Methods for treating APOL-1-dependent focal segmental glomerulosclerosis

Abstract

The present application describes methods for inhibiting APOL1 and treating APOL1-mediated diseases, which comprise administering Compound I and / or a pharmaceutically acceptable salt thereof. The present application also describes a pharmaceutical composition comprising Compound I and / or a pharmaceutically acceptable salt thereof.

Description

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 986,096 filed on March 6, 2020, the contents of which are incorporated herein by reference in their entirety. The present disclosure relates to methods for 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), the methods comprising administering Compound 1, a pharmaceutically acceptable salt thereof, and / or a deuterated derivative of Compound 1 or a salt thereof. The present disclosure also provides a pharmaceutical composition comprising a therapeutic dose of Compound 1, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof.

[0002] NDKD is a kidney disease that involves damage to the podocytes or glomerular vascular bed that is not attributable to diabetes. FSGS is a rare kidney disease with an estimated global incidence of 0.2 to 1.1 / 100,000 / year. FSGS and NDKD are caused by damage to the podocytes, which are part of the glomerular filtration barrier, leading to proteinuria. Patients with proteinuria are at higher risk for developing end-stage kidney disease (ESKD) and for proteinuria-related complications such as infections or thromboembolic events. There is no standardized treatment regimen or approved medication 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 based on blood pressure control and blockade of the renin-angiotensin system.

[0003] FSGS and NDKD can be divided into distinct subgroups based on the underlying etiology. A homogeneous subgroup of FSGS is characterized by the presence of independent common sequence variants in the apolipoprotein L1 (APOL1) gene, called G1 and G2, which are referred to as "APOL1 risk alleles". G1 encodes a pair of related nonsynonymous amino acid changes (S342G and I384M), G2 encodes 2 amino acid deletions near the C-terminus of the protein (N388del:Y389del), and G0 is the ancestral (low-risk) allele. A unique phenotype of NDKD has also been found in patients with APOL1 genetic risk variants. In both APOL1-mediated FSGS and NDKD, higher degrees of proteinuria and more rapid renal function loss occur in patients with two risk alleles compared to patients with the same disease who have no or only 1 APOL1 genetic risk variant.

[0004] The APOL1 gene is expressed in multiple organs in humans, including the liver and kidneys. APOL1 protects against parasitic infections caused by Trypanosoma brucei (Tbbrucei). APOL1 is endocytosed by T. brucei and transported to lysosomes, where it inserts into the lysosomal membrane and forms holes that cause swelling and death of the parasite. Although all three APOL1 variants (G0, G1, and G2) have the ability to lyse T. brucei, the APOL1 G1 and G2 variants provide additional protection against parasite species that have evolved serum resistance-associated proteins (SRAs) that inhibit APOL1 G0; these species cause sleeping sickness. The G1 and G2 variants escape inhibition by SRA; G1 provides additional protection against Tbgambiense (which causes West African sleeping sickness), while G2 provides 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 proteinuria, decreased renal function, podocyte abnormalities, and glomerulosclerosis. Consistent with these data, the G1 and G2 variants of APOL1 play a causal role in inducing FSGS and accelerating its progression in humans. Individuals with APOL1 risk alleles (i.e., homozygotes or compound heterozygotes for APOL1 G1 or APOL1 G2 alleles) have an increased risk of developing FSGS, and if they develop FSGS, they will be at risk of a rapid decline in renal function. Therefore, inhibition of APOL1 may have a positive effect on individuals carrying APOL1 risk alleles.

[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 APOL1-induced lysis of Trypanosoma brucei. Compound I can be depicted as having the following structure:

[0007]

[0008] Compound 1, its preparation method and physicochemical data are disclosed in co-pending U.S. application No. 16 / 717,099 and PCT International Application No. PCT / US2019 / 066746 (disclosed as "Compound 2"), both of which are incorporated herein by reference in the present disclosure.

[0009] The present disclosure provides methods for inhibiting APOL1-induced cell death and treating APOL1-mediated diseases, including APOL1-mediated kidney diseases such as FSGS and / or NDKD, by administering a pharmaceutical composition 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. The methods and pharmaceutical compositions disclosed herein provide treatment for individuals with APOL1-mediated kidney diseases associated with one or more APOL1 risk alleles and with or without proteinuria (i.e., for individuals with nephrotic range proteinuria, the protein to creatinine ratio is >3 g / g; for individuals with sub-nephrotic range proteinuria, the protein to creatinine ratio is >0.15 g / g to <3.0 g / g). The methods and pharmaceutical compositions disclosed herein provide treatment for individuals with APOL1-mediated kidney diseases associated with one or more APOL1 risk alleles, with or without nephrotic range proteinuria.

[0010] In some embodiments, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of Compound 1, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative of Compound 1.

[0011] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising Compound 1, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative of Compound 1, which may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier. In some embodiments, the present disclosure provides a method for treating APOL1-mediated kidney diseases, including FSGS and / or NDKD, comprising administering Compound 1, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative of Compound 1 to a subject in need thereof, optionally as part of a pharmaceutical composition comprising at least one additional active ingredient. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 An XRPD diffraction pattern of Compound 1 Form A is depicted.

[0013] Figure 2 Depicted is the solid state of Compound 1 Form A 13 C NMR spectroscopy.

[0014] definition

[0015] As used throughout this disclosure, "Compound 1" 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 drawn as having the following structure:

[0016]

[0017] Compound I may 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.

[0018] As used herein, the term "APOL1" means apolipoprotein L1 protein and the term "APOL1" means apolipoprotein L1 gene.

[0019] 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 renal function and is associated with 2 common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del).

[0020] As used herein, the term "NDKD" means non-diabetic kidney disease, which is a kidney disease involving damage to the podocyte or glomerular vascular bed that is not attributable to diabetes and is associated with 2 common APOL1 genetic variants (G1: S342G: I384M and G2: N388del: Y389del). This includes, but is not limited to, hypertensive kidney disease, lupus, minimal change nephropathy, membranous nephropathy, steroid-resistant or steroid-sensitive nephrotic syndrome, and allogeneic renal transplant dysfunction. In some embodiments, it includes chronic kidney disease in non-diabetic patients with hypertension and proteinuria ≥ 0.2 g / g but does not include chronic kidney disease caused by infection, malignancy, obstructive or autoimmune disorders.

[0021] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0022] As used herein, the term "treatment" generally refers to the improvement of APOL1-mediated diseases, including the improvement of APOL1-mediated kidney diseases such as but not limited to FSGS and / or NDKD, or the improvement of 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, the following: complete or partial remission, reduction in the risk of renal failure (e.g., ESRD) and disease-related complications (e.g., edema, susceptibility to infection, or thromboembolic events). The improvement of any of these symptoms or the reduction of their severity can be easily assessed according to methods and techniques known in the art or subsequently developed.

[0023] As used herein, a "therapeutically effective" amount of Compound 1 refers to an amount of Compound 1, a deuterated derivative of Compound 1, or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof that produces the desired effect of its administration (e.g., improving symptoms of APOL1-mediated renal disease, reducing the severity of APOL1-mediated renal disease or symptoms of APOL1-mediated renal disease, and / or reducing the progression of APOL1-mediated renal disease or symptoms of APOL1-mediated renal disease, improving symptoms of FSGS and / or NDKD, reducing the severity of FSGS and / or NDKD or symptoms of FSGS and / or NDKD, and / or slowing or reducing FSGS and / or NDKD or the progression of symptoms of FSGS and / or NDKD). The exact amount of a therapeutically effective dose will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding). In some embodiments, the therapeutically effective dose of Compound 1 is 2 mg to 250 mg. Other suitable therapeutically effective doses are disclosed herein.

[0024] As used herein, "ULN" means "upper limit of normal."

[0025] As used herein, the term "in combination with" when referring to two or more compounds, agents or additional active pharmaceutical ingredients means that the two or more compounds, agents or active pharmaceutical ingredients are administered to the patient before, simultaneously with, or after each other.

[0026] When referring to the compounds of the present disclosure, the term "compound" refers to a collection of molecules having the same chemical structure except that there may be isotopic variations between the constituent atoms of the molecules, unless otherwise specified 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). Therefore, it should be clear to those skilled in the art that a compound represented by a specific chemical structure containing an indicated deuterium atom will also contain a smaller amount of isotopologues having hydrogen atoms at one or more specified deuterium positions in the structure. The relative amount of such isotopologues in the compounds of the present disclosure will depend on many factors, including the isotopic purity of the reagents used to prepare the compounds and the incorporation efficiency of the isotopes in the various synthetic steps used to prepare the compounds. However, as explained above, the relative amount of all such isotopologues will be less than 49.9% of the compound. In other embodiments, the relative amount of all such isotopologues 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.

[0027] As used herein, the terms "crystalline form" and "form" refer interchangeably to a crystal structure (or polymorph) having a specific molecular packing arrangement in the 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 1" refers to a unique crystalline form that can be identified and distinguished from one another by any one or more characterization techniques, including, for example, XRPD, single crystal X-ray diffraction, and SSNMR. In some embodiments, Compound 1 crystalline Form A is characterized by an X-ray powder diffraction pattern having one or more signals at one or more specified 2θ values ​​(°2θ).

[0028] As used herein, the term "SSNMR" refers to the analytical characterization method of solid-state nuclear magnetic resonance. SSNMR spectra can be recorded under ambient conditions for any magnetically active isotopes present in the sample. Typical examples of active isotopes of 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 Pt.

[0029] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded using a diffractometer under ambient conditions in transmission or reflection geometry.

[0030] As used herein, the terms "X-ray powder diffraction pattern", "X-ray powder diffraction pattern", "XRPD pattern" refer interchangeably to an experimentally obtained pattern that plots signal position (on the abscissa) versus signal intensity (on the ordinate). For amorphous materials, an X-ray powder diffraction pattern may include one or more broad signals; while for crystalline materials, an X-ray powder diffraction pattern may include one or more signals, each identified by its angular value measured in degrees 2θ (°2θ), plotted on the abscissa of the X-ray powder diffraction pattern, which may be expressed as "signal at °2θ of ...", "signal at 2θ values ​​of ...", and / or "signal at at least ... selected from 2θ values ​​of ...".

