutical composition of embodiment 32, wherein the composition comprises 60 mg of compound I. 37. The pharmaceutical composition of embodiment 32, wherein the composition comprises 75 mg of compound I. 38. The pharmaceutical composition according to any one of embodiments 31 to 37, wherein compound I is substantially pure crystalline form A. 39. The pharmaceutical composition according to any one of embodiments 31 to 37, wherein compound I is in crystalline form A. [Example]

[0084] Example 1: Synthesis of Compound I Part A: Synthesis of Starting Materials Preparation S2 [ka] Step 1. Synthesis of methyl (2S,3R)-2,4-dibromo-3-hydroxy-butanoate (C7) Potassium (2R,3R)-2,3,4-trihydroxybutanoate C6 (10 g, 57.1 mmol) was stirred with HBr in acetic acid (154 g, 103 mL of 30% w / w, 570.8 mmol) for 16 h. Anhydrous MeOH (250 mL) was added, and the mixture was heated at reflux for 4 h. The mixture was concentrated to dryness, and the residue was dissolved in EtOAc (100 mL). The solution was washed with water (50 mL) and brine (50 mL), then dried over NaSO and concentrated in vacuo. Purification by silica gel chromatography (gradient: 15-20% EtOAc in hexanes) afforded the product as a colorless liquid (13 g, 83%). 1 H NMR(400MHz,CDCl3)δ 4.71(d,J=3.4Hz,1H),4.17-4.14(m,1H),3.82(s,3H),3.53-3.44(m,2H).

[0085] Step 1. Alternative procedure for the synthesis of methyl (2S,3R)-2,4-dibromo-3-hydroxy-butanoate (C7) Potassium (2R,3R)-2,3,4-trihydroxybutanoate C6 (280 g) was stirred with a 33% solution of HBr in acetic acid (1 L) at room temperature for 24 hours. The reaction mixture was then poured into MeOH (5 L). The mixture was stirred at room temperature for 8 hours and then at 65 °C for 4 hours. The mixture was concentrated, and the residue was dissolved in MeOH (1.2 L), and then concentrated sulfuric acid (30 mL) was slowly added. The mixture was heated under reflux for 6 hours and then concentrated. The residue was taken up with EtOAc (400 mL). The resulting solution was washed with water (250 mL), dried over NaSO, filtered, and concentrated in vacuo to give the product (375 g, 74%) as an oil that solidified upon storage at 4 °C.

[0086] Step 2. Synthesis of methyl (2R,3S)-3-(bromomethyl)oxirane-2-carboxylate (C8) Methyl (2R,3R)-2,4-dibromo-3-hydroxybutanoate C7 (524.8 g, 1.9 mol) was dissolved in acetone (4.5 L) in a 12 L round-bottom flask equipped with an overhead stirrer. The reaction was cooled to 0 °C in an ice bath, and Cs2CO3 (994 g, 3.1 mol) was added. The reaction was stirred at 0 °C for 30 minutes and then at room temperature for 2 hours. The mixture was filtered, washed with acetone, and then concentrated in vacuo to give a dark gray oil residue. The product was dissolved in CHCl2 and filtered over a short plug of silica gel, eluting with CHCl2 (approximately 1 L). The filtrate was concentrated in vacuo to give the product as a clear yellow oil (377.3 g, quantitative). 1 H NMR(300MHz,CDCl3)δ 3.83(s,3H),3.71-3.61(m,2H),3.61-3.53(m,1H),3.46(dd,J=9.9,6.6Hz,1H)ppm. 13 C NMR(75MHz,CDCl3)δ 167.58,55.89,53.52,52.77,26.83ppm.

[0087] Step 2. Alternative procedure for the synthesis of methyl (2R,3S)-3-(bromomethyl)oxirane-2-carboxylate (C8) To a solution of methyl (2R,3R)-2,4-dibromo-3-hydroxybutanoate C7 (200 g, 0.73 mol) in acetone (2.0 L) was added anhydrous K2CO3 (151.1 g, 1.1 mol) while maintaining the reaction temperature at 0-5 °C. The reaction was stirred at 0-5 °C for 2 h and then gradually warmed to room temperature over 4 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was distilled under vacuum at 75-80 °C / 200-300 Pa to give the product as a colorless liquid (105 g, 74%).

[0088] Step 3. Synthesis of methyl (2R,3R)-3-(azidomethyl)oxirane-2-carboxylate (C9) Methyl (2R,3S)-3-(bromomethyl)oxirane-2-carboxylate C8 (52.6 g, 269.7 mmol) was dissolved in DMF (500 mL) in a 3 L round-bottom flask equipped with a magnetic stir bar. NaN3 (25.3 g, 388.4 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction was poured into water and extracted with EtOAc. The extract was washed with water, dried over MgSO4, and concentrated in vacuo to give a dark red oil. The oil residue was dissolved in CHCl2 and filtered over a plug of silica gel, eluting with CHCl2. The filtrate was concentrated in vacuo to give the product as a clear, pale red oil (40.8 g, 96%). 1 H NMR(300MHz,CDCl3)δ 3.87-3.74(m,3H),3.67-3.55(m,2H),3.47(dd,J=13.3,5.1Hz,1H),3.38(ddd,J=6.3,5.0,4.4Hz,1H). 13 C NMR(75MHz,CDCl3)δ 167.76,54.81,52.67,51.32,48.74.

[0089] Step 4. Synthesis of (1R,5R)-6-oxa-3-azabicyclo[3.1.0]hexan-2-one (C10) A 2 L three-neck flask equipped with an overhead stirrer was charged with methyl (2R,3R)-3-(azidomethyl)oxirane-2-carboxylate C9 (67 g, 402.5 mmol) in toluene (500 mL), stirred for 10 min, and then warmed to 80 °C. Bu3SnH (220 mL, 817.8 mmol) and AIBN (2 g, 12.2 mmol) were dissolved in toluene (500 mL) and then added to the reaction over 3 h using an addition funnel. The resulting reaction mixture was stirred at 80–87 °C for 1 h, then cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between acetonitrile (2 L) and pentane (1 L), stirred for 10 min, and the acetonitrile phase (bottom) was separated. The acetonitrile phase was washed with pentane (2 × 500 mL) and concentrated in vacuo to give a pale yellow solid. The solid residue was triturated with pentane (ca. 200 mL) to give the product as a yellow solid which was used without further purification (52 g, 98%). 1 H NMR(300MHz,CDCl3)δ 5.89(s,1H),4.00(q,J=2.5Hz,1H),3.74-3.50(m,2H),3.44(dd,J=12.4,2.4Hz,1H). 13 C NMR(75MHz,CDCl3)δ 173.24,53.28,52.18,44.00.

[0090] Step 5. Synthesis of (3S,4R)-3-amino-4-hydroxy-pyrrolidin-2-one (S2) A Parr vessel containing (1R,5R)-6-oxa-3-azabicyclo[3.1.0]hexan-2-one C10 (60 g, 605.5 mmol) and NH3 (1.5 L, 58.6 mol) was pressurized to 200 psi and stirred at 18 °C for 2 days. NH3 was released from the vessel to provide a gray solid. Heptane was added, and the mixture was stirred for 30 minutes. The solid was filtered, and the filter cake was then isolated, followed by the EtOAc and heptane solid. The mixture was concentrated in vacuo to give the product (55 g, 78%). 1H NMR(300MHz,D2O)δ 4.13 (q,J=7.2Hz,1H),3.53(dd,J=10.4,7.4Hz,1H),3.36(d,J=7.5Hz,1H),3.05(dd,J=10.4,6.8Hz,1H).

[0091] Alternative preparation S2 [ka] Steps 1 and 2. Synthesis of N-Boc(3S,4R)-3-amino-4-hydroxypyrrolidin-2-one (C12) At -60 °C, ammonia gas was condensed into an autoclave containing a frozen solution of methyl (2R,3S)-3-(bromomethyl)oxirane-2-carboxylate C8 (81 g, 0.42 mol) in 1,4-dioxane (160 mL) until approximately 400 mL of liquid was collected. The autoclave was closed and gradually warmed to room temperature, then heated at 50-60 °C for 2 h. The autoclave was then cooled back to -60 °C and depressurized. The reaction mixture was gradually warmed to evaporate the liquid ammonia, leaving a viscous residue. The residue was taken up in MeOH (500 mL), and the suspension was treated with a 28% solution of sodium methoxide in MeOH (86 g, 0.42 mol). The mixture was stirred at room temperature for 30 min and then concentrated. The residue was dissolved in water (500 mL), and then a solution of Na2CO3 (89 g, 0.84 mol) and Boc2O (110 g, 0.5 mol) in THF (200 mL) was added. The mixture was stirred at room temperature for 10 hours. The aqueous phase was then saturated with NaCl and extracted with THF (3 × 200 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was triturated with warm MTBE (200 mL), and the precipitated solid was collected by filtration, washed with MTBE, and dried under vacuum to give the product as a white solid (28 g, 31% yield).

[0092] Step 3. Synthesis of (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (S2) To a solution of N-Boc-(3S,4R)-3-amino-4-hydroxypyrrolidin-2-one C12 (28 g, 129 mmol) in EtOH (300 mL) heated at 50-60 °C was added a solution of HCl in EtOH (5.0 M, 75 mL). The reaction mixture was maintained at 50-60 °C for 2 h. The suspension was cooled to room temperature, and the solid was collected by filtration, washed with EtOH, and dried in vacuo to give the product as an off-white solid (18 g, 90%). 1 H NMR(500MHz,DMSO-d6)δ 8.73(brs,3H),8.28(s,1H),6.03(s,1H),4.42-4.37(m,1H),3.74(d,J=6.8Hz,1H),3.48-3.39(m,1H),3.03-3.00(m,1H).

[0093] Preparation S12 (3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid) (S12) [ka] Step 1. Synthesis of 2,4-difluoro-6-[2-(4-fluorophenyl)ethynyl]aniline (C49) Method A: Sonagashira Coupling Method. To a flask containing 2,4-difluoro-6-iodo-aniline C48 (134 g, 525.5 mmol), NEt3 (1.3 L) was added, followed by DMF (250 mL), 1-ethynyl-4-fluorobenzene (83.5 g, 695.1 mmol), CuI (20.5 g, 107.6 mmol), and PdCl2(PPh3)2 (25 g, 35.6 mmol). The mixture was allowed to stir at room temperature for approximately 2 hours. The solvent was removed under reduced pressure, and water (500 mL) was added. The mixture was extracted with ethyl acetate, filtered, and concentrated in vacuo. The product mixture was filtered through a silica gel plug (eluent: CHCl2), followed by a second silica plug filtration (eluent: 30-40% EtOAc in heptane). Silica gel chromatography (Gradient: 0-20% EtOAc in heptane) gave the product (87 g, 60%) as a pale yellow oil. 1H NMR(300MHz,CDCl3)δ 7.58-7.45(m,2H),7.14-7.02(m,2H),6.92(ddd,J=8.8,2.8,1.7Hz,1H),6.87-6.71(m,1H),4.15(s,2H).LCMS m / z 248.0[M+H] + .

[0094] Step 2. Synthesis of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole (C50) Method B: Amine-alkyne cyclization (CuI promotion). To a solution of 2,4-difluoro-6-[2-(4-fluorophenyl)ethynyl]aniline C49 (46 g, 167.5 mmol) in DMF (600 mL) was added CuI (1.9 g, 10.0 mmol), and the reaction was heated to reflux. Water (800 mL) was added, and the mixture was extracted with MTBE. The mixture was then washed with saturated NaCl solution, dried over NaSO, and concentrated in vacuo to give the product, which was used in the subsequent step without further purification (41 g, 87%). 1 H NMR(300MHz,CDCl3)δ 8.43(s,1H),7.72-7.58(m,2H),7.27-7.15(m,2H),7.09(dd,J=9.0,2.1Hz,1H),6.85-6.63(m,2H).LCMS m / z 248.0[M+H] + .

[0095] Step 3. Synthesis of methyl (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoate (C51) Method C: Reductive Alkylation (TFA-Promoted). A 12 L flask equipped with an overhead stirrer was charged with 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C50 (300 g, 1.2 mol), CHCl (3 L), methyl 3,3-dimethoxypropanoate (195 mL, 1.4 mol), and TFA (300 mL, 3.9 mol). The mixture was heated to reflux for 4 h. Additional CHCl was added to facilitate stirring. Upon cooling to room temperature, the solid product was filtered, washed with a minimum of CHCl, and dried to give the product (388 g, 96%). 1 H NMR(400MHz,DMSO-d6)δ 12.66(s,1H),7.77-7.57(m,4H),7.56-7.37(m,2H),7.19(ddd,J=11.0,9.7,2.1Hz,1H),6.47(d,J=16.1Hz,1H),3.69(s,3H).LCMS m / z 332.4[M+H] + .