[0031] As used herein, a "signal" or "peak" refers to a point in an XRPD pattern where the intensity, measured in counts, is at a local maximum. One of ordinary skill in the art will recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may not be apparent, for example, to the naked eye. Indeed, one of ordinary skill in the art will recognize that some industry-recognized methods are capable of and are applicable to determining whether a signal is present in a pattern, such as Rietveld refinement.

[0032] As used herein, "signal at °2θ", "signal at a 2θ value of..." and / or "signal at at least ... 2θ values ​​selected from..." refers to the X-ray reflection positions (°2θ) as measured and observed in an X-ray powder diffraction experiment.

[0033] The repeatability of the angle value is within the range of ±0.2°2θ, ie the angle value can be at the stated angle value +0.2°2θ, at the angle value −0.2°2θ, or at any value between these two endpoints.

[0034] The terms "signal intensity" and "peak intensity" refer interchangeably to the relative signal intensity within a given X-ray powder diffraction pattern. Factors that may affect the relative signal or peak intensity include sample thickness and preferred orientation (eg, crystalline particles are not randomly distributed).

[0035] As used herein, the term "X-ray powder diffraction pattern having signals at 2θ values ​​of" refers to an XRPD pattern containing X-ray reflection positions (° 2θ) as measured and observed in an X-ray powder diffraction experiment.

[0036] As used herein, an X-ray powder diffraction pattern is "substantially similar to a [particular] pattern" when at least 90% (e.g., at least 95%, at least 98%, or at least 99%) of the signals in the two diffraction patterns overlap. In determining "substantial similarity," one of ordinary skill in the art will understand that even for the same crystalline form, there may be variations in the intensity and / or signal positions in an XRPD diffraction pattern. Thus, one of ordinary skill in the art will understand that a signal maximum in an XRPD diffraction pattern, referred to herein as 2θ degrees (°2θ), typically means that the value is reported ±0.2°2θ, which is a variance recognized in the industry.

[0037] As used herein, an SSNMR spectrum is "substantially similar to a [particular] figure" when at least 90% (e.g., at least 95%, at least 98%, or at least 99%) of the signals in the two spectra overlap. In determining "substantial similarity," one of ordinary skill in the art will appreciate that even for the same crystalline form, there may be variations in the intensity and / or signal positions in the SSNMR spectra. Thus, one of ordinary skill in the art will appreciate that a reference herein to a maximum value (in ppm) of a signal in an SSNMR spectrum generally means that the value is reported ±0.2 ppm, which is a variance recognized in the industry.

[0038] As used herein, a crystalline form is "substantially pure" when it represents an amount equal to or greater than 90% by weight of the sum of all solid forms in a sample as determined by methods according to the art, such as quantitative XRPD. In some embodiments, a solid form is "substantially pure" when it represents an amount equal to or greater than 95% by weight of the sum of all solid forms in a sample. In some embodiments, a solid form is "substantially pure" when it represents an amount equal to or greater than 99% by weight of the sum of all solid forms in a sample.

[0039] As used herein, the term "pharmaceutically acceptable salt" refers to a salt form of a compound of the present disclosure, wherein the salt is non-toxic. Pharmaceutically acceptable salts of compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0040] Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of the article reproduced below provides the following pharmaceutically acceptable salts.

[0041] Table 1. Exemplary pharmaceutically acceptable salts

[0042]

[0043]

[0044] Non-limiting examples of pharmaceutically acceptable acid addition 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, ascorbic acid, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 alkyl) 4 Salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium and magnesium. Other 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, low carbon alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0045] As used herein, a "deuterated derivative of Compound I" refers to a form of Compound I in which at least one hydrogen has been replaced with a deuterium atom. It should be recognized that, depending on the source of the chemical materials used in the synthesis, some variation in natural isotopic abundance will occur in the synthesized compounds. Despite this variation, the concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the extent of stable isotopic substitution of the deuterated derivatives described herein. Therefore, unless otherwise specified, when referring to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen has been replaced with deuterium at a level far above its natural isotopic abundance (typically about 0.015%). In some embodiments, the deuterated derivatives of the present disclosure have an isotopic enrichment factor 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) per deuterium atom.

[0046] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0047] In some embodiments, the present disclosure also relates to methods of treatment using isotopically labeled compounds of Compound 1 (which in some embodiments are referred to as Compound 1) or pharmaceutically acceptable salts thereof, wherein the formulas and variables of such compounds and salts are each and independently as described above or in any other embodiment described above, with the proviso that one or more atoms therein have been replaced with one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of atoms normally found in nature (isotopic labeling). Examples of isotopes that are commercially available and suitable for the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively. 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 p. 32 p. 35 S. 18 F and 36 Cl.

[0048] Isotope-labeled compounds and salts can be used in a variety of beneficial ways. They can be used in pharmaceuticals and / or various types of assays, such as substrate tissue distribution assays. For example, tritium ( 3 H) and / or carbon-14 ( 14C) 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. 2 H) The labeled compound is therapeutically useful and is comparable to non 2 H-labeled compounds have potential therapeutic advantages. In general, deuterium ( 2 H) labeled compounds and salts can have higher metabolic stability due to the kinetic isotope effect described below. Higher metabolic stability is directly converted into increased half-life in vivo or lower dosage, which can be desirable. Isotope-labeled compounds and salts can generally be prepared by replacing non-isotope-labeled reactants with readily available isotope-labeled reactants by the procedures disclosed in the synthetic schemes and related descriptions, examples and preparations herein.

[0049] In some embodiments, isotopically labeled compounds and salts are deuterated ( 2 In some embodiments, isotopically labeled compounds and salts are deuterated ( 2 H) label, in which one or more hydrogen atoms have been replaced by deuterium. Deuterium is represented by "D" in chemical structures.

[0050] Through the primary kinetic isotope effect, deuterium ( 2 H) labeled compounds and salts relative to non-deuterated ( 2 H) labeled compounds or salts may undergo altered oxidative metabolic rates. The primary kinetic isotope effect is a change in the rate of a chemical reaction caused by isotopic nuclear exchange, which in turn is caused by a change in the ground state energy required to form a covalent bond after the isotope exchange. The exchange of heavier isotopes generally results in a decrease in the ground state energy of a chemical bond, and therefore in a reduction in rate-limiting bond breakage. If bond breakage occurs in or near a saddle point region along the coordinates of a multi-product reaction, the product distribution ratio can change significantly. For example, if deuterium is bonded to a carbon atom at a non-exchangeable position, then k M / k D = 2-7 ​​rate differences are typical. For further discussion, see SL Harbeson and RD Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, which is incorporated herein by reference in its entirety.

[0051] When used in conjunction with the dosage, amount or weight percentage of the ingredients of a composition or dosage form, the terms "about" and "approximately" include the value of the specified dosage, amount or weight percentage or the range of the dosage, amount or weight percentage that a person of ordinary skill in the art believes can provide a pharmacological effect equivalent to the pharmacological effect obtained from the specified dosage, amount or weight percentage. The terms "about" and "approximately" can refer to an acceptable error of a specific value determined by those skilled in the art, which depends in part on how to measure or determine the value. 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.

[0052] One of ordinary skill in the art will recognize that when disclosing an amount of "a compound or a deuterated derivative thereof or a pharmaceutically acceptable salt of a compound or a deuterated derivative thereof," the amount of the pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound or a deuterated derivative thereof. It should be noted that the amounts of the compounds or pharmaceutically acceptable salts thereof disclosed herein are in 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 pharmaceutically acceptable salt of Compound I at a concentration equal to 100 mg of Compound I.

[0053] As used herein, the administration of a "daily" amount of Compound I or its 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 the patient may be administered once or more in a day, such as twice a day or three times a day (wherein each of the multiple administrations includes administering an amount of Compound I or its 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 its deuterated derivative or a pharmaceutically acceptable salt thereof may consist of administering Compound I or its deuterated derivative or a pharmaceutically acceptable salt thereof in the form of a single composition (e.g., a single dose, such as a single tablet or a single capsule) or in the form of multiple compositions (e.g., multiple doses, such as multiple (i.e., two or more) tablets and / or capsules).

[0054] In some embodiments, Compound 1 used in the methods and compositions of the present invention is in crystalline Form A. In some embodiments, Compound 1 is in substantially pure crystalline Form A. In some embodiments, Compound 1 Form A is characterized by an X-ray powder diffraction pattern substantially similar to Figure 1In some embodiments, Compound 1 Form A is characterized by an X-ray powder diffraction pattern having signals at at least two 2θ 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 1 Form A is characterized by an X-ray powder diffraction pattern having signals at at least three 2θ 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 1 Form A is characterized by an X-ray powder diffraction pattern having signals at at least four 2θ 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 1 Form A is characterized by an X-ray powder diffraction pattern having signals at at least five 2θ 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 1 Form A is characterized by an X-ray powder diffraction pattern having signals at at least six 2θ 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 1 Form A is characterized by an X-ray powder diffraction pattern having signals at at least seven 2θ 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 1 Form A is characterized by an X-ray powder diffraction pattern having signals at at least eight 2θ 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 1 Form A is characterized by an X-ray powder diffraction pattern having signals at the following 2θ 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.

[0055] In some embodiments, Compound 1 Form A used in the methods and compositions of the invention is characterized by an X-ray powder diffraction pattern having a signal at at least one 2θ 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 1 Form A is characterized by an X-ray powder diffraction pattern 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 1 Form A is characterized by an X-ray powder diffraction pattern 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 1 Form A is characterized by an X-ray powder diffraction pattern 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 1 Form A is characterized by an X-ray powder diffraction pattern 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 1 Form A is characterized by an X-ray powder diffraction pattern 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 1 Form A is characterized by an X-ray powder diffraction pattern having signals at at least seven 2θ 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 1 Form A is characterized by an X-ray powder diffraction pattern 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 1 Form A is characterized by an X-ray powder diffraction pattern having signals at at least nine 2θ 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 1 Form A is characterized by an X-ray powder diffraction pattern having signals at at least ten 2θ 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.

[0056] In some embodiments, Compound 1 used in methods and compositions of the invention is Compound 1 Form A. In some embodiments, Compound 1 used in methods and compositions of the invention is substantially pure Form A.

[0057] In some embodiments, Compound 1 Form A used in the methods and compositions of the invention is characterized by 13The CNMR spectrum has a signal at at least one ppm value selected from 178.7±0.2ppm, 154.4±0.2ppm, 127.8±0.2ppm, 125.2±0.2ppm, 102.0±0.2ppm, 59.3±0.2ppm, 38.9±0.2ppm, and 24.4±0.2ppm. In some embodiments, Compound 1 Form A is characterized by 13 The C NMR spectrum 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. In some embodiments, Compound 1 Form A is characterized by 13 The C NMR spectrum 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. In some embodiments, Compound 1 Form A is characterized by 13 The C NMR spectrum 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. In some embodiments, Compound 1 Form A is characterized by 13 The C NMR spectrum had 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.

[0058] In some embodiments, Compound I is a substantially crystalline solid. In some embodiments, the crystalline solid consists of 75% to 99% Form A, relative to the total weight of crystalline solid Compound I. In some embodiments, the crystalline solid consists of 80% to 99% Form A, relative to the total weight of crystalline solid Compound I. In some embodiments, the crystalline solid consists of 85% to 99% Form A, relative to the total weight of crystalline solid Compound I. In some embodiments, the crystalline solid consists of 90% to 99% Form A, relative to the total weight of crystalline solid Compound I. In some embodiments, the crystalline solid consists of 95% to 99% Form A, relative to the total weight of crystalline solid Compound I.

[0059] In some embodiments, the present disclosure provides methods of treating APOL1-mediated diseases with Compound 1, Compound 1 Form A, deuterated derivatives of Compound 1, and / or pharmaceutically acceptable salts of Compound 1 or deuterated derivatives thereof. In some embodiments, Compound 1, Compound 1 Form A, deuterated derivatives of Compound 1, and / or pharmaceutically acceptable salts of Compound 1 or deuterated derivatives thereof are administered daily. In some embodiments, Compound 1, Compound 1 Form A, deuterated derivatives of Compound 1, and / or pharmaceutically acceptable salts of Compound 1 or deuterated derivatives thereof are administered once a day or multiple times a day, such as twice a day or three times a day. In some embodiments, Compound 1, Compound 1 Form A, deuterated derivatives of Compound 1, and / or pharmaceutically acceptable salts of Compound 1 or deuterated derivatives thereof are administered once a day. In some embodiments, Compound 1, Compound 1 Form A, deuterated derivatives of Compound 1, and / or pharmaceutically acceptable salts of Compound 1 or deuterated derivatives thereof are administered twice a day. In some embodiments, Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof is administered three times a day.

[0060] In some embodiments, Compound 1, Compound 1 Form A, deuterated derivatives of Compound 1, and / or pharmaceutically acceptable salts of Compound 1 or deuterated derivatives thereof are administered as a single composition. In some embodiments, Compound 1, Compound 1 Form A, deuterated derivatives of Compound 1, and / or pharmaceutically acceptable salts of Compound 1 or deuterated derivatives thereof are administered as multiple compositions (e.g., each administration as multiple tablets and / or multiple pills). Thus, in some embodiments, Compound 1, Compound 1 Form A, deuterated derivatives of Compound 1, and / or pharmaceutically acceptable salts of Compound 1 or deuterated derivatives thereof are administered once daily as a single composition. In some embodiments, Compound 1, Compound 1 Form A, deuterated derivatives of Compound 1, and / or pharmaceutically acceptable salts of Compound 1 or deuterated derivatives thereof are administered once daily as multiple compositions, and the multiple compositions are administered simultaneously.

[0061] In some embodiments, a therapeutically effective amount of Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof is administered at a daily dose 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 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of a deuterated derivative thereof is administered at a daily dose 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.

[0062] In some embodiments, Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof is administered once a day, twice a day, or three times a day 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 to 75 mg, 30 to 60 mg, or 15 mg to 45 mg. In some embodiments, Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof is administered once a day, twice a day, or three times a day 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. In some embodiments, Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof is administered once a day 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 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. Compound 1 Form A, deuterated derivatives of Compound 1, and / or pharmaceutically acceptable salts of Compound 1 or deuterated derivatives thereof are 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 (i.e., the total amount per day) in two portions (which may be equal or unequal) throughout the day.Reference to administering Compound I, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt of a deuterated derivative thereof in an amount "twice a day" refers to administering an amount of Compound I, Compound I Form A, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof twice a day, wherein each of the two administrations comprises administering an amount of Compound I, Compound I Form A, a deuterated derivative of Compound I, and / or a pharmaceutically acceptable salt thereof that is less than the daily amount, but wherein the sum of these amounts administered in one day equals the daily amount.

[0063] 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 every 8 hours ("q8h"), every 12 hours ("q12h"), or every 24 hours ("q24h"). In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of deuterated derivatives thereof are administered once every 8 hours (q8h). In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of deuterated derivatives thereof are administered once every 12 hours (q12h). In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of deuterated derivatives thereof are administered once every 24 hours (q24h).

[0064] In some embodiments, Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof is administered once 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.

[0065] In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or a pharmaceutically acceptable salt of Compound I or a deuterated derivative thereof is administered once every 24 hours (q24h) 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. In some embodiments, Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or a pharmaceutically acceptable salt thereof is administered once every 24 hours (q24h) 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.

[0066] 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 once every 24 hours (q24h) in an amount of 15 mg. 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 once every 24 hours (q24h) in an amount of 30 mg. 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 once every 24 hours (q24h) in an amount of 45 mg. 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 once every 24 hours (q24h) in an amount of 60 mg. In some embodiments, Compound 1, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof is administered once every 24 hours (q24h) in an amount of 75 mg.

[0067] In some embodiments, Compound 1 Form A is administered once every 24 hours (q24h) in an amount of 15 mg. In some embodiments, Compound 1 Form A is administered once every 24 hours (q24h) in an amount of 30 mg. In some embodiments, Compound 1 Form A is administered once every 24 hours (q24h) in an amount of 45 mg. In some embodiments, Compound 1 Form A is administered once every 24 hours (q24h) in an amount of 60 mg. In some embodiments, Compound 1 Form A is administered once every 24 hours (q24h) in an amount of 75 mg.

[0068] In some embodiments, Compound 1 Form A is administered once every 24 hours (q24h) in an amount of 15 mg to 30 mg. In some embodiments, Compound 1 Form A is administered once every 24 hours (q24h) in an amount of 30 mg to 45 mg. In some embodiments, Compound 1 Form A is administered once every 24 hours (q24h) in an amount of 45 mg to 60 mg. In some embodiments, Compound 1 Form A is administered once every 24 hours (q24h) in an amount of 60 mg to 75 mg.

[0069] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof, and the composition may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from the following: Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof, and at least one pharmaceutically acceptable carrier.

[0070] Compound 1, Compound 1 Form A, deuterated derivatives of Compound 1, and / or pharmaceutically acceptable salts of Compound 1 or deuterated derivatives thereof can be administered in a single pharmaceutical composition or in separate pharmaceutical compositions. Such pharmaceutical compositions can be formulated for administration once a day (i.e., every 24 hours (q24h)) or multiple times a day, such as twice a day or three times a day.

[0071] 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 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), enkephalinase inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, renin inhibitors, immunosuppressants such as tacrolimus, mycophenolate mofetil, 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, enkephalinase inhibitors, and systemic corticosteroids (e.g., prednisone or prednisone equivalents). In certain embodiments, Compound 1, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof is administered in combination with an ACE inhibitor (ACEi) and an ARB. In certain embodiments, Compound 1, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof is administered in combination with an ACE inhibitor (ACEi), an ARB, and prednisone or a prednisone equivalent.

[0072] As used herein, the term "angiotensin converting enzyme inhibitor" or "ACE inhibitor" refers to a class of drugs, such as small molecule organic chemical compounds (≤1 kDa) or large biological molecules 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, which block the formation of the natural chemical angiotensin I that narrows blood vessels, thereby causing relaxation of blood vessels and a reduction in blood, which results in lower blood pressure and reduced oxygen demand by the heart. Non-limiting examples of ACE inhibitors include lisinopril, Lisinopril and hydrochlorothiazide Benazepril (Lotensin), captopril (Capoten), enalapril Zofenopril, Perindopril Trandolapril Quinapril Ramipril

[0073] As used herein, the term "angiotensin receptor blocker" or "ARB" refers to a class of drugs, such as substances such as small organic chemical compounds (≤1 kDa) or large biological molecules 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, which block the action of angiotensin I that narrows blood vessels (unlike ACE inhibitors that block formation), thereby causing relaxation of blood vessels and a reduction in blood, which results in lower blood pressure and reduced oxygen demand by the heart. Non-limiting examples of ARBs include losartan Irbesartan Olmesartan Telmisartan Candesartan Valsartan Fimasartan, Azilsartan Eprosartan and losartan potassium-hydrochlorothiazide

[0074] As used herein, the term "renin inhibitor" refers to a class of drugs, such as substances, such as small organic chemical compounds (≤ 1 kDa) or large biological molecules 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 Aliskiren should not be taken without an ACE inhibitor or ARB because of the risk of serious complications, including stroke.

[0075] As used herein, the term "enkephalinase inhibitor" refers to a class of drugs, such as substances, such as small molecule organic chemical compounds (≤1 kDa) 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, which prevent the activity of enkephalinase on signaling peptides such as enkephalin, substance P, endothelin, atrial natriuretic peptide. Enkephalinase is expressed in many types of tissues, but is particularly abundant in the kidney. It is a zinc-dependent metalloproteinase that cleaves and inactivates several peptide hormones, including glucagon, enkephalin, 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, olapatrilat, ecamprol, and candoxatril.