[0096] Step 4. Synthesis of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate (C52) Method D: Pd(OH)2-catalyzed transfer hydrogenation. To a suspension of (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoate C51 (80 g, 236.5 mmol) in EtOH (1.5 L) under a nitrogen atmosphere, Pd(OH)2 (6 g of 20% w / w 8.5 mmol) and ammonium formate (160 g, 2.5 mol) were added. The mixture was heated at reflux for approximately 3 hours and then filtered to remove the catalyst. The filtrate was concentrated in vacuo to give the product as an off-white solid, which was used without further purification (82 g, 100%). 1H NMR(300MHz,CDCl3)δ 8.18(s,1H),7.65-7.47(m,2H),7.27-7.14(m,2H),7.14-7.00(m,1H),6.76(ddd, J=10.8,9.4,2.2Hz,1H),3.65(s,3H),3.27-3.04(m,2H),2.75-2.49(m,2H).LCMS m / z 334.3[M+H] + .

[0097] Step 5. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid (S12) Method E: Ester hydrolysis using LiOH. LiOH (67 g, 2.8 mol) was added to a solution of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate C52 (217 g, 651.1 mmol) in THF (1 L) and water (100 mL). The mixture was heated at reflux for 2 h and then cooled overnight. THF was removed by concentration under reduced pressure, and water was added (approximately 1 L). The mixture was cooled on an ice bath, and HCl (250 mL of 11.7 M, 2.9 mol) was added to adjust the pH to approximately 4. EtOAc (300 mL) was added, and the aqueous layer was extracted with additional EtOAc (100 mL). The combined organic extracts were dried over sodium sulfate (NaSO), filtered through a plug of silica gel, and rinsed with EtOAc. The filtrate was concentrated in vacuo to give an orange oil (50–75 mL). Heptane (approximately 50 mL) was added and the mixture was cooled on dry ice. Upon stirring, a crystalline solid formed. The mixture was stirred on an ice bath until the crystallization process was complete. The solid was filtered, washed with heptane, and air-dried to give the product (208 g, 96%). 1 H NMR(300MHz,CDCl3)δ 8.15(s,1H),7.60-7.46(m,2H),7.27-7.15(m,2H),7.09(dd,J=9.1,2.2Hz,1H) ,6.77(ddd,J=10.8,9.4,2.2Hz,1H),3.26-3.05(m,2H),2.78-2.57(m,2H).LCMS m / z 320.0[M+H] + .

[0098] Alternative preparation S12 Step 3. Synthesis of methyl (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoate (C51) A reactor was charged at ambient temperature with 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C50 (4.0 kg, 16.5 mol), CHCl (37 L), and methyl 3,3-dimethoxypropanoate (2.6 L, 18.1 mol), followed by TFA (3.9 L, 51.0 mol). The resulting mixture was heated to reflux for 6 hours. The batch was then cooled to 20°C, charged with n-heptane (2 volumes), and filtered. The filter cake was dried under vacuum at 45°C to give the product in approximately 90% yield. 1 H NMR(300MHz,DMSO-d6)δ 12.63(s,1H),7.76-7.54(m,4H),7.55-7.39(m,2H),7.18(ddd,J=11.1,9.7,2.2Hz,1H),6.46(d,J=16.1Hz,1H),3.69(s,3H).LCMS m / z 332.1[M+H] + .

[0099] Step 4. Synthesis of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate (C52) Methyl (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoate C51 (1.5 kg, 9.06 mol) was slurried in THF (7 L) in a vessel. Pd(OH) (10 g of 20 wt% Pd(OH) (approximately 50% water, 0.014 mol) was added. The mixture was purged three times with N, then once with H, and the vessel was pressurized to 50 psi with H. The mixture was stirred at 20 °C until H uptake ceased. After 1.5 h, the mixture was purged three times with N and filtered through Solka-Floc with a THF (2 vol) rinse. The resulting filtrate was concentrated in vacuo at 45 °C (to 1.5 vol), charged with cyclohexane (1 vol), and concentrated again at 45 °C (to 1.5 vol). The slurry was cooled to 15-20° C. and filtered. The filter cake was then washed with cold cyclohexane (1 volume) and dried under vacuum at 45° C. to give the product in 95% yield.

[0100] Step 5. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid (S12) A mixture of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate C52 (9 kg, 27 mmol) in 2-MeTHF (54 L, 6 vol) and MeOH (8.1 L, 0.9 vol) was charged with 20% KOH (2 equiv., 54 mol). The mixture was stirred at 35 °C for 6 h. The mixture was then distilled under vacuum to 27 L (3 vol) and cooled to 10-15 °C. Water (7.5 L) and 2-MeTHF (16 L) were charged, and the resulting biphasic mixture was adjusted to pH ∼2 with 6 M HCl. The temperature was adjusted to 20 °C, and the phases were separated. The organic phase was washed with water (15 L), filtered through Celite® with a 2-MeTHF rinse (18 L, 2 vol), and concentrated under vacuum to 18 L (2 vol). 18 L (2 volumes) of n-heptane was charged and the batch was again concentrated under vacuum to 18 L (3 volumes). This cycle was repeated once more, seeding the batch. 16 L (1.8 volumes) of n-heptane was charged and the temperature was adjusted to 20°C. The slurry was stirred for 2 hours, filtered, and the cake was washed with 2 x 18 L (2 x 2 volumes) n-heptane. The filter cake was dried under vacuum at 45°C to give the desired product in 90% yield. 1 H NMR(300MHz,CDCl3)δ 8.28(s,1H),7.53(ddd,J=8.7,5.4,2.8Hz,2H),7.27-7.13(m,2H),7.08(dd,J=9.1,2.1Hz,1H),6.76(ddd, LCMS m / z 320.4[M+H] + .