[0076] As used herein, the term "sodium-glucose co-transporter 2 inhibitor" or "SGLT2 inhibitor" refers to a class of drugs, such as substances, such as small molecule organic chemical compounds (≤1 kDa) or large biological molecules 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, which have the activity of inhibiting sodium-glucose transporter 2 (SGLT2). Non-limiting examples of SGLT2 inhibitors include empagliflozin Canagliflozin Dapagliflozin Repagliflozin (including repagliflozin etabonate BHV091009, ipragliflozin IASP-1941 or ), HM41322, bepagliflozin, erpagliflozin Sogliflozin, Rupagliflozin, Togliflozin Sergliflozin etabonate or any pharmaceutically acceptable salt thereof. Other examples of SGLT2 inhibitors are described in WO01 / 027128, WO04 / 013118, WO04 / 080990, EP1852439A1, WO01 / 27128, WO03 / 099836, WO2005 / 092877, WO2006 / 034489, WO2006 / 064033, WO2006 / 117359, WO2 006 / 117360, 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.

[0077] As used herein, the term "systemic corticosteroids" refers to corticosteroids administered orally or by injection, and does not include corticosteroids used in the eye, ear or nose, and on the skin. Non-limiting examples of systemic corticosteroids include prednisone or prednisone equivalents (e.g., prednisolone, methylprednisolone), beclomethasone, betamethasone, dexamethasone, hydrocortisone, and triamcinolone.

[0078] As used herein, the term "mineralocorticoid receptor antagonist" refers to a class of drugs, such as substances, such as small molecule organic chemical compounds (≤1 kDa) or large biomolecules such as peptides (e.g., soluble peptides), proteins (e.g., antibodies), nucleic acids (e.g., siRNA) or a conjugate combining any two or more of the foregoing, which has the activity of antagonizing the effect of aldosterone (a mineralocorticoid) on the mineralocorticoid receptor. Small molecule mineralocorticoid receptor antagonists can be steroidal or non-steroidal compounds, and can be spironolactone, in which the structural features of cyclic esters are screwed to another ring system. Non-limiting examples of mineralocorticoid receptor antagonists include spironolactone, eplerenone, canrenone, finerenone and mexrenone.

[0079] In some embodiments, the present disclosure provides a pharmaceutical composition comprising 2 mg to 250 mg of Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 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 to 75 mg, 30 to 60 mg, or 15 mg to 45 mg of Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 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.

[0080] 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 its deuterated derivative, and at least one pharmaceutically acceptable carrier.

[0081] 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.

[0082] In some embodiments, the patient receiving Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof, or a pharmaceutical composition comprising the same is in a fasting state. As used herein, a patient in a "fasting state" does not eat or drink any food or beverage (except water) for at least two hours (such as at least four hours) before and at least two hours after administration of Compound 1, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof, or a pharmaceutical composition comprising the same.

[0083] In some embodiments, the patient to whom 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 administered is in a fed state. As used herein, a patient in a "fed state" has not eaten or drunk any food or beverage (except water) for at least eight hours (such as at least ten hours) before starting a meal and has started a meal within 30 minutes of administering 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 has eaten the entire meal in 30 minutes or less. In some embodiments, no additional food is allowed for at least two hours (such as four 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, unlimited drinking of water may be initiated 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, unlimited drinking of water may be initiated at least one hour after administration. In some embodiments, the meal is a high-fat meal, such as a meal containing a total of about 800-1000 calories and containing 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 a total of about 500-600 calories and containing 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 a total of about 500-600 calories and containing about 30-35% fat and / or about 20 grams of fat.

[0084] The pharmaceutical composition comprising Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, at least one pharmaceutically acceptable is selected from a pharmaceutically acceptable filler, a disintegrant, a surfactant, a binder, a lubricant.

[0085] As used herein, "at least one pharmaceutically acceptable carrier" includes any and all solvents, diluents, other liquid vehicles, dispersing aids, suspending aids, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders and lubricants suitable for the specific dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York disclose various carriers for formulating pharmaceutical compositions and known techniques for preparing them. Unless any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesirable biological effects or otherwise interacting with any other components of the pharmaceutical composition in a harmful manner, its use is expected to be within the scope of the present disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), mixtures of saturated vegetable fatty acid partial glycerides, water, salts and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars (such as lactose, glucose, and sucrose) , starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), 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, ethanol, phosphate buffer, nontoxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives and antioxidants.

[0086] The pharmaceutical compositions described herein can be used to treat APOLI-mediated diseases, including APOL1-mediated kidney diseases, such as FSGS and / or NDKD. In some embodiments, the pharmaceutical compositions described herein can be used to treat APOL1-mediated kidney diseases. In some embodiments, the pharmaceutical compositions described herein can be used to treat FSGS. In some embodiments, the pharmaceutical compositions described herein can be used to treat NDKD.

[0087] Any suitable pharmaceutical formulation known in the art can be used for the composition comprising Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof. In some embodiments, the pharmaceutical composition employed in the therapy of the present disclosure is a tablet. In some embodiments, the tablet is suitable for oral administration.

[0088] In some embodiments, pharmaceutical compositions of the present disclosure (including but not limited to tablets) comprise Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or a pharmaceutically acceptable salt of Compound I or its deuterated derivatives, and cellulose. In some embodiments, pharmaceutical compositions of the present disclosure (including but not limited to tablets) comprise Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or a pharmaceutically acceptable salt of Compound I or its deuterated derivatives, and cross-linked sodium carboxymethylcellulose. In some embodiments, pharmaceutical compositions of the present disclosure (including but not limited to tablets) comprise Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or a pharmaceutically acceptable salt of Compound I or its deuterated derivatives, and sodium stearyl fumarate. In some embodiments, pharmaceutical compositions of the present disclosure (including but not limited to tablets) comprise Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or a pharmaceutically acceptable salt of Compound I or its deuterated derivatives, and lactose monohydrate. In some embodiments, pharmaceutical compositions of the present disclosure (including but not limited to tablets) comprise Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or its deuterated derivatives, and hypromellose acetate succinate. In some embodiments, pharmaceutical compositions of the present disclosure (including but not limited to tablets) comprise Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or its deuterated derivatives, cellulose, and cross-linked sodium carboxymethyl cellulose. In some embodiments, pharmaceutical compositions of the present disclosure (including but not limited to tablets) comprise Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or its deuterated derivatives, cellulose, cross-linked sodium carboxymethyl cellulose, and lactose monohydrate. In some embodiments, pharmaceutical compositions of the present disclosure (including but not limited to tablets) comprise Compound 1, Compound 1 Form A, deuterated derivatives of Compound 1, and / or pharmaceutically acceptable salts of Compound 1 or deuterated derivatives thereof, cellulose, cross-linked sodium carboxymethyl cellulose, hypromellose acetate succinate, and lactose monohydrate. In some embodiments, pharmaceutical compositions of the present disclosure (including but not limited to tablets) comprise Compound 1, Compound 1 Form A, deuterated derivatives of Compound 1, and / or pharmaceutically acceptable salts of Compound 1 or deuterated derivatives thereof, cellulose, cross-linked sodium carboxymethyl cellulose, lactose monohydrate, hypromellose acetate succinate, and sodium stearyl fumarate.

[0089] In some embodiments, tablets containing 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 include a coating. In some embodiments, tablets containing Compound I, Compound I Form A, deuterated derivatives of Compound I, and / or pharmaceutically acceptable salts of Compound I or deuterated derivatives thereof further include a coating comprising polyvinyl alcohol (PVA), polyethylene glycol (PEG), titanium dioxide, and talc, which is referred to herein as a "non-functional film coating". An exemplary embodiment of a tablet containing 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 including 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 deuterated derivatives thereof using conventional tablet film coating methods.

[0090] Table 2. Exemplary tablets containing 15 mg Compound I and a film coating.

[0091] Components Component function Content (%w / w) Amount per tablet (mg) Compound I Active ingredients 15.00 15.00 Microcrystalline Cellulose Thinner 78.50 78.50 Croscarmellose Sodium Disintegrants 3.90 3.90 Sodium Stearyl Fumarate Lubricants 2.60 2.60 total - 100.00 100.00

[0092] In some embodiments, disclosed herein is a method for treating, lessening the severity of, or symptomatically treating an APOL1-mediated disease in a patient, wherein the disease includes an APOL1-mediated kidney disease such as FSGS and / or NDKD, the method comprising administering to a patient suffering from FSGS or NDKD an effective amount of Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof as disclosed herein; or a pharmaceutical composition comprising Compound 1, Compound 1 Form A, a deuterated derivative of Compound 1, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof.

[0093] Non-limiting embodiments of the present disclosure include:

[0094] 1. A method for treating an APOL1-mediated disease, the method comprising administering Compound I to a patient in need thereof:

[0095]

[0096] deuterated derivatives thereof, and / or pharmaceutically acceptable salts of Compound I or its deuterated derivatives and in a daily amount of 2 mg to 100 mg.

[0097] 2. The method of embodiment 1, wherein the APOL1-mediated disease is an APOL1-mediated kidney disease.

[0098] 3. The method of embodiment 2, wherein the APOL1-mediated kidney disease is APOL1-dependent focal segmental glomerulosclerosis (FSGS).

[0099] 4. The method of embodiment 2, wherein the APOL1-mediated kidney disease is non-diabetic kidney disease (NDKD).

[0100] 5. The method according to any one of embodiments 1-4, wherein the patient has an APOL1 genotype.

[0101] 6. The method according to any one of embodiments 1-4, wherein the patient has nephrotic range proteinuria.

[0102] 7. The method according to any one of embodiments 1-4, wherein the patient does not suffer from nephrotic range proteinuria.

[0103] 8. The method according to 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 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.

[0104] 9. The method according to 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 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 per day.

[0105] 10. The method according to 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.

[0106] 11. The method according to 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 a day or multiple times a day.

[0107] 12. The method according to 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 every 24 hours (q24h).

[0108] 13. The method according to any one of embodiments 1-12, wherein the method comprises administering Compound I or a deuterated derivative thereof.

[0109] 14. The method according to any one of embodiments 1-12, wherein the method comprises administering a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof.

[0110] 15. The method according to 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 contained in a pharmaceutical composition.

[0111] 16. The method according to embodiment 15, wherein the pharmaceutical composition is a tablet.

[0112] 17. The method according to embodiment 16, wherein the tablet is suitable for oral administration.