[0101] Part B: Synthesis of Compound (I) [ka] Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide (I) A 2 L three-necked RB flask equipped with a magnetic stirrer, temperature probe, and nitrogen inlet was charged with 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid S12 (90.5 g, 283.5 mmol) and (3S,4R)-3-amino-4-hydroxy-pyrrolidin-2-one S2 (39.9 g, 343.6 mmol) in DMF (1.65 L) and stirred for 15 minutes. CDMT (61.1 g, 348 mmol) was added. The mixture was then cooled to approximately 2 °C on an ice bath. N-methylmorpholine (131 mL, 1.2 mol) was added dropwise over 20 minutes, and the mixture was heated at 30 °C overnight. The reaction mixture was added to approximately 4.5 L of ice water and extracted with EtOAc (1.2 L × 4). The combined organic layers were washed with 1.2 L of 1 M HCl (3 times), then with water (1.2 L) and brine (1.2 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The mixture was washed through a silica gel plug (1.8 L of silica gel), eluting first with 25% EtOAc in dichloromethane (8 L) to remove impurities, followed by hot EtOAc (8 L) to elute the product. The EtOAc filtrate was concentrated in vacuo. TBME was then added (400 mL), and the mixture was allowed to stir overnight. Filtration of the resulting solid gave the product as a white solid. 62 g, 52%) 1 H NMR(300MHz,CD3OD)δ 7.70-7.58(m,2H),7.29-7.13(m,3H),6.73(ddd,J=11.1,9.6,2.2Hz,1H),4.34(td,J=7.6,6.8Hz, 1H),4.21(d,J=7.8Hz,1H),3.56(dd,J=9.9,7.6Hz,1H),3.20-3.04(m,3H),2.65-2.53(m,2H).LCMS m / z 418.2[M+H] + . Optical rotation: [α] D 20.7 =-14.01 (c=1.0, 10 mg in 1 mL of MeOH).

[0102] Alternative Procedure for the Synthesis of Compound I Step 1. Synthesis of methyl (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoate (C51) A solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C50 (100 g, 1.0 equiv.) in dichloromethane (850 mL, 8.5 vol.) was stirred at 22°C. Methyl 3,3-dimethoxypropionate (63 mL, 1.1 equiv.) was charged, followed by trifluoroacetic acid (96 mL, 3.1 equiv.), which was rinsed forward with dichloromethane (25 mL, 0.25 vol.). The batch was heated to 38°C and stirred at that temperature. After 4 hours, the batch was cooled to 22°C and charged with n-heptane (200 mL, 2 vol.). The mixture was stirred at 22°C for 1 hour more. The slurry was filtered, and the reactor and filter cake were washed with n-heptane (1 x 2 vol. (200 mL) and 1 x 3 vol. (300 mL)). The resulting solid was dried under vacuum with a nitrogen bleed at 45° C. to give the product C51 (127.7 g, 95% yield).

[0103] Step 2. Synthesis of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate (C52) The hydrogenation agent was charged with methyl (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoate C51 (100.4 g, 1.0 equiv.) followed by Pd(OH)2 / C (0.014 equiv.). The vessel was sealed and three vacuum / purge cycles were performed with N2. 2-MeTHF (2000 mL, 20 volumes) was charged using residual vacuum, and the resulting mixture was stirred at 22 °C. The vessel was sealed and three vacuum / purge cycles were performed with N2, followed by one vacuum / purge cycle with hydrogen (H2). The temperature was adjusted to 22 °C, and the vessel was pressurized with 20 psi of H2. The mixture was stirred at 22 °C for 4 hours. Three vacuum / purge cycles were performed with nitrogen (N2). The batch was filtered through a pad of Hyflo® and the filter cake was washed with 2-MeTHF (2 × 300 mL, 2 × 3 volumes). The combined filtrate was placed under vacuum and distilled to a total volume of 2.0–3.0 at ≤45.0 °C. The batch temperature was adjusted to 22 °C and the vessel was charged with n-heptane (1000 mL, 10 volumes) over at least 1 hour. Vacuum was applied and the filtrate was distilled to a total volume of 3.5–4.5 at ≤45.0 °C. The slurry was cooled to 22 °C and allowed to stir for at least 1 hour. The slurry was filtered and the filter cake was washed with n-heptane (1 × 1 volume (100 mL) and 1 × 0.5 volumes (50 mL)). The solid was dried under vacuum with a nitrogen bleed at 45 °C to give the product C52 (91.9 g, 91% yield).

[0104] Step 3. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid (S12) A mixture of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate C52 (80.0 g, 1.0 eq) and 2-MeTHF (480 mL, 6 vol) was stirred at 22 °C and treated with methanol (72 mL, 0.9 vol). A solution of KOH (27.1 g, 2.0 eq) in water (107 mL, 1.3 vol) was charged over approximately 20 minutes. The resulting mixture was heated to an internal temperature of 35 °C and stirred for 3 hours. The temperature was adjusted to 22 °C. A vacuum was applied and the mixture was distilled to a total volume of 3.0 at up to 45 °C. The internal temperature was adjusted to 12 °C. The mixture was then charged with water (64 mL, 0.8 vol) and 2-MeTHF (304 mL, 3.8 vol). 6N HCl (75 mL, 0.9 vol) was charged slowly to the mixture with vigorous stirring until the batch reached a pH of less than 3. The internal temperature was adjusted to 22°C, and the biphasic mixture was stirred for 0.5 hours or more. Agitation was stopped, and the phases were allowed to separate for 0.5 hours or more. The lower aqueous phase was removed. Water (160 mL, 2 vol) was charged to the reactor at 22°C, and the biphasic mixture was stirred for 0.5 hours or more. Agitation was stopped, and the phases were allowed to separate for 0.5 hours or more. The lower aqueous phase was removed, and the batch was filtered through a pad of Hyflo®. The reactor and filter cake were rinsed with 2-MeTHF (160 mL, 2 vol). A vacuum was applied, and the combined filtrate was distilled at up to 40.0°C to a total volume of 2-3 ml. The vessel was charged with n-heptane (160 mL, 2 volumes), vacuum was applied, and the filtrate was distilled to a total volume of 2 at below 40.0°C (this process was repeated one additional time). The mixture was then charged with additional n-heptane (144 mL, 1.8 volumes). The internal temperature was adjusted to 40°C and stirred for 2 hours or more. The internal temperature was adjusted to 22°C over a minimum of 5 hours and stirred for 16 hours or more. The slurry was filtered. The filter cake was washed with n-heptane (3 x 40 mL, 3 x 0.5 volumes). The solid was dried under vacuum with a nitrogen bleed at 45°C to give the product S12 (72.6 g, 95% yield).

[0105] Step 4. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide (Compound I) A mixture of S12 (50.0 g, 1.0 equiv.), (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride S2 (25.1 g, 1.05 equiv.), and CDMT (30.3 g, 1.1 equiv.) in DMF (250 mL, 5 vol.) was stirred and cooled to 0° C. The reactor was charged with NMM (60 mL, 3.5 equiv.) over 1 h while maintaining the internal temperature below 5° C. The batch was stirred at approximately 5° C. for 1 h. The batch was warmed to 22° C. over at least 1 h and stirred at 22° C. for 16 h. The batch was cooled to 0° C. Water (250 mL, 5 vol.) was charged while maintaining the internal temperature below 20° C. The mixture was charged with a 90 / 10 mixture of EtOAc / IPA (1000 mL, 20 vol.). 6N HCl (40 mL, 0.8 vol) was then charged while maintaining an internal temperature below 10°C until a pH of approximately 1-3 was achieved. The internal temperature was adjusted to 22°C, and the biphasic mixture was stirred for ≥0.5 h. Stirring was stopped, and the phases were allowed to separate for ≥0.5 h. The lower aqueous phase was removed. The aqueous layer was back-extracted with a 90 / 10 mixture of EtOAc / IPA (2 x 250 mL, 2 x 5 vol) at 22°C. The combined organic phases from the extraction were washed with water (5 x 500 mL, 5 x 10 vol) at 22°C by mixing for ≥0.5 h and allowing each wash to stand for ≥0.5 h. The batch was polish filtered. A vacuum was applied, and the organic phase was distilled at <50°C to a total volume of 9.5-10.5. The mixture was charged with EtOAc (500 mL, 10 volumes), vacuum was applied, and the organic phase was distilled below 50°C to a total volume of 9.5-10.5 (this process was repeated once more). The mixture was charged with EtOAc (300 mL, 6 volumes) and n-heptane (200 mL, 4 volumes). The resulting slurry was heated to 50°C and stirred for 17 hours or more. The mixture was then cooled to 22°C over 2 hours and stirred for 1 hour or more. The slurry was filtered. The filter cake was washed with 1:1 EtOAc / n-heptane (2 x 150 mL, 2 x 3 volumes). The solid was dried under vacuum with a nitrogen bleed below 45°C to give compound I (52.6 g, 80% yield).

[0106] Recrystallization of Compound I Compound 2 (37.6 g, 1.0 equiv.) was charged to a reactor, followed by a 3:1 mixture of IPA / water (240 mL, 6.4 vol.). The slurry was heated to an internal temperature of 75° C. The batch was cooled to an internal temperature of 55° C. and stirred at that temperature for at least 0.5 hours. The batch was seeded with 0.5 wt.% of a previously prepared batch of compound 2 as a suspension in a 3:1 mixture of IPA / water (4 mL, 0.1 vol.). The mixture was stirred at 55° C. for not less than 1.5 hours. Water (218 mL, 5.8 vol.) was added over a minimum period of 5 hours, maintaining the temperature at 55° C. The slurry was cooled to 22° C. over not less than 5 hours and stirred for not less than 2 hours. The slurry was filtered. The filter cake was washed with 2:3 IPA / water (2×114 mL, 2×3 vol.). The solid was dried under vacuum with a nitrogen bleed at up to 45° C. to give Compound I (34.5 g, 92% yield).

[0107] Compound I Form A A reactor was charged with 12.3 kg of Compound I, followed by a 3:1 mixture of 2-propanol / water. Agitation was initiated, and the mixture was heated to 75°C to achieve complete dissolution. The mixture was cooled to 55°C over 1 hour and stirred at that temperature for 30 minutes. Agitation was continued for 1.5 hours. Water (5.8 volumes) was charged at 55°C over 5 hours, after which the mixture was cooled to 22°C over 6 hours. The mixture was stirred at 22°C for 2 hours and then filtered under vacuum. The resulting wet cake was washed with a 3:1 mixture of 2-propanol / water (2.74 volumes x 2) and pulled dry under vacuum. The wet cake was further dried under vacuum at 45°C with a nitrogen bleed to give 11.2 kg of Form A.

[0108] X-ray powder diffraction study of Compound I Form A The powder X-ray powder diffraction diffractogram (FIG. 1) of Compound I Form A was obtained at room temperature using a PANalytical Empyrean diffractometer equipped with a PIXcel 1D detector. The peaks are listed in Table 11 below. [Table 3]

[0109] Solid-state NMR of Compound I Form A Compound I Form A 13 A C CPMAS (FIG. 2) was acquired at 275 K using the following parameters: 12.5 kHz spinning, 29.5 ppm adamantane reference. Peaks are listed in Table 12 below. Carbon peaks highlighted in bold are unique to Form A with respect to the following forms: Hydrate A, Hydrate C, and the amorphous form. [Table 4]

[0110] Example 3: Preparation of coated tablets containing 15 mg of Compound I The following materials can be used in this exemplary preparation of a tablet containing 15 mg of Compound I, as shown in Table 3. [Table 5-1] [Table 5-2]

[0111] In this exemplary preparation, Compound I, intragranular microcrystalline cellulose, and croscarmellose sodium are sieved, combined, and blended in a bin blender. Sieved intragranular sodium stearyl fumarate is added to the bin blender, and the mixture is blended. The mixture is then dry-granulated and milled to form milled granules. These milled granules are added to a bin blender, to which sieved extragranular microcrystalline cellulose and sieved extragranular croscarmellose sodium are added. The resulting blend is then discharged and then loaded into a tablet press. The blend is compressed into tablets and then discharged. A non-functional film coating can optionally be applied to tablets containing Compound I using a conventional tablet film coating process.

[0112] Example 4. Efficacy of Compound I for treating APOL1-mediated focal segmental glomerulosclerosis Inclusion criteria for a Phase 2, open-label, single-arm, 2-part study of Compound I: 1. Participants were aged between 18 and 65 years old. 2. Participants must be between 18.0 and 40.0 kg / m 2 and a body mass index (BMI) of >50 kg. 3. Participants will have FSGS diagnosed by kidney biopsy, excluding tip variants confirmed through the eligibility screening process. 4. Participant has an APOL1 genotype of G1 / G1, G2 / G2, or G1 / G2 obtained in a clinical research assay, which can be confirmed by Sanger sequencing. 5. Participants will have a UPCR ratio of ≥ 3 g / g and < 10 g / g (Cohort 1) or ≥ 1 g / g and < 2.7 g / g (Cohort 2) in their first morning void urine at three measurements collected on at least three separate days within a seven-day period during the screening period (all three measurements must meet this criterion). 6. Participants must meet the minimum blood pressure requirement of 45 mL / min / 1.73 m based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 2 Estimated glomerular filtration rate (eGFR) of ≥ 30 mL / min / 1.73 m (Cohort 1) 2 or greater (Cohort 2), and had an eGFR of 30 to less than 40 mL / min / 1.73 m 2 Participants must have an eGFR of 50% or less, or tubulointerstitial fibrosis described as absent, mild, or moderate on kidney biopsy (Cohort 2). 7. Participants have no plans to start, stop, or change the administration of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), neprilysin inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, renin inhibitors, systemic corticosteroids, tacrolimus, or mycophenolate from 28 days prior to screening through the follow-up period. 8. Participants receiving low-dose corticosteroids (≤10 mg / day of prednisone or prednisone equivalent) or permitted immunosuppressants (e.g., tacrolimus or mycophenolate) must be receiving a stable dose for 28 days prior to screening.