[0113] 18. The method according to embodiment 17, wherein the tablet for oral administration comprises 15 mg of Compound I.

[0114] 19. The method according to any one of embodiments 16-18, wherein the tablet comprises cellulose, croscarmellose sodium and / or sodium stearyl fumarate.

[0115] 20. The method according to embodiment 19, wherein the tablet further comprises a coating comprising polyvinyl alcohol (PVA), polyethylene glycol (PEG), titanium dioxide and talc.

[0116] 21. The method according to any one of embodiments 1-20, wherein the patient is in a fasting state.

[0117] 22. The method according to any one of embodiments 1-20, wherein the patient is in a fed state.

[0118] 23. A method according to any one of embodiments 1 to 22, wherein Compound 1, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof is administered in combination with one or more therapeutic agents selected from the group consisting of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, renin inhibitors, enkephalinase inhibitors, immunosuppressants, and mineralocorticoid receptor antagonists.

[0119] 23(a). A method according to embodiment 23, wherein the immunosuppressant is selected from tacrolimus, cyclosporine, mycophenolate mofetil and systemic corticosteroids.

[0120] 24. The method according to embodiment 23(a), wherein the systemic corticosteroid is prednisone or a prednisone equivalent.

[0121] 25. A method according to any one of embodiments 1 to 22, wherein Compound 1, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of Compound 1 or a deuterated derivative thereof is administered in combination with one or more therapeutic agents selected from the group consisting of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), renin inhibitors, and prednisone equivalents.

[0122] 26. The method according to 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.

[0123] 27. The method according to 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 ACEi, ARB and prednisone.

[0124] 28. The method according to any one of embodiments 1-27, wherein the patient is not co-administered any immunosuppressive agent other than systemic corticosteroids, tacrolimus, cyclosporine, and mycophenolate mofetil.

[0125] 29. The method according to any one of embodiments 1 to 28, wherein Compound I is in substantially pure crystalline Form A.

[0126] 30. The method according to any one of embodiments 1 to 28, wherein compound I is in crystalline Form A.

[0127] 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, its deuterated derivative and / or a pharmaceutically acceptable salt of Compound I or its deuterated derivative.

[0128] 32. A pharmaceutical composition according to 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 1, its deuterated derivative and / or a pharmaceutically acceptable salt of Compound 1 or its deuterated derivative.

[0129] 33. A pharmaceutical composition according to embodiment 32, wherein the composition comprises 15 mg of Compound I.

[0130] 34. A pharmaceutical composition according to embodiment 32, wherein the composition comprises 30 mg of Compound I.

[0131] 35. A pharmaceutical composition according to embodiment 32, wherein the composition comprises 45 mg of Compound I.

[0132] 36. A pharmaceutical composition according to embodiment 32, wherein the composition comprises 60 mg of Compound I.

[0133] 37. A pharmaceutical composition according to embodiment 32, wherein the composition comprises 75 mg of Compound I.

[0134] 38. The pharmaceutical composition of any one of embodiments 31 to 37, wherein Compound I is in substantially pure crystalline Form A.

[0135] 39. The pharmaceutical composition of any one of embodiments 31 to 37, wherein Compound I is in crystalline Form A.

[0136] Example 1: Synthesis of Compound I

[0137] Part A: Synthesis of starting materials

[0138] Preparation of S2

[0139] (3S,4R)-3-Amino-4-hydroxy-pyrrolidin-2-one (S2)

[0140]

[0141] Step 1. Synthesis of (2S,3R)-2,4-dibromo-3-hydroxy-butyric acid methyl ester (C7)

[0142] Potassium (2R,3R)-2,3,4-trihydroxybutyrate C6 (10 g, 57.1 mmol) was stirred with HBr / acetic acid (154 g, 103 mL 30% w / w, 570.8 mmol) for 16 hours. Anhydrous MeOH (250 mL) was added and the mixture was heated under reflux for 4 hours. 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) and then with Na 2 SO 4 Dry and concentrate in vacuo. Purify by silica gel chromatography (Gradient: 15-20% EtOAc / hexanes) to give the product as a colorless liquid (13 g, 83%). 1 H NMR (400 MHz, CDCl 3) δ4.71 (d, J = 3.4Hz, 1H), 4.17-4.14 (m, 1H), 3.82 (s, 3H), 3.53-3.44 (m, 2H).

[0143] Step 1. Alternative procedure for the synthesis of (2S,3R)-2,4-dibromo-3-hydroxy-butyric acid methyl ester (C7)

[0144] (2R, 3R)-2,3,4-trihydroxybutyrate potassium C6 (280g) and 33% HBr / acetic acid solution (1L) were stirred at room temperature for 24 hours. The reaction mixture was then poured into MeOH (5L). The mixture was stirred at room temperature for 8 hours and then stirred at 65°C for 4 hours. The concentrated mixture was dissolved in MeOH (1.2L) and then concentrated sulfuric acid (30mL) was slowly added. The mixture was heated at reflux for 6 hours and then concentrated. The residue was absorbed with EtOAc (400mL). The resulting solution was washed with water (250mL), dried with Na2SO4, filtered and concentrated in vacuo to obtain the product in the form of an oil, which solidified when stored at 4°C (375g, 74%).

[0145] Step 2. Synthesis of methyl (2R, 3S)-3-(bromomethyl)oxirane-2-carboxylate (C8)

[0146] In a 12 L round bottom flask equipped with an overhead stirrer, (2R,3R)-2,4-dibromo-3-hydroxy-butyric acid methyl ester C7 (524.8 g, 1.9 mol) was dissolved in acetone (4.5 L). The reaction was cooled to 0 °C in an ice bath and Cs 2 CO 3 (994 g, 3.1 mol). 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 grey oily residue. The product was dissolved in CH 2 Cl 2 The mixture was filtered through a short plug of silica gel and washed with CH 2 Cl 2 The filtrate was concentrated in vacuo to give the product (377.3 g, quantitative) as a clear yellow oil. 1 H NMR (300 MHz, CDCl 3 ) δ3.83 (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 (75 MHz, CDCl 3 )δ167.58, 55.89, 53.52, 52.77, 26.83ppm.

[0147] Step 2. Alternative procedure for the synthesis of methyl (2R,3S)-3-(bromomethyl)oxirane-2-carboxylate (C8)

[0148] To a solution of (2R, 3R)-2,4-dibromo-3-hydroxy-butyric acid methyl ester C7 (200 g, 0.73 mol) in acetone (2.0 L) was added anhydrous KCO (151.1 g, 1.1 mol) while maintaining the reaction temperature at 0-5 ° C. The reactant was stirred at 0-5 ° C for 2 hours and then gradually warmed to room temperature over 4 hours. 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 obtain the product (105 g, 74%) as a colorless liquid.

[0149] Step 3. Synthesis of methyl (2R,3R)-3-(azidomethyl)oxirane-2-carboxylate (C9)

[0150] In a 3 L round bottom flask equipped with a magnetic stir bar, (2R,3S)-3-(bromomethyl)oxirane-2-carboxylic acid methyl ester C8 (52.6 g, 269.7 mmol) was dissolved in DMF (500 mL). NaN 3 (25.3 g, 388.4 mmol) and the mixture was stirred at room temperature for 1 hour. The reactant was poured into water and extracted with EtOAc. The extract was washed with water and MgSO 4 Drying and concentration in vacuo gave a dark red oil. The oily residue was dissolved in CH 2 Cl 2 The mixture was filtered through a silica gel plug and washed with CH 2 Cl 2 The filtrate was concentrated in vacuo to give the product (40.8 g, 96%) as a clear light red oil. 1 H NMR (300 MHz, CDCl 3 ) δ3.87-3.74 (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 (75 MHz, CDCl 3 )δ167.76, 54.81, 52.67, 51.32, 48.74.

[0151] Step 4. Synthesis of (1R, 5R)-6-oxa-3-azabicyclo[3.1.0]hexane-2-one (C10)

[0152] A 2L 3-neck flask 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 minutes, and then heated to 80°C. Bu 3 SnH (220 mL, 817.8 mmol) and AIBN (2 g, 12.2 mmol) were dissolved in toluene (500 mL) and then added to the reaction using an additional funnel over 3 hours. The resulting reaction mixture was stirred at 80-87 °C for 1 hour, 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 minutes, and then the acetonitrile phase (bottom) was separated. The acetonitrile phase was washed with pentane (2 x 500 mL) and concentrated in vacuo to give a pale yellow solid. The solid residue was triturated with pentane (~200 mL) to give the product as a yellow solid, which was used without further purification (52 g, 98%). 1 H NMR (300 MHz, CDCl 3 )δ5.89 (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 (75 MHz, CDCl 3 )δ173.24, 53.28, 52.18, 44.00.

[0153] Step 5. Synthesis of (3S,4R)-3-amino-4-hydroxy-pyrrolidin-2-one (S2)

[0154] A mixture containing (1R, 5R)-6-oxa-3-azabicyclo[3.1.0]hexane-2-one C10 (60 g, 605.5 mmol) and NH 3 The Parr vessel (1.5 L, 58.6 mol) was pressurized to 200 psi and stirred at 18 °C for 2 days. NH 3 To provide a grey solid. Heptane was added and the mixture was stirred for 30 minutes. The solid was filtered, the filter cake was separated, and then EtOAc and heptane were separated into the solid. The mixture was concentrated in vacuo to give the product (55 g, 78%). 1 H NMR (300 MHz, D 2 O) δ4.13 (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).

[0155] Alternative preparation S2

[0156] (3S,4R)-3-Amino-4-hydroxypyrrolidin-2-one hydrochloride (S2)

[0157]

[0158] Steps 1 and 2. Synthesis of N-Boc-(3S,4R)-3-amino-4-hydroxypyrrolidin-2-one (C12)

[0159] At -60°C, ammonia gas was condensed into an autoclave containing a frozen solution of (2R, 3S)-3-(bromomethyl)oxirane-2-carboxylic acid methyl ester C8 (81 g, 0.42 mol) in 1,4-dioxane (160 mL) until approximately 400 mL of liquid was collected. The autoclave was closed, allowed to gradually warm to room temperature, and then heated at 50-60°C for 2 hours. 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 28% sodium methoxide / MeOH solution (86 g, 0.42 mol). The mixture was stirred at room temperature for 30 minutes and then concentrated. The residue was dissolved in water (500 mL) and then Na 2 CO 3 (89 g, 0.84 mol) and Boc 2 O (110 g, 0.5 mol) in THF (200 mL). 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 organic phases were combined and washed with Na 2 SO 4 The residue was triturated with warm MTBE (200 mL) and the precipitated solid was collected by filtration, washed with MTBE and dried in vacuo to give the product as a white solid (28 g, 31% yield).