[0113] The clinical trial will include two cohorts. Cohort 1 and Cohort 2 will be allowed to receive stable, low-dose systemic corticosteroids (up to 10 mg / day of prednisone or prednisone equivalent), tacrolimus, and mycophenolate, but will not be allowed to receive other immunosuppressants. The subjects and dosing schedules for Cohort 1 and Cohort 2 will be identical.

[0114] Initially, participants undergo screening assessments and provide informed consent during a 28-day screening period. Screening assessments include, but are not limited to, vital signs, height and weight, electrocardiograms, serum chemistry, and UPCR (urine protein / creatinine ratio) analyses. Risk allele status (APOL1 genotype) will be assessed at any time prior to treatment initiation (e.g., during the screening period).

[0115] All participants will receive a 15 mg dose q24h for 2 weeks, followed by a 45 mg dose q24h for 11 weeks. After the final dose, participants will be followed for up to 12 weeks for off-treatment proteinuria assessment. Participants who discontinue Compound I early will be scheduled for an early end-of-treatment visit as soon as possible after the decision to terminate study drug treatment. These participants will continue to complete all other scheduled study visits for efficacy assessments (i.e., UPCR (urine protein / creatinine ratio), UACR (urine albumin-to-creatinine ratio)) until the final follow-up visit. After the final dose of study drug, participants will be followed monthly for up to 12 weeks or until UPCR returns to baseline, whichever occurs first. All subjects will complete a safety follow-up visit 28 (± 7) days after the final dose of study drug.

[0116] Proteinuria will be assessed at multiple time points throughout the treatment and follow-up periods. The time points for the primary analysis are Day 1 and Week 13.

[0117] Study participants include male and female subjects with a diagnosis of FSGS and a confirmed APOL1 genotype. Participants will receive a 15 mg q24h dose of Compound I for two weeks and a 45 mg q24h dose of Compound I for 11 weeks.

[0118] The primary endpoint for evaluating the effect on FSGS is the percent change from baseline in UPCR at week 13. As used herein, "baseline value" refers to the most recent measurement (scheduled or unscheduled) collected before the first dose of investigational drug. For ECG, the baseline value is defined as the average of the pre-treatment measurements (three replicates) before the first dose of Compound I. "Change from baseline (absolute change)" is calculated as the post-baseline value - baseline value. "Relative change from baseline" is calculated as 100% x (post-baseline value - baseline value) / baseline value, and is expressed as a percentage.

[0119] Example 5: Efficacy of Compound I for treating APOL1-mediated non-diabetic kidney disease Inclusion criteria for a Phase 2, double-blind, placebo-controlled, dose-ranging study of Compound I: 1. Participants were aged between 18 and 60 years old. 2. Participants must be between 18.0 and 40.0 kg / m 2 and a body mass index (BMI) of >50 kg. 3. Participant has an APOL1 genotype of G1 / G1, G2 / G2, or G1 / G2 as determined by clinical research assay. 4. Participants have a UPCR ratio of 0.2 g / g or greater and less than 3 g / g in early morning urine on three separate occasions collected on at least three separate days within a seven-day period during the screening period (all three measurements must meet this criterion). 5. Participants must meet the minimum blood pressure requirement of 30 mL / min / 1.73 m based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 2 have a glomerular filtration rate (GFR) of 100 or more. 6. Participants have no plans to start, stop, or change the administration of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), neprilysin inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, or renin inhibitors during the treatment period. 7. Participants with a history of hypertension and currently receiving a stable dose (for at least 4 weeks) of antihypertensive medication.

[0120] Initially, participants undergo screening assessments and provide informed consent during a 28-day screening period. Screening assessments include, but are not limited to, vital signs, height and weight, electrocardiograms, serum chemistry, and UPCR (urine protein / creatinine ratio) analyses. Risk allele status (APOL1 genotype) will be assessed at any time prior to treatment initiation (e.g., during the screening period).

[0121] Participants will be randomized to receive either Compound I or a placebo dose. They will then receive a low, medium, or high dose of Compound I for 13 weeks. The Compound I dose will be determined prior to study initiation using available data from clinical and nonclinical studies. Participants who discontinue Compound I early will be scheduled for an early termination visit as soon as possible after the decision to terminate study drug treatment. These participants will continue to complete all other scheduled study visits for assessment of efficacy (i.e., UPCR (urinary protein / creatinine ratio), UACR (urinary albumin-to-creatinine ratio)) until completion of the final follow-up visit. All subjects will complete a safety follow-up visit 28 (± 7) days after the last dose of study drug.

[0122] Proteinuria will be assessed at multiple time points throughout the treatment and follow-up periods. Primary analysis time points are Day 1 and Week 13.

[0123] Study participants include male and female subjects with a confirmed APOL1 genotype and without diabetes / autoimmune-induced nephropathy. Participants will receive placebo or a low, medium, or high dose of Compound I for 13 weeks.

[0124] The primary endpoint for evaluating the effect on APOL1-mediated non-diabetic kidney disease is the percent change from baseline in UPCR at week 13. As used herein, "baseline value" is the average of the three screening UPCR values ​​used to determine eligibility. The primary analysis is based on a repeated measures mixed-effects model (MMRM) with change from baseline as the dependent variable.