[0160] Step 3. Synthesis of (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (S2)

[0161] 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 kept at 50-60° C. for 2 hours. 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%). 1H 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).

[0162] Preparation of S12

[0163] (3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid) (S12)

[0164]

[0165] Step 1. Synthesis of 2,4-difluoro-6-[2-(4-fluorophenyl)ethynyl]aniline (C49)

[0166] Method A: Sonagashira coupling method. To a flask containing 2,4-difluoro-6-iodo-aniline C48 (134 g, 525.5 mmol) was added NEt 3 (1.3 L), then DMF (250 mL), 1-ethynyl-4-fluoro-benzene (83.5 g, 695.1 mmol), CuI (20.5 g, 107.6 mmol) and PdCl 2 (PPh 3 ) 2 (25 g, 35.6 mmol). The mixture was stirred at room temperature for 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 plug of silica gel (eluent: CH 2 Cl 2 ), followed by a second silica plug filtration (eluent: 30-40% EtOAc / heptane). Silica gel chromatography (Gradient: 0-20% EtOAc / heptane) afforded the product as a light yellow solid (87 g, 60%). 1 HNMR (300 MHz, CDCl 3 ) δ7.58-7.45 (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] + .

[0167] Step 2. Synthesis of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole (C50)

[0168] Method B: Amine-alkyne cyclization method (CuI promoted). 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 under reflux. Water (800 mL) was added and the mixture was extracted with MTBE. The mixture was then washed with saturated NaCl solution and washed with Na 2 SO 4 Drying and then concentration in vacuo gave the product which was used in the subsequent step without further purification (41 g, 87%). 1 H NMR (300 MHz, CDCl 3 )δ8.43 (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). LCMSm / z248.0[M+H] + .

[0169] Step 3. Synthesis of (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoic acid methyl ester (C51)

[0170] Method C: Reductive alkylation method (TFA promoted). A 12 L flask with an overhead stirrer was charged with 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C50 (300 g, 1.2 mol), CH 2 Cl 2 (3 L), methyl 3,3-dimethoxypropionate (195 mL, 1.4 mol) and TFA (300 mL, 3.9 mol). The reaction was heated to reflux for 4 h. Additional CH 2 Cl 2 After cooling to room temperature, the solid product was filtered and the mixture was stirred for 2 hours with minimal CH 2 Cl 2 Washing and drying gave the product (388 g, 96%). 1 H NMR (400 MHz, DMSO-d 6 ) δ12.66 (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] + .

[0171] Step 4. Synthesis of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate (C52)

[0172] Method D: Pd(OH) 2 Catalytic transfer hydrogenation. To a suspension of (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoic acid methyl ester C51 (80 g, 236.5 mmol) in EtOH (1.5 L) under nitrogen atmosphere was added Pd(OH) 2 (6 g 20% ​​w / w 8.5 mmol) and ammonium formate (160 g, 2.5 mol). The mixture was heated at reflux for ~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%). 1 H NMR (300 MHz, CDCl 3 )δ8.18(s, 1H), 7.65-7.47(m, 2H), 7.27-7.14(m, 2H), 7.14-7.00(m, 1H), 6.76(d dd, 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] + .

[0173] Step 5. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid (S12)

[0174] Method E: Ester hydrolysis with LiOH. 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) was added LiOH (67 g, 2.8 mol). The mixture was heated at reflux for 2 hours and then allowed to cool overnight. THF was removed by concentration under reduced pressure and water (approximately 1 L) was added. The mixture was cooled in an ice bath and HCl (250 mL, 11.7 M, 2.9 mol) was added to adjust the pH to ~4. EtOAc (300 mL) was added and the aqueous layer was extracted with more EtOAc (100 mL). The organic extracts were combined and washed with sodium sulfate (Na 2 SO 4) and dried, filtered through a silica plug and rinsed with EtOAc. The filtrate was concentrated in vacuo to give an orange oil (50-75 mL). Heptane (~50 mL) was added and the mixture was cooled on dry ice. A crystalline solid formed after stirring. 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 (300 MHz, CDCl 3 )δ8.15 (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] + .

[0175] Alternative preparation S12

[0176] Step 3. Synthesis of (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoic acid methyl ester (C51)

[0177] The reactor was charged with 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C50 (4.0 kg, 16.5 mol), CH 2 Cl 2 (37 L) and methyl 3,3-dimethoxypropionate (2.6 L, 18.1 mol) were added, followed by TFA (3.9 L, 51.0 mol) at ambient temperature. The resulting mixture was heated to reflux for 6 hours. The batch was then cooled to 20°C, n-heptane (2 vol) was added and filtered. The filter cake was dried under vacuum at 45°C to give the product in a yield of 90%. 1 H NMR (300 MHz, DMSO-d 6 ) δ12.63 (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] + .

[0178] Step 4. Synthesis of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate (C52)

[0179] (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoic acid methyl ester C51 (1.5 kg, 9.06 mol) was slurried in THF (7 L) in a container. Pd(OH) 2 (10 g 20% ​​w / w, ~50% water, 0.014 mol). The mixture was treated with N 2 Purge three times, then rinse with H 2 Purge once and use H 2 The vessel was pressurized to 50 psi. The mixture was agitated at 20 °C until H 2 After 1.5 hours, N 2 (×3) The mixture was purged and filtered through Solka-Floc, rinsing with THF (2 vol). The filtrate was concentrated under vacuum 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 vol) and dried under vacuum at 45°C to give the product in 95% yield.

[0180] Step 5. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid (S12)

[0181] To 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 added 20% KOH (2 eq., 54 mol). The mixture was stirred at 35 °C for 6 hours. The mixture was then vacuum distilled to 27 L (3 vol) and cooled to 10-15 °C. Water (7.5 L) and 2-MeTHF (16 L) were added and the pH of the resulting biphasic mixture was adjusted to pH ~2 with 6M HCl. The temperature was adjusted to 20 °C and the phases were separated. The organic phase was washed with water (15 L) and purified by Filter, rinse with 2-MeTHF (18 L, 2 vol), and vacuum concentrate to 18 L (2 vol). Add 18 L (2 vol) of n-heptane and vacuum concentrate the batch to 18 L (3 vol) again. Repeat the cycle again and seed the batch. Add 16 L (1.8 vol) of n-heptane and adjust the temperature to 20°C. Stir the slurry for 2 hours, filter and wash the filter cake with 2 x 18 L (2 x 2 vol) of n-heptane. Vacuum dry the filter cake at 45°C to give the desired product in a yield of ~90%. 1 HNMR (300 MHz, CDCl 3)δ8.28 (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 (d dd, J=11.3, 9.4, 2.2Hz, 1H), 3.91-3.69 (m, 4H), 3.28-3.07 (m, 2H), 2.79-2.53 (m, 2H), 2.00-1.74 (m, 3H). LCMS m / z 320.4[M+H] + .

[0182] Part B: Synthesis of Compound (I)

[0183]

[0184] Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propionamide (I)

[0185] A 2L 3-neck RB flask 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 ~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 x 4). The organic layers were combined and washed with 1.2 L 1M HCl (×3), then with water (1.2 L) and brine (1.2 L). 2 SO 4 The mixture was dried, filtered and concentrated. The mixture was washed through a plug of silica gel (1.8 L silica gel), first eluted with 25% EtOAc / dichloromethane (8 L) to remove impurities, then eluted with hot EtOAc (8 L) to elute the product. The EtOAc filtrate was concentrated in vacuo. TBME (400 mL) was then added and the mixture was stirred overnight. The resulting solid was filtered to give the product as a white solid. 62 g, 52%) 1 H NMR (300 MHz, CD 3OD) δ7.70-7.58 (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] + .

[0186] Optical rotation: [α] D 20.7 = -14.01 (c = 1.0, 10 mg in 1 mL MeOH).

[0187] Alternative procedure for the synthesis of compound I

[0188] Step 1. Synthesis of (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoic acid methyl ester (C51)

[0189] A solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C50 (100 g, 1.0 eq) in dichloromethane (850 mL, 8.5 vol) was stirred at 22°C. Methyl 3,3-dimethoxypropanoate (63 mL, 1.1 eq) was added followed by trifluoroacetic acid (96 mL, 3.1 eq) and then rinsed with dichloromethane (25 mL, 0.25 vol). The batch was heated to 38°C and stirred at this temperature. After 4 hours, the batch was cooled to 22°C and n-heptane (200 mL, 2 vol) was added. The mixture was stirred at 22°C for NLT 1 hour. 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 obtained solid was dried under vacuum with nitrogen bleed at 45°C to give product C51 (127.7 g, yield 95%).

[0190] Step 2. Synthesis of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate (C52)

[0191] The hydrogenator was charged with (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoic acid methyl ester C51 (100.4 g, 1.0 equiv) and then charged with Pd(OH) 2 / C (0.014 equivalent). Seal the container and 2Perform three vacuum / purge cycles. Charge 2-MeTHF (2000 mL, 20 vol) using residual vacuum and stir the resulting mixture at 22 °C. Seal the vessel and purge with N 2 Three vacuum / purge cycles were performed followed by hydrogen (H 2 ) was performed once with a vacuum purge cycle. The temperature was adjusted to 22°C and 20 psi H 2 The vessel was pressurized. The mixture was stirred at 22°C for 4 hours. 2 Perform three vacuum / purge cycles. The batch was filtered through a pad and the filter cake was rinsed with 2-MeTHF (2×300 mL, 2×3 vol). The filtrates were combined, placed under vacuum and distilled to 2.0 to 3.0 total volumes at ≤45.0°C. The batch temperature was adjusted to 22°C and n-heptane (1000 mL, 10 vol) was added to the container over at least 1 hour. Vacuum was applied and the filtrate was distilled to 3.5 to 4.5 total volumes at ≤45.0°C. The slurry was cooled to 22°C and stirred for no less than 1 hour. The slurry was filtered and the filter cake was washed with n-heptane (1×1 vol (100 mL) and 1×0.5 vol (50 mL)). The solid was dried under vacuum at 45°C with a stream of nitrogen to give the product C52 (91.9 g, 91% yield).

[0192] Step 3. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid (S12)

[0193] 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 added 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. Vacuum was applied and the mixture was distilled to 3.0 total volumes at ≤45°C. The internal temperature was adjusted to 12°C. Water (64 mL, 0.8 vol) and 2-MeTHF (304 mL, 3.8 vol) were then added to the mixture. 6N HCl (75 mL, 0.9 vol) was slowly added to the mixture with vigorous stirring until the batch reached a pH <3. The internal temperature was adjusted to 22°C and the biphasic mixture was stirred for no less than 0.5 hours. Stirring was stopped and the phases were allowed to separate for no less than 0.5 hours. The lower aqueous phase was removed. Water (160 mL, 2 vol) was added to the reactor at 22°C and the biphasic mixture was stirred for no less than 0.5 hours. Stirring was stopped and the phases were allowed to separate for no less than 0.5 hours. The lower aqueous phase was removed and passed through The batch was filtered through a pad. The reactor and filter cake were rinsed with 2-MeTHF (160 mL, 2 vol). A vacuum was applied and the combined filtrate was distilled to 2-3 total volumes at ≤40.0°C. A container was charged with n-heptane (160 mL, 2 vol), a vacuum was applied, and the filtrate was distilled to 2 total volumes at ≤40.0°C (repeat this step once more). Additional n-heptane (144 mL, 1.8 vol) was then added to the mixture. The internal temperature was adjusted to 40°C and stirred for not less than 2 hours. It took at least 5 hours to adjust the internal temperature to 22°C and stir for not less than 16 hours. The slurry was filtered. The filter cake was washed with n-heptane (3×40 mL, 3×0.5 vol). The solid was dried under vacuum with a stream of nitrogen at 45°C to give the product S12 (72.6 g, 95% yield).

[0194] 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)

[0195] A mixture of S12 (50.0 g, 1.0 eq), (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride S2 (25.1 g, 1.05 eq) and CDMT (30.3 g, 1.1 eq) in DMF (250 mL, 5 vol) was agitated and cooled to 0°C. NMM (60 mL, 3.5 eq) was charged to the reactor over not less than 1 hour while maintaining the internal temperature ≤ 5°C. The batch was stirred at ~5°C for not less than 1 hour. The batch was warmed to 22°C over at least 1 hour and stirred at 22°C for 16 hours. The batch was cooled to 0°C. Water (250 mL, 5 vol) was added while maintaining the internal temperature < 20°C. A 90 / 10 mixture of EtOAc / IPA (1000 mL, 20 vol) was added to the mixture. 6N HCl (40 mL, 0.8 vol) was then added while maintaining the internal temperature <10°C until pH ~1-3 was reached. The internal temperature was adjusted to 22°C and the biphasic mixture was stirred for not less than 0.5 hours. Stirring was stopped and the phases were allowed to separate for not less than 0.5 hours. The lower aqueous phase was removed. The aqueous layer was back extracted with a 90 / 10 mixture of EtOAc / IPA (2×250 mL, 2×5 vol) at 22°C. The organic phases from the extraction were combined and washed with water (5×500 mL, 5×10 vol) at 22°C, mixing for not less than 0.5 hours and settling for not less than 0.5 hours for each wash. The batch was polished and filtered. Vacuum was applied and the organic phase was distilled at <50°C to 9.5-10.5 total volumes. EtOAc (500 mL, 10 vol) was added to the mixture, vacuum was applied, and the organic phase was distilled at <50°C to 9.5-10.5 total volumes (this step was repeated once more). EtOAc (300 mL, 6 vol) and n-heptane (200 mL, 4 vol) were added to the mixture. The resulting slurry was heated to 50°C and stirred for not less than 17 hours. The mixture was then cooled to 22°C over 2 hours and stirred for not less than 1 hour. The slurry was filtered. The filter cake was washed with 1:1 EtOAc / n-heptane (2×150 mL, 2×3 vol). The solid was dried under vacuum with a nitrogen stream at ≤45°C to give Compound I (52.6 g, 80% yield).

[0196] Recrystallization of Compound I

[0197] The reactor was charged with compound 2 (37.6 g, 1.0 eq) 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 this temperature for at least 0.5 hours. The batch was seeded with a 0.5 wt % previously generated 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 while maintaining the temperature at 55°C for a minimum of 5 hours. The slurry was cooled to 22°C in 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 stream of nitrogen at ≤45°C to give compound I (34.5 g, 92% yield).

[0198] Compound 1 Form A

[0199] 12.3 kg of Compound I was charged to the reactor, followed by a 3:1 mixture of 2-propanol / water. Agitation was started and the mixture was heated to 75°C to achieve complete dissolution. The mixture was cooled to 55°C over 1 hour and agitated at this temperature for 30 minutes. Agitation was continued for 1.5 hours. Water (5.8 vol) was added at 55°C, and the addition was completed over 5 hours, after which the mixture was cooled to 22°C over 6 hours. The mixture was agitated at 22°C for 2 hours and then vacuum filtered. The resulting wet cake was washed with a 3:1 mixture of 2-propanol / water (2.74 vol×2) and vacuum dried. The wet cake was further dried at 45°C under vacuum with a nitrogen stream to obtain 11.2 kg of Form A.

[0200] X-ray Powder Diffraction of Compound 1 Form A

[0201] The powder X-ray diffraction pattern of Compound 1 Form A was acquired at room temperature using a PANalytical Empyrean diffractometer equipped with a PIXcel ID detector ( Figure 1 ). The peaks are listed in Table 11 below.

[0202] Table 3. Peak Listing from the Powder X-ray Powder Diffraction Diffraction Pattern of Form A

[0203]

[0204]

[0205] Solid State NMR of Compound 1 Form A

[0206] Compound I Form A was acquired at 275 K using the following parameters: 12.5 kHz spinning; referenced to adamantane 29.5 ppm 13 CCPMAS( Figure 2 ). The peaks are listed below in Table 12. Carbon peaks highlighted in bold are unique to Form A relative to the following forms: Hydrate A, Hydrate C, and the amorphous form.

[0207] Table 4. From Form A 13 C CPMAS peak list

[0208]

[0209]

[0210] Example 3: Preparation of coated tablets containing 15 mg of Compound I

[0211] The following materials may be used in this exemplary preparation of a tablet containing 15 mg of Compound I, as shown in Table 3.

[0212] Table 5. Exemplary tablets containing 15 mg of Compound I.

[0213]

[0214] In this exemplary preparation, Compound I and internal microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose are sieved, combined in a box blender, and blended. The sieved internal sodium stearyl fumarate is added to the box blender, and the mixture is blended. The mixture is then dry granulated and milled to form milled particles. These milled particles are added to the box blender, and then the sieved external microcrystalline cellulose and the sieved external cross-linked sodium carboxymethyl cellulose are added thereto. The mixture is blended. The sieved external sodium stearyl fumarate is added to the box blender, and the mixture is blended. The resulting blend is discharged and then loaded into a tablet press. The blend is compressed into tablets and then discharged. Optionally, a non-functional film coating is applied to tablets containing Compound I using a conventional tablet film coating method.

[0215] Example 4: Efficacy of Compound I in treating APOL1-mediated focal segmental glomerulosclerosis

[0216] Inclusion criteria for a Phase 2, open-label, single-arm, 2-part study of Compound I:

[0217] 1. Participants are aged between 18 and 65 years old (inclusive);

[0218] 2. Participants' body mass index (BMI) was 18.0 to 40.0 kg / m 2 (inclusive), and the total weight is > 50kg;

[0219] 3. Participants have been diagnosed with FSGS by renal biopsy, excluding tip variant, as confirmed through the eligibility review process;

[0220] 4. The participant's APOL1 genotype is G1 / G1, G2 / G2, or G1 / G2, determined by clinical research, which can be confirmed by Sanger sequencing;

[0221] 5. During the screening period, participants had a UPCR ratio of ≥3 g / g and <10 g / g (Cohort 1) or a UPCR ratio of ≥1 g / g and <2.7 g / g (Cohort 2) in the first morning urination for 3 measurements collected on at least 3 separate days over a 7-day period (all 3 measurements must meet this criterion);

[0222] 6. Participants with ≥45 mL / min / 1.73 m according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula 2 (Cohort 1) Estimated glomerular filtration rate (eGFR) or ≥30 mL / min / 1.73 m 2 eGFR (Cohort 2); eGFR ≥30 to <40 mL / min / 1.73 m 2 Participants must have tubulointerstitial fibrosis ≤50% or described as absent, mild, or moderate on renal biopsy (Cohort 2); and

[0223] 7. Participants had 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 mofetil from 28 days before screening to the follow-up period.

[0224] 8. Participants using low-dose corticosteroids (≤10 mg / day of prednisone or prednisone equivalents) or permitted immunosuppressants (e.g., tacrolimus or mycophenolate mofetil) must have maintained a stable dose for 28 days prior to screening.

[0225] The clinical trial included two cohorts. Cohorts 1 and 2 were allowed to take stable low-dose systemic corticosteroids (≤10 mg / day of prednisone or prednisone equivalents), tacrolimus, and mycophenolate mofetil, but no other immunosuppressants were allowed. The goals and dosing schedules of cohorts 1 and 2 were the same.

[0226] Initially, participants underwent screening assessments and provided informed consent during a 28-day screening period. Screening assessments included, but were not limited to, vital sign analysis, height and weight, electrocardiogram measurements, serum chemistry, UPCR (urine protein to creatinine ratio), etc. Risk allele status (APOL1 genotype) was assessed at any time prior to treatment initiation (e.g., during the screening period).