[0125] The foregoing description discloses and describes merely exemplary embodiments of the present disclosure. Those skilled in the art will readily appreciate from such description and the accompanying drawings and claims that various changes, modifications, and variations can be made therein without departing from the spirit and scope of the present disclosure, as defined in the following claims. The present invention provides, for example, the following items. (Item 1) 1. A method for treating an APOL1 mediated disease, comprising administering to a subject a compound of formula I, [ka] a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof, to a patient in need thereof, and in a daily amount of from 2 mg to 100 mg. (Item 2) Item 10. The method of item 1, wherein the APOL1-mediated disease is an APOL1-mediated renal disease. (Item 3) 3. The method of item 2, wherein the APOL1-mediated renal disease is APOL1-dependent focal segmental glomerulosclerosis (FSGS). (Item 4) 3. The method of claim 2, wherein the APOL1-mediated kidney disease is non-diabetic kidney disease (NDKD). (Item 5) 5. The method according to any one of items 1 to 4, wherein the patient has an APOL1 genotype. (Item 6) 5. The method according to any one of items 1 to 4, wherein the patient has nephrotic range proteinuria. (Item 7) 5. The method according to any one of items 1 to 4, wherein the patient does not have proteinuria in the nephrotic syndrome range. (Item 8) 8. The method of any one of items 1 to 7, wherein Compound I, its deuterated derivative, and / or a pharmaceutically acceptable salt of Compound I or its deuterated derivative is administered in a daily amount of 5 mg to 200 mg, 10 mg to 150 mg, 15 mg to 100 mg, 20 mg to 80 mg, 25 mg to 75 mg, 30 mg to 60 mg, or 15 mg to 45 mg. (Item 9) 8. The method of any one of items 1 to 7, wherein Compound I, its deuterated derivative, and / or a pharmaceutically acceptable salt of Compound I or its deuterated derivative is administered in a daily amount of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 100 mg. (Item 10) 10. The method of any one of items 1 to 9, wherein Compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered in a daily amount of 15 mg or 45 mg. (Item 11) 11. The method of any one of items 1 to 10, wherein Compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered once daily or multiple times daily. (Item 12) 11. The method of any one of items 1 to 10, wherein Compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered every 24 hours (q24h). (Item 13) 13. The method of any one of items 1 to 12, wherein the method comprises administering Compound I or a deuterated derivative thereof. (Item 14) 13. The method of any one of items 1 to 12, wherein the method comprises administering a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof. (Item 15) 15. The method of any one of items 1 to 14, wherein Compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is comprised in a pharmaceutical composition. (Item 16) Item 16. The method of item 15, wherein the pharmaceutical composition is a tablet. (Item 17) 17. The method of embodiment 16, wherein the tablet is suitable for oral administration. (Item 18) 18. The method according to item 17, wherein the tablet for oral administration contains 15 mg of compound I. (Item 19) 19. The method of any one of items 16 to 18, wherein the tablet comprises cellulose, croscarmellose sodium, and / or sodium stearyl fumarate. (Item 20) 20. The method of claim 19, wherein the tablet further comprises a coating comprising polyvinyl alcohol (PVA), polyethylene glycol (PEG), titanium dioxide, and talc. (Item 21) 21. The method of any one of items 1 to 20, wherein the patient is in a fasting state. (Item 22) 21. The method according to any one of items 1 to 20, wherein the patient is in a fed state. (Item 23) 23. The method of any one of items 1 to 22, wherein compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of compound I or a deuterated derivative thereof is administered in combination with one or more therapeutic agents selected from an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a sodium-glucose cotransporter-2 (SGLT2) inhibitor, a renin inhibitor, a neprilysin inhibitor, a systemic corticosteroid, tacrolimus, cyclosporine, mycophenolate, and a mineralocorticoid receptor antagonist. (Item 24) 24. The method of claim 23, wherein the systemic corticosteroid is prednisone or a prednisone equivalent. (Item 25) 23. The method of any one of items 1 to 22, wherein compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of compound I or a deuterated derivative thereof is administered in combination with one or more therapeutic agents selected from an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a renin inhibitor, and a prednisone equivalent. (Item 26) 23. The method of any one of items 1 to 22, wherein Compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered in combination with an ACE inhibitor (ACEi) and an ARB. (Item 27) 23. The method of any one of items 1 to 22, wherein compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of compound I or a deuterated derivative thereof is administered in combination with an ACEi, an ARB, and prednisone. (Item 28) 28. The method of any one of items 1 to 27, wherein the patient is not concurrently administered any immunosuppressive agents other than systemic corticosteroids, tacrolimus, cyclosporine, and mycophenolate. (Item 29) 29. The method according to any one of items 1 to 28, wherein compound I is in substantially pure crystalline form A. (Item 30) 29. The method according to any one of items 1 to 28, wherein compound I is in crystalline form A. (Item 31) A pharmaceutical composition comprising 5 mg to 200 mg, 10 mg to 150 mg, 15 mg to 100 mg, 20 mg to 80 mg, 25 to 75 mg, 30 to 60 mg, or 15 mg to 45 mg of Compound I, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof. (Item 32) 32. The pharmaceutical composition of item 31, wherein the composition comprises 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 100 mg of Compound I, its deuterated derivative, and / or a pharmaceutically acceptable salt of Compound I or its deuterated derivative. (Item 33) 33. The pharmaceutical composition according to item 32, wherein the composition comprises 15 mg of Compound I. (Item 34) 33. The pharmaceutical composition according to item 32, wherein the composition comprises 30 mg of Compound I. (Item 35) 33. The pharmaceutical composition according to item 32, wherein the composition comprises 45 mg of Compound I. (Item 36) 33. The pharmaceutical composition according to item 32, wherein the composition comprises 60 mg of Compound I. (Item 37) 33. The pharmaceutical composition of item 32, wherein the composition comprises 75 mg of Compound I. (Item 38) 38. The pharmaceutical composition according to any one of items 31 to 37, wherein compound I is in substantially pure crystalline form A. (Item 39) 38. The pharmaceutical composition according to any one of items 31 to 37, wherein compound I is in crystalline form A.

Claims

1. A composition for treating an APOL1-mediated disease, comprising: (a) Compound I: 【Transformation 8】 (b) a deuterated derivative of Compound I; (c) a pharmaceutically acceptable salt of Compound I, and (d) a pharmaceutically acceptable salt of said deuterated derivative of Compound I. and one or more compounds selected from wherein Compound I, the deuterated derivative of Compound I, the pharmaceutically acceptable salt of Compound I, or the pharmaceutically acceptable salt of the deuterated derivative of Compound I is formulated for administration to a patient in need thereof and in a daily amount equivalent to 2 mg to 250 mg of Compound I.

2. The composition of claim 1, wherein the APOL1-mediated disease is an APOL1-mediated kidney disease.

3. The composition of claim 2, wherein the APOL1-mediated kidney disease is APOL1-dependent focal segmental glomerulosclerosis (FSGS).

4. The composition of claim 2, wherein the APOL1-mediated kidney disease is non-diabetic kidney disease (NDKD).

5. The composition of claim 1 , wherein the patient has an APOL1 genotype.

6. 10. The composition of claim 1, wherein the patient has nephrotic range proteinuria.

7. 10. The composition of claim 1, wherein the one or more compounds selected from Compound I, the deuterated derivative of Compound I, the pharmaceutically acceptable salt of Compound I, and the pharmaceutically acceptable salt of the deuterated derivative of Compound I are formulated for administration in a daily amount equivalent to 5 mg to 200 mg, 10 mg to 150 mg, 15 mg to 100 mg, 20 mg to 80 mg, 25 to 75 mg, 30 to 60 mg, or 15 mg to 45 mg of Compound I.

8. 2. The composition of claim 1, wherein the one or more compounds selected from Compound I, the deuterated derivative of Compound I, the pharmaceutically acceptable salt of Compound I, and the pharmaceutically acceptable salt of the deuterated derivative of Compound I are formulated for administration in a daily amount equivalent to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 100 mg of Compound I.

9. 2. The composition of claim 1, wherein the one or more compounds selected from Compound I, the deuterated derivative of Compound I, the pharmaceutically acceptable salt of Compound I, and the pharmaceutically acceptable salt of the deuterated derivative of Compound I are formulated for administration in a daily amount equivalent to 15 mg of Compound I.

10. The composition of claim 1, wherein the one or more compounds selected from Compound I, the deuterated derivative of Compound I, the pharmaceutically acceptable salt of Compound I, and the pharmaceutically acceptable salt of the deuterated derivative of Compound I are formulated for administration in a daily amount equivalent to 45 mg of Compound I.

11. 10. The composition of claim 1, wherein the composition is formulated for once-daily or multiple-daily administration.

12. 10. The composition of claim 1, wherein the composition is formulated for administration every 24 hours (q24h).

13. 2. The composition of claim 1, wherein the composition comprises Compound I or a deuterated derivative thereof.

14. The composition of claim 1 , wherein the composition comprises Compound I.

15. The composition of claim 1 , wherein the composition is a pharmaceutical composition.

16. 16. The composition of claim 15, wherein the pharmaceutical composition is in the form of a tablet.

17. The composition of claim 16, wherein the tablet is suitable for oral administration.

18. 18. The composition of claim 17, wherein the tablet for oral administration contains 15 mg of Compound I.

19. The composition of claim 17, wherein the tablet for oral administration contains 45 mg of compound I.

20. 17. The composition of claim 16, wherein the tablet comprises one or more additional ingredients selected from cellulose, croscarmellose sodium, and sodium stearyl fumarate.

21. 21. The composition of claim 20, wherein the tablet further comprises a coating comprising polyvinyl alcohol (PVA), polyethylene glycol (PEG), titanium dioxide, and talc.

22. The composition of claim 1 , wherein the patient is in a fasting state.

23. The composition of claim 1 , wherein the patient is in a fed state.

24. 10. The composition of claim 1, wherein the composition is formulated for administration in combination with one or more therapeutic agents selected from an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a renin inhibitor, and prednisone.

25. 10. The composition of claim 1, wherein the composition is formulated for administration in combination with an ACE inhibitor (ACEi) and an ARB.

26. 10. The composition of claim 1, wherein the composition is formulated for administration in combination with an ACEi, an ARB, and prednisone.

27. 2. The composition of claim 1, wherein Compound I is a substantially pure crystalline Form A characterized by an X-ray powder diffractogram having signals with at least two 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 26.3±0.2, 26.7±0.2, and 28.6±0.

2.

28. 2. The composition of claim 1, wherein Compound I is crystalline Form A characterized by an X-ray powder diffractogram having signals with at least two 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 26.3±0.2, 26.7±0.2, and 28.6±0.

2.

29. The tablet, 61% microcrystalline cellulose (intragranular), 2.4% croscarmellose sodium (intragranular), 1.6% sodium stearyl fumarate (intragranular), 17.5% microcrystalline cellulose (extragranular), 1.5% croscarmellose sodium (extragranular), and 1.0% Sodium stearyl fumarate (extragranular) 17. The composition of claim 16, further comprising:

30. A composition for treating an APOL1-mediated disease, comprising: Compound I: 【Transformation 8】 Including, wherein Compound I is formulated for administration to a patient in need thereof and in a daily amount of 15 mg.

31. A composition for treating an APOL1-mediated disease, comprising: Compound I: 【Transformation 8】 Including, wherein Compound I is formulated for administration to a patient in need thereof and in a daily amount of 45 mg.

32. (a) Compound I: 【Transformation 8】 (b) a deuterated derivative of Compound I; (c) a pharmaceutically acceptable salt of Compound I, and (d) a pharmaceutically acceptable salt of said deuterated derivative of Compound I. One or more compounds selected from A pharmaceutical composition comprising Compound I in an amount equivalent to 2 mg to 250 mg, 10 mg to 150 mg, 15 mg to 100 mg, 20 mg to 80 mg, 25 to 75 mg, 30 to 60 mg, or 15 mg to 45 mg.

33. 33. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition comprises one or more compounds selected from Compound I, the deuterated derivative of Compound I, the pharmaceutically acceptable salt of Compound I, and the pharmaceutically acceptable salt of the deuterated derivative of Compound I in an amount equivalent to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 100 mg of Compound I.

34. 34. The pharmaceutical composition of claim 33, wherein the pharmaceutical composition comprises 15 mg of Compound I.

35. 34. The pharmaceutical composition of claim 33, wherein the pharmaceutical composition comprises 45 mg of Compound I.

36. 33. The pharmaceutical composition of claim 32, wherein Compound I is a substantially pure crystalline Form A characterized by an X-ray powder diffractogram having signals with at least two 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 26.3±0.2, 26.7±0.2, and 28.6±0.

2.

37. 33. The pharmaceutical composition of claim 32, wherein compound I is crystalline form A characterized by an X-ray powder diffractogram having signals with at least two 2-theta values ​​selected from 9.5±0.2, 13.2±0.2, 14.4±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, 26.3±0.2, 26.7±0.2, and 28.6±0.

2.

38. The pharmaceutical composition comprising: 61% microcrystalline cellulose (intragranular), 2.4% croscarmellose sodium (intragranular), 1.6% sodium stearyl fumarate (intragranular), 17.5% microcrystalline cellulose (extragranular), 1.5% croscarmellose sodium (extragranular), and 1.0% Sodium stearyl fumarate (extragranular) 33. The pharmaceutical composition of claim 32, which is a tablet further comprising:

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