[0227] All participants received a dose of 15 mg q24h for 2 weeks and a dose of 45 mg q24h thereafter for 11 weeks. After the last dose, participants were followed up for up to 12 weeks to evaluate proteinuria after treatment cessation. Participants who discontinued taking Compound I in advance were scheduled for an early treatment termination visit as soon as possible after deciding to terminate study drug treatment; these participants continued to complete all other planned study visits to assess efficacy (i.e., UPCR (urine protein to creatinine ratio), UACR (urine albumin to creatinine ratio)) until the last follow-up was completed. After the last dose of study drug, participants were followed up monthly for up to 12 weeks or until UPCR returned to baseline, whichever occurred first. All subjects completed safety follow-up 28 (± 7) days after the last dose of study drug.

[0228] Proteinuria was assessed at multiple time points throughout treatment and follow-up. The primary analysis time points were day 1 and week 13.

[0229] Study participants included male and female subjects diagnosed with FSGS and with confirmed APOL1 genotype. Participants received a dose of 15 mg q24h of Compound I for 2 weeks and a dose of 45 mg q24h of Compound I for 11 weeks.

[0230] The primary endpoint for evaluating the effect on FSGS is the percentage change of UPCR relative to baseline at week 13. As used herein, "baseline value" is the most recent measurement (planned or unplanned) collected before the first dose of study drug. For ECG, the baseline value is defined as the mean value of the pre-treatment measurement (repeated three times) before the first dose of Compound I. "Change relative to baseline (absolute change)" is calculated as the post-baseline value minus the baseline value. Calculate "change relative to baseline" and express it as a percentage, i.e. 100% × (post-baseline value minus baseline value) / baseline value.

[0231] Example 5: Efficacy of Compound I in treating APOL1-mediated non-diabetic kidney disease

[0232] Inclusion criteria for a Phase 2, double-blind, placebo-controlled, dose-ranging study of Compound I:

[0233] 1. Participants must be between 18 and 60 years old (inclusive);

[0234] 2. Participants' body mass index (BMI) was 18.0 to 40.0 kg / m 2 (inclusive), and the total weight is > 50kg;

[0235] 3. The participant's APOL1 genotype is G1 / G1, G2 / G2 or G1 / G2, determined through clinical research;

[0236] 4. During the screening period, participants had a UPCR ratio of ≥0.2 g / g and <3 g / g in the first morning urination for 3 measurements collected on at least 3 separate days over a 7-day period (all 3 measurements must meet this criterion);

[0237] 5. Participants with ≥30 mL / min / 1.73 m2 according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula 2 Glomerular filtration rate (GFR); and

[0238] 6. Participants had 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.

[0239] 7. Participants with a history of hypertension and currently receiving a stable dose (at least 4 weeks) of antihypertensive medication.

[0240] Initially, participants underwent screening assessments and provided informed consent during a 28-day screening period. Screening assessments included, but were not limited to, vital sign analysis, height and weight, electrocardiogram measurements, serum chemistry, UPCR (urine protein to creatinine ratio), etc. Risk allele status (APOL1 genotype) was assessed at any time prior to treatment initiation (e.g., during the screening period).

[0241] Participants will be randomly assigned to receive a dose of Compound I or placebo. Participants will receive a low, medium or high dose of Compound I for the next 13 weeks. The dose of Compound I will be determined before the start of the study using available data from clinical and nonclinical studies. Participants who discontinue Compound I early will be scheduled for an early treatment termination visit as soon as possible after deciding to discontinue study drug treatment; these participants continue to complete all other planned study visits to assess efficacy (ie, UPCR (urine protein to creatinine ratio), UACR (urine albumin to creatinine ratio)) until the last follow-up. All subjects completed safety follow-up 28 (± 7) days after the last dose of study drug.

[0242] Proteinuria was assessed at multiple time points throughout treatment and follow-up. The primary analysis time points were day 1 and week 13.

[0243] Study participants included male and female subjects with confirmed APOL1 genotype and without diabetes / autoimmune kidney disease. Participants received placebo or low, medium or high doses of Compound I for 13 weeks.

[0244] The primary endpoint to assess the effect on APOL1-mediated non-diabetic kidney disease is the percentage change in UPCR from baseline at Week 13. As used herein, "baseline value" is the average of the 3 screening UPCR values ​​used to determine eligibility. The primary analysis will be based on a mixed effects model (MMRM) for repeated measures with the change from baseline as the dependent variable.

[0245] The foregoing discussion discloses and describes only exemplary embodiments of the present disclosure. Those skilled in the art will readily recognize from such discussion and from the accompanying drawings and claims that various changes, modifications and variations may be made therein without departing from the spirit and scope of the present disclosure as defined in the following claims.

Claims

1. Use of Compound I or a pharmaceutically acceptable salt of Compound I in the preparation of a medicament for treating focal segmental glomerulosclerosis (FSGS) and / or non-diabetic kidney disease (NDKD) in a patient in need thereof: Wherein the drug is formulated as a tablet, which provides a daily amount equivalent to 2 mg to 100 mg of Compound I.

2. The use according to claim 1, wherein the medicament is used to treat focal segmental glomerulosclerosis (FSGS).

3. The use according to claim 1, wherein the medicament is for the treatment of non-diabetic kidney disease (NDKD). The use according to claim 1 , wherein the patient has an APOL1 genotype.

5. The use according to claim 1, wherein the patient suffers from nephrotic range proteinuria.

6. The use according to any one of claims 1-5, wherein the tablet is formulated for administration to provide a daily amount of Compound I equivalent to 15 mg to 100 mg, 20 mg to 80 mg, 25 to 75 mg, 30 to 60 mg or 15 mg to 45 mg.

7. The use according to any one of claims 1 to 5, wherein the tablet is formulated for administration to provide a daily amount of Compound I 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.

8. The use according to any one of claims 1 to 5, wherein the tablet is formulated for administration to provide a daily amount of Compound I equivalent to 15 mg or 45 mg.

9. The use according to any one of claims 1 to 5, wherein the tablet is formulated for administration to provide a daily amount of Compound I equivalent to 15 mg.

10. The use according to any one of claims 1 to 5, wherein the tablet is formulated for administration to provide a daily amount of Compound I equivalent to 45 mg.

11. The use according to any one of claims 1 to 5, wherein the tablet is formulated for multiple daily administration.

12. The use according to any one of claims 1-5, wherein the tablet is formulated for administration once every 24 hours (q24h).

13. The use according to any one of claims 1-5, wherein the tablet comprises Compound I.

14. The use according to any one of claims 1-5, wherein the tablet comprises a pharmaceutically acceptable salt of Compound 1.

15. The use according to any one of claims 1 to 5, wherein the tablet is suitable for oral administration.

16. The use according to claim 15, wherein the tablet for oral administration comprises 15 mg of Compound I.

17. The use according to any one of claims 1 to 5, wherein the tablet comprises cellulose, croscarmellose sodium and / or sodium stearyl fumarate.

18. The use according to any one of claims 1 to 5, wherein the tablet further comprises a coating comprising polyvinyl alcohol (PVA), polyethylene glycol (PEG), titanium dioxide and talc.

19. The use according to any one of claims 1-5, wherein the tablet is formulated for administration in combination with one or more therapeutic agents selected from: angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, renin inhibitors, neprilysin inhibitors, prednisone, prednisolone or methylprednisolone.

20. The use according to claim 19, wherein the one or more therapeutic agents are selected from prednisone, prednisolone or methylprednisolone.

21. The use according to any one of claims 1-5, wherein the tablet is formulated for administration in combination with one or more therapeutic agents selected from the group consisting of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), renin inhibitors, prednisone, prednisolone and methylprednisolone.

22. The use according to any one of claims 1-5, wherein the tablet is formulated for combined administration with an ACE inhibitor (ACEi) and an ARB.

23. The use according to any one of claims 1-5, wherein the tablet is formulated for administration in combination with an ACEi, an ARB and prednisone.

24. The use according to any one of claims 1 to 5, wherein the amount of crystalline Form A in Compound I determined by quantitative XRPD is equal to or greater than 90% by weight of the sum of all solid forms of Compound I.

25. The use according to any one of claims 1 to 5, wherein Compound I is in crystalline form A.

26. The use according to any one of claims 1 to 5, wherein the tablet further comprises: (a) an intragranular component comprising: 61% microcrystalline cellulose, 2.4% croscarmellose sodium, and 1.6% sodium stearyl fumarate; and (b) an extragranular component comprising: 17.5% microcrystalline cellulose, 1.5% croscarmellose sodium, and 1.0% Sodium stearyl fumarate.

27. A pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt of Compound 1: The amount is 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.

28. The pharmaceutical composition of claim 27, wherein the composition comprises Compound 1 or a pharmaceutically acceptable salt of Compound 1 in an amount equivalent to 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 1.

29. The pharmaceutical composition of claim 27, wherein the composition comprises 15 mg of Compound I.

30. The pharmaceutical composition of claim 27, wherein the composition comprises 30 mg of Compound I.

31. The pharmaceutical composition of claim 27, wherein the composition comprises 45 mg of Compound I.

32. The pharmaceutical composition of any one of claims 27 to 31, wherein the amount of crystalline Form A in Compound I as determined by quantitative XRPD is equal to or greater than 90% by weight of the sum of all solid forms of Compound I.

33. A pharmaceutical composition according to any one of claims 27 to 31, wherein Compound I is in crystalline Form A.

34. A pharmaceutical composition according to any one of claims 27 to 31, wherein the composition is in the form of a tablet.

35. The pharmaceutical composition of claim 33, wherein the composition is in the form of a tablet.

36. The pharmaceutical composition of claim 35, wherein the tablet is suitable for oral administration.

37. The pharmaceutical composition according to claim 27, wherein the pharmaceutical composition further comprises: (a) an intragranular component comprising: 61% microcrystalline cellulose, 2.4% croscarmellose sodium, and 1.6% sodium stearyl fumarate; and (b) an extragranular component comprising: 17.5% microcrystalline cellulose, 1.5% croscarmellose sodium, and 1.0% Sodium stearyl fumarate.

